Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][CH:13]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:14]=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.FC(F)(F)C(O)=O>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[Cl:1][C:2]1[C:3]2[N:4]([CH:14]=[C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:12]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)CC(C=O)Nc1nc2ccccc2nc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)Cc1cn2c(n1)c(Cl)nc1ccccc12
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of the 2-(3-chloroquinoxalin-2-ylamino)-4-methylpentanal (1.03 g, 3.71 mmol) in 8 mL of trifluoroacetic anhydride was added 0.2 mL trifluoroacetic acid at room temperature. The reaction mixture was stirred at that temperature overnight. The solvents were removed under reduced pressure. And then 20 mL of saturated aqueous sodium bicarbonate was added. The resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography eluted with ethyl acetate and hexanes to give the titled compound (630 mg, 65%). MS: MH+=260:262=3:1. 1H NMR (300 MHz, CDCl3): δ 8.05 (m, 1H), 7.93 (s, 1H), 7.86 (m, 1H), 7.67 (m, 1H), 7.59 (m, 1H), 2.87 (d, 2H), 2.17 (m, 1H), 1.02 (d, 6H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>ClCCl>[Cl:12][S:13]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][C:9]([NH2:11])=[O:10])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: NC(=O)COc1ccccc1
Solvent: ClCCl
Product: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of phenoxyacetamide (50 g, 0.333 mol) in dichloromethane (500 mL) was added dropwise chlorosulfonic acid (174.7 g, 1.5 mol) at 0° C. at such a rate to maintain internal temperature between 0 to +5° C. (about 45 min). Some solid formed during this addition. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. The lower layer in the reaction mixture was added into a vigorously stirring mixture of water (500 mL) and crushed-ice (1500 g). The solid was collected, washed with water (750 mL), and pressed well with a rubber dam. The solid was suspended in acetone (100 mL), stirred for 30 min and collected. After drying, the title compound was isolated as a white solid, weighed 67.3 g (81%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1(=[O:12])[NH:10][C:9](=[O:11])[CH:8]=[CH:7]1>>[CH:2]12[O:1][CH:5]([CH2:4][CH2:3]1)[CH:8]1[CH:7]2[C:6](=[O:12])[NH:10][C:9]1=[O:11]
Reactant: O=C1C=CC(=O)N1
Reactant: c1ccoc1
Product: O=C1NC(=O)C2C3CCC(O3)C12

Procedure:
This compound can be obtained by Diels-Alder reaction of furan with maleimide, for example in analogy to Fisera, L., Melnikov, J., Pronayova, N., Ertl, P., Chem. Pap. 1995, 49 (4), 186–191.
Reaction SMILES: C([NH:4][C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[C:7]([O:27][CH3:28])[CH:6]=1)(=O)C.[OH-].[Na+]>Cl>[NH2:4][C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:18]2)=[C:7]([O:27][CH3:28])[CH:6]=1
Reactant: COc1cc(NC(C)=O)ccc1OCCCN1CCN(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(N)ccc1OCCCN1CCN(c2ccccc2)CC1
Yield: 66.6 %

Procedure:
A mixture of 23.6 g of 1-[3-(4-acetamido-2-methoxyphenoxy)-n-propyl]-4-phenyl-piperazine, 200 ml of 10% hydrochloric acid and 60 ml of conc. hydrochloric acid is refluxed for 2.5 hours. The mixture is adjusted to pH 11 by adding an aqueous 10% sodium hydroxide solution thereto. After cooling, the crystalline precipitates are collected by filtration, and then recrystallized from benzene. 14 g of 1-[3-(4-amino-2-methoxyphenoxy)-n-propyl]-4-phenyl-piperazine are thereby obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1Cl.[C:10]([CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)#[N:11].C(N(CC)CC)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[N:14]1[CH2:15][CH2:16][CH:12]([C:10]#[N:11])[CH2:13]1
Reactant: N#CC1CCNC1
Reactant: Clc1c(Br)cncc1Br
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: N#CC1CCN(c2c(Br)cncc2Br)C1

Procedure:
General procedure C was followed using 3,5-dibromo-4-chloropyridine (71 mg, 0.26 mmol), 3-cyanopyrrolidine (25 mg, 0.26 mmol), NMP (3 mL) and triethylamine (72 μL, 0.52 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 99:1) to furnish the title compound E22 as a white solid (9 mg, 10%), m.p. 159-161° C.; umax (CHCl3)/cm−1 3022, 3008, 1678, 1591, 1446, 1235; m/z (ESI) C10H12Br2N3O requires 347.9342, found [M+H]+ 347.9339.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:4]=1[CH2:19]Cl.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:10][O:9][C:7]1[CH:8]=[C:3]2[C:4](=[CH:5][C:6]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:19][N:28]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:2]2
Reactant: NCc1ccccc1
Reactant: COc1cc(CCl)c(CCl)cc1OCc1ccccc1
Product: COc1cc2c(cc1OCc1ccccc1)CN(Cc1ccccc1)C2

