Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:17]=[CH:16][C:12]([C:13]([Cl:23])=[O:14])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-(5-chloro-1H-benzoimidazol-2-yl)-benzoic acid (1.0 mmol) (CAS 204514-08-9) and oxalyl chloride (2.0 mmol) in dichloromethane (0.10M), add 2 drops of dimethylformamide as a catalyst. Stir at room temperature for 2 hours. After this time, concentrate the reaction in vacuo. Assume total conversion to the acid chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1.[CH:21](=O)[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C>[O:26]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:21][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: O=Cc1ccco1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(CCN)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(CCNCc2ccco2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
4.0 g of 1,1-dimethylethyl 2-[[4-(2-aminoethyl)phenyl]thio]-2-methyl-propanoate [(P. J. Brown et al., J. Med. Chem. 42, 3785-88 (1999)] are dissolved in 100 ml of methanol and treated with 2.6 g of furfural. 9.3 ml of glacial acetic acid are added and the mixture is boiled briefly (10 min). The mixture is then cooled to 0° C., and 4.25 g of sodium cyanoborohydride are added a little at a time. The mixture is then stirred at room temperature overnight. 1 N HCl is added until the mixture is acidic, and the mixture is stirred for 30 min. The mixture is concentrated slightly and made basic using sat. NaHCO3 solution. The mixture is then extracted twice with ethyl acetate and the extracts are washed (sat. NaCl solution) and dried and concentrated. Chromatographic purification (dichloromethane/methanol 15+1) gives 2.4 g of the title compound as a colourless oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH3:24]
Reactant: CCC=O
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.36 ml (5 mmol) of propionaldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1:1→1:2→1:4) to yield 1.37 g (75.8%, light orange oily substance) of the desired product.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12]Br)=[CH:6][C:5]=1[O:14][CH2:15][CH3:16].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12][N:18]=[N+:19]=[N-:20])=[CH:6][C:5]=1[O:14][CH2:15][CH3:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1cc(CBr)c(C#N)cc1C(=O)NC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(CN=[N+]=[N-])c(C#N)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After next dissolving N1-methyl-4-(bromomethyl)-5-cyano-2-ethoxybenzamide in dimethylformamide (100 ml), sodium azide (6 g) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to yield the title compound (15.5 g).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:42])=[C:30]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@@H:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:42])=[C:30]([NH:32][S:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)c1ccc(O)c(NS(=O)(=O)c2ccccc2)c1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(=O)(=O)c5ccccc5)c4)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and N-[5-((R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-phenylsulfonamide (which was obtained in Example 32) according to the procedure of Example 73 as a white solid; mp>150° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.39(m, 4 H), 1.85(m, 4 H), 2.64 (m, 2 H), 2.89(s, 3 H), 4.48(m, 1 H), 6.77(d, J=6 Hz, 1 H), 6.86(m, 2 H), 7.02(m, 2 H), 7.48(m, 2 H), 7.72(d, J=6 Hz, 1H); MS (ES) m/z: 597.0 (MH+, 100%); HRMS Calcd. for C29H32N4O6S2(MH+): 597.1836. Found: 597.1827.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:20][C@H:10]2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:5][CH:4]=1.ClC1C=CC=CC=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[SH:35]>CO>[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35][C@@H:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C@@H:10]([OH:20])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]
Reactant: COc1ccc([C@@H]2O[C@H]2C(=O)Nc2ccccc2)cc1
Reactant: Nc1ccccc1S
Solvent: CO
Solvent: Clc1ccccc1
Product: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxy-N-phenylpropionamide (539 mg) and chlorobenzene (5 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (275 mg) and ferric chloride hexahydrate (0.054 mg) in methanol (0.1 ml) is added immediately to the reaction mixture. The mixture is stirred at the same temperature for 5 minutes, and cooled to room temperature. The precipitated crystals are collected by filtration, washed with chlorobenzene, and dried at 50° C. to give (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)-N-phenylpropionamide (582 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH:40]1[C:45](=[O:49])[NH:46][O:47][CH3:48])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:30])([F:29])[F:31])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:41][CH:40]1[C:45](=[O:49])[NH:46][O:47][CH3:48])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CONC(=O)C1CNCCN1C(=O)OC(C)(C)C
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CONC(=O)C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-methoxycarbamoyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-Methoxycarbamoyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:4][CH2:3]1.[Cl:6][C:7]1[CH:12]=[C:11](I)[CH:10]=[C:9]([Cl:14])[N:8]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([CH:2]2[CH2:4][CH2:3]2)[CH:10]=[C:9]([Cl:14])[N:8]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: [Zn+]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Clc1cc(C2CC2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Cyclopropylzinc bromide (0.5 M in tetrahydrofuran, 15 mL, 7.3 mmol) was added to a mixture of 2,6-dichloro-4-iodopyridine (1.0 g, 3.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (211 mg, 0.182 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. After being stirred at room temperature for 4 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=100:1) to provide 2,6-dichloro-4-cyclopropylpyridine. MS ESI calc'd. for C8H8Cl2N [M+H]+ 188. found 188. 1H NMR: (400 MHz, CDCl3) δ 6.89 (s, 2H), 1.87-1.80 (m, 1H), 1.18-1.13 (m, 2H), 0.84-0.80 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH:18]=O>>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=c1cc(N2CCN(Cc3ccc(F)c(F)c3)CC2)nc[nH]1

