Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:36]=[CH:35][C:18]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:23]([F:34])[CH:22]=3)=[CH:17][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:36]=[CH:35][C:18]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([F:34])[CH:22]=3)=[CH:17][CH:16]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(C(C)(C)C)cc3C(C)(C)C)cc2)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(C(C)(C)C)n(Cc2ccc(CNc3ccc(CCC(=O)O)c(F)c3)cc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of ethyl 3-[4-({4-[(3,5-di-tert-butyl-1H-pyrazol-1-yl)methyl]benzyl}amino)-2-fluorophenyl]propanoate (0.96 g, 1.9 mmol) in a mixture of methanol (8 mL) and tetrahydrofuran (8 mL) was added 1 M aqueous sodium hydroxide solution (4.0 mL), and the mixture was stirred at 60° C. for 2 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60% ethyl acetate/hexane), and recrystallized from ethyl acetate-hexane to give the title compound (0.77 g, yield 89%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[C:20]([Cl:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:33][CH2:34][CH2:35][C:36]#[CH:37])(=O)=O>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20]([Cl:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)[N:8]2[CH2:37][CH2:36][CH2:35][C:34]#[CH:33])=[C:4]([NH2:22])[N:3]=1
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1nc(F)nc2nc(Cc3cc4c(cc3Cl)OCO4)[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc3c(cc2Cl)OCO3)nc2c(N)nc(F)nc21

Procedure:
A solution of 2-Fluoro-8-(6-chloro-benzo[1,3]dioxol-5-ylmethyl)adenine (11 mg, 0.034 mmol), Cs2CO3 (11 mg, 0.034 mmol) and pent-4-ynyl tosylate (10.5 mg, 0.044 mmol) in anhydrous DMF (85 L) was stirred at 50° C. for 1 h. Following solvent removal, the product (4.2 mg, 31.9%) was collected through silica gel column purification (EtOAc:hexanes:CHC13:i-PrOH at 10:20:20:1). 1H NMR (400 MHz, CDC13) 6.89 (s, 1H), 6.61 (s, 1H), 5.98 (bs, 2H), 5.96 (s, 2H), 4.27 (s, 2H), 4.13 (t, J=7.5 Hz, 2H), 2.24-2.10 (m, 2H), 2.00-1.91 (m, 3H); 13C NMR (100 MHz, CDC13) 1597, 158.0, 156.3, 150.6, 147.7, 147.2, 126.2, 125.3, 110.0, 102.0, 82.3, 69.9, 42.2, 31.4, 28.1, 15.8; MS m/z 388.1 (M+H)+. HPLC: (a) 98.1% (65% water-35% acetonitrile); (b) 97.0% (35% to 45% acetonitrile).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:32]([C:36]#[C:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][CH:34]=[N:35][C:11]2=3)(=O)=O)C=CC=CC=1>CO>[CH3:31][N:28]1[CH2:27][CH2:26][N:25]([C:22]2[CH:21]=[CH:20][C:19]([C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[NH:10][C:11]3[N:35]=[CH:34][CH:33]=[C:32]([C:36]#[C:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:12]4=3)=[CH:24][CH:23]=2)[CH2:30][CH2:29]1
Reactant: CN1CCN(c2ccc(-c3ccc4c(c3)c3c(C#Cc5ccccc5)ccnc3n4S(=O)(=O)c3ccccc3)cc2)CC1
Solvent: CO
Product: CN1CCN(c2ccc(-c3ccc4[nH]c5nccc(C#Cc6ccccc6)c5c4c3)cc2)CC1
Yield: 81 %

Procedure:
9-Benzenesulfonyl-6-[4-(4-methylpiperazin-1-yl)-phenyl]-4-phenylethynyl-9H-pyrido[2,3-b]indole underwent typical procedure A. The trituration procedure in MeOH afforded the desired compound in 81% yield as a brown solid. 1H-NMR (300 MHz, DMSO) δ=12.07 (s, 1H), 8.69 (d, J=2.2 Hz, 1H), 8.46 (d, J=5.1 Hz, 1H), 7.82-7.74 (m, 3H), 7.63-7.54 (m, 6H), 7.34 (d, J=5.1 Hz, 1H), 7.04 (d, J=8.7 Hz, 2H), 3.23-3.14 (m, 4H), 2.49-2.44 (m, 4H), 2.24 (s, 3H). 13C-NMR (101 MHz, DMSO) δ=152.27 (Cq), 149.85 (Cq), 145.83 (CH), 137.99 (Cq), 132.28 (Cq), 131.46 (2 CH), 131.23 (Cq), 129.68 (CH), 128.97 (2 CH), 126.94 (2 CH), 125.66 (CH), 122.62 (Cq), 121.43 (Cq), 120.52 (Cq), 118.69 (CH), 116.77 (CH), 115.58 (2 CH), 114.46 (Cq), 111.68 (CH), 96.75 (Cq), 86.54 (Cq), 54.42 (2 CH2), 47.87 (2 CH2), 45.54 (CH3). HRMS (ESI): calcd. for C30H27N4: 443.2230. found: 443.2247.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[CH:11][NH:12][CH:13]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1C(=O)C2=CC=CC=C2C1=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[CH:11][N:12]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: COc1ccccc1-c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1-c1cn(CCCCN)cn1
Yield: 72.8 %

