Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[C:22]=3[CH3:28])=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:29]([CH3:31])[CH3:30])[NH:11]1.C(N(CC)CC)C.[Cl:39][CH2:40][C:41](Cl)=[O:42]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:41](=[O:42])[CH2:40][Cl:39])[C:22]=3[CH3:28])=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:29]([CH3:31])[CH3:30])[NH:11]1
Reactant: O=C(Cl)CCl
Reactant: Cc1c(N)cccc1Cc1nc2n(-c3c(Cl)cc(Cl)cc3Cl)[nH]c(C(C)C)c-2c(=O)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cccc1NC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Part A: To a stirred, cooled (0° C.) solution of 110 mg (0.23 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-amino-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 4 mL of THF was added 0.084 mL (0.6 mmol) of triethylamine followed by 0.024 mL (0.3 mmol) of chloroacetyl chloride. The solution was stirred 2 h, warming to ambient temperature. The reaction was quenched by dropwise addition of 5 mL of 0.5 N aq. HCl, and the resulting solid was collected by filtration. The product was washed with water then 1:1 ether-hexanes and air-dried to afford 96 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(chloroacetamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 237-238° C. 1H NMR (300 MHz, DMSO) δ 12.42(s, 1H); 9.69(s, 1H); 7.93(s, 2H); 7.15(d, 1H, J=7.3 Hz); 7.07(t, 1H, J=7.7 Hz); 6.95(d, 1H, J=8.7 Hz); 4.25(s, 2H); 3.90(s, 2H); 3.20-3.33(m, 1H); 2.07(s, 3H); 1.30(d, 6H, J=6.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[N+:21]([O-])=O.[Sn](Cl)Cl>CCO.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[NH2:21]
Reactant: Cc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1N
Temperature: 50 °C
Yield: 98.6 %

Procedure:
7-(4-Methyl-3-nitrophenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.27 g, 0.83 mmol) was dissolved in EtOH/1,4-dioxane (20 ml, 1:1) at ambient temperature under an atmosphere of nitrogen and tin(II) chloride (0.80 g, 4.13 mmol) added. This stirred mixture was warmed at 50° C. for 6 h. The solvents were removed in vacuo, ice-water/NaHCO3 was added and extracted with dichloromethane. These extracts were washed with water and saturated brine then dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica gel, dichloromethane) gave 0.24 g of the title compound as a red solid: 1H NMR (400 MHz, CDCl3) δ 2.26 (3H, s), 3.75–3.85 (2H, br), 7.22 (1H, d, J 7.8), 7.40 (1H, dd, J 1.7, 7.8), 7.43 (1H, d, J 1.7), 8.55 (1H, s), 8.76 (1H, s); MS (ES+) m/z 294 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:5]2=[O:17].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH3:18][S:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:5]2=[O:17])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CN1C(=O)c2ccc(N)cc2C1=O
Solvent: c1ccncc1
Product: COC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Yield: 108.6 %

