Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@H:12]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][C:6]=2[CH:5]=[C:4]([Cl:31])[N:3]=1.[CH:32]1([CH2:36][OH:37])[CH2:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CS(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:31][C:4]1[N:3]=[C:2]([O:37][CH2:36][CH:32]2[CH2:35][CH2:34][CH2:33]2)[C:7]2[N:8]([CH2:23][C@H:24]3[CH2:25][CH2:26][C@H:27]([CH3:30])[CH2:28][CH2:29]3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@H:12]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][C:6]=2[CH:5]=1
Reactant: OCC1CCC1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(Cl)c32)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(OCC4CCC4)c32)CC1
Temperature: 100 °C

Procedure:
To a solution of 4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine (Example 2.1, Step 2; 400 mg, 0.87 mmol) in DMSO (5 mL) was added cyclobutylmethanol (337 mg, 3.92 mmol), Cs2CO3 (848 mg, 2.61 mmol) and BINAP (108 mg, 0.17 mmol). The reaction mixture was deoxygenated by purging with nitrogen for 10 minutes and then Pd2dba3 (159 mg, 0.17 mmol) was added. The reaction was again deoxygenated for 5 minutes by purging with nitrogen. The reaction flask was sealed, and the mixture was heated at 100° C. for 16 h. The reaction mixture was then cooled, diluted with water (30 ml) and EtOAc (60 mL), and the organic layer was separated. The organic layer was washed with water (2×10 mL), followed by saturated brine (2×30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column (30% EtOAc/petroleum ether) to yield 6-chloro-4-(cyclobutylmethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine. MS ES/APCl calc'd. for C29H37ClN4O2 [M+H]+ 509. found 509.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:23])=[C:18]([CH:22]=1)[C:19](O)=O>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:23])=[C:18]([CH2:19][C:10]2[S:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH:22]=1
Reactant: Clc1cccc(-c2cccs2)c1
Reactant: Cc1ccc(Br)cc1C(=O)O
Product: Cc1ccc(Br)cc1Cc1ccc(-c2cccc(Cl)c2)s1

Procedure:
2-(3-Chlorophenyl)thiophene obtained in Reference Example 85-(1) and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were treated in a manner similar to Reference Example 5 to give the target compound as colorless oil.
Reaction SMILES: CC1C(C(OC(C)(C)C)=O)CCC(Cl)C1.[CH3:16][CH2:17][O:18][C:19]([CH:21]1[CH:26]([CH3:27])[CH2:25][CH2:24][CH:23]([I:28])[CH2:22]1)=[O:20].C[C@H]1[C@H](C(O)=O)CC=CC1.CC1C(C(O)=O)CC=CC1>>[I:28][C@H:23]1[CH2:22][C@@H:21]([C:19]([O:18][CH2:17][CH3:16])=[O:20])[C@H:26]([CH3:27])[CH2:25][CH2:24]1
Reactant: CCOC(=O)C1CC(I)CCC1C
Agent: CC1CC(Cl)CCC1C(=O)OC(C)(C)C
Agent: CC1CC=CCC1C(=O)O
Agent: C[C@@H]1CC=CC[C@H]1C(=O)O
Product: CCOC(=O)[C@@H]1C[C@H](I)CC[C@H]1C
Yield: 15 %

Procedure:
Test compounds: Liquid trimedlure (UOP Chemicals, East Rutherford, N.J.) (98% pure; density 1.02 g/ml) and ceralure (Agrisense/Biosys, Palo Alto, Calif.) (98% pure; density 1.43 g.ml) were purchased from commercial sources. The 2 g polymeric plug (Agrisense/Biosys, Palo Alto, Calif.) was the same product used by action agencies such as USDA-APHIS and California Department of Food and Agriculture (CDFA) in their surveillance and detection programs against medfly. The enantiomers of ceralure B1 (ethyl-cis-5-iodo-trans-2-methylcyclohexane-1-carboxylate) (henceforth referred to as the 1R,2R,5R and 1S,2S,5S enantiomers respectively) were synthesized using the 9 step process (described above) which yielded both enantiomers with high purity (97% ) and an overall yield of 15%. The racemic mixture of the two enantiomers was produced starting from racemic (5), which is (1RS, 6RS)-6-methyl-3-cyclohexene-1-carboxylic acid, using the above described process used to produce ethyl (1R,2R,5R)-5-iodo-2-methylcyclohexane-1-carboxylate (4a).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]#[CH:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.Cl.[NH2:24][CH:25]1[C:36](=[O:37])[N:27]2[C:28]([C:33]([OH:35])=[O:34])=[C:29]([Cl:32])[CH2:30][S:31][C@H:26]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]#[CH:17])[C:10]([NH:24][CH:25]2[C:36](=[O:37])[N:27]3[C:28]([C:33]([OH:35])=[O:34])=[C:29]([Cl:32])[CH2:30][S:31][C@H:26]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reactant: C#CCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 1.5 h
