Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:10][CH:9]1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([N:37]1[CH2:38][CH2:39][N:40]([C:29]([C@@H:9]2[CH2:10][C@H:11]([NH:13][CH2:14][C:15]3[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=3)[CH2:12][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:30])[CH2:41][CH2:42]1)=[O:36])[CH3:33]
Reactant: O=C(O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(C(=O)[C@@H]2C[C@H](NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CN2Cc2ccccc2)CC1
Yield: 7.5 %

Procedure:
As described for Example 56d, 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid (65 mg, 0.146 mmol) was converted, using piperazine-1-carboxylic acid ethyl ester instead of 1-(3-trifluoromethyl-phenyl)-piperazine, to the title compound (6.8 mg, 7.5%) as light yellow oil. MS m/e=587.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[C:10](/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11]\[C:12]([O:14]CC)=[O:13])=[CH:7][C:6]=2[CH:23]=1.CC1C=CC2OC(/C(/C3C=CC=CC=3)=C/C(OCC)=O)=CC=2C=1.CC1C=CC2OC(/C(/C3C=CC=CC=3)=C\C(O)=O)=CC=2C=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[C:10](/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:7][C:6]=2[CH:23]=1
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1cc2cc(C)ccc2o1
Agent: CCOC(=O)/C=C(\c1ccccc1)c1cc2cc(C)ccc2o1
Agent: Cc1ccc2oc(/C(=C\C(=O)O)c3ccccc3)cc2c1
Product: Cc1ccc2oc(/C(=C/C(=O)O)c3ccccc3)cc2c1

Procedure:
By a procedure similar to that of example 1.85.4, starting from a mixture of (Z)-ethyl 3-(5-methyl-2-benzofuranyl)-3-phenylacrylate and (E)-ethyl 3-(5-methyl-2-benzofuranyl)-3-phenylacrylate, a mixture of (Z)-3-(5-methyl-2-benzofuranyl)-3-phenylacrylic acid and (E)-3-(5-methyl-2-benzofuranyl)-3-phenylacrylic acid was obtained as yellowish solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][O:22][CH2:21][CH2:20][O:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[O:19]1[CH2:20][CH2:21][O:22][CH2:23][CH:18]1[C:17]1[C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][N:28]=[C:3]([CH2:2][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH:4]=3)=[N:13][C:12]=2[C:14]([O:24][CH3:25])=[CH:15][CH:16]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(CN4CCOCC4)c3)nc12
Yield: 62 %

Procedure:
A suspension of 100 mg (0.24 mmol) (+)-2-chloromethyl-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide, 155 mg (0.48 mmol) cesium carbonate and 0.42 ml (4.76 mmol) morpholine was ultrasonicated at room temperature for 10 min. The reaction mixture was then concentrated in vacuo. Flash chromatography (1/1 acetone/hexane) followed by trituration in ether and hexane afforded 70 mg (62%) (+)-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-2-morpholin-4-ylmethyl-isonicotinamide as an off-white solid. [α]D20=+89.2° (c=0.49, CHCl3), ES-MS m/e (%): 471 (M+H+, 100).
Reaction SMILES: C[O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N+:19]([O-])=O)=[C:15]([CH:18]=1)[CH:16]=O>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[CH:16][N:7]([C:6]3[CH:8]=[CH:9][C:3]([OH:2])=[CH:4][CH:5]=3)[N:19]=2)[CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Product: Oc1ccc(-n2cc3cc(Cl)ccc3n2)cc1