Procedure:
The procedure of Example 26 is repeated using 1.0 g of bis(chloromethyl)-4-methoxy-5-(phenylmethoxy)benzene and 0.6 mL of benzyl amine. This affords 0.74 g of the desired product as a beige solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.[CH3:12][NH2:13]>CO>[OH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([NH:13][CH3:12])=[O:2]
Reactant: CN
Reactant: COC(=O)c1cccc(O)c1
Solvent: CO
Product: CNC(=O)c1cccc(O)c1
Yield: 60.6 %

Procedure:
A solution of 3-hydroxybenzoic acid methyl ester (2.00 g, 0.0131 mol), methylamine (0.06 mol) and methanol (30 mL) was heated to 155° C. for 12 hours in a sealed tube. The solvent was removed in vacuo and the product was purified by column chromatography over silica gel using a gradient elution from 5 to 8% methanol in dichloromethane to give 1.20 g (60.4%) of 3-hydroxy-N-methylbenzamide as a yellow solid. MS [M+H] 152.2, 1H NMR (CDCl3) δ (ppm) 7.55 (s, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.01 (m, 1H), 6.65 (b, 1H), 6.20 (b, 1H), 3.03 (d, J=4.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19]>ClCCl.CN(C)C=O>[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]1[CH2:26][CH2:27][CH:28]([NH:31][C:4]([C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[C:8]([F:11])[CH:7]=2)=[O:6])[CH2:29][CH2:30]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(F)cnc2Cl)CC1
Reaction time: 4 h
Yield: 39.5 %

Procedure:
2-Chloro-5-fluoro nicotinic acid (3.00 g, 0.017 mol) (see Preparation 41), was dissolved in dichloromethane (100 ml) and N,N-dimethylformamide (1 drop) was added, followed by oxalyl chloride (3.0 ml, 0.034 mol). The reaction mixture was held at room temperature for 4 hours, after which time the solvent was removed in vacuo. The residue was suspended in dichloromethane (100 ml) and triethylamine (5 ml) added followed by addition of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (5.40 g, 0.026 mol) (Preparation 42a). The reaction mixture was then held under an atmosphere of nitrogen at room temperature for a further 18 hours. The reaction mixture was then washed with water (100 ml) and the organic phase dried over anhydrous magnesium sulphate. The solvent was removed in vacuo, and the residue triturated with ethyl acetate/pentane: (1:1, by volume, 10 ml) giving {4-[(2-chloro-5-fluoro-pyridine-3-carbonyl)amino]-cyclohexyl}-carbamic acid tert-butyl ester (2.5 g, 80:20 syn:anti) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1>CCO>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: CCO
Product: Nc1c(Cl)ncnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4,6-dichloro-5-nitroprimidine (E-1) (20.0 g, 104 mmmol) and stannous chloride dihydrate (117.7 g, 520 mmol) in EtOH (300 mL) is stirred at reflux for 2 h. The resulting mixture is allowed to cool to RT and then concentrated in vacuo. The residue is poured into ice water (300 mL) and neutralized with saturated NaHCO3 aqueous solution to adjust the pH value to 5-6. The resulting mixture is stirred at RT for 30 min and then extracted with ethyl acetate (3×200 mL). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 4,6-dichloropyrimidine-5-amine (E-2).
Reaction SMILES: [F:1][C:2]1([F:35])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:32][CH3:33])=[C:27]([C:29](O)=[O:30])[CH:28]=5)[C:20]([CH3:34])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[CH3:36][NH:37][CH3:38].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[F:35][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:32][CH3:33])=[C:27]([C:29]([N:37]([CH3:38])[CH3:36])=[O:30])[CH:28]=5)[C:20]([CH3:34])=[CH:19][CH:18]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1C(=O)N(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a solution of 6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6′-methoxy-3-methyl-2,3′-bipyridine-5′-carboxylic acid (72 mg, 0.15 mmol), dimethyl amine (10 mg, 0.23 mmol), and triethylamine (42 μL, 0.30 mmol) in N,N-dimethylformamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (68 mg, 0.18 mmol) and the reaction mixture was stirred at 80° C. overnight. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (51 mg, 67%). ESI-MS m/z calc. 510.49. found 511.5 (M+1)+. Retention time 1.81 minutes.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][S-:13].[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:12][S:13][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 23 h
Yield: 90.1 %

