Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[C:11]2[C:22]3=[C:23]4[N:18]([CH2:19][CH2:20][CH2:21]3)[CH:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15](=[O:27])[C:14]4=[CH:13][CH:12]=2)(=O)=O)=CC=1.[F:29][C:30]([F:38])([F:37])[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CS(C)=O.Cl>O>[F:29][C:30]([F:38])([F:37])[N:31]1[CH2:36][CH2:35][N:34]([C:11]2[C:22]3=[C:23]4[N:18]([CH2:19][CH2:20][CH2:21]3)[CH:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15](=[O:27])[C:14]4=[CH:13][CH:12]=2)[CH2:33][CH2:32]1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c(=O)c(C(=O)O)cn4c3c2CCC4)cc1
Reactant: FC(F)(F)N1CCNCC1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cn2c3c(c(N4CCN(C(F)(F)F)CC4)ccc3c1=O)CCC2
Yield: 52.4 %

Procedure:
A mixture of 3.4 g of 8-(p-toluenesulfonyloxy)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of 1-trifluoromethylpiperazine and 200 ml of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 150° to 160° C. for 18 hours under nitrogen gas flow at a pressure of 10 atms. After completion of the reaction, the solvent and excessive piperazine compound were removed by distillation under reduced pressure and a mixture of methanol and ethanol was added to the residue. The precipitates formed were collected by filtration and washed with ether. The crystals obtained were suspended in a mixture of 200 ml of water and 40 ml of a 10% aqueous hydrochloric acid solution and insoluble substances were removed by filtration. The filtrate was rendered neutral with saturated aqueous solution of sodium bicarbonate and purified through column chromatography using Amberlite LH-20 (a trade name for a product of Tokyo Organic Chemical Industries Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 1.7 g of 8-(4-trifluoromethyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300° C. or more.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(O)=O.N>O>[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:12]1
Reactant: O=Cc1cccc(O)c1
Reactant: CC1CCCNC1
Agent: N
Solvent: O=CO
Solvent: O
Product: CC1CCCN(Cc2cccc(O)c2)C1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
24.4 g (0.2 mol) of 3-hydroxybenzaldehyde are mixed with 40 ml (about 0.4 mol) of 3-methylpiperidine and 20 ml (about 0.52 mol) of 100% formic acid with cooling and then stirred for 2 hours at 120° C. When the reaction mixture has cooled to room temperature, it is poured into water and rendered alkaline with ammonia, and the precipitated solid is filtered off and recrystallised from ethanol.
Reaction SMILES: [S:1]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15](=[O:22])[CH2:14][CH2:13][CH2:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:33])(=O)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1.C(NC(C)C)(C)C.C([Li])CCC>[F:33][CH:14]1[C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])[CH2:12][CH2:13]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC(F)C(=O)c3ccccc32)cc1
Temperature: -78 °C
Yield: 78.6 %

Procedure:
In 150 ml of tetrahydrofuran was dissolved 3.55 ml of diisopropylamine, and 14.9 ml of n-butyllithium was added dropwise while stirring at -78° C. in an atmosphere of argon. After 30 minutes of stirring under ice-cooling, the reaction mixture was cooled to -78° C., 60 ml of tetrahydrofuran solution containing 6.39 g of 1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one was added dropwise thereto and the resulting mixture was stirred for 30 minutes. Then, 90 ml of tetrahydrofuran solution containing 8.94 g of N-fluorobenzenesulfonimide was added dropwise, and the mixture was stirred for 1 hour while gradually increasing the temperature to 0° C. After adding saturated ammonium chloride aqueous solution to the reaction solution, the mixture was concentrated under a reduced pressure. Ethyl acetate was added thereto to separate the water layer, and the organic layer was washed with saturated sodium thiosulfate aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in that order. The organic layer was then dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting residue was applied to silica gel column chromatography, which was eluted with chloroform to obtain 5.31 g of 4-fluoro-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH:2]=1.[H][H]>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:2]1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4cccnc4)cc3)oc12
Agent: O=[Pt]=O
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCCNC4)cc3)oc12
Yield: 9.8 %

