Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:26]=[CH:25][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C=C(c1ccc(C(=O)O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(c1ccc(CO)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoic acid in 10 mL of THF was added 300 mg of LiAlH4 at 0° C. The mixture was stirred at room temperature overnight. The excess LiAlH4 was quenched with EtOAc (3 mL). The mixture was stirred for 30 min. 1N HCl was added. A sequence of extraction with EtOAc, filtering, concentration in vacuo and column chromatography yielded 180 mg of the desired alcohol and 103 mg of its acetate. The acetate formed was dissolved in 2 mL of THF, 1 mL of MeOH and 1 mL of H2O. NaOH (0.2 mL of a 1N solution, 0.2 mmol) was added. The mixture was stirred at room temperature for 1 hour. NH4Cl solution was added, and the alcohol product was extracted with EtOAc. After drying over MgSO4, filtering, concentration in vacuo and chromatography, 73.5 mg of the alcohol product was obtained. Total yield of the alcohol was therefore 253.5 mg.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=O)=O.II.O.[Cl-].[Na+]>C(O)(=O)C.II>[SH:2][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: II
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc(S)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
3-Chlorosulfonylbenzoic acid (156.0 g, 0.707 mol), acetic acid (240 mL), and red phosphorus (78.5 g, 2.53 mol) were placed in a 2-L three-neck flask. The mixture was heated to 110° C. and stirred while a solution of iodine (2.82 g, 0.011 mol) in acetic acid (66 mL) was added dropwise over about 30 min, so as to maintain the color of iodine vapor. The stirred mixture was cooled to 100° C. and treated dropwise with 41 mL (2.3 mol) of water over a 10-min period, then heated at reflux temperature for 1.5 h and subsequently cooled to 90° C. Following the addition of saturated sodium chloride solution (250 mL) and water (500 mL), the mixture was kept at 0-5° C. for 1 h and filtered. The damp filter cake was slurried with 450 mL of acetone, and the excess red phosphorus was removed by filtration; then the acetone was evaporated from the filtrate while adding 500 mL of water. The resultant solid was filtered off and dried under vacuum to give 100.1 g (92%) of 3-mercaptobenzoic acid, mp 138-141° C. (lit. mp 138-141° C.); 1H NMR (400 MHz, in CDCl3 w/TMS, ppm) 3.59 (s, SH), 7.36 (t, J=7.8 Hz, H-5), 7.51 and 7.90 (2d, J=7.8 Hz, H-4 and H-6), 8.03 (s, H-2); {1H}13C NMR (100 MHz, in CDCl3 w/TMS, ppm) 171.77 (C═O), 134.49 (C-4), 132.24 (C-1), 130.86 (C-2), 130.34 (C-3), 129.42 (C-5), 127.59 (C-6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40][N:41]([CH2:51][CH2:52][O:53][CH3:54])[C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH2:51][CH2:52][O:53][CH3:54])=[O:50])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCCN(CCOC)C(=O)CN1CCNCC1
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCOC)CCOC)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N,N-bis-(2-methoxy-ethyl)-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 16) in an analogous manner as described in example 25. LR-MS: 763.4 [(M+H)+]
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39][P:40]([O:45][CH2:46][CH3:47])([O:42][CH2:43][CH3:44])=[O:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:17]3[C:13]=2[CH2:14][N:15]([CH3:51])[C:16]3=[O:50])[CH2:8][CH2:7]1)(=O)=O.[CH3:52][N:53](C=O)C>>[C:52]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([CH2:39][P:40](=[O:41])([O:42][CH2:43][CH3:44])[O:45][CH2:46][CH3:47])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:17]3[C:13]=2[CH2:14][N:15]([CH3:51])[C:16]3=[O:50])[CH2:8][CH2:7]1)#[N:53]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OS(C)(=O)=O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C#N)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 100 °C