Procedure:
To a solution of methyl 2-(5-amino-1,3-dioxoisoindolin-2-yl)acetate (380 mg, 1.622 mmol) in pyridine (10 ml), methanesulfonyl chloride (190 μl, 2.434 mmol) was added, and the mixture was reacted overnight at room temperature. The solvent was evaporated and the resulting crude was partitioned between 1N HCl (10 ml) and EtOAc (10 ml); aqueous phase was extracted with EtOAc (3×20 ml) and the organic phase was dried over sodium sulfate. The solvent was removed affording title compound as a brown solid (550 mg, MS/ESI+ 312.9 [MH]+). It was used in the next step without any additional purification.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:34])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH2:35]([C:42](Cl)=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[C:10]([O:14][C:15](=[O:34])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][NH:33][C:42](=[O:43])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CN)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(CNC(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Diisopropylethylamine (0.17 ml, 1.02 mmol) was added in one portion to a stirred solution of [1-(4-aminomethyl-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.25 g, 0.68 mmol) in DCM (10 ml) at room temperature. To this mixture was added benzyl carbonyl chloride (0.1 g, 0.68 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 20 ml), NaOH (1M solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.32 g, 97% yield) as a white solid. δH (500 MHz, DMSO) 8.67 (t, J=5.99 Hz, 1 H) 7.66 (d, J=8.20 Hz, 2 H) 7.47 (d, J=8.35 Hz, 2 H) 7.19-7.36 (m, 5 H) 6.85 (d, J=7.25 Hz, 1 H) 4.38 (d, J=5.99 Hz, 2 H) 3.51 (s, 2 H) 3.46 (d, J=11.82 Hz, 2 H) 3.21 (br. s., 1 H) 2.33-2.43 (m, 3 H) 1.76 (d, J=10.56 Hz, 2 H) 1.30-1.45 (m, 12 H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH:17]3[CH2:19][CH:14]2[CH2:15][N:16]3[CH:20]([CH3:22])[CH3:21])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:6](=[O:31])[N:7]2[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30].[Cl:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH:17]3[CH2:19][CH:14]2[CH2:15][N:16]3[CH:20]([CH3:22])[CH3:21])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[C:6](=[O:31])[N:7]2[C:23]1[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: COc1ccc(CN2Cc3c(Br)cc(CN4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: OB(O)c1ccc(F)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(CN2Cc3c(-c4ccc(F)cc4Cl)cc(CN4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
To a solution of 5-bromo-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (200 mg, 0.31 mmol) and 2-chloro-4-fluoro-benzene boronic acid (98 mg, 0.62 mmol) in toluene (3 mL) and ethanol (0.3 mL) was added sodium carbonate (2M solution, 0.39 mL) and tetrakis(triphenylphosphine)palladium (0) (18 mg, 0.0155 mmol). The flask was evacuated and purged with nitrogen a few times. The reaction mixture was heated to reflux for 2 h and diluted with methylene chloride. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by preparative thin layer chromatography using 5% of 2N ammonium in methanol/methylene chloride as eluent provided the 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.03 (s, 3H), 1.08 (s, 3H), 1.64 (m, 2H), 2.40 (m, 1H), 2.57 (brs, 1H), 2.83 (t, 1H, J=7.3 Hz), 2.90 (brs, 1H), 3.14 (s, 1H), 3.53 (m, 2H), 3.63 (t, 1H, J=13.2 Hz), 3.81 (s, 3H), 4.11 (abq, 2H, J=14.9 Hz), 4.55 (abq, 2H, J=14.9 Hz), 6.22 (s, 1H), 6.78 (s, 1H), 6.84 (d, 2H, J=8.4 Hz), 6.99 (t, 1H, J=8.0 Hz), 7.12 (dd, 1H, J1=8.4 Hz, J2=6.0 Hz), 7.21 (d, 3H, J=8.7 Hz), 7.38 (t, 1H, J=8.0 Hz), 7.54 (m, 2H). MS (API-ES+): 695 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]2[O:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.Cl.[OH2:31]>C(#N)C>[OH:23][CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:14]=1)[CH2:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:31]
Reactant: O
Reactant: c1ccc(C2=NCC(c3cccc(OCc4ccc5ccccc5n4)c3)O2)nc1
Agent: Cl
Solvent: CC#N
Product: O=C(NCC(O)c1cccc(OCc2ccc3ccccc3n2)c1)c1ccccn1

Procedure:
A solution of 3.9 g (0.01 mol) of 4,5-dihydro-5-[3-[(2-quinolinyl)methoxy]phenyl]-2-(2-pyridyl)-1,3-oxazole in 100 ml of acetonitrile, 10 ml of water, and 1 ml of concentrated hydrochloric acid is heated on a steam bath for 5 hours. The solvents are evaporated and the residue is dissolved in a mixture of aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate solution is separated and washed with dilute aqueous sodium chloride solution. The ethyl acetate solution is dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue is dissolved in hot ethyl acetate and the solution is distilled with hexane to obtain crystals (2.2 g), m.p. 126°-129° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:18][CH2:19][N:20]([CH2:23][C:24]5[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=5)[CH2:21][CH:22]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:18][CH2:19][N:20]([CH2:23][C:24]5[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=5)[CH2:21][CH:22]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(CN2CC=C(c3cc4c(-c5cc(F)ccc5OC)ncnc4[nH]3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCN(Cc4ccc(C(=O)O)cc4)CC3)cc12
Reaction time: 12 h

