Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]#[N:37]>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]#[N:37]
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccsc3C#N)c2)OC1(C)C
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccsc4C#N)c3)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]thiophene-2-carbonitrile as described in Example 65 to give 3-{2-fluoro-5-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]phenyl}thiophene-2-carbonitrile as a buff-coloured solid: δH (400 MHz, CDCl3) 1.57 (6H, s), 7.10 (1H, d, J 7), 7.41-7.44 (2H, m), 7.60-7.64 (1H, m), 7.71 (1H, d J 5), 7.84 (1H, dd, J 7 and 2), 7.87 (1H, s), 8.88 (1H, d, J 7).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.Br[C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1>>[CH3:23][N:19]1[CH:20]=[CH:21][N:22]=[C:18]1[NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=1
Reactant: Cn1ccnc1Br
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Product: Cn1ccnc1Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
A solution of 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.5 g, 2.28 mmol) in 2-Bromo-1-methyl-1H-imidazole (0.367 g, 2.28 mmol) was heated in a CEM discover microwave synthesizer (50 W) at 125° C. until the reaction was complete. The reaction mixture was cooled and used directly in the next procedure. MS: [M+H]+ 300
Reaction SMILES: [Cl-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[O:27]=[C:28]1[N:36]([CH2:37][CH2:38][CH3:39])[C:35]2[NH:34][C:33]([C:40]34[CH2:47][CH2:46][C:43]([CH:48]=O)([CH2:44][CH2:45]3)[CH2:42][CH2:41]4)=[N:32][C:31]=2[C:30](=[O:50])[N:29]1[CH2:51][CH2:52][CH3:53]>C1COCC1>[CH2:51]([N:29]1[C:30](=[O:50])[C:31]2[N:32]=[C:33]([C:40]34[CH2:47][CH2:46][C:43]([CH:48]=[CH2:2])([CH2:44][CH2:45]3)[CH2:42][CH2:41]4)[NH:34][C:35]=2[N:36]([CH2:37][CH2:38][CH3:39])[C:28]1=[O:27])[CH2:52][CH3:53]
Reactant: CCCn1c(=O)c2nc(C34CCC(C=O)(CC3)CC4)[nH]c2n(CCC)c1=O
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC12CCC(c3nc4c(=O)n(CCC)c(=O)n(CCC)c4[nH]3)(CC1)CC2
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
To a stirred suspension of methyl triphenylphosphonium chloride (1.07 g, 3.0 mmol) in THF (20 ml) at 0° C. was added n-BuLi (1.4 M in hexane, 2.14 ml, 3.0 mmol). The resulting reddish-brown mixture was stirred at this temperature for 0.5 h and then at rt for 0.5 h. A solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (372 mg, 1.0 mmol) in THF (10 ml) was added over a period of 20 minutes and the resulting mixture was stirred overnight (12 h). The reaction mixture was partitioned between saturated aqueous NH2Cl2 (20 ml) and EtOAc (20 ml) and the aqueous phase was extracted with EtOAc (20 ml). The combined organic extracts were washed with saturated aqeuous NaCl (50 ml), dried (MgSO4), filtered and evaporated in vacuo to afford an oil that was purified by radial chromatography (2 mm plate) using a gradient of 0-5% MeOH in CH2Cl2 as eluent. Product-containing fractions were combined and concentrated to afford 140 mg (38%) of a white solid. MS: 371 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[C:3]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28](C)[C:29](=O)OC(C)(C)C)[N:14]=2)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[CH3:43][N:2]([CH3:1])[C:3]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][CH3:29])[N:14]=2)[CH2:10][CH2:11]1
Reactant: COc1cccc(N(C)C)c1CN1CCC(Nc2nc(NCCCCN(C)C(=O)OC(C)(C)C)nc3ccccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCCCNc1nc(NC2CCN(Cc3c(OC)cccc3N(C)C)CC2)c2ccccc2n1

Procedure:
A solution of Compound 101 (39 mg, 0.07 mmol) and trifluoroacetic acid (0.2 ml, 0.35 mmol) in dichloromethane (3 mL) was stirred at room temperature for 2 h. The product (Compound 102) was purified by basic alumina flash column chromatography using 3% MeOH and 97% CH2Cl2 solution as eluent.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([OH:12])([C:10]#[CH:11])[CH3:9].[CH3:13][C:14]([C:16](Cl)=[O:17])=[CH2:15]>N1C=CC=CC=1>[C:16]([O:12][C:8]([CH3:9])([C:10]#[CH:11])[CH3:7])(=[O:17])[C:14]([CH3:15])=[CH2:13]
Reactant: C#CC(C)(C)O
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C#CC(C)(C)OC(=O)C(=C)C
Reaction time: 6 h
Yield: 62 %

