Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=1[Cl:20].C([O-])([O-])=O.[Cs+].[Cs+].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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=2[Cl:20])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: COc1cc(Br)c(Cl)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(Cl)ncc2C)c(Cl)cc1Cl

Procedure:
To a solution of 2-chloro-5-methylpyrimidin-4-amine (44.8 mg, 0.31 mmol) in 1,4-dioxane (20 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene (96 mg, 0.37 mmol), Cs2CO3 (408 mg, 1.25 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 70 mg, 0.12 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1×100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo. The crude product was used for next reaction without purification.
Reaction SMILES: B.O1CCCC1.[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:9]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]([OH:9])[CH3:7])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@H](O)c1cccc(Cl)c1
Reaction time: 0.17 h
Yield: 102.7 %

Procedure:
To a solution of borane-tetrahydrofuran (77.6 mL, 77.62 mmol, Aldrich, 1 M solution in THF) and (R)-MeCBS (12.9 mL, 12.9 mmol, Aldrich, 1M solution in toluene) was added a solution of 3-chloroacetophenone (20.0 g, 129.37 mmol) in anhydrous tetrahydrofuran slowly over 30 min at room temperature. After complete addition, the reaction mixture was stirred for 10 min, quenched with 2N hydrochloric acid over 30 min. The reaction mixture was extracted with ether, dried, filtered and concentrated to afford 20.8 g of (S)-1-(3-chlorophenyl)ethanol as a viscous liquid.
Reaction SMILES: [Mg].II.[CH:4](Br)=[CH2:5].[CH3:7][C:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=1/[CH:16]=[CH:17]/[C:18]([CH3:20])=[O:19]>O1CCCC1>[CH3:7][C:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH3:14])([CH3:15])[C:9]=1/[CH:16]=[CH:17]/[C:18]([OH:19])([CH:4]=[CH2:5])[CH3:20]
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Reactant: C=CBr
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)(O)/C=C/C1=C(C)CCCC1(C)C
Temperature: -30 °C
Yield: 87.5 %

Procedure:
1.3 mols of magnesium turnings are placed in a 3 L four-necked flask. 100 ml of tetrahydrofuran (THF) and a iodine crystal are added thereto. 50 ml of a 15% vinyl bromide solution in tetrahydrofuran are added with stirring and under nitrogen atmosphere. The solution immediately decolourizes, while the Grignard starts to form with an exothermic reaction: the mixture is cooled to −30° C. and one mol of beta-ionone dissolved in 500 ml of THF and 950 mL of the above 15% vinyl bromide solution are added at the same time through two dropping tunnels, at such a rate that temperature remains below −15 20° C. After completion of the addition, the cooling bath is removed and the reaction mixture is brought to room temperature. After 2 hours the reaction mixture is poured into 2 ml of ice-water containing 10 g of ammonium chloride under stirring, then is extracted with 700 ml of ethyl acetate. The organic phase is washed twice with 100 ml of 15% sodium chloride aqueous solution and dried over sodium sulfate. Solvent is evaporated off under reduced pressure and the resulting thick oil is distilled under vacuum, collecting 202 g of distillate, consisting of vinyl beta-ionol of purity higher than 95%, as determined by NMR analysis (yield: 87.5%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)N=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
A mixture of 4-bromo-2-fluorobenzaldehyde (10 g, 47 mmol), tert-butyl amine (6.1 mL, 57 mmol) and 4 Å powder molecular sieves (8.0 g) in 160 mL CH2Cl2 (160 mL) was stirred at rt for 18 h. The reaction mixture was filtered through a pad of celite and concentrated to give the title compound (9.9 g, 78%). MS (ESI): mass calcd. for C11H13BrFNO, 258.1; m/z found, 260.0 [M+H]+. 1H NMR (CDCl3): 10.32 (s, 1H), 8.48 (s, 1H), 7.89 (t, J=8.1 Hz, 1H), 7.50-7.20 (m, 1H), 1.49-1.08 (m, 9H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.C(O)C.Cl>O>[F:1][C:2]([F:14])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
In a nitrogen atmosphere, 30.1 g (0.14 mol) of p-(2,2,2-trifluroethoxy) nitrobenzene, 82.1 g (1.47 mol) of reduced iron, 120 ml of ethanol and 40 ml of water were placed in a three-necked flask, to which 1.4 ml of concentrated hydrochloric acid was dropped under stirring and then refluxed for one hour. After cooling to a room temperature, it was separated by filtration, and the reaction solution was poured into iced water (about 2 liter), and precipitated solids were washed with water and then dried, to obtain 24.4 g (0.13 mol) of p-(2,2,2-trifluoroethoxy) aniline as pink solids. The yield was 94% and the melting point was 69.4° C.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>N.CO.[Pd]>[NH2:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:13]1[CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:11][CH:12]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Agent: N
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
A solution of compound 81 (0.5 g, 1.364 mmol) in 2 M NH3 in methanol (20 mL) was treated with Pd—C (0.05 g) and flushed with hydrogen gas. The reaction was stirred at room temperature for over night (16 h) under hydrogen atm. (balloon pressure). The solution was filtered using celite bed and washed with CH2Cl2:methanol (1:1, 3×20 mL). The solvent was evaporated and crude was purified by column chromatography (EtOAc: Hexanes, 1:1) to obtain compound 82 (0.46 g, quantitative) as a solid in 1:2 ratio of diastereomers. 1H NMR (DMSO-d6) δ 1.38, 1.41 (2s, 9H), 1.46-1.84 (m, 6H), 2.02-2.17 (m, 2H), 2.53-2.57 (m, 1H), 2.60-2.72 (2s, 3H), 3.82-3.85 (m, 1H), 4.41 (brs, 2H), 6.42-6.50 (m, 1H), 6.66-6.68 (m, 1H), 6.85-6.87, 6.99-7.06 (2m, 2H), 10.23, 10.28 (2s, 1H); ESI-MS m/z (%): 366 (M.Na+, 8), 344 (MH+, 10), 288 (100).
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(Cl)(=O)=[O:35])=CC=1.OO.[OH-].[Na+]>CO.O>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:35]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1[S+](c1ccccc1)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccccc1[S+](=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 16.1 %