Procedure:
4-(5-chloro-2H-indazol-2-yl)phenol was prepared using a method analogous to that described for Intermediate (Q10), starting from 4-methoxyaniline and 5-chloro-2-nitrobenzaldehyde. Yellow solid. 1HNMR (400 MHz Methanol-d4) δ 8.60 (d, J=1.6 Hz, 1H), 7.71-7.75 (m, 3H), 7.65 (d, J=9.2 Hz, 1H), 727 (dd, J=9.2, 2.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C1CCC(=O)CC1
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of ethyl 4-hydroxycyclohexanecarboxylate (16 g, 93 mmol), 4-methylmorpholine N-oxide (16.32 g, 139.5 mmol) and CH2Cl2 (180 mL) was added tetrapropylammonium perruthenate (0.8 g, 2.3 mmol) in small portions at a rate that maintained the reaction temperature at 35-40°. The reaction slowly cooled and was stirred overnight. The resulting mixture was filtered through silica with CH2Cl2 to afford 13.46 g (85%) of the title compound as a colorless oil. 1H NMR (CDCl3): d 4.19 (q, 2), 2.75 (m, 1), 2.5 (m, 2), 2.37 (m, 2), 2.19 (m, 2), 2.04 (m, 2).
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]([CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[O:21]=[C:22]1[N:28]([CH2:29][CH2:30][CH2:31][CH:32]=O)[CH2:27][CH2:26][CH2:25][O:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:3]([CH:4]([CH3:20])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:14])=[O:13])=[CH:10][CH:11]=1)[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:27][CH2:26][CH2:25][O:24][CH2:23][C:22]1=[O:21])[CH3:2]
Reactant: O=CCCCN1CCCOCC1=O
Reactant: CCN[C@@H](C)Cc1ccc(S(=O)(=O)c2nccs2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CCCCN1CCCOCC1=O)C(C)Cc1ccc(S(=O)(=O)c2nccs2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of ethyl-{(S)-1-methyl-2-[4-(thiazole-2-sulfonyl)phenyl]ethyl}-amine (0.326 g, 1.02 mmole), 4-(3-oxo-[1,4]oxazepan-4-yl)-butyraldehyde (0.22 g, 1.2 mmole), and sodium triacetoxyborohydride (0.3 g, 1.4 mmole) in 1,2-dichloroethane (10 mL) was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was partitioned between 5% hydrochloric acid and diethyl ether. The aqueous phase was brought to pH 12 with 25% sodium hydroxide and the mixture was extracted with dichloromethane. The organic phase was dried (magnesium sulfate) and concentrated to give 4-(4-{ethyl-[2-(4-thiazole-2-sulfonylphenyl)-1-methylethyl]amino}butyl)-[1,4]oxazepan-3-one, 145, as an oil. Anal.: Calcd. for C23H34ClN3O4S2.1H2O: C, 51.72; H, 6.79; N, 7.87%; Found C, 51.71; H, 6.49 N 7.82%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([O:20][CH3:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12]CC2C=CC=CC=2)[CH:7]=1>CO>[CH3:1][O:2][C:3](=[O:22])[CH:4]([O:20][CH3:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1
Reactant: COC(=O)C(Cc1cccc(OCc2ccccc2)c1)OC
Solvent: CO
Product: COC(=O)C(Cc1cccc(O)c1)OC
Reaction time: 8 h

Procedure:
A solution of 3-(3-Benzyloxy-phenyl)-2-methoxy-propionic acid methyl ester in methanol was treated with a catalytic amount of C—Pd (0.1 eq) and then H2 was bubbled through the mixture and stirred overnight. The mixture reaction was concentrated and reconstituted in ethyl acetate, filtered through a pad of celite and concentrated in vacuo to give the title compound.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][CH3:19])[N:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:20])=[C:14]2[CH:15]=[N:16][N:17]([CH2:18][CH3:19])[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1O