Procedure:
In 25 mL Schlenk tube, trans-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexyl methanesulfonate (Compound 283A, 130.0 mg, 0.17 mmol) was dissolved in DMF (13.0 mL, 168 mmol) and was added degassed (3×) with argon. The reaction was heated at 100° C. under an atmosphere of argon for 7 hrs. The reaction was dissolved in EtOAc and washed with water (2×) and brine (1×) respectfully. The organic layer was collected and concentrated in vacuo to a solid and was purified by CombiFlash®Rf 4X Organic Purification System [dried loaded on 12 g silica load cartridge, 40 g RediSep® Normal-phase GOLD Silica Flash Column, elution gradient: 0→4% MeOH in DCM] to afford 37.4 mg (31.7%) of the desired product. 1H NMR (400 MHz, MeOD) δ 8.49 (br. s., 1H), 8.33 (s, 1H), 7.85 (d, J=7.58 Hz, 1H), 7.33 (d, J=8.59 Hz, 1H), 7.03-7.09 (m, 1H), 6.93 (td, J=2.27, 8.08 Hz, 1H), 4.51 (s, 2H), 4.08 (quin, J=7.26 Hz, 4H), 3.90 (s, 3H), 3.33 (s, 1H), 3.27 (s, 1H), 3.17 (s, 4H), 2.68 (d, J=5.56 Hz, 1H), 2.10 (d, J=10.36 Hz, 2H), 1.75-1.93 (m, 6H), 1.28 (t, J=7.07 Hz, 6H). MS (ES+): m/z 687.17/688.20 (100/70) [MH+]. HPLC: tR=1.54 min (Micromass TOF: polar—3 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][OH:22])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:58][C:59]([F:63])([F:62])[CH2:60]O>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][CH2:60][C:59]([F:63])([F:62])[F:58])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO)CC1
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOCC(F)(F)F)CC1
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
According to the procedure of Tet. Let. 35, 5997-6000 (1994), combine 4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (10 mmol) and di-t-butyl dicarbonate (10 mmol) in tetrahydrofuran (100 mmol). After 18 hours, evaporate in vacuo to give 1-t-butoxycarbonyl-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane. Combine 1-t-butoxycarbonyl-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.66 g, 1.84 mmol) and 1,1'-(azodicarbonyl)dipiperidine (0.50 g, 2 mmol) in toluene (20 mL). Add tributylphosphine (0.5 mL, 2 mmol). After 10 minutes, add 2,2,2-trifluoroethanol (0.7 mL, 10 mmol). Heat to 55° C. After 6 hours, cool to ambient temperature. After 18 hours, concentrate the reaction mixture to give a residue. Chromatograph the residue on silica gel eluting sequentially with hexane and then 30% ethyl acetate/hexane to give 1-t- butoxycarbonyl-4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([OH:17])=O)[N:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([N:30]3[CH2:29][CH2:28][N:27]([CH:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)[CH2:32][CH2:31]3)=[O:17])[N:10]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: O=C(O)Cn1ccc(NC(=O)c2ccc(Cl)cc2)n1
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(C(=O)Cn3ccc(NC(=O)c4ccc(Cl)cc4)n3)CC2)CC1

Procedure:
Using general method A, using THF instead of DMF as solvent, [3-(4-chloro-benzoylamino)-pyrazol-1-yl]-acetic acid (example 59.2) was reacted with 1-(N-methyl-4-piperidyl)-piperazine to give 4-chloro-N-(1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazol-3-yl)-benzamide. Off-white solid. MS 445.4 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:28])[C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:24][CH:25]=1
Reactant: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C(CC(NC(=O)c2ccc(Cl)cc2)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
479 Milligrams of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate prepared in Example 3 and 70 mg of 50% sodium hydride (in oil) were admixed in 5 ml of dimethylformamide, and the mixture was stirred at a room temperature for 1 hour. Then a solution containing 0.23 g of methyl iodide in 3 ml of dimethylformamide was added dropwise gradually to the mixture, and the whole reaction mixture was stirred at a room temperature for 4 hours. The reaction mixture was poured into a large volume of water, and the organic material was extracted with chloroform, then the chloroform layer was washed with water and dried. Chloroform was removed by evaporation to yield 125 mg of 2-(4-chlorobenzoylamino)-3-(1-methyloxindol-3-yl)propionic acid.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:19])([F:18])[C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1.Cl[CH2:21][CH2:22][O:23][CH2:24][CH2:25]Cl>CN(C=O)C>[F:7][C:8]([F:18])([F:19])[C:9]1[CH:10]=[C:11]([C:15]2([C:16]#[N:17])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:12]=[CH:13][CH:14]=1
Reactant: ClCCOCCCl
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(F)(F)F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 162.8 %

