Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[CH2:6]([C@H:9]1[O:11][C@H:10]1[CH2:12][OH:13])[CH2:7][CH3:8].C(Cl)Cl.[OH2:17]>>[CH2:6]([C@@H:9]1[O:11][C@@H:10]1[C:12]([OH:17])=[O:13])[CH2:7][CH3:8]
Reactant: CCC[C@H]1O[C@H]1CO
Reactant: O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC[C@@H]1O[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A flask was charged with 34 ml of CCl4, 34 ml of acetonitrle and 2 g of (2S, cis)-3-propyloxiranemethanol. Then 11 g of NaIO4 in 51 ml of water were added, followed by 86 mg of RuCl3 to this biphasic solution. The mixture was stirred vigorously for 3 hrs at RT and 100 ml of methylene chloride was added. The organic phase was separated and water phase was extracted with methylene chloride. The combined black organic phase was dried over MgSO4 and concentrated. The residue was diluted with ether and filtered through celite to give colorless solution. After evaporation of solvent a pure product was obtained (yield 67%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])O.[Na+].C1C(=O)N(Br)C(=O)C1>CC1(C)N([O])C(C)(C)CCC1.ClCCl>[CH:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCCCCCCC=O
Yield: 88.1 %

Procedure:
1-Octanol (2.0 g, 15.4 mmol), sodium hydrogencarbonate (1.6 g, 18.5 mmol), TEMPO (24 mg, 0.15 mmol) and dichloromethane (15 ml) were put in a 50-ml egg plant type flask. The suspension was cooled to less than 10° C. in an ice bath, and thereto was added NBS (3.0 g, 16.9 mmol) divided in three portions. The insoluble materials were filtered off and the filtrate was washed with 5% aqueous sodium bicarbonate solution. The crude product was purified by distillation to give 1-octanal (1.74 g, yield 88%).
Reaction SMILES: [I-].[CH2:2]([N+:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH:19]=[O:20])[CH3:3].[OH-].[Na+].O.[BH4-].[Na+]>CO>[CH2:2]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH:19]=[O:20])[CH3:3]
Reactant: CC[n+]1ccccc1CCc1ccccc1NC=O
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN1CCCCC1CCc1ccccc1NC=O
Reaction time: 2 h

