Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[C:20]2[C:21]3[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=[CH:27][C:19]=2[CH:18]([NH:28][CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1.Cl>ClCCl>[CH:8]([O:11][C:12]([N:14]1[C:20]2[C:21]3[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=[CH:27][C:19]=2[CH:18]([N:28]([C:1](=[O:3])[CH3:2])[CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([C:40]([F:43])([F:41])[F:42])[CH:31]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9]
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc3c(c21)CCC3
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1ccc1c2CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.4 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (349 mg, 1.15 mmol) followed by titanium isopropoxide (414 mg, 1.46 mmol) to 6-Oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (300 mg, 1.04 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (4.3 mL) and sodium borohydride (59 mg, 1.56 mmol) and stir the mixture under nitrogen at room temperature for 45 min. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-6-(3,5-Bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (443 mg, 83%). Add acetic anhydride (0.24 mL, 2.52 mmol) dropwise to a solution of the amine (184 mg, 0.36 mmol) and pyridine (0.25 mL, 3.06 mmol) in dichloromethane (3.1 mL). Stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (149 mg, 74%); MS (ES+): 557 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([C:27](=O)[NH:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.CSC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:32])[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC(=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Solvent: CSC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Temperature: 65 °C
Yield: 24.6 %

Procedure:
To a stirred solution of (4S,5R)-5-[4-(6-Ethylcarbamoyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester (0.21 g, 0.459 mmol) in dry tetrahydrofuran (5.25 mL) is added 2 M toluene solution of BH3.dimethylsulfide (0.104 g, 1.378 mmol) at 0° C. Reaction heated to 65° C. for 16 hours. Quenched with Methanol (2 mL). Volatiles were removed under reduced pressure to obtain crude material purified by column chromatography eluting in 6% methanol in CH2Cl2 to afford title compound (0.05 g): 1H-NMR (400 MHz, DMSO-d6): δ: 1.09 (t, 3H, J=7.15 Hz), 1.43 (s, 9H), 1.51 (s, 3H), 1.63 (s, 3H), 3.15 (m, 2H), 3.82-3.89 (m, 2H), 3.95 (s, 2H), 4.10 (m, 1H), 4.45-4.55 (m, 2H), 5.12 (d, 1H, J=7.24 Hz), 7.52 (d, 1H, J=8.20 Hz), 7.57 (d, 2H, J=8.20 Hz), 7.75 (d, 2H, J=8.24 Hz), 8.09 (dd, 1H, J=7.88 Hz, J=2.08 Hz), 8.84 (d, 1H, J=1.92 Hz). LC-MS (m/z): [M+H]=444.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[O:31])[O:29][N:28]=[C:27]([CH3:32])[C:26]=2[CH:33]=1.CN1CCCN(C)C1=O>O1CCCC1>[OH:11][C:10]([C:13]([F:16])([F:15])[F:14])([CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17])[CH2:12][NH:21][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[O:31])[O:29][N:28]=[C:27]([CH3:32])[C:26]=2[CH:33]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Cc1noc(=O)c2ccc(N)cc12
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1ccc2c(=O)onc(C)c2c1)C(F)(F)F

Procedure:
584 mg of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl-oxiran, 282 mg of 6-amino-4-methyl-2,3-benzoxazin-1-one and 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2[1H]-pyrimidinone are heated to 120° C. for 6 hours. After 1 ml of tetrahydrofuran is added, it is chromatographed on silica gel, and the title compound is eluted with hexane/ethyl acetate/tetrahydrofuran (55:40:5), flash point 178-179° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[C:7](=[O:12])[C:6]=12.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[C:7](=[O:12])[C:6]=12)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(C)CC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(c1OCc1ccccc1)C(=O)N(C)CC2
Temperature: 25 °C

