Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([N:18]=O)[CH2:14][CH2:13]1)=[O:10].C([O-])([O-])=O.[Na+].[Na+]>O.CO>[NH2:18][N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:9]([C:3]2[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=2[Cl:1])=[O:10])[CH2:13][CH2:14]1
Reactant: Cc1[nH]c(C(=O)NC2CCN(N=O)CC2)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCN(N)CC2)c(Cl)c1Cl
Temperature: 70 °C

Procedure:
A 20% solution of TiCl3 (36 ml, 27 mmol) in water was added to a solution of 3,4-dichloro-5-methyl-N-(1-nitrosopiperidin-4-yl)-1H-pyrrole-2-carboxamide (Intermediate 87, 2.8 g, 9.2 mmol) in 60 ml of MeOH. The mixture was heated to 70° C. for 1 hour. Aqueous Na2CO3 was added to basify the mixture, which was filtered through Celite rinsing through with MeOH until no more material eluted. The filtrate was concentrated and the residual aqueous solution was saturated with NaCl before being extracted 6 times with DCM. The combined organic layers were dried (MgSO4) and solvent was removed to give product as a beige solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Li+].[OH-].O.Cl>[Cl-].[Na+].O.C(Cl)Cl.CO>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A mixture of methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (8.52 g, 18.3 mmol), LiOH (3.84 g, 91.5 mmol), water (30 mL) and methanol (60 mL) was stirred at room temperature overnight. The aqueous layer was acidified with 2 N HCl to pH around 1. Brine (30 mL) was added to the solution. White solid was precipitated out from the solution. The solid was filtered off and washed with water. The aqueous layer was extracted with ethyl acetate twice. The combined organic layers were concentrated under vacuum to give a solid. All solid was dissolved in DCM and combined into one batch. Solvent was concentrated to give crude residue. The crude residue was then triturated with ether to give 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid as a white solid (7.72 g, 86%). LC-MS m/z 452 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:21])[C:18]=3[F:20])[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:21][C:17]1[C:18]([F:20])=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:3][CH2:4]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)c(F)c32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)cnc5ccc(F)c(F)c54)CC3)nc2N1
Yield: 41.5 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7,8-difluoroquinoxalin-2(1H)-one (Intermediate 153, 130 mg, 0.42 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (70 mg, 0.42 mmol), and sodium triacetoxy borohydride (270 mg, 1.30 mmol) were reacted as described for Example 69 to give 82 mg (41%) of the free base of the product.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[N+]=[N-])=[CH:7][CH:6]=1)([OH:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C1COCC1>[C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1)([OH:3])=[O:2]
Reactant: [N-]=[N+]=NCCCCc1ccc(CC(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCCCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
Azide 7 (1.7 g, 7.2 mmol) and triphenylphosphine (1.9 g, 7.2 mmol) were dissolved in a 10% solution of water in THF (66 mL) and stirred overnight at 25° C. Then more triphenylphosphine (0.8 g, 3 mmol) was added and the heating was continued at 60° C. (oil bath) for 6 h. The solvent was removed under reduced pressure and the residue was treated with 2M HCl (100 mL) and extracted with ethyl acetate (2×50 mL). The water fraction was collected and ammonium hydroxide was added until the pH reached approximately 13. The mixture was extracted with ethyl acetate (2×100 mL) then the organic fraction was washed with brine, water and dried with sodium sulfate. Ethyl acetate was removed under reduced pressure to give 0.8 g (53%) of amine 8.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O1CCCC1.[S:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[N:7]1([CH2:6][C:5]2[CH:13]=[CH:14][C:2]([NH:1][CH:23]3[CH2:24][CH2:25][S:20][CH2:21][CH2:22]3)=[CH:3][CH:4]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: O=C1CCSCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1cc(NC2CCSCC2)ccc1CN1CCOCC1
Reaction time: 8 h