Procedure:
A reactor was charged with 550 parts of benzene, 74 parts of pyridine and 65.5 parts of 2-methyl-3-butyn-2-ol. To this were added 90 parts of methacryl chloride dropwise over one hour while keeping the inner temperature at 20° C. Then the reaction mixture was kept at 50° C. for 6 hours, suction filtered, evaporated and distilled in vacuo. 2-Methyl-3-butyn-2-yl methacrylate boiling at 56°-58° C./12 mmHg was obtained in a yield of 62% of theory. The product was identified by the IR spectrum thereof.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:14].[CH2:22]([NH:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH3:24]>>[NH2:9][S:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([N:25]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:23][CH3:24])[N:18]=[CH:17][N:16]=2)=[O:14])=[C:2]([CH3:1])[CH:7]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CCCNC(C)C
Product: CCCN(c1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2C)ncn1)C(C)C

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (2-methyl-4-sulfamoyl-phenyl)amide (Intermediate 17) and propyl-isopropylamine (Matrix), the title compound was obtained as a white solid.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:15])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([NH2:14])[C:10]([CH3:13])=[N:11][CH:12]=1.C(#N)C.Cl.[Cl:20][C:21]([NH2:23])=[NH:22]>C(O)(=O)C>[ClH:20].[ClH:1].[ClH:20].[CH3:15][N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:14][C:21]([NH2:23])=[NH:22])[C:10]([CH3:13])=[N:11][CH:12]=1
Reactant: N=C(N)Cl
Reactant: Cc1ncc(CCCN(C)C)cc1N
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1ncc(CCCN(C)C)cc1NC(=N)N
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 136.9 %

Procedure:
A 1 L, three-neck, round-bottom flask equipped with an overhead stirrer, a reflux condenser, an N2 inlet tube, and a temperature probe was charged with 5-(3-(dimethylamino)propyl)-2-methylpyridin-3-amine hydrochloride (25 g, 0.109 mol). Acetonitrile (275 mL, 11 vol) was added to it followed by acetic acid (25 mL, 1 vol). The initial suspension turned into a clear solution after the addition of acetic acid. Chloroformamidine hydrochloride (15.6 g, 0.136 mol, 1.25 equiv) was added to the solution resulting in a suspension. The reaction was heated at 40° C. for 30 min and at 50° C. for another 30 min. Then the temperature was raised to 60° C. and the reaction was continued at this temperature. After 1-2 h at 60° C., the reaction mixture became turbid and after 3-4 h, solid started separating out. The reaction was continued at 60° C. for 20 h and was judged complete by LC-MS analysis. The reaction was cooled to ambient temperature and the solid was collected by filtration (N2 flow was used during the filtration). The filter cake was washed with acetonitrile (50 mL, 2 vol). The solid was dried under high vacuum overnight to obtain N-{5-[3-(Dimethylamino)propyl]-2-methylpyridin-3-yl}guanidine trihydrochloride (32.1 g, 85% recovery) as a light brown solid. Elemental analysis Calcd: C, 41.81; H, 7.02; Cl, 30.85; N, 20.32. Found: C, 41.09; H, 6.72; Cl, 31.51; N, 20.47. 1H NMR (500 MHz, DA)) δ ppm: 8.57 (s, 1H), 8.45 (s, 1H), 3.22-3.19 (m, 2H), 2.90 (t, 2H, J=10 Hz), 2.86 (s, 6H), 2.69 (s, 3H), 2.15-2.07 (m, 2H); ESI-MS m/z 236 (M+H, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.F[C:13]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=1[C:15]#[N:16].O.[OH-].[Li+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=2[C:15]#[N:16])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(F)c(C#N)c1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
Combine 4-fluoro-2-nitro-phenylamine (2.9 g, 18.50 mmol), 2-fluoro-5-methyl-benzonitrile (2.5 g, 18.50 mmol) and lithium hydroxide monohydrate (2.4 g, 57.20 mmol) in methyl sulfoxide (DMSO, 40 ml). Heat the resulting mixture to 55° C. for 40 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 250 ml of ice water and stir for one hour. Filter the resulting mixture and collect the precipitate. Chromatograph the solid using flash chromatography and elute with mobile phase: 90% hexanes, 5% ethyl acetate, and 5% dichloromethane. Obtained 2.267 g of the title compound (8.36 mmol, 45% yield) as an orange amorphous solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH3:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1.C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][C:4]([C:17]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:23])=[CH:3][CH:2]=2)[CH2:10][CH2:11]1)[CH3:16]
Reactant: O=C1CCC(=O)O1
Reactant: CC[C@H]1CC[C@H](CCc2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: S=C=S
Product: CC[C@H]1CC[C@H](CCc2ccc(C(=O)CCC(=O)O)cc2)CC1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A mixture of 1-phenyl-2-(trans-4-ethylcyclohexyl)ethane (200.0 g, 0.93 mol), pulverized succinic acid anhydride (111.6 g, 1.11 mol) and CS2 (500 ml) was cooled with ice down to 0° to 5° C. Pulverized anhydrous aluminum chloride (248.0 g, 1.86 mol) was gradually added to the mixture. After removing the ice bath, the mixture was agitated for one hour and successively agitated for 2 hours on a water bath at 60° C. The resulting material was allowed to stand overnight. The reaction material was poured into a mixture of ice (500 g) and 6N-HCl (300 ml). The mixture was agitated sufficiently and CS2 and water were distilled off on a water bath, to obtain a residue. Toluene was added to the residue and then heated under reflux. After separating water by means of a DeanStoke type water separator, the resulting liquid was filtered off while hot and recrystallized to obtain the following 3-(4-(2-(trans-4-ethylcyclohexyl)ethyl)benzoyl)propanic acid (214 g, m.p.: 141.2°-142.6° C.). ##STR8##
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.[C:22]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])([CH3:25])([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:27]=1)=[O:6]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: O=C(O)c1cccnc1Br
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cccc(NC(=O)c2cccnc2Br)c1
Reaction time: 12 h
Yield: 59 %

