Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=3[O:36][CH3:37])[CH2:6][CH2:5]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 83.4 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H-indazole (3.0 g, 15 mmol), K2CO3 (1.6 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into water and a white solid separated from solution. The solid was collected, dried and afforded 5.1 g of product. Recrystallization from ethanol yielded 3.6 g, the compound, which upon chromatography (preparative HPLC on silica gel, eluting with methylene chloride/methanol-9:1) gave 3.0 g (49%) of an off-white solid. Recrystallization from ethanol afforded the analytically pure 1-[4-[3-[4-(1-1H-indazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=171-173° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1(N[S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])C=CC=CC=1>C1COCC1>[C:13]([N:20]1[CH2:25][CH2:24][C:23]([O:26][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[CH:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 90 %

Procedure:
To a stirring solution of diisopropylamine (38.7 mL, 275 mmol) in THF (900 mL) at 0° C. was added dropwise via an addition funnel a solution of n-BuLi in hexanes (1.6 MN 171.5 mL, 276 mmol). After 25 min, the solution was cooled to −78° C. To this solution was added dropwise via an addition funnel a solution of 1-Boc-4-piperidinone (50 g, 250.9 mmol) in THF (300 mL). After 30 min, a solution of N-phenyltrifluoromethanesulfonamide (95.9 g, 268.5 mmol) in THF (300 mL) was added and the solution was warmed to 0° C. After 3 h, the solvents were evaporated in vacuo and the residue was loaded into a silica gel column with a minimal amount of dichloromethane and eluted with 5% ethyl acetate/hexanes. The product containing fractions were combined and concentrated in vacuo to give 74.84 g (90%) of a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:16]2[CH:15]=[CH:14][C:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:29])([F:28])[F:1])=[CH:4][CH:5]=4)=[N:10][S:11][C:12]=3[CH:17]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: FC(F)(F)c1ccc(-c2nsc3cc(C#CCCCN4CCC4)ccc23)cc1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and azetidine were converted to yield 6-(5-Azetidin-1-yl-pent-1-ynyl)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole as orange oil, MS: 401 (MH+).
Reaction SMILES: CON(C)[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14].C[Li].O.[C:22](OCC)(=O)C>O1CCCC1.C(OCC)C>[F:14][C:13]([F:16])([F:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:6]=[CH:5][C:4](=[O:17])[CH3:22]
Reactant: CON(C)C(=O)C=Cc1ccccc1C(F)(F)F
Reactant: CCOC(C)=O
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(=O)C=Cc1ccccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
11 g of N-methoxy-N-methyl-3-(2-trifluoromethylphenyl)acrylamide are dissolved in 150 ml of dry tetrahydrofuran under a nitrogen atmosphere, cooled to −78° C. and treated dropwise with 36 ml of a 1.4N solution of methyllithium in diethyl ether in 10 minutes. The solution is subsequently furthermore stirred at −78° C. for 2 h and then hydrolysed with water. 200 ml of ethyl acetate are now added at ambient temperature and the mixture is washed three times with saturated sodium chloride solution. The organic phase is finally separated, dried with magnesium sulfate and evaporated under reduced pressure. After purifying by flash chromatography, the title compound is thus obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH:17]=[O:18])[NH:14][C:13]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH2:17][OH:18])[NH:14][C:13]1=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC[C@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(N[C@H]1C(=O)N[C@@H]1CCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a solution of (3R,4R)-3-benzyloxycarbonylamino-4-(2-oxoethyl)azetidin-2-one (850 mg) in methanol (17 ml) was added sodium borohydride (123 mg) at 0° C. and the mixture was stirred for 15 minutes at 0° C. Acetic acid (0.37 ml) was added to the mixture at 0° C. After stirring for 15 minutes at 0° C., the mixture was evaporated in vacuo. The residue was chromatographed on silica gel (17 g) eluting with a mixture of methylene chloride and methanol (20:1-10:1) to give a crystalline solid. This crude crystals were washed with ether and dried over phosphorous pentoxide to give (3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one (748 mg).
Reaction SMILES: [NH2:1][C:2]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)([CH3:15])[CH2:3][NH:4][C:5]1([C:11](OC)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CC(O)=O.C([O-])(O)=O.[Na+]>>[F:23][C:18]1[CH:17]=[C:16]([C@@:2]2([CH3:15])[NH:1][C:11](=[O:12])[C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[NH:4][CH2:3]2)[CH:21]=[C:20]([F:22])[CH:19]=1
Reactant: COC(=O)C1(NCC(C)(N)c2cc(F)cc(F)c2)CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@]1(c2cc(F)cc(F)c2)CNC2(CCCCC2)C(=O)N1

