Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:20]2[CH2:25][C@@H:24]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[ClH:48]>C(OCC)(=O)C>[ClH:48].[ClH:48].[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([C@H:20]2[CH2:25][C@@H:24]([C:26]([CH:28]3[CH2:29][CH2:30]3)=[O:27])[CH2:23][NH:22][CH2:21]2)[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:18])=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)C2CC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-(cyclopropylcarbonyl)piperidine-1-carboxylate (95 mg) was dissolved in ethyl acetate (3.2 ml), 4 M hydrogen chloride-ethyl acetate solution (0.8 ml) was added, and the mixture was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC, and fractions eluted with water-acetonitrile (9:1) to acetonitrile were collected. The mixture was basified (pH 10) with saturated aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (5 ml), 4 M hydrogen chloride-ethyl acetate solution (75 μl) was added and the mixture was stirred for 1 min and concentrated under reduced pressure to give the object compound (48 mg).
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:15][NH:16]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH3:27][C:28]1[S:32][C:31]([C:33](O)=[O:34])=[N:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:15][NH:16]2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[C:5]([NH:9][C:33]([C:31]2[S:32][C:28]([CH3:27])=[CH:29][N:30]=2)=[O:34])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cnc(C(=O)O)s1
Reactant: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cnc(C(=O)Nc2cccc(N(C)c3ccc4c(C=Cc5ccccc5)n[nH]c4c3)c2)s1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a solution of N-methyl-N-(3-styryl-1H-indazol-6-yl)-benzene-1,3-diamine, prepared in Example 11, (26 mg, 0.075 mmol) and 5-methyl-thiazole-2-carboxylic acid (64 mg, 0.45 mmol) in DMF (0.375 mL) at 23° C. under an atmosphere of argon was added HATU (171 mg, 0.45 mmol). After 1 h, TLC analysis (CH2Cl2:EtOAc 8:2) indicated no starting material. The reaction was quenched with saturated NaHCO3(aq) (2 mL) then diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), decanted and concentrated under reduced pressure. The oil was suspended in MeOH (2 mL) and K2CO3 (62 mg, 0.45 mmol) was added. The resulting mixture was stirred at 23° C. under an atmosphere of argon. After 1 h TLC analysis (CH2Cl2:EtOAc 8:2) indicated no starting material. The reaction was diluted with EtOAc (15 mL) and the organic phase was washed with brine (3 mL), decanted and concentrated under reduced pressure to a solid. The crude material was purified by silica gel chromatography (eluting with CH2Cl2:EtOAc 85:15) to give the title compound after purification by semi-prep. HPLC (9.9 mg, 28%). Rf sm 0.25, Rf p 0.39 (hexane:EtOAc 8:2); LCMS (ESI+) [M+H]/z Calc'd 466, found 466. Anal. Calc'd C, (69.65), H, (4.98), N, (15.04) S, (6.89). Found: C, (69.24), H, (5.35), N, (13.97) S, (5.95).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH:4]([NH:33]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:44])[CH:4]([NH2:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(N2CCC(CN(C(=O)OC(C)(C)C)c3ccccn3)CC2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1ccc(N2CCC(CN(C(=O)OC(C)(C)C)c3ccccn3)CC2)cc1

Procedure:
1.3 g (2.16 mmol) of (3) and 130 mg Pd/C (10%) in 50 ml methanol were stirred under a hydrogen atmosphere for 3 h. The reaction mixture was filtered over a pad of Celite and the solvent was evaporated to give crude (4) as oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]1(/C=C/C(N)=O)[CH2:21][NH:22]C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH3:4].[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:22][CH2:21][C:7]1[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:9](=[O:16])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13](/[CH:11]=[CH:10]/[C:9]([NH2:8])=[O:16])=[CH:12][CH:11]=2
Reactant: CCCCOC1c2ccccc2C(=O)N(CC(C)C)C1(/C=C/C(N)=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(/C=C/C(N)=O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenamide (0.14 g, 0.3 mmol) in ethyl acetate (5 mL) was added a solution of 4N hydrogen chloride in ethyl acetate (5 mL) and the obtained solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diisopropyl ether to give (E)-3-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide hydrochloride (0.11 g, 91.7%) as crystals.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]1.I[CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[CH3:15][Si:16]([CH2:19][N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]1)([CH3:18])[CH3:17]
Reactant: C1=CNc2ccccc2C=C1
Reactant: C[Si](C)(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CN1C=CC=Cc2ccccc21
Temperature: 50 °C
Yield: 89 %

