Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].O>C(Cl)Cl>[C:26]([NH:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1)(=[O:28])[CH3:27]
Reactant: NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
A portion (70 mg) of the compound obtained in Example 81 was dissolved in anhydrous methylene chloride (10 ml) and to the solution were added pyridine (22 mg) and acetic anhydride (29 mg). The mixture was stirred for 20 minutes at room temperature. To the reaction mixture was added water, followed by extraction with methylene chloride. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:2-1:1-2:1) to yield 50 mg (61%) of the titled compound as a pale brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH2:58][O:59][CH3:60])=[N:56][C:52]=2[CH:51]=1.ClCl>CN(C)C=O.ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:61][C@H:57]([C:55]1[NH:54][C:53]2[CH:62]=[CH:63][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][O:59][CH3:60])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 87 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethyl amine in dimethylformamide. Yield: 87%; Rf value: 0.59 (silica gel; dichloromethane/methanol=95:5); C22H20Cl2N4O3 (459.33); mass spectrum: (M+H)+=459/461/463 (chlorine isotope) and (M−H)−=457/459/461 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:49])[C:7]=1[CH:8]([O:41][Si](CC)(CC)CC)[CH2:9][N:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:49][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH:8]([OH:41])[CH2:9][N:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:23][CH2:24][C@H:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:27]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(Cc3ccc(F)cc3)CC(O[Si](CC)(CC)CC)c3c(Cl)cncc3Cl)c2C(F)(F)F)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(Cc3ccc(F)cc3)CC(O)c3c(Cl)cncc3Cl)c2C(F)(F)F)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of compound 1-1 (15 g, 20.2 mmol) in THF (20 mL) was added TBAF (1.0 M in THF, 40.4 mL, 40.4 mmol) dropwise at 0° C., and the mixture was allowed to warm up from 0° C. to room temperature while stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: 70% EtOAc/hexane) to provide compound 1-2 (9.9 g, 84% over two steps) as a yellow-brown gum. 1H NMR (CDCl3) rotomers present δ 8.42 and 8.38 (2H, 2×s); 7.57 and 7.53 (1H, 2×s); 7.41-7.35 and 7.14-7.09 (4H, 2×m); 5.61-5.45 (1H, m); 5.10-4.50 (3H, m); 4.25-3.90 (4H, m); 3.31-3.15 (1H, m); 2.23-2.16 (6H, m); 1.65-1.51 (2H, m); 1.28-1.23 (3H, m); LCMS: 631 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:24][CH:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:27][CH2:26]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: NC1CCN(C2CCCCC2)CC1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=S(=O)(NC1CCN(C2CCCCC2)CC1)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 0 °C

Procedure:
7.8 Grams of 4-(7-Chloro-4-quinolylamino)-benzenesulphonyl chloride hydrochloride [prepared as in Example 1(b)] were added in portions to a stirred ice-cooled mixture of 3.63 grams of 4-amino-1-cyclohexyl-piperidine and 21.2 grams of sodium carbonate in 60 milliliters of water and 50 milliliters of chloroform. After stirring overnight at room temperature the chloroform layer was separated, washed with water, dried and evaporated to give a brown solid. This was triturated with hexane, the resultant solid dissolved in chloroform and diiso-propyl ether added to precipitate a solid which was triturated with hexane to give 1.9 grams of the title compound as the hemihydrate. Melting point 192°-193°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+:29]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.N[C@@H](C(O)=O)C.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH2:29])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: C[C@@H](N)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: COc1ccc(CC(C)N)cc1

Procedure:
To a flask containing 1.5 g of a substrate 1-(4-methoxyphenyl)-2-propanone, 4.94 g of D-glucose, 6.1 mg of NAD+, 4.88 g of D-alanine, and 4.0 mg of pyridoxal phosphate, 30 ml of a culture fluid of the E. coli HB101 (pNTASPAG), obtained in Example 11, which expresses TAS, PALDH, and GDH were added. The resultant product was stirred at 30° C. while being adjusted to a pH of 6.8 by drippage of 5 N aqueous solution of sodium hydroxide. During the reaction, the reaction liquid was sampled. From the sample, 1-(4-methoxyphenyl)-2-aminopropane was extracted by the addition of ethyl acetate after basifying the sample with 6 N aqueous solution of sodium hydroxide. The amount of 1-(4-methoxyphenyl)-2-aminopropane produced was measured by analyzing 1-(4-methoxyphenyl)-2-aminopropane under the following HPLC conditions. Further, by the law of the art, 1-(4-methoxyphenyl)-2-aminopropane thus obtained was acted on by 3,5-dinitrobenzyl chloride to form a dinitrobenzyl derivative. After that, the dinitrobenzyl derivative was analyzed under the following HPLC conditions, whereby the optical purity thereof was measured.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1.[O-]C1C=CC=CC=1.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.O>[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH:27][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]4)=[C:4]([O:14][CH3:15])[CH:3]=3)=[N:23]2)=[CH:19][CH:18]=1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Reactant: Nc1ccn(Cc2ccc(F)cc2)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2ccn(Cc3ccc(F)cc3)n2)ccc1-n1cnc(C)c1
Temperature: 130 °C