Procedure:
To a solution of ethyl 8-hydroxy-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (25.0 g, 104.9 mmol) in DMF (500 mL), potassium carbonate (58 g, 420 mmol) and benzyl bromide (14.9 mL, 126 mmol) was added. The reaction mixture was stirred at rt over night. The mixture was filtered and the filtrate concentrated under vacuum. The residue was partitioned between dichloromethane and brine. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate to give titled material.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[C:6]([C:10]1[S:11][S+:12]=[CH:13][C:14]=1[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:9])([CH3:8])[CH3:7].[CH3:20][OH:21]>C(N(CC)CC)C>[CH3:20][O:21][C:10]1([C:6]([CH3:9])([CH3:8])[CH3:7])[C:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:13][S:12][S:11]1
Reactant: CO
Reactant: CC(C)(C)Cc1c[s+]sc1C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Product: COC1(C(C)(C)C)SSC=C1CC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a sample of 136.8 grams of the product prepared as described in Example 2B, i.e., 3-tert-butyl-4-neopentyl-1,2-dithiolium perchlorate, and 180 grams of methanol was added over a 10 minute period 44 grams of triethylamine. The mixture was stirred for 20 minutes. The solvent was removed under diminished pressure and the residue taken up in ether and water. The etheral solution was washed two times with water, dried over anhydrous magnesium sulfate, filtered and distilled under diminished pressure to remove the ether. The product, 3-methoxy-3-tertiarybutyl-4-neopentyl 1,2-dithiole, was isolated as 96 grams (88.8% of theory) of an oil, n.m.r. (CCl4) τ in ppm, 3.81, 1H singlet (vinyl); 6.81, 3H singlet (methoxy); 7.23, 1H doublet (diastereotopic, J=15 cps, neopentyl proton); 7.82, 1H doublet (diastereotopic, J=15 cps, neopentyl proton); 8.63, 9H singlet (t-butyl) and 8.97, 9H singlet (t-butyl).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([C:12]2[C:13]3[C:20]([C:21]([O:23][CH2:24]C)=[O:22])=[CH:19][NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH:8]=[CH:9][C:10]=1[F:11].Cl>>[NH2:4][C:5]1[CH:6]=[C:7]([C:12]2[C:13]3[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3ccc(F)c(N)c3)c12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1c[nH]c2ncnc(-c3ccc(F)c(N)c3)c12
Temperature: 60 °C

Procedure:
To a sodium methoxide solution (5.71 mL, 25.0 mmol, 25 wt. % in methanol) was added ethyl 4-(3-amino-4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (150 mg, 0.500 mmol) and the reaction mixture heated at 60° C. for 1 hour. The reaction mixture was neutralized with 1 M HCl and then extracted with ethyl acetate (×3). The combined organic fractions were dried with sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by MPLC (0-10% methanol-dichloromethane) gave methyl 4-(3-amino-4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C14H13FN4O2 [M+H]+, 287, found 287.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([Si](C)(C)[O:35][CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][N:41]([NH2:44])[CH2:40][CH2:39]1)(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:44][N:41]3[CH2:42][CH2:43][CH:38]([CH2:37][CH2:36][OH:35])[CH2:39][CH2:40]3)=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC1CCN(N)CC1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NN1CCC(CCO)CC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 4-[2-(t-butyl-dimethyl-silanyloxy)-ethyl]-piperidin-1-ylamine trifluoroacetate (1:1) as starting materials; the silyl protecting group was lost during reaction and work-up; LC-MS (UV peak area/ESI) 94.9%, 458.1448 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[N:14][N:13]=[N:12]1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[N:13]=[N:14][CH:15]=[N:11]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1nnn[nH]1
Product: O=[N+]([O-])c1ccc(-n2ncnn2)cc1

