Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][OH:8].[F:9][C:10]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O>O.C(O)C>[F:9][C:10]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[N:7][OH:8]
Reactant: COc1cccc(C=O)c1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc(C=NO)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To a stirred solution of sodium hydrogen carbonate (2.73 g, 32.5 mmol) in water (50 mL) was added hydroxylamine hydrochloride (2.30 g, 33.2 mmol) in portions over 30 min. The resultant solution was added to a vigorously stirred suspension of 2-fluoro-3-methoxybenzaldehyde (5.00 g, 32.5 mmol) in ethanol (45 mL) and the reaction mixture stirred at RT for 16 hr. The resultant precipitate was removed by filtration and washed with water (3×100 mL) and then allowed to dry in air to afford 2-fluoro-3-methoxybenzaldehyde oxime (14) (4.69 g, 85%) as a white crystalline solid: m/z 170 (M+H)+ (ES+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:17]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]2[C:26]([O:28][C:29](=O)[C:19]=2[CH:18]=1)=[O:27]>C(O)(=O)C>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:4]1[CH:3]=[C:2]([N:1]2[C:26](=[O:27])[C:20]3[C:19](=[CH:18][CH:17]=[C:22]([C:23]([OH:25])=[O:24])[CH:21]=3)[C:29]2=[O:28])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(-c2nc3ccccc3o2)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4ccccc4o3)c1)C2=O
Yield: 77 %

Procedure:
2-(3-Aminophenyl)benzoxazole (500 mg, 2.4 mmol) and 1,2,4-benzenetricarboxylic anhydride (546 mg, 2.4 mmol) in acetic acid (25 ml) were heated to reflux overnight. On cooling the precipitate was filtered, washed with acetic acid and dried to give the title compound 710 mg (71%). 1H NMR (CDCl3) δ 8.44(dd, J=1.5, 7.9 Hz, 1H), 8.36(d, J=4.5 Hz, 2H) 8.28(dt, J=1.5, 7.2 Hz, 1H), 8.12(d, J=7.9 Hz, 1H), 7.86–7.39(m, 4H), 7.45(m, 2H). MS 383 m/z (M−H)−.
Reaction SMILES: Br.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)C(C)C)C>CO>[OH:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH2:2][N:3]([CH2:15][CH2:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5]2
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc2c(c1)CCNC2
Agent: Br
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCN1CCc2cc(O)ccc2C1
Yield: 79.8 %

Procedure:
A solution of 1,2,3,4-tetrahydroisoquinolin-6-ol hydrobromide (345 mg, 1.5 mmol), tert-butyl acrylate (0.44 ml, 3.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.6 ml, 15.0 mmol) in MeOH was irradiated in the microwave at 90° C. for 1800 s. Removal of the solvents gave the residue which was purified on ISCO column (2% to 5% MeOH/CH2Cl2) to provide the title compounds (332 mg, 80%). 1H NMR (400 MHz, CD3OD) δ 6.85 (d, 1H), 6.55 (dd, 1H), 6.54 (s, 1H), 3.55 (s, 2H), 2.83 (m, 4H), 2.76 (m, 2H), 2.54 (dd, 2H), 1.45 (s, 9H). MS (ESI) m/z: Calculated: 277.17; Observed: 277.90 (M++1).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[C:21]([NH:23][CH3:24])=[O:22]>>[CH:26]1([CH2:25][C@H:20]([NH:19][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:21](=[O:22])[NH:23][CH3:24])[CH2:28][CH2:27]1
Reactant: CNC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CNC(=O)[C@H](CC1CC1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (S)-2-amino-3-cyclopropyl-N-methyl-propionamide hydrochloride (1:1) (Example 24b) as starting materials, and isolated (77 mg, 89%) as light yellow oil; LC-MS (UV peak area, ESI) 100%, 359.2081 (M+H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f19) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19]O.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: OCCOC1CCCCO1
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCOC1CCCCO1)c1cnc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
A solution of 5-chloro-pyrazine-2-carboxylic acid (prepared as in Example 29, 3.15 g, 19.94 mmol) in methylene chloride (50 mL) was treated with 2-(tetrahydropyran-2-yloxy)ethanol (2.91 g, 19.94 mmol). The solution was cooled to 0° C. and then was treated with triethylamine (5.60 mL, 39.88 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (5.07 g, 19.94 mmol). The mixture was stirred at 0° C. for 15 min and then at 25° C. for 24 h. The mixture was extracted with methylene chloride and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) afforded 5-chloro-pyrazine-2-carboxylic acid 2-(tetrahydro-pyran-2-yloxy)-ethyl ester as a colorless oil (3.41 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(COC)OC.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1cc(Cl)ncn1
Yield: 74.7 %