Procedure:
(Tolyl)diphenylsulphonium hexafluorophosphate (1.08 g, 2.57 mol) is dissolved with stirring in methanol (40 ml) with cooling in ice-water. p-Toluenesulphonyl chloride (2.38 g, 12.5 mmol) is added slowly. After 15 mins a solution of hydrogen peroxide (30% in water, 3.5 g, 31 mmol) and sodium hydroxide (1.24 g, 31 mmol) in water (25 ml) is added dropwise over 10 min. After a further one and a half hours the reaction mixture is filtered and evaporated in vacuo. Water is added and the resulting solid is collected and washed with water and ether, to give (tolyl)diphenylsulphoxonium hexafluorophosphate (0.88 g, 79%) identical to authentic material.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>CC(C)=O.O.C(O)C>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Reaction time: 12 h
Yield: 71.2 %

Procedure:
A suspension of p-hydroxybenzoic acid (200 g, 1.2 mole), benzyl chloride (190 g, 1.5 mole) and potassium carbonate (165 g, 1.2 mole) in acetone (1200 ml) was reacted with stirring for 12 hours under reflux. After cooling, the precipitate was filtered off, and the filtrate was concentrated until 400 ml. H2O (1 l) was added with stirring to the residue and the mixture was allowed to stand. The organic layer was separated, and concentrated, and the residue was added to a solution of NaOH (60 g, 1.5 mole) in H2O (1 l) and ethanol (500 ml), followed by stirring for 4 hours to be dissolved. Then conc. hydrochloric acid (200 ml) was added to make pH 1. The precipitate was filtered, washed with H2O and with ethanol, and dried to give 195 g of 4-benzyloxybenzoic acid as white crystals having a m.p. of 191.2°-192.6° C.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.ClC1C=CC=CC=1.[C:18]([NH:21][CH:22]([C:28](=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:19]>O>[C:18]([NH:21][C@H:22]([C@H:28]([OH:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:19]
Reactant: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: O
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@@H](NC(C)=O)C(=O)OCC
Temperature: 40 °C
Reaction time: 15.5 h
Yield: 95.4 %

