Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:16][C:17]=1[CH3:18])[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:16][C:17]=1[CH3:18]
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2ccccc2)sc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CO)ccc1OCc1nc(-c2ccccc2)sc1C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzaldehyde (1.15 g) in tetrahydrofuran (10 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.13 g) at room temperature. After stirring the reaction mixture for 2 hrs, water was added, and the precipitated crystals were collected by filtration to give {3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]phenyl}methanol as colorless crystals (1.05 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[F:22][CH2:23][C:24](OCC)=[O:25]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:24](=[O:25])[CH2:23][F:22])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reactant: CCOC(=O)CF
Product: O=C(CF)N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Yield: 39 %

Procedure:
trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) was dissolved in 1 mL of ethyl fluoroacetate. The resulting mixture was heated to reflux for 2 h. Evaporation followed by crystallisation from methanol gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2-fluoroacetamide (4.7 mg, 39%). Data: (m/z)=361 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].[C:12]([O-])([O-])=[O:13].[K+].[K+].[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].C(O)C>CC(C)=O>[CH3:1][C:2]1[CH:9]([C:8]([CH3:11])([O:13][CH3:12])[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)[O:10][CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CCOC(=O)CBr
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)COC1C(C)=CC(C=O)=CC1(C)OC
Yield: 65.5 %

Procedure:
The compound was prepared according to general procedure E with 3,5-dimethyl-4-hydroxybenzaldehyde (3.3 mmol) in dry acetone (20 ml), anhydrous K2CO3 (4.3 mmol), and ethylbromoacetate (5 mmol) at reflux for 1 h. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 774 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 580 mg of purified compound were obtained (74% yield). 1H NMR (250 MHz, CDCl3): δ 1.26 (t, J=7.2 Hz, 3H), 2.33 (s, 6H), 4.23 (q, J=7.2 Hz, 2H), 4.42 (s, 2H), 7.50 (s, 2H), 9.82 (s, 1H) 13C NMR (126 MHz, CDCl3): δ 15.2, 17.4, 62.2, 70.1, 131.6, 132.8, 133.8, 161.7, 169.5, 192.1
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[C:13]([NH:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:14]([NH2:34])[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][C:17]=1[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:18][C:17]1[N:16]=[C:15]([N:19]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:14]2[N:34]=[C:36]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:35]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:13]=2[C:12]=1[CH3:11]
Reactant: Cc1nc(N(Cc2ccccc2)Cc2ccccc2)c(N)c(NCCc2ccccc2)c1C
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cc1nc(N(Cc2ccccc2)Cc2ccccc2)c2nc(Cc3ccccc3)n(CCc3ccccc3)c2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenylacetyl chloride (0.6 mL, 4.5 mmole) was added to a solution of 5,6-dimethyl-N4 -(2-phenylethyl)-N2,N2 -bis(phenylmethyl)pyridine-2,3,4-triamine (1 96 g, 4.5 mmole) in methylenechloride (100 mL) and the resulting mixture was stirred at ambient temperature overnight. A catalytic amount of p-toluenesulfonic acid was added and stirring was continued at ambient temperature over the weekend. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate then concentrated under vacuum to provide an oil. The oil was purified by silica gel column chromatography eluting with 5-10% ethyl acetate in hexane to provide 1.8 g of the desiredproduct as a white solid, m.p. 139°14 141° C. Analysis: Calculated for C37H36N4 : % C, 82.80; % H, 6.76; % N, 10.44; Found: % C, 82.86; % H, 6.78; % N, 10.36.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
4-Hydroxybenzaldehyde of the formula (7) (100 g), potassium carbonate (226 g) and dimethylformamide (500 ml) were taken in a reaction flask and stirred for 15 minutes. Benzylchloride (114 g) was then added at room temperature and the reaction mass was stirred at the same temperature for a period of 8–10 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with 10% aq. sodium hydroxide solution followed by water. The solvent was removed under reduced pressure and the resulting residue was triturated with pet. ether to afford the title compound of the formula (8) (160–165 g, 93–95%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]=O)=[N:20][CH:21]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(O)(=O)C>ClCCCl.CCOC(C)=O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:20][CH:21]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Brc1ccc(CN2CCOCC2)nc1
Reaction time: 2 h
Yield: 38.7 %

