Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.CO.C(Cl)Cl.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:14])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(O)cc1
Yield: 95.7 %

Procedure:
A solution of tert-butyl 2-[4-(benzyloxy)benzoyl]hydrazinecarboxylate (975 mg, 2.85 mmol) in presence of catalytic amount of Pd—C 10% in ethanol (40 mL) is hydrogenated for 3 hours. After filtration on celite, the residue is purified on column chromatography (silica gel, 10% MeOH in CH2Cl2) and tert-butyl 2-(4-hydroxybenzoyl)hydrazine carboxylate (0.688 g, yield: 96%) was identified by NMR spectroscopy.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
Boron tribromide (64.58 g) was added dropwise to a stirred solution of ethyl 5-methoxyindole-2-carboxylate (20 g) in dichloromethane (1000 ml) at −78° C. under an atmosphere of argon. The reaction was allowed to warm to room temperature and stirred for a further 2 hours. The reaction was poured into ice/saturated aqueous sodium hydrogen carbonate solution with stirring and extracted with ethyl acetate. Combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution, water, aqueous saturated sodium chloride solution and dried. The solution was concentrated in vacuo and the residue was purified by column chromatography using 0-60% diethyl ether: iso-hexane as eluent to yield product as a white solid (9.02 g, 48%). NMR: δ 1.31) (t, 3H), 4.29 (q, 2H), 6.79 (dd, 1H), 6.90 (dd. 1H), 7.22 (d, 1H), 8.84 (s, 1H), 11.52 (brs, 1H); m/z 206 (M+H+).
Reaction SMILES: CN1C(=O)CCC1.[CH2:8]([NH:15][C:16]1[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=[C:18](S(C)(=O)=O)[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[Cl:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[CH:35][C:36]=1[OH:37].C(N(C(C)C)CC)(C)C>O>[CH2:8]([NH:15][C:16]1[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:40][CH2:39][CH2:38][C:33]2[CH:34]=[CH:35][C:36]([OH:37])=[C:31]([Cl:30])[CH:32]=2)[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)c1ncc(C(N)=O)c(NCc2ccccc2)n1
Reactant: NCCc1ccc(O)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(NCCc2ccc(O)c(Cl)c2)nc1NCc1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
To 8 ml NMP solution of 750 mg of 4-benzylamino-2-methylsulfonylpyrimidine-5-carboxamide were added 765 mg of 2-(3-chloro-4-hydroxyphenyl)ethylamine hydrochloride and 1.07 ml of diisopropylethylamine, followed by stirring a 110° C. for 1 hour. The reaction mixture was cooled down to room temperature, and then mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol:aqueous ammonia) and the resulting crude crystals were recrystallized (methanol-ethyl acetate) to obtain 280 mg of 4-benzylamino-2-{[2-(3-chloro-4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:46])/[CH:24]=[CH:25]/[C:26]3[CH:45]=[CH:44][C:29]([O:30][CH2:31][CH2:32][N:33]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:28][CH:27]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C1COCC1.NN>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:46])/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][NH2:33])=[CH:44][CH:45]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)[C@H]2c2ccc3c(c2)CCO3)cc1
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: NCCOc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)[C@H]2c2ccc3c(c2)CCO3)cc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 25.3 %

Procedure:
To a solution of (E)-(R)-2-[2-(4-{3-[1-(2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-oxo-propenyl}-phenoxy)ethyl]isoindole-1,3-dione (0.85 g, 1.4 mmol) in 50 mL of MeOH:THF was added hydrazine (0.38 mL, 3 equiv., 35% in water). The resulting mixture was stirred at 45° C. for 4 hours. Evaporation in vacuo and flash chromatography with DCM:MeOH (80.20) as eluting solvent gave the title compound (0.17 g, 26%) as yellow powder. MP: 186° C. Analysis for C30H29N3O3. 0.3CH2Cl2 : Calculated: C,72.06; H,5.91; N,8.32; Found C,72.12; H,6.08; N,8.6%. [α]D20 =-285 (c=0.29, MeOH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C=O)C.C(OCC)(=O)C>[CH3:18][N:19]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:15](=[O:17])/[CH:14]=[CH:13]/[C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[CH:32][CH:33]=1)[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(-c2ccc(/C=C/C(=O)O)o2)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(/C=C/C(=O)Nc3ccc(CN(C)C4CCOCC4)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.1 %