Procedure:
To a solution of 3-fluoro-4-nitrophenol (2 g, 12.7 mmol) in dry DMF (67 mL) were added by aliquots 2 equivalents of sodium thiomethoxide (1.78 g, 25.5 mmol) followed by 3 equivalents of potassium carbonate (5.27 g, 38.2 mmol). The mixture was stirred at RT for 23 hours and then water (100 mL) was added. The mixture was extracted with EtOAc, and the combined organic layers washed successively with water (60 mL) and brine (60 mL) and then dried over MgSO4. The solvent was evaporated under vacuum to provide the title compound (2.12 g, 90%) as a yellow powder.
Reaction SMILES: C([N:3]([CH2:6]C)[CH2:4][CH3:5])C.NC1C=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18].CI>CO>[CH3:6][NH:3][C:4]1[CH:5]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18]
Reactant: CCN(CC)CC
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CO
Solvent: CI
Product: CNc1cc([N+](=O)[O-])ccc1O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Triethylamine (2 ml, 14.4 mmol) was added to a solution of 2-amino-4-nitrophenol (1) (1.54 g, 10 mmol) and methyl iodide (1 ml, 16 mmol) in methanol (10 ml). After 1 hour at 40° C., further methyl iodide (1 ml) and triethylamine (1 ml) were added and the mixture was stirred at 40° C. for a further 2 hours. The reaction mixture was concentrated to dryness in vacuo, the residue was added to aqueous 2N sodium acetate solution and the mixture was extracted with ethyl acetate. The organic phase was dried with sodium sulfate and chromatographed on silica gel (eluent dichloromethane/methanol 95/5). Yield 880 mg (52%).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:16]([O:18]C)=[O:17].[I-].[Li+].O>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1cnc2c3ccccc3ncn2c1=O
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc2c3ccccc3ncn2c1=O
Temperature: 150 °C
Reaction time: 2 h
Yield: 15.1 %

Procedure:
A mixture of methyl 4-oxo-4H-pyrimido[1,2-c]-quinazoline-3-carboxylate (6.3 g) and lithium iodide (15.8 g) in N,N-dimethylformamide (100 ml) was stirred for 2 hours and a half at 150° C. and then cooled to ambient temperature. To the reaction mixture was added water separated by filtration, washed with water (600 ml) and dried to give crystalline 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylic acid (0.9 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH3:13].CN(C)C(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=[C:2]([Br:1])[N:3]=2)=[CH:18][CH:17]=1)[CH3:13]
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(Nc2nc(Br)cn3ccnc23)cc1
Temperature: 160 °C

