Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([OH:22])=[O:21])=[C:8]([CH3:23])[NH:7][C:6]=1[CH3:24])=[O:4].[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43]Br)=[CH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([O:22][CH2:43][CH2:42][O:41][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][CH2:33][NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])=[CH:40][CH:39]=2)=[O:21])=[C:8]([CH3:23])[NH:7][C:6]=1[CH3:24])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 20 h

Procedure:
3.3 g (100 mmol) of 1,4-dihydro-2.6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-methyl ester, 3.5 g (10 mmol) of the bromoethoxy compound from step 1b), and 2.8 g (20 mmol) of potassium carbonate are heated at boiling in 50 ml of acetonitrile while stirring and under reflux. After approximately 20 hours, the reaction mixture is filtered and the filtrate is concentrated by evaporation under reduced pressure. The residue is dissolved in ethyl acetate and washed with water, and the organic phase is concentrated by evaporation in vacuo. Crude 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-tertiary butoxycarbonylaminoethyl)-phenoxy]-ethyl}-ester 5-methyl ester is thus obtained and is used further in crude form.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:38])[CH2:12][CH2:13][C:14]([NH:16][CH2:17][C:18]2[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]3[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]3=[N:22][C:23]=2[CH2:24][CH3:25])=[O:15])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.[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>[CH2:29]([N:26]1[C:21]2=[N:22][C:23]([CH2:24][CH3:25])=[C:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][C:11]([NH:10][CH2:9][C:4]3[CH:3]=[C:2]([C:45]4[CH:44]=[CH:43][CH:42]=[C:41]([CH:39]=[O:40])[CH:46]=4)[C:7]([CH3:8])=[CH:6][CH:5]=3)=[O:38])[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]2[CH:28]=[N:27]1)[CH3:30]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(C)c(Br)c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(C)c(-c2cccc(C=O)c2)c1
Yield: 59 %

Procedure:
A mixture of N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1.16 g, 1.981 mmol), (3-formylphenyl)boronic acid (0.372 g, 2.481 mmol), tetrakis (triphenylphosphine) palladium (0) (0.081 g, 0.07 mmol), and sodium carbonate (0.530 g, 5.00 mmol) in 1,4-dioxane (12 mL) and water (4 mL) under an N2 atmosphere was microwaved for 30 min at 140° C. The reaction mixture was diluted with EtOAc and water and the layers were separated. The organic layer was washed with saturated NaCl, dried over Na2SO4, and then evaporated giving a viscous taffy. It was purified on a Chromatotron Plate Silica Gel (1000μ) eluting with CH2Cl2— MeOH (97:3) to afford N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-6-methyl-3-biphenylyl)methyl]butanediamide (713.9 mg, 47.1%) as a viscous, nearly colorless, foam, taffy. LC-MS m/z 611.5 (M+H)+, 0.86 min (ret time).
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13](Cl)=[CH:12][C:11]=2[C:10]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22][C:9]1=2)(=O)=O.O>CO.[Pd]>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:6][CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22][C:9]1=2
Reactant: CN1CCc2c(n(CC(OS(C)(=O)=O)c3ccccc3F)c3ccc(Cl)cc23)CC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CN1CCc2c(n(CCc3ccccc3F)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.9 %