Procedure:
A mixture of 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole (WO2009076352, Example 1; 50 mg, 0.19 mmol), 1-(4-fluoro-benzyl)-1H-pyrazol-3-ylamine (45 mg, 0.40 mmol), sodium phenoxide (35 mg, 0.57 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (3 mg, 0.003 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene=Xanthphos (7 mg, 0.012 mmol) in dioxane (2 ml) was heated under an argon atmosphere in the microwave to 130° C. for 15 min. The mixture was diluted with water, extracted with dichloromethane and the product purified by chromatography on silica gel using dichloromethane/methanol as eluent. The title compound was obtained as a light yellow solid (Yield=42%). MS ISP (m/e): 378.4 (100) [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[O:4][C:3]=1C(OCC)=O.[ClH:16]>>[ClH:16].[O:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2](=[O:1])[CH2:3]1
Reactant: CCOC(=O)c1oc2cccnc2c1O
Agent: Cl
Product: O=C1COc2cccnc21

Procedure:
Ethyl 3-hydroxyfuro[3,2-b]pyridine-2-carboxylate (6.90 g, 25.8 mmol) was dissolved in 10% hydrochloric acid (50 mL), and heated under reflux for 3 h. Evaporation of the hydrochloric acid solution gave furo[3,2-b]pyridin-3(2H)-one hydrochloride (9.0 g). A portion of the furo[3,2-b]pyridin-3(2H)-one hydrochloride was converted to its free base by treatment with saturated sodium bicarbonate and extraction with chloroform in preparation for the following step.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][OH:18])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:6][NH:7][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][OH:18])[CH2:11][CH2:10]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCO)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1CC[C@H](C#CCO)CC1
Reaction time: 0.25 h

Procedure:
A solution of 9.0 g (33.66 mmol) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 185 ml CH2Cl2 was treated at 0° C. with 136 ml of TFA (for 30 min). After 15 min at this temperature, the reaction was evaporated, treated with cold (0° C.) 1 N NaOH (saturated with NaCl) and extracted with CH2Cl2/MeOH 9:1 (3×). The organic phase was dried over Na2SO4 and evaporated to yield 5.84 g (quantitative) of trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol, MS: 167 (M).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)[CH3:2].[Li]CCCC.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S@@:27](/[N:29]=[CH:30]/[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[CH:38][CH:37]=[CH:36]3)=[O:28])=[CH:23][CH:22]=1.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([CH:30]([NH:29][S@:27]([C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:26][CH:25]=2)=[O:28])[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[CH:38][CH:37]=[CH:36]3)=[CH:7][CH:6]=1)[CH3:2]
Reactant: Cc1ccc([S@](=O)/N=C/c2cccc3cccnc23)cc1
Reactant: CCN(CC)C(=O)c1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(C(N[S@@](=O)c2ccc(C)cc2)c2cccc3cccnc23)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 23.1 %

Procedure:
N,N-diethyl 4-iodo-benzamide (3.1 g, 10 mmol) was dissolved in dry toluene/THF (9:1, 200 mL) and cooled to −78° C. under nitrogen. n-BuLi (7.8 mL, 1.3 M in hexane, 10 mmol) was added dropwise during 5 to 10 min. After further 5 min, 3 (1.0 g, 3.4 mmol) was added dissolved in toluene (1 mL). The solution was stirred 10 min, then NH4Cl (aq.) was added. Concentration, aqueous workup and chromatography on silica gave a total of 0.70 g (44%) of a 70:30 mixture of diastereomers. The pure major isomer 5 (0.37 g) was obtained by one more chromatography. 1H NMR (CDCl3): δ1.2 (m, 6H), 2.4 (s, 3H), 3.4 (m, 4H), 6.35 (d, J=7.5 Hz, 1 H), 6.61 (d, J=7.5 Hz,1 H), 7.15-7.55 (m, 11H), 7.75 (m, 1H), 8.12 (m, 1H), 8.75 (m, 1H).
Reaction SMILES: C([N:4]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]3[C:31]([F:32])=[CH:30][C:29]([F:33])=[C:28]([NH2:34])[C:24]=3[C:25](=[O:27])[CH:26]=2)=[CH:17][C:16]=1[F:35])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])(=O)C.[OH-].[Na+]>C(O)C>[NH2:34][C:28]1[C:24]2[C:25](=[O:27])[CH:26]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:16]([F:35])[CH:17]=3)[O:22][C:23]=2[C:31]([F:32])=[CH:30][C:29]=1[F:33]
Reactant: CCOC(=O)CCCCCN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCCCC(=O)O)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 75.9 %