Procedure:
To a solution of Example 71 (60 mg, 0.127 mmol) in 5 mL dioxane was added 6 M sodium hydroxide (212 μL, 1.270 mmol). The reaction mixture was held at 50° C. for 12 hours and then diluted with 25 mL water. The aqueous mixture was extracted with ethyl acetate (2×), and the organic fractions were discarded. The aqueous layer was diluted with an equal amount of ethyl acetate and made slightly acidic with 2.5 M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2×), and the combined organic fractions were washed with brine, dried over magnesium sulfate and concentrated to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H) 8.76 (s, 1H) 7.92 (d, J=7.93 Hz, 2H) 7.47 (d, J=8.24 Hz, 2H) 7.28-7.39 (m, 2H) 7.15-7.27 (m, 1H) 6.54 (s, 1H) 6.28 (d, J=1.53 Hz, 1H) 3.78 (s, 3H) 3.68 (s, 2H) 3.14 (s, 2H) 2.65 (t, J=5.49 Hz, 2H) 2.50 (s, 3H). MS (ESI+) m/z 459.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(Cl)(Cl)=O.[CH3:21]O>>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH3:21])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of 4-methyl-3,5-dinitro-benzoic acid (3) (35.1 g, 155 mmol) in anhydrous methanol (250 mL) is slowly added thionyl chloride (4 mL, 54 mmol). The resulting solution is heated to reflux for 16 hours. The solution is cooled to room temperature and then further cooled in an ice-water bath. The solid that forms is filtered and dried to give 4-methyl-3,5-dinitro-benzoic acid, methyl ester (32) (33.5 g, 139.5 mmol, 90% yield), as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[CH2:30]([NH2:33])[C:31]#[CH:32].ClCCl>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:14]([NH:33][CH2:30][C:31]#[CH:32])=[O:25])[CH2:7]1
Reactant: O=C(NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Reactant: C#CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 62.9 %

Procedure:
Example 58 was prepared in an analogous manner to Example 43 from Intermediate 14 (0.12 g) and propargylamine (0.014 g) using dichloromethane and triethylamine at a temperature of 22° C. to yield the title compound (0.057 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])=[C:16]([O:33][CH3:34])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:36]1C=C(S(Cl)(=O)=O)C=C[CH:41]=1>>[CH2:36]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])=[C:16]([O:33][CH3:34])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:41]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(F)c2)cc2c1CCN2S(=O)(=O)c1cccc(F)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cccc(F)c2)CC3)cc1F

Procedure:
2-Fluoro-4-{[1-(3-fluoro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 489.08 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 5 was performed using 3-fluoro-benzenesulfonyl chloride and yielded 2-fluoro-4-{[1-(3-fluoro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f21) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.[C:25](Cl)(=[O:30])/[CH:26]=[CH:27]/[CH2:28][CH3:29]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[N:12]1[CH2:17][CH2:16][N:15]([C:25](=[O:30])/[CH:26]=[CH:27]/[CH2:28][CH3:29])[CH2:14][CH2:13]1
Reactant: Cc1cccc2c(N3CCNCC3)ccnc12
Reactant: CC/C=C/C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC/C=C/C(=O)N1CCN(c2ccnc3c(C)cccc23)CC1
Yield: 9 %