Procedure:
2-(9-Chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(2-fluorophenyl)ethyl methanesulfonate (530 mg, 0.001177 mol) was dissolved in methanol and 10% Pd—C (62 mg, 0.5885 mmol) was added. A drop of water was added and the reaction mass is stirred at RT for 24 h under hydrogen atmosphere. The reaction mass was filtered through Celite and the filtrate concentrated to obtain the crude compound. The crude was purified by preparative HPLC to obtain 140 mg desired compound. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.60 (s, 1H), 7.30-7.20 (m, 2H), 7.20-7.15 (d, 1H), 7.10-7.00 (t, 12H), 7.00-6.90 (t, 1H), 6.90-6.80 (t, 1H), 4.40-4.30 (t, 2H), 3.90-3.85 (t, 2H), 3.60-3.50 (t, 2H), 3.30-3.10 (m, 4H), 3.10 (t, 2H), 2.90 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:17]([C:18]([OH:20])=O)=[C:5]2[CH:6]=[C:7]([CH3:16])[CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:4]2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[C:42]([O:46][C:47](=[O:56])[NH:48][C:49]([CH3:55])([CH2:52][CH2:53][CH3:54])[CH2:50][NH2:51])([CH3:45])([CH3:44])[CH3:43].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:42]([O:46][C:47](=[O:56])[NH:48][C:49]([CH3:55])([CH2:52][CH2:53][CH3:54])[CH2:50][NH:51][C:18]([C:17]1[C:2]([CH3:1])=[N:3][N:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])=[CH:8][C:7]([CH3:16])=[CH:6][C:5]=12)=[O:20])([CH3:45])([CH3:44])[CH3:43]
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Reactant: Cc1cc(OCCC(C)C)n2nc(C)c(C(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCCC(C)C)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 45 mg (0.163 mmol) of 2,5-dimethyl-7-(3-methylbutoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 8A in 3 ml of tetrahydrofuran was admixed with 30 mg (0.177 mmol) of 1-hydroxybenzotriazole and 30 mg (0.177 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The resulting solution was stirred at room temperature for 15 min, and then 45.7 mg (0.212 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 152A were added, followed by 0.85 ml (0.212 mmol) of N,N-diisopropylethylamine. The mixture was stirred at room temperature for a further 18 h. The solvent was drawn off under reduced pressure and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was removed and washed with water and aqueous sodium chloride solution, dried with a phase separation cartridge and dried further under reduced pressure, which gave 80 mg (61% of theory, 54% pure) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=O.[C:14](#[N:17])[CH:15]=C.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH:4]=[CH:15][C:14]#[N:17]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc([N+](=O)[O-])cc1C=CC#N

Procedure:
0.336 g (1.5 millimols) of palladium acetate, 29.93 g (150 millimols) of 2-methyl-5-nitrobenzoyl chloride, 9.94 g (187.5 millimols) of acrylonitrile and 27.80 g (150 millimols) of tri-n-butylamine, in 150 ml of p-xylene, are stirred for 80 minutes at 130°. The mixture is then extracted, and dried, as described in Example 68. The crude product is chromatographed on silica gel in toluene and is then recrystallised from carbon tetrachloride/cyclohexane. 6.3 g (22% of theory) of white crystals, of melting point 115.6° C., are obtained. Analysis for C10H8N2O2 : calculated C 63.83%, H 4.29%, N 14.89%; found C 63.8%, H 4.2%, N 15.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CCCC)=[O:24])=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[H][H]>N.CO.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:5]([CH3:34])([CH3:6])[CH3:4])=[O:24])=[CH:18][C:17]=3[CH2:30][NH2:31])=[CH:13][CH:12]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: [H][H]
Reactant: CCCCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CN)c1
Yield: 29.1 %