Procedure:
367 mg (0.818 mmol) of Compound 56 obtained in Example 56 was dissolved in 10 ml of ethanol, 1.23 ml of a 2N aqueous solution of sodium hydroxide was added and the mixture was stirred at room temperature for 17 hours. The precipitated crystals were collected by filtration to give 261 mg (69%) of Compound 57.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH2:33][C:34]2[CH:39]=[CH:38][C:37](Br)=[CH:36][CH:35]=2)[NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[Cl:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1>>[C:1]([O:5][C:6](=[O:41])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:46]3[CH:47]=[CH:48][C:43]([Cl:42])=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)[NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(Br)cc2)NS(=O)(=O)c2cccnc2)n1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccc(Cl)cc3)cc2)NS(=O)(=O)c2cccnc2)n1
Yield: 84.6 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 9-(b) except for using tert-butyl({6-[(4-bromobenzyl)(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}tert-butoxycarbonylamino)acetate (187 mg, 0.289 mmol) obtained in Example 9-(a), and using 4-chlorophenylboronic acid (70.6 mg, 0.452 mmol) in place of 4-fluorophenylboronic acid to afford the title compound (166 mg) as a colorless oil. (Yield: 84%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[Cl:9].[CH2:10]([C:17]#[CH:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:18]#[C:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[Cl:9]
Reactant: C#CCc1ccccc1
Reactant: Clc1cccc(I)c1Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Clc1cccc(C#CCc2ccccc2)c1Cl
Temperature: 25 °C

Procedure:
1,2-Dichloro-3-iodobenzene (4.39 g, 16.1 mmol), benzylacetylene (1.96 g, 16.9 mmol), copper(I) iodide (26 mg, 0.14 mmol) and bistriphenylphosphinepalladium(II)chloride (113 mg, 0.16 mmol) were combined in triethylamine (100 mL) and heated at reflux for 2 hours. The reaction was allowed to cool to room temperature and then was partitioned between saturated sodium chloride and diethylether. The organic phase was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel (eluting with hexane) to provide the title compound. MS (DCI/NH3) m/z 278 (M+NH4)+; 1H NMR (CDCl3) δ 3.90 (s, 2H), 7.13 (t, 1H), 7.2-7.5 (m, 7H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:27]=[CH:26][C:13]([CH2:14][CH:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=2)[C:5]2[CH:28]=[CH:29][CH:30]=[CH:31][C:4]=2[O:3]1.[OH-].[Na+]>O1CCCC1>[O:1]=[C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][CH:15]([C:16]([OH:18])=[O:17])[C:21]([OH:23])=[O:22])=[CH:26][CH:27]=2)[C:5]2[CH:28]=[CH:29][CH:30]=[CH:31][C:4]=2[O:3]1
Reactant: CCOC(=O)C(Cc1ccc(OCCn2c(=O)oc3ccccc32)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccc(OCCn2c(=O)oc3ccccc32)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Dissolve the compound obtained in Example 2 (1.5 g) in tetrahydrofuran (20 ml). Add 2N sodium hydroxide (8 ml) to the reaction mixture, cooled to 0° C. using an ice bath. Stir magnetically at ambient temperature for 72 hours. Remove the tetrahydrofuran by evaporation under reduced pressure. Take up the resulting residue in a 6N hydrochloric acid solution to pH 1 and extract twice with 50 ml of ether each time. Dry the organic phase over magnesium sulphate and remove the ether by evaporation under reduced pressure. Crystallise the resulting oil from isopropyl ether and recrystallise the resulting precipitate from cyclohexane.
Reaction SMILES: C([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:7][CH:6]=1)(O)=O.[H-].C([Al+]CC(C)C)C(C)C.[O:32]1CCCC1>C1(C)C=CC=CC=1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][OH:32])=[CH:6][N:7]=[C:8]1[S:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCSc1ncc(CO)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-carboxymethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole (3.74 g, 11.5 mmol) in dry tetrahydrofuran (50 mL) was cooled to -78° C. under argon, and a solution of diisobutyl aluminum hydride in toluene (30 mL of 1M) was added dropwise. The mixture was stirred at -78° C. for 1.5 hours, then allowed to slowly warm to room temperature, The reaction was quenched by pouring onto iced dilute acetic acid, the product was extracted into methylene chloride, and the organic extracts were washed with water, 5% sodium carbonate solution and brine. The dried, concentrated product was a light tan solid (3.32 g). Crystallization from ethanol/water gave-1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole; mp 98°-101° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:12]=[CH:11][C:10]=1[C:22]1[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=1.CN(C)C=O.[C:34]1(=O)[CH2:37][CH2:36][CH2:35]1.C([BH3-])#N.[Na+]>CO.C(Cl)Cl.C([O-])(O)=O.[Na+].C(O)(=O)C>[CH:34]1([N:19]2[CH2:20][CH2:21][CH:16]([O:15][C:13]3[CH:12]=[CH:11][C:10]([C:22]4[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=4)=[C:9]([F:8])[CH:14]=3)[CH2:17][CH2:18]2)[CH2:37][CH2:36][CH2:35]1
Reactant: O=C1CCC1
Reactant: O=C1CCC(c2ccc(OC3CCNCC3)cc2F)=NN1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(OC3CCN(C4CCC4)CC3)cc2F)=NN1
Temperature: 60 °C

