Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[C:6]([C@@H:9]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]=2[S:21][CH2:20]1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:8])=[O:7].C(=O)(O)[O-].[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O>[CH2:44]([O:7][C:6]([C@@H:9]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]=2[S:21][CH2:20]1)[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCc2ccccc2)C(=O)O)CSc2ccccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCc2ccccc2)C(=O)OCc2ccccc2)CSc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A mixture of 10 ml of N,N-dimethylformamide, 0.3 g of tert-butyl 3(R)-[1(S)-carboxy-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate obtained in Example 43, 0.5 g of sodium bicarbonate and 0.15 g of benzyl bromide is stirred at room temperature overnight. The mixture is diluted with water (100 ml) and extracted with ethyl acetate (200 ml). The extract is washed successively with 0.1N hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.35 g of tert-butyl 3(R)-[1(S)-benzyloxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: S([O-])(O[CH3:5])(=O)=O.[S:7]([NH:17][C:18]1[C:19]([O:30][CH3:31])=[C:20]([N+:27]([O-:29])=[O:28])[C:21]([O:25][CH3:26])=[C:22]([Cl:24])[CH:23]=1)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[Na+]>>[S:7]([N:17]([C:18]1[C:19]([O:30][CH3:31])=[C:20]([N+:27]([O-:29])=[O:28])[C:21]([O:25][CH3:26])=[C:22]([Cl:24])[CH:23]=1)[CH3:5])([C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[CH:15][CH:16]=1)(=[O:8])=[O:9]
Reactant: COS(=O)(=O)[O-]
Reactant: COc1c(Cl)cc(NS(=O)(=O)c2ccc(C)cc2)c(OC)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: COc1c(Cl)cc(N(C)S(=O)(=O)c2ccc(C)cc2)c(OC)c1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
0.022 mole (2.1 ml) of methyl sulphate was added at 30°-35° C. to a solution of 0.02 mole (7.7 g) of 5-(N-tosylamino)-2,4-dimethoxy-3-nitrochlorobenzene prepared in the previous step in 25 ml of a normal solution of sodium hydroxide. Stirring was continued for 15 minutes after completion of the addition. The expected product precipitated upon dilution of the reaction mixture with iced water. After thorough draining and washing with water, the product obtained was recrystallized from alcohol.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:42]=[CH:41][C:27]([C:28]([N:30]2[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]([O:38]CC)=[O:37])[CH2:31]2)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22].C(O)C.[OH-].[Na+].Cl>O1CCCC1>[F:44][C:2]([F:1])([F:43])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:42]=[CH:41][C:27]([C:28]([N:30]2[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]([OH:38])=[O:37])[CH2:31]2)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ncc(C(F)(F)F)cn4)cc3C)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-c2ncc(C(F)(F)F)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a reaction mixture of ethyl (3R)-1-(4-((4,4,4-trifluoro-1-(2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)butyl)amino)benzoyl)piperidine-3-carboxylate (4.96 g), ethanol (16 ml) and tetrahydrofuran (16 mL) was added 1M aqueous sodium hydroxide solution (15.9 mL) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from ethyl acetate/diisopropyl ether to give the title compound (4.37 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].N1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[Cl:26]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:27]([C:22]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Cc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