Procedure:
Using the procedure of Stage A of Example 1, 6 g of the product of Stage A, 1.99 g of sodium hydride and 9.93 g of N-4-bromobutyl phthalimide were reacted to obtain 6.15 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH3:12])=[O:10].[CH3:13][O:14][CH2:15]COC.[H-].[Na+].COCCl>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:13][O:14][CH3:15])[C:9]([NH:11][CH3:12])=[O:10]
Reactant: COCCOC
Reactant: CNC(=O)Nc1ccccc1F
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CNC(=O)N(COC)c1ccccc1F
Reaction time: 0.25 h

Procedure:
To a stirred solution of 8.4 g. (0.05 mol) of N-(2-fluorophenyl)-N'-methyl urea dissolved in 200 ml. of 1,2-dimethoxyethane there was added 2.4 g. of a 50% dispersion of sodium hydride (0.05 mol) in mineral oil. The resulting mixture was stirred for 15 minutes more. Then 4.2 g. (0.05 mol) of chloromethyl methyl ether was added dropwise. After all ether was added, the mixture was stirred for 16 hours. At the end of this time it was filtered through a layer of magnesium sulfate. The filtrate was evaporated to give an oily residue which crystallized upon standing. These crystals were washed with hexane and then dried to give 6.2 g. of product, melting point 57°-59°C. Analysis: Calculated for C10H13FN2O2 : F, 8.96%; Found: F, 8.97%. The infrared spectrum showed strong adsorptions at 6.1, 6.6, 6.7, 6.9, 7.8, 9.1 and 13.5μ. The NMR spectra was consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:15][N:16]([CH3:30])[CH2:17][CH2:18][CH2:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][OH:29])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:30][N:16]([CH3:15])[CH2:17][CH2:18][CH2:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][O:29][C:2]2[C:7]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]3[CH3:14])=[N:6][CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: C[C@@H]1CNCCN1c1nccnc1Cl
Reactant: CN(C)CCCc1ncccc1OCCO
Product: C[C@@H]1CNCCN1c1nccnc1OCCOc1cccnc1CCCN(C)C
Yield: 58 %

Procedure:
The procedure in Example 18, Step 4, starting from 2-chloro-3-[(2R)-2-methylpiperazin-1-yl]pyrazine* (0.48 g, 2.28 mmol) and 2-({2-[3-(dimethylamino)propyl]pyridin-3-yl}oxy)ethanol (from Step 1; 0.46 g, 2.07 mmol) was followed. The crude product was purified on a column of silica (100 mm, i.d.=30 mm) with CHCl3/MeOH/NH4OH (80:20:0.5; 200 mL, followed by 60:40:1) as eluent to give 0.48 g (58%) of the title compound as a colorless oil. HRMS m/z calcd for C21H32N6O2 (M)+ 400.2587. found 400.2571. *Reported in WO 00/76984, Example 192, Step 2.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([C:11]1[NH:12][C:13]([C:20]([O:22][CH3:23])=[O:21])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C>CCOCC>[CH3:3][N:15]1[C:14]([C:16]([O:18][CH3:19])=[O:17])=[C:13]([C:20]([O:22][CH3:23])=[O:21])[N:12]=[C:11]1[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1nc(Cc2ccccc2)[nH]c1C(=O)OC
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1nc(Cc2ccccc2)n(C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of diazomethane (1.5 g, 35.7 mmol) in ether (100 ml) was slowly added at 0° C. with stirring to a suspension of the above ester (18.59 mmol) in ether (100 mL). After the addition was completed, the solution was stirred at room temperature overnight. Excess diazomethane was decomposed by the slow and careful addition of dilute acetic acid and the mixture was concentrated in vacuo. Water (50 mL) was added and the mixture was thoroughly extracted with dichloromethane. The organic phase was washed with water, saturated sodium bicarbonate and again with water. The solution was dried and the solvent was removed in vacuo to give dimethyl 1-methyl-2-benzyl-4,5-imidazole dicarboxylate.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:6]=[CH:5][N:4]=1.[C:16]([C:19]1[C:28]([CH3:29])=[CH:27][C:22]2[N:23]=[C:24]([SH:26])[NH:25][C:21]=2[CH:20]=1)(=[O:18])[CH3:17].[OH-].[Na+]>C(O)C.C(Cl)Cl.[Cl-].[Na+].O>[C:16]([C:19]1[C:28]([CH3:29])=[CH:27][C:22]2[NH:23][C:24]([S:26][CH2:2][C:3]3[C:8]([O:9][CH3:10])=[C:7]([O:11][CH2:12][CH:13]4[CH2:15][CH2:14]4)[CH:6]=[CH:5][N:4]=3)=[N:25][C:21]=2[CH:20]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1cc2[nH]c(S)nc2cc1C
Reactant: COc1c(OCC2CC2)ccnc1CCl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1c(OCC2CC2)ccnc1CSc1nc2cc(C(C)=O)c(C)cc2[nH]1