Procedure:
Potassium tert-butoxide (4.00 g, 35.6 mmol, 2.20 eq) was added to a stirred solution of 2-(3-(trifluoromethyl)phenyl)acetonitrile (2.53 mL, 16.2 mmol, 1.0 eq) in DMF (30 mL) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 10 minutes at 0° C. before 1-chloro-2-(2-chloroethoxy)ethane (2.09 mL, 17.8 mmol, 1.1 eq) was added dropwise via syringe. The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The reaction mixture was then cooled to 0° C. and quenched with 10% HCl. The aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give the product as an orange oil (6.73 g).
Reaction SMILES: C(O[CH2:4][NH:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([NH:12][CH2:13][C:14]2[S:15][C:16]([O:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:8][N:7]=1)C.[BH4-].[Na+].O.C(OCC)(=O)C>CS(C)=O>[CH3:4][NH:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([NH:12][CH2:13][C:14]2[S:15][C:16]([O:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:8][N:7]=1
Reactant: CCOCNc1ccc(C(=O)NCc2ccc(Oc3cccc(C)c3)s2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNc1ccc(C(=O)NCc2ccc(Oc3cccc(C)c3)s2)cn1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 88.2 %

Procedure:
To a solution of 6-(ethoxymethyl-amino)-N-(5-m-tolyloxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-155 (70 mg, 0.17 mmol) in dimethylsulfoxide (5 mL) was added sodium borohydride (20 mg, 0.51 mmol), and the solution was stirred for 20 minutes at 120° C. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with brine once. The organic layer was passed through a glass filter lined with NH silica gel, and eluted thoroughly with ethyl acetate. The solvent was evaporated in vacuo, and the title compound (53 mg, 0.15 mmol, 88.2%) was obtained as a light brown solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([CH:8]1[CH2:12][C:11]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:10]=2[O:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC2Cc3ccccc3O2)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1ccc2c(c1)CC(Cc1ccccc1)O2
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A solution of 2-benzyl-2,3-dihydrobenzofuran (1.9 g, 9 mmole) in 25 ml carbon tetrachloride was cooled to 0° C. and a solution of 0.46 ml (9 mmole) bromine in 5 ml carbon tetrachloride was added at 0° C. The mixture was warmed to room temperature, washed with water, sodium bicarbonate solution, and water again. The solvent was then evaporated to afford 2.5 g of crude product which was purified by column chromatography on silica gel, eluting with hexane to afford 1.0 g (38.5%) of the desired compound, m.p. 70°-72° C.
Reaction SMILES: [NH2:1][C:2]1([C:35](OC)=[O:36])[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:32](=[CH:33][CH:34]=2)[C:13]2=[N:14][O:15][C:16]([C:17]4[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:19][N:18]=4)=[C:12]2[CH2:11][CH2:10]3)[CH2:3]1.CCO.[BH4-].[Na+].[OH-].[Na+]>O.ClCCl>[NH2:1][C:2]1([CH2:35][OH:36])[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:32](=[CH:33][CH:34]=2)[C:13]2=[N:14][O:15][C:16]([C:17]4[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[O:19][N:18]=4)=[C:12]2[CH2:11][CH2:10]3)[CH2:3]1
Reactant: COC(=O)C1(N)CCC(c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: NC1(CO)CCC(c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Methyl 1-amino-3-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)cyclopentanecarboxylate (Preparation 121F, 160 mg, 0.306 mmol) was mixed with EtOH (2 mL), dichloromethane (1 mL) and sodium borohydride (57.8 mg, 1.528 mmol). The mixture was stirred at room temperature overnight. Next, 2N aqueous sodium hydroxide solution (5 mL) was added. The mixture was stirred at 40° C. for 30 min. and cooled. Water (10 mL) was added. The mixture was extracted with EtOAc (10 mL, 2×5 mL). The combined ethyl acetate extracts were dried (sodium sulfate) and concentrated under reduced pressure to give a (1-amino-3-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)cyclopentyl)methanol (151 mg, 0.305 mmol, 100% yield) as a foam solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[N:3]1[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>C(O)(C(F)(F)F)=O>[NH2:28][C:24]1([C:21]2[CH:20]=[CH:19][C:18]([C:9]3[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:11][C:4]4[N:3]([C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[C:2](=[O:1])[CH2:7][O:6][C:5]=4[N:8]=3)=[CH:23][CH:22]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(c3cccnc3)C(=O)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(c3cccnc3)C(=O)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 60.8 %