Procedure:
4,6-dichloropyrimidine (6.0 g, 40 mmol) and 2-methoxyphenylboronic acid (4.41 g, 29 mmol) were added to a solution of dimethoxyethane (120 mL) and water (18 mL), followed by the addition of NaHCO3 (6.72 g, 80 mmol) and (PPh3)2PdCl2 (0.84 g). to this end the reaction mixture was allowed to reflux for 8 h, and then the solvent removed under reduced pressure. The residue was taken up in CH2Cl2 (100 mL), and the resulting solution washed with water, dried over anhydrous K2CO3, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chropatography on silica gel (eluent CH2Cl2) and recrystallized from hexanes yielding 4-chloro-6-(2-methoxyphenyl)-pyrimidine (4.78 g; 75%).
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][N:5]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[CH2:6][CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[CH2:9][CH2:10][NH2:11]>C(O)C.[Pd]>[OH:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][N:5]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[CH2:6][CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH2:9][CH2:10][NH2:11]
Reactant: NCCN(CCN(Cc1ccccc1O)Cc1ccccc1O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: NCCN(CCN(Cc1ccccc1O)Cc1ccccc1O)Cc1ccc(N)cc1
Reaction time: 24 h

Procedure:
In 40 mL of absolute ethanol was dissolved 400 mg of bis(2-hydroxybenzyl)-4-(p-nitrobenzyl)diethylenetriamine (prepared in Example 1) and 100 mg of palladium on activated charcoal (10% Pd). The mixture was hydrogenated at 40 psi (275.8 kPa) for 24 hours. The catalyst was removed by filtration. The ethanolic solution was evaporated to provide bis(2-hydroxybenzyl)-4-(p-aminobenzyl)diethylenetriamine, and was characterized by: 1H NMR (CDCl3), carbon protons only; amine and hydroxyl protons were not included: δ 2.6 (s, 8H), 3.4 (s, 2H), 3.8 (s, 4H), 6.4-7.2 (m, 12H). 13C NMR (CDCl3) δ 46.06, 52.35, 53.48, 58.74, 115.08, 116.33, 118.87, 122.50, 128.35, 128.62, 130.03, 145.74, 158.31.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:22]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]4[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=4[N:23]=3)[CH2:19][CH2:20]O)=[CH:14][CH:13]=2)=[N:4]1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:65])C(=O)C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:65][CH2:20][CH2:19][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([C:5]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:17][CH:16]=1)[C:22]1[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1nc(-c2ccc(C(CCO)c3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(C(CCBr)c3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of 3-{4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl}-3-(1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-benzo[d]imidazol-2-yl)propan-1-ol (80 mg) and PPh3 (43.7 mg) in DMF (2 mL) was added NBS (27.0 mg) at room temperature. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The mixture was neutralized with saturated NaHCO3 aqueous solution at 0° C. and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (75 mg).
Reaction SMILES: [I:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=[O:15]>O1CCCC1.[Li+].[OH-].CO>[I:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cnn(-c2cccc(F)c2)c1I
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2cccc(F)c2)c1I
Reaction time: 8 h
Yield: 90 %

