Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[CH:37]=[CH:36][C:17]([C:18]([O:20][CH:21]2[CH2:26][CH2:25][C:24]([C:34]#[N:35])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:23][CH2:22]2)=[O:19])=[CH:16][CH:15]=1.C(C1(CCCCCCC)CCC(O)CC1)#N.C(OC1C=CC(C(O)=O)=CC=1)C1C=CC=CC=1.[C:71]([O:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])(=[O:75])[CH:72]([CH3:74])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:34]([C:24]1([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:23][CH2:22][CH:21]([O:20][C:18]([C:17]2[CH:36]=[CH:37][C:14]([O:13][CH:72]([CH3:74])[C:71]([O:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])=[O:75])=[CH:15][CH:16]=2)=[O:19])[CH2:26][CH2:25]1)#[N:35]
Reactant: CCCCCCCC1(C#N)CCC(OC(=O)c2ccc(O)cc2)CC1
Reactant: CCCCCCOC(=O)C(C)O
Agent: CCCCCCCC1(C#N)CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C(O)c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCC1(C#N)CCC(OC(=O)c2ccc(OC(C)C(=O)OCCCCCC)cc2)CC1
Reaction time: 1 h

Procedure:
A solution of 11.5 g of diethylazodicarboxylate in tetrahydrofuran is added to a mixture of 20.6 g of 4-cyano-4-heptylcyclohexyl p-hydroxybenzoate (obtainable by esterification of 4-cyano-4-heptylcyclohexanol with p-benzyloxybenzoic acid and cleavage of the benzyl group by catalytic hydrogenation), 11.5 g of optically active hexyl lactate and 15.7 g of triphenylphosphine in 150 ml of tetrahydrofuran, stirring is carried out for one hour at 50° and the solvent is removed after 12 hours. The residue is dissolved in 100 ml of hot toluene, cooled down, filtered and the filtrate purified as usual by chromatography and crystallization. Optically active hexyl p-(4-cyano-4-heptylcyclohexyloxycarbonyl)phenoxypropionate is obtained.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[N:6]([CH2:21][C:22](O)=[O:23])[N:5]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[F:32][C:33]1[C:38]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:37][CH:36]=[CH:35][C:34]=1[NH:44][C:45]([C@@H:47]1[CH2:52][C@@H:51]2[C@@H:49]([CH2:50]2)[NH:48]1)=[O:46].CCCP(=O)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:32][C:33]1[C:38]([O:39][C:40]([F:43])([F:41])[F:42])=[CH:37][CH:36]=[CH:35][C:34]=1[NH:44][C:45]([C@@H:47]1[CH2:52][C@@H:51]2[C@@H:49]([CH2:50]2)[N:48]1[C:22](=[O:23])[CH2:21][N:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:9][CH:8]=2)[C:4]([C:1](=[O:3])[CH3:2])=[N:5]1)=[O:46]
Reactant: CC(=O)c1nn(CC(=O)O)c2ccc(OCc3ccccc3)cc12
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1F)[C@@H]1C[C@H]2C[C@H]2N1
Agent: CCCP(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2F)c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-acetyl-5-benzyloxy-indazol-1-yl)-acetic acid (1.38 g, 4.30 mmol, prepared as described in Part A), (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-trifluoro methoxy-phenyl)-amide trifluoroacetate (1.80 g, 4.30 mmol) and propylphosphonic anhydride (50% in EtOAc, 3.80 ml, 6.46 mmol) in CH2Cl2 (40 ml) was added DIPEA (2.25 mL, 12.91 mmol) and the resulting mixture was stirred at RT for 2 h. The mixture was concentrated and the crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 0:1). MS (UPLC-MS): 611 [M+H]+; tR (HPLC conditions f): 2.40 min.
Reaction SMILES: [ClH:1].[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])C[CH2:3]1.C(NC(=O)NC1C=CC(C2N=C(N3CCOC[C@@H]3C)C3CN(C(OC(C)(C)C)=O)CC=3N=2)=C(F)C=1)C>>[ClH:1].[CH2:2]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:18]3[CH2:23][NH:22][CH2:21][C:19]=3[N:20]=2)=[C:11]([F:31])[CH:10]=1)=[O:7])[CH3:3]
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OC(C)(C)C)C3)c(F)c1
Agent: Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)c(F)c1