Procedure:
8-Methyl-4-piperazin-1-yl-quinoline (22.7 mg, 0.1 mmol) was dissolved in dichloromethane (1 ml), triethylamine was added (1 ml of a 0.12 M solution in dichloromethane) followed by a solution of (E)-pent-2-enoyl chloride (1 ml, 0.12 M in dichloromethane). The mixture was shaken briefly, washed with 5% sodium bicarbonate solution (2×), water and evaporated to dryness. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 2.8 mg of a solid (0.009 mmol, 9%).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[C:19]([Br:27])=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[OH:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[K+].[Br:34]Br.O>C(O)(=O)C>[Br:34][C:8]1[CH:9]=[C:10]([C:12]2[C:24]3[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=3[C:19]([Br:27])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:11]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7]=1[OH:28]
Reactant: BrBr
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(C4CCCC4)c3)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a suspension of 2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.0 g, 4.4 mmol) and potassium acetate (4.4 g, 44.3 mmol) in glacial acetic acid (60 mL) was added dropwise over a period of 17 minutes a solution of bromine (0.27 mL, 5.3 mmol) in glacial acetic acid (8 mL). The thick reaction mixture was diluted with glacial acetic acid (20 mL). After stirring at room temperature for 2 h the reaction mixture was poured into water (500 mL). The solution was extracted once with diethyl ether (250 mL), and then with diethyl ether (100 mL). The combined extracts were washed twice with water (100 mL). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (98:2), followed by trituation with petroleum ether gave the title compound as a white solid (1.2 g, 52%): mp 189.5-191° C.; (DMSO-d6): δ9.19 (s, 1H), 8.18 (d, 1H), 7.65-7.61 (m, 1H), 7.50-7.47 (m, 2H), 7.33 (d, 1H), 7.11 (d, 1H), 3.42 (quintet, 1H), 2.43 (s, 3H), 2.00-1.97 (m,2H), 1.69-1.46 (m, 6H), 1.60 (s, 3H); MS(EI): [M+], 2 bromine isotope pattern, 528 (46%), 530 (100%), 532 (52%); Anal. Calc. for C25H22Br2OS: C, 56.62; H, 4.18; N, 0.00. Found: C, 55.78; H, 4.12; N, 0.05.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>C(Cl)(Cl)(Cl)Cl>[CH3:9][C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Br:8])=[CH:16][C:15]=1[CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1COc1ccccc1C
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccccc1COc1ccc(Br)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
NBS (1.46 g, 8.23 mmol) was added to a solution of 31.1 (1.59 g, 7.48 mmol) in carbon tetrachloride (8 mL). The reaction was stirred at 60° C. overnight and filtered to remove succinimide. The filtrate was concentrated in vacuo and purified via radial chromatography (15% diethyl ether in hexanes) to yield 0.65 g (25%) of 2-(2-methyl-benzyloxy)-5-bromotoluene (31.2). LC/MSD m/e: 314.2 (M+Na).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:5]=O.N1C=CC=CC=1.Cl.[O:25]([NH2:27])[CH3:26]>O>[CH3:26][O:25][N:27]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:2]([OH:1])[CH:3]=1
Reactant: CON
Reactant: O=Cc1ccc(OCCN2CCCC2)c(O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CON=Cc1ccc(OCCN2CCCC2)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
An amount of 3-hydroxy-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (150 mg, 0.64 mmol) is added pyridine (3.5 ml) at room temperature, followed by addition of methoxylamine hydrogen chloride (58.2 mg, 0.70 mmol). The mixture is stirred at ambient temperature for 24 h, and 4 mL of water is added. After the solvents were evaporated, the residue is dissolved 8 mL of anhydrous ether, washed successively with 2 mL of aqueous sodium bicarbonate, 2 mL of sodium bisulfite, and 2 mL of brine. Dried over magnesium sulfate, evaporated to give a yellow solid (100 mg). MS (ESI) m/z 265.8 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:10]([CH3:19])[N:9]2[CH3:20])=[CH:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:33]N1C(=O)CCC1=O.CCOC(C)=O>C(Cl)Cl>[Br:33][CH2:19][C:10]1[N:9]([CH3:20])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12](=[O:13])[C:11]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1c(C)n(C)n(-c2ccc(F)cc2)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CBr)n(C)n(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (1.2 g, 4.3 mmol) and azobisisobutyronitrile (AIBN) (0.09 g, 0.06 mmol) in DCM is added N-bromosuccinimide (NBS) (0.9 g, 4.3 mmol) in three portions at RT. The resulting reaction mixture is stirred at RT overnight. The mixture is concentrated and the residue is purified by silica gel column chromatography eluting with PE:EtOAc (4:1) to give the product as a white solid (1.3 g, 84% yield). MS (m/z) 357.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:29](=[O:37])[N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:28]=[CH:27][C:16]([C:17]([O:19]CC4C=CC=CC=4)=[O:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[N:8]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[CH2:3][C:4]([C:29](=[O:37])[N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:28]=[CH:27][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: [H][H]
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCc4ccccc4)cc3)cc2N=C(N)C1
Agent: [Pd]
Solvent: CO
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)O)cc3)cc2N=C(N)C1

Procedure:
Benzyl 4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate (0.025 g, 0.0504 mmol) was suspended in 1 ml of methanol, and 25 mgs of 10% Pd/C (Degussa type) was added and the mixture was hydrogenated under a balloon of hydrogen for one hour. This mixture was then filtered through GF/F filter paper, and the filtrate was concentrated to 16 mgs of 4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoic acid (78%). 1H-NMR (400 MHz, DMSO-d6) δ 7.98-8.03 (m, 2H), 7.76-7.82 (m, 2H), 7.38-7.43 (m, 1H), 7.33-7.37 (m, 1H), 7.27-7.31 (m, 1H), 6.92 (br s, 1H), 6.76 (s, 1H), 3.28-3.36 (m, 4H, partially obscurred by water peak), 2.74 (s, 2H), 1.51-1.62 (m, 4H), 0.71-0.97 (m, 6H); m/z (APCI-pos) M+1=406.2.