Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]1)=[C:8]2[C:38]([OH:40])=O)(=[O:4])=[O:3].[C:41]1([C@@H:47]([NH2:49])[CH3:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]1)=[C:8]2[C:38]([NH:49][C@H:47]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:48])=[O:40])(=[O:3])=[O:4]
Reactant: C[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C[C@H](NC(=O)c1c(CN2CCC(N3CCOCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12)c1ccccc1
Temperature: 50 °C
Yield: 49.2 %

Procedure:
A mixture of 6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.200 g, 0.346 mmol), (1S)-1-phenylethanamine (0.063 g, 0.519 mmol), EDC (0.266 g, 1.39 mmol), HOBT (0.053 g, 0.346 mmol) and N,N-diisopropylethylamine (0.605 mL, 3.46 mmol) in N,N-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) was heated to 50° C. overnight. The solvent was removed under reduced pressure, and the residue was dissolved in DMSO and purified via HPLC (Waters, Sunfire, 30×75 mm column, 50 mL/min, 20-60% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated to afford 6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-N-[(1S)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (0.116 g, 47% yield). MS (m/z) 681.3 (M+H+).
Reaction SMILES: C([Li])(C)(C)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][N:8]=1.[I:17]I>C1COCC1.C(OCC)(=O)C.O>[Cl:6][C:7]1[CH:12]=[C:11]([I:17])[C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][N:8]=1
Reactant: COCOc1ccc(Cl)nc1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cnc(Cl)cc1I
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
Add tert-buty lithium (1.7 M in pentane, 72 mL, 123 mmol) to a solution of 2-chloro-5-methoxymethoxy-pyridine (10.8 g, 62 mmol) in THF (300 mL) at −70° C. dropwise over 10 min. Stir the resulting solution at −70° C. for 30 min. Add a solution of iodine (23 g, 92 mmol) in THF (150 mL) dropwise over 30 min. Stir the resulting solution at −70° C. for 1 hour. Remove the ice bath and allow the reaction to warm to room temperature. Dilute the mixture with ethyl acetate and water and isolate the phases. Extract the aqueous phase with two portions of ethyl acetate. Combine the organic extracts and wash with two portions of aqueous sodium thiosulfate, one portion of water, one portion of saturated aqueous sodium chloride, dry over sodium sulfate, filter and concentrate in vacuo. Triturate the resulting solid with hexane. Collect the solid by vacuum filtration and wash the solid with hexane. Dry the solid under vacuum to give the title compound (10.8 g, 58%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.98 (s, 1H), 5.43 (s, 2H), 3.40 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([CH3:21])[N:14]=1>ClCCl.O.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH:19]=[O:20])[CH:16]=[C:15]([CH3:21])[N:14]=1
Reactant: COc1cc(CO)cc(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C=O)cc(C)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 50 ml of dichloromethane containing 1.67 ml of oxalyl chloride there was added dropwise 1.36 ml of DMSO at −78° C. under a nitrogen atmosphere, and the mixture was stirred at −78° C. for 30 minutes. Next, 10 ml of a dichloromethane solution containing (2-methoxy-6-methyl-pyridin-4-yl)methanol was added dropwise, and the mixture was stirred at −78° C. for 30 minutes. After then adding 6.7 ml of triethylamine to the reaction mixture over a period of 10 minutes, the mixture was stirred for 30 minutes while raising the temperature from −78° C. to room temperature. Water was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.9 g) as a light yellow oil.
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[CH2:19]([O:21][C:22]1[C:31]([O:32][CH2:33][CH3:34])=[C:30]([O:35][CH2:36][CH3:37])[C:29]([N+:38]([O-:40])=[O:39])=[C:28]2[C:23]=1[CH2:24][O:25][C:26]2=[O:27])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]1[CH:24]1[C:23]2[C:28](=[C:29]([N+:38]([O-:40])=[O:39])[C:30]([O:35][CH2:36][CH3:37])=[C:31]([O:32][CH2:33][CH3:34])[C:22]=2[O:21][CH2:19][CH3:20])[C:26](=[O:27])[O:25]1
Reactant: COc1cc2c(c(OC)c1OC)C=[N+](C)CC2
Reactant: CCOc1c2c(c([N+](=O)[O-])c(OCC)c1OCC)C(=O)OC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOc1c(OCC)c2c(c([N+](=O)[O-])c1OCC)C(=O)OC2C1c2c(cc(OC)c(OC)c2OC)CCN1C

Procedure:
235 g (0.647 mole) of 2-methyl-6,7,8-trimethoxy-3,4-dihydro-isoquinolinium iodide (described in J. Chem. Soc. 1951, 1150), 201.4 g of 4,5,6-triethoxy-7-nitrophthalide and 107 g of potassium carbonate are added to 1.240 liters of methanol. After stirring for 24 hours at a temperature below the boiling point of the solvent, 730 ml of water is added and the reaction solution is allowed to crystallise. The crystals are collected by filtration, washed with water and dried, providing 270 g of C27H34O10N2.
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][C:5]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:3]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:4][C:5]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:35][CH:34]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(Br)cn3)cccc2s1
Reactant: OB(O)c1ccc(F)cc1
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: C1COCCO1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(-c4ccc(F)cc4)cn3)cccc2s1
Temperature: 160 °C

Procedure:
To a mixture of N-{4-[5-bromo-4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazol-2-yl}-acetamide, (Example 145(b)), (51 mg, 0.1 mmol) and 4-fluorophenylboronic acid (18 mg, 0.13 mmol, Aldrich) in dioxane (1 mL) was added Pd(PPh3)4 (6 mg, 0.005 mmol, Aldrich) and aqueous Na2CO3 (16 mg in 0.2 mL of water). The reaction mixture was heated in microwave synthesizer at 160° C. for 30 min. Purification by silica gel chromatography (EtOAc/hexanes) gave the title compound as a white solid. MS (ESI, pos. ion) m/z: 524 (M+1). Mp: 112.3–130.1° C.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:8])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[C:1]([NH:4][C:5](=[O:8])[CH2:6][S:7][C:16](=[O:17])[CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)NC(=O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC(=O)CSC(=O)Cc1ccccc1

Procedure:
One-half of the aqueous solution prepared in Step A. above was taken and ice was added while nitrogen was bubbled through the stirred solution. There was then added 4.65 g. (0.03 mole) of phenylacetyl chloride, and after that, with good stirring, there was added over 20 minutes a solution of 1.2 g. (0.03 mole) of sodium hydroxide in 30 ml. of water. Ice was added in intervals while the reaction mixture was stirred an additional hour. The water was then decanted from the solid product, after which it was triturated with cold water and decanted, then triturated with 0.5 ml. of acetic acid in 50 ml. of cold water and decanted. The solid was taken up in dichloromethane, dried, then evaporated to an oil. The oil was triturated with petroleum ether, after which it solidified, yielding 3.2 g. The product was recrystallized from dichloromethane/petroleum ether to yield 2.0 g. This material was chromatographed on a Waters high pressure liquid chromatography apparatus using silica gel and hexane: ethylacetate (2:1) as the eluent. A total of 800 mg. of product was obtained having an m.p. of 123°-124° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10](=[O:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>CN(C=O)C.[Cl-].[NH4+]>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][N:17]=[C:16]2[O:12][C:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][N:9]=1
Reactant: O=C1CC(c2ccccc2)=NN1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cc(-c4ccccc4)[nH]n3)c2cc1OC
Temperature: 60 °C
Yield: 83.2 %

Procedure:
3-Phenyl-4,5-dihydro-1H-pyrazol-5-one (160 mg, 1 mmol), (J. Org. Chem., 1967, 32, 3321-3324), was added in portions over 10 minutes to a suspension of sodium hydride (40 mg, 1 mmol, prewashed with THF) in DMF (3 ml) under nitrogen. After stirring for 20 minutes at ambient temperature 4-chloro-6,7-dimethoxyquinazoline (112 mg, 0.5 mmol) was added and the mixture was heated for 20 minutes at 60° C. After cooling, the mixture was diluted with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10). The volatiles were removed by evaporation, the residual solid was dissolved in methylene chloride and 3M ethereal hydrogen chloride (1 ml) was added. After removal of the solvent by evaporation, the residue was triturated with ether, collected by filtration and dried under vacuum to give 6,7-dimethoxy-4-(5-phenylpyrazol-3-yloxy)quinazoline (145 mg, 75%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[CH:34]([SH:37])([CH3:36])[CH3:35]>C1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([S:37][CH:34]([CH3:36])[CH3:35])=[N:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)S
Reactant: O=C(Nn1cncn1)c1ccc(F)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)SC(=Nn1cncn1)c1ccc(F)cc1

Procedure:
A solution of 1.83 g (8.9 mmol) of 4-fluoro-N-(1H-1,2,4-triazol-1-yl)-benzamide and 1.05 g (8.9 mmol) of phosphorous pentachloride and 20 mL of phosphorous oxychloride is heated at reflux for 1 h. Solvent is stripped and the residue dissolved in 30 mL of benzene. Triethylamine (1.4 mL, 10 mmol) and 1.0 g (13 mmol) of isopropyl mercaptan is added and the solution is heated at reflux for 4 h. The solution is diluted with ethyl acetate and washed with water and brine. Drying (MgSO4) and removal of solvent gives product which is purified by chromatography on silica gel.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2ccc3ccccc32)cc1
Reaction time: 12 h
Yield: 66.1 %

Procedure:
Soc., Jpn., 55:1116-1120 (1982)). The above general procedure was followed using of 4-chlorotoluene (126 mg, 1.00 mmol), indole (117 mg, 1.00 mmol), 4 mol % Pd(dba)2, 4 mol % tri-t-butylphosphine, and cesium carbonate (1.50) in 1.0 mL of toluene. After 12 hours at 100° C., the reaction mixture was adsorbed onto silica gel and chromatographed with 10% ethyl acetate/hexanes to give 137 mg (66%) of N-(4-methylphenyl)indole. 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J=7.8 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.40 (d, J=7.8 Hz, 2H), 7.34-7.33 (m, 3H), 7.23 (t, J=7.8 Hz, 1H), 7.18 (t, J=7.8 Hz, 1H), 5 6.68 (d, J=2.4 Hz, 1H), 2.46 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 137.4, 136.4, 136.1, 130.2, 129.3, 128.2, 124.4, 122.3, 121.2, 120.3, 110.6, 103.3, 21.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([CH2:15][OH:16])[CH2:13][OH:14])[O:8][CH2:7][CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:5]2.[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[O:29][CH2:28][C:27]([CH:34]=O)=[CH:26]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[O:29][CH2:28][C:27]([CH:34]1[O:16][CH2:15][CH:12]([C:11]3[CH:10]=[C:9]4[C:4]([CH2:5][CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:7][O:8]4)=[CH:3][C:2]=3[F:1])[CH2:13][O:14]1)=[CH:26]2
Reactant: O=CC1=Cc2cc(F)cc(F)c2OC1
Reactant: CCCCCC1COc2cc(C(CO)CO)c(F)cc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCCC1COc2cc(C3COC(C4=Cc5cc(F)cc(F)c5OC4)OC3)c(F)cc2C1

Procedure:
1.30 g (4.39 mmol) of 2-(6-fluoro-3-pentylchroman-7-yl)propane-1,3-diol and 900 mg (4.59 mmol) of 6,8-difluoro-2H-chromene-3-carbaldehyde are dissolved in 50 ml of dichloromethane and heated under reflux on a water separator for 5 h in the presence of 50 mg of p-toluenesulfonic acid. The solution is subsequently washed with sat. sodium hydrogencarbonate soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is recrystallised from heptane/toluene, giving 6,8-difluoro-3-[5-(6-fluoro-3-pentylchroman-7-yl)-1,3-dioxan-2-yl]-2H-chromene (trans:cis=80:20) as a colourless solid.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:50])([F:52])[F:51])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCOc1ccccc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CCCOc1ccccc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Ethyl 4-(2′-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-yloxy)-butyrate (157 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-(2′-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-yloxy)-butyric acid (146 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (197 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2′-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-yloxy)-butyric acid sodium salt (146 mg). MS (m/z): 741 [M−Na]−
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:17][CH:18]([C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27])[CH3:19].[N:28]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:35][CH2:34][CH2:33][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:17][CH:18]([C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26])[CH3:19]
Reactant: NCCN1CCCC1
Reactant: CC(Oc1cc(-c2ccc(C(=O)O)cc2)cnc1N)c1c(Cl)cccc1Cl
Product: CC(Oc1cc(-c2ccc(C(=O)NCCN3CCCC3)cc2)cnc1N)c1c(Cl)cccc1Cl

Procedure:
4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide was prepared following procedure 4 starting from 4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid and 2-pyrrolidin-1-yl-ethylamine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.C(N(C(C)C)CC)(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:34]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCNC(=O)c3ccccc3)c3ccccc23)CC1
Reaction time: 19 h
Yield: 75.2 %

Procedure:
tert-Butyl 6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0401 g, 0.122 mmol) was dissolved in THF (2 mL) at rt under N2. Diisopropylethylamine (0.028 mL, 0.0205 g, 0.158 mmol, 1.30 equiv.) and benzoyl chloride (0.017 mL, 0.0205 g, 0.146 mmol, 1.20 equiv.) were added, then the reaction mixture was stirred for 19 h. Citric acid (10%) was added and the reaction mixture was stirred for 15 min. The reaction mixture was extracted with EtOAc and the organic layer was washed sequentially with 10% citric acid, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product (0.056 g) was chromatographed (SiO2 25 g, eluted with 1:1 hexane:EtOAc) to give tert-butyl 6-[2-(benzoylamino)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0398 g) in 75% yield. 1H NMR (300 MHz, CDCl3) δ 1.45, 1.48, 2.96-3.05, 3.60-3.70, 3.74, 4.36-4.42, 6.29, 7.10-7.19, 7.31-7.43, 7.46-7.53, 7.63; MS (ESI+) for C26H31N3O3 m/z 434.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=1)[CH3:2].Cl[C:36]([O:38][CH3:39])=[O:37]>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:16]=2[CH2:25][N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:36]([O:38][CH3:39])=[O:37])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CNCc2ccccc2)c1
Reactant: COC(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-(benzylamino-methyl)-4-trifluoromethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and methyl chloroformate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12>ClCCl.C(O)(C(F)(F)F)=O>[F:25][C:19]1[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1)nn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.1 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (450 mg, 0.86 mmol, 1.00 equiv) in dichloromethane (40 mL) and CF3COOH (10 mL). The resulting solution was stirred for 3 h at 25° C. and then concentrated under vacuum. The resulting solution was diluted with 50 mL of dichloromethane and washed with aqueous sodium bicarbonate and brine. The organics were dried over anhydrous sodium sulfate and concentrated under vacuum to give 400 mg (crude) of 3-[4-(2,3-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.