Procedure:
Triethylamine (1.32 g, 13.05 mmol) and formic acid (350 mg, 7.82 mmol) were added to a chlorobenzene solution (10.0 ml) of RuCl[(R,R)-TsDPEN](p-cymene) complex (17.6 mg, 0.03 mmol) and ethyl 2-acetylamino-3-oxooctadecanoate (1.00 g, 2.61 mmol) synthesized in the same method as Example 1. After the reaction mixture was stirred for 15.5 hours at 40° C., water (10 mL) was added thereto and separation operation was carried out at 40° C. to obtain the organic layer. It was confirmed by comparative analysis of the organic layer with sample product using HPLC that the organic layer contained 0.96 g of the title compound (yield: 96%). Further, anti-form:syn-form was 95:5 and the optical purity of the anti-form was 97% ee.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:21][S:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][O:14][C:13]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:12][CH2:11]1.C(N(CC)C(C)C)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1.C(=O)([O-])[OH:53].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][C:2]1[C:3]([CH2:21][S:22]([C:23]2[NH:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[O:53])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][O:14][C:13]2([CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[O:12][CH2:11]1
Reactant: Cc1c(OCC2COC3(CCOCC3)OC2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C([O-])O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)c1ccccc1
Product: Cc1c(OCC2COC3(CCOCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 43.7 %

Procedure:
To a toluene (dehydrated) (1.5 ml)-water (1.35 μl, 74.8 μmol) solution of 2-(((3-methyl-4-(1,5,9-trioxaspiro[5.5]undec-3-ylmethoxy)pyridin-2-yl)methyl)thio)-1H-benzimidazole (150 mg, 340 μmol), which was separately obtained in the same manner as described in the steps (10a) to (10d) of Example 10, D-(−)-diethyl tartrate (51.2 μl, 299 μmol) was added and the mixture was stirred at 50° C. for 5 minutes in a nitrogen atmosphere. Titanium (IV) isopropoxide (44.2 μl, 150 μmol) was added and the resultant mixture was stirred for further one hour. After the mixture was cooled on ice, N,N-diisopropylethylamine (39.1 μl, 224 μmol) was added, and cumene hydroperoxide (188 μl, 1.02 mmol as the content was regarded as 80%) was added dropwise in a nitrogen atmosphere, the mixture was stirred at 0° C. to room temperature for 7 hours. After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol) to obtain the title compound (68 mg, yield: 43.7%) as a light yellow foam.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[I:27]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CCCCCC>[I:27][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
3.33 g (10 mmol) of 9-bromo-10-phenylanthracene was dissolved in 80 mL of tetrahydrofuran (abbreviation: THF), and cooled to −78° C. Then, in a reaction solution thereof, 7.5 mL (12.0 mmol) of n-buthyllithium (abbreviation: n-BuLi) (1.6 mol/L hexane solution) was dropped by a dropping funnel and then stirred for one hour. A solution in which 5 g (20.0 mmol) of iodine dissolved in 20 mL of THF was dropped therein, and the further stirred for 2 hours at −78° C. After reaction, a sodium thiosulfate aqueous solution was added therein and stirred. An organic layer was washed with a sodium thiosulfate aqueous solution and saturated saline, and then dried with magnesium sulfate. The mixture was filtrated naturally, then the filtrate was concentrated, and then recrystallized with ethanol, 3.1 g of 9-iodo-10-phenylanthracene that was a target substance was obtained as a light yellow solid at a yield of 83% (Synthesis scheme (b-3)).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2=[O:21])=[CH:13][CH:12]=1.CC(O)=O>C1COCC1.O>[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH:17]([C:3]([O:6][CH3:7])=[O:8])[C:18]2=[O:21])=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CCc2ccc(OC)cc2C1=O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 9.99 g, 250 nmuol) in THF (100 mL), was added dimethyl carbonate (21.0 mL, 249 mmol). The mixture was heated to 65° C. and a solution of 7-methoxy-1-tetralone (20.00 g, 114 nmuol) in THF (100 mL) was added. The reaction mixture was allowed to stir vigorously at 65° C. for 2 h. After this time the reaction became very vigorous, and gas was evolved. The heating bath was removed for 10 min then heating continued for an additional 1 h. AcOH (18.00 mL, 317 mmol) was added slowly, followed by water (100 mL). The mixture was extracted with Et2O (2×) and the organic solutions were combined, washed with water and saturated NaHCO3 solution, dried over Na2SO4, filtered and evaporated. The residue was purified by filtration through a pad of silica to yield methyl 7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate as an oil. (25.2 g, 95%). LCMS: (FA) ES+ 235.0, ES− 233.0.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([OH:13])[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(N(CC)CC)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[CH2:11][CH:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CCl)CNCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Product: OC1CN(Cc2ccccc2)C1
Yield: 92.6 %