Procedure:
Sodium triacetoxyborohydride (1.6 gm, 7.5 mmol) was added to a solution of 5-bromopicolinaldehyde (1.0 g, 5.4 mmol) and morpholine (0.54 g, 6.2 mmol) in 1,2-dichloroethane (10 mL) and this was left stirring for 2 hr. Acetic acid (0.35 mL, 6.2 mmol) was added and the reaction was left stirring over the weekend. It was diluted with EtOAc and washed with sat. aq. NaHCO3 followed by brine. This was concentrated, captured on a SCX column, washed with MeOH, and released with 2 N NH3 in MeOH to give 4-((5-bromopyridin-2-yl)methyl)morpholine (537 mg, 2.09 mmol, 39% yield) as a brown oil. MS (ESI) m/z 256.96 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.61 (1H, d, J=2.44 Hz), 7.77 (1H, dd, J=8.24, 2.44 Hz), 7.33 (1H, d, J=8.24 Hz), 3.67-3.77 (4H, m), 3.60 (2H, s), 2.42-2.57 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=O)[CH:5]=[CH:6][CH:7]=1.C1(C)C(C)=CC=CC=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[NH:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCCO
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: OCCCNC1=Nc2ccccc2C1(O)c1cccc(Cl)c1
Reaction time: 24 h

Procedure:
3-(m-Chlorophenyl)-3-hydroxy-3H-indol-2-one (25.9 g., U.K. specification No. 1,125,671), xylene (400 ml.), 3-aminopropanol (15 g.) and toluene-p-sulphonic acid (150 mg.) were heated under reflux, with stirring, in an apparatus fitted with a water separator. After 24 hours, 6.9 ml. of water and 3-aminopropanol had been collected. The mixture was cooled and the xylene removed under reduced pressure leaving a yellow crystalline material which was recrystallised from ethyl acetate to give the title compound (14.33 g.), m.p. 164° to 165°C. (Found C, 64.45; H, 5.4; N, 8.85. C17H17Cl2N2O2 requires C, 64.75; H, 5.6; N, 8.7%).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:38][CH2:37][C@:21]3([N:25](C(OC(C)(C)C)=O)[C@H:24]([C:33]([O:35][CH3:36])=[O:34])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[CH3:51][Si]([N-][Si](C)(C)C)(C)C.IC.C(O)(C(F)(F)F)=O>O1CCCC1>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:47])[C:16]([N:18]2[CH2:38][CH2:37][C@:21]3([NH:25][C@:24]([CH3:51])([C:33]([O:35][CH3:36])=[O:34])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:49])[F:48])[CH:8]=1
Reactant: COC(=O)[C@@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-1,2-dicarboxylate (Intermediate 43, 1 g, 1.421 mmol) in dry Tetrahydrofuran (THF) (16 ml) at −78° C. LiHMDS 1M in THF (2.132 ml, 2.132 mmol) was added and the reaction mixture was stirred for 10 mins at r.t. iodomethane (0.355 ml, 5.68 mmol) was then added and the reaction mixture was stirred for 30 mins at r.t. The reaction was quenched with brine (1 ml), diluted with water (10 ml) and extracted with ethyl acetate (3×30 ml). Combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in Dichloromethane (15 ml) and the stirring solution was cooled at 0° C. TFA (5 ml, 64.9 mmol) was added and the reaction mixture was stirred at 0° C. for 1.30 h. The solvent and the excess of TFA were evaporated in vacuo. The residue was dissolved in 20 ml of ethyl acetate and washed with NaHCO3 sat. sol. (5 ml). The organic layer was dried, filtered and evaporated and the residue was purified by flash chromatography on silica gel using a Biotage SNAP 50 g as column and Cyclohexane to Cyclohexane/Ethyl acetate 1:1 as eluent affording the title compounds:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][S:9]2(=[O:14])=[O:13])[CH:5]=[CH:4][C:3]=1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].O>ClCCl>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([C:15]([C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH2:10][S:9]3(=[O:14])=[O:13])=[CH:7][C:2]=2[NH:1][C:38](=[O:40])[CH3:39])=[O:16])[CH2:18][CH2:19]1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N)CC2)c(C)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ccc(C)cc2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[2-Amino-4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (100 mg) described in Example 103 was dissolved in dichloromethane (2 mL), triethylamine (0.07 mL) and acetyl chloride (0.03 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (24 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([C:14]([F:17])([F:16])[F:15])=[N:11][NH:12][CH:13]=2)O1.Cl[C:20]1[C:29]([N:30]([CH:32]([CH3:34])[CH3:33])[CH3:31])=[N:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:35]([O:37][CH3:38])=[O:36])[CH:26]=2)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH:32]([N:30]([CH3:31])[C:29]1[C:20]([C:9]2[C:10]([C:14]([F:15])([F:16])[F:17])=[N:11][NH:12][CH:13]=2)=[N:21][C:22]2[C:27]([N:28]=1)=[CH:26][C:25]([C:35]([O:37][CH3:38])=[O:36])=[CH:24][CH:23]=2)([CH3:34])[CH3:33]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2c[nH]nc2C(F)(F)F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2nc(-c3c[nH]nc3C(F)(F)F)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (536.0 mg, 2.05 mmol) in DME (5 mL) and water (0.5 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (200.0 mg, 0.68 mmol), sodium carbonate (217.0 mg, 2.05 mmol) and Pd(PPh3)4 (39 mg, 0.03 mmol) with stirring for 0.5 h at 90° C. in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to get a residue, which was purified by a silica gel column with 2%-10% ethyl acetate in petroleum to afford methyl 3-(isopropyl(methyl)amino)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)quinoxaline-6-carboxylate as a light yellow solid (80 mg, 30%).
Reaction SMILES: [CH2:1]([CH:13]1[CH2:18][C:17](=O)[CH2:16][CH2:15][C:14]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:21](#[N:25])[CH2:22][C:23]#[N:24].O>NCCC(O)=O.C(Cl)(Cl)Cl>[C:23]([C:22]([C:21]#[N:25])=[C:14]1[CH2:15][CH2:16][C:17](=[C:22]([C:21]#[N:25])[C:23]#[N:24])[CH2:18][CH:13]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])#[N:24]
Reactant: CCCCCCCCCCCCC1CC(=O)CCC1=O
Reactant: N#CCC#N
Agent: NCCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCC1CC(=C(C#N)C#N)CCC1=C(C#N)C#N
Reaction time: 8 h