Procedure:
2-Chloromethyl-4-cyclopropylmethoxy-3-methoxypyridine (50 mg, 0.22 mmol) and 5-acetyl-6-methyl-2-mercaptobenzimidazole (50 mg, 0.24 mmol) were dissolved in ethanol (15 ml). The pH value of the solution was adjusted to 9 (0.2M NaOH) whereupon the solution was refluxed for 10 min. After concentration of the reaction mixture at reduced pressure the residue was taken up in methylene chloride (10 ml) and brine (2 ml). The phases were separated and the organic phase was dried over sodium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on silica (ethyl acetate). Yield: 40 mg (46%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:41]=[CH:40][C:31]2[NH:32][C:33](=[O:39])[CH2:34][CH2:35][C:36]([CH3:38])([CH3:37])[C:30]=2[CH:29]=1>>[Cl:26][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[N:7][C:2]([NH:27][C:28]2[CH:41]=[CH:40][C:31]3[NH:32][C:33](=[O:39])[CH2:34][CH2:35][C:36]([CH3:38])([CH3:37])[C:30]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: Clc1ncc(Cl)c(Nc2ccc(N3CCOCC3)cc2-n2cccn2)n1
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4-n4cccn4)n3)cc21

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-morpholin-4-yl-2-pyrazol-1-yl-phenyl)-amine was reacted with 7-amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 7-[5-Chloro-4-(4-morpholin-4-yl-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a lyophylate (7%); 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.39 (s, 1H), 9.31 (s, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.98 (bd, 1H), 7.82 (s, 1H), 7.59 (d, J=8.08 Hz, 1H), 7.41 (s, 1H), 7.12 (s, 1H), 6.98 (d, J=11.11 Hz, 1H), 6.79 (d, J=8.59 Hz, 1H), 6.54 (s, 1H), 3.78 (m, 4H), 3.21 (m, 4H), 2.15 (m, 2H), 1.95 (m, 2H), 1.27 (s, 6H); MS (m/e) 559.54 (M+H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.COC1C=C(OC)C=CC=1C[N:17]([CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[NH:39][C:40]([C:42]3[C:50]4[C:45](=[CH:46][C:47]([O:53][CH3:54])=[C:48]([O:51][CH3:52])[CH:49]=4)[N:44]([CH3:55])[CH:43]=3)=[CH:41][C:34]=12)[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[OH-].[Na+]>ClCCl.C1(C)C=CC=CC=1.O>[CH3:52][O:51][C:48]1[CH:49]=[C:50]2[C:45](=[CH:46][C:47]=1[O:53][CH3:54])[N:44]([CH3:55])[CH:43]=[C:42]2[C:40]1[NH:39][C:35]2=[N:36][CH:37]=[CH:38][C:33]([CH2:32][NH:17][S:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=3)(=[O:19])=[O:20])=[C:34]2[CH:41]=1
Reactant: COc1ccc(CN(Cc2ccnc3[nH]c(-c4cn(C)c5cc(OC)c(OC)cc45)cc23)S(=O)(=O)c2ccc(OC(F)(F)F)cc2)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2c(-c3cc4c(CNS(=O)(=O)c5ccc(OC(F)(F)F)cc5)ccnc4[nH]3)cn(C)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.3 %

