Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([N+:17]([O-:19])=[O:18])=[C:7]([CH:16]=1)[O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1.C([O:22][C:23](=O)[C:24]([F:27])([F:26])[F:25])C.C(N(CC)CC)C>CO>[N+:17]([C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:16][C:7]=1[O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:23](=[O:22])[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:14]1)([O-:19])=[O:18]
Reactant: N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1)C(F)(F)F
Reaction time: 8 h

Procedure:
A reaction mixture of 0.071 g trans-4-(5-fluoro-2-nitro-phenoxy)-cyclohexylamine hydrochlorid, 0.05 g ethyltrifluoroacetate and 0.075 g triethylamine in 2 ml methanol was stirred overnight. The mixture was concentrated and partitioned between 5 ml EtOAc and 5 ml water. The organic phase was washed with water, HCl solution (2M) and water. The organic phase was dried and the solvent evaporated.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:17][CH2:16][C@H:15]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@H:14]2[OH:28])(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Li+]>CN(C)C=O>[N:29]([CH2:12][C@@H:13]1[O:17][CH2:16][C@H:15]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C@H:14]1[OH:28])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CS[C@H]2CO[C@@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H]2O)cc1
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2CO[C@@H](CN=[N+]=[N-])[C@@H]2O)cc1
Temperature: 70 °C
Reaction time: 65 h
Yield: 32.6 %

Procedure:
A mixture of 2.0 g of product from Example 324, 0.460 g of lithium azide and 2 ml of N,N-dimethylformamide is stirred at 70° C. for 65 hours. The reaction mixture is concentrated in vacuo. The residue is purified by chromatography (Silica gel: 30% ethyl acetate/hexane) to give 0.454 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][O:18][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCCCC2C[C@H]1CO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2CC3CCCCC3N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a stirred solution of [1-tert-butoxycarbonyl-(2S)-octahydroindolyl]methanol (947 mg, 3.7 mmol), methyl 4-hydroxybenzoate (565 mg, 3.7 mmol), and Ph3P (1.2 g, 4.5 mmol) in THF (10 ml) was added DIAD (984 mg, 4.5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (9/1, v/v) as eluent to give methyl 4-[1-tert-butoxycarbonyl-(2S)-octahydroindolylmethoxy]benzoate (700 mg, 50%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.10-2.25 (m, 11H), 1.45 (s, 9H), 3.88 (s, 3H), 3.70-4.20 (m, 3H), 4.36 (br s, 1H), 6.94 (d, J=8.8H z, 2H), 7.96 (d, J=8.5H z, 2H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[C:12]([N:16]=[C:17]=[S:18])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([NH:16][C:17]([NH:1][C@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4])=[S:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@@H](CO)Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccccc1
Yield: 98.8 %

Procedure:
The process is performed as in Example 2, starting with 5 g of (R)-(+)-2-amino-3-phenyl-1-propanol in 50 cm3 of ethanol and 5.7 g of tert-butyl isothiocyanate at a temperature in the region of 20° C. for 16 hours. After an identical work-up, 8.7 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(phenylmethyl)ethyl]thiourea are obtained in the form of a white solid melting at 107° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[NH:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1.CCN(CC)CC.[CH2:29]([O:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>C(Cl)Cl>[CH2:29]([O:36][C:37]([N:14]1[C@H:13]([C:11](=[O:12])[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:20])([F:1])[F:21])[CH:5]=2)[CH2:17][CH2:16][C@@H:15]1[CH2:18][OH:19])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-5-hydroxymethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (797 mg, 2.62 mmol) (prepared as described in Scheme B3) in CH2Cl2 (10 mL) was added under nitrogen atmosphere Et3N (440 μl, 3.14 mmol) and benzylchloroformate (406 μl, 2.88 mmol) and the mixture was further stirred at RT overnight. CH2Cl2 and HCl 0.1N were added, the layers were separated and the aqueous one re-extracted with CH2Cl2. The crude organic extracts were washed with brine dried over Na2SO4, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 1:1) to give the title compound. MS (LC-MS): 439 [M+H]+; tR (HPLC conditions b) 4.88 min.
Reaction SMILES: [CH2:1]([C:3]1([O:35][C:36](=[O:45])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)[CH3:2].[CH:46]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][CH2:47]1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:38]([O:37][C:36]([O:35][C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH2:26][CH2:27][CH2:28][O:29][C:50]([CH:46]2[CH2:49][CH2:48][CH2:47]2)=[O:51])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(Cl)C1CCC1
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)C1CCC1
Temperature: 21 °C
Reaction time: 5 h