Procedure:
The title compound was prepared from 4-fluoronitrobenzene (2 g) and tetrazole (1 g) as described in Description 61 as a yellow solid (0.83 g, 31%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].O>C1(C)C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH:3]=[CH:4][C:5]=1[Cl:11])(=[O:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cc(N)ccc1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(NS(C)(=O)=O)ccc1Cl
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
1-(5-Amino-2-chlorophenyl)ethanone (411 mg; synthesized by the process reported by Radziejewski et al., Heterocycles, vol. 26, pp. 1227-1238, 1987) was dissolved in toluene (5 mL), and pyridine(235 μL) and methanesulfonyl chloride (225 μL) were added. The resulting mixture was stirred at room temperature for 50 minutes. After adding water (50 mL), the reaction mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with an aqueous 1 N hydrochloric acid solution (50 mL) and saturated brine (50 mL) and then dried over anhydrous sodium sulfate (5 g). The solvent was distilled off under reduced pressure to yield N-(3-acetyl-4-chlorophenyl)methanesulfonamide (595 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@@H:25]([CH:32]([CH3:34])[CH3:33])/[CH:26]=[C:27](/[C:29]([OH:31])=[O:30])\[CH3:28])[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:12])([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:35]([O:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47]O)=[CH:45][CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CN(C1C=CC=CN=1)C>ClCCl>[CH3:1][NH:2][C@H:3]([C:13]([NH:15][C@H:16]([C:21]([N:23]([C@H:25]([CH:32]([CH3:34])[CH3:33])/[CH:26]=[C:27](\[CH3:28])/[C:29]([O:31][CH2:47][C:46]1[CH:49]=[CH:50][C:43]([O:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:44][CH:45]=1)=[O:30])[CH3:24])=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[C:4]([CH3:11])([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@@H](/C=C(\C)C(=O)OCc1ccc(OCc2ccccc2)cc1)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of N,β,β-trimethyl-L-phenylalanyl-N1-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]-N1,3-dimethyl-L-valinamide (287 mg, 0.607 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine hydrochloride (0.728 mmol), 4-(benzyloxy)benzyl alcohol (137 mg, 0.638 mmol) and dimethylaminopyridine (0.12 mmol) in anhydrous dichloromethane (12 mL) are stirred under a nitrogen atmosphere at room temperature for 20 hours. The solvent is removed, the residue taken up in methanol, and the product purified by reverse phase HPLC (0.01% trifluoroacetic acid in water/acetonitrile) to give the title compound as a white gum, 208 mg, MS: m/z 670.4 (M+1).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([N:17]1[C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[C:27]([NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][CH2:40][CH2:41][NH2:42])[CH:34]=[CH:33]2)=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(OP(C#N)(=O)OCC)C>CN(C)C=O.O>[CH2:10]([N:17]1[C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[C:27]([NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][CH2:40][CH2:41][NH:42][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9])[CH:34]=[CH:33]2)=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCCn1ccc2cc(NC(=O)c3nc4ccc(Cl)cc4n3Cc3ccccc3)ccc21
Reactant: O=C(O)c1cccnc1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCCn1ccc2cc(NC(=O)c3nc4ccc(Cl)cc4n3Cc3ccccc3)ccc21)c1cccnc1
Temperature: 0 °C
Yield: 75.4 %

Procedure:
To 0.29 g of nicotinic acid was added 50 ml of dimethylformamide, further 1.2 g of 1-benzyl-6-chloro-2-[1-(3-aminopropyl)indol-5-ylaminocarbonyl]-benzimidazole and 0.7 ml of triethylamine were added, the mixture was stirred under cooling at 0° C. Next, 0.49 g of diethylcyanophosphonate was dissolved in 20 ml of dimethylformamide and added thereto and the reaction mixture was stirred at room temperature for 1 day. After the reaction was finished, water was added then the whole mixture was extracted with ethyl acetate, the extract thus obtained was washed with water and an aqueous solution saturated with sodium chloride. The washed extract was dried with anhydrous magnesium sulfate, then the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to a silica gel column chromatography (eluent: 2% methanol/dichloromethane), recrystallized from chloroform, there was obtained 1 g of 1-benzyl-6-chloro-2-{1-[3-(pyridin-3-ylcarbonylamino)propyl]indol-5-ylaminocarbonyl}benzimidazole as in the form of yellow needle crystals.
Reaction SMILES: [Cl:1][C:2]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[N:8][CH:7]=[C:6]([Cl:18])[C:3]=1[C:4]#[N:5].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[Cl:1][C:2]1[C:9]([N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:19](=[O:21])[CH3:20])=[N:8][CH:7]=[C:6]([Cl:18])[C:3]=1[C:4]#[N:5]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1Nc1ncc(Cl)c(C#N)c1Cl
Product: CC(=O)N(c1ccccc1C)c1ncc(Cl)c(C#N)c1Cl
Temperature: 180 °C
Yield: 86.8 %

