Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[C:11]([N:21]2[C:33](=[O:34])[C:32]3[S:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[C:24]=3[CH2:23][CH2:22]2)(B2OC(C)(C)C(C)(C)O2)[CH:10]=[C:9]([F:35])[CH:8]=[CH:7]1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:21]2[C:33](=[O:34])[C:32]3[S:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[C:24]=3[CH2:23][CH2:22]2)=[CH:10][C:9]([F:35])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:59][O:60][CH2:61]4)[CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CC(=O)OCC1C=CC(F)=CC1(B1OC(C)(C)C(C)(C)O1)N1CCc2c(sc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Yield: 56.1 %

Procedure:
Following Example 148h, 400 mg of (4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 212b and 336 mg of 5-bromo-1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridine-2(1H)-one 210c were reacted to give 211a as a yellow solid (319 mg, 56%). LCMS: (M+H)+ 713
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Br:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10]>C(Cl)(Cl)(Cl)Cl>[Br:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10][P:1]([Cl:5])([Cl:3])=[O:2]
Reactant: CC(C)(CO)CBr
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CBr)COP(=O)(Cl)Cl
Reaction time: 8 h

Procedure:
To a solution of 18.35 g of phosphorous oxychloride in 55 ml of carbon tetrachloride was added dropwise a solution of 3-bromo-2,2-dimethyl-1-propanol in 20 ml of carbon tetrachloride. This mixture was stirred overnight, evaporated in vacuo, then evaporated twice from toluene at 35° C. and dried. The residue was distilled on Kugelrohr 100° C., 0.3 mm giving the desired compound as a colorless oil.
Reaction SMILES: [SiH:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[SiH](Cl)(Cl)Cl.[CH2:12]([Cl:16])[C:13](=[CH2:15])[CH3:14]>>[Si:1]([CH2:14][CH:13]([CH2:12][Cl:16])[CH3:15])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: CC[SiH](CC)CC
Reactant: C=C(C)CCl
Agent: Cl[SiH](Cl)Cl
Product: CC[Si](CC)(CC)CC(C)CCl
Yield: 82.3 %

Procedure:
In a 100 ml apparatus, there were combined 11.6 g (0.1 mol) of Et3SiH, 13.6 g (0.1 mol) of Cl3SiH, and 9.1 g of methallyl chloride, followed by addition of 0.05 ml Pt catalyst solution at 21° C. There was a rapid and exothermic reaction to 61° C. in 2 min. Reaction appeared to have stopped and was heated to reflux over 4 hrs. when VPC showed complete reaction. Vacuum distillation yielded 17.03 g (82.5%) of Et3SiCH2CHMeCH2Cl, indicating that Cl3SiH is an effective promoter for the reaction of Et3SiH with methallyl chloride.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=O)=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:9]([C:5]5[C:6]([CH3:8])=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=5)=[O:11])[CH:45]=[CH:44][CH:43]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: CCn1cc(C)c(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCn1cc(C)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n1
Yield: 52.1 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-4-methyl-1H-pyrazole-3-carboxylic acid (150 mg, 0.970 mmol), tetrahydrofuran (7 mL), oxalyl chloride (93.0 μL, 1.07 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (150 mg, 52%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N:9]=[CH:10]N(C)C)=[C:4]([Cl:14])[N:3]=1.P(=O)(O)(O)[OH:16]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:16])=[C:4]([Cl:14])[N:3]=1
Reactant: O=P(O)(O)O
Reactant: CN(C)C=Nc1c(Cl)nc(N)nc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1nc(Cl)c(NC=O)c(Cl)n1
Yield: 72 %