Procedure:
0.053 g of para-toluenesulfonic acid is added to a solution of 0.050 g of N-(2,4-dimethoxybenzyl)-N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-4-trifluoromethoxybenzenesulfonamide in 2 cm3 of dichloromethane and 5 cm3 of toluene, at a temperature in the region of 20° C. The reaction medium is stirred at this same temperature for 24 hours, at room temperature, and then heated at a temperature in the region of 60° C. for 24 hours. After cooling, the reaction medium is concentrated under reduced pressure. 5 cm3 of water and 10 cm3 of dichloromethane are added. The reaction medium is basified to pH 9 with 1N sodium hydroxide. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue obtained is purified on preparative LC/MS (water/acetonitrile/TFA). The solid obtained is taken up in 5 cm3 of dichloromethane and 2 cm3 of water, and then basified with 1N sodium hydroxide to pH 9. 0.008 g of N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-4-trifluoromethoxybenzenesulfonamide is obtained, the characteristics of which are as follows:
Reaction SMILES: COC(=O)[CH:4]([CH2:9][C:10]1[C:11]([NH:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])=[N:12][C:13]([CH3:22])=[CH:14][C:15]=1[NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:5](OC)=[O:6].P(=O)(O)(O)O>O.[OH-].[Na+]>[CH2:18]([CH:17]([N:16]1[C:15]2[C:10](=[C:11]([NH:23][C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[CH3:32])[N:12]=[C:13]([CH3:22])[CH:14]=2)[CH2:9][CH2:4][C:5]1=[O:6])[CH2:20][CH3:21])[CH3:19]
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CC(C(=O)OC)C(=O)OC
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(CC)N1C(=O)CCc2c1cc(C)nc2Nc1c(C)cc(C)cc1C
Temperature: 25 °C
Yield: 76.2 %

Procedure:
A mixture of 2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonic acid dimethyl ester (100 mg, 0.219 mmol), 85% phosphoric acid (3 ml) and water (3 ml) was heated at reflux for 2 hours. The reaction mixture was cooled to rt, diluted with water and neutralized to pH 6 with dilute NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness to give 61 mg of a yellow foam. The oil was purified through silca gel column chromatography using 10% EtOAc in hexane as eluent to give 41 mg of the title compound as a tan solid, mp 44-46° C. 1H NMR (CDC13) δ 6.87(s,2H), 6.36(s,1H), 5.64(brs,1H), 4.21(m,1H), 2.51(m,2H), 2.37(m,2H), 2.29(s,3H), 2.27(s,3H), 2.11(s,6H), 2.02(m,2H), 1.76(m,2H), 0.86(t,6H) ppm.
Reaction SMILES: [CH3:1]O.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)[C:14]#[N:15].C[O-].[Na+].CI>O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)([CH3:1])[C:14]#[N:15]
Reactant: CO
Reactant: N#CC(Sc1nc2ccccc2s1)c1cccc(Oc2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(C#N)(Sc1nc2ccccc2s1)c1cccc(Oc2ccccc2)c1
Reaction time: 2.5 h
Yield: 77 %

Procedure:
Methanol (5 ml) was added to 945 mg of alpha-(2-benzothiazolylthio)(m-phenoxyphenyl)acetonitrile, and the mixture was stirred under ice cooling in an argon atmosphere. Then, 1.0 ml of a 2.7 M methanol solution of sodium methoxide was added, and the mixture was stirred under ice cooling for 10 minutes. Methyl iodide (0.25 ml) was then added. The mixture was stirred under ice cooling for 30 minutes, and then at room temperature for 2.5 hours. Then, 30 ml of water was added, and the reaction mixture was extracted with 20 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene and methylene chloride) to afford 752 mg (yield 77%) of alpha-(2-benzothiazolylthio)-alpha-(m-phenoxyphenyl)propionitrile as an oil.
Reaction SMILES: NC1C=C(C=CC=1)O[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=O)[CH:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[C:26]([F:29])([F:28])[F:27].ClC1C=CN=C(C#N)C=1>>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:7]2[C:8]([C:12]#[N:14])=[N:9][CH:10]=[CH:11][CH:6]=2)=[CH:21][C:20]=1[C:26]([F:27])([F:28])[F:29]
Reactant: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Reactant: Nc1ccc(O)cc1C(F)(F)F
Agent: N#Cc1cc(Cl)ccn1
Product: N#Cc1ncccc1Oc1ccc(N)c(C(F)(F)F)c1