Procedure:
60% sodium hydride in mineral oil (39 mg, 0.96 mmol, 1.3 equiv) was added to a stirred solution of benzazepine 25 (180 mg, 0.74 mmol, 1.0 equiv) in tetrahydrofuran (9.3 mL) at 25° C. The resulting brown suspension was stirred at 25° C. for 1 h. (Iodomethyl)trimethylsilane (0.55 mL, 3.7 mmol, 5.0 equiv) was added via syringe at 25° C. The reaction vessel was sealed under argon and heated to 50° C. via oil bath for 30 m. The reaction mixture was cooled to 25° C. and approximately 50% of the solvent volume was removed by sweeping with nitrogen. The crude reaction mixture was loaded directly onto a column and purified by silica gel column chromatography (5% triethylamine in ethyl acetate) to afford 31 (151 mg, 62% yield) as an off-white amorphous solid. Rf=0.41 (5% triethylamine in ethyl acetate); 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H, ArH), 6.48 (s, 1H, ArH), 5.89 (s, 2H, OCH2O), 3.56 (m, 2H, CH2), 3.02 (br s, 2H, NCH2Si), 2.91 (m, 2H, CH2), 2.59 (m, 2H, CH2), 2.49 (m, 2H, CH2), 0.13 (s, 9H, Si(CH3)3); 13C NMR (125 MHz, CDCl3) δ 200.86, 169.37, 146.18, 145.19, 132.71, 127.17, 110.46, 109.47, 108.06, 100.92, 57.78, 46.78, 36.22, 33.37, 28.08, −1.26; IR (neat film) 2953 (w, br), 1647 (w), 1556 (s), 1488 (m), 1445 (m), 1353 (w), 1248 (m), 1039 (m), 843 (m) cm−1; HRMS (EI) m/z: Calcd for C18H23NO3Si (MH+) 330.1525, observed 330.1525.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[F:16].[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:17])=[C:8]([F:16])[CH:9]=2)=[O:13])[CH2:30][CH2:31]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)c(F)c1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)c(F)c3)CC2)c(C)c1
Yield: 57.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-3-fluorobenzoic acid (272 mg) described in Preparation Example 26 and 1-(2,4-dimethylphenyl)piperazine (199 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (258 mg) was obtained.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: CC=CCC1Cc2ccc(Cl)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=CCC1Cc2ccc(Cl)cc2C1=O
Reaction time: 0.75 h
Yield: 85 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 45 minutes while stirring through a solution, cooled to -70°, of 10.3 g of (RS)-2-(2-buten-1-yl)-6-chloro-1-indanone in 200 ml of anhydrous dichloro-methane and 100 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 5.13 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 60 ml of dichoromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate, concentrated in a vacuum and the crude product obtained was recrystallized from ethyl acetate/hexane. 8.29 g (85%) of (RS)-2-(2-oxoethyl)-6-chloro-1-indanone were obtained as a white solid with m.p. 80°.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:16]([C:22]([NH2:25])([CH3:24])[CH3:23])=[N:17]2.C(N(CC)C(C)C)(C)C.C(O)CCC>>[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:16]([C:22]([NH:25][C:2]1[N:10]=[CH:9][N:8]=[C:7]3[C:3]=1[N:4]=[CH:5][NH:6]3)([CH3:23])[CH3:24])=[N:17]2
Reactant: Brc1ncnc2nc[nH]c12
Reactant: CC(C)(N)c1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(Nc1ncnc2[nH]cnc12)c1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 62 h

Procedure:
A mixture of 6-bromopurine (0.2423 g, 1.218 mmol), 2-(5-chloro-3-(3-fluoro-phenyl)quinoxalin-2-yl)propan-2-amine (0.3845 g, 1.218 mmol), and N,N-diisopropylethylamine (0.6363 mL, 3.653 mmol) in 1-butanol (7.000 mL, 1.218 mmol) was stirred at 100° C. After 62 h, the mixture was removed from the heat and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 30% of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to give N-(2-(5-chloro-3-(3-fluorophenyl)quinoxalin-2-yl)propan-2-yl)-9H-purin-6-amine as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.84 (1H, s), 8.12 (1H, dd, J=8.4, 1.0 Hz), 8.00 (2H, dd, J=7.5, 1.1 Hz), 7.80-7.91 (1H, m), 7.78 (1H, s), 6.88-7.19 (3H, m), 6.75 (1H, s), 6.41 (1H, s), 1.94 (6H, s); LC-MS (ESI) m/z 434.2 [M+H]+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH2:9]([C:11]1[CH:19]=[C:18]([C:20]([F:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])[CH:17]=[C:16]([CH2:30][CH3:31])[C:12]=1[C:13](Cl)=[O:14])[CH3:10]>>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:13](=[O:14])[C:12]2[C:11]([CH2:9][CH3:10])=[CH:19][C:18]([C:20]([F:29])([C:21]([F:24])([F:22])[F:23])[C:25]([F:26])([F:27])[F:28])=[CH:17][C:16]=2[CH2:30][CH3:31])[CH:6]=[CH:5][CH:4]=1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(CC)c1C(=O)Cl
Reactant: Nc1cccc(N)c1
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(CC)c1C(=O)Nc1cccc(N)c1