Procedure:
Method as described for (R)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (intermediate 33) step 3 using (S)-tert-butyl 2-(4-(3-ethylureido)-2-fluorophenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6-(7H)-carboxylate (example 153)
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)[N:24]=[CH:23][C:22]=1[C:36]([NH:38][C:39]1[CH:40]=[N:41][C:42]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:43]([CH3:45])[CH:44]=1)=[O:37].O>ClCCl>[CH3:20][C:21]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][N:27]=2)[N:24]=[CH:23][C:22]=1[C:36]([NH:38][C:39]1[CH:44]=[C:43]([CH3:45])[C:42]([CH:46]2[CH2:51][CH2:50][N:49]([CH:3]3[CH2:2][O:1][CH2:4]3)[CH2:48][CH2:47]2)=[N:41][CH:40]=1)=[O:37]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(C2COC2)CC1
Reaction time: 5 h
Yield: 35.5 %

Procedure:
3-Oxetanone (121 mg) and sodium triacetoxyborohydride (143 mg) were added at room temperature to a solution of 5-methyl-N-[5-methyl-6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (250 mg) described in Reference Example 171 in dichloromethane (24 ml), and stirred at the same temperature for five hours. After completion of the reaction, water was added and extracted with ethyl acetate. The organic solution was dried over anhydrous sodium sulfate and concentrated. 1N Aqueous solution of sodium hydroxide (20 ml) was added to the resulting residue, solid was collected by filtration purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (100 mg) as a white solid.
Reaction SMILES: O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH3:15][N:16]([CH3:67])[C:17]([C@H:19]1[N:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[CH2:22][C@@H:21]([S:37][C:38]2[C@H:39]([CH3:66])[C@@H:40]3[C@@H:57]([C@H:58]([O:60][Si](C)(C)C)[CH3:59])[C:56](=[O:65])[N:41]3[C:42]=2[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])[CH2:20]1)=[O:18]>CO>[CH3:67][N:16]([CH3:15])[C:17]([C@H:19]1[N:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[CH2:22][C@@H:21]([S:37][C:38]2[C@H:39]([CH3:66])[C@@H:40]3[C@@H:57]([C@H:58]([OH:60])[CH3:59])[C:56](=[O:65])[N:41]3[C:42]=2[C:43]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=2)=[O:44])[CH2:20]1)=[O:18]
Reactant: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 84.3 %

Procedure:
8 mg (0.039 mmol) of citric acid hydrate were added to 2 ml of a solution containing 55 mg of 4-nitrobenzyl (1R,5S,6S)-2-[(3S,5S)-5-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-3-pyrrolidinylthio]-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 18) in methanol, and the resulting mixture was stirred at room temperature for 35 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through 5 g of silica gel, using a 1:9 by volume mixture of methanol and ethyl acetate as the eluent, to give 42 mg (yield 84%) of the title compound as a vitreous solid.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13](CC#N)=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>>[N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH2:21][C:20]([OH:23])=[O:22])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N#CCc1ccc(-c2cn3ccccc3n2)cc1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)Cc1ccc(-c2cn3ccccc3n2)cc1

Procedure:
A mixture of 2 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetonitrile, 10 ml of glacial acetic acid and 10 ml of concentrated hydrochloric acid is heated under reflux for 1 hour. The solvent is distilled off under reduced pressure, and water is added to the residue. The mixture is alkalified with 10% sodium hydroxide, and then filtered. The filtrate is adjusted to pH 6 by addition of 10% hydrochloric acid. The crystalline precipitate is filtered off and washed with water to give 1.2 g of 4-(imidazo[1,2-a]-pyridin-2-yl)phenylacetic acid as colorless crystals melting at 220°-222°C with decomposition.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([NH:25][C:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=S)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:32]([O:31][C:29]([NH:28][C:26]([NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:4]2[C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: Nc1cccc(-c2ncccc2C(F)(F)F)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2C(F)(F)F)c1)NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a suspension of 3-(3-trifluoromethylpyridin-2-yl)aniline (200 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (278 mg) and diisopropylethylamine (0.336 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (279 mg), and the mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane:ethyl acetate=4:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-trifluoromethylpyridin-2-yl)phenyl)guanidine (234 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][S:9]2)=[CH:4][CH:3]=1.[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH:7]1[C:6](=[O:12])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:9][CH2:8]1
Reactant: BrBr
Reactant: O=C1CCSc2cc(Cl)ccc21
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc(Cl)cc2SCC1Br