2-Aminophenylacetic acid methyl ester (10.2 g, 39.45 mmol) was dissolved in DCM (200 ml). There were then added first pyridine (12.4 ml, 151.71 mmol) and 3,4-dichlorobenzenesulfonyl chloride (11.8 ml, 75.87 mmol) in DCM (50 ml). The reaction solution was stirred overnight and then diluted with DCM and washed in succession with 0.5 M KHSO4 solution, saturated NaHCO3 solution and saturated NaCl solution, dried over sodium sulfate and concentrated. Purification was carried out by column chromatography on silica gel (DCM).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:34][C:35]2[C:36]3[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[N:41][C:37]=3[N:38]=[CH:39][N:40]=2)=[CH:10][CH:9]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=3)=[O:33])=[CH:17][C:16]=2[NH:34][C:35]2[C:36]3[CH:44]=[CH:43][C:42]([CH:45]([CH3:47])[CH3:46])=[N:41][C:37]=3[N:38]=[CH:39][N:40]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(C(F)(F)F)cc4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(C(F)(F)F)cc4)ccc3Oc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 172e was dissolved in a 1:1 mixture of TFA in DCM and stirred at room temperature for 2 hrs. The solvent was removed under vacuum and the crude oil was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (85 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.75 (d, J=6.99 Hz, 6 H), 7.21 (d, J=8.09 Hz, 2 H), 7.29-7.35 (m, 2 H), 7.38 (d, J=8.82 Hz, 1 H), 8.14 (d, J=8.82 Hz, 2 H), 8.25 (d, J=8.46 Hz, 1 H), 8.40 (d, J=8.46 Hz, 3 H), 8.56 (d, J=1.84 Hz, 1 H), 9.26 (s, 1 H), 9.37 (d, J=8.82 Hz, 1 H), 10.98 (s, 1 H); MS (ESI+) m/z 559 (M+TFA+H)+; (ESI−) m/z 557 (M+TFA−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][C:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@:9]1([C:14](=[O:16])[NH:36][S:33]([C:30]2([CH3:29])[CH2:32][CH2:31]2)(=[O:35])=[O:34])[CH2:11][C@H:10]1[CH:12]=[CH2:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(C)CC1
Temperature: 85 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
To a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid (25 g, 110 mmol) in THF (300 mL) was added CDI (205 g, 127 mmol) and the reaction mass was heated at 85° C. for 1 h. The reaction mass was cooled to rt and to this reaction mass was added 1-methylcyclopropane-1-sulfonamide (17.7 g, 131 mmol) followed by DBU (33.2 mL, 33.5 mmol). The reaction mixture was stirred at rt for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH˜2 by using aq. 1.5 N HCl solution. The precipitated solid was isolated via filtration and washed with water to get desired compound (22 g, 58%) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.01-11.17 (m, 1H), 7.17-7.33 (m, 1H), 5.35-5.51 (m, 1H), 5.18-5.29 (m, 1H), 4.99-5.09 (m, 1H), 2.21 (s, 1H), 1.69 (dd, J=7.78, 5.27 Hz, 1H), 1.40 (d, J=3.01 Hz, 14H), 1.20 (dd, J=9.29, 5.27 Hz, 1H), 0.82-0.96 (m, 2H). MS: MS m/z 343 (M++1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Br:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH2:20]Br>>[Br:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH2:20][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: Clc1ccc(CBr)c(Br)c1
Product: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2Br)c1

Procedure:
1-(2-Bromo-4-chloro-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 2-bromo-1-bromomethyl-4-chloro-benzene following General Procedure A.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