Procedure:
A mixture of 3,5-dichloro-2-(o-tolylamino)isonicotinonitrile (700 mg, 2.52 mmol) and acetic anhydride (10 mL, 106 mmol) was heated in a sealed tube to 180° C. for 20 h. The mixture was cooled to room temperature and concentrated. Silica gel chromatography, loading with dichloromethane-hexanes (1:1) and eluting with 5 to 30% ethyl acetate in hexanes, gave N-(3,5-dichloro-4-cyanopyridin-2-yl)-N-o-tolylacetamide (700 mg, 87% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.44 (1H, s), 7.28-7.43 (4H, m), 2.41 (3H, br. s), 2.04 (3H, s); MS (ES+) m/z: 320 (M+H); LC retention time: 3.38 min (analytical HPLC Method A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.CS(O[CH2:17][CH2:18][CH2:19][O:20][CH3:21])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:6]=2[CH:11]=1
Reactant: COCCCOS(C)(=O)=O
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCCn1c(=O)oc2ccc(Br)cc21
Temperature: 70 °C
Yield: 102 %

Procedure:
A mixture of 5-bromobenzo[d]oxazol-2(3H)-one (1.1 g), 3-methoxypropyl methanesulfonate (1.297 g) and potassium carbonate (2.131 g) in acetonitrile (25 mL) was heated at 70° C. for 16 h. Water was added and the mixture was extracted with ethyl acetate (3 times). The organic layers were dried (MgSO4), evaporated and purified by flash chromatography (silica, isohexane-acetone (5:1) as eluent) to give the sub-titled compound (1.50 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Br:15])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].CC1(C)C(C)(C)OB(/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:15][C:12]1[CH:11]=[C:4]([CH:3]=[C:2](/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6]
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(Br)cc(C(=O)NC2CC2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC/C=C/c1cc(C(=O)NC2CC2)cc(Br)c1C
Temperature: 100 °C

Procedure:
To a solution of 3,5-dibromo-N-cyclopropyl-4-methylbenzamide (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.1 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was heated at 100° C. for 1 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow-orange oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=O)[CH2:8]Br)([O-:3])=[O:2].[NH2:14][C:15]([NH2:17])=[S:16]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[N:14]=[C:15]([NH2:17])[S:16][CH:8]=2)[CH:11]=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: NC(N)=S
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Yield: 93.1 %

Procedure:
A solution of 3-nitrophenacyl bromide (244 mg, 1.00 mmol) and thiourea (76.1 mg, 1.00 mmol) in DMF (2 mL) was stirred at 60° C. for 16 h. The mixture was concentrated in vacuo to obtain a yellow solid that was then washed with H2O and dried to yield a yellow solid (206 mg). The solid was dissolved in DMSO and purified by SCX column (4×6 mL capacity), eluted with CH2Cl2 (4×6 mL), MeOH (4×12 mL) and then released by NH3 (7 N in MeOH, 4×6 mL) to give a light-yellow solid of 4-(3-aminophenyl)-thiazol-2-ylamine. 1H NMR (DMSO-d6, 400 MHz): δ=7.24 (brs, 2H), 7.35 (s, 1H), 7.65-7.69 (m, 1H), 8.10-8.13 (m, 1H), 8.23-8.26 (m, 1H), 8.62 (t, 1H, J=1.8 Hz). MS (ES+): m/z 223.12 (45) [M}+]. HPLC: tR=2.82 min (ZQ2000, polar—5 min). The combined CH2Cl2 and MeOH solution was concentrated in vacuo to give a yellow solid of 4-(3-aminophenyl)-1H-imidazole-2-thiol. 1H NMR (DMSO-d6, 400 MHz): δ=7.75 (t, 1H, J=8.0 Hz), 8.01 (d, 1H, J=0.8 Hz), 8.17-8.20 (m, 1H), 8.35-8.37 (m, 1H), 8.56 (d, 1H, J=1.6 Hz), 8.72 (t, 1H, J=1.8 Hz), 12.56 (s, 1H). MS (ES+): m/z 222.12 (15) [MH+]. HPLC: tR=2.97 min (ZQ2000, polar 5 min).
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:29])[C:14]([CH2:26][CH2:27]Cl)=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1OCCOCCOCCOCCOCCOC1.C[C:49]#[N:50]>>[CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:29])[C:14]([CH2:26][CH2:27][C:49]#[N:50])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CCc2c(C)c(CCCl)c(C)c(NC(=O)C(C)(C)C)c21
Reactant: CC#N
Agent: C1COCCOCCOCCOCCOCCO1
Product: CCCCCCCCN1CCc2c(C)c(CCC#N)c(C)c(NC(=O)C(C)(C)C)c21