Procedure:
Ethyl 5-iodo-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylate (589 mg, 1.64 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL), 1.5 N LiOH (1.6 mL) and methanol (1.5 mL) and the mixture was stirred overnight. Most of the tetrahydrofuran was removed by gently blowing a stream of nitrogen over the reaction mixture. Water and 1 N HCl (2.4 mL) was added and the mixture was sonicated well to precipitate the carboxylic acid. The carboxylic acid was filtered and rinsed with water. After drying under vacuum, 5-iodo-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylic acid was obtained (488 mg, 1.47 mmol, 90% yield). This material was used for the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]4[C:33](=O)[CH2:32][CH2:31][CH2:30][C:27]=4[CH:28]=3)[CH:23]=[N:22]2)=[CH:17][CH:16]=1>COCCOC>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]4[C:33](=[CH:5][C:3]#[N:4])[CH2:32][CH2:31][CH2:30][C:27]=4[CH:28]=3)[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: O=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: N#CC=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of sodium hydride (60% in oil, 12.0 g, 300 mmol) in DME (600 mL) was added diethyl (cyanomethyl)phosphonate (53.1 g, 300 mmol) at a dropwise rate under nitrogen. After gas evolution ceases (about 30 min), 1-(4-fluorophenyl)-7,8-dihydro-1H-benzo[f]indazol-5(6H)-one (4, R1=4-Fluorophenyl) (42.0 g, 150 mmol) was added in portions. The reaction was stirred at rt for about 3 h, then the reaction was concentrated under reduced pressure and the residue was dissolved with EtOAc (1000 mL) and sat. aq. NH4Cl (500 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (330 g) using a gradient of 70-100% DCM in heptane. Product fractions were combined and concentrated under reduced pressure to yield 2-(1-(4-fluorophenyl)-7,8-dihydro-1H-benzo[f]indazol-5(6H)-ylidene)acetonitrile (27, R1=4-Fluorophenyl) as a 2:1 mixture of isomers (42.9 g, 94%); LC/MS, method 3, Rt=2.57 min, MS m/z 304 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.60 (bs, 0.33H), 8.50 (d, J=0.9 Hz, 0.33H), 8.42 (bs, 0.67H), 8.40 (d, J=0.9 Hz, 0.67H), 7.88-7.76 (m, 2H), 7.67 (bs, 0.33H), 7.64 (bs, 0.67H), 7.52-7.36 (m, 2H), 6.32 (t, J=1.6 Hz, 0.67H), 5.73 (t, J=1.5 Hz, 0.33H), 3.03-2.95 (m, 2H), 2.90-2.83 (m, 1H), 2.71-2.64 (m, 1H), 1.93-1.81 (m, 2H).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][CH2:7][CH2:8][N:9]1[C@@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[C@@H:17]([C:27](O)=[O:28])[C:16]2[C:11](=[CH:12][C:13]([N+:30]([O-:32])=[O:31])=[CH:14][CH:15]=2)[C:10]1=[O:33].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Br:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:19]3[CH:20]=[C:21]([O:25][CH3:26])[CH:22]=[CH:23][C:24]=3[C:27](=[O:28])[C:17]=2[C:16]2[C:11](=[CH:12][C:13]([N+:30]([O-:32])=[O:31])=[CH:14][CH:15]=2)[C:10]1=[O:33]
Reactant: COc1cccc([C@H]2[C@@H](C(=O)O)c3ccc([N+](=O)[O-])cc3C(=O)N2CCCBr)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc2c(c1)-c1c(c3ccc([N+](=O)[O-])cc3c(=O)n1CCCBr)C2=O
Temperature: 25 °C
Yield: 55.1 %