To a solution of 4-bromo-2-hydroxybenzonitrile (2 g, 10 mmol) in DMF (15 mL) and was added iodomethanel (2.87 g, 20.2 mmol) and potassium carbonate (2.79 g, 20.2 mmol) at room temperature. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 4-bromo-2-methoxybenzonitrile (2.08 g) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=8.0 Hz, 1H), 7.10 (dd, J=8.4, 1.6 Hz, 1H), 7.06 (d, J=1.6 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C@@H:11]2[CH2:13][C@H:12]2[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[F:10]>CO>[F:3][C:4]1[CH:5]=[C:6]([C@@H:11]2[CH2:13][C@H:12]2[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Methanol (322.2 g) and 30% sodium hydroxide aqueous solution (65.5 g, 1.8 molar equivalents) were added to a solution of ethyl(1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxylate (48.2 wt % toluene solution, net 61.22 g, 270.6 mmol). The mixture was heated at 65° C. with stirring for 2 hours. The resultant mixture was concentrated under reduced pressure, then toluene and water were added to the concentrate. The mixture was acidified with 35% hydrochloric acid. The organic layer was separated and concentrated under reduced pressure. (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxylic acid was obtained as resultant concentrate (net 52.55 g, yield: 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C@@H:10]([CH2:13][O:14][Si](C(C)(C)C)(C)C)[CH2:9][CH2:8]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C@@H:10]([CH2:13][OH:14])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1O[C@@H](CO[Si](C)(C)C(C)(C)C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cccc2c1O[C@@H](CO)CC2
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a solution of tert-butyl(dimethyl)silyl [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl ether (4.50 g, 14.6 mmol) in tetrahydrofuran (150 mL) at 0° C. is added excess tetrabutylammonium fluoride (1.0 M in tetrahydrofuran) and the reaction mixture is allowed to stir at 22° C. for 30 min. The solvent is removed in vacuo and the residue is purified by flash column chromatography (silica, ethyl acetate:hexanes 1:1) to give 2.49 g (88%, 40% ee) of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methanol as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:25]O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]#[N:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C#N)cc1OCc1ccccc1
Yield: 87.4 %

Procedure:
3-Benzyloxy-4-methoxybenzaldehyde (50 g, 0.21 mol) was added to a solution of sodium acetate (33.9 g, 0.41 mol) and hydroxylamine hydrochloride (28.73 g, 0.41 mol) in acetic acid (200 ml) and the resulting suspension was heated to reflux for 18 h. After cooling, the reaction mixture was partitioned between CH2Cl2 and H2O and the aqueous phase was further extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and evaporated to afford the subtitle compound as a buff-coloured solid (43.9 g, 89%). Rf 0.70 (toluene/EtOAc 4/1, v/v).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[N:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24](O)=[CH:23]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:24]2[CH:25]=[N:26][C:27]3[C:22]([CH:23]=2)=[N:21][C:20]([O:19][CH3:18])=[CH:29][CH:28]=3)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: COc1ccc2ncc(O)cc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)cc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
[1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.19 mmol, 1.0 eq) is added at room temperature to a stirred solution of 6-methoxy-[1,5]naphthyridin-3-ol (37 mg, 0.19 mmol, 1.0 eq) in tetrahydrofuran (5 mL), followed by triphenylphosphine polymer-bound (3 mmol/g, 193 mg, 0.58 mmol, 3.0 eq) and diisopropyl azodicarboxylate (115 μL, 0.58 mmol, 3.0 eq). After 3 hours stirring at room temperature, the polymer-bound is filtered off and washed successively with tetrahydrofuran (5 mL), dichloromethane (5 mL) and methanol (5 mL). The resulting solution is concentrated and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 4:1:0 to 0:9:1, v/v/v) to afford {1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as an orange solid (35 mg, 33% yield).