Procedure:
To a stirred solution of 2-bromonicotinic acid (1.01 g, 5 mmol) dissolved in anhydrous dichloromethane (8 mL) were added EDCI (1.34 g, 7 mmol) and 3-tert-butylaniline (0.74 g, 5 mmol) at room temperature and the reaction mixture was stirred for 12 hours. The mixture was then diluted with dichloromethane, followed by saturated sodium bicarbonate and water wash. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain 2-bromo-N-(3-tert-butylphenyl)nicotinamide in 59% yield (950 mg). Rt: 2.44 min (20-100-5 method). MS: (ES) m/z 333, 335 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:7]([F:20])=[CH:8][C:9]([CH3:19])=[C:10]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([F:20])=[CH:8][C:9]([CH3:19])=[C:10]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(=O)c1cc(N)c(F)cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1cc(NC(C)=O)c(F)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Acetyl chloride (3.12 g, 40 mmol) was added to a 0° C. solution of ethyl 2-(5-amino-4-fluoro-2-methylphenyl)-2-oxoacetate (9 g, 40 mmol) and Et3N (8.1 g, 80 mmol) in CH2Cl2 (80 mL). The resulting mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure to give ethyl 2-(5-acetamido-4-fluoro-2-methylphenyl)-2-oxoacetate (10.7 g, 100% yield), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 8.71 (d, J=6.0 Hz, 1 H), 7.37 (brs, 1 H), 6.95 (d, J=8.7 Hz, 1 H), 4.39 (q, J=7.2 Hz, 2 H), 2.50 (s, 3H), 2.10 (s, 3 H), 1.40 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@H:34]5[C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=6[CH2:41][C@H:33]5[O:32][C:31]4=[O:42])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@H:34]5[C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=6[CH2:41][C@H:33]5[O:32][C:31]4=[O:42])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)O[C@@H]6Cc7ccccc7[C@@H]65)nc34)cc2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@@H]2Cc3ccccc3[C@@H]2N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
To (3aS,8aR)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (45 mg, 0.077 mmol) in DCM (5 mL) was added TFA (1 mL) and the reaction was stirred at ambient temperature for 6 hours. The reaction was concentrated to dryness and the residue dissolved in MeOH and added to 2N HCl in ether. After concentration, the residue was purified by reverse phase chromatography (SP4, 12M, water/CH3CN 100:0 to 0:100, 20 column volumes) to yield (3aS,8aR)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (3.5 mg, 10% yield) as a pale yellow solid. LCMS (APCI+) m/z 454.2 [M+H]+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH:13]([NH2:16])([CH3:15])[CH3:14]>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:16][CH:13]([CH3:15])[CH3:14])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(C)N
Solvent: O
Product: CC(C)NC(=O)c1ccccc1N
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A round-bottomed flask was charged with isatoic anhydride (5.0 g, 0.030 mol) and 30 mL water. Isopropylamine (4.64 mL, 0.049 mol) was added slowly to the reaction mixture. The product precipitated from the reaction mixture. After 1 h, the reaction mixture was filtered and washed with water to give 4.12 g (71% yield) of a white solid
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:6].C(N=C=NC(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:48]([NH2:56])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:9]=1[C:10]([NH:56][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:12])=[O:6]
Reactant: NCCc1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccc(Oc3ccccc3)cc2C(=O)O)cc1Cl
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(Oc3ccccc3)cc2C(=O)NCCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A solution of 43D (17 mg, 0.043 mmol) in DMF (1 mL) was treated with diisopropylcarbodiimide (6 mg, 0.047 mmol) and HOBt (12 mg, 0.086 mmol). The reaction was stirred for 1 hour at room temperature and then phenethylamine (104 mg, 0.86 mmol) was added. The resulting solution was stirred for 3 hours at room temperature, and then concentrated. The crude material was purified by chromatography (SiO2, 5% to 20% EtOAc in Hexanes) to afford 43E (16 mg, 75%). HPLC retention time=4.50 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([F:10])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc(Br)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1ccc(Br)cc1F
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a stirred solution of (4-bromo-2-fluorophenyl)methanamine (5.834 g, 28.592 mmol) in pyridine were added methanesulfonyl chloride (4.2 mL, 54.325 mmol) at 0° C. The reaction mixture was stirred for 1 h, then diluted with dichloromethane. The mixture was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography to give N-(4-bromo-2-fluorobenzyl)methanesulfonamide (7.597 g, 93%).
Reaction SMILES: O.[C:2]([O:5][C:6]1[CH:7]=[C:8]([O:16][C:17](=[O:19])[CH3:18])[CH:9]=[C:10]([O:12][C:13](=O)[CH3:14])[CH:11]=1)(=[O:4])[CH3:3].[H-].[Na+].C(Cl)[C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1.Cl>CN(C=O)C>[C:17]([O:16][C:8]1[CH:7]=[C:6]([O:5][C:2](=[O:4])[CH3:3])[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)[CH:9]=1)(=[O:19])[CH3:18]
Reactant: ClCc1ccccc1
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(OC(C)=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1cc(OCc2ccccc2)cc(OC(C)=O)c1
Reaction time: 16 h