Procedure:
2-(4-(Pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide (100 mg, 0.35 mmol) and platinum (IV) oxide monohydrate (55 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by pre-HPLC. 11 mg of 2-(4-(piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 11%. 1H-NMR (400 MHz, DMSO-d6) δ 1.45 (s, 3H), 1.74-1.77 (m, 2H), 1.89-1.96 (m, 2H), 2.87-2.90 (m, 1H), 3.06-3.09 (m, 2H), 7.85-7.90 (brs, 2H), 7.94-7.96 (d, J=8.0 Hz, 2H), 8.26-8.28 (d, J=8.2 Hz, 2H); LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:25][C:26]1[CH:27]=[C:28]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=2)[CH:29]=[N:30][CH:31]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:25][C:26]2[CH:27]=[C:28]([C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=3)[CH:29]=[N:30][CH:31]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: CCOc1ccc(N(Cc2cncc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-ethoxyphenyl)amino]piperidine (641 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCCCCC>ClC(Cl)Cl>[CH3:6][O:5][C:1](=[O:4])[CH:2]([C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:3]
Reactant: COC(=O)CS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: COC(=O)C(S)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Dissolve 5.0 mL (55.0 mmol) methyl thioglycolate and 14.3 g (55.0 mmol) triphenylmethanol in 80 mL trichloromethane. Then slowly drop 6.9 mL (55.0 mmol) boron trifluoride ethyl ether complex into the solution and stir the solution at room temperature. Use thin layer chromatography (TLC)(chloroform:hexane=1:1) to follow the reaction. After starting material disappeared completely, wash the reaction solution with water (2×100 mL). The organic phase is dried by anhydrous sodium sulfate and then the solvent is removed by vacuum evaporation to get 18.6 g (97.5%) Triphenylmethyl thioglycolic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=[CH:5]2.[Br-].[Li+].[CH3:22][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=2)[CH:3]=1
Reactant: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Reactant: C[Mg]Br
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2cc(Br)ccc2c1
Temperature: 80 °C
Yield: 47 %

Procedure:
Under an atmospheric argon gas flow, trifluoromethane sulfonic acid-6-bromo-2-naphthyl ester in an amount of 32 g (90 mmol), dichloro (diphenylphosphinoferrocene)palladium in an amount of 3.6 g (5% by mol), lithium bromide in an amount of 7.8 g (90 mmol) and desiccated tetrahydrofuran in an amount of 100 milliliter were placed into a three neck flask with cooling pipe and having a capacity of 500 milliliter, and then, the resultant solution was cooled down to −20° C. After slowly dripping methylmagnesiumbromide in an amount of 90 milliliter (90 mmol, 1 mol/liter (tetrahydrofuran)) into the flask, the resultant solution was stirred under heating at the temperature of 80° C. for 4 hours. After the reaction terminated, adding dilute hydrochloric acid in an amount of 100 milliliter into the reacted solution, an organic layer was separated and washed with the use of sodium bicarbonate solution and sodium chloride solution, followed by drying with the use of magnesium sulfate. After removing the solvent by distillation by means of a rotary evaporator, the resultant crude product was refined by means of column chromatography (silicagel, hexane/dichloromethane=90/10), and as a result, 9.4 g of aimed compound (white crystal) was obtained (yield: 47%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: C=CCOC(=O)Cl
Product: C=CCOC(=O)Oc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) with allyl chloroformate (274 μl) was performed according to the methods described in example 1g. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH3:25])[C:18](=[O:26])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH3:25])[C:18](=[O:26])[CH2:17]3)[CH2:9]1
Reactant: CCN1C(=O)Cc2cc(N3C[C@@H](CN)OC3=O)cc(F)c21
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1C(=O)Cc2cc(N3C[C@H](CNC(=O)OC)OC3=O)cc(F)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.117 ml, 1.53 mmol) is added dropwise to (R)-5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-1-ethyl-7-fluoro-1,3-dihydro-indol-2-one (0.414 g, 1.02 mmol) and diisopropylethylamine (0.709 ml, 4.06 mmol) in dichloromethane (5 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (5% MeOH/DCM) to give the title compound as a yellow solid. HPLC r.t. 4.04 min; 1H NMR (300 MHz, CDCl3) 7.30 (s, 1H), 7.23 (dd, J=2, 13.2 Hz, 1H), 5.13 (t, 1H), 4.74-4.81 (m, 1H), 4.03 (t, J=9.2 Hz, 1H), 3.90 (q, J=6.8 Hz, 2H), 3.80 (dd, J=6.8, 9.2 Hz, 1H), 3.69 (s, 3H), 3.53-3.67 (m, 2H), 1.28 (t, J=6.8 Hz, 3H); MS for C16H18FN3O5 m/z 352.1 (M+H)+.
Reaction SMILES: [Br:1][CH:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)C.[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:12]([O-:15])(=[O:14])=[O:13].[Na+:16]
Reactant: CCCCCC(Br)Br
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCCCCCBr
Temperature: 25 °C

