Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[C:3]([O:7][C:8](=[O:25])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C:18]2([CH3:24])[CH3:23])=[CH:12][N:11]=1)([CH3:6])([CH3:5])[CH3:4].[C:26](=O)([O-])[O-].[K+].[K+]>COCCOC>[C:3]([O:7][C:8](=[O:25])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH3:26])[CH2:19][C:18]2([CH3:24])[CH3:23])=[CH:12][N:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCNCC2(C)C)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CI
Product: CN1CCN(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(C)(C)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
Methyl iodide (954 μL, 15.3 mmol, 1.3 equiv) was added dropwise to a suspension of [5-(2,2-dimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (Step 109.3) (3.8 g, 11.8 mmol) and potassium carbonate (2.13 g, 15.4 mmol, 1.3 equiv) in DME (25 mL). The reaction mixture was heated to 50° C., stirred for 2 h, allowed to cool, quenched by addition of a H2O and extracted with DCM. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 98:1:1) to afford 1.94 g of the title compound as an off-white solid. Title compound: ESI-MS: 335.3 [M+H]+; TLC: Rf=0.31 (DCM/MeOH, 9:1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:50])[C:23]([CH3:49])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:50])[C:23]([CH3:49])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccc(OC)c3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
Piperidine (0.096 g, 1.128 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.324 g, 1.692 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-methoxyphenoxy)benzoic acid (0.247 g, 0.564 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.165 g, 0.327 mmol, 58%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C@H:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH2:8][C@H:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][NH:5]1.[CH3:25][O:26][CH2:27][CH2:28]Br>CN(C)C=O>[CH3:25][O:26][CH2:27][CH2:28][N:5]1[CH2:6][C@H:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][CH2:9][C@@H:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](c2ccccc2)CNC1=O
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1C[C@H](c2ccccc2)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 6.2 mg, 0.158 mmol) was added to a solution of tert-butyl (3R,6R)-2-oxo-6-phenylazepan-3-ylcarbamate (40 mg, 0.131 mmol) and 2-bromoethyl methyl ether (0.013 mL, 0.138 mmol) in N,N-dimethylformamide (2 mL) at 0° C. After addition, the mixture was allowed to warm to ambient temperature. After 4 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (41 mg). MS 363 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=[O:8].[H-].[Na+].[CH3:12]I.O>CN(C)C=O>[CH3:12][O:8][C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: Cn1cccc1C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The solution of 1,325 g of 1-methylpyrrole-2-carboxylic acid in 2,400 ml of dimethylformamide is added to the suspension prepared from 568.5 g of 50% sodium hydride in mineral oil and 2,400 ml of dimethylformamide, while stirring under nitrogen and cooling with ice. Thereupon 1,000 ml of dimethylformamide are added, followed by 4,316 g of methyl iodide while stirring and keeping the temperature below 88°. Stirring is continued overnight at room temperature, whereupon the mixture is cooled to 10° and combined with 10,600 ml of water. It is extracted thrice with 5,300 ml of diethyl ether, the extract washed with 5,300 ml of 10% aqueous sodium carbonate and 5,300 ml of water, dried and evaporated, to yield the 1-methylpyrrole-2-carboxylic acid methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4](C1C=CC(C)=CC=1)=[O:5].O.C1(C)C=CC(S(O)(=O)=[O:26])=CC=1.OO>O1CCCC1.O>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4]([OH:5])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2Cl)cc1
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)cc1Cl
Temperature: 20 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
12.4 g (0.05 mol) of 2-chloro-4-fluoro-4'-methylbenzophenone in 30 ml of tetrahydrofuran were added dropwise to a solution of 19.0 g (0.1 mol) of toluene-4-sulfonic acid hydrate and 3.8 g (0.1 mol) of 90% hydrogen peroxide in 100 ml of tetrahydrofuran. The mixture was subsequently stirred for 12 h at 20° C. and then diluted with 100 g of water. Further processing as described in Example 22 gave 7.6 g (43.5 mmol, 87%) of 2-chloro-4-fluorobenzoic acid (m.p. 181°-186° C.).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH:28]1[CH:29]=[CH:30][C:25]([C:24]([O:23][CH2:1][C@H:2]2[O:7][CH:6]([O:8][C@:9]3([CH2:18][O:19][C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:13][C@H:12]([CH2:14][O:15][C:24]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@@H:11]([OH:16])[C@@H:10]3[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]2[OH:22])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:27]=1
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O[C@@H]1[C@H](O)[C@@H](O)C(O[C@]2(COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](O)[C@@H]2O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.8 %