Procedure:
333 g of N-benzyl-3-amino-1-chloropropan-2-ol was taken up in 1665 ml of triethylamine and 10 g of tetrabutylammonium iodide was added. The resulting mixture was stirred under reflux for 13 hours, after which it was cooled, the hydrochloride precipitate filtered off and the filtrate washed twice with triethylamine. The combined filtrates were evaporated to yield 252 g of an oil, which was crystallized from 250 ml of toluene and 50 ml of hexane to yield 180.8 g of l as white crystals, m.p.: 66°-67° C., being a yield (based on amino-propanol) of 66.5% .
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2>CO.O>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[C:7]1[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH:8]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1
Yield: 100.1 %

Procedure:
To a solution of 56.11 gm (306 mMol) potassium hydroxide in 300 mL methanol were added 38 mL (306 mMol) 1-methyl-4-piperidone followed by 30.0 gm (153 mMol) 5-bromo-1H-indole. The reaction mixture was stirred at reflux for 18 hours. The reaction mixture was then cooled to ambient and diluted with 1.5 L water. The resultant white solid was filtered, washed sequentially with water and diethyl ether, and then dried under vacuum to give 44.6 gm (100%) 5-bromo-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([S:9][C:10]1C=[CH:17][CH:16]=[CH:15][C:11]=1C(O)=O)[CH3:8].CN(C=O)C>C(Cl)Cl>[CH2:7]([S:9][C:10]1[CH:11]=[CH:15][CH:16]=[CH:17][C:1]=1[C:2]([Cl:4])=[O:3])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCSc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCSc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Oxalyl chloride (113 μL, 1.3 mmol) was added slowly to a stirring suspension of 2-(ethylthio)benzoic acid (1-A) (182 mg, 1.0 mmol) and 3 μL DMF in methylene chloride (2 mL). After stirring for 3.5 h at room temperature, the mixture was concentrated in vacuo to give 2-(ethylthio)benzoyl chloride (1-B).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=O)=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl-].[NH4+]>C1COCC1>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:22])=[CH:23][CH:24]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide (32.0 mg) obtained in Example 142 in THF (10 ml) were added pyridine (0.032 mL) and trifluoroacetic anhydride (0.028 mL) at 0° C., and the mixture was stirred overnight at room temperature. Pyridine (0.032 mL) and trifluoroacetic anhydride (0.028 mL) were added thereto, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give a mixture containing the title compound and the raw material (4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide. To a solution of the obtained 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide in THF were added triethylamine (0.055 mL) and trifluoroacetic anhydride (0.028 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was combined with the mixture containing the title compound, and purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.10 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].[CH3:16]I>CN(C)C=O>[CH3:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CI
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(C)c2c1
Yield: 86.9 %

Procedure:
The reaction was carried out in a manner similar to Reference Example 4 except for using 3.00 (17.1 mmol) of methyl 6-indolecarboxylate, 0.68 g (17.1 mmol) of 60% sodium hydroxide, 4.86 g (34.4 mmol) of methyl iodide and 60 ml of dimethylformamide. Thus 2.75 g (86.9%) of methyl 1-methyl-6-indolecarboxylate was obtained.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:7].CI>O1CCCC1>[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:1])[CH3:7]
Reactant: [Li]CCCC
Reactant: CCc1ccccn1
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of butyllithium (1.6M in hexanes, 50 mL) was added dropwise over 20 min to a solution of 2-ethylpyridine (9.34 mL) in tetrahydrofuran (50 mL) at −70° C. The mixture was stirred for 2 h then methyl iodide (5 mL) was added dropwise over 15 min. The resulting orange slurry was allowed to warm to RT and stirred overnight. The solvent was evaporated and the residue diluted with diethylether (100 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), then dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a yellow oil. Yield 9.1 g.