Procedure:
253 g. [[(1-Ethyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester (0.09 mol.) are dissolved in 770 g. of diphenyl ether. The reaction mixture is heated to 235°-250° (bath temperature) and allowed to react at this temperature for 1-2 hours while the resulting ethanol is continuously distilled off. The last amount of alcohol is removed by means of a water aspirator. The diphenyl ether is separated by distillation with a fractionating column in vacuo. The 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is obtained at b.p. 0.05 115°-120°, yield 195 g. (92%), m.p. 85°-87°. The compound is recrystallized from ligroin (90°-100°), m.p. 87°-89°. Hydrolysis of this product with aqueous sodium hydroxide yields 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, m.p. 201°-202°.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:27]([F:28])=[CH:26][C:13]([C:14]([C:16](=[CH:22]N(C)C)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[C:12]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[N:11]=2)[CH2:6]1)(=[O:3])[CH3:2].Cl.C(Cl)(Cl)Cl.O>C(O)C.C(OCC)C>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[C:12]3[C:13]([C:14](=[O:15])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][N:29]3[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])=[CH:26][C:27]=2[F:28])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Yield: 98.6 %

Procedure:
In 4 ml of ethanol was suspended 200 mg of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]-3-(N,N-dimethylamino)acrylate, and 0.4 ml of 1N hydrochloric acid was added thereto, after which the resulting mixture was subjected to reaction at room temperature for 5 minutes. Subsequently, to the reaction mixture were added 10 ml of chloroform and 10 ml of water, and the organic layer was separated, washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 4 ml of diethyl ether, after which crystals were collected by filtration to obtain 180 mg (yield 98.6%) of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 39.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1.Cl[O:17]OC1C=C(C=CC=1)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][OH:17])=[N:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(COc2ccccc2)cn1
Reactant: O=C(O)c1cccc(OOCl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCc1ccc(COc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 48 %

Procedure:
To a solution of 2-methyl-5-phenoxymethyl-pyridine described in Preparation Example 186 (323 mg, 1.62 mmol) in methylene chloride was added 3-chloroperoxylbenzoic acid (473 mg, 1.78 mmol, 65%) at 0° C., and the solution was stirred at room temperature for 7 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then partitioned with ethyl acetate. The organic layer was separated, washed with an aqueous solution of saturated sodium bicarbonate and brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo. Acetic anhydride (4 mL) was added to this residue, which was then stirred for 30 minutes at 120° C. This reaction solution was cooled to room temperature, then, the solvent was evaporated in vacuo. Ethanol (5 mL), and an aqueous solution of 5N sodium hydroxide (2 mL) were added to this residue, and the solution was stirred at room temperature for 45 minutes. This reaction solution was concentrated in vacuo, the residue was partitioned in water and ethyl acetate. The organic layer was separated, washed with brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (heptane/ethyl acetate=1/1), and the title compound (167 mg, 48%) was obtained as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([NH:14][CH3:15])=[O:13])=[N:10][CH:11]=1.[H-].[Na+].Cl[C:19]1[C:20]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:26][S:25][C:21]=2[N:22]=[CH:23][N:24]=1.C(O)(=O)C>CN(C)C(=O)C>[CH3:15][NH:14][C:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:19]2[C:20]3[C:27]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:26][S:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:11][N:10]=1)=[O:13]
Reactant: CNC(=O)c1ccc(OCCCO)cn1
Reactant: Clc1ncnc2scc(-c3ccncc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1ccc(OCCCOc2ncnc3scc(-c4ccncc4)c23)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 683.3 %