Procedure:
To a solution of 1-ethyl-2-(o-formamidophenethyl)pyridinium iodide (44.8 g., 0.117 mole), 50% NaOH (11.2 g., 0.14 mole), and water (40 ml.) in methanol (330 ml.) is added portionwise NaBH4 (5.32 g., 0.14 mole). The solution is stirred for 2 hr. and evaporated. Water is added to the residue thus obtained and the mixture extracted with ether. The ethereal extracts are dried (MgSO4) and evaporated. The residue taken up in 200 ml. of ethanol and hydrogenated in a Parr apparatus using 5 g. of 10% palladium on carbon as catalyst affords 1-ethyl-2-(2-formamidophenethyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([N:8]2[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=3)([OH:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:26])[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][C:30](=[O:44])[C:31](/[N:33]=[C:34](/NC(=O)C(OC)=O)\SC)=[O:32].C(#N)C.O>C(O)CCC>[CH3:28][O:29][C:30](=[O:44])[C:31]([NH:33][C:34]1[NH:25][C:20]2[CH:19]=[C:18]([C:16]3([OH:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:26])[N:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:27])[CH:23]=[CH:22][C:21]=2[N:24]=1)=[O:32]
Reactant: Nc1ccc(C2(O)c3ccccc3C(=O)N2c2cccc(Cl)c2F)cc1N
Reactant: COC(=O)C(=O)/N=C(/NC(=O)C(=O)OC)SC
Solvent: CCCCO
Solvent: CC#N
Solvent: O
Product: COC(=O)C(=O)Nc1nc2ccc(C3(O)c4ccccc4C(=O)N3c3cccc(Cl)c3F)cc2[nH]1
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of 2-(3-chloro-2-fluorophenyl)-3-(3,4-diaminophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (0.10 g, 0.26 mmol) and methyl{[(1Z)-{[(methyloxy)(oxo)acetyl]amino}(methylthio)methylidene]amino}(oxo)acetate (67 mg, 0.26 mmol) in n-butanol (2.0 mL) was heated to 80° C. for 5 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The resulting crude product was purified by reverse phase preparative HPLC (CH3CN/25 mM aqueous ammonium acetate). The fractions were collected, and the solvent was concentrated. The aqueous residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an oily residue, which was lyophillized from a mixture of acetonitrile-water (5.0 mL) to give methyl({6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}amino)(oxo)acetate (48 mg, 38% yield. 1H NMR (400 MHz, DMSO-d6): 11.86 (d, 1H), 7.87 (d, 1H), 7.65 (m, 2H), 7.53 (t, 1H), 7.33 (t, 1H), 7.30 (d, 1H), 7.25 (s, 1H), 7.20 (t, 1H), 6.99 (d, 1H), 6.91 (d, 1H), 3.57 (s, 3H); 13C NMR (400 MHz, DMSO-d6): 67.0, 92.5, 110.0, 113.8, 114.1, 115.7, 120.8, 121.4, 123.9, 125.3, 125.6, 126.0, 126.2, 129.5, 129.8, 130.5, 130.7, 134.3, 134.8, 150.3, 155.7, 155.8, 163.5, 166.2; MS (EI) for C24H16ClFN4O4: 436 (M−CO2CH3).
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[C:10]([CH3:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:28])=[N+:7]2[O-].C1(S(Cl)(=O)=O)C=CC=CC=1.[CH3:39][NH:40][CH3:41]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:15]([O:14][CH2:13][C@H:12]([C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:26])[N:7]=[C:6]([CH2:28][N:40]([CH3:41])[CH3:39])[CH:5]=[CH:4]2)[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CNC
Reactant: Cc1cc2c(ccc(C)[n+]2[O-])c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc2nc(CN(C)C)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 110 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a stirred solution of (S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline 1-oxide (25 mg, 0.055 mmol) in toluene (3 mL) was added benzenesulfonyl chloride (0.06 mL, 0.24 mmol). The mixture was stirred at 110° C. for 16 hours, then cooled to room temperature. Dimethylamine (2 mL 2 M solution in methanol, excess) was added. The mixture was stirred at room temperature for 16 h, then diluted in ethyl acetate (30 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product as a white solid (11 mg, 42%). LCMS-ESI+ (m/z): 479.3, 481.3 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:4][OH:5])[CH3:3].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C.O1CCCC1>[CH2:6]([O:13][C:14]([NH:1][C@@H:2]([CH3:3])[CH2:4][OH:5])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](CO)NC(=O)OCc1ccccc1

Procedure:
A procedure similar to that described in Preparation 7 was repeated, except that 14.55 g of L-alaninol, 126 ml of a 30-35% w/v solution of benzyloxycarbonyl chloride in toluene, 29.6 ml of triethylamine and 100 ml of anhydrous tetrahydrofuran were used, to give 8.15 g of the title compound, melting at 79° C. to 80° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]([S:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[O:15]>C(Cl)Cl>[CH3:12][N:13]([S:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:9])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(SC(C)(C)C)C(=O)Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)S(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
4.3 g of 80% m-chloroperbenzoic acid dissolved in 50 ml of methylene chloride were added dropwise to a solution of 6.15 g of N-methyl-N-tert.-butylthio-N'-(3,4-dichlorophenyl)-urea in 60 ml of methylene chloride cooled to 0° C. and after stirring the mixture at 0° C. for 20 minutes, the insolubles were removed by filtration. The organic phase was washed with an aqueous saturated solution of sodium bicarbonate, then with water and dried. The solvent was distilled off under reduced pressure and the residue was crystallized from isopropyl ether to obtain 5.5 g of N-methyl-N-tert.-butylsulfinyl-N'-(3,4-dichlorophenyl)-urea melting at 118° C.
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[O:34])=[CH:29][C:28]=1[N+:42]([O-])=O>>[NH2:42][C:28]1[CH:29]=[C:30]([C:33]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[O:34])[CH:31]=[CH:32][C:27]=1[O:26][CH3:25]
Reactant: COc1ccc(C(=O)N2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: COc1ccc(C(=O)N2CCN(C)CC2)cc1N