Procedure:
A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22 (0.48 g) is treated with tetrahydrofuran (10 mL) and terahydrothiopyran-4-one (0.35 gm) under an argon atmosphere. The solution is treated with acetic acid (0.20 mL) followed by sodium triacetoxyborohydride (0.80 g). After stirring overnight, the mixture is concentrated under reduced pressure. The residue is partitioned between dichloromethane and dilute aqueous sodium hydroxide. The aqueous is back-extracted with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from cyclohexane to afford 0.53 g of N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-thiopyran-4-amine as a tan solid.
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[N:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1
Reactant: CCOC(=O)CI
Reactant: FC(F)(F)c1cc(Br)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(C(F)(F)F)cc1Br
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A suspension of 5-bromo-3-(trifluoromethyl)-1H-pyrazole (i.e. the product of Example 11, Step B) (2.73 g, 12.7 mmol) and potassium carbonate (2.0 g, 14.5 mmol) in N,N-dimethylformamide (20 mL) was treated with ethyl iodoacetate (3.0 ml, 25.3 mmol), and the resulting mixture was stirred at 95° C. for 3 h. The resulting mixture was diluted with ethyl acetate, washed with water, and dried (MgSO4). The reaction mixture was concentrated in vacuo and further purified by medium-pressure liquid chromatography using 0-50% of ethyl acetate in hexanes as eluant to give 2.84 g of the title compound as a brown oil.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:9]1[CH:14]=[C:13]([CH:23]=[CH2:24])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1NC(=O)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(NC(=O)C(F)(F)F)c(C(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of N-(2-benzoyl-4-bromophenyl)-2,2,2-trifluoroacetamide (a) (0.37 g, 1.0 mmol) in degassed dry toluene (10 mL) was added a solution of tetrakis(triphenyl-phosphine) palladium [Pd(PPh3)4] in toluene (5 mL) under argon. The mixture was heated to reflux and tributyl(vinyl)tin (0.29 mL, Immol) was added in a dropwise fashion. After refluxing overnight, the mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel [hexanes: ethyl acetate (9:1)] to give N-(2-benzoyl-4-vinylphenyl)-2,2,2-trifluoro-acetamide (b) (0.22 g, 70%). 1H NMR (300 MHz, CDCl3) δ 12.0 (s, 1H), 8.62 (d, J=10.9 Hz, 1H), 7.80-7.60 (m, 5H), 7.60-7.43 (m, 2H), 6.65 (dd, J=11, 19.6 Hz, 1H), 5.69 (d, J=19.6 Hz, 1H), 5.29 (d, J=11 Hz,1H). MS: 320.2 (M+H).
Reaction SMILES: [CH:1]1([N:6]([CH3:30])[C:7]2[N:8]=[C:9]3[C:15]([C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:14][N:13](COCC[Si](C)(C)C)[C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.O.O.O.C([O-])(=O)C.[Na+]>ClCCl>[CH:1]1([N:6]([CH3:30])[C:7]2[N:8]=[C:9]3[C:15]([C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(c1cnc2c(n1)c(C(=O)C(C)(C)C)cn2COCC[Si](C)(C)C)C1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1)C1CCCC1
Reaction time: 16 h

Procedure:
A solution of impure 1-[2-(cyclopentyl-methyl-amino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one, prepared according to general procedures as described in these Examples, (0.030 g, 0.071 mmol) in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred for 3 h, then concentrated, chasing with toluene, to a yellow oil. The oil was dissolved in 1 mL of ethanol and treated with sodium acetate trihydrate (0.103 g, 0.760 mmol). The yellow mixture was stirred for 16 h, then concentrated to a yellow solid. Column chromatography (two columns: first run, 0→40% EtOAc/hexanes; second run, 66% ether/hexanes) afforded 0.0045 g (21% from impure, 12% two-step) of 1-[2-(cyclopentyl-methyl-amino)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[CH3:10][CH:11]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[CH2:12][NH2:13].O>C(O)(=O)C>[CH3:10][CH:11]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:19][CH:20]=1)[CH2:12][N:13]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8]
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: CC(CN)Cc1ccc(C(C)(C)C)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(CN=C(O)/C(Cl)=C(/Cl)C(=O)O)Cc1ccc(C(C)(C)C)cc1
Yield: 39.2 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 20.5 g (0.1 mol) of 2-methyl-3-(4-tert.-butylphenyl)-propylamine are stirred in 100 ml of glacial acetic acid under reflux for 4 hours. 100 ml of water are added, the oil which has separated out is extracted with methylene chloride, the methylene chloride phase is concentrated and the residue is recrystallized from ethanol. 14.6 g (41.2% of theory) of dichloromaleic acid N-[2-methyl-3-(4-tert.-butylphenyl)-propyl]-imide of melting point 64°-65° C. are obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:27][C:28]1[CH:29]=[C:30]([OH:35])[CH:31]=[CH:32][C:33]=1[F:34].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:35][C:30]2[CH:31]=[CH:32][C:33]([F:34])=[C:28]([F:27])[CH:29]=2)[N:11]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To an oven-dried round bottom flask was added toluene (1 mL), the product of Example 112 (0.050 g; 0.122 mmol), and 3,4-difluorophenol (0.016 g; 0.122 mmol), and cesium carbonate (0.044 g; 0.134 mmol). The reaction mixture was heated at 100° C. and stirred for 4 hours. The reaction mixture was allowed to cool to room temperature, then it was partitioned between ethyl acetate and 2N aq. NaOH solution. The organic portion was separated and washed with more 2N aq. NaOH solution (2×), brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-10% ethyl acetate:hexane) to afford the desired product: m/e=504 (M+1) Rt=4.61 min on LCMS.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[N:3]=1.Cl.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4](/[CH:13]=[CH:14]/[C:15]2[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)nc(/C=C/c2cccc([N+](=O)[O-])c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(N2CCCC2)nc(/C=C/c2cccc(N)c2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.7 %