Procedure:
tert-Butyl 1-(4-(2-oxo-7-phenyl-1-(pyridin-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (30 mg, 0.055 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (15 mg, 49% yield). 1H-NMR (500 MHz, MeOD) δ 8.62-8.77 (2H, m), 7.98 (1H, d), 7.68 (1H, dd), 7.36 (2H, d), 7.39 (2H, d), 7.15-7.24 (3H, m), 6.97-7.05 (2H, m), 6.77 (1H, s), 5.14 (2H, s), 2.66-2.77 (2H, m), 2.46-2.58 (2H, m), 2.13-2.25 (1H, m), 1.86-1.97 (1H, m). LCMS (Method A) RT=3.71 min, M+2H+=450.20.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH2-].[Na+].N.[CH3:25]I.[Cl-].[NH4+].Cl>CCOCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1C
Reactant: CI
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(C)c1ccc(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 1 h

Procedure:
A solution of 6.68 g. (0.0219 mole) of ethyl 5-(ρ-chlorobenzoyl)-1-methylpyrrole-2-acetate in 50 ml. of ether is added to a solution of 0.94 g. (0.024 mole) of sodamide in about 150 ml. of liquid ammonia at -33° C. The mixture is allowed to reflux for 15 minutes and 3.10 g. (0.0219 mole) of methyl iodide is added. The mixture is stirred for one hour; then the ammonia is allowed to boil off. Ether and enough ammonium chloride to neutralize any anion are added. The mixture is poured into dilute hydrochloric acid and the ether solution is separated and washed with sodium bisulfite solution, sodium bicarbonate solution and brine. It is dried over anhydrous magnesium sulfate and evaporated to give about 6.8 g. of an oily residue which crystallized upon standing. The solid is recrystallized successively from cyclohexane and methanol to give a white crystalline solid, ethyl 5-(ρ-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetate, M.P. 67°-68° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[NH:42][CH2:41][CH2:40][N:39]2[C:43](=[O:46])[CH2:44][CH2:45][C@@H:38]12.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[CH2:41][CH2:40][N:39]4[C:43](=[O:46])[CH2:44][CH2:45][C@H:38]4[CH2:37]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1CC[C@H]2CNCCN12
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3C(=O)CC[C@H]3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 43.7 %

Procedure:
A 8 ml sealed vial was charged with 100 mg (0.187 mmol) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 78.6 mg (0.561 mmol) of (8aS)-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 52 mg (0.374 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with dichloromethane; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 52 mg of the title compound as pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=[C:16]3[N:24](C(OC(C)(C)C)=O)[CH:25]=[CH:26][C:15]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([C:14]2[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=[C:16]3[NH:24][CH:25]=[CH:26][C:15]=23)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COC(=O)c1cnc2c(ccn2C(=O)OC(C)(C)C)c1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cnc2[nH]ccc2c1N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
1-tert-Butyl 5-methyl 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-1,5-dicarboxylate (0.34 g, 0.74 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.5 mL) was then added. The reaction was stirred at room temperature for 4 hours and then concentrated to dryness. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid methyl 4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.19 g, 98.9% yield) was collected and dried as the dihydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:25])([F:24])[S:20](Cl)(=[O:22])=[O:21]>CC(C)=O>[F:18][C:19]([F:25])([F:24])[S:20]([O:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=[N+]([O-])c1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(F)c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
A mixture consisting of 2-fluoro-6-nitrophenol (20 g, 0.14 mol) and potassium carbonate (20 g, 0.14 mol) in acetone (350 mL) was stirred at room temperature for 20 minutes. A solution of trifluoromethanesulfonyl chloride (23.7 g, 0.14 mol) in acetone (100 mL) was added dropwise at room temperature. Stirring was continued for 3 hours. The reaction was filtered, and the filtrate was concentrated. The residue was dissolved in diethyl ether (300 mL), washed with 0.1N NaOH, water, dried (MgSO4), filtered and evaporated to give 21.5 g of the title compound.