Procedure:
In another experiment, a slurry of 2-amino-4,6-dichloro-5-{[(dimethyl -amino)methylene]amino}-pyrimidine (Example 2, 25.0 g, 0.107 mol) in 1.5 M aqueous potassium phosphate buffer (300 mL, prepared as above) was gently refluxed for 4 hours. pH was maintained at 3.2 by addition of 85% phosphoric acid, as required throughout this period. The precipitate was filtered, washed with water (3×10 mL), methanol (2×10 mL), and dried (50° C., 25 mm Hg) to give the title compound as an off-white powder (16.0 g, 72%) with purity identical to that of the characterized sample described above (elemental analysis and 1H-NMR).
Reaction SMILES: O[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH3:21][C:3]1([CH3:22])[CH:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4]1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccccc1
Yield: 82 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 243, the title compound was synthesized in the same manner as in Example 271. Yield: 82%. Melting point: 182-183° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C@H:24]1[NH:29][C@@H:28]([CH3:30])[CH2:27][N:26]([C:31](=[O:43])[CH2:32][CH2:33][C:34]2[C:35]([CH3:42])=[C:36]([CH:40]=O)[NH:37][C:38]=2[CH3:39])[CH2:25]1.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:40]\[C:36]1[NH:37][C:38]([CH3:39])=[C:34]([CH2:33][CH2:32][C:31]([N:26]2[CH2:27][C@H:28]([CH3:30])[NH:29][C@H:24]([CH3:23])[CH2:25]2)=[O:43])[C:35]=1[CH3:42])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1C[C@@H](C)N[C@@H](C)C1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (122 mg, 0.34 mmol), 4-[3-((3R, 5S)-3,5-dimethyl-piperazin-1-yl)-3-oxo-propyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (139 mg, 1.4 eq.) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 72 hours. The reaction was concentrated and purified on a silica gel column to give the titled compound as a dark brown orange solid.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[C:49]1([S:55](Cl)(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(Cl)Cl>[CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([S:55]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)(=[O:57])=[O:56])[CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCN(S(=O)(=O)c2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 7 (200 mg, 0.37 mmol) is dissolved in dry CH2Cl2 (4 mL) and the flask sealed under N2. DIEA (96 μL, 0.56 mmol) is added, followed by benzenesulfonyl chloride (46 μL, 0.36 mmol), then the mixture stirred at RT for 2 h. The reaction is subsequently diluted with CH2Cl2 (50 mL) and washed with sat. NaHCO3 (50 mL), brine (50 mL) and dried (Na2SO4). After filtration, the solvent is removed under reduced pressure to afford an oil which is purified by flash chromatography on silica gel (25% Et2O/CH2Cl2). The title compound is isolated as a colourless glass (216 mg, 86% yield): 1H NMR δ (CDCl3) 7.51-7.86 (m, 5H), 7.03-7.25 (m, 4H), 6.69 (v br s, 1H), 6.04 (br d, J=8.2 Hz, 1H), 5.16-5.25 (m, 1H), 4.29-4.75 (br m, 3H), 3.47-4.21 (br m, 3H), 2.69-2.88 (br m, 5H), 2.38-2.67 (m, 2H), 1.81-2.09 (m, 5H), 1.55 (s, 3H), 1.46 (s, 9H), 1.23-1.31 (br m, 2H), 0.84-0.92 (br m, 3H), 0.76 (d, J=6.7 Hz, 2H); LCMS (APCl+) 685.6 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)N1CCCCC1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)N4CCCCC4)nc3cc21

Procedure:
Piperidine-1-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol) and 1-piperidinecarbonyl chloride. The title compound was obtained as light brown powder (101 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[N:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2
Reactant: COc1ccccc1C=O
Reactant: Cc1ccc2c(N)cccc2n1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccccc1C=Nc1cccc2nc(C)ccc12
Yield: 118.4 %

Procedure:
To 1.74 g (11 mmol) 5-amino-2-methylquinolin and 1.33 ml (11 mmol) 2-methoxybenzaldehyde in 33 ml toluene are added 50 μl acetic acid and 2 g molecular sieve. The mixture is heated over 2 hours under reflux and filtrated through a path of cellites after cooling. The solvent is evaporated and the residue is two times azeothrophed with small portions of toluene. 3.6 g of [1-(2-methoxyphenyl)methylidene]-(2-methylquinolin-5-yl)amine are obtained as a yellow oil. 2.25 ml (26 mmol) 1,1,1-Trifluoroepoxypropane in 38 ml THF and 11 ml hexane are cooled to −100° C. and 15 ml of a 1.6 M n-butyl lithium solution in hexane are added over one hours while the temperature does not exceed −95° C. 10 Minutes after complete addition 3.6 g (11 mmol) raw [1-(2-methoxyphenyl)methylidene]-(2-methylquinolin-5-yl)amine in 49 ml THF are added over one hour while the temperature does not exceed −95° C. After one hour at −100° C. 12 ml diethyl ether are added and the reaction mixture is warmed to −10° C. over one hour. The reaction was quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer was extracted twice with diethyl ether, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (acetone in hexane 0 to 30%) yields 4.27 g {(2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methyl}-2-methylquinolin-5-amine as mixture of diastereomeres.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[Cl:14].Cl>CO>[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[Cl:14]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(C(=O)O)cc1Cl
Temperature: 45 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
1 N NaOH (11 mL; 11 mmol) was added to a solution of methyl 4-amino-3-chlorobenzoate (2 g; 10.8 mmol) in MeOH (20 mL) at 45° C. The reaction mixture was stirred for 5 h at 45° C. and overnight at room temperature. More 1N NaOH was added (5 mL; 5 mmol) and the reaction was stirred at 45° C. for 2 h. After concentration of solvent was added 1N HCl (16 ml). The solid precipitate was filtered and dried to give 4-amino-3-chlorobenzoic acid, C, as a with solid (1.75 g; 10.2 mmol). Yield 94.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][CH3:25])=[CH:19][CH:18]=1.[Cl:34]N1C(=O)CCC1=O>CN(C=O)C>[Cl:34][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][CH3:25])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 37.4 %