Procedure:
A mixture of Compound 53 (70 mg, 0.11 mmol), 4-dimethylaminopyridine (27 mg, 0.22 mmol), and cyclobutanecarbonyl chloride (26 mg, 0.22 mmol) in 2.0 mL of dichloromethane was stirred at 21° C. for 5 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford a crude product, which was chromatographed to give the desired product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][N:3]=[CH:2]1.[N:14]1[C:22]2[C:17]3[C:18](=[CH:23][CH:24]=[CH:25][C:16]=3[C:15]=1S)[CH:19]=[CH:20][CH:21]=2>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][O:12][CH3:13])[C:15]2[C:16]3[CH:25]=[CH:24][CH:23]=[C:18]4[C:17]=3[C:22](=[CH:21][CH:20]=[CH:19]4)[N:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: SC1=Nc2cccc3cccc1c23
Reactant: COCCNCCCn1ccnc1
Solvent: CCO
Product: COCCN(CCCn1ccnc1)C1=Nc2cccc3cccc1c23

Procedure:
The reaction of 2-methoxyacetyl chloride and 3-(1H-imidazol-1-yl)propanamine in the presence of triethylamine leads to the formation of N-(3-(1H-imidazol-1-yl)propyl)-2-methoxyacetamide, which by reduction with borane gives N-(3-(1H-imidazol-1-yl)propyl)-2-methoxyethylamine. The latter amine reacts with molar equivalents of benz(cd)indol-2-thiol and mercuric acetate in refluxing ethanol, under the conditions of Example 55 to yield the title compound.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH2:19][N:20]([C:23]([CH:25]2[CH2:27][CH2:26]2)=[O:24])[CH2:21][CH3:22])[CH:11]=1)C.[Li+].[OH-].CO>C1COCC1>[CH:25]1([C:23]([N:20]([CH2:19][C:13]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=2[C:10]2[CH:11]=[C:6]([CH2:5][C:4]([OH:28])=[O:3])[CH:7]=[N:8][CH:9]=2)[CH2:21][CH3:22])=[O:24])[CH2:27][CH2:26]1
Reactant: CCOC(=O)Cc1cncc(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1cc(F)ccc1-c1cncc(CC(=O)O)c1)C(=O)C1CC1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
(5-{2-[(N-Cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-fluoro-phenyl}-pyridin-3-yl)-acetic acid ethyl ester (0.202 g, 0.53 mmol) was dissolved in THF (5.25 mL) and treated with 1N aqueous LiOH (2.63 mL, 2.63 mmol) and a small amount of MeOH. The reaction was stirred at 35° C. for 30 minutes. The mixture was concentrated, and the residue was diluted with H2O and washed with EtOAc. The aqueous layer was acidified with 1N aqueous HCl to pH 6 and extracted with EtOAc, and the combined organic layers were washed with H2O and brine, and then dried over Na2SO4, filtered, and concentrated to give Compound 23.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[C:33]([N:34]=2)=[CH:32][CH:31]=[C:30]([C:35]2([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:37][CH2:36]2)[N:29]=3)=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[S:27][C:28]4[C:33]([N:34]=3)=[CH:32][CH:31]=[C:30]([C:35]3([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36][CH2:37]3)[N:29]=4)=[CH:24][CH:25]=2)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: Fc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2)C[C@H]1C(=O)O
Temperature: 95 °C