Procedure:
Thionyl chloride (10 mL) was slowly added to a solution of cis-4-carboxy-N-(3-chloropropyl)-3,4-dihydro-3-(4-methoxyphenyl)-7-nitro-1(2H)isoquinolone (48, 1.94 g, 4.18 mmol) in benzene (60 mL). The reaction mixture was heated at reflux for 30 min, allowed to cool to room temperature, and concentrated. The residue was diluted with nitrobenzene (80 mL), chilled in an ice bath, and aluminum chloride (3.00 g, 22.5 mmol) was added. The reaction mixture was removed from the bath and heated at 100° C. for 1 h. Water (200 mL) was added, and the solution was extracted with CHCl3 (3×70 mL). The combined organic layers were washed with sodium bicarbonate (3×75 mL) and brine (75 mL), and dried over sodium sulfate. The solution was concentrated, hexanes (250 mL) were added, and the liquid was decanted. The solid was washed with hexanes (100 mL) and the liquid was decanted again. The solid was purified by silica gel column chromatography, eluting with chloroform-methanol, 20:1, to provide a red-orange solid (1.02 g, 55%): mp 282-284° C. (dec). IR (Film) 1699, 1667, 1612, 1555, 1499, 1332, 1159, 1078, 840, 785, 688, 662 cm−1; 1H NMR (CDCl3, 300 MHz) δ 8.85 (d, J=2.5 Hz, 1H), 8.70 (d, J=8.9 Hz, 1H), 8.55 (d, J=8.9 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.38 (s, 1H), 7.06 (d, J=8.3 Hz, 1H), 4.60 (t, J=7.3 Hz, 2H), 3.91 (s, 3H), 3.75 (t, J=6.4 Hz, 2H), 2.36 (t, J=7.0 Hz, 2H); EIMS m/z (rel intensity) 444 (M+, 100), 442 (M+, 100), 363 [(M-Br)+, 69]; HRESIMS calcd for C20H15BrN2O5 442.0164 (MH+). found 442.0158 (MH+); Anal. Calcd for C20H15BrN2O5.0.8H2O: C, 52.49; H, 3.66; N, 6.12; Br, 17.46. Found: C, 52.20; H, 3.54; N, 5.96; Br, 17.46.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:6]([N+:8]([O-])=O)[CH:7]=1>C(OCC)(=O)C.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]([F:14])([F:15])[F:16])=[C:6]([CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)ccc1OCC(F)(F)F
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cc(F)ccc1OCC(F)(F)F
Temperature: 22.5 °C
Reaction time: 14 h
Yield: 90.1 %

Procedure:
A mixture of 0.66 g of Compound 8A and 0.07 g of Raney-Nickel in 20 mL of ethyl acetate was stirred for 14 hours at 20-25° C. The catalyst was filtered off. The mixture was diluted with water. The organic layer was separated and the mixture extracted with 2×40 mL of ethyl acetate. The combined organic layers were washed with 20 mL of brine, dried over sodium sulphate and evaporated to dryness in vacuo to afford 0.52 g (90.6%) of Compound 8B as an oil.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[OH:10][CH2:11][C:12]1[C:18]2[N:19]([CH3:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:17]=2[CH:16]=[CH:15][NH:14][CH:13]=1>>[CH2:6]([N:5]([CH2:4][CH2:3][N:14]1[CH2:15][CH2:16][C:17]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]([CH3:26])[C:18]=2[CH:12]([CH2:11][OH:10])[CH2:13]1)[CH2:8][CH3:9])[CH3:7]
Reactant: CCN(CC)CCCl
Reactant: Cn1c2c(c3ccccc31)C=CNC=C2CO
Agent: Cl
Product: CCN(CC)CCN1CCc2c(n(C)c3ccccc23)C(CO)C1

Procedure:
In accordance with the procedure described in example 18, the condensation of 1-chloro-2-diethylaminoethane hydrochloride with 5-hydroxymethyl-6-methylazepino[4,5-b]indole yields the product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:18](COCC[Si](C)(C)C)[C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl(O)(=O)(=O)=O>C(O)(=O)C.O>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(F)c(N)c(C(=O)O)c3)cc12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(F)c(N)c(C(=O)O)c3)cc12
Reaction time: 17 h
Yield: 105.9 %