Yield: 63.7 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer, 1.27 g.), N,N-dimethylformamide (400 mg.), phosphoryl chloride (850 mg.) and ethyl acetate (11.2 ml.) were treated in a conventional manner to give the activated acid solution. The activated acid solution was added to a solution of 7-amino-3-chloro-3-cephem-4-carboxylic acid hydrochloride (2 g.), trimethylsilylacetamide (6 g.) and bis(trimethylsilyl)acetamide (3 ml.) in ethyl acetate (40 ml.) at -15° C. all at once, and stirred at -5° to -10° C. for 1.5 hours. After adding water (30 ml.) to the resultant solution, the ethyl acetate layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate. Ethyl acetate was added to the aqueous extract, adjusted to pH 2.0 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was crystallized with a mixture of ethyl acetate and diisopropyl ether. The precipitates were collected by filtration and dried to give 7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), yellow powder.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:15]([C:17]1[N:18]([CH2:31][CH2:32][CH2:33][C:34]#[CH:35])[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH3:16]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:15]([C:17]1[N:18]([CH2:31][CH2:32][CH2:33][C:34]#[C:35][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH3:16]
Reactant: Ic1ccccc1
Reactant: C#CCCCn1c(CC)nc2c(N)nc3ccccc3c21
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCC#Cc1ccccc1
Reaction time: 1 h
Yield: 26.3 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.095 g, 0.03 eq.), iodobenzene (0.685 g, 1.1 eq.), triethylamine (0.923 g, 3 eq.), and copper (I) iodide (0.035 g, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(4-pentynyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.85 g, 3.0 mmol, 1.0 eq.) in DMF. The reaction mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 4/96 methanol/dichloromethane) to provide an oil. The oil was recrystallized from a mixture of ethanol and 1,2-dichloroethane. The resulting solid was dissolved in 1:1 mixture of ethanol and 1,2-dichloroethane, treated with activated charcoal, combined with a few drops of 10% sodium hydroxide, heated, and then filtered while still hot. The filtrate was concentrated under reduced pressure to provide 0.28 g of 2-ethyl-1-(5-phenyl-4-pentynyl)-1H-imidazo[4,5-c]quinolin-4-amine as white granules, mp 199.0-202.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.18 (dd, J=8.2, 1.0 Hz, 1H), 7.60 (dd, J=8.3, 0.9 Hz, 1H), 7.35-7.48 (m, 6H), 7.09 (ddd, J=8.2, 7.1, 1.2 Hz, 1H), 6.46 (s, 2H), 4.61 (t, J=7.8 Hz, 2H), 3.01 (q, J=7.4 Hz, 2H), 2.66 (t, J=6.5 Hz, 2H), 2.09 (m, 2H), 1.38 (t, J=7.4 Hz, 3H); MS (APCI) m/z 355 (M+H)+; Anal. calcd for C23H22N4.0.02C2H4Cl2: C, 77.64; H, 6.24; N, 15.72. Found: C, 77.68; H, 6.19; N, 15.64.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([C:17]([C:24]#[N:25])=[C:18]([CH:21]1[CH2:23][CH2:22]1)OC)#[N:16].[H-].[Na+]>CO>[NH2:25][C:24]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:18]([CH:21]2[CH2:23][CH2:22]2)[C:17]=1[C:15]#[N:16]
Reactant: COC(=C(C#N)C#N)C1CC1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(C2CC2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (3.8 g) and 1,1-dicyano-2-cyclopropyl-2-methoxyethylene (2.23 g) in methanol (30 ml) was stirred and treated with sodium hydride (80%, 30 mg). After 4 hours the solution was evaporated in vacuo and the residue was dissolved in ethyl acetate (40 ml), treated with charcoal and washed with water. The organic phase was evaporated in vacuo, the residual oil was dissolved in petroleum ether and crystals of 5-amino-4-cyano-3-cyclopropyl-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole, m.p. 197°-199° C., were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[F:49]>C(#N)C>[Cl:42][C:43]1[CH:44]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:46]=[CH:47][C:48]=1[F:49]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(F)c(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 17.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-chloro-4-fluorobenzenesulfonyl chloride (0.0280 mL, 0.195 mmol) to obtain 4-(3-chloro-4-fluorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.00740 g, yield 17%).