Procedure:
A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (0.18 mol), 4-aminobenzoic acid ethyl ester (2) (0.18 mol), and N,N-dimethylacetamide (30 mL) is heated at 160° C. for 30 min. The mixture is cooled to room temperature, treated with ethyl acetate (150 mL), stirred, and filtered to afford an orange/brown solid. This solid is slurried with ethyl acetate and saturated sodium bicarbonate solution to give 4-(6-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid ethyl ester (18) freebase.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([O:12]C)OC.Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>C1COCC1.C([Li])CCC>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])=[C:3]([CH:4]=1)[CH:9]=[O:12]
Reactant: COC(OC)c1cc(C)ccc1Br
Reactant: C=CCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCCc1ccc(C)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
Step AI (4): 1-Bromo-2-(dimethoxymethyl)-4-methylbenzene (615 mg, 2.51 mmol) was dissolved in THF (10 mL) under N2 atmosphere at −78° C. n-Butyllithium (1.6 M, 3.1 mL) was added and the reaction mixture was stirred for 30 min. 5-Bromopent-1-ene (0.31 mL, 2.64 mmol) was added. The reaction mixture was warmed to rt and stirred for 18 h. The reaction was quenched with the addition of HCl (1.0 N) and was further stirred at rt for 1 h. The reaction mixture was extracted with EtOAc and washed with brine. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give 5-methyl-2-(pent-4-enyl)benzaldehyde (45 mg, 10%) as a colorless oil. LC-MS (M+H)+=189.41.
Reaction SMILES: [OH:1][C:2]1([CH2:26][OH:27])[CH2:7][CH2:6][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[O:11])[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C1COCC1.CN(C1C=CN=CC=1)C>[OH:1][C:2]1([CH2:26][O:27][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=2[O:35][CH3:34])[CH2:7][CH2:6][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[O:11])[CH2:4][CH2:3]1
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(O)(CO)CC1
Reactant: COc1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(O)(COC(=O)c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To solution of 1-hydroxy-1-hydroxymethyl-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-cyclohexane (Example 168, 20.2 mg, 0.055 mmol) in 2.0 mL of THF was added DMAP (2 mg), pyridine (0.054 mL, 0.67 mmol) and 2-methoxybenzoyl chloride (0.050 mL, 0.34 mmol). The solution was stirred at rt for 18 h and was quenched with methanol (0.5 mL). The volatiles were removed by vacuum and the residue was filtered through a plug of silica gel, concentrated and the residue was purified by HPLC (Waters RCM, μ Porosil, 25 mm×10 cm) using a mixture of (5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane, 3.0/9.0 to 8.0/0.0, mL/min) to give the separated isomers of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([NH:10][C@H:11]([C@H:27]([OH:29])[CH3:28])[C:12]([NH:14][NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].N1C=CN=C1.[CH3:36][C:37]([Si:40](Cl)([CH3:42])[CH3:41])([CH3:39])[CH3:38]>CN(C=O)C>[Si:40]([O:29][C@H:27]([CH3:28])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:30])[C:12]([NH:14][NH:15][C:16](=[O:26])[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:13])([C:37]([CH3:39])([CH3:38])[CH3:36])([CH3:42])[CH3:41]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
To a pre-cooled (0° C.) solution of N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-nitrobenzohydrazide (12.0 g, 27.79 mmol) in DMF (650 mL) was added imidazole (15.13 g, 222.31 mmol) then TBSCl (16.75 g, 111.15 mmol). The reaction was warmed slowly to room temperature, stirred for 72 h, cooled to 0° C. and quenched with H2O (600 mL). The solution was extracted with EtOAc (700 mL). The organic extract was washed with H2O (2×300 mL) and 5% aq. citric acid (3×250 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a light yellow oil, which was purified by flash chromatography over silica gel (30-40% EtOAc in hexanes) to provide the title compound as a colourless solid (8.50 g, 56%): 1H NMR (400 MHz, d6-DMSO, δ in ppm) 10.93 (s, 1H), 10.57 (s, 1H), 8.34 (dm, J=8.8 Hz, 2H), 8.07 (dm, J=9.0 Hz, 2H), 7.59 (d, J=8.6 Hz, 1H), 6.84 (d, J=9.0 Hz, 1H), 5.69 (d, J=8.4 Hz, 1H), 5.28 (s, 1H), 4.38 (pentet, J=6.3 Hz, 1H), 4.16 (dd, J=6.5, 8.0 Hz, 1H), 2.26 (s, 3H), 1.27 (d, J=6.3 Hz, 3H), 0.85 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:38]3[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=3)=[C:14]([C:34]([O:36][CH3:37])=[O:35])[N:15]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:22][CH:21]=3)[C:16]2=[O:19])=[CH:11][C:10]=1[O:50][CH3:51])C1C=CC=CC=1>O1CCCC1.CO.[C].[Pd]>[C:30]([O:29][C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([N:15]2[C:14]([C:34]([O:36][CH3:37])=[O:35])=[C:13]([C:38]3[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=3)[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:50][CH3:51])[CH:11]=3)[C:16]2=[O:19])=[CH:21][CH:22]=1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OCc3ccccc3)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of the compound obtained in Example 4 (17.0 g) in a mixture of tetrahydrofuran (150 ml) and methanol (100 ml) is added palladium-carbon (1.0 g) under nitrogen atmosphere, and the mixture is subjected to catalytic reduction (3 atms) for one hour. The palladium-carbon is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 2-[4-(tert-butoxycarbonylamino)phenyl]-7-hydroxy-6-methoxy-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (13.3 g) as listed in Table 2.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[N:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)ccn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.6 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic-acid tert-butylamide (0.44 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (MeOH, dichloromethane) yielded the title compound as a white solid (0.11 g, 21%). MS (ISP) 532.0 [(M+H)+]; mp 262.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@@H:12]1[CH2:16][C@@H:15]([C:17](O)=[O:18])[C@H:14]([C:20]([N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)=[O:21])[CH2:13]1)(=[O:11])=[O:10].[CH2:28]1[C:30]([NH2:33])([C:31]#[N:32])[CH2:29]1.Cl>>[C:31]([C:30]1([NH:33][C:17]([C@@H:15]2[CH2:16][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:13][C@H:14]2[C:20]([N:22]2[CH2:23][C:24]([F:27])([F:26])[CH2:25]2)=[O:21])=[O:18])[CH2:28][CH2:29]1)#[N:32]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)C[C@H]1C(=O)N1CC(F)(F)C1
Reactant: N#CC1(N)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 117, step 7, using (1R,2R,4S)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid and 1-amino-cyclopropyl cyanic hydrochloride. Off-white solid. MS (EI): 490.1 (M+H)+.