Procedure:
Water (4.3 ml, 236 mmol) in DMF (20 ml) was added drop wise at room temperature with stirring to a mixture of acetic acid 3,5-diacetoxy-phenyl ester (refer Kawamoto. H. et. al. Synth. Commun. M, 531, 1996) (35 g, 139 mmol), NaH (5.66 g, 236 mmol) and benzyl chloride (19.16 ml, 166 mmol) in dry DMF (300 ml). The reaction mixture was stirred overnight (˜16 h), poured into chilled dil. aqueous HCl and extracted with CH2Cl2 to obtain the crude title compound which was purified using flash chromatography (silica ge, 20-50% CH2Cl2 in PE 60-80° C.). Yield, 12.5 g (30%), white solid; mp: 129-30° C.; MS (EI): 300 (M+), 258, 216, 91 (100%); analysis: C17H16O5 requires: C, 67.99; H, 5.37 found: C, 67.50; H, 5.40%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:31]I>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:13]([CH3:31])[CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:15]([F:16])([F:17])[F:18])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)/C=C/c1ccc(C#N)cc1)C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
120.0 mg (0.30 mmol) of (2E)-3-(4-cyanophenyl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)-phenyl]ethyl}acrylamide from Synthesis Example 1, Stage 1 were initially charged in 2 ml of N,N-dimethylformamide and admixed at 0° C. with 19.7 mg (0.45 mmol) of sodium hydride (55% oil dispersion). After addition of 64.1 mg (0.45 mmol) of methyl iodide, the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed three times with water and dried over sodium sulphate. The solvent was distilled off under reduced pressure and the residue purified by preparative HPLC (solvent=water (A)+acetonitrile (B), gradient=40 min. from 10% B to 100% B, flow=18 ml/min).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH:19][CH3:20])[CH:13]=2.[F:21][CH:22]([F:26])[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[F:21][CH:22]([F:26])[C:23]([N:19]([C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=3[I:1])[NH:11]2)=[CH:16][CH:15]=1)[CH3:20])=[O:24]
Reactant: O=C(O)C(F)F
Reactant: CNc1ccc2cc(-c3c(I)ccnc3OC)[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1nccc(I)c1-c1cc2ccc(N(C)C(=O)C(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
A solution of [2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-methyl-amine (30 mg, 0.08 mmol) in CH2Cl2 (5 mL) was added 2,2-difluoroacetic acid (11 mg, 0.12 mmol) and HATU (45 mg, 0.12 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 2,2-difluoro-N-[2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-N-methyl-acetamide (12 mg, 33%) as a white solid. MH+ 457.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[H-].[Na+].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20]
Reactant: ClCc1cccc(Cl)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccc(Cl)c1
Yield: 42.1 %

Procedure:
Using 0.16 g of 3-chlorobenzyl chloride, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.12 g of 2-(3-chlorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (82)).