Reaction SMILES: CCN(CC)CC.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].Br[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([N:23]2[CH2:28][CH2:27][C@:26]([CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][C:24]2=[O:40])[CH3:22])=[CH:17][CH:16]=1.CN(C)C=O>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O>[OH:39][C:36]([CH3:37])([CH3:38])[CH2:35][C@@:26]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:25][C:24](=[O:40])[N:23]([C@H:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]#[C:12][Si:9]([CH3:11])([CH3:10])[CH3:8])=[CH:20][CH:19]=2)[CH3:22])[CH2:28][CH2:27]1
Reactant: C#C[Si](C)(C)C
Reactant: CC(c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(C#C[Si](C)(C)C)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
CuI (0.18 g), Pd(PPh3)2Cl2 (0.33 g), and NEt3 (2.22 mL) were added successively to a flask charged with a stir bar, trimethylsilylacetylene (1.31 mL), (S)-3-[1-(4-bromo-phenyl)-ethyl]-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (2.00 g), and N,N-dimethylformamide (15 mL) and kept at room temperature under argon atmosphere. The flask was tightly sealed and the mixture was heated to 90° C. The mixture was stirred at 90° C. overnight and then cooled to ambient temperature. Water (80 mL) and ethyl acetate (200 mL) were added and the resulting mixture was filtered over Celite. The organic phase of the filtrate was separated and washed with brine and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 3:1->0:1) to afford the title compound as an oil. Yield: 0.27 g (34% of theory); LC-MS (Method 1): tR=4.27 min; Mass spectrum (ESI+): m/z=450 [M+H]+.
Reaction SMILES: [I:1]I.N(OC(C)(C)C)=O.N[C:11]1[CH:12]=[C:13]([C:25](=[O:27])[CH3:26])[S:14][C:15]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24]>C(#N)C>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[S:16][C:15]1[S:14][C:13]([C:25](=[O:27])[CH3:26])=[CH:12][C:11]=1[I:1]
Reactant: CC(=O)c1cc(N)c(Sc2ccc(Cl)cc2Cl)s1
Reactant: II
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CC(=O)c1cc(I)c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 60 °C
Yield: 99.7 %

Procedure:
To a dark solution of I2 (0.958 g 7.5 mmol) in acetonitrile (20 mL), was added t-butyl nitrite (0.4 g, 3.75 mmol) slowly. The resulting solution was heated to 60° C. for 20 min. To the above solution, was added dropwise of a solution of 1-[4-amino-5-(2,4-dichlorophenyl)sulfanyl-2-thienyl]ethanone (0.8 g, 2.5 mmol) in acetonitrile (20 mL). The resulting mixture was heated at 60° C. for 2 hours. After this time the reaction mixture was quenched with sodium hydroxide aqueous solution (1 M), and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4) and concentrated. The crude solid was purified by silica gel chromatography using a 98:2 mixture of hexane and ethyl acetate as eluent to afford the title product as a yellow solid (1.07 g, 46.2% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.16 (1H, s), 7.82 (1H, dd), 7.47 (1H, dd), 7.05 (1H, dd), 2.54 (3H, s). MS m/z: 428.7 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH:22]2[CH2:27][CH2:26][N:25](C(OCC)=O)[CH2:24][CH2:23]2)[CH:5]=[CH:6][CH:7]=1>Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC(c2c(-c3cccc(Br)c3)c3ccc(C)nc3n(CC)c2=O)CC1
Agent: Cl
Product: CCn1c(=O)c(C2CCNCC2)c(-c2cccc(Br)c2)c2ccc(C)nc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