Procedure:
A mixture of 2 g (0.0071M) of thus obtained 2-dodecyl-1,4-cyclohexane-dione and 1.4 g (0.0212M) of malononitrile was heated in a water bath to make a solution. β-alanine as a catalyst and 2 ml of water were added to the solution and stirred at a temperature between 40° C. and 50° C. for 8 hours to react the mixture. After cooling, the reacted mixture was dissolved in chloroform, and rinsed with water and dried. The dried material was concentrated under reduced pressure, and purified through silica gel column chromatography. As a result, 1.26 g of white crystal of 1,4-bis-(dicyanomethylene)-2-dodecyl cyclohexane was obtained. The obtained compound had a melting point of 97° C. and an infrared absorption band of 2250 cm-1 which corresponds to a cyano group.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[N:7][NH:8]2)=[CH:4]C=1C#N.S(=O)(=O)(O)O.[C:30]([OH:33])(=[O:32])[CH3:31]>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[N:7][NH:8]2)=[CH:4][C:31]=1[C:30]([OH:33])=[O:32]
Reactant: CC(=O)O
Reactant: N#Cc1cc2c(/C=C/c3ccc4ccccc4c3)n[nH]c2cc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc2c(/C=C/c3ccc4ccccc4c3)n[nH]c2cc1F
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a suspension of 588 mg of 6-fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazole-5-carbonitrile in 3 mL of acetic acid and 1 mL of water was added 3 mL of concentrated sulfuric acid, and stirred at 110° C. for 1 hours. After allowing to cool, the reaction solution was added with ice, and extracted with a mixed solvent of 30 mL ethyl acetate/15 mL tetrahydrofuran. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resultant crude product was dissolved in 6 mL of 1,4-dioxane, added with 6 mL of 4N lithium hydroxide, and stirred at 120° C. for 15 hours. The reaction solution was made acidic with 5N hydrochloric acid, and then extracted with a mixed solvent of 30 mL ethyl acetate/20 mL tetrahydrofuran. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 477 mg of the title compound as ocher crystals.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4]N.[N:6]1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>ClCCl.O>[Cl:2][CH2:3][CH2:4][C:16]1([S:19]([NH2:6])(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH2:15]1
Reactant: c1ccncc1
Reactant: NCCCl
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)C1(CCCl)C=CC(Cl)=CC1
Reaction time: 0.17 h