Procedure:
(3-Amino-4-methoxy-phenyl)-(4-methyl-piperazin-1-yl)-methanone was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with (4-Methoxy-3-nitro-phenyl)-(4-methyl-piperazin-1-yl)-methanone. LC/MS (E/I+) 250.08 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([N:17]4[CH:22]=[CH:21][C:20]([Sn](C)(C)C)=[CH:19][C:18]4=[O:27])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35](SC)=[N:34][C:33]=2[CH:39]=1.[ClH:40]>C1COCC1.C(Cl)Cl.CCOCC.[Cu](Br)Br>[ClH:40].[CH3:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35]([C:20]3[CH:21]=[CH:22][N:17]([C:13]4[CH:12]=[C:11]5[C:16](=[CH:15][CH:14]=4)[N:8]([CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:9]=[CH:10]5)[C:18](=[O:27])[CH:19]=3)=[N:34][C:33]=2[CH:39]=1
Reactant: C[Sn](C)(C)c1ccn(-c2ccc3c(cnn3CCN3CCCC3)c2)c(=O)c1
Reactant: CSc1nc2cc(C)ccc2o1
Agent: Br[Cu]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc2oc(-c3ccn(-c4ccc5c(cnn5CCN5CCCC5)c4)c(=O)c3)nc2c1
Temperature: 70 °C
Yield: 24 %

Procedure:
1-(1-(2-(Pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-4-(trimethylstannyl)pyridin-2(1H)-one (prepared according to Example 30, step a) (250 mg, 0.530 mmol), 5-methyl-2-(methylthio)benzo[d]oxazole (198 mg, 1.11 mmol), copper(II) bromide (331 mg, 1.16 mmol) and palladium tetrakistriphenylphosphine (61 mg, 0.053 mmol) were stirred in dry THF (6 mL) under a nitrogen atmosphere. The mixture was heated to 70° C. for 20 h. Upon cooling, the mixture was diluted with THF, filtered through celite and rinsed with THF/methylene chloride. The organics were concentrated and purified by flash chromatography (40 g ISCO column eluting with methylene chloride and methanol/ammonia (10:1); 100% methylene chloride to 15% methanol/ammonia over 35 min at 40 mL/min) then further purified by Preparatory HPLC. The appropriate fractions were concentrated and partitioned between methylene chloride and Na2CO3. The organics were dried with Na2SO4, filtered, and concentrated to provide the free base. This was dissolved in methylene chloride (2 mL) and treated with 1 equivalent of 2 M HCl in Et2O, and the mixture was concentrated to provide the title compound (55.8 mg, 24%) as a yellow solid: mp 270-280° C.; 1H NMR (500 MHz, CD3OD) δ 8.27 (s, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.88 (d, J=7.1 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.64-7.61 (m, 2H), 7.58-7.55 (dd, J=8.9, 1.9 Hz, 1H), 7.44 (d, J=1.7 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.24-7.22 (dd, J=7.1, 1.9 Hz, 1H), 4.89 (t, J=5.7, 2H), 3.88 (t, J=5.7, 2H), 3.74-3.70 (m, 2H), 3.21-3.16 (m, 2H), 2.51 (s, 3H), 2.20-2.16 (m, 2H) 2.04-2.01 (m, 2H); ESI MS m/z 440 [M+H]+; HPLC (Method C) 98.7% (AUC), tR=13.1 min.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[F:16][C:17]1[C:27]2[CH2:26][CH2:25][CH2:24][C:23](=[O:28])[N:22]([CH:29]=[CH2:30])[C:21]=2[C:20]([F:31])=[CH:19][C:18]=1[F:32].[NH4+].[Cl-]>C(Cl)Cl>[CH:29]1([N:22]2[C:23](=[O:28])[CH2:24][CH2:25][CH2:26][C:27]3[C:17]([F:16])=[C:18]([F:32])[CH:19]=[C:20]([F:31])[C:21]2=3)[CH2:1][CH2:30]1
Reactant: CC[Zn]CC
Reactant: C=CN1C(=O)CCCc2c(F)c(F)cc(F)c21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ICI
Product: O=C1CCCc2c(F)c(F)cc(F)c2N1C1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
An oven-dried 250 mL round-bottom flask was fitted with a stirbar and septa and flushed with nitrogen. Diethyl zinc (12.0 mL, 1.0 M/hexanes, 12.0 mmol) was added and cooled to 0° C. Trifluoroacetic acid (0.90 mL, 11.7 mmol) was added in a careful, dropwise manner over 5 minutes, and the reaction was then stirred for 15 minutes. Methylene chloride (10 mL) and diiodomethane (1.20 mL, 14.9 mmol) were then added, and the reaction was stirred for an additional 20 minutes. A solution of the product of Step 1 (1.01 g, 4.19 mmol) in methylene chloride (20 mL) was then added, and the reaction was stirred overnight with gradual warming to room temperature. After 25 hours, the reaction was poured into saturated aqueous NH4Cl solution (50 mL) and extracted with methylene chloride (3×50 mL). The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (0% to 20% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:16][C@@H:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@H:18]2[OH:30])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)C>[C:1]1([CH2:7][N:8]([CH2:16][C@@H:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]2[OH:30])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN(Cc2ccccc2)Cc2ccccc2)[C@H](O)C1
Solvent: CC(C)O
Product: O[C@@H]1CNCC[C@H]1CN(Cc1ccccc1)Cc1ccccc1
Yield: 100.9 %