To 1.28 g of 4-(3-bromophenyl)-3-(1-ethoxycarbonylpiperidin-4-yl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one was added 20 ml of concentrated hydrochloric acid, followed by stirring at 100° C. for 3 hours. The solvent was evaporated and, after the residue was made alkaline by adding concentrated aqueous ammonia, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After removal of the solvent from the organic layer, the resulting crude crystals were recrystallized from acetonitrile and then recrystallized from ethanol-water to obtain 357 mg of 4-(3-bromophenyl)-1-ethyl-7-methyl-3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[C@:16]1([CH3:27])[C:21]([F:23])([F:22])[CH2:20][C@@:19]([F:25])([CH3:24])[C:18](=[S:26])[NH:17]1.C(O)(C(F)(F)F)=O>ClCCl.C1(C)C=CC=CC=1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@@:16]2([CH3:27])[NH:17][C:18](=[S:26])[C@:19]([F:25])([CH3:24])[CH2:20][C:21]2([F:23])[F:22])[CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c([C@@]2(C)NC(=S)[C@@](C)(F)CC2(F)F)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(F)CC(F)(F)[C@@](C)(c2cc(N)ccc2F)NC1=S
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
tert-butyl (4-fluoro-3-((2R,5S)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)carbamate (1.15 g, 2.83 mmol) was dissolved in dichloromethane (13 ml). The solution was cooled to 0° C. and TFA (6.5 ml, 84 mmol) was added. The solution was stirred at 0° C. for 1 h 20 min. The reaction was diluted with toluene (25 mL) and concentrated to approx 10 mL under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 (25 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure to afford (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione (548 mg (70% purity), 63.2% yield). The crude product was used in the next reaction step without further purification. LC-MS (m/z) 307.2 (MH+) tR=0.49 minutes (Method B) 1H NMR (600 MHz, CDCl3) δ 7.93 (bs, 1H), 6.93-6.88 (m, 1H), 6.66-6.61 (m, 1H), 6.59-6.55 (m, 1H), 2.62-2.57 (m, 2H), 1.90 (s, 3H), 1.86 (d, J=22.4 Hz, 3H) [α]D20=−211° (589 nm, c=0.1 g/100 mL, MeOH
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:36]=[C:37](S(N)(=O)=O)[CH:38]=[CH:39][CH:40]=1>>[CH2:2]1[C:37]2[C:38](=[CH:39][CH:40]=[C:35]([NH:34][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:36]=2)[CH2:5][CH2:4][NH:3]1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared by a procedure similar to Example 27, Step D using N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-aminobenzenesulfonamide: 1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H); 9.87 (s, 1H); 8.84 (d, 1H); 8.53 (d, 1H); 7.92 (d, 1H); 7.81 (d, 1H); 7.57 (m, 1H); 7.47 (m, 1H); 7.38 (m, 2H); 7.25 (m, 3H); 7.12 (m, 3H); 6.98 (s, 1H); 6.90 (d, 1H); 6.68 (d, 1H); 6.57 (d, 1H); 5.48 (br s, 1H). HRMS (ESI): (M+H)+ calculated 598.1473, found 598.1467.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[C:13]([N+:14]([O-])=O)=[C:12]([O:17][CH:18]([F:20])[F:19])[N:11]([CH3:21])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O1CCCC1.[H][H]>[Ni].C(O)C>[F:1][C:2]1[C:3]([C:9]2[C:13]([NH2:14])=[C:12]([O:17][CH:18]([F:19])[F:20])[N:11]([CH3:21])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1nc(-c2ncc(Cl)cc2F)c([N+](=O)[O-])c1OC(F)F
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1nc(-c2ncc(Cl)cc2F)c(N)c1OC(F)F

Procedure:
4.2 g of 3-(3-fluoro-5-chloro-2-pyridyl)-4-nitro-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example H47) are initially introduced into the reaction vessel together with 40 ml of tetrahydrofuran, and 5.8 g of Raney nickel in ethanol are added. Hydrogenation is carried out under normal pressure and at a temperature of 30-35° C. After uptake of 728 ml of hydrogen, the hydrogenation is interrupted and the reaction mixture is filtered over Hyflo. After removal of the solvent in vacuo, 3.15 g of the desired title compound are obtained as a brown solid of melting point 92-94° C.