Procedure:
To a suspension of 480 mg (1.57 mmol) of (E)-4-methyl-2-[2-(3-nitro-phenyl)-vinyl]-6-pyrrolidin-1-yl-pyrimidine in 12 ml ethanol were added at RT 1.41 g (6.28 mmol) stannous chloride dihydrate followed by dropwise addition of 1 ml 36% HCl. The mixture was stirred at RT for 12 h, the pH adjusted to pH 7 by dropwise addition of 3N NaOH and then extracted several times with AcOEt. The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The residue was applied to a silica gel column with CH2Cl2/MeOH (10/1) as eluent. Combination of the purified fractions and evacuation in vacuo gave 289 mg (65.7%) of the desired (E)-3-[2-(4-methyl-6-pyrrolidin-1-yl-pyrimidin-2-yl)-vinyl]-phenylamine as a yellow solid. ISP mass spectrum, m/e: 281.2 (M+1 calculated for C17H20N4: 281).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[H-].[Na+].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[C:18]([O:17][C:16]([N:15]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:14])[F:13])=[CH:7][N:6]2[C:2]=1[Cl:1])[S:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:33])=[O:32])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(C(F)(F)F)cn2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1nc2ccc(C(F)(F)F)cn2c1Cl)S(=O)(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of compound 9-C (0.100 g, 0.300 mmol) in DMF (5 mL) at room temperature was added 60% NaH (0.012 g, 0.300 mmol) and the reaction mixture was stirred for 10 minutes. Benzenesulfonyl chloride (0.053 g, 0.300 mmol) was added and the reaction mixture was stirred at room temperature overnight. DMF was removed in vacuo and water and methylene chloride were added. The organic layer was washed with H2O (2×), brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford the crude product. The crude material was purified by flash column chromatography (SiO2) eluting with a gradient of 0-100% ethyl acetate in hexane to afford compound 9-D (0.040 g, 28%); MS m/z (M+H+) 476.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH:26]2[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]2)=[CH:20][C:19]=1[NH:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:17].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[CH2:27][CH:26]([CH2:25][NH:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]([NH:15][C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][C:4]5[CH:44]=[C:45]([F:47])[CH:46]=[C:2]([F:1])[CH:3]=5)[CH:7]=4)[NH:11][N:10]=3)=[O:17])=[C:19]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:20]=2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC(CNc2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc(NCC2CNC2)cc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
tert-butyl 3-({[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]amino}methyl)azetidine-1-carboxylate (738 mg, 1.1 mmol) was dissolved in DCM (12 mL) and TFA (3 mL) was added. The resulting reaction solution was stirred for 3 hours at room temperature. The mixture was diluted with DCM and extracted with 10% aqueous NH3. Aqueous phase was extracted several time with DCM. Collected organic phases were washed with brine, dried over sodium sulfate and evaporated to dryness. Column chromatography purification on silica gel using dichloromethane/methanol/NH3 5N in MeOH 70:30:1 as the eluant, afforded 150 mg of the title compound.
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: CO
Solvent: C1CCOC1
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: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(C(C)C)CC)(C)C.[OH:35][C:36]([CH2:38][CH:39]1[NH:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])=[O:37].ClCl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:44]1[CH2:43][CH2:42][NH:41][C:40](=[O:45])[CH:39]1[CH2:38][C:36]([OH:35])=[O:37])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: O=C(O)CC1NCCNC1=O
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCNC(=O)C2CC(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 32 %