Procedure:
5-(3-Hydroxypropoxy)-N-methylpyridine-2-carboxamide (52 mg, 0.25 mmol) in N,N-dimethylacetamide (2.0 mL, 22 mmol) was treated with sodium hydride (11 mg, 60%, 0.27 mmol) at ambient temperature. After 1.5 hours, the mixture was added to a solution of 4-chloro-5-pyridin-4-ylthieno[2,3-d]pyrimidine (62 mg, 0.025 mmol) in N,N-dimethylacetamide (1.0 mL) and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was then quenched by the addition of acetic acid (0.12 mL, 2.0 mmol) and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with 5% aqueous sodium bicarbonate (2×30 mL) and the organic layer was concentrated. The product was purified by silica gel chromatography using 3 to 5% methanol in ethyl acetate to give 72 mg (68%) of N-methyl-5-{3-[(5-pyridin-4-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}pyridine-2-carboxamide as a white solid. MS [M+H] 422.0, 1H NMR (CDCl3) δ (ppm) 8.74 (s, 1H), 8.66 (s, 1H), 8.54 (d, J=3.9 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.05 (d, J=2.7 Hz, 1H), 7.90-7.73 (m, 2H), 7.33 (s, 1H), 7.28 (dd, J=7.8, 4.8 Hz, 1H), 7.11 (dd, J=8.7, 2.7 Hz, 1H), 4.62 (t, J=6.0 Hz, 2H), 3.76 (t, J=6.0 Hz, 2H), 3.01 (d, J=4.8 Hz, 3H), 2.13 (t, J=6.0 Hz, 2H).
Reaction SMILES: C([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5](COCC[Si](C)(C)C)[N:4]=1)=C.FC1C(OC=O)=C(F)C(F)=C(F)C=1F>C(Cl)Cl.CCOC(C)=O>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]=[N:4]1
Reactant: C=Cc1nn(COCC[Si](C)(C)C)c2ccccc12
Agent: O=COc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1ccc2[nH]ncc2c1
Reaction time: 3 h
Yield: 190.5 %

