Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[CH:20]([CH:22]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH:23]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=O.C(O)(=O)C>O1CCCC1>[OH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:23]1[CH:22]([CH:20]=[CH:3][C:2](=[O:1])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:30][CH2:29][C:24]21[O:25][CH2:26][CH2:27][O:28]2
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(C=CC1CCC2(OCCO2)C1CCCCCCCO)CCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
A solution of dimethyl 2-oxo-4-phenylbutylphosphonate [2.5g; prepared as described hereinafter in Example 9(iv)] in anhydrous tetrahydrofuran (50 ml.) was added to a stirred suspension of sodium hydride (0.24 g.) in tetrahydrofuran (20 ml.). The mixture was stirred at room temperature in an atmosphere of nitrogen for 24 hours, then treated dropwise with a solution of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [2.7 g; prepared as described hereinbefore in Example 1(iv)] in tetrahydrofuran (30 ml.) and stirred for a further 2 hours in an atmosphere of nitrogen. The mixture was acidified to pH 4 by the addition of glacial acetic acid, the solvents were removed in vacuo and the residue was extracted with diethyl ether. The ethereal solution was washed with aqueous sodium bicarbonate solution (10% w/v) and then with water and dried over anhydrous magnesium sulphate. Evaporation of the solution gave 6-(7-hydroxyheptyl)-7-(3-oxo-5-phenylpent-1-enyl)-1,4-dioxaspiro[4,4] nonane (3.9 g.), in the form of a yellow oil (νmax 955 cm-1, 990 cm-1, 1625 cm-1, 1665 cm-1, 1690 cm-1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[CH:21][C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:24][N:25]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[CH:21][C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:27]=[N:26]1
Reactant: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(Cl)nn12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(-c3cnn(C)c3)nn12

Procedure:
A mixture of 7-[(S)-1-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.045 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18.9 mg, 0.091 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (18.8 mg, 0.136 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=2.07 (d, J=6.6 Hz, 3H), 3.98 (s, 3H), 6.47 (q, J=6.6 Hz, 1H), 6.81 (d, J=1.8 Hz, 1H), 7.49 (d, J=9.9 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.88 (s, 1H), 7.97 (s, 1H), 8.02 (s, 1H), 8.10 (d, J=9.6 Hz, 1H). MS (ES+): m/z 377.04 (100) [MH+]. HPLC: tR=1.95 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH:4]=[C:3]1[C:22](O)=[O:23].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[C:3]([C:22]([N:56]2[CH2:57][CH2:58][N:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=3)[CH2:54][CH2:55]2)=[O:23])=[CH:4][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:20])([F:21])[F:19])=[CH:15][CH:16]=2)=[O:9])=[CH:6]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1C(=O)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.15 mmol) of 1-methyl-4[({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]-1H-pyrrole-2-carboxylic acid (Example 5A) are initially charged in 1 ml of DMF, and 56 mg (0.18 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and 8.9 mg (0.07 mmol) of 4-(dimethylamino)pyridine (DMAP) are added. 29 mg (0.18 mmol) of 1-(2-pyridyl)piperazine are then added, and the mixture is stirred at RT for 8 h. The reaction solution is purified by RP-HPLC (acetonitrile/water). This gives a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18].C1(C)C=CC=CC=1>[OH-].[Na+]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:13])(=[O:12])[NH:18][C:17]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=2[Cl:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Nc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(S(=O)(=O)Nc2ccc(Cl)cc2Cl)ccc1Cl
Reaction time: 6 h