Procedure:
The procedure of Hough, Mufti, and Khan, Carbohydrate Res., Vol. 21, pp. 144-147 (1972), is modified as shown below. To a solution of 15 g of sucrose (43.82 mmol) in 225 ml of pyridine, a solution of 54.95 g of trityl chloride (197.1 mmol, 4.5 equiv.) in 50 ml of pyridine is added dropwise over a period of 30 minutes. The reaction mixture is then stirred at room temperature for 4 days. After 4 days, the solution is concentrated to a brown syrup, which is dissolved in methylene chloride. This solution is further washed successively with 1M hydrochloric acid, saturated sodium bicarbonate solution, water, and brine and then dried over anhydrous sodium sulfate. The methylene chloride solution is then concentrated in vacuo and the residue applied on a column of silica gel packed in methylene chloride:acetone (4:1) and eluted with that solvent. The 1',6,6'-tri-O-tritylsucrose is obtained (28.59 g) in 58.8% yield as an off-white solid with a melting point of 127° to 130° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=O)[CH2:11][CH3:12])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:11][CH3:12])=[CH:20][CH:19]=1
Reactant: CCC(=O)c1ccc2[nH]ncc2c1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
To a stirred mixture of Zn power (1.65 g, 10.0 eq) in dry THF at rt under N2 was slowly added TiCl4 (4.0 eq, 1.1 mL). The resulting mixture was heated at reflux for 1 h and cooled to rt. A mixture of 1-(1H-indazol-5-yl)propan-1-one (1.3 g, 3.0 eq) and (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (0.7 g, 1.0 eq) in dry THF was added, warmed to 80° C., refluxed for additional 1 h, quenched with Na2CO3 (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the title product (0.3 g, 70%, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.53 (s, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.71-6.88 (m, 1H), 6.72 (d, J=8.8 Hz, 2H), 6.43 (d, J=8.8 Hz, 1H), 4.35 (t, J=7.2 Hz, 1H), 4.24 (t, J=7.2 Hz, 1H), 3.83 (t, J=6.0 Hz, 1H), 3.70 (t, J=6.0 Hz, 1H), 2.47-2.54 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(OC([N:8]([O:30]C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:20]=3[N:19]=[C:18]2[CH2:28][CH3:29])=[CH:13][CH:12]=1)=O)(C)(C)C.Cl.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:26][C:24]1[C:23]([Cl:27])=[CH:22][C:21]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH:8][OH:30])=[CH:16][CH:15]=3)[C:18]([CH2:28][CH3:29])=[N:19][C:20]=2[CH:25]=1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCNO)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-[4-(2-{(tert-butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino}ethyl)phenyl]-5,6-dichloro-2-ethyl-1H-benzimidazole (step 1, 174 mg, 0.3 mmol) and 2N hydrochloric acid (3 mL) in ethyl acetate (20 mL) was stirred at room temperature for 1 day. The reaction mixture was poured into water (100 mL), neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to afford 162 mg (quant.) of the title compound as a yellow oil: 1H-NMR (CDCl3) δ 10.35 (2H, br.s), 7.89 (1H, s), 7.46–7.50 (2H, m), 7.29 (2H, d, J=6.8 Hz), 7.17 (1H, s), 3.37 (2H, t, J=6.9 Hz), 3.12 (2H, t, J=6.9 Hz), 2.80 (2H, q, J=6.9 Hz), 1.34 (3H, m).
Reaction SMILES: [BH4-].[Na+].CC(O)C.[CH:7]([C:9]1[C:17]2[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=O.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>[C].[Pd].O>[CH3:7][C:9]1[C:17]2[C:12](=[C:13]([NH:18][S:31]([C:28]3[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=3)(=[O:33])=[O:32])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1c[nH]c2c([N+](=O)[O-])cccc12
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1c[nH]c2c(NS(=O)(=O)c3ccc(S(C)(=O)=O)cc3)cccc12
Yield: 61 %