Procedure:
Dissolve 7-chlorothiochroman-4-one (10 gms., 50.3 mmols) in chloroform (100 ml.) and cool the solution to 0°-5° C. Add bromine (2.60 ml., 50.3 mmols) dropwise over a 10-minute period. Stire the reaction mixture at room temperature for one hour, then add chloroform (100 ml.) and extract with 10% aqueous sodium sulfite (100 ml.) followed by water (200 ml.). Dry the chloroform solution over anhydrous magnesium sulfate, filter and evaporate in vacuo to a residue. Recrystallize the residue from cyclohexane to give 3-bromo-7-chlorothiochroman-4-one, m.p. 109°-110° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[I:17]I.S(=O)(O)[O-].[Na+]>O>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: II
Reactant: Nc1c(F)cccc1C(=O)O
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1c(F)cc(I)cc1C(=O)O
Yield: 63 %

Procedure:
To a solution of 999 mg (6.44 mmol) of 2-amino-3-fluorobenzoic acid in 35 mL of water was added 500 mg (5.95 mmol) of sodium bicarbonate. The reaction was stirred and 1.77 g (6.99 mmol) of iodine was slowly added. The reaction was stirred at room temperature for 48 hours. To the solution was added an aqueous solution of sodium bisulfite and the solution was stirred vigorously for 30 minutes. The precipitate was collected by vacuum filtration and washed with water. The brown solid was dried overnight to afford 1.14 g (4.06 mmol, 63% yield) of 2-amino-3-fluoro-5-iodo-benzoic acid. 1H NMR (500 MHz, DMSO-d6) δ 7.79 (t, 1H), 7.58 (dd, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4]>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: CC(C)C(O)c1cccnc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 80.6 %

Procedure:
In dichloromethane (60.0 mL) was dissolved 2-methyl-1-(pyridin-3-yl)propan-1-ol (2.16 g, 14.3 mmol) obtained in Step 1. Manganese dioxide (107 g) was added and the mixture was stirred at room temperature for 7 hours. After the reaction mixture was filtered through Celite, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give 2-methyl-1-(pyridin-3-yl)propan-1-one (1.72 g, 81% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=2[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])(=[O:17])=[O:16])=[O:13])[N:4]=1.ClCCl.[C:33](OC(=O)C)(=[O:35])C>C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[C:22]([NH:24][CH:33]=[O:35])[CH:21]=[CH:20][C:19]=2[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])(=[O:17])=[O:16])=[O:13])[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(N)ccc2C(=O)N(C)C)n1
Solvent: O=CO
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(NC=O)ccc2C(=O)N(C)C)n1