Procedure:
602 Parts of 2-chloro-5-chlorosulfonylbenzoic acid are added to a solution of 830 parts of 2,4-dichloroaniline in 600 parts of toluene at 60° and the mixture is stirred for 6 hours at the same temperature. Insoluble material is then dissolved in dilute sodium hydroxide solution, the aqueous layer is separated off and acidified with dilute hydrochloric acid and the product is filtered off and washed with water. After redissolving in sodium hydroxide solution, reprecipitation with hydrochloric acid and drying, 592 parts of 2-chloro-5-[2,4-dichlorophenyl-sulfamoyl]-benzoic acid are obtained as a colorless powder of melting point 174° C.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:8]=[C:7]([Cl:9])[C:6]([C:10](Cl)=[O:11])=[CH:5][N:4]=1.C(OCC)C>O1CCOCC1>[Cl:2][C:3]1[N:8]=[C:7]([Cl:9])[C:6]([C:10]([NH2:1])=[O:11])=[CH:5][N:4]=1
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Reactant: N
Solvent: C1COCCO1
Solvent: CCOCC
Product: NC(=O)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
A solution of ammonia (14 g) in 1,4-dioxane (500 ml) was added drop-wise to an ice-cooled stirred solution of 2,4-dichloro-5-pyrimidinecarbonyl chloride (78 g, crude) in 1,4-dioxane (400 ml) under nitrogen. The ice-bath was removed and the solution was stirred for 30 min and concentrated. The solid residue was partitioned between ethyl acetate (500 ml) and saturated aqueous sodium bicarbonate (500 ml), the organic washed with saturated aqueous sodium bicarbonate (500 ml, ×2), followed by brine (300 ml). The organic phase was dried (sodium sulphate) and concentrated to give a yellow solid. To the residue was added diethyl ether (50 ml) and the resulting suspension was treated under ultrasonic wave for 8 min then filtered. The residue was washed with ethyl ether (50 ml) to give the title compound as a white solid (30 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[CH2:5]2.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]([O:19][C:15](=[O:18])/[CH:16]=[CH:17]/[C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[CH2:5][C:4]=2[CH:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC1(C)Cc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CC(C)(C)C(=O)N2
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6-bromo-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one (434 mg, 1.7 mmol), tert-butyl acrylate (1.23 mL, 8.5 mmol) and (i-Pr)2EtN (0.9 mL, 5.1 mmol) in DMF (25 mL) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (38 mg, 0.17 mmol) and P(o-tol)3 (103 mg, 0.34 mmol) then heated to 110° C. for 22 h. The hot mixture was filtered through a pad of celite and washed with ethyl acetate (50 mL). The filtrate was diluted with H2O (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, then brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting brown solid was then triturated with a diethyl ether followed by filtration to yield the white solid product. Yield 178 mg (35%); 1H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.52 (d, J=16.1 Hz, 1H), 6.52 (d, J=15.8 Hz, 1H), 2.80 (s, 2H), 1.49 (s, 9H), 1.09 (s, 6H); ESI MS m/z 303 [C17H22N2O3+H]+
Reaction SMILES: [O:1]1[CH2:14][CH:2]1[CH2:3][O:4][C:5]1[C:6]([N+:11]([O-:13])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:17][CH2:16]1.C(Cl)Cl>C(O)(C)C>[OH:1][CH:2]([CH2:3][O:4][C:5]1[C:6]([N+:11]([O-:13])=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:19][CH2:20]1
Reactant: O=C1NCCN1C1CCNCC1
Reactant: O=[N+]([O-])c1ncccc1OCC1CO1
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C1NCCN1C1CCN(CC(O)COc2cccnc2[N+](=O)[O-])CC1

Procedure:
A mixture of 46.0 g of 3-(2,3-epoxy-propoxy)-2-nitropyridine and 35.0 g of 1-(4-piperidyl)-imidazolidin-2-one in 500 ml of isopropanol is refluxed for 2 hours. Working up analogously to Example 1 using methylene chloride as the extracting agent yields crude 1-{1-[2-hydroxy-3-(2-nitro-3-pyridyloxy)-propyl]-4-piperidyl}-imidazolidin-2-one, which after recrystallisation from isopropanol melts at 154°-158°.
Reaction SMILES: C[O:2][C:3]([C:5]1([Cl:30])[C:7]2([CH2:12][CH2:11][C:10]([C:28]#[N:29])([C:13]3[C:21]4[C:20]5[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=5[O:18][C:17]=4[C:16]([O:26][CH3:27])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[O:6]1)=[O:4].C[O-].[Na+].Cl>C(O)C.O>[Cl:30][C:5]1([C:3]([OH:4])=[O:2])[C:7]2([CH2:8][CH2:9][C:10]([C:28]#[N:29])([C:13]3[C:21]4[C:20]5[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=5[O:18][C:17]=4[C:16]([O:26][CH3:27])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)[O:6]1
Reactant: COC(=O)C1(Cl)OC12CCC(C#N)(c1ccc(OC)c3oc4ccccc4c13)CC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2(C#N)CCC3(CC2)OC3(Cl)C(=O)O)c2c1oc1ccccc12

Procedure:
At room temperature and under nitrogen, to a solution of 2-chloro-6-cyano-6-(4-methoxy-dibenzofuran-1-yl)-1-oxa-spiro[2.5]octane-2-carboxylic acid methyl ester (0.300 g, 0.0007 mol) (as obtained in step 1) in a mixture of ethanol (5 ml) and water (0.15 ml) was added sodium methoxide (0.190 g, 0.0035 mol). The reaction mass was refluxed for 1 hr, and once the product has formed, the reaction mass was brought to room temperature and the pH was adjusted to 2 with dil. HCl and extracted with Ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under vacuum to get the 2-chloro-6-cyano-6-(4-methoxy-dibenzofuran-1-yl)-1-oxa-spiro[2.5]octane-2-carboxylic acid. Yield 0.180 g (64%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+]([O-])=O)=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:14]1(OC)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1ccccc1Cl

Procedure:
Compound 29 was prepared by reacting 2-chloro-5-nitrobenzoic acid chloride with anisole in the presence of aluminum trichloride to produce a chlorobenzophenone compound; the chlorobenzophenone compound was reduced in the presence of trifluoromethanesulfonic acid and triethylsilane to produce a chlorodiphenylmethane compound; the chlorodiphenylmethane compound was treated with lithium sulfide and 2,2-dibutyl-3-(methanesulfonato)propanal to produce 1-(2,2-dibutyl-3-oxopropylthio)-2-((4-methoxyphenyl)methyl)-4-dimethylaminobenzene (40); and 40 was oxidized with m-chloroperbenzoic acid to produce 29. The first step of that method of preparing compound 29 requires the use of a corrosive and reactive carboxylic acid chloride that was prepared by the reaction of the corresponding carboxylic acid with phosphorus pentachloride. Phosphorus pentachloride readily hydrolyzes to produce volatile and hazardous hydrogen chloride. The reaction of 2,2-dibutyl-3-(methanesulfonato)propanal with the lithium sulfide and the chlorodiphenylmethane compound required the intermediacy of a cyclic tin compound to make the of 2,2-dibutyl-3-(methanesulfonato)propanal. The tin compound is expensive and creates a toxic waste stream.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][CH:4]=1.[H][H]>CC(O)C.[C].[Pd]>[OH:1][CH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)/C=C/c1cccc(CO)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: COC(=O)CCc1cccc(CO)n1
Yield: 98.9 %

Procedure:
The above compound was also prepared as follows: To a solution of 50.02 g of methyl 3-(6-hydroxymethylpyridin-2-yl)-trans-acrylate in IPA 502 mL, was added 2.51 g of 5% palladium-carbon (containing 50% water) under argon atmosphere, the reaction mixture was stirred under 1-4 atom hydrogen atmosphere at 50° C. for 2.5 hours. After cooling, the catalyst was filtrated off and the solvent was removed off under reduced pressure from the reaction mixture, which gave 50 g of methyl 3-(6-hydroxymethylpyridin-2-yl)propionate as a brown oil.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:24])=[C:5]([C:25](OC)=[O:26])[N:4]=1)#[N:2].[NH2:29][CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:24])=[C:5]([C:25]([NH:29][CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:26])[N:4]=1)#[N:2]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3cccc4ccccc34)ccc2c1O
Reactant: CCOC(=O)C(C)(C)CN
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccc4ccccc34)ccc2c1O

Procedure:
Methyl 1-cyano-4-hydroxy-7-(naphthalen-1-yloxy)isoquinoline-3-carboxylate (15 mg, 0.04 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (24 mg, 0.16 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 16 mg. MS: (−) m/z 482.30 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Cl[C:11]1[C:12](=[O:25])[NH:13][C:14](=[O:24])[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[C:12](=[O:25])[NH:13][C:14](=[O:24])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: O=C1NC(=O)C(c2cccc(F)c2F)=C1Cl
Reactant: Nc1cc(F)cc(F)c1
Agent: Cl
Solvent: CO
Product: O=C1NC(=O)C(c2cccc(F)c2F)=C1Nc1cc(F)cc(F)c1

Procedure:
A solution of 3,5-difluoroaniline (161 mg, 0.00125 mol) and 3-chloro-4-(2,3-di-fluorophenyl)-1H-pyrrole-2,5-dione (122 mg, 0.0005 mol) in methanol (2 mL) was heated in a sealed tube at 65° C. for 8 days. The mixture was acidified with aqueous hydrochloric acid (1M) and extracted with ethyl acetate. The combined organic solutions were washed with water and brine, dried with magnesium sulphate, evaporated and the residue triturated with hexane-dichloromethane (95:5 v/v) to afford the title compound as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]([C:9]1[NH:10][C:11](=[O:21])[C:12]([OH:20])=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=1)([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[CH2:28]([O:20][C:12]1[C:11](=[O:21])[N:10]2[C:9]([C:6]([CH3:7])([CH3:8])[O:5][CH2:4][CH2:3][CH2:2]2)=[N:14][C:13]=1[C:15]([OH:17])=[O:16])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc(C(C)(C)OCCCCl)[nH]c(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 135.7 %

Procedure:
A suspension of intermediate 33, ethyl 2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate, (0.205 g, 0.64 mmol) and anhydrous potassium carbonate (0.361 g, 2.6 mmol) in anhydrous dimethylformamide (4 mL) was stirred at 60° C. for 5 hours. The reaction mixture was treated with benzyl bromide (0.122 g, 0.71 mmol) and stirred for 16 hours. Following this, 2 mL of H2O was added and the mixture stirred for an additional 24 hours. Solvent was removed by rotary evaporator and the resulting residue suspended in 0.5 N hydrochloric acid (16 mL). The crude product was extracted with ethyl acetate (2×15 mL), then dried (sodium sulfate), filtered, and concentrated to dryness by rotary evaporator to give 0.299 g (Yield>100%) of the title compound as a solid. LC/MS [M+H]+=345.21.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1.[F:21][C:22]([F:27])([F:26])[C@@H:23]([NH2:25])[CH3:24].O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:25][C@@H:23]([CH3:24])[C:22]([F:27])([F:26])[F:21])[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2Cl)c(F)c1
Reactant: C[C@H](N)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 5,7-dichloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]-pyrimidine (200 g, 0.627 mol) in anhydrous DMF (1000 mL) is added (S)-2,2,2-trifluoro-1-methyl-ethylamine (177 g, 1.57 mol). The solution is stirred from about 20° C. to about 30° C. for 24 h. The reaction mixture is added to cold water (3000 mL) slowly over 30 min. The mixture is stirred for 30 min at 10-20° C. The solid product is filtered and washed with water (2×500 mL). The crude product is dissolved into IPA (1000 mL) at 50° C. Water (2000 mL) is added to precipitate the product over 30 min. The mixture is cooled to 0° C. over 1 h and stirred for 1 h at this temperature. The solid is filtered and dried at 65° C./10 mmHg for 20 h to give a light yellow solid (204 g, 82%, 98% HPLC area purity and 99% ee).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:15][C:14]3=[CH:16][S:17][CH:18]=[C:13]3[N:12]=2)[CH:4]=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:23]([O:22][C:20]([N:12]1[C:13]2=[CH:18][S:17][CH:16]=[C:14]2[N:15]=[C:11]1[S:10][CH2:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccnc(CSc2nc3cscc3[nH]2)c1
Product: COc1ccnc(CSc2nc3cscc3n2C(=O)OCc2ccccc2)c1
Yield: 106.9 %

Procedure:
1.4 g (5 mmol) of 2-(4-methoxy-2-picolylmercapto)-1H-thieno[3,4-d]imidazole were reacted in analogy to Example 15 with 0.8 ml (5 mmol) of benzyl chloroformate (90-95%). 2.2 g of oily crude product were obtained and were chromatographed on silica gel (35-70μ) with toluene/ethyl acetate (1:5). The product crystallized from diethyl ether. Melting point 102°-104° C.
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Product: c1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and benzylamine (0.5 ml) as described above; yield: 0.072 g (26.2%); MS m/z: 276.5 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 5.39 (s, 2H); 6.99-7.01 (m, 2H); 7.20-7.29 (m, 3H); 7.63 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 7.83 (d, 1H, 3J=8.7 Hz); 7.93 (br s, 1H); 8.79 (s, 1H); 9.09 (s, 1H); HPLC (METHOD [A]): rt 7.81 min (100%)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[CH3:33][CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:42][CH2:43][CH:34]2[CH3:33])=[O:9])=[CH:10][C:11]([F:14])=[CH:12][N:13]=1
Reactant: CC1CCc2ccccc2N1
Reactant: O=C(O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCc2ccccc2N1C(=O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Temperature: 120 °C
Yield: 22.2 %

Procedure:
A solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinic acid (36.3 mg, 0.12 mmol, 1.0 equiv) in thionyl chloride (492 mg, 300 μL, 4.14 mmol, 34.5 equiv; [CAS RN 7719-09-7]) was heated to 100° C. over night. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (155 mg, 204 μL, 1.20 mmol, 10.0 equiv; [CAS RN 7087-68-5]) and 2-methyl-1,2,3,4-tetrahydro-quinoline (22.1 mg, 0.15 mmol, 1.25 equiv; [CAS RN 1780-19-4]) and the reaction mixture heated by microwave irradiation to 120° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 11.5 mg (22%) of the title compound. MS (ISP): 430.8 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[S:9][C:10]2[CH:17]=[CH:16][C:15]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)=[CH:14][C:11]=2[C:12]=1[CH3:13])(=[O:7])=[O:6].[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].N1C=CN=C1>CN(C=O)C.CCOCC>[Si:28]([O:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[S:9][C:10]2[CH:17]=[CH:16][C:15]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)=[CH:14][C:11]=2[C:12]=1[CH3:13])(=[O:7])=[O:6])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: COC(=O)c1ccc(-c2ccc3sc(S(=O)(=O)NCCO)c(C)c3c2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(-c2ccc3sc(S(=O)(=O)NCCO[Si](C)(C)C(C)(C)C)c(C)c3c2)cc1

Procedure:
A solution of Example 398B (200 mg, 0.5 mmol), tert-butyldimethylsilyl chloride (85 mg, 0.55 mmol) and imidazole (36 mg, 0.6 mmol) in DMF (5 mL) at room temperature was stirred for 24 hours, diluted with ether, filtered through a pad of silica gel, and concentrated to provide the desired product.