Procedure:
To tent-Butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (1.09 g, 2.22 mmol) in 6 ml of 7 N ammonia in methanol at ambient temperature was added Raney-Ni (0.019 g) and the reaction was stirred under a balloon of hydrogen gas at ambient temperature. The reaction was filtered and concentrated to give tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(aminomethyl)phenyl)acetate (0.160 g, 15%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][CH2:8]Br.[CH3:10][C:11]1([CH3:25])[C:15]([CH3:17])([CH3:16])[O:14][B:13]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[O:12]1>CC#N>[F:7][CH2:8][O:24][C:21]1[CH:20]=[CH:19][C:18]([B:13]2[O:14][C:15]([CH3:17])([CH3:16])[C:11]([CH3:25])([CH3:10])[O:12]2)=[CH:23][CH:22]=1
Reactant: FCBr
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(OCF)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cs2CO3 (651.6 mg, 2.0 mmol) and then FCH2Br (446.6 mg, 4.0 mmol) were added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (220 mg, 1.0 mmol)) in CH3CN (10 ml). After stirring at room temperature overnight, the mixture was filtered and concentrated. Purification by column chromatography afforded 2-(4-(fluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: LCMS tR=1.39 Min (5 min run, UV254nm). Mass calculated for, M+ 252.1, observed LC/MS m/z 253.1 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:19][CH3:20])([C:13]2[S:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:21]>C1COCC1>[CH2:11]([C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[C:5]([CH3:21])[CH:6]=1)([C:13]1[S:14][CH:15]=[C:16]([CH3:18])[CH:17]=1)[CH2:19][CH3:20])[CH3:12]
Reactant: CCC(CC)(c1ccc(C(=O)OC)c(C)c1)c1cc(C)cs1
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CO)c(C)c1)c1cc(C)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a 0° C. solution of 4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-benzoic acid methyl ester (6.7 g, 21.2 mmol) in THF (100 ml) is added 1M LiA1H4/THF (32 ml, 32 mmol). After stirring at RT for 2 h, the reaction is quenched with water (1 ml) followed by 5N NaOH solution (1 ml) and water (3 ml). The mixture is filtered and the filtrate is concentrated to give the title compound as a clear oil (6 g, 98%).
Reaction SMILES: [OH-].[Li+].[CH2:3]([N:5]1[CH2:9][CH2:8][C@@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[S:18]([NH:21][C:22]2[C:31]([C:32]([O:34]C)=[O:33])=[C:30]3[C:25]([CH:26]4[CH2:36][CH:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:20])=[O:19])[CH2:6]1)[CH3:4]>O1CCOCC1.O>[CH2:3]([N:5]1[CH2:9][CH2:8][C@@H:7]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[S:18]([NH:21][C:22]2[C:31]([C:32]([OH:34])=[O:33])=[C:30]3[C:25]([CH:26]4[CH2:36][CH:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:19])=[O:20])[CH2:6]1)[CH3:4]
Reactant: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 85 °C
Yield: 67.3 %

Procedure:
Lithium hydroxide (0.111 g) was added to a solution of methyl (1aRS,7bSR)-5-[2-((R)-1-ethyl-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 95, 0.13 g) in a mixture of dioxane (4 mL) and water (1 mL) and the mixture was stirred and heated at 85° C. overnight. After cooling, the mixture was filtered and the filtrate was acidified by addition of 10% aqueous citric acid (1 mL) and then extracted with DCM. The organic extract was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with diethyl ether and the solid was collected by filtration to give (1aRS,7bSR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.085 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)c(Cl)c(OC)c1OC
Reaction time: 6 h

Procedure:
Combine methyl 2-chloro-3,4,5-trimethoxybenzoate (2.0 g, 7.8 mmol) and a 1 M aqueous solution of sodium hydroxide (100 mL, 100 mmol) in methanol (50 mL). After 6 hours, adjust the pH to about 2 using a 1 M aqueous hydrochloric acid solution and extract with dichloromethane. Dry the combined organic layers over MgSO4, filter, and concentrate in vacuo to give the title compound: Rf=0.81 (silica gel, 10% methanol/85% c.hloroform/5% acetic acid).
Reaction SMILES: Br.Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:17][CH2:16]1>>[NH2:14][C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:22]3[C:23]([CH3:26])=[CH:24][CH:25]=[C:20]([C:19]([NH:18][CH:15]4[CH2:17][CH2:16]4)=[O:36])[CH:21]=3)=[CH:4][CH:5]=2)[N:10]=1
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: Br
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2csc(N)n2)cc1

Procedure:
Example 5 was prepared using 4-(4-bromophenyl)-2-thiazolamine monohydrobromide and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: C(S([C:11]1[N:16]=[C:15]2[N:17]([CH2:29][C:30]3[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=3)[C:33]([O:35][CH3:36])=[O:34])[C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Br:27])[CH2:20][C:14]2=[CH:13][N:12]=1)(=O)=O)C1C=CC=CC=1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[NH:40]([C:11]1[N:16]=[C:15]2[N:17]([CH2:29][C:30]3[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=3)[C:33]([O:35][CH3:36])=[O:34])[C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Br:27])[CH2:20][C:14]2=[CH:13][N:12]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1cccc(CN2C(=O)N(c3ccccc3Br)Cc3cnc(S(=O)(=O)Cc4ccccc4)nc32)c1
Product: COC(=O)c1cccc(CN2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 100 °C
Yield: 20 %