Procedure:
Following General Procedure H, (R)-tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (0.67 g, 1.5 mmol) was reacted with N-chlorosuccinimide (0.29 g, 1.6 mmol) in DMF (10 mL) to afford the desired product (0.28 g, 35%) as a brown solid: ESI MS m/z 499 [C26H27ClN2O4S+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13](/[CH:15]=[C:16]2\[CH2:17][N:18]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][C:21]\2=[O:22])[N:12]=[N:11]1)=[O:5])[CH3:2].[BH4-].[Na+]>>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13](/[CH:15]=[C:16]2\[CH2:17][N:18]([C:23]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][CH:21]\2[OH:22])[N:12]=[N:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCCn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)nn1
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)CCCCn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)nn1
Yield: 98.2 %

Procedure:
(E)-3-({1-[4-(Ethoxycarbonyl)butyl]-1H-1,2,3-triazol-4-yl}methylidene)-1-(triphenylmethyl)piperidin-4-one (18.87 g) was allowed to react with sodium borohydride (1.32 g) in a similar manner to that described in Example 132 (d). The crude product obtained by extraction was purified by chromatography on silica gel using a mixture of ethyl acetate and hexane (4:6 to 6:4), followed by a mixture of methanol and dichloromethane (5:9 to 10:90) as eluents to afford the title compound as a pale brown amorphous solid (18.59 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[N:13][N:14]=[C:4]2[CH:3]=1>C(N)C(C)C>[CH3:10][CH:11]([CH3:2])[CH2:6][NH:5][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[N:13][N:14]=[C:4]2[CH:3]=1
Reactant: Clc1cc2nnnn2c2cnccc12
Solvent: CC(C)CN
Product: CC(C)CNc1cc2nnnn2c2cnccc12

Procedure:
A suspension of 5-chlorotetrazolo[1,5-a][1,7]naphthyridine (20 g) in isobutylamine (100 mL) was heated at reflux for several hours. The reaction mixture was concentrated under vacuum. The residue was taken up in dichloromethane, washed with water, dried over magnesium sulfate then concentrated under vacuum. The residue was recrystallized from toluene to give a material that was a mixture by thin layer chromatography. The material was purified by flash chromatography, silica gel eluting with dichloromethane, 5-20% ethyl acetate in dichloromethane, and 10% methanol in dichloromethane. The fractions with the slower moving material were concentrated to provide N5-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-5-amine as a solid, m.p. 220-221° C. Analysis: Calculated for C12H14N6: % C, 59.49; % H, 5.82; % N, 34.69; Found: % C, 59.35; % H, 5.89; % N, 34.88.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[CH:18]([OH:21])([CH3:20])[CH3:19].S(=O)(=O)(O)O>C(OC)(C)(C)C>[C:1]1([S:7]([O:21][CH:18]([CH3:20])[CH3:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: CN1CCOCC1
Solvent: COC(C)(C)C
Product: CC(C)OS(=O)(=O)c1ccccc1