Procedure:
To a solution of (E)-3-[5—(4-methylphenyl)furan-2-yl]acrylic acid (200 mg), 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (212 mg) and triethylamine (0.15 ml) in DMF (10 ml) was added diethyl cyanophosphate (0.16 ml) at 0° C., and the mixture was stirred at room temperature for 3 hours. To the mixture was added ethyl acetate; and the mixture was washed with water and saturated sodiumlchloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:50→1:25→1:10) to give (E)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-3-[5—(4-methylphenyl)furan-2-yl]acrylic amide (Compound 210) (87 mg) as brown amorphous. 1H-NMR (200 MHz, CDCl3) δ 1.53-1.85 (4H, m), 2.21 (3H, s), 2.38(3H, s), 2.54-2.72 (1H, m), 3.31-3.44 (2H, m), 3.56 (2H, s), 3.98-4.11 (2H, m), 6.52 (1H, d, J=15.4 Hz), 6.67-6.69 (2H, m), 7.22 (2H, d, J=8.0 Hz), 7.29 (2H, d, J=8.4 Hz), 7.41 (1H, s), 7.48-7.64 (5H, m).
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]([CH:11]([CH3:13])[CH3:12])[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([N:3]([CH2:1][CH3:2])[C@@H:4]([CH:11]([CH3:12])[CH3:13])[CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCN[C@H](CN1CCCC1)C(C)C
Solvent: ClCCl
Product: CCN(C(=O)c1ccc(Br)cc1)[C@H](CN1CCCC1)C(C)C
Yield: 14.6 %

Procedure:
To a solution of (S)—N-ethyl-3-methyl-1-(pyrrolidin-1-yl)butan-2-amine (0.1 g, 0.54 mmol) (for synthesis, see e.g. EP254545) in DCM (2 mL) was TEA (0.075 mL, 0.54 mmol) and 4-bromobenzoyl chloride (0.119 g, 0.54 mmol) added. The resultant mixture was stirred at rt overnight. The mixture was washed with H2O (2 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (29 mg, 15%). Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ 0.77-1.13, 1.30, 1.66-2.06, 2.26-2.59, 2.62-2.91, 3.00-3.29, 3.43-3.69, 7.27-7.42, 7.52-7.70. Total no of protons: 27. HRMS (M+H)+: calculated 367.1385. found 367.1384.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH:34]1[CH2:35][CH2:36][N:37]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:38][CH2:39]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Fc1ccc(C2CCNCC2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCN2CCC(c3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 4-(2,4-difluorophenyl)piperidine (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography using a 95/5.0/0.5-mixture of DCM/MeOH/NH4OH as an eluent to give 7-(2-(4-(2,4-difluorophenyl)piperidin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=463.98). 1H NMR (DMSO-d6, 400 MHz), δ 1.68 (m, 4H), 2.12 (m, 2H), 2.55 (m, 1H), 2.73 (t, 2H, J=6.0 Hz), 3.04 (m, 2H), 4.26 (t, 2H, J=6.4 Hz), 6.59 (d, 1H, J=3.6 Hz), 6.71 (m, 1H), 7.09 (m, 1H), 7.18 (m, 2H), 7.26 (m, 1H), 7.33 (m, 1H), 7 49 (br s, 2H, NH2), 7.91 (s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][N:12]=1.[CH2:18]([O:20][C:21](Cl)=[O:22])[CH3:19]>N1C=CC=CC=1>[CH2:18]([O:20][C:21](=[O:22])[NH:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:16]=1)[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccnc(C2=Cc3ccccc3CC2)c1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccnc(C2=Cc3ccccc3CC2)c1
Reaction time: 72 h
Yield: 34 %

