Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=[O:33])[CH:26]([NH:31][CH3:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35].C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=[O:33])[CH:26]([N:31]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:39][CH:40]=2)[CH3:32])[CH2:27][CH:28]([CH3:29])[CH3:30])[C:17](=[O:23])[NH:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reactant: CC(C)(C)c1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)N(C)Cc1ccc(C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 40 %

Procedure:
2-(Methyl-amino)-4-methyl-pentanoic acid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (0.5 mmol) was dissolved in THF (10 mL) and treated with 4-tert-butyl-benzyl bromide (0.75 mmol) and diisopropylethylamine (1.5 mmol). The reaction was stirred at 50° C. for 15 hours. Then the reaction mixture was allowed to cool to room temperature and concentrated to dryness. The residue was chromatographed on silica gel eluting with a gradient of 25% EtOAc/Hexanes to give the title compound with the yield of 40%.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][C:37](O)=[O:38])=[CH:35][C:30]=2[O:29][CH2:28]1>>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][C:37]([NH:26][C@H:23]3[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]4[C:5]4[CH:6]=[C:7]5[CH:11]=[CH:10][CH:9]=[C:8]5[O:3][CH:4]=4)[CH2:25][CH2:24]3)=[O:38])=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(Cc1ccc2c(c1)OCO2)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (79 mg, 65%), MS (ISP) m/z=489.3 [(M+H)+], mp 177° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-(benzo[1,3]dioxol-5-yl)-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:8][C:6]1[CH:5]=[C:4]([N:22]2[CH2:23][CH2:24][CH:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]([F:11])([F:25])[F:26])[CH2:20][CH2:21]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: FC(F)(F)c1ccccc1C1CCNCC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(Cl)cc(N2CCC(c3ccccc3C(F)(F)F)CC2)n1
Temperature: 210 °C
Reaction time: 0.33 h
Yield: 117.7 %

Procedure:
2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), 4-(2-trifluoromethyl-phenyl)-piperidine hydrochloride (0.266 g, 1 mmol), and cesium carbonate (0.684 g, 2.1 mmol) were dissolved in a mixture of 1,4-dioxane (5 ml) and H2O (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210° C. for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in 5% methanol in CH2Cl2 (20 ml), dried over Na2SO4 and concentrated to get the crude intermediate, 4-chloro-6-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-pyrimidin-2-ylamine (0.42 g) which was directly used in the following step.
Reaction SMILES: CN1CCOCC1.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([OH:25])=O.O.OC1C2N=NNC=2C=CC=1.Cl.[CH2:38]([O:45][C:46]([NH:48][CH2:49][CH2:50][NH2:51])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:51][CH2:50][CH2:49][NH:48][C:46](=[O:47])[O:45][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:25]
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: NCCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: O=C(NCCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
N-methylmorpholine (0.47 ml) was added to a solution of (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid (352.6 mg) [see Preparation 3], hydroxybenzotriazole hydrate (338.4 mg), N-benzyloxycarbonyl-1,2-diaminoethane hydrochloride (499.5 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (552.7 mg) in dichloromethane (15 ml). The reaction mixture was stirred at room temperature for 18 hours, after which time the mixture was diluted with water and the organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 1:1, changing to 1:9, by volume, hexane:ethyl acetate to afford benzyl N-[2-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)ethyl]carbamate (550 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][C@@H:6]([C:23](O)=[O:24])[NH:7][C:8](=[O:22])[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[CH3:30][O:31][C:32]([C:34]1[CH:35]=[C:36]([CH2:40][O:41][CH2:42][C@@H:43]([C:45]([NH2:47])=[O:46])[NH2:44])[CH:37]=[CH:38][CH:39]=1)=[O:33].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][C@@H:6]([C:23]([NH:47][C:45](=[O:46])[C@H:43]([CH2:42][O:41][CH2:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:32]([O:31][CH3:30])=[O:33])[CH:35]=1)[NH2:44])=[O:24])[NH:7][C:8](=[O:22])[CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)O)c1
Reactant: COC(=O)c1cccc(COC[C@H](N)C(N)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)c1cccc(COC[C@H](N)C(=O)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanine (1.0 g, 2.68 mmol) and O-[[3-(methoxycarbonyl)phenyl]methyl]-L-serinamide HCl (0.774 g, 2.68 mmol), 1-hydroxybenzotriazole hydrate (0.452 g, 2.95 mmol, and N-methylmorpholine (1.18 mL, 1.085 g, 10.72 mmol) in CH2Cl2 (50 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (0.771 g, 4.02 mmol) in one portion and the mixture is stirred at room temperature for 16 hours. The solution is then washed with 1 N HCl (100 mL), saturated aqueous NaHCO3 (1×50 mL), water (1×50 mL) and brine (1×50 mL), dried over MgSO4, and evaporated. The residual solid is triturated with hot methanol to yield N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-O-[[3-(methoxycarbonyl)phenyl]methyl]-L-serinamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[N:8]=[C:9]([O:29][CH2:30][CH2:31][CH3:32])[C:10]3[N:15]=[C:14]([C:16]4[CH:26]=[C:25]([CH3:27])[C:19]([O:20][CH2:21][C:22](Cl)=[O:23])=[C:18]([CH3:28])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Cl.[C:36]([O:40][C:41](=[O:44])[CH2:42][NH2:43])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>ClCCl>[C:36]([O:40][C:41](=[O:44])[CH2:42][NH:43][C:22](=[O:23])[CH2:21][O:20][C:19]1[C:18]([CH3:28])=[CH:17][C:16]([C:14]2[O:13][C:11]3[N:12]=[C:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]=[C:9]([O:29][CH2:30][CH2:31][CH3:32])[C:10]=3[N:15]=2)=[CH:26][C:25]=1[CH3:27])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(=O)Cl)c(C)c3)nc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(=O)NCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.3 %