Procedure:
175 mg (0.34 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid was dissolved in 5 mL of glacial acetic acid. 250 μL of 70% perchloric acid was added and the resulting mixture left at ambient temperature for 17 h. The resulting solution was diluted with 85 mL of water and the resulting precipitate filtered off and dried by suction to afford 137 mg (0.36 mmol, 106%) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid as a brown solid. MS: m/z 379.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[O:8][CH3:9].[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH3:9][O:8][C:3]1[S:4][C:5]([CH3:7])=[CH:6][C:2]=1[B:10]([OH:15])[OH:11]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1sc(C)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1sc(C)cc1B(O)O
Temperature: -70 °C
Reaction time: 0.67 h

Procedure:
A stirred mixture of 3-bromo-2-methoxy-5-methylthiophene (Step B, 296 mg, 1.43 mmol) and triisopropyl borate (396 μL, 2.15 mmol) in toluene/THF (2.3/0.6 mL) was cooled to −70° C. under an atmosphere of N2. n-Butyl lithium (2.0M in pentane, 1.07 mL, 2.15 mmol) was added dropwise via a syringe pump over 1 h. The reaction stirred at −70° C. for 40 min more and was quenched with 2N HCl (2 mL) at −20° C. The reaction was partitioned between EtOAc (15 mL) and H2O (15 mL). The aqueous layer was extracted with EtOAc (10 mL); the combined organic layers were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford (2-methoxy-5-methyl-3-thienyl)boronic acid as a yellow oil. This material was used without further purification.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: NS(=O)(=O)c1cccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)c1

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (360 mg, 1 mmol) and commercially available 3-bromobenzene-1-sulfonamide (216 mg, 1 mmol) according to general procedure II. Obtained as an off-white solid (70 mg, 13%). MS (ISP) 510.4 [(M+H)+]; mp 240° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.CCN(CC)CC.Cl.[NH2:21][OH:22]>CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[N:21]\[OH:22])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)/C(=N/O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To the solution of 6-methoxy-2,3-dihydro-1H-inden-1-one (6.5 g, 40 mmol) in 100 mL of MeOH was added Et3N (11.1 mL, 80 mmol) and hydroxylamine hydrochloride (3.9 g, 56 mmol). The mixture was stirred at rt for 2 h. The mixture was evaporated and redissolved in EtOAc, the organic phase was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give (E)-6-methoxy-2,3-dihydro-1H-inden-1-one oxime (intermediate 16) (6.6 g, 93%).
Reaction SMILES: [C:1]12[CH:7]([C:8]([OH:10])=O)[C:4]([CH2:5][CH2:6]1)=[CH:3][CH:2]=2.[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:13]1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:8]([CH:7]3[C:4]4[CH2:5][CH2:6][C:1]3=[CH:2][CH:3]=4)=[O:10])[CH2:13]2)=[CH:20][CH:21]=1
Reactant: O=C(O)C1C2=CC=C1CC2
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1C2=CC=C1CC2

Procedure:
7-Norbornadienecarboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-7-norbornadienecarboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[Cu][C:13]#[N:14]>CN1CCCC1=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[CH2:9][C:10]#[N:11]
Reactant: N#C[Cu]
Reactant: N#CCc1cc(Br)ccc1N
Solvent: CN1CCCC1=O
Solvent: O
Product: N#CCc1cc(C#N)ccc1N
Temperature: 25 °C

Procedure:
2 mmol of (2-Amino-5-bromo-phenyl)-acetonitrile [882855-95-0] and 4 mmol of copper (I) cyanide are heated at 200° C. in 2 ml of N-methylpyrrolidinone for 4 h. After cooling to room temperature, the solution is diluted with water and extracted with ethyl acetate (3×). The organic layer is separated, dried over magnesium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.