Procedure:
In a 25 mL round bottom flask, 6-[2-fluoro-4-(piperidin-4-yloxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one trifluoroacetic acid salt (420 mg, 1.0 mmol) was dissolved in methanol (10 mL), N,N-dimethylformamide (4 mL), and acetic acid (0.4 mL). Cyclobutanone (0.23 mL, 3.0 mmol), and then sodium cyanoborohydride (0.32 g, 5.0 mmol) were added. The reaction was heated to 60° C. for 2 h. The reaction was cooled and diluted with methylene chloride and NaHCO3 sol. to pH 9. The organics were extracted three times and the solvent concentrated under vacuum. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) followed by salt formation with ethereal HCl produced 210 mg (54%). Mp>300° C. MS m/z 346 (M+H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[N:19][C:12]=3[N:13]([CH2:17][CH3:18])[C:14](=[O:16])[N:15]=2)[CH:7]=[CH:8][CH:9]=1.C(O)C>CC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[N:19][C:12]=3[N:13]([CH2:17][CH3:18])[C:14](=[O:16])[N:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C=O)nc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(CO)nc21
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
Sodium borohydride (35 mg, 0.9 mmol) was added to a mixture of 1.16 g (3.7 mmol) of 4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one-7-carbaldehyde and 20 ml of ethanol under ice-cooling, followed by stirring for 30 minutes under ice-cooling. The reaction solution was mixed with acetone and concentrated under a reduced pressure, and the resulting residue was mixed with water and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate-chloroform) and further recrystallized from acetonitrile-ethanol to give 271 mg of 4-(3-chlorophenyl)-1-ethyl-7-hydroxymethylpyrido[2,3-d]pyrimidin-2(1H)-one. The yield was 23%.
Reaction SMILES: [F:1][C:2]1[C:9](F)=[C:8]([F:11])[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:3]=1[NH:4][CH3:5].Cl.[F:16][C:17]([F:25])([F:24])[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+].N>CN(C=O)C>[F:1][C:2]1[C:9]([N:21]2[CH2:22][CH2:23][CH:18]([C:17]([F:25])([F:24])[F:16])[CH2:19][CH2:20]2)=[C:8]([F:11])[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:3]=1[NH:4][CH3:5]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CNc1c([N+](=O)[O-])cc(F)c(F)c1F
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CNc1c([N+](=O)[O-])cc(F)c(N2CCC(C(F)(F)F)CC2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,3,4-trifluoro-N-methyl-6-nitroaniline (1.5 g, 7.3 mmol), 4-trifluoromethyl-piperidine hydrochloride (2.76 g, 14.6 mmol), K2CO3 (2.01 g, 14.6 mmol) and DMF (10 mL) was stirred at rt overnight under Ar atmosphere. The mixture was poured into aqueous ammonia and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. Crystallization from EtOAc/PE gave the sub-title compound.