Procedure:
N-(1-Octyl-5-chloroethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.0 g) was dissolved in CH3CN (30 ml), and NaCH (3.7 g) and 18-crown-6 (0.1 g) were added, which was followed by refluxing for 17 hr under a nitrogen atmosphere. CH3CN was evaporated under reduced pressure, and water (100 ml) was added to the obtained residue. The mixture was extracted twice with AcOEt (100 ml). The AcOEt layer was washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate, and AcOEt was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: AcOEt/benzene=1/10-1/5) to give 1.14 g of N-(1-octyl-5-cyanoethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: C(O)(=O)C.[C:5]1([NH:11][NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][C:14](=O)[CH2:15][CH3:16]>C(O)C>[CH3:13]/[C:14](=[N:12]\[NH:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH2:15][CH3:16]
Reactant: NNc1ccccc1
Reactant: CCC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC/C(C)=N/Nc1ccccc1

Procedure:
Add acetic acid (1.00 mL, 17.45 mmol) and phenyl hydrazine (1.98 mL, 20.00 mmol) to a solution of 2-butanone (2.15 mL, 24.00 mmol) in ethanol (90 mL) at room temperature. Stir the reaction for 1 hr., then remove the solvents in vacuo to give N-[1-methyl-prop-(E)-ylidene]-N′-phenyl-hydrazine as a crude orange oil (3.21 g, 99%). MS (ES): m/z=163 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][O:40][C:41]3[C:46]([Cl:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:42]=3[Cl:49])=[CH:33][CH:32]=2)[CH2:21][NH:22]C(=O)OC(C)(C)C)=[C:16]([CH3:50])[CH:15]=1)(=[O:3])[CH3:2].Cl>CCOCC.CCOC(C)=O>[ClH:47].[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][O:40][C:41]3[C:42]([Cl:49])=[CH:43][C:44]([CH3:48])=[CH:45][C:46]=3[Cl:47])=[CH:33][CH:32]=2)[CH2:21][NH2:22])=[C:16]([CH3:50])[CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)NCCCc1ccccc1-c1ccc(C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 2, step 5 using tert-butyl (2-{2′-[(acetylamino)propyl]-3-methylbiphenyl-4-yl}-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propyl)carbamate from step 1 as starting materials. Following flash chromatography the desired material (colorless oil) was dissolved in CH2Cl2/Et2O (1/1). HCl (4M in dioxane) was added in excess and the resulting suspension was triturated with Et2O to afford after filtration the title compounds as an off white salt. 1H NMR (500 MHz, CD3OD): δ 7.45 (d, 1H), 7.31-7.11 (m, 7H), 7.06 (s, 1H), 6.98 (d, 2H), 6.83 (d, 2H), 4.33 (brd, 4H), 3.55-3.49 (m, 1H), 3.44-3.34 (m, 2H), 3.07-3.01 (m, 3H), 2.86 (dd, 1H), 2.66-2.63 (m, 2H), 2.31 (s, 3H), 2.14 (s, 3H), 1.90 (s, 3H), 1.65-1.61 (m, 2H).