Procedure:
A solution of methyl 1-{[2-amino-2-(3,5-difluorophenyl)propyl]amino}cyclohexanecarboxylate from Step F (205 mg, 0.628 mmol), and AcOH (0.36 mL, 6.28 mmol) in xylenes (5 mL) was heated at 80° C. for 3 h, allowed to cool, then poured into saturated aqueous NaHCO3 (5 mL). The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of EtOAc:MeOH—100:0 to 92:8, to give the racemic product. The enantiomers were separated by HPLC, using a ChiralPak AD column and eluting with hexane:EtOH:Et2NH—40:60:0.1. The first major peak to elute was (3R)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one, the title compound, and the second major peak to elute was (3S)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one. MS: m/z=295 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:20][CH3:21])[C:10]=1OCCN1CCOCC1)[C:6]#[N:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:41]1[CH2:46][CH2:45][CH:44](O)[CH2:43][CH2:42]1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[CH3:21][O:20][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[CH:44]1[CH2:45][CH2:46][O:41][CH2:42][CH2:43]1)[C:6]#[N:7]
Reactant: OC1CCOCC1
Reactant: COc1cc(C#N)cc(OC)c1OCCN1CCOCC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C#N)cc(OC)c1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 g 3,5 Dimethoxy-4-hydroxy-benzonitrile (for synthesis see: benzonitrile for Example 18), 28 g triphenylphosphine and tetrahydro-4H-pyran-4-ol was suspended in 150 mL tetrahydrofuran at 0° C. before 25 g di-tert-butylazodicarboxylate (DBAD) was added. The reaction was stirred overnight at ambient temperature. After this time the solvent was distilled off and the residue was dissolved in ethyl acetate. The organic phase was extracted with 2N sodium hydroxide (×2), 4N hydrochloric acid (×3), saturated sodium chloride solution, dried and concentrated. The residue was purified with silica gel chromatography (SiO2: cyclohexane/ethyl acetate 5:1) and the appropriate fractions were combined and concentrated. The residue was dissolved in formic acid and stirred at 50° C. for 2 h, concentrated and dissolved in ethyl acetate. The organic phase was washed with 2N hydrochloric acid and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[NH:13][C:12](=[O:21])[N:11]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:10]2=[O:27])=[O:6].[BH4-].[Na+].Cl>CO.O>[OH:6][CH:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[C:17]([F:18])([F:19])[F:20])[NH:13][C:12](=[O:21])[N:11]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:10]2=[O:27])[CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCC(=O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCC(O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Yield: 94.5 %

Procedure:
A solution of N-[6-(3-methoxy-propionyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (118 mg, 0.288 mmol) in MeOH (3 mL) at r.t. was treated with NaBH4 (77 mg, 2.03 mmol), added portionwise over a period of 3 h. After disappearance of the starting material, the reaction mixture was acidified with 2M aq HCl and diluted with water. The aqueous phase was extracted with EtOAc (2×), the organic phases were combined, washed with brine and dried (Na2SO4) and evaporated. The white powder obtained was purified by MPLC(RP-C18 column (particle size 5-21 μM) with CH3CN/water 1:2. The fractions containing the product were combined, the acetonitrile is distilled off and the residual water phase was extracted with EtOAc. The organic phase was washed with brine and dried (Na2SO4) and the solvent was removed in vacuo to provide the title compound (112 mg, 94%) as a white powder, mp 180-184° C. 1H-NMR (DMSO-d6, 400 MHz): 11.80 (br s, 1H), 10.35 (br s, 1H), 8.33 (s, 1H), 7.45 (s, 1H), 5.65 (d, J=6 Hz, 1H), 4.98-4.92 (m, 1H), 3.60-3.52 (m, 1H), 3.42-3.35 (m, 1H), 3.20 (s, 3H), 3.15 (s, 3H), 1.86-1.67 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=1)[C:5](O)=[O:6].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57]>ClCCl>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=1)[C:5]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[O:6]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(Cl)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(Cl)c1F
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
3-chloro-4-(4-chloro-3-(trifluoromethyl)phenoxy)-2-fluorobenzoic acid (Preparation 153, 0.133 g, 0.360 mmol) was slurried in dichloromethane (0.6 mL). N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (100 mg, 0.54 mmol), 1-hydroxybenzotriazole (49 mg, 0.36 mmol) and N,N-diisopropylethylamine (75 μL, 0.43 mmol) were added to the slurry. The reaction mixture was stirred 20 minutes then methanesulfonamide (100 mg, 1.1 mmol) was added and the stirring continued for 18 hours at ambient temperature. The solvent was removed in vacuo to leave a residue. The residue was purified by semi-preparative reverse phase HPLC (Phenomenex 100×21.2 mm 10 micron C18 column. 20 mL/minutes. Gradient 85% A to 100% B over 25 minutes. Solvent A: 7800 water/200 acetonitrile/8 trifluoroacetic acid. Solvent B: 7200 acetonitrile/800 water/8 trifluoroacetic acid, 254 nM UV detection) to afford the title compound as a white solid (132 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:8]1([C:6]2[N:7]=[C:3]([CH2:2][N:23]3[CH2:24][CH2:25][N:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:21][CH2:22]3)[S:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCc1nc(-c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2csc(CN3CCN(c4ccccc4)CC3)n2)cc1
Yield: 75 %