Procedure:
A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (162.1 mg, 0.701 mmol) in DMF (4.0 mL) was slowly added to a suspension of sodium hydride (60% w/w in mineral oil) (58 mg, 1.45 mmol) in DMF (4.0 mL), and the resulting mixture was heated at 95° C. for 5 min. 2-(4-Fluorophenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine (75.3 mg, 0.217 mmol) was then added, and the resulting solution was heated at 95° C. for 18 h. The reaction mixture was subsequently cooled to 25° C. and diluted with EtOAc (5 mL). Excess NaH was quenched with water (5 mL), and the resulting mixture was diluted with 0.1N aq. HCl (40 mL) and extracted with EtOAc. The combined extracts were sequentially washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenoxy)pyrrolidine-2-carboxylic acid as a yellow solid. MS (ESI) m/z: Calculated: 557.2; Observed: 557.8 (M++1).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([O:9][C:10]([C:12]1[C:18]2[NH:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][C:25]=3[C:17]=2[C:16]([CH3:28])([CH3:27])[CH2:15][N:14]([C:29](=[O:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:13]=1)=[O:11])[CH3:8].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:7]([O:9][C:10]([C:12]1[C:18]2[NH:19][C:20]3[CH:21]=[C:22]([O:26][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[CH:23]=[CH:24][C:25]=3[C:17]=2[C:16]([CH3:28])([CH3:27])[CH2:15][N:14]([C:29](=[O:37])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(O)ccc21
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(OC(=O)N(C)C)ccc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
Dimethylcarbamoyl chloride (0.2 mL, 2.17 mmol) was added dropwise to a stirred solution of 3-(4-fluorobenzoyl)-8-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (199 mg, 0.47 mmol), 4-dimethylaminopyridine (DMAP) (20 mg), and triethylamine (0.8 mL, 5.74 mmol) in anhydrous DCM (15 mL) at 0° C. under nitrogen, and the resulting mixture was stirred at 50° C. for 5 hours. The solvents were removed in vacuo, and the residue was purified by chromatography on silica gel eluting with DCM-20% MeOH/DCM (90:10) to give the title compound (171 mg, 74%); 1H-NMR (CDCl3): δ 10.62 (1H, s), 7.78 (s, 1H), 7.74 (1H, d), 7.63-7.59 (2H, m), 7.16-7.10 (3H, m), 6.84 (1H, dd), 4.24 (2H, q), 4.08 (2H, brs), 3.14 (3H, s), 3.03 (3H, s), 1.59 (6H, s), 1.23 (3H, t); MS (ES): 494 (MH+).
Reaction SMILES: O=[C:2]1C2C=NN(C3CCCCO3)C=2C2C=CC(C3C(NC(=O)C)=NC=CC=3)=CC=2[N:3]1CC(F)(F)F.[O:36]=[C:37]1[C:46]2[CH2:47][N:48](C3CCCCO3)[NH:49][C:45]=2[C:44]2[CH:43]=[CH:42][C:41]([C:56]3[C:57]([NH:62][C:63](=[O:65])[CH3:64])=NC=[CH:60][CH:61]=3)=[CH:40][C:39]=2[N:38]1[CH2:66][C:67]([F:70])([F:69])[F:68].[ClH:71]>O>[ClH:71].[O:36]=[C:37]1[C:46]2[CH:47]=[N:48][NH:49][C:45]=2[C:44]2[CH:43]=[CH:42][C:41]([C:56]3[CH:61]=[CH:60][N:3]=[CH:2][C:57]=3[NH:62][C:63](=[O:65])[CH3:64])=[CH:40][C:39]=2[N:38]1[CH2:66][C:67]([F:68])([F:69])[F:70]
Reactant: CC(=O)Nc1ncccc1-c1ccc2c3c(cnn3C3CCCCO3)c(=O)n(CC(F)(F)F)c2c1
Reactant: CC(=O)Nc1ncccc1-c1ccc2c3c(c(=O)n(CC(F)(F)F)c2c1)CN(C1CCCCO1)N3
Agent: Cl
Solvent: O
Product: CC(=O)Nc1cnccc1-c1ccc2c3[nH]ncc3c(=O)n(CC(F)(F)F)c2c1
Yield: 66 %

Procedure:
The product is obtained according to the procedure described in Step 3.4. starting with N-{3-[4-oxo-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-7-yl]pyrid-2-yl}acetamide and N-{3-[4-oxo-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-7-yl]pyrid-2-yl}acetamide, in the form of a white powder (hydrochloride, 1.5 H2O; yield 66%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:18]([OH:20])=O)=[C:4]([Cl:21])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:37]=1[CH2:38][NH2:39].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:18]([NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:36]=2[O:35][CH3:34])=[O:20])=[C:4]([Cl:21])[CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=C(O)c1cnn(C2CCOC2)c1-c1ccc(Br)cc1Cl
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cnn(C3CCOC3)c2-c2ccc(Br)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-5-(4-bromo-2-chlorophenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylic acid (1 g) was dissolved in DCM (20 mL), and CDI (611 mg) was added, followed by stirring at room temperature for one hour. 2,4-dimethoxybenzylamine (0.809 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for two hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with DCM. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 40%) to give the title compound (1.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)=[N:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Oc2ncc(Cl)cn2)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Oc2ncc(Cl)cn2)ccc1O
Yield: 53.5 %