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, PFTU, diisopropylethylamine, and 3-(hydroxycarbonylmethyl)piperazin-2-one in dimethylformamide. Yield: 32%; C23H21Cl2N5O5 (518.355); mass spectrum: (M+H)+=518/520/522 (chlorine isotope).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:20])[CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.Cl(O)(=O)(=O)=O.[Pt](=O)=O>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]([CH3:20])[CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1
Agent: O=[Pt]=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CC(CC1CCC(C(C)(C)C)CC1)CN1CCCCC1

Procedure:
7 g of platinum dioxide and 7 g of active carbon are suspended in 500 ml of glacial acetic acid and pre-hydrogenated. Subsequently, a solution of 36.8 g of 1-[3-(p-tert.butyl-phenyl)-2-methyl-propyl]-piperidine in 1000 ml of glacial acetic acid and 67 ml of perchloric acid is added and the mixture is hydrogenated at 25° C. The catalyst is removed by filtration and the filtrate is treated with 110 g of potassium acetate dissolved in 100 ml of water. The precipitated potassium perchlorate is filtered, and the filtrate is evaporated on a rotary evaporator. The crystalline residue is made alkaline with 2-N sodium hydroxide, the free base is extracted with 500 ml of ether, washed neutral with water, dried over sodium sulphate and evaporated. By distillation there is obtained pure 1-[3-(4-tert.butyl-cyclohexyl)-2-methyl-propyl]-piperidine of boiling point 102° C./0.02 Torr.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].CO[C:8]1[C:9]2[C:10](=[N:14][O:15][N+:16]=2[O-:17])[N:11]=[CH:12][N:13]=1>CO>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:8]1[C:9]2[C:10](=[N:14][O:15][N+:16]=2[O-:17])[N:11]=[CH:12][N:13]=1
Reactant: COCCN
Reactant: COc1ncnc2no[n+]([O-])c12
Solvent: CO
Product: COCCNc1ncnc2no[n+]([O-])c12
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A solution of 1.8 g (24 mmol) of methoxyethylamine in 5 ml of methanol is added dropwise to a suspension of 4.0 g (24 mmol) of 7-methoxy[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide in 120 ml of methanol. The starting material goes into solution and immediately thereafter the product precipitates from the reaction mixture. After 30 minutes, the precipitate is filtered off with suction and washed with methanol. 3.4 g (68%) of 7-(2-methoxyethylamino)-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](Br)([CH:14]([Br:25])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Br:25])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(Br)C2(Br)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)O)cc2)CC1
Yield: 87.2 %

Procedure:
A solution of compound 4 (5.4 g 11 mmol) in methanol (300 mL) and 2.0 M NaOH (100 mL) was heated at 40° C. for 3 hrs. The solid was collected by filtration, and dried overnight under vacuum. The dry salt was dissolved in 40% acetonitrile/water, and was adjusted to pH 2 using concentrated HCl. The desired product compound 5 (3.8 g, 87%) was isolated as a white powder by filtration: 1H NMR (CDCl3) δ1.45 (s, 9H), 2.22 (dd, J=5.5 Hz, 6.1 Hz, 2H), 2.64 (dd, J=5.5 Hz, 6.1 Hz, 2H), 3.34 (dd, J=5.5 Hz, 6.1 Hz, 2H), 3.54 (dd, J=5.5 Hz, 6.1 Hz, 2H), 7.35 (d, J=6.7 Hz, 2H), 8.08 (d, J=6.7 Hz, 2H); 13 C NMR (CDCl3) δ28.3, 31.5, 34.2, 44.0, 115.3, 128.7, 129.4 130.3, 137.7, 145.2, 154.6, 170.3.