Procedure:
580 mg (15.3 mmol) of sodium borohydride and 150 mg of 10% palladium-carbon were added to a 2-propanol suspension (25 ml) containing 300 mg (1.58 mmol) of 3-formyl-7-nitro-1H-indole, followed by refluxing for 6 hours. After water was added to the reaction system, the catalyst was filtered off. The filtrate was extracted with ethyl acetate, and the extract was washed with brine and then dried over magnesium sulfate. The solvent was evaporated, and the residue was dissolved in 5 ml of pyridine. The mixture was reacted and treated with 170 mg (0.67 mmol) of 4-(methylsulfonyl)benzenesulfonyl chloride in the same manner as in Example 1a, to give 149 mg of the title compound.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([NH:20][CH2:21][C:22]1[CH:23]=[C:24]([CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][C:28]([C:32]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)=[O:33])=[C:27]2[OH:43])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C(=O)CCC1>[CH2:13]([N:20]1[CH2:21][C:22]2[C:31]3=[C:26]([C:27](=[O:43])[C:28]([C:32]([NH:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=4)=[O:33])=[CH:29][N:30]3[C:1]1=[O:2])[CH:25]=[C:24]([CH2:44][N:45]1[CH2:46][CH2:47][O:48][CH2:49][CH2:50]1)[CH:23]=2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(CNCc3ccccc3)cc(CN3CCOCC3)cc2c1O
Solvent: CN1CCCC1=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)CN(Cc1ccccc1)C2=O
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (82 mg) in NMP (2.0 mL) is added over 15 min to a solution of 8-((benzylamino)methyl)-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (Preparation 29, 106 mg) in NMP (6 mL). After an additional 15 min, the solvent is removed under reduced pressure and the residual solid is triturated with methanol to afford 93 mg of the title compound. Physical characteristics: M.p. 201-204° C.; 1H NMR (CDCl3) δ2.44, 3.58, 3.70, 4.67, 4.73, 4.87, 7.3-7.45, 7.51, 8.19, 9.90, 10.1; Anal. Found: C, 66.67; H, 5.31; N, 9.99; Cl, 6.35.
Reaction SMILES: O.[C:2](=[O:5])([O-:4])[O-].[K+].[K+].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[N:21]3[N:22]=[C:23]([N:25]4C(=O)[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]4=[O:35])[N:24]=[C:20]3[N:19]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:18]([CH3:46])=[C:17]2[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:12][CH:11]=1)#[N:9].Cl>C(O)C>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[N:21]3[N:22]=[C:23]([NH:25][C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=4[C:2]([OH:4])=[O:5])=[O:35])[N:24]=[C:20]3[N:19]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:45])[F:44])[CH:37]=3)[C:18]([CH3:46])=[C:17]2[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:14][CH:15]=1)#[N:9]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(N3C(=O)c4ccccc4C3=O)nn2C1c1ccc(C#N)cc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(NC(=O)c3ccccc3C(=O)O)nn2C1c1ccc(C#N)cc1
Temperature: 50 °C
Yield: 87.4 %

Procedure:
Water (1 ml) and potassium carbonate (23.1 mg, 167 μmol, 2 eq.) were added to a solution of ethyl 7-(4-cyanophenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methyl-4-[3-(trifluoromethyl)-phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (50.0 mg, 83.5 μmol; Example 1) in ethanol (6.25 ml). In a closed, pressure-proof glass tube, the reaction mixture was heated at 50° C. 1 N hydrochloric acid (670 μl, 670 μmol, 8 eq.) was then added, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Gromsil C18 column, 10 μm, 250×30 mm; mobile phase: acetonitrile-water-0.1% TFA 10:90→100:0). This gave the product as a solid (45 mg, 87% of theory).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[N:13]=[C:14]([CH2:17][N:18]4[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]4)[S:15][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[N:13]=[C:14]([CH2:17][N:18]4[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]4)[S:15][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(OCC4CC4)c3)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnn(Cc2nc(-c3cccc(OCC4CC4)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution (4 mL) of the compound (340 mg, 0.89 mmol) obtained in Example 47a in ethanol was added 2N aqueous sodium hydroxide solution (1.8 mL, 3.6 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (180 mg, 57%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][CH2:14][CH2:13][CH2:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: OCCCc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Cl)c(CCCBr)c1
Yield: 94.3 %

Procedure:
Compound 57-2 (6.32 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (7.64 g) and N-bromosuccinimide (5.18 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (7.53 g) as a colorless oil.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:16])[CH2:8][CH:9]([CH3:15])[C:10](OCC)=[O:11].[C:23]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:16]([CH2:29][C:25]2[CH:24]=[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][CH:26]=2)[C:10](=[O:11])[CH:9]([CH3:15])[CH2:8]1
Reactant: CCOC(=O)C(C)CC(N)c1ccccc1-c1ccccc1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Product: CC1CC(c2ccccc2-c2ccccc2)N(Cc2cccc(-c3ccccc3)c2)C1=O

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-([1,1′-biphenyl]-2-yl)-4-amino-2-methylbutanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.05 min.; [M+H]+: 417.80 g/mol.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:29]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[CH:29]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cncc(N2CCOCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cncc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a suspension of 60% sodium hydride (535 mg, 13.7 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (1.65 g, 13.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 1.38 mmol) and 1,1′-carbonyldiimidazole (442 mg, 2.76 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [3,3-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (256 mg, 40%) as a white solid: LC/MS m/e calcd for C24H30N4O4S (M+H)+: 471.6, observed: 471.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Clc1ccc(CNc2ccc(Br)cn2)cc1
Reaction time: 8 h

Procedure:
5-Bromo-pyridin-2-ylamine (9, 4.0 g, 23 mmol) was dissolved in 100 mL of acetonitrile and 4-chloro-benzaldehyde (10, 3.2 g, 23 mmol) was added. Triethylsilane (11.0 mL, 69 mmol) was added followed by trifluoroacetic acid (5.0 mL, 65 mmol). The reaction was heated to reflux and stirred overnight. The solvent was removed under vacuum and the residue was poured into a solution of 1M potassium carbonate. This was extracted with ethyl acetate and the organic portion was isolated and washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting solid was washed with ether to give the desired compound. The remaining material was purified with silica gel chromatography eluting with a gradient of 0-25% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide additional compound (11, 6.36 g, 92%).