Procedure:
200 mg of {4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetyl chloride were dissolved in 2 ml of dichloromethane, and the solution was slowly added to a solution of 67 mg of glycine tert-butyl ester hydrochloride and 121 mg of triethylamine in 3 ml of dichloromethane. The mixture was stirred for 18 h at room temperature. Then the solvent was distilled off in vacuo and the product was isolated via preparative HPLC (method HPLC2) to yield 53 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]#[N:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([CH3:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:32])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]#[N:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([CH3:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:32])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C)CCOCC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cn(C(CC2(C)CCOCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
210 mg (431 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoate (racemate) in 4.3 ml of dichloromethane and 598 μl (7.76 mmol) of TFA were reacted according to General Method 6A. Yield: 210 mg (purity 83%, 94% of theory)
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:21]=3)[CH2:16][CH:15]2[C:36](=[O:45])[N:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44])[CH3:38])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-]>CN(C=O)C>[CH2:39]([N:37]([CH3:38])[C:36]([CH:15]1[CH2:16][CH:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:21]=2)[CH2:18][CH:14]1[C:12]([NH:11][C:6]1([C:4]([OH:5])=[O:3])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:13])=[O:45])[CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-c3ccccc3)nc3ccccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-c3ccccc3)nc3ccccc23)CC1C(=O)NC1(C(=O)O)CC1C=C
Temperature: 130 °C
Yield: 50.8 %

Procedure:
Compound 28 (0.17 g, 0.27 mmol) was dissolved in DMF (2.5 mL) and transferred to a microwave vial. LiOH (aq, 2 M, 8 mL) was added and the reaction was heated in the microwave at 130° C. for 1 h. Quenched the reaction with HCl (aq, 1M) to pH 1 and extracted with DCM (3×20 mL). Combined organic phases were washed with HCl (aq, 1M, 20 mL) and H2O (3×30 mL). Water phase was back-extracted with DCM (2×30 mL). Organic phases were dried over MgSO4, filtered and evaporated. Purified by flash chromatography (DCM/MeOH) to yield the title compound (0.08 g, 49%).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[C:15]([O:21]C)=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.Br>[NH2:20][C:17]1[NH:16][C:15](=[O:21])[C:14]([C:12]2[CH:11]=[CH:10][C:9]3[N:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:6]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]4[CH:33]=[N:32][CH:31]=[N:30]4)=[N:7][C:8]=3[CH:13]=2)=[CH:19][N:18]=1
Reactant: COc1nc(N)ncc1-c1ccc2c(c1)nc(-c1ccccc1-n1cncn1)n2C(C)(C)C
Agent: Br
Solvent: C1CCOC1
Product: CC(C)(C)n1c(-c2ccccc2-n2cncn2)nc2cc(-c3cnc(N)[nH]c3=O)ccc21
Temperature: 70 °C
Reaction time: 12 h
Yield: 67.9 %

Procedure:
To a vial are added 5-[1-tert-butyl-2-(2-1,2,4-triazol-1-yl-phenyl)-1H-benzimidazol-5-yl]-4-methoxy-pyrimidin-2-ylamine (Example 44) (47 mg, 0.107 mmol) in THF (2 mL) and HBr (1 mL). The reaction mixture is stirred at 70° C. for 12 hours. The solvent is concentrated. The residue is purified by prep HPLC, with 5-95% acetonitrile/water as gradient to afford the title compound (31 mg, 68%) as a white-gray glass solid. LCMS (ESMS): m/z 427.72 (M++1)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14].O>CO.CCOC(C)=O>[CH3:12][N:13]([CH3:14])[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CNC
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(N(C)C)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 95 %

Procedure:
To a solution of 6-chloro-2-methyl-3-nitropyridine (0.5 g, 2.9 mmol) in MeOH (5 mL) was added dimethylamine in water (1.2 mL, 11.6 mmol) and the reaction mixture was heated at 60° C. for 4 h. The reaction mixture was then diluted with EtOAc, extracted with water and washed with brine. The organic layer was dried over sodium sulphate and concentrated to yield the title compound (0.5 g, 95%). LCMS (ES+) 182 (M+H)+, RT 2.74 minutes (method 1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][N:1]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: c1cnc2ncccc2c1
Agent: [Pd]
Solvent: CCO
Product: c1cnc2c(c1)CCCN2
Yield: 100.9 %

Procedure:
1,8-Naphthyridine (1.0 g, 7.68 mmole) was hydrogenated (50 psi) with 10% Pd/C (100 mg) in absolute ethanol (40 mL) for 18 hr. The mixture was filtered through a pad of Celite® and the filtrate was concentrated to give the title compound (1.04 g) which was sufficiently pure for use in the next step: MS (ES) m/e 135 (M+H)+.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[C:10]1([C:12](=[CH:14][CH:15]=[CH:16]C=1)[OH:13])[OH:11].OO>CC(C)=O>[CH:9]1[C:8]2[CH:16]=[CH:15][CH:14]=[C:12]([OH:13])[C:10](=[O:11])[C:7]=2[C:5]([OH:6])=[C:3]([OH:4])[C:1]=1[OH:2]
Reactant: Oc1ccccc1O
Reactant: Oc1cccc(O)c1O
Agent: OO
Solvent: CC(C)=O
Product: O=c1c(O)cccc2cc(O)c(O)c(O)c12
Yield: 17.2 %

Procedure:
Pyrogallol (1 g) and catechol (1.5 g) were dissolved in a mixture of acetone-pH 5.0 phosphate citrate buffer (1:10, v/v, 50 mL), which contained 2 mg horseradish peroxidase. While being stirred, 2.0 mL of 3.13% H2O2 was added four times during 45 minutes. The reaction mixture was extracted by ethyl acetate (50 mL×3). After concentration, the residue was subjected to Sephadex LH 20 column eluted with acetone-water solvent system (45%). 300 mg Purpurogallin was obtained.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:10][CH:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].Cl.[NH2:25][OH:26]>CO>[N:1]1([CH2:6][CH:7]2[CH2:10][CH:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:25][OH:26])=[NH:16])=[CH:17][CH:18]=3)[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: N#Cc1ccc(C2CC(CN3CCCC3)C2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1ccc(C2CC(CN3CCCC3)C2)cc1
Temperature: 70 °C
Yield: 29.5 %

Procedure:
To a stirring solution of Example 222 (4-(3-Pyrrolidin-1-ylmethyl-cyclobutyl)-benzonitrile) