Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)=[CH:2]1.[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[N:13]=2)=[CH:2]1
Reactant: Fc1cnc(Cl)nc1NCc1csc2ccccc12
Reactant: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(NCc3csc4ccccc34)n2)c1

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of benzothiophen-3-ylmethylamine (244 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine. The reaction of N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-(benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. (40 mg, 36%). 1H NMR (CDCl3): δ 4.45 (br, 1H), 4.95 (dd, J=1.2 and 5.4 Hz, 2H), 5.33 (br, 1H), 6.40 (ddd, J=1.2, 2.4 and 8.1 Hz, 1H), 6.85 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.91 (br, 1H), 7.05 (t, J=8.1 Hz, 1H), 7.26 (m, 1H), 7.39–7.47 (m, 3H), 7.81 (dd, J=1.2 and 5.1 Hz, 1H), 7.84 (d, J=3.3 Hz, 1H), 7.92 (m, 1H); 19F NMR (282 MHz, CDCl3): δ −168.89; LCMS: ret. time: 21.91 min.; purity: 99.34%; MS. (m/e): 366.96 (MH+).
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32]>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])[C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
The title compound is prepared following the procedures of Daisley, R. W.; Hanbali, J. R. Synth. Commun., 763, (1981) as follows. Dibenzyl malonate (3.47 mL, 13.9 mmol) is added dropwise to a stirred mixture of 60% oil dispersion of sodium hydride (556 g, 13.9 mmol) in toluene (20 mL). After 1 hr, the mixture is treated with a solution of 4-chloro-3-nitropyridine (2.0 g, 12.6 mmol) in toluene (10 mL) and then heated at reflux for 2 hr. After cooling to room temperature, the reaction is concentrated and the residue is treated with 1M aq hydrochloric acid (6 mL) and extracted with ethyl acetate. The combined extract is washed with saline, dried, filtered and concentrated. The residue is purified by chromatography eluting with pentane-20% ethyl acetate. Product containing fractions are combined and concentrated to give 2-(3-nitropyridin-4-yl)malonic acid dibenzyl ester (1.72 g, 33.6% yield) as a yellow oil.
Reaction SMILES: C1(NC=CP(=O)(OCC)[O:11][CH2:12][CH3:13])CCCCC1.[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([CH:33]=O)=[C:31]([CH:35]([CH3:37])[CH3:36])[N:30]=[C:29]3[NH:38][CH:39]=[CH:40][C:28]=23)=[CH:23][CH:22]=1.O.O.C(O)(=O)C(O)=O>O1CCCC1.O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:32](/[CH:33]=[CH:13]/[CH:12]=[O:11])=[C:31]([CH:35]([CH3:37])[CH3:36])[N:30]=[C:29]3[NH:38][CH:39]=[CH:40][C:28]=23)=[CH:25][CH:26]=1
Reactant: CCOP(=O)(C=CNC1CCCCC1)OCC
Reactant: CC(C)c1nc2[nH]ccc2c(-c2ccc(F)cc2)c1C=O
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc2[nH]ccc2c(-c2ccc(F)cc2)c1/C=C/C=O

Procedure:
A solution of 11 g (42 mmol) of diethyl 2-(cyclohexylamino)-vinyl-phosphonate in 60 ml of tetrahydrofuran are added dropwise under argon in the course of 10 min to a suspension of 2.52 g (84 mmol) of 80% strength sodium hydride in 60 ml of anhydrous tetrahydrofuran. 9.9 g (35 mmol) of the compound from Example VIII dissolved in 100 ml of tetrahydrofuran are added dropwise at reflux. The mixture is allowed to boil under reflux for 90 min and is cooled, treated with water and extracted several times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and concentrated in vacuo. The residue is dissolved in 300 ml of toluene and heated under reflux for 1 h with 22.9 g (182 mmol) of oxalic acid dihydrate in 350 ml of water. The mixture is cooled, the phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness in vacuo. The residue is dissolved in dichloromethane and filtered through 400 g of silica gel 230-400 mesh in a glass suction filter. The mixture is eluted without sucking dry using petroleum ether/ethyl acetate 1:1, the eluate is concentrated in vacuo and the residue is stirred thoroughly in ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([NH2:48])[CH:46]=2)[N:41]([CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)[N:40]=1>CN(C=O)C>[NH:32]1[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N:30]=[C:31]1[C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([NH:48][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[CH:46]=2)[N:41]([CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)[N:40]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.6 %

Procedure:
3-Fluorobenzoic acid (10 mg, 0.029 mmol), HOBt (6 mg, 0.044 mmol), EDC (9 mg, 0.045 mmol) and sodium bicarbonate (2.5 mg, 0.029 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (10 mg, 0.029 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (8 mg) as a off white solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (d, 1H, J=1.6 Hz), 8.15-8.13 (m, 2H), 7.95 (s, 1H), 7.58 (m, 2H), 7.52 (d, 1H, J=9.6 Hz), 7.42-7.36 (m, 2H), 7.21 (m, 2H), 5.69 (dd, 1H, J=2.4 and 9.2 Hz), 3.99 (m, 1H), 3.72 (m, 1H), 2.55 (m, 1H), 2.06 (m, 2H), 1.67 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]2[CH2:12][O:11]2)=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5].[OH:14][CH2:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>C(O)C>[C:4]([C:3]1[C:2]([F:1])=[C:9]([CH:10]([OH:11])[CH2:12][N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17][C@@H:16]2[CH2:15][OH:14])[CH:8]=[CH:7][C:6]=1[F:13])#[N:5]
Reactant: N#Cc1c(F)ccc(C2CO2)c1F
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2F)[C@@H](CO)C1

Procedure:
2,6-difluoro-3-(oxiran-2-yl)benzonitrile (3.70 g, 20.4 mmol) and (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (6.63 g, 30.6 mmol) were dissolved in ethanol (36.0 mL) then placed in 3-20 mL sealed tubes and microwaved at 140° C. for 1 h. The solvents were evaporated and the combined residue was purified by chromatography through a 120 g ISCO Redi-sep column with 50% to 100% ethyl acetate/hexane solvent system to yield the title compound LC-MS (IE, m/z): 398 [M+1]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7]1[C:16]2[O:15][CH2:14][C:13](=[O:17])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:4].[C:18]1([CH:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:25][CH2:26][CH2:27]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C1COCC1>[C:3]([O:6][C:7]1[C:16]2[O:15][CH2:14][C:13](=[O:17])[N:12]([CH2:27][CH2:26][O:25][CH:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: BrCCOC(c1ccccc1)c1ccccc1
Reactant: CC(=O)Oc1cccc2c1OCC(=O)N2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc2c1OCC(=O)N2CCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
Anhydrous THF (15 ml) was added to sodium hydride (106 mg) to form a suspension, and a solution of 8-acetoxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (498 mg) in anhydrous DMF (5 ml) was added to the resulting suspension, and the mixture was stirred at room temperature for 1 hour. 2-diphenylmethoxyethyl bromide (980 mg) was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction solution was poured into a 3% citric acid aqueous solution, and then extracted with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified by medium-pressure column chromatography (solvent:ethyl acetate/cyclohexane=1/3) to obtain the colorless oily object compound (640 mg, yield 66%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:39])[C@:7]1([O:34][Si](C)(C)C)[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:31])([C@@H:22]([O:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:32])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:33])(=[O:3])[CH3:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:4][CH2:5][C:6](=[O:39])[C@:7]1([OH:34])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:31])([C@@H:22]([O:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:32])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(O[Si](C)(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
A solution of (11β,16β)-9-fluoro-16-methyl-3,20-dioxo-11,17-bis[(trimethylsilyl)oxy]pregna-1,4-dien-21-yl acetate (26 g, ˜43 mmol) in 430 mL of tetrahydrofuran (THF) was cooled to 0° C. and neat acetic acid (4.95 mL, 86.5 mmol) was added followed by dropwise addition of a 1.0 M solution of tetra-n-butylammonium fluoride in THF (43.3 mL, 43.3 mmol). After stirring at 0° C. for 4 hours, the ice bath was removed and the reaction was allowed to warm to room temperature and stir for an additional 16 hours. Most of the THF was removed by rotary evaporation in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with water, sat. NH4Cl, water, sat. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated under vacuum to give an off-white solid. Purification by flash chromatography through a 1.6 kg column of silica gel eluting with 4% MeOH in dichloromethane provided 16.1 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH:23]=1)[CH:21]=O>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH2:21][C:12]2[S:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:14][CH:13]=2)[CH:23]=1
Reactant: CCOc1cccc(-c2cccs2)c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: CCOc1cccc(-c2ccc(Cc3cc(Br)ccc3Cl)s2)c1

Procedure:
The above 2-(3-ethoxyphenyl)thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 9 to give 5-bromo-2-chloro-1-(5-(3-ethoxyphenyl)-2-thienylmethyl)benzene as colorless oil. APCI-Mass m/Z 407/409 (M+H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:25]([C:30]([NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=2)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:37]([C:36]3[CH:35]=[CH:34][C:33]([NH:32][C:30]([C:25]4[C:24]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:31])=[CH:41][CH:40]=3)=[O:38])[CH2:6][C:5]=12
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
To a solution of 0.65 g of 10,11-dihydro-5H-pyrrolo[2, 1-c][1,4]benzodiazepine and 0.52 g of N, N-diisopropylethylamine in 25 ml of methylene chloride is added 1.34 g of 4-[([1, 1'-biphenyl]-2-carbonyl)amino]-benzoyl chloride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is dissolved in methylene chloride and passed through hydrous magnesium silicate two additional times to give upon concentration in vacuo to give 1.02 g of the desired product as a residue. M+ =482.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[N:18]=[C:17]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])=[O:20])[C:16]([OH:36])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>C(Cl)(Cl)Cl>[CH3:47][C:37]1[CH:42]=[CH:41][C:40]([S:43]([O:36][C:16]2[C:17]([C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[S:30]([N:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])=[O:20])=[N:18][C:9]([Br:8])=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CNC(=O)c1nc(Br)c2cccnc2c1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Oc2c(C(=O)NCc3ccc(F)cc3S(=O)(=O)N(C)C)nc(Br)c3cccnc23)cc1
Reaction time: 5 h

Procedure:
Triethylamine (0.65 mL, 4.66 mmol) was added slowly to a suspension of 5-bromo-N-{2-[(dimethylamino)sulfonyl]-4-fluorobenzyl}-8-hydroxy-1,6-naphthyridine-7-carboxamide (1.50 g, 3.10 mmol) in chloroform (15 mL) to give a yellow cloudy solution. p-Toluenesulfonyl chloride (0.71 g, 3.73 mmol) was then added slowly and the mixture was aged at 40° C. for five hours. The mixture was quenched with 10% KHSO4 solution and the layers were separated. The aqueous layer was extracted twice more with CHCl3. The combined organic extracts were washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a crude yellow oil. The oil was dissolved in a minimal amount of CHCl3 and purified on an Isco column (110 g silica) running a 0 to 2.5% MeOH/CHCl3 gradient over 30 minutes. The collected fractions were concentrated in vacuo to afford the desired material as a white solid foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([CH:18]([CH3:20])[CH3:19])=[CH:13][C:14]([OH:17])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([CH:18]([CH3:19])[CH3:20])=[CH:13][C:14]([O:17][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CC1CCn2c1cc1c(C(C)C)cc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC1CCn2c1cc1c(C(C)C)cc(OCc3ccccc3)cc12
Reaction time: 1 h

Procedure:
To the compound of Step 3 (130 mg, 0.45 mmol) in DMF (2 mL) at 0° C., was added benzyl bromide (100 mL) and Cs2CO3 (300 mg, 0.92 mmol). The reaction mixture was warmed to r.t for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound (130 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36].N1C=CC=CC=1>O1CCCC1>[F:27][C:3]1[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[F:28])(=[O:37])=[O:36]
Reactant: Cc1ncc(-c2cnc3[nH]cc(C(=O)c4c(F)ccc(N)c4F)c3c2)cn1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ncc(-c2cnc3[nH]cc(C(=O)c4c(F)ccc(NS(=O)(=O)c5ccccc5F)c4F)c3c2)cn1
Temperature: 60 °C
Yield: 41.2 %

Procedure:
To (3-amino-2,6-difluoro-phenyl)-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone (50, 0.220 g, 0.602 mmol) in 4.01 mL of tetrahydrofuran, 2-fluoro-benzenesulfonyl chloride (20, 0.352 g, 1.807 mmol) and pyridine (0.146 mL, 1.807 mmol) are added and the reaction is heated at 60° C. overnight. The reaction is partitioned between brine/water and ethyl acetate/tetrahydrofuran. The organic layer is separated and the solvent is removed under vacuum. The resulting residue is purified by silica gel column chromatography eluting with 0-10% methanol in dichloromethane, then triturated with ethyl acetate/heptane to provide the desired compound as a light tan solid (P-1520, 0.130 g, 0.248 mmol, 41.2% yield).
Reaction SMILES: C([C:6]([CH:22](OCC)OCC)([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)[C:7]#[N:8])(OCC)=O.[OH-].[K+].[NH2:31][C:32]([NH2:34])=[NH:33]>C(O)C>[NH2:34][C:32]1[N:33]=[C:7]([NH2:8])[C:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:22][N:31]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(C#N)(Cc1cc(OC)c(OC)c(OC)c1)C(OCC)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC

Procedure:
A solution of α-carbethoxy-α-diethoxymethyl-β-(3,4,5-trimethoxyphenyl)propionitrile (7.9 g, 0.02 mol) and an equivalent amount of potassium hydroxide in ethanol (50 ml) was heated at reflux for one hour. A solution of guanidine (0.07 mol) in ethanol (50 ml) was added, and reflux was resumed. Some ethanol was allowed to boil off bringing the reaction temperature up to 85°. After about 20 hours at reflux the mixture was allowed to cool, and the product was filtered and washed with ethanol. The crude product was purified by treating with hot aqueous acetic acid and reprecipitation with ammonium hydroxide. The yield of purified trimethoprim (m.p. 197°-198°) was 3.6 g (62%), its identity being confirmed by an NMR spectrum.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>N1C=CC=CC=1>[NH2:1][C:2]1[NH:3][C:4](=[S:32])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=S)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 135 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of 75 (1 g, 2.26 mmol) in pyridine (50 mL) was added at room temperature P2S5 (2.13 g, 4.79 mmol). The solution was refluxed gently (bath temperature 130-140° C.) for 29 h. The reaction mixture was evaporated to dryness in vacuo. The excess P2S5 was decomposed by the addition of H2O (40 mL) at 60° C. The mixture was stirred for 1 h at 60° C. and then cooled to room temperature. The mixture was extracted with CHCl3 (3×40 mL). The dried (MgSO4) organic layer was evaporated to yield a syrup, which was purified by flash column chromatography (silica, acetone/CHCl3=15%) to afford 0.93 g (90%) of 88 as a yellow solid: 1H (400 MHz, d6-DMSO) δ 12.50 (s, 1H), 7.35 (br s, 2H), 5.89 (m, 2H), 5.51 (t, J=6.4 Hz, 1H), 4.36 (dd, J=12.0, 4.0 Hz, 1H), 4.24 (m, 1H), 4.10 (q, J=6.0 Hz, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H); MS (+)-ES [M+H]+ m/z 459.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[N:15](C)[CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19]>ClC(Cl)(Cl)C>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18]([N:15]1[CH:10]2[CH2:11][CH2:12][CH:13]1[CH:14]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9]2)=[O:19]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1C2C=C(c3ccc(Cl)cc3)CC1CC2
Solvent: CC(Cl)(Cl)Cl
Product: O=C(OCC(Cl)(Cl)Cl)N1C2C=C(c3ccc(Cl)cc3)CC1CC2
Yield: 92.3 %

Procedure:
Racemic 3-(4-Chloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene (4.98 g, 21.31 mmol) in 1,1,1-trichloroethane (60 mL) was heated at reflux and 2,2,2-trichloroethyl chloroformate (3.23 mL, 23.44 mmol) was added dropwise over 10 minutes. The reaction was refluxed for 3 hours, cooled and concentrated to a clear oil. Silica gel flash chromatography using 5% methanol/chloroform as the eluent yielded racemic 3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylic acid 2,2,2-trichloro-ethyl ester (7.77 g, 92.2%) as a clear oil which had the following properties: 1H NMR CDCl3 δ: 7.25 (s, 4H), 6.41 (m, 1H), 4.85 (m, 1H), 4.73 (s, 1H), 4.68-4.76 (m, 2H), 3.12 (d, J=17 Hz, 1H), 2.25 (m, 2H), 2.03 (m, 2H), 1.75 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]([C:20](=[O:21])[CH2:19][Cl:18])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Nc2c(F)cc(F)cc2Cl)cc1
Product: Cc1ccc(N(C(=O)CCl)c2c(F)cc(F)cc2Cl)cc1

Procedure:
A mixture of 230 g (0.9 mol) N-(2′-chloro-4′,6′-difluorophenyl)-4-methylaniline and 325 ml (4.06 mol) of chloroacetyl chloride is heated under a nitrogen atmosphere for one hour at 50°. The solvent is evaporated under reduced pressure to give an oil to which 200 ml of chlorobenzene is added. The solvent is evaporated under reduced pressure to completely remove the chloroacetyl chloride, giving N-(2′-chloro-4′,6′-difluorophenyl)-N-chloroacetyl-4-methylaniline as an oil.