Procedure:
6-(3-Benzamidobenzoyl)-3-E-2-aminophenyl)ethenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (0.17, 0.28 mmol) was dissolved in 3 mL of methylene chloride. To this was added formic acid pentafluorophenyl ester (0.12 g, 0.56 mmol) dropwise. After 3 h, the reaction mixture was diluted with 40 mL of EtOAc and was washed with 50/50 NaHCO3 (2×30 mL) and the organic layer was filtered through a silica plug. The residue was purified by radial chromatography through silica eluting with hexane:EtOAc/CH2Cl2 (1:1:1) which afforded 6-(3-benzamidobenzoyl)-3-E-(2-formamidophenyl)ethenyl]-(2-trimethylsilanyl)-ethoxymethyl)-1H-indazole as a clear oil (63 mg, 40%). 1H NMR (CDCl3) δ 8.48-8.36 (m, 1H), 8.20-7.84 (m, 4H), 7.61-7.52 (m, 5H), 7.41-7.32 (m, 4H), 7.26-7.01 (m, 4H), 6.82 (t, 1H, J=14.2 Hz), 3.48-3.23 (m, 2H), 0.95-0.87 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]([C@H:18]2[C:27]3[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=3)[CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)=[O:17])[CH:5]=[C:6]([F:14])[C:7]=1[C:8]([CH3:13])([CH3:12])[CH2:9][O:10][CH3:11].[ClH:37].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:37].[F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]([C@H:18]2[C:27]3[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=3)[CH2:21][CH2:20][NH:19]2)=[O:17])[CH:5]=[C:6]([F:14])[C:7]=1[C:8]([CH3:12])([CH3:13])[CH2:9][O:10][CH3:11]
Reactant: COCC(C)(C)c1c(F)cc(NC(=O)[C@H]2c3ccc(OC)cc3CCN2C(=O)OC(C)(C)C)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: COCC(C)(C)c1c(F)cc(NC(=O)[C@@H]2NCCc3cc(OC)ccc32)cc1F
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of tert-butyl (R)-1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (200 mg, 0.40 mmol) in ethyl acetate (3 mL) was added 4M hydrogen chloride/ethyl acetate (4 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to give (R)—N-(3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (175 mg, 0.397 mmol, 100%) as white crystals.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:49]=[CH:48][C:11]([CH2:12][N:13]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:14]2[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]3[CH:22]=[C:23]([CH:36]([OH:38])[CH3:37])[CH:24]=[N:25][C:26]=3[NH:27][C:28]3[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[N:15]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:38][CH:36]([C:23]1[CH:24]=[N:25][C:26]([NH:27][C:28]2[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[C:21]([C:16]2[N:15]=[C:14]([N:13]([CH2:12][C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:49][CH:48]=3)[CH2:39][C:40]3[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)[N:19]=[C:18]([CH3:20])[N:17]=2)[CH:22]=1)[CH3:37])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)OS(C)(=O)=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Methanesulfonyl chloride (0.164 mL, 2.119 mmol) was added to a solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (331.1 mg, 0.558 mmol) and triethylamine (0.350 mL, 2.510 mmol) in CH2Cl2 (7.5 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 30 min. The reaction mixture was then partitioned between CH2Cl2 (40 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl methanesulfonate (356.1 mg, 0.530 mmol, 95% yield) as a yellow-brown solid, which was used directly in Step 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]=1[C:5](OC)=[O:6].[CH3:16][NH2:17].CCO>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]=1[C:5]([NH:17][CH3:16])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Reactant: CN
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)c1cc([N+](=O)[O-])ccc1OC
Temperature: 20 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of methyl 2-methoxy-5-nitrobenzoate (389 mg, 1.84 mmol) in THF (3.0 mL) was added 33% MeNH2/EtOH solution (2.0 mL, 16.0 mmol) and the mixture was stirred at 20° C. overnight. The solution was evaporated and the residue was chromatographed (SiO2 230-400 mesh) eluting with 7:3 hexanes/EtOAc to remove 2-(methylamino)-5-nitrobenzoate derivatives. Further elution with EtOAc provided the title compound (268.5 mg, 70% yield) as a yellowish solid: LCMS (ES) m/z 211 (M+H).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2CCC(=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-:8])=[O:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:5]=[C:4]1[CH2:17][CH2:16][N:15]([C:12]2[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=2)[CH2:2][CH2:3]1
Reactant: [Li]CCCC
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (1.07 g, 3 mmol) in THF (10 mL) was added 2.5 M n-BuLi solution (1.6 mL, 4 mmol) at −70° C. The mixture was warmed to r.t. and stirred for 15 min then cooled once more to −70° C. A solution of 1-(4-nitro-phenyl)-piperidin-4-one (396 mg, 1.8 mmol) in THF (10 mL) was added then the mixture was allowed to warm to r.t. and stirred overnight. The reaction was quenched by addition of ice and extracted with ethyl acetate. The combined organic layers were then washed with water, brine and dried over sodium sulfate. Concentration to dryness afforded 4-methylene-1-(4-nitrophenyl)-piperidine (240 mg, 61%) as a solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].Br[CH2:16][CH:17]=[CH2:18]>ClCCl>[CH3:7][O:6][C:4](=[O:5])[C@H:3]([NH:2][CH2:18][CH:17]=[CH2:16])[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: COC(=O)[C@H](N)c1ccc(Cl)cc1
Reactant: C=CCBr
Agent: Cl
Solvent: ClCCl
Product: C=CCN[C@@H](C(=O)OC)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
In a 25 mL round-bottomed flask, (R)-methyl 2-amino-2-(4-chlorophenyl)acetate hydrochloride (1.000 g, 4.24 mmol, Eq: 1.00) and 3-bromoprop-1-ene (564 mg, 394 μL, 4.66 mmol, Eq: 1.1) were combined with dichloromethane (10.0 mL) to give a light yellow solution. The reaction mixture was heated to 22° C. and stirred for 1 h. The reaction mixture was stirred at 25° C. for 18 h. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 25% to 60% EtOAc in hexanes) to yield the title compound (331 mg; 33%) as a yellow oil. MS (ESI): m/z=376.1 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][N:27](C3CCCCO3)[CH:28]=2)=[CH:12][C:11]=1[F:35])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:35][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCCC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCCC[C@@H]1c1cn[nH]c1
Yield: 73.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide (150 mg, 0.22 mmol) prepared in Example 81a, triethylsilane (0.15 mL), trifluoroacetic acid (1.5 mL), dichloromethane (1.5 mL) and methanol (1.5 mL), to yield the title compound (70 mg, 72%) as a colorless solid.