Procedure:
A solution of 2-(3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine (0.80 g, 3.6 mmol) in pyridine (20 ml) was cooled to 0° C. and ethylchloroformate (0.47 g, 4.3 mmol) was slowly added. Stirring was continued for 72 hr. Then the solvent was evaporated and the residue was partitioned (AcOEt/H2O). The organic phase was dried (MgSO4), concentrated and chromatographed (SiO2 with CH2Cl2/CH3OH=98/2) to give the title compound (0.36 g, 36%) as a yellow oil. MS: m/e=294 (M+).
Reaction SMILES: C[O:2][C:3]([C:5]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])([CH3:7])[CH3:6])=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])([CH3:7])[CH3:6])([OH:4])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(NC(=O)c1ccc(F)cc1F)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of N-(1-methoxycarbonyl-1-methylethyl)-2,4-difluorobenzamide obtained in Example 30 (1.51 g, 5.9 mmol) in methanol (10 ml) was added 4N aqueous NaOH (10 ml), and stirred at room temperature for 30 min. The methanol was evaporated and the resulting mixture was acidified with 4N hydrochloric acid and extracted with ethyl acetate. The extract was dried over Na2SO4 and the solvent was evaporated under a reduced pressure to give the title compound (1.42 g; 99%).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=2)=O)[CH:6]=[C:5]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:4]=[CH:3]1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([C:5]2[CH:6]=[C:7]3[C:2](=[CH:3][CH:4]=2)[NH:1][C:33](=[O:35])[CH:34]=[C:8]3[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=2)=[O:25])=[CH:23][CH:22]=1
Reactant: NC1C=CC(C(=O)c2ccc(Cl)cc2)=CC1C(=O)c1cccc(I)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(I)c3)c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
[6-Amino-3-(4-chloro-benzoyl)-cyclohexa-2,4-dienyl]-(3-iodo-phenyl)-methan-one (60 g, 130 mMol) was dissolved in anhydrous toluene (450 mL) under an atmosphere of dry N2. To this solution was added 180 mL of triethylamine (NEt3), 50 mL of acetic anhydride (Ac2O) and 1.60 g (13.0 mMol) of 4-dimethylaminopyridine (DMAP). The reaction mixture was then heated to reflux and stirred at this temperature for 20 hours. The reaction mixture was cooled to ambient temperature and the precipitate was collected via suction filtration. The solid was washed with ethyl ether (Et2O) and dried under vacuum to give of the titled compound (63 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:17])[N:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29]>CN(C)C=O>[CH3:29][O:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25][N:6]1[C:5](=[O:8])[N:4]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[C:3](=[O:17])[C:2]([CH3:1])=[N:7]1
Reactant: Cc1n[nH]c(=O)n(C(=O)c2ccccc2)c1=O
Reactant: COC(CCBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CCn1nc(C)c(=O)n(C(=O)c2ccccc2)c1=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 6-methyl-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (P2, 90 mg, 0.389 mmol) in N,N-Dimethylformamide (DMF) (0.6 mL), potassium carbonate (64.6 mg, 0.467 mmol) and 3-bromo-1,1-bis(methyloxy)propane (commercially available from Aldrich, 0.071 mL, 0.467 mmol), were added and the mixture was stirred at rt overnight. The day after the reaction mixture was quenched with water and diluted with AcOEt. Organic phase was washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure. Crude product was purified by flash chromatography (Cy 100% to Cy/AcOEt 6:4) affording the title compound 2-[3,3-bis(methyloxy)propyl]-6-methyl-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (92 mg, 0.276 mmol, 70.9% yield) as a clear oil.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:2][C:3]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)=[O:4]>C(OCC)(=O)C.[C].[Pd]>[NH:2]([C:3]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)=[O:4])[NH:1][C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)NNC(=O)OCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNC(=O)OCCc1ccc(N)cc1
Yield: 58.8 %

Procedure:
To a solution of tert-butyl 2-(4-nitrophenyl)ethyl hydrazine-1,2-dicarboxylate (9.780 g, 30.00 mmol) in ethyl acetate (100 ml) was added 10% palladium carbon (980.0 mg, containing 50% water), and the mixture was hydrogenated at room temperature and atmospheric pressure. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was suspended in a mixture of hexane (70 ml) and ethyl acetate (30 ml), filtered and dried under reduced pressure to give 2-(4-aminophenyl)ethyl tert-butyl hydrazine-1,2-dicarboxylate (5.207 g, 17.63 mmol, yield 58.8%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:24]3[CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22][CH2:23]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: CC1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1CCN(C2=Nc3cc(Br)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A mixture of 4.73 g (0.0150 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1000 ml of toluene was heated under nitrogen, with stirring, until a solution resulted. Then there was added 14.9 g (0.150 mole) of 4-methylpiperidine, followed by 8.54 g (0.045 mole) of titanium tetrachloride. The mixture was refluxed for 3 hours, cooled to room temperature and filtered. The filtrate was stirred with 500 ml of 2N sodium hydroxide solution for 15 minutes and the layers were separated. The aqueous phase was extracted with 250 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to an oil which solidified. The solid was triturated twice with hexane to afford 4.9 g (83%) of product. Recrystallization from ethyl acetate provided the analytical sample, mp 177°-179° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][NH:12][N:11]=1>C1(C)C=CC=CC=1>[CH2:1]([NH:9][C:10]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][NH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c[nH]nc1NCc1ccccc1
Reaction time: 3 h