Procedure:
A mixture of intermediate (27) (0.284 mol) in 2-propanol (1000 ml) and a mixture of 6N HCL in 2-propanol (250 ml) was stirred and refluxed for 15 minutes and then cooled. The solvent was evaporated. A 5% aqueous NaOH solution (750 ml) was added. The mixture was extracted three times with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 88.95 g of (trans)-4-[[bis(phenylmethyl)amino]methyl]-3-piperidinol (intermediate 28).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:20][N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][C:19]([CH2:22][C:23]([NH:33][CH2:32][CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[O:25])=[CH:20][N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(-c2ncc(CC(=O)O)s2)c1-c1ccc(F)cc1
Reactant: NCC1CCOCC1
Product: CC(C)(C)n1ncc(-c2ncc(CC(=O)NCC3CCOCC3)s2)c1-c1ccc(F)cc1

Procedure:
Using the compound obtained in step 2 and (tetrahydro-2H-pyran-4-yl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH:7]1[CH:6]=[C:5]2[CH:4]=[CH:3][CH:2]=[C:1]([NH:22][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:10]2=[CH:9][CH:8]=1
Reactant: Oc1cccc2ccccc12
Reactant: Nc1cccc2ccccc12
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc2c(Nc3cccc4ccccc34)cccc2c1
Temperature: 220 °C
Yield: 93 %

Procedure:
144 parts of α-naphthol, 143 parts of α-naphthylamine and 15 parts of triphenyl phosphite are mixed and heated to 220° C. The elimination of water commences at this temperature and has ended when the internal temperature reaches 250° C. 18 parts of water are removed in the course of 10 hours. After distilling off excess α-naphthol and α-naphthylamine, 250 parts of 1,1'-dinaphthylamine, of melting point 97° - 102° C, are obtained at 256° - 257°/5 mm Hg. This corresponds to a yield of 93% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][C:12]([OH:18])=[C:13]([OH:17])[CH:14]=3)[C:9]2=[O:19])=[CH:4][CH:3]=1>S(=O)(=O)(O)O.C(OC(=O)C)(=O)C>[C:13]([O:17][C:13]1[CH:14]=[C:15]2[C:10]([C:9](=[O:19])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:16]2)=[CH:11][C:12]=1[O:18][C:9](=[O:19])[CH3:10])(=[O:17])[CH3:12]
Reactant: O=C1c2cc(O)c(O)cc2CN1c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc2c(cc1OC(C)=O)C(=O)N(c1ccc(Cl)cc1)C2
Temperature: 0 °C

Procedure:
2-(4-Chloro-phenyl)-5,6-dihydroxy-2,3-dihydro-isoindol-1-one (0.79 g of raw material) and acetic anhydride (10 ml) was stirred in 80° C. with one drop of sulfuric acid as a catalyst for one hour. The mixture was poured into ice water, filtered and recrystallized from acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](N3CCN(CC)CC3)[C:11]3[CH:22]=[CH:23][S:24][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.C(N(CC)CC)C.CC([OH:62])(C#C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:62])[C:11]3[CH:22]=[CH:23][S:24][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: CCN1CCN(c2nc(-c3ccc(Br)cc3)cc3sccc23)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=c1[nH]c(-c2ccc(Br)cc2)cc2sccc12
Yield: 109.5 %