Procedure:
A mixture of crude 2-chloromethyl-4-phenylthiazole (4.19g; 0.02 mole), N-phenylpiperazine (3.24 g; 0.02 mole) and finely-powdered, anhydrous sodium carbonate in absolute ethanol (60 ml) was stirred and boiled under reflux for 8 hours. The solvent was evaporated to dryness, solid residue suspended in water (100 ml) and then extracted with 2 × 100 ml CH2Cl2. The extracts were washed with water and dried over anhydrous MgSO4. On evaporation of the solvent, and recrystallisation of the residue from benzene/60°-80° C. petroleum ether mixture (with charcoal treatment) there was obtained the required product (5.03 g; 75%) having m.p. 142°-3° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9](O)=[O:10])([O-:3])=[O:2].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([Cl:23])=[O:10])([O-:3])=[O:2]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1

Procedure:
To a solution of 3-nitrocinnamic acid (5.0 g) in dry Toluene (100 ml), oxalyl chloride (11.33 ml) was carefully added, followed by dry DMF (0.1 mL). The resulting yellow solution was refluxed for 3 hrs and then evaporated to dryness, to get the 3-nitro cinnamoyl chloride as a solid residue, This solid residue was dissolved in THF, the resulting solution was cooled at 0° C., and 2M methylamine (13 ml) was added to the reaction mixture, the reaction mixture was stirred for 30 min. Solvents were evaporated under vacuum, the crude material was re-crystallised from diethylether to afford the title compound (4 gm).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1>>[NH:19]1[CH2:18][CH2:17][CH:16]([N:14]2[CH:15]=[C:11]([C:8]3[CH:9]=[C:10]4[N:2]([O:1][CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][C:38]([F:39])([F:40])[F:41])=[CH:33][CH:32]=5)[CH:3]=[CH:4][C:5]4=[N:6][CH:7]=3)[CH:12]=[N:13]2)[CH2:21][CH2:20]1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(O)c4c3)cn2)CC1
Product: FC(F)(F)Oc1ccc(COn2ccc3ncc(-c4cnn(C5CCNCC5)c4)cc32)cc1

Procedure:
The entitled compound is prepared from tert-butyl 4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate and 1-(bromomethyl)-4-(trifluoromethoxy)benzene as described in the last 2 steps of Example 18.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38]N)=[CH:34][CH:33]=1>>[CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[C:36]4[C:35](=[CH:34][CH:33]=[C:32]([CH3:31])[CH:37]=4)[NH:38][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3)c(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide and 1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 480.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH3:34][C:35]1[C:39]([Sn](CCCC)(CCCC)CCCC)=[CH:38][O:37][N:36]=1.C(OCC)(=O)C.O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])=[CH:3][C:2]=1[C:39]1[C:35]([CH3:34])=[N:36][O:37][CH:38]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1conc1C
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1nocc1-c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 100 °C
Reaction time: 24 h

Procedure:
5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (25 mg, 0.042 mmol), tetrakis(triphenylphosphine)palladium (2.5 mg, 0.0022 mmol) and 3-methyl-4-(tributylstannyl)isoxazole [synthesized as described by D. Uchiyama in Heterocycles, 43, 6, 1301, 1996] (32 mg, 0.086 mmol) were mixed in DME (0.45 ml) in an argon filled vial. The vial was closed and heated with stirring at 100° C. for 24 h. The reaction mixture was poured into a mixture of ethyl acetate and water. The mixture was shaken, the water phase was removed and the organic phase was dried over sodium sulphate. The product was purified by preparative HPLC. Yield: 12 mg, 0.022 mmol (52%).
Reaction SMILES: [N:1](OCCCC)=[O:2].[C:8]1([N:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18](C)[C:17]=2[CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[K+].O>CN(C)C=O.C(O)(=O)C>[C:8]1([N:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([NH:1][OH:2])[C:17]=2[CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCON=O
Reactant: Cc1c(C(=O)N(c2ccccc2)c2ccccc2)ccc(S(C)(=O)=O)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(C(=O)N(c2ccccc2)c2ccccc2)ccc(S(C)(=O)=O)c1NO
Temperature: 0 °C