Procedure:
N-(3-Amino-phenyl)-2,6-diethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzamide was prepared from benzene-1,3-diamine and 2,6-diethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzoyl chloride (Example I4) using the same procedure. 1H-NMR (CDCl3, 400 MHz): 7.4 (m, 3H), 7.22 (s, 1H), 7.15 (t, 1H), 6.72 (dd, 1H), 6.52 (dd, 1H), 2.80 (q, 4H), 1.30 (t, 6H) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)=[O:2].O[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34](=[O:36])(=[O:35])[NH:33][C:32](=[O:37])[CH:31]=2)=[CH:26][CH:25]=1.C([SiH](CC)CC)C>Cl.O1CCOCC1>[O:35]=[S:34]1(=[O:36])[C:30]([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][O:2][CH2:1][C:3]3[CH:21]=[CH:20][C:6]([O:7][C:8]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:9]=4[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=3)=[CH:25][CH:26]=2)=[CH:31][C:32](=[O:37])[NH:33]1
Reactant: COC(=O)c1c(OC)cccc1Oc1ccc(C=O)cc1
Reactant: O=C1C=C(c2ccc(CO)cc2)S(=O)(=O)N1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1c(OC)cccc1Oc1ccc(COCc2ccc(C3=CC(=O)NS3(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 5.6 %

Procedure:
Methyl 2-(4-formylphenoxy)-6-methoxybenzoate (0.071 g, 0.24 mmol) and 5-[4-(hydroxymethyl)phenyl]isothiazol-3(2H)-one 1,1-dioxide (0.050 g, 0.21 mmol) were dissolved in 4 M hydrogen chloride in 1,4-dioxane (2.1 m). The reaction was stirred at ambient temperature for 1.25 h. Triethylsilane (0.13 mL, 0.84 mmol) was added and stirred for 18 h. The reaction was quenched with acetone and evaporated. The product was purified on a 50 mm Luna C18 column using a 20–100% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 30 mL per minute over a 30 minute period. The product was lyophilized to give a white powder (6 mg, 6%). 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.32 (m, 2H), 6.71 (s, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.49 (d, J=8.3 Hz, 1H), 4.62 (m, 2H), 4.55 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H); LCMS found for C26H23NNaO8S (M+Na)+: m/z=532.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([OH:18])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:19])[C:10]=2[CH3:20])=[CH:5][CH:4]=1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]([CH3:19])[C:10]([CH3:20])=[C:9]2[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1ccc(-c2c(C)n(C)c3c(O)cccc23)cc1
Product: CCOC(=O)C(C)(C)Oc1cccc2c(-c3ccc(OC)cc3)c(C)n(C)c12

Procedure:
The above compound was prepared from 3-(4-methoxy-phenyl)-1,2-dimethyl-1H-indole-7-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[C:24]([O:27][CH2:28][C:29]([CH2:34][O:35][C:36](=[O:38])[CH3:37])([CH3:33])[C:30]([OH:32])=[O:31])(=[O:26])[CH3:25]>>[C:36]([O:35][CH2:34][C:29]([CH3:33])([C:30]([O:32][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:31])[CH2:28][O:27][C:24](=[O:26])[CH3:25])(=[O:38])[CH3:37]
Reactant: CC(=O)OCC(C)(COC(C)=O)C(=O)O
Reactant: ON=C1CCOCC1
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: CC(=O)OCC(C)(COC(C)=O)C(=O)OC1(N=O)CCOCC1

Procedure:
2-Methyl-2-((4-nitrosotetrahydro-2H-pyran-4-yloxy)carbonyl)propane-1,3-diyl diacetate was prepared from tetrahydro-pyran-4-one oxime and bis(3-acetoxy-2-acetoxymethyl-2-methyl-propionate)iodobenzene (synthesized from iodobenzene diacetate and 3-acetoxy-2-acetoxymethyl-2-methyl-propionic acid which was in turn synthesized using the reported method J. Am. Chem. Soc., 118, 1996, 6388-6395) using conditions of General Method 4. 1H NMR (250 MHz, CHLOROFORM-d) δ 4.32 (4H, s), 3.98-4.17 (2H, m), 3.54-3.74 (2H, m), 2.28-2.46 (2H, m), 2.13 (6H, s), 1.77-1.94 (2H, m), 1.40 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:22]([O:24]CC2C=CC=CC=2)=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([C:22]([OH:24])=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C=C(C(=O)OCc2ccccc2)c2ccc(CC(C)C)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CC(C(=O)O)c2ccc(CC(C)C)cc2)cc1
Reaction time: 18 h