Procedure:
A mixture of 0.655 g (1.1 mmol) of methyl 3-[[7-benzylsulfonyl-3-(2-bromophenyl)-1,2,3,4-tetrahydro-2-oxopyrimido[4,5-d]pyrimidin-1-yl]methyl]benzoate and 0.55 ml (6 mmol) of aniline was heated at 100° C. for 2 hours. The reaction mixture was partitioned between dichloromethane(10 ml) and 2M hydrochloric acid (10 ml) and the dichloromethane layer separated, washed with saturated aqueous sodium bicarbonate (10 ml), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel using 1:1 ethyl acetate/hexane as the eluent. Product containing fractions were combined and evaporated to give 120 mg (20%) of methyl 3-[[7-anilino-3-(2-bromophenyl)-1,2,3,4-tetrahydro-2-oxopyrimido[4,5-d]pyrimidin-1-yl]methyl]benzoate as a white solid of melting point 79-82° C. [Mass spectrum (ESI) MH+ =546].
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][C:13]1[N:18]=[C:17]2[S:19][C:20]3[CH2:21][N:22]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:24][C:25]=3[C:16]2=[C:15]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[C:14]=1[Cl:43].C(N(CC)CC)C>ClCCl>[CH2:26]([N:22]1[CH2:23][CH2:24][C:25]2[C:16]3[C:17]([S:19][C:20]=2[CH2:21]1)=[N:18][C:13]([CH2:12][NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[C:14]([Cl:43])[C:15]=3[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2c(Cl)c(CNS(=O)(=O)c3ccccc3)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Benzenesulfonyl chloride (0.156 g) was added to a mixture of the compound (0.35 g) obtained in Example 18B, triethylamine (0.096 g) and dichloromethane (8 ml) under ice-cooling, the mixture was stirred for 1 hour, the reaction mixture was washed successively with water, an aqueous saturated solution of sodium bicarbonate and water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to yield 7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-2-phenylsulfonylaminomethyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine (0.25 g, 55%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 153 to 154° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([O:16][C:17](=[O:26])[NH:18][CH:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:26])[NH:18][CH:19]1[CH2:20][CH2:21][CH:22]([NH:25][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=2[OH:1])[CH2:23][CH2:24]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: O=C(O)c1ccc(O)cc1O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2ccc(O)cc2O)CC1
Yield: 26.1 %