Procedure:
To a stirred mixture of dibromohexane (81.0 g), ethanol (120 ml) and water (50 ml) is added dropwise an aqueous solution (50 ml) of sodium sulfite (12.5 g) under reflux over 2 hours. After additional refluxing for 2 hours, the reaction mixture is allowed to cool and unreacted dibromohexane is removed and then the resulting solution is concentrated under reduced pressure. 95% Ethanol (200 ml) is added and the mixture is allowed to cool at room temperature overnight and precipitated crystals are collected by filtration to give the title compound as colorless prisms. The filtrate is concentrated and is allowed to cool overnight and precipitated crystals are collected by filtration to give additional title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:7]1[CH:16]2[CH:8]1[CH2:9][C:10]1[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Na+].[OH-].[Na+]>O>[N:1]1([CH:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:16][CH:8]2[OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CC1OC21
Reactant: C1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1Cc2ccccc2C1N1CCCCC1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
At 50° C. and over 5 minutes, 50 ml of piperidine and 50 ml of water were added to 21.25 g of 2,3-epoxy-indane and the mixture was maintained for 2 hours with stirring at this temperature. The solution was then cooled to 20° C. and was saturated with sodium chloride. 5 ml of sodium hydroxide were added, followed by extraction with ether. The extracts were concentrated to dryness under reduced pressure and the residue was taken up in 200 ml of ethyl acetate at 40° C., filtered, dried, and the solvents were eliminated under reduced pressure. The residue was taken up in isopropyl ether, filtered and taken to dryness to obtain 26.82 g of crude product which was purified by chromatography over silica, (eluent: ethyl acetate with 1% of triethylamine) to obtain [trans (±)] 2,3-dihydro-1-piperidinyl-1H-inden-2-ol melting at about 82° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1([C:11](=[O:14])[CH2:12]Br)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:15][O:16][P:17]([O:20]C)[O:18][CH3:19]>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]([C:8]1([C:11](=[O:14])[CH2:12][P:17]([O:18][CH3:19])([O:16][CH3:15])=[O:20])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: COP(OC)OC
Reactant: CCCCOC(=O)C1(C(=O)CBr)CC1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C1(C(=O)CP(=O)(OC)OC)CC1
Yield: 59 %

Procedure:
A solution of 16 3.42 g (13.0 mmol) and trimethylphosphite (1.95 mL, 2.05 g, 16.5 mmol) in toluene (45 mL) was refluxed for 15 hours. The solvent and remaining trimethyl phosphite were then distilled off, and the residue was purified by column chromatography (2-10% isopropanol/hexane) to give 2.26 g (7.74 mmol; 59% yield) of 17. 1H NMR (500 MHz, CDCl3) δ 0.95 (3H, t, J=7.3 Hz), 1.39 (2H, m), 1.57-1.67 (6H, m), 3.75 (2H, d, JH-P=22.1 Hz), 3.78 (6H, d, JH-P=11.1 Hz), 4.15 (2H, t, J=6.7 Hz). 13C NMR (125 MHz, CDCl3) δ 13.7, 19.2, 20.6, 30.5, 35.3, 39.8, 40.8, 52.9 (d, JC-P=6.0 Hz), 170.8, 197.0 (d, JC-P=6.3 Hz). MS (EI) m/z 292 (15, M+), 264 (17), 236 (21), 218 ((45), 191 (18), 163 (22), 150 (59), 126 (100); exact mass (ESI) calculated for C12H21O6PNa ([M+Na]+) 315.0973, found 315.0963.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][C:5]([Cl:17])=[CH:4][N:3]=1.[BH4-].[Na+].O>C(O)C>[NH2:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:6][C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Cl)cnc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CCc1cc(Cl)cnc1N
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of t-butyl (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoate (500 mg, 2.0 mmol) in ethanol (10 ml) at RT was added sodium borohydride (317 mg, 8.4 mmol) portionwise and the mixture stirred for 16 h. After the addition of water, the ethanol removed in vacuo and the mixture extracted with diethyl ether. The ethereal extracts were dried over MgSO4, evaporated to dryness and purified by column chromatography upon silica gel using hexane-EtOAc (7:3) as eluant to give t-butyl 3-(2-amino-5-chloro-3-pyridinyl)propanoate as a colourless oil (340 mg, 1.3 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]2[O:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[CH:25]1([O:24][C:22]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][C:12]3[O:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1ccc(Cn2ccc3ccc(N)cc32)o1
Reactant: O=C(Cl)OC1CCCC1
Product: COC(=O)c1ccc(Cn2ccc3ccc(NC(=O)OC4CCCC4)cc32)o1
Yield: 53 %