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][C:10]2[CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH:13]=[CH:14][CH:15]=2)=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[N:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][CH:13]=3)[CH2:17][CH2:18]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(COCc2cccc(N3CCN(c4ccncc4)CC3)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCc1cccc(N2CCN(c3ccncc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
1-(3-{[(4-Methoxybenzyl)oxy]methyl}phenyl)-4-(pyridin-4-yl)piperazine (308 mg) was mixed with dichloromethane (2 ml), and TFA (1 ml) was added thereto. The reaction mixture was stirred at room temperature for 1 hour, and then the reaction mixture was concentrated under reduced pressure. To the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution and CHCl3, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography to obtain {3-[4-(pyridin-4-yl)piperazin-1-yl]phenyl}methanol (167 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[CH:15](O)=O>>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][CH:15]=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: O=CO
Product: CC1(C)C(=O)Nc2cc3[nH]cnc3cc21

Procedure:
288 mg. (1.51 mmole) 5,6-diamino-3,3-dimethylindolin-2-one and 66 mg. (1.43 mmole) formic acid are heated for 1 hour at 100° C. After the addition of a further 24 mg. (0.52 mmole) formic acid, the reaction mixture is further heated to 100° C. for 60 minutes. Thereafter, trituration is carried out with 0.5 ml. amounts of diethyl ether, followed by suction filtration. There are obtained 277 mg. (91% of theory) of the title compound in the form of pale crystals; m.p. 278°-280° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].[CH:13]([N-]C(C)C)(C)C.[Li+].IC.C([O-])(O)=O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=[O:12]
Reactant: O=C1CCc2c(F)cc(F)cc21
Reactant: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1Cc2c(F)cc(F)cc2C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
According to Scheme 3, step 1: to a solution of 4,6-difluoro-indan-1-one (5.0 g, 29.8 mmol) in dry tetrahydrofuran (100 ml) at −78° C. a 2M solution of lithiumdiisopropylamide (16.4 ml, 32.7 mmol) in tetrahydrofuran was added dropwise and the mixture was stirred for 1 h at −78° C. Then iodomethane (4.64 g, 32.7 mmol) was added and the mixture was slowly warmed to 25° C. After addition of aqueous saturated NaHCO3 the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SO4 and filtered, solvents were evaporated in vacuo. The crude product was purified by silica gel chromatography (eluting with 0% to 100% ethyl acetate in heptane to give 1.15 g of 4,6-Difluoro-2-methyl-indan-1-one (7a).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:12][N:13]([CH2:14][CH:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH3:16])[CH3:18]
Reactant: CN(C)CCCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(C)CN(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (1.0 g, 6.58 mmol), 3-dimethylamino-1-propanol (1.01 g, 9.87 mmol), and triphenylphosphine (2.6 g, 9.87 mmol) at 0° C. in THF (20 mL) was added dropwise diisopropyl azodicarboxylate (1.99 g, 9.87 mmol). After stirring for 16 h at room temperature the solution was concentrated and the residue purified by column chromatography (silica gel, methanol/dichloromethane) to yield the title compound as an oily solid (1.25 g, 5.2 mmol). MS(ESI): 238.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[N:5]=[N:6][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:8][N:9]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH:12][CH:10]([C:7]1[N:6]=[N:5][C:4]([S:3][CH3:2])=[N:9][CH:8]=1)[CH3:11])=[O:18]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CSc1ncc(C(C)N)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1ncc(C(C)NC(=O)c2cccc(Br)c2)nn1
Reaction time: 18 h
Yield: 83.8 %

Procedure:
To a stirred solution of 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethanamine hydrochloride (Intermediate 4) (10 g, 49 mmol) in N,N-dimethylformamide (100 mL) was added 3-bromobenzoic acid (11 g, 54 mmol), O-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospahte (20 g, 52 mmol) and triethylamine (24 mL, 170 mmol). After stirring for 18 hours the solution was concentrated under reduced pressure to approximately 50 mL. The solution was diluted with ethyl acetate (200 mL) and washed with 0.1N HCl (2×100 mL) and saturated sodium bicarbonate solution (100 mL). The solution was dried with magnesium sulfate and filtered, and silica gel (25 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (0:100) to ethyl acetate:hexanes (40:60) using a RediSep silica gel cartridge (120 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 3-bromo-N-{1-[3-(methylthio)-1,2,4-triazin-6-yl]ethyl}benzamide (14.5 g) as a white solid. 1H NMR (CDCl3): δ8.47(s, 1H), 7.95 (dd, J=1.8, 1.7 Hz, 1H), 7.72 (ddd, J=7.9, 1.6, 1.1 Hz, 1H), 7.64 (ddd, J=7.9, 2.0, 1.1 Hz, 1H), 7.32 (dd, J=8.0, 7.7 Hz, 1H), 7.20 (d, J=7.2 Hz, 1H), 5.47 (dq, J=7.2, 7.0 Hz, 1H), 2.68 (s, 3H), 1.70 (d, J=7.0 Hz, 3H). MS m/z 353, 355 (M+1, M+3).