Procedure:
2,4-Dihydroxy benzoic acid (1.6 g, 10.38 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (2.22 g, 10.38 mmol) and other reagents as described in Example 9(e) were used to afford 0.95 g of the required product. 1H NMR (DMSO-d6): δ 1.20 (4H, m), 1.4 (9H, m), 2.1 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 6.2 (2H, d), 6.74 (1H, s), 7.7 (1H, s), 8.26 (1H, s), 10.0 (1H, brs), 13.0 (1H, brs).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[C:13]1([CH3:20])[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[OH-].[K+]>[Cr].[Co]>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([C:18]1[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1cccc(C)c1
Agent: [Co]
Agent: [Cr]
Agent: [K+]
Product: Cc1ccc(C(=O)c2ccccc2[N+](=O)[O-])c(C)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
2-Nitrobenzoic acid (16.7 g, 0.1 mol) and m-xylene (11.7 g, 0.11 mol) were charged in a 300 cc Hastelloy-C autoclave. The reaction mixture was heated to 50° C. and stirred for 3 hours. Most of the HF was vented through a KOH scrubber and the product was transferred to a flask containing ice (100 g). The contents of the flask were neutralized to a pH=7. A brown solid (11.5 g) precipitated which was removed via filtration and discarded. The filtrate was extracted with ethyl acetate (2×100 mL). The ethyl acetate layer was dried and concentrated to afford the product (94% pure) (9.7 g, 35% yield) of 2-nitro-2',4'dimethyl benzophenone. A small portion (5.0 g) of the product was purified via Kugelrohr distillation to afford a yellow solid (4.2 g); m.p. 78°-80° C.
Reaction SMILES: C([N:8]1[C:20]2[C:19]([O:21][CH2:22][CH2:23][CH2:24]Br)=[C:18]3[N:26](C(OC(C)(C)C)=O)[C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][C:32]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:41])[CH:13]=2)(OC(C)(C)C)=O.C([CH:49]([NH2:56])[CH:50]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]1)(OC(C)(C)C)=O>>[Cl:41][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:20]1[C:19]([O:21][CH2:22][CH2:23][CH2:24][N:52]3[CH2:53][CH2:54][CH2:55][CH:50]([CH2:49][NH2:56])[CH2:51]3)=[C:18]3[NH:26][C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][C:32]=4[C:17]3=[CH:16][C:15]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(OCCCBr)c21
Reactant: CC(C)(C)OC(=O)C(N)C1CCCNC1
Product: NCC1CCCN(CCCOc2c3[nH]c4ccc(Cl)cc4c3cc3c2[nH]c2ccc(Cl)cc23)C1
Reaction time: 8 h
Yield: 99 %

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the staring material is 5,7-diBOC-2,10-dichloro-6-(3-bromopropoxy)indolo[2,3-b]carbazole and the reagent is 3-(Boc-aminomethyl)piperidine. The reaction can be completed at room temperature overnight 1H-NMR (400 MHz, CDCl3) δ ppm 9.76 (s, 2 H), 8.34 (s, 1 H), 8.08 (s, 2 H), 7.40-7.31 (m, 4 H), 4.35 (t, J=5.6 Hz, 2 H), 3.35-3.20 (m, 2 H), 2.89-2.75 (m, 2 H), 2.70-2.53 (m, 2 H), 2.18-1.71 (m, 9 H), 1.17-1.03 (m, 2 H); MS (ESI) m/z 493.2 (M−H)−; MS (ESI) m/z 495.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH:15]=[CH:14][CH2:13][C@@H:12]1[CH2:11][N:10]([C@@H](C1C=CC=CC=1)C)[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClC(Cl)C>[C:1]([O:5][C:6]([C@@:8]12[CH:15]=[CH:14][CH2:13][C@@H:12]1[CH2:11][N:10]([C:32]([O:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:33])[CH2:9]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@H]2CC=C[C@@]2(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@]12C=CC[C@@H]1CN(C(=O)OCc1ccccc1)C2
Temperature: 40 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
[(1S,5S)-3-[(1R)-1-Phenylethyl]-3-azabicyclo[3.3.0]oct-7-en-1-yl]carboxylic acid tert-butyl ester (370 mg, 1.18 mmol) was dissolved in dichloroethane (3 mL). Benzyloxycarbonyl chloride (1.01 g, 5.90 mmol) was added, and the mixture was stirred at 40° C. for three hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (10% ethyl acetate/hexane) to give 385 mg of the title compound as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[C:25]([F:32])[CH:24]=4)=[CH:19][C:17]=3[N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[F:32][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[N:18][C:17]=3[CH:19]=2)[CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]
Reactant: NC(=O)c1ccc(-c2ccc3oc(C4CCN(Cc5ccccc5)CC4)nc3c2)cc1F
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1ccc(-c2ccc3oc(C4CCNCC4)nc3c2)cc1F
Reaction time: 16 h
Yield: 102.5 %

Procedure:
Intermediate 24 (100 mg, 0.23 mmol) dissolved in MeOH (10 ml) and added Pd/C (100 mg). This mixture was stirred under 60 Psi hydrogen atmosphere in an autoclave for 16. After 16 h, reaction mass filtered through celite and celite was washed with MeOH. MeOH was removed on rotavapour to obtain the titled compound (80 mg) as an off-white solid.