Procedure:
Using a similar procedure to that described in EX.22, but starting from methyl 5-(6-aminoindol- 1-ylmethyl)furan-2-carboxylate and cyclopentyl chloroformate, there was obtained methyl 5-[6-(cyclopentyloxycarbonyl)aminoindol-1-ylmethyl]furan-2-carboxylate in 53% yield, as an off-white solid; partial NMR: 1.5-200 [br m, 8H, (CH2)4 ], 6.2 (d, 1H, CH.CH=C), 6.6 (br.s, 1H,NH).
Reaction SMILES: C[O:2][C:3]1[C:4]([O:14]C)=[CH:5][C:6]2[S:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]=2[CH:13]=1.CO>ClCCl>[OH:2][C:3]1[C:4]([OH:14])=[CH:5][C:6]2[S:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]=2[CH:13]=1
Reactant: COc1cc2sn(C)c(=O)c2cc1OC
Solvent: CO
Solvent: ClCCl
Product: Cn1sc2cc(O)c(O)cc2c1=O
Temperature: -10 °C

Procedure:
To a suspension of 5,6-dimethoxy-2-methylbenzo[d]isothiazol-3-one (0.35 g) in dichloromethane (30 ml) boron tribromide (3.1 ml, 1 M solution in dichloromethane) was added at −40° C. The mixture was allowed to warm to −10° C. Next day methanol (30 ml) was added and the mixture was evaporated to dryness. To the residue sodium sulfite solution (9 ml, 5% in water) and brine (9 ml) were added. After stirring at 0° C. the precipitate was filtered.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH:17]([OH:18])[CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:4]([F:24])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:49]1[C:50]([O:57][CH3:58])=[N:51][C:52]([CH3:56])=[CH:53][C:54]=1[CH3:55]>CN(C=O)C.O>[F:24][C:4]1[CH:3]=[C:2]([C:49]2[C:50]([O:57][CH3:58])=[N:51][C:52]([CH3:56])=[CH:53][C:54]=2[CH3:55])[CH:7]=[CH:6][C:5]=1[C:8]1[N:12]([CH:13]2[CH:17]([OH:18])[CH2:16][O:15][CH2:14]2)[N:11]=[CH:10][C:9]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: COc1nc(C)cc(C)c1Br
Reactant: CCOC(=O)c1cnn(C2COCC2O)c1-c1ccc(Br)cc1F
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(C2COCC2O)c1-c1ccc(-c2c(C)cc(C)nc2OC)cc1F
Temperature: 90 °C

Procedure:
Ethyl 5-(4-bromo-2-fluorophenyl)-1-[(3RS,4SR)-4-hydroxytetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (3.8 g), bis(pinacolato)diboron (2.90 g), potassium acetate (2.80 g) and Pd(dppf)Cl2-DCM complex (480 mg) were added to DMF (38.3 mL), and the mixture was stirred at 90° C. in a nitrogen atmosphere. After stirring the reaction mixture for about two hours, a solution of 3-bromo-2-methoxy-4,6-dimethylpyridine obtained in Preparation Example 26 (3.09 g) in DMF (15 mL), and water (22 mL) were added, and the mixture was warmed to 120° C. and further stirred for about five hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was passed through a silica gel pad (NH silica gel, eluting with ethyl acetate). The filtrate was concentrated to about 200 mL and then partitioned by adding brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 70% to 90%) to give the title compound (2.26 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[C:45]([F:53])[CH:44]=1.O>C(#N)C>[F:53][C:45]1[CH:44]=[C:43]([Cl:42])[CH:48]=[CH:47][C:46]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(Cl)cc3F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.3 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was added with triethylamine (0.0540 mL, 0.390 mmol) and 4-chloro-2-fluorobenzenesulfonyl chloride (0.0450 g, 0.195 mmol), followed by stirring at room temperature for 12 hours. The reaction mixture was added with water and the solvent was evaporated. The residue was added with water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then filtered through a column filled with SCX (positive-ion exchange resin). The SCX was washed with 2 mol/L ammonia-methanol solution and the filtrate was evaporated to obtain 4-(2-fluoro-4-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0116 g, yield 27%).