Procedure:
11.6 g (100 mmol) of 2-chloroethylamine HCl were suspended in dichloromethane. 13.8 g (175 mmol) of pyridine were added, the mixture was stirred for 10 minutes and then 15.8 g (75 mmol) of 4-chlorobenzenesulfonyl chloride, dissolved in dichloro-methane, were added dropwise. The reaction mixture was heated under reflux for 8-10 hours, then treated with water and adjusted to a pH of 1-2 using HCl. The organic phase was washed three times with 3% strength HCl and the aqueous phase was extracted by shaking 3-4 times with dichloromethane. The combined organic phases were dried using Na2SO4, evaporated in the and recrystallized from ethanol. The yield was 11 g.
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:3]1[CH:8]=[N:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[N:4]=1.[Cl:25]CCl>>[Cl:25][C:17]1[C:11]2[C:12](=[N:13][CH:14]=[C:9]([C:5]3[N:4]=[C:3]([N:2]([CH3:1])[CH2:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:8]=[N:7][CH:6]=3)[CH:10]=2)[NH:15][CH:16]=1
Reactant: CN(CC1CCOCC1)c1cncc(-c2cnc3[nH]ccc3c2)n1
Reactant: ClCCl
Product: CN(CC1CCOCC1)c1cncc(-c2cnc3[nH]cc(Cl)c3c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound N-methyl-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2-amine (143) (20 mg, 1.0 eq) in dichloromethane (5 mL) was added n-chlorosuccinamide (2.0 eq) and the resulting reaction mixture was stirred at room temperature overnight. After completion of the reaction the solvents were removed and extracted into CH2Cl2. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 to retain the crude material. The combined organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed by rotary evaporator. The crude material was purified by flash column with 100-200 mesh silica gel employing 40% EtOAc/hexane eluents to obtain the pure off-white coloured solid of 6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine compound 144.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#N)=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[OH-:19].[Na+].Cl.O1CCCC1.C[OH:28].O>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]([OH:28])=[O:19])=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
4-Morpholino-3-(trifluoromethyl)benzonitrile (2.1 g, 8.016 mmol) was dissolved in a mixture of tetrahydrofurane/methanol/water (1:1:1, v/v/v, 20 mL), sodium hydroxide (1.9 g, 48.10 mmol) was added thereto and stirred for 40 hours with reflux. The reaction mixture was cooled to room temperature and 1N hydrochloride was added slowly thereto to pH 3˜4. The resulting solid was filtered, washed with water and dimethyl ether and then dried to obtain the title compound (694 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[CH:2].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])#[CH:2]
Reactant: Oc1ccccc1
Reactant: C#Cc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#Cc1cccc(C(=O)Oc2ccccc2)c1

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added a solution having 692 mg (7.35 mmol) of phenol and 3.4 ml (42 mmol) of pyridine dissolved in 7 ml of dichloromethane under ice-cooling and then the resultant mixture was stirred at room temperature for one hour. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue. The mixture was extracted with 35 ml of ethyl acetate, the extract was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (Hexane/AcOEt=10/1) using silica gel to obtain 0.55 q of phenyl 3-ethynylbenzoate which is a desired product as yellow solid. (Yield: 35%)
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][N:8](C(OC)=O)[C@H:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:6]1)(=[O:3])[CH3:2].Br.O>C(O)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C@@H:7]2[CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:9][NH:8]2)=[CH:21][CH:20]=1
Reactant: COC(=O)N1CC[C@H](NC(C)=O)C[C@H]1Cc1ccc(Cl)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N[C@H]1CCN[C@H](Cc2ccc(Cl)cc2)C1
Reaction time: 16 h

Procedure:
Methyl (2R*,4S*)-4-acetylamino-2-(4-chlorobenzyl)piperidine-1-carboxylate (30.0 g, 92.3 mmol) are treated with 51.8 ml 33% strength hydrogen bromide in acetic acid. After 16 hours, the mixture is treated with 200 ml of water and washed twice with toluene. The aqueous phase is rendered basic and extracted twice with ethyl acetate. The organic phases are dried on potassium carbonate and evaporated on a rotary evaporator. The title compound crystallizes from EtOHI ethyl acetate as the hydrochloride. M.p.: 288-289° C. TLC: methylene chloride/methanolconc. ammonia (90:9:1) Rf =0.17, FD-MS: (M+1)+ =267.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[O:1]1[CH2:5][CH2:4][CH:3]([O:6][S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH2:2]1
Reactant: OC1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of tetrahydrofuran-3-ol (500 mg, 5.67 mmol) in pyridine (10 ml) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (1.08 g, 5.67 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated in vacuo to yield crude oil (1.2 g).