Procedure:
6-[4-(3,4-Difluoro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3,4-difluorobenzaldehyde. Mass spectrum (ES) MH+=307.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:36])[N:13]2[C:16](=[C:30](S(C)(=O)=O)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.O>C1C=CC=CC=1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:36])[N:13]2[C:16](=[C:30]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)S(C)(=O)=O
Reactant: C1COCCN1
Solvent: O
Solvent: c1ccccc1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 2.17 h
Yield: 97.1 %

Procedure:
To a solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyl-ethylidene)acetate (298 mg) in benzene (3 ml) is added morpholine (0.095 ml) at 7 to 10° C. After 130 minutes, the reaction mixture is filtered to give filtrate, which is poured into iced water, and is extracted with methylene chloride. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]-hept-2-en-6-yl]-α-(1-morpholinoethylidene)-acetate (284 mg). Foam. Yield: 97.1%.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([S:33](=[O:40])(=[O:39])[NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:28]=5)[N:20]4[N:19]=3)[CH:15]=2)[CH2:10][CH:9]1[OH:41])(C)(C)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C(Cl)Cl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[NH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[CH:28]=[C:29]([S:33]([NH:34][C:35]([CH3:37])([CH3:36])[CH3:38])(=[O:39])=[O:40])[CH:30]=[CH:31][CH:32]=5)[N:20]4[N:19]=3)[CH:15]=2)[CH2:10][CH:9]1[OH:41]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5c(c4)C(NC(=O)OC(C)(C)C)C(O)C5)nn23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5c(c4)C(N)C(O)C5)nn23)c1

Procedure:
The titled compound was prepared through an acid catalyzed deprotection using {6-[7-(3-tert-butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-2-hydroxy-indan-1-yl}-carbamic acid tert-butyl ester and trifluoroacetic acid in methylene chloride to provide as a light brown lyophilate. LCMS (E/I+) 493 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.05 (s, 1H), 8.50 (s, 1H), 8.45 (d, 1H, J=7.7 Hz), 8.38 (s, 3H), 7.88 (d, 1H, J=8.2 Hz), 7.83 (dd, 1H, J=7.8 Hz), 7.70 (t, 1H, J=7.8 Hz), 7.62 (broad s, 2H), 7.31 (d, 1H, J=8.3 Hz), 7.24 (d, 1H, J=4.7 Hz), 7.02 (d, 1H, J=4.7 Hz), 5.56 (s, 1H), 4.37 (s, 2H), 3.25 (dd, 1H, J=5.8, 16 Hz), 2.75 (d, 1H, J=16, 20 Hz), 1.11 (s, 9H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:25]=[CH:24][C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.II>CC(C)=O>[O:4]=[C:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:25]=[CH:24][C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: II
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(C2CCC(=O)CC2)cc1
Reaction time: 72 h
Yield: 60.2 %

Procedure:
tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-yl)benzylcarbamate (935 mg, 2.6 mmol) was dissolved in acetone (15 ml) together with iodine (68 mg, 0.26 mmol). The mixture was stirred at reflux temperature for 4 hours and at room temperature for 72 hours. The mixture was partially evaporated and then diluted with CH2Cl2 (50 ml). The organic phase was washed with NaHSO3 (50 ml, sat aq), water (50 ml) and brine (50 ml) followed by drying over MgSO4 and evaporation. The product was purified by flash chromatography using pet.ether/EtOAc (3:1) as eluent to give 475 mg (60%) of the title compound as clear syrup.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[CH:18][C:19](OC)=[O:20])=[CH:14][CH:15]=2)[CH:10]=[C:9]1C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[CH:18][CH2:19][OH:20])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C=Cc1ccc2c(c1)cc(C)n2C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2cc(C=CCO)ccc21
Temperature: -5 °C
Yield: 69.1 %

Procedure:
To a solution of methyl 5-(2-methoxycarbonyl-vinyl)-indole-1-carboxylic acid tert-butyl ester (4.64 g, 15.3 mmol, 1.0 eq.) in THF (87 mL) at −30° C. was added LiAlH4 (1 N in THF, 18.6 mL, 1.2 eq.) by syringe pump over 20 min and the resulting mixture was stirred and warmed to −5° C. After cooling back to −30° C., the reaction was then quenched by slow addition of acetone (10 mL) keeping temperature below −15° C., poured into Rochelle salt at 0° C., stirred for 1 h and the separated aqueous layer was extracted with EtOAc. The combunede organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purification by column chromatography (methylene chloride to 2% acetone/methylene chloride) to give 5-(3-hydroxy-propenyl)-indole-1-carboxylic acid tert-butyl ester (2.89 g, 70%) or or similarly 6-(3-hydroxy-propenyl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]1(=[O:12])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH2:2]1.[Br:13]Br>C(O)(=O)C>[Br:13][CH:2]1[C:1](=[O:12])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C1CC=CC2=C1CCCCC2
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1C2=C(C=CC1Br)CCCCC2
Reaction time: 4 h

Procedure:
2-bromobenzocycloheptan-1-one was prepared by dissolving benzocycloheptan-1-one (25.15 g, 0.157 mol) in acetic acid (200 mL, 99.8%) in a 500 mL three neck flask. Bromine (25.15 g, 0.157 mol) and acetic acid (10 mL) were placed in a dropping funnel. The bromine was slowly added dropwise to the flask over 4 hours at room temperature. The reactor was kept under a static blanket of nitrogen throughout. Then the reaction was held at room temperature for an additional four hours. The reaction mixture was washed with water (200 mL×2) and dried over sodium sulfate. A brown colored liquid (30.2 g) as a crude product was obtained after filtration from the sodium sulfate. The purity of the product was 96.4% by GC (area %).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=3)[N:34]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:33]=2)[CH:29]=[CH:28][N:27]=1.[N:63]1([CH2:72][C:73]2([OH:80])[CH2:78][CH2:77][CH2:76][CH:75]([NH2:79])[CH2:74]2)[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[N:64]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:63]1([CH2:72][C:73]2([OH:80])[CH2:78][CH2:77][CH2:76][C@@H:75]([NH:79][C:41]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[N:34]([C:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[N:33]=[C:32]4[C:30]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:25])[CH:31]=3)=[O:42])[CH2:74]2)[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[N:64]1
Reactant: NC1CCCC(O)(Cn2ncc3ccccc32)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)N[C@@H]4CCCC(O)(Cn5ncc6ccccc65)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.11 mmol) was added to a suspension of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.1 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of 1((1H-indazol-1-yl)methyl)-3-aminocyclohexanol (0.1 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]1=[O:22])[CH3:2].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][C:37]=2[F:43])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:42][C:39]3[CH:40]=[CH:41][C:36]([N:33]4[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:31][CH2:32]4)=[C:37]([F:43])[CH:38]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]1=[O:22])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Reactant: CCn1c(=O)c(-c2ccccc2)cc2cnc(S(C)=O)nc21
Product: CCn1c(=O)c(-c2ccccc2)cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)nc21
Yield: 21.1 %

Procedure:
8-ethyl-2-(methylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (120 mg, 0.38 mmol) and 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (113 mg, 0.38 mmol) were stirred at 120° C. for 3 h. The reaction mixture was purified by silica gel column chromatography using hexane:ethyl acetate (3:2). The isolated product was recrystallized from isopropanol to give the title compound (45 mg, 0.08 mmol, 21%) as a pale yellow solid. ESMS m/z 545 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:30]1[CH:29]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:26][CH:31]=1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (5.25 g, 38.6 mmol) and diisopropyl azodicarboxylate (DIAD, 8.49 g, 42 mmol) in THF (30 ml) was added drop wise to a solution of Ethyl 3-hydroxyphenylacetate (6.66 g, 37 mmol) and triphenylphosphine (11 g, 42 mmol) in THF (100 ml). The reaction mixture was stirred at room temperature for 4 hours, diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([CH:13]=[O:14])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:13]([C:10]2[CH:11]=[CH:12][C:7]3[N:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=3)[CH:9]=2)[OH:14])=[CH:18][CH:17]=1
Reactant: CC(C)c1nnc2ccc(C=O)cn12
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(C(O)c3ccc(F)cc3)cn12
Reaction time: 20 h

Procedure:
To a solution of 3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine-6-carbaldehyde (404.6 mg, 2.13 mmol) in THF (8 mL) at ambient temperature was added 4-fluorophenylmagnesium bromide (3 mL, 1.0 M in THF). The resulting reaction was stirred for 20 hours, then quenched with water, followed by saturated NaHCO3. The reaction mixture was extracted with ethyl acetate, the organics dried over sodium sulfate, and concentrated to give the above named compound (591.3 mg, 97%).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>O>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])[C:3]([O:5][CH2:29][CH3:30])=[O:4]
Reactant: O=C(O)C(Br)CCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(Br)CCCCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
In 50 ml of ethanol is dissolved 6.8 g of 2-bromo-9-phthalimidononanoic acid, and 5 ml of conc. sulfuric acid is added to the solution. After the solution is left standing overnight, the solution is diluted with 100 ml of water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is washed with 50 ml of aqueous sodium bicarbonate solution and 50 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is purified by silicagel column chromatography (hexane:ethyl acetate=6:1) to give 6.3 g of ethyl 2-bromo-9-phthalimidononanoate as a colorless oil.