Procedure:
This material is prepared by a method analogous to that described for preparation of 2C, starting from 4-amino-3-(trifluoromethyl)phenol and 4-chloro-2-cyanopyridine.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[N+:1]([CH2:3][C:4]([N:12]1[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]1)=[O:6])#[C-:2]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CN1CCNCC1
Product: [C-]#[N+]CC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Prepared in accordance with Method B with methyl isocyanoacetate (1.0 g, 10.09 mmol) and N-methylpiperazine (1.37 mL, 15.14 mmol). The reaction mixture was stirred overnight at RT and then concentrated. The residue was dissolved in dichloromethane (50 mL) and evaporated. The residue was coevaporated three times with a mixture of CH2Cl2:cyclohexane=50:50 (3×10 mL). After drying 2-isocyano-1-(4-methyl-piperazin-1-yl)-ethanone VIB 01128 was obtained as yellow solid (1.67 g, 99% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[C:24]1[O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[N:28]=1.Br[C:33]1C=C(/C=C/C(C2C=C(Cl)C(Cl)=C(Cl)C=2)C(F)(F)F)C=[CH:44][C:34]=1[C:35]([NH:37]C(C)(C)C(O)=O)=O.[CH3:64]CN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:16]=[C:17]([Cl:23])[C:18]([Cl:22])=[C:19]([Cl:21])[CH:20]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[C:24]([NH:28][C:27]([CH3:29])([CH3:30])[C:26]([NH:37][CH2:35][C:34]([CH3:44])([CH3:64])[CH3:33])=[O:31])=[O:25]
Reactant: CC1(C)N=C(c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)OC1=O
Reactant: CC(C)(NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)C(C)(C)NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 0 °C

Procedure:
(E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-4,4-dimethyloxazol-5(4H)-one: A 25 mL round bottomed flask was charged with (E)-2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamido)-2-methylpropanoic acid (400 mg, 0.70 mmol), CH2Cl2 (10 mL) and stirred at 0° C. EDC.HCl (134 mg, 0.70 mmol) was added in one portion as a solid and the reaction mixture was allowed to warm toward ambient temperature and continued to stir for 1 h. The reaction was diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered and evaporated to give a dark oil. The crude product was purified via flash chromatography eluting with 50% hexanes/CH2Cl2 to afford the title compound as an off white foam (220 mg, 57): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.1 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.42 (d, J=7.8 Hz, 3H), 6.56 (d, J=15.9 Hz, 1H), 6.45 (dd, J=15.9, 7.7 Hz, 1H), 4.12 (p, J=8.5 Hz, 1H), 1.57 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −68.55; ESIMS m/z 554 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]=[C:10]1[CH2:17][CH2:18][CH3:19].C([O-])(=O)C.[Na+].[Br:33]Br>C(O)(=O)C.C1(C)C=CC=CC=1>[Br:33][C:13]1[C:14](=[O:15])[N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:3][C:2]=2[F:1])[C:10]([CH2:17][CH2:18][CH3:19])=[N:11][C:12]=1[CH3:16]
Reactant: CCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 70 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of 3′-fluoro-4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.4 g) and sodium acetate (0.32 g) in acetic acid (20 mL) was added bromine (0.2 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was diluted with toluene and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, 1 M aqueous sodium thiosulfate solution, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.65 g, 38%) as a colorless solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[N:19]=[C:20]([CH:23]=[CH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[O:21][CH:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[C:35]([BH3-])#N.[Na+].Cl>C(#N)C>[CH3:35][N:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)=[CH:11][CH:12]=1)[CH2:17][C:18]1[N:19]=[C:20]([CH:23]=[CH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)[O:21][CH:22]=1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(CNc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CN(Cc1coc(C=Cc2ccc(C(F)(F)F)cc2)n1)c1ccc(CCCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of [4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethyl}-amine 2 (0.03 g, 0.06 mmol) in acetonitrile (2 ml) formaldehyde (36%, 0.1 ml) and sodium cyanoborohydride (0.012 g, 0.019 mmol) are added. After stirring at room temperature for 10 min the pH is set to 2 by adding conc. hydrochloric acid and stirring is continued for 2 h. The solvents are evaporated, the crude product suspended in water (10 ml) and the pH adjusted to 9 with aqueous ammonia. The mixture is extracted with ethyl acetate (3×25 ml), the organic phase washed with brine and dried over sodium sulfate. After concentration in vacuo the oily residue is precipitated with heptanes to yield methyl-[4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethyl}-amine 3 as a light yellow solid. Yield 31 mg (100%); m.p. 112–114° C.