Procedure:
To a stirred solution of 4-[2-Benzyloxycarbonyl-2-(4-isobutyl-phenyl)-vinyl]-benzoic acid methyl ester (1.8 g, 4.2 mmol) in acetic acid (30 mL) was added palladium on activated carbon (˜150 mg). The flask was purged with hydrogen and stirred under hydrogen atmosphere for 18 h. TLC and LC/MS analysis indicated that the reaction had gone to completion. The reaction was filtered through celite and concentrated by rotary evaporation. Toluene (100 mL) was added and the reaction was concentrated to dryness yielding 4-[2-Carboxy-2-(4-isobutyl-phenyl)-ethyl]-benzoic acid methyl ester as a colorless solid, 1.33 g (93%). LC-MS m/z=341 [C21H24O4+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([Cl:15])[CH:6]=1)[CH:2]=[CH2:3].O=S(Cl)Cl.[CH3:20]O>>[CH2:1]([O:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9]([O:11][CH3:20])=[O:10])=[C:7]([Cl:15])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Cl)c(C(=O)O)cc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: C=CCOc1cc(Cl)c(C(=O)OC)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of compound 21 (17.0 g, 58.0 mmol) in MeOH (380 mL) was added dropwise SOCl2 (21.1 mL, 291 mmol) at 0° C. under an atmosphere of nitrogen. The mixture was stirred at 0° C. for 30 min and then, stirred at 0° C. for 14 hours. The mixture was concentrated in vacuo and poured into aq. saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide the crude product 39 (17.7 g, 99%) as a white solid.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Cl:14].CN(C1C=CC=CC=1)[CH:17]=[O:18].S(=O)(=O)(O)O>O1CCCC1.CCOCC>[Cl:14][C:8]1[C:7]([Cl:6])=[CH:12][CH:11]=[C:10]([F:13])[C:9]=1[CH:17]=[O:18]
Reactant: CN(C=O)c1ccccc1
Reactant: Fc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
Butyl lithium (48 ml of 1.6M in hexane, 52.3 mmoles) was added with stirring over 1.5 hours under nitrogen to a solution of 1,2-dichloro-4-fluorobenzene (7.85 g, 47.6 mmoles) in dry tetrahydrofuran (120 ml) at -68°. The solution wa stirred at -68° for 2 hours and then N-methyl-N-phenylformamide (6.48 ml) in dry tetrahydrofuran (15 ml) was added over 1.5 hours. After a further 1.5 hours at -68°, the reaction mixture was poured into 10% aqueous sulphuric acid and ether. The ethereal layer was separated, washed with brine, dried (Na2SO4) and evaporated to give the desired aldehyde (8 g). M+ 196/194/192, nmr (CDCl3)δ10.5 (s,H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([NH:8][C@@H:9]([CH3:36])[C@H:10]([O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[N:24]=[CH:23]2)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=[O:7])(=[O:3])N>C(O)(=O)C>[F:35][C:32]1[CH:33]=[CH:34][C:29]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:19][C@H:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)[C@@H:9]([N:8]4[C:6](=[O:7])[CH2:5][NH:4][C:1]4=[O:3])[CH3:36])=[CH:28][CH:27]=3)[CH:23]=[N:24]2)=[CH:30][CH:31]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CNC(N)=O)c1
Solvent: CC(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N2C(=O)CNC2=O)c1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
2-(carbamoylamino)-N-[(1R,2S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]acetamide (270, 141 mg, 0.29 mmol) was dissolved in acetic acid (3 mL). The reaction was heated at 120° C. with stirring for 20 h. The HOAc was evaporated and the product was purified by preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](Br)[CH:15]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][N:20]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:20]3[CH:21]=[CH:22][C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:24][C:19]3=[N:18][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccnc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3cc(C(C)(C)C)ccn23)CC1
Yield: 23.7 %

Procedure:
The title compound was prepared from 470 mg of 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)piperidine (from Procedure 23, Step C) and 277 mg of 2-amino-4-t-butyl pyridine (from Step A) in 12 mL ethanol using a procedure analogous to that described in Example 235 , Step A to provide 130 mg of the title compound as a solid.