Procedure:
Benzenesulfonyl chloride (50 g, 283 mmol) was added to a solution of 4-methylmorpholine (57 g, 2 equiv.) and isopropyl alcohol (66 g, 3.9 equiv.). After reaction completion (ca. 3 hours), 250 mL of methyl tert-butyl ether (MTBE) and 60 mL of 3M sulfuric acid were added. The rich MTBE layer was washed with aqueous sodium chloride solution. The rich MTBE solution was solvent exchanged into tetrahydrofuran solution. The rich tetrahydrofuran solution containing 56 g (96 M %, HPLC area % 97) of the title compound was used as is in the next step (Example 5).
Reaction SMILES: [CH:1]([C@@H:4]1[NH:27][C:26]2[O:28][C:23](=[N:24][N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2[CH:29]=[C:30]3[C:15](=[CH:16][CH:17]=2)[C:14]([CH:31]=[CH2:32])=[CH:13][N:12]=[C:11]3[O:10][C@H:9]2[CH2:33][N:6]([C@H:7]([C:34]([O:36][CH3:37])=[O:35])[CH2:8]2)[C:5]1=[O:38])([CH3:3])[CH3:2]>CCO.[Pd]>[CH2:31]([C:14]1[C:15]2[C:30]3=[CH:29][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]4[O:28][C:26]([NH:27][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:38])[N:6]5[CH2:33][C@H:9]([O:10][C:11]3=[N:12][CH:13]=1)[CH2:8][C@H:7]5[C:34]([O:36][CH3:37])=[O:35])=[N:25][N:24]=4)=[CH:17][CH:16]=2)[CH3:32]
Reactant: C=Cc1cnc2c3cc(ccc13)CCCCc1nnc(o1)N[C@@H](C(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)OC)O2
Agent: [Pd]
Solvent: CCO
Product: CCc1cnc2c3cc(ccc13)CCCCc1nnc(o1)N[C@@H](C(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)OC)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 9 mM solution of methyl (3R,5S,8S)-8-isopropyl-7-oxo-22-vinyl-2,27-dioxa-6,9,11,12,24-pentaazapentacyclo[16.6.2.13,6.110,13.021,25]octacosa-1(24),10,12,18,20,22,25-heptaene-5-carboxylate (from Step 1) in EtOH was added 10% Pd/C (0.1 eq) and the resulting reaction mixture was stirred at RT under H2 atmosphere for 2 h. The catalyst was filtered off through a pad of CELITE and the volatiles were removed under reduced pressure to give the title compound as a colorless oil. MS (ES+) C28H35N5O5 requires: 521. Found: 522 (M+H+).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:34]([F:37])([F:36])[F:35])[O:15][N:14]=[C:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]([NH:28][CH2:29][CH2:30][S:31]([CH3:33])=[O:32])=[O:27])=[CH:18][CH:17]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1.[OH-].[Na+]>C(O)(=O)C.O>[Cl:10][C:8]1[CH:7]=[C:6]([C:11]2([C:34]([F:36])([F:35])[F:37])[O:15][N:14]=[C:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]([NH:28][CH2:29][CH2:30][S:31]([CH3:33])(=[O:1])=[O:32])=[O:27])=[CH:18][CH:17]=3)[CH2:12]2)[CH:5]=[C:4]([Cl:3])[CH:9]=1
Reactant: OO
Reactant: CS(=O)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
H2O2 (0.056 mL, 30% in H2O) was added to a stirred solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-(methylsulfinyl)ethyl]-1-naphthalenecarboxamide (i.e. the product of Example 2, 100 mg) in acetic acid (1.0 mL). The reaction mixture was stirred at 60° C. for 4 h, then cooled to room temperature, diluted with water, adjusted to pH 4 with 1.0 M aqueous NaOH solution, and extracted with chloroform. The organic extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound (100 mg), a compound of this invention, as a white solid. 1H NMR (CDCl3): δ 8.80 (d, 1H), 8.29 (d, 1H), 7.43-7.66 (m, 7H), 6.94 (br t, 1H), 4.24 (d, 1H), 4.04 (q, 2H), 3.40 (t, 2H), 3.01 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:18]1([CH2:24]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH:18]1([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrCC1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CCCCC2)cc1
Temperature: 50 °C

Procedure:
To a solution of methyl 4-hydroxybenzoate 23-1 (24.3 g, 160 mmol) in 250 mL of DMF was added 62 g (190 mmol) of Cs2CO3 followed by 20.4 mL (146 mmol) of cyclohexylmethyl bromide. The resulting slurry was then heated at 50° C. for 20 h. The solvent was distilled under reduced pressure and the residue was taken up in 500 mL of EtOAc. The organic phase was extracted with 1N NaOH (2×150 mL), water (5×150 mL) and brine (150 mL), dried (MgSO4) and concentrated to afford product 23-2 as a white solid.