Reaction SMILES: CS(C1N=C(OC)C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2Cl)N=1)(=O)=O.[CH3:28][O:29][C:30]1[N:35]=[C:34](S(C)(=O)=O)[C:33]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[C:32]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][C:48]=2[Cl:54])[N:31]=1.C([Li])CCC.[F:60][C:61]1[CH:66]=[CH:65][C:64]([OH:67])=[CH:63][CH:62]=1>>[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:67][C:64]2[CH:65]=[CH:66][C:61]([F:60])=[CH:62][CH:63]=2)[C:33]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[C:32]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][C:48]=2[Cl:54])[N:31]=1
Reactant: COc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Reactant: Oc1ccc(F)cc1
Agent: COc1nc(S(C)(=O)=O)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Product: COc1nc(Oc2ccc(F)cc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
A mixture of 2-(methylsulfonyl)-4-methoxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-pyrimidine and 2-methoxy-4-(methylsulfonyl)-5-(4-chloro-phenyl)-6-(2,4-dichlorophenyl)-pyrimidine (Example 113) was reacted with 1.1 equivalents each of n-butyl lithium and 4-fluorophenol by the procedure described in Reference Example 6 and 7 to afford a mixture of 2-(4-fluorophenyloxy)-4-methoxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl) and 2-methoxy-4-(4-fluorophenyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine which was separated by flash column chromatography on silica gel. Only the LRf was characterized. 2-methoxy-4-(4-fluorophenyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (LRf): HPLC/MS: m/e=475 (M++1); Rt=4.61 min. 1H-NMR 400 MHz (CDCl3): 3.89 (s, 3H), 6.75-6.79 (m, 2H), 6.91-6.96 (m, 2H), 7.10-7.34 (m, 7H).
Reaction SMILES: B(Br)(Br)Br.[CH3:5][CH:6]([CH3:32])[CH2:7][C:8]([C:10]1[CH:29]=[CH:28][C:13]2[O:14][C:15]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[CH:21][C:16]=3[CH2:17][O:18][C:19](=[O:20])[C:12]=2[C:11]=1[O:30]C)=[O:9].CO>ClCCl>[OH:30][C:11]1[C:12]2[C:19](=[O:20])[O:18][CH2:17][C:16]3[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([O:25][CH3:26])[C:15]=3[O:14][C:13]=2[CH:28]=[CH:29][C:10]=1[C:8](=[O:9])[CH2:7][CH:6]([CH3:5])[CH3:32]
Reactant: COc1cc(C)cc2c1Oc1ccc(C(=O)CC(C)C)c(OC)c1C(=O)OC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C)cc2c1Oc1ccc(C(=O)CC(C)C)c(O)c1C(=O)OC2
Reaction time: 1.5 h

Procedure:
10.8 ml of a 1M boron tribromide solution in dichloromethane are added dropwise at -70° C. under argon to a solution of 6.2 g (16.1 mmol) of 3-(3-methyl-1-butanonyl)-4,11-dimethoxy-9-methyl-7H-dibenzo[b,g][1,5]-dioxocin-5-one in 160 ml of dichloromethane. After 1.5 h, 6 ml of methanol are added and the solution is brought to room temperature after a further 40 minutes. It is washed with sodium hydrogen carbonate solution and water, dried over magnesium sulphate and concentrated in vacuo. The residue is purified on a silica gel column using petroleum ether/ethyl acetate 6:1.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[C:12]([N+:22]([O-])=O)[CH:11]=3>[Pd].C(O)(=O)C>[NH2:22][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][C:13]=1[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:3]1[C:2]([CH3:1])([CH3:25])[C:6](=[O:7])[O:5][C:4]=1[CH:8]=[CH:9]2
Reactant: CC1(C)C(=O)Oc2ccc3cc([N+](=O)[O-])c(Cn4cncn4)cc3c21
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)C(=O)Oc2ccc3cc(N)c(Cn4cncn4)cc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1,1-dimethyl-7-nitro-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone (0.035 g), glacial acetic acid (2 ml) and 10% palladium-on-carbon (0.01 g) was stirred under an atmosphere of hydrogen at room temperature and atmospheric pressure for 2 h. The mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and the residue was partitioned between ethyl acetate and equeous sodium hydrogen carbonate solution. The ethyl acetate phase was dried and evaporated to dryness under reduced pressure, and the residue was purified by flash chromatography using methanol:ethyl acetate, 1:99 v/v. as eluant, to give 7-amino-1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone, m.p. 160°-163°.