Procedure:
A solution of 0.7 g (6.9 mmol) of n-butyl nitrite (97%) and 2 g (5.3 mmol) of N,N-diphenyl-2,3-dimethyl-4-methylsulfonyl-benzamide in 30 ml of dimethylformamide is cooled to from −55 to −60° C., and a solution of 1.4 g (12 mmol) of potassium tert-butoxide in 10 ml of dimethylformamide is added dropwise at this temperature, over a period of 20 minutes. The reaction is monitored by HPLC. For work-up, initially 10 ml of water are added, and the mixture is then adjusted to pH 5-6 using glacial acetic acid. The mixture is then poured onto 100 ml of ice-water and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This gives 3.0 g of a partially crystalline crude product, which is purified by silica gel chromatography using the mobile phase toluene/acetone.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[NH:23][NH2:24]>C(Cl)Cl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:24][NH:23][C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 2.5 h
Yield: 68.1 %

Procedure:
A solution of 4-chloro-3-nitroquinoline (5.00 g, 24.0 mmol) in 120 mL of anhydrous CH2Cl2 was treated with triethylamine (6.7 mL, 48.2 mmol) and tert-butyl carbazate (3.20 g, 24.2 mmol). After stirring under nitrogen for 2.5 hour (h), an additional portion of tert-butyl carbazate (3.2 g, 24.2 mmol) was added. After stirring overnight, the deep red solution was washed with H2O (2×) and brine. The organic portion was dried over Na2SO4 and concentrated to give a red foam. The material was passed through a SiO2 column eluting with 2.5% methanol/CH2Cl2. The resulting red powder was treated with 5:1 hexanes/CH2Cl2 and filtered. The solid was washed several times with hexanes and was dried under vacuum to give tert-butyl N′-(3-nitroquinolin-4-yl)hydrazinecarboxylate (4.97 g) as an orange powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:22])=[O:21])[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([NH2:36])[CH:33]=[N:34][CH:35]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:36][C:32]1[CH:33]=[N:34][CH:35]=[C:30]([N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[CH:31]=1)=[C:3]([CH3:23])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH3:22])=[O:21])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccc2S(C)=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using (+/−)-4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfinyl)phenyl)quinoline (30.0 mg, 0.085 mmol) and 5-morpholinopyridin-3-amine in toluene to give 5,7-difluoro-3-methyl-2-(2-(methylsulfinyl)phenyl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.22 (1H, dd, J=7.9, 1.1 Hz), 7.96 (1H, d, J=2.3 Hz), 7.81 (1H, d, J=2.2 Hz), 7.73 (1H, td, J=7.7, 1.3 Hz), 7.63 (1H, td, J=7.5, 1.3 Hz), 7.50 (1H, ddd, J=9.2, 2.5, 1.4 Hz), 7.39 (1H, dd, J=7.6, 1.2 Hz), 7.20 (1H, d, J=14.1 Hz), 7.08 (1H, ddd, J=13.9, 8.4, 2.5 Hz), 6.60 (1H, t, J=2.2 Hz), 3.80-3.93 (4H, m), 3.12-3.28 (4H, m), 2.87 (3H, s), 1.98 (3H, s). Mass Spectrum (ESI) m/e=495.2 (M+1).
Reaction SMILES: C[Si](C)(C)[O-].[Na+].[NH2:7]/[C:8](/[C:15]([F:18])([F:17])[F:16])=[CH:9]\[C:10]([O:12]CC)=O.[NH2:19][C:20]1[C:21]([O:34][CH3:35])=[C:22]([NH:28][C:29](=O)[O:30]CC)[C:23]([F:27])=[CH:24][C:25]=1[Cl:26].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>CN(C=O)C>[NH2:19][C:20]1[C:21]([O:34][CH3:35])=[C:22]([N:28]2[C:10](=[O:12])[CH:9]=[C:8]([C:15]([F:16])([F:17])[F:18])[NH:7][C:29]2=[O:30])[C:23]([F:27])=[CH:24][C:25]=1[Cl:26]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c(N)c1OC
Agent: C[Si](C)(C)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(N)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)[nH]c1=O

Procedure:
This compound was prepared using 4.0 grams (0.036 mole) of sodium trimethylsilanolate, 6.6 grams (0.036 mole) of ethyl 3-amino4,4,4-trifluorocrotonate, 8.5 grams (0.032 mole) of ethyl N-(3-amino4-chloro-6-fluoro-2-methoxyphenyl)carbamate, and 2.2 grams (0.014 mole) of DBU in 75 mL of DMF. This preparation differs from well-known literature preparations for pyrimidinedione rings in that sodium trimethylsilanolate and DBU were used rather than sodium hydride. The yield of title compound was 1.7 grams. The NMR spectrum was consistent with the proposed structure.