Procedure:
6-(4-Bromophenyl)-4-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine (0.96 g) was heated under reflux in the presence of bistriphenylphosphine dichloride (48 mg), triphenylphosphine (174 mg) and cuprous iodide (46 mg), in 2-methyl-3-butyn-2-ol (0.26 g), pyridine (15 ml) and triethylamine (30 ml) for 1.5 hr. The reaction solution was evaporated, and the resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system), to give 0.80 g of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[C:42]([NH:47][C:48](=[O:50])[CH3:49])[CH:43]=[CH:44][C:45]=1[F:46]>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>[F:46][C:45]1[C:40]([C:33]2[CH:32]=[CH:31][C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)[CH:3]([CH3:4])[CH3:5])=[CH:35][CH:34]=2)=[CH:41][C:42]([NH:47][C:48](=[O:50])[CH3:49])=[CH:43][CH:44]=1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)Nc1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Nc1ccc(F)c(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 33.4 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.19 g), N-(3-bromo-4-fluorophenyl)acetamide (990 mg) and tetrakis(triphenylphosphine)palladium(0) (0.21 g), the title compound (870 mg) was obtained as a pale-yellow amorphous powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28]O)=[O:25])([CH3:22])([CH3:21])[CH3:20].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][O:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(CC=C(C)C)c(OC)cc1O
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(CC=C(C)C)c(OC)cc1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 49 %

Procedure:
2.00 g of methyl 2-hydroxy-4-methoxy-5-(3-methyl-2-butenyl)benzoate, 1.29 g of N-(t-butoxycarbonyl)-2-aminoethanol, and 2.31 g of triphephenylphosphine were dissolved in 50 ml of tetrahydrofuran. The obtained mixture was cooled on ice. Thereafter, 1.73 ml of diisopropylazodicarboxylate was added to the reaction solution at the same temperature, and the temperature was then raised to a room temperature. After completion of the reaction, the reaction solution was concentrated. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), so as to obtain 1.54 g of methyl 2-(2-t-butoxycarbonylaminoethoxy)-4-methoxy-5-(3-methyl-2-butenyl)benzoate. The obtained product was dissolved in 15 ml of methanol, and the obtained mixture was cooled on ice. Thereafter, 10 ml of a 4 N hydrochloric acid-ethyl acetate solution was added to the reaction solution. After completion of the reaction, the reaction solution was concentrated under a reduced pressure. Ethyl acetate was added to the residue, and the obtained mixture was adjusted to be approximately pH 11 with addition of a 5 N sodium hydroxide aqueous solution and a saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. 1.06 g of the obtained residue was dissolved in 20 ml of toluene, and the obtained solution was heated to reflux. After completion of the reaction, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 601 mg of the subject compound.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH3:31])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28]#[N:29])=[C:23]([Cl:30])[CH:22]=3)=[N:17]2)=[O:12])[NH:8][N:7]=1)(=[O:5])[CH3:4].Cl>C(O)C>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:11]([C:9]3[NH:8][N:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:10]=3)=[O:12])[CH3:31])[N:17]=2)[CH:26]=[C:25]([F:27])[C:24]=1[C:28]#[N:29]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)[nH]n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)[nH]n1
Yield: 57.5 %

Procedure:
Sodium borohydride (8.21 mg, 0.217 mmol) was added into a flask under nitrogen atmosphere. Dry ethanol was added and the mixture was stirred. (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (45 mg, 0.108 mmol) in dry ethanol was added slowly and the mixture was stirred at RT for 2.5 h. pH of the reaction mixture was adjusted to ˜2 by addition of 1M HCl and the mixture was evaporated to dryness. The product was purified by Flash-chromatography. Yield 57.5%. 1H-NMR (400 MHz; DMSO): 1.13 (d, 3H), 1.37 (d, 3H), 4.22-4-51 (m, 3H), 4.73-4.85 (m, 1H), 5.38 (d, 1H), 6.39 (s, 1H), 6.99 (d, 1H), 7.82 (d, 1H), 7.86 (d, 1H), 7.97 (d, 1H), 8.09 (d, 1H), 13.00 (s, 1H)