Procedure:
A solution of 1.9 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-5-amino-2-dimethylaminocarbonylbenzenesulfonamide and 10 ml of dichloromethane is added dropwise to the mixed anhydride, prepared in situ from 0.5 ml of formic acid and 1.0 ml of acetic anhydride in accordance with standard methods. After the end of reaction, the reaction mixture is concentrated and the residue is washed with water and ethyl acetate, to give 1.8 g of desired product; purity>92% (HPLC).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:5][CH:4]=1)=O.C(O)(=O)C.[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[C:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=3[O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:7][CH:8]=2)[CH2:37][CH2:36]1)(=[O:34])[CH3:33]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C=O)cc2)c(OCCCOC)c1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(-c2ccc(CN3CCN(C(C)=O)CC3)cc2)c(OCCCOC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Ethyl 3-[4′-formyl-2-(3-methoxypropoxy)biphenyl-4-yl]propanoate (1 g, 2.7 mmol) was dissolved in dichloroethane (20 mL). At 0° C., acetic acid (0.02 mL, 0.4 mmol) was added, followed by N-acetylpiperazine (0.38 g, 3 mmol) and sodium triacetoxyborohydride (0.86 g, 4 mmol) portionwise. The mixture was stirred at room temperature overnight. At 0° C., saturated aqueous sodium bicarbonate was added. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with brine and water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 1.02 g (78%) of the desired product as a brown oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15]([CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=3[F:31])[CH2:16]2)[CH2:12]1)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[OH:37][C:35]([C:34]([F:39])([F:38])[F:33])=[O:36].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15]([CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=3[F:31])[CH2:16]2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCCN1CC2CN(CCOc3ccc(C#N)cc3F)CC(C1)O2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(OCCN2CC3CN(CCCN)CC(C2)O3)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3-{7-[2-(4-Cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}-propyl)-carbamic acid isopropyl ester (5.8 g, from step (ii) above) was taken in dry dichloromethane (25 ml) and cooled to 0° C. Trifluoroacetic acid (75 ml) was added drop by drop and the reaction mixture was stirred at RT for 2 h under nitrogen atmosphere. Solvent and trifluoroacetic acid were evaporated under reduced pressure to give the TFA salt of the sub-title compound (9 g) as an oil.
Reaction SMILES: [C:1]([C:3]([CH3:23])([CH2:20][S:21][CH3:22])[C:4]([N:6]([C:8]1[S:9][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[N:11][N:12]=1)[CH3:7])=[O:5])#[N:2].[H][H]>C(O)(=O)C.[Pt]=O>[NH2:2][CH2:1][C:3]([CH3:23])([CH2:20][S:21][CH3:22])[C:4]([N:6]([C:8]1[S:9][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[N:11][N:12]=1)[CH3:7])=[O:5]
Reactant: [H][H]
Reactant: CSCC(C)(C#N)C(=O)N(C)c1nnc(-c2cncc(F)c2)s1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CSCC(C)(CN)C(=O)N(C)c1nnc(-c2cncc(F)c2)s1

Procedure:
A suspension of 2-cyano-N-[5-(5-fluoro-3-pyridyl)-1,3,4-thiadiazol-2-yl]-N,2-dimethyl-3-methylsulfanyl-propanamide (157 mg, 0.4 mmol) and platinum oxide (131 mg, 0.6 mmol) in glacial acetic acid (8 mL) was reduced under 45 psi of hydrogen at room temperature for 16 hours, filtered through Celite and concentrated under reduced pressure. The residue was treated with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (3×50 mL). Organic extracts were concentrated under reduced pressure and purified by reversed phase silica chromatography eluting with an aqueous acetonitrile mobile phase. Yield 33 mg (21%): mp 154-157° C.; IR (KBr thin film) 1656, 1383 cm−1; 1H NMR (400 MHz, CDCl3) δ 11.17 (br, 1H), 9.02 (t, J=1.6 Hz, 1H), 8.43 (d, J=2.8 Hz, 1H), 8.11 (ddd, J=9.8, 2.8, 1.8 Hz, 1H), 3.87 (d, J=2.9 Hz 1H), 3.48 (s, 3H), 3.47 (d, J=2.9 Hz, 1H), 2.99 (d, J=12.7 Hz, 1H), 2.78 (d, J=13.6 Hz, 1H), 2.20 (s, 3H), 1.41 (s, 3H); ESIMS (m/z) 356 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:10]2[CH2:14][N:13]([C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:12](=[O:23])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1([CH:10]2[CH2:14][N:13]([C@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:12](=[O:23])[CH2:11]2)[CH2:7][CH2:8][CH2:9]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C2=CC(=O)N([C@@H](C)c3ccccc3)C2)CCC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)C1(C2CC(=O)N([C@@H](C)c3ccccc3)C2)CCC1
Yield: 72.6 %