Procedure:
21.2 g of benzaldehyde is added to a suspension of 25 g of 3-amino-4-ethoxycarbonylpyrazole in 200 ml of toluene. The whole is boiled while separating water. In 3 hours a total of 5 ml of water collects. After the toluene has been evaporated, 50 ml of methanol and 50 ml of THF are added and, under cooling, 23 g of NaBH4 is added at 0°-5° C. After 4 hours' at room temperature, the solvent mixture is drawn off; then 200 ml of ice water is added the whole is extracted three times with 150 ml of methylene chloride each time and the extract is dried over Na2SO4. After concentration, an oil remains that is recrystallized from ligroin/toluene; m.p. 99°-100° C.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][C:12]([NH2:15])=[N:11]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.Cl>O1CCOCC1>[F:17][C:3]([F:2])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(3-trifluoromethyl-phenyl)-4,5-dihydro-1H-pyrazol-3-ylamine hydrochloride salt (200 mg, 0.88 mmol) (Example 3A) in dioxane (50 mL) was added triethylamine (0.069 mL, 0.88 mmol) followed by 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (200 mg, 0.88 mmol). The mixture was stirred at room temperature for 24 h and then poured onto dichloromethane. 2N hydrochloric acid was added and the organics extracted with 2N hydrochloric acid (3×50 mL). The acid layer was basified with 10N potassium hydroxide and extracted with dichloromethane (3×50 mL). The combined organics were dried (Na2SO4), filtered and evaporated to dryness. The residue dissolved in diethyl ether and 1M hydrochloric acid in diethyl ether was added to form a brown solid which was collected and dried (171 mg, 86%). MS (ES) m/z: 228.1 [M+H].
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[C:12](O)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>O.C([Sn]=O)CCC.O>[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)CCCCCCCO
Agent: CCCC[Sn]=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CCCCCCCOC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
Isodecyl alcohol (306 grams; 1.94 moles), benzoic acid (242 grams; 1.98 moles), toluene (50 ml) and butyltinoxide hydrate (1 gram) were placed into a glass reaction flask equipped with stirrer, thermometer, heating mantle, 12" column packed with 1/4" glass rings, Dean-Stark water trap and condenser. The mixture was stirred for four hours allowing the temperature to increase from 30° C. to 204° C. After reaction mixture was cooled to 100° C., soda ash (100 ml; 20% solution) was added and the temperature increased from 65° to 95° C. After ten minutes, the alkaline bottom layer was separated and a mixture of soda ash (50 ml; 20% solution) and chlorox (140 ml) added to the reaction mixture. After the bottom layer was removed, the mixture was dried and the toluene was removed by heating to 182° C. at 45 mmHg. The desired product (491 grams) was obtained after filtration representing a yield of 96.7%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:19](=[C:21]([C:25]#[N:26])[CH:22]=[CH:23][CH:24]=3)[N:20]=2)=[CH:14][CH:13]=[CH:12][N:11]=1>O1CCCC1>[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:19](=[C:21]([C:25]#[N:26])[CH:22]=[CH:23][CH:24]=3)[N:20]=2)=[CH:14][C:13]([Br:1])=[CH:12][N:11]=1
Reactant: N#Cc1cccc2oc(-c3cccnc3N)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: N#Cc1cccc2oc(-c3cc(Br)cnc3N)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
1-Bromopyrrolidine-2,5-dione (199 mg) was added to a stirred solution of 2-(2-amino-3-pyridyl)-1,3-benzoxazole-4-carbonitrile (240 mg) dissolved in tetrahydrofuran (5 ml) over a period of 5 minutes. The resulting solution was stirred at 25° C. for 2 hours. The solvent was evaporated and the residue was washed with water. The residue was basified with 7 M ammonia in methanol and adsorbed on silica gel with methylene chloride. The crude product was purified by flash chromatography on silica gel eluting with 1 to 2% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(2-amino-5-bromopyridin-3-yl)benzo[d]oxazole-4-carbonitrile (205 mg) as a solid. NMR Spectrum: (CDCl3): 7.47 (dd, 1H), 7.70 (dd, 1H), 7.82 (dd, 1H), 7.97 (bs, 2H), 8.31 (d, 1H), 8.41 (d, 1H); Mass spectrum: M+H+ 315-317
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[CH:32]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([N:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)[CH:32]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2ccnc(N3CCNCC3)c2)OC1(C)C
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccnc(N5CCNCC5)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedure analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine (from Aldrich). LCMS calculated for C25H29N6O2 (M+H)+: m/z=445.2. Found 445.2.