Procedure:
A solution of 4-(5-chloro-2-pyrimidyloxy)phenol (1.4 g) in acetic acid (20 ml) was treated with fuming nitric acid (0.5 g) at 25° C. After 4 hours the mixture was poured into water and extracted with chloroform (2×100 ml). The chloroform extracts were dried (Mg2O4) and evaporated to a yellow solid which was chromatographed on silica gel (40 g). Elution with chloroform gave 4-(5-chloro-2-pyrimidyloxy)-2-nitrophenol (0.9 g) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1([F:36])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=5)[C:30](O)=[O:31])[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:39])=O.CN(C)C=O>ClCCl>[F:1][C:2]1([F:36])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=5)[C:30]([Cl:39])=[O:31])[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-(3-(1-(2,2-di fluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid (1.26 g, 2.58 mmol) in dichloromethane (5 mL) was added thionyl chloride (922 mg, 564 μL, 7.75 mmol) and N,N-dimethyl formamide (20 μL). The reaction mixture was stirred at room temperature for 30 minutes before it was evaporated to dryness to yield 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoyl chloride as a yellow solid.
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([C:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=3)[N:12]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[C:11]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C1COCC1.O>[CH:4]1([C:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=3)[N:12]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:11]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)CCn1c(-c2ccccc2CNCCN(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Lithium hydroxide monohydrate (1 eq) was added to a solution of methyl 3-cyclohexyl-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-1-(3-methoxy-3-oxopropyl)-1H-indole-6-carboxylate in a mixture THF:H2O (4:1, 0.1 M). The mixture stirred at RT for 1 h. The reaction was quenched with 1 N HCl and the solvent evaporated in vacuo. The residue was washed with the minimum amount of Et2O and the solid residue filtered to obtain the title compound (82%); MS (ES+) m/z 506 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:39]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:40])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3CCCCC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (13 mg, 28 μmol) was dissolved in abs. pyridine (0.65 ml). At room temperature, cyclohexanecarbonyl chloride (8.3 mg, 57 μmol, 2 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Kromasil C18 column, 20×50 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (12.5 mg, 83% of theory).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1ccc2ccccc2c1
Agent: [Li+]
Solvent: CI
Product: CCOC(=O)C(C)c1ccc2ccccc2c1
Yield: 108.7 %

Procedure:
5 g (23 mmol) of ethyl 2-naphthylacetate, 23.3 mL (1.0 M, 23 mmol) of lithium bis(trimethylsilyl)amide, and 1.5 mL (24 mmol) of methyl iodide were reacted as described in Preparation 11 to yield 5.71 g of a dark oil. Chromatography eluting with a solvent gradient of hexane to hexane/ethyl acetate 19:1 gave the title compound 2.85 g (54%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[NH2-].[Li+].N>O>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccn1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: N
Agent: [Li+]
Agent: [NH2-]
Solvent: O
Product: OC(Cc1ccccn1)(c1ccccc1)c1ccccc1
Temperature: 125 °C
Reaction time: 5 h

Procedure:
Benzophenone, 32.4 kg (177.8 mole), α-picoline, 33.1 kg (355.5 moles), and lithium amide, 4.54 kg (197.4 moles) are charged into a 30 gallon reactor arranged for reflux operation. The mixture is stirred, rapidly heated to 125° C. and maintained at this temperature. The rate of ammonia evolution will gradually increase and after about 3 to 4 hours of reaction time only occasional heating is required to maintain the desired temperature and a rapid evolution of ammonia. After about 5 hours, a vigorous surge of ammonia evolution is noted. Following the ammonia surge, external heating is continued and the reaction maintained at 125° C. for an additional 6 to 8 hours. The reaction mixture is cooled to 70°-80° C. and rapidly added to approximately 230 liters of water at 25° C. Stirring is continued for approximately 30 minutes and the solid removed by filtration. The filter cake is thoroughly washed with water and dried at 60° -70° C. yielding 42-6 kg of α,α-diphenyl-2-pyridineethanol having a m.p. of 147°-51° C.