Procedure:
4-(1-Ethoxycarbonylcyclobutyl)-1-[(S)-1-phenylethyl]-3-pyrrolin-2-one (9.57 g, 31 mmol) was dissolved in ethanol (150 ml), and the solution was mixed with platinum oxide (230 mg) and stirred for 18 hours in a hydrogen atmosphere. After completing the reaction, the reaction solution was filtered and concentrated, and the resulting residue was applied three times to a silica gel chromatography column and eluted with an eluant of n-hexane:ethyl acetate=1:1, to thereby obtain optical isomer A (2.3 g, 24%) and optical isomer B (7.1 g, 74%) of the title compound each in an oily form.
Reaction SMILES: C1(C)C=CC=CC=1.C1COCC1.Cl.[OH:14][C@@:15]([C:43]1[CH:44]=[C:45]2[C:50](=[CH:51][CH:52]=1)[CH:49]=[C:48]([C:53]([NH:55][CH3:56])=[O:54])[CH:47]=[CH:46]2)([C:19]1[N:20]=[CH:21][N:22](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:23]=1)[CH2:16][CH2:17][OH:18]>O.CO>[OH:14][C@@:15]([C:43]1[CH:44]=[C:45]2[C:50](=[CH:51][CH:52]=1)[CH:49]=[C:48]([C:53]([NH:55][CH3:56])=[O:54])[CH:47]=[CH:46]2)([C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[CH2:16][CH2:17][OH:18]
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3c[nH]cn3)ccc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
To a mixture of toluene (100 mL), THF (20 mL) and 1 mol/L hydrochloric acid (100 mL) was added 6-[(1S)-1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (10.0 g, 17.6 mmol). The reaction mixture was stirred vigorously at 60° C. for 2 hr. The reaction mixture was allowed to cool to room temperature. The aqueous layer was separated, and the obtained aqueous layer was washed twice with methyl tert-butyl ether (100 mL and 50 mL). To the obtained aqueous layer was added methanol (10 mL), and then carbonate (10.6 g) and water (10 mL) were added thereto. The obtained slurry was stirred overnight at room temperature. The obtained crystals were collected by filtration, and washed with 10% aqueous methanol. The obtained wet crystals were dried under reduced pressure to give crude crystals (5.56 g). To a mixture of methanol (30 mL) and water (3 mL) were added the crude crystals (4 g). After stirring at 50° C. for 1 hr, water (50 mL) was added to the slurry at 50° C. over 1 hr. The slurry was stirred at 50° C. for 1 hr, and then allowed to cool to room temperature. After stirring for 3 hr at room temperature, the crystals were collected by filtration and washed with water. The obtained wet crystals were dried under reduced pressure to give 6-[(1S)-1,3-dihydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (3.69 g, 11.3 mmol). yield 89%.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:19][C:14]3=[N:13][CH:12]=2)=[CH:7][CH:6]=1.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39]([N:43]=[C:44]=[O:45])[CH:40]=[CH:41][CH:42]=1.C(N(CC)CC)C>CS(C)=O>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]3[CH:17]=[CH:16][N:15]4[C:11]([C:8]5[CH:7]=[CH:6][C:5]([CH2:4][NH:3][C:44]([NH:43][C:39]6[CH:40]=[CH:41][CH:42]=[C:37]([C:36]([F:35])([F:46])[F:47])[CH:38]=6)=[O:45])=[CH:10][CH:9]=5)=[CH:12][N:13]=[C:14]4[CH:19]=3)=[CH:25][CH:24]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CN)cc5)cnc4c3)cc2)CC1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CNC(=O)Nc6cccc(C(F)(F)F)c6)cc5)cnc4c3)cc2)CC1
Yield: 52.5 %

Procedure:
Combine {4-[3-(4-aminomethyl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone, bis hydrochloride (0.30 g, 0.56 mmol), 3-trifluoromethylphenyl isocyanate (0.1 mL, 0.73 mmol) and triethylamine (0.4 mL, 2.9 mmol) in DMSO (10 mL). Filter the solution through 10 g SCX column eluting with methanol→2 N ammonia in methanol. Concentrate fractions containing product to give a residue. Purify by chromatography (5% methanol in dichloromethane→10% methanol in dichloromethane→10% 2 N ammonia methanol in dichloromethane) to afford product (0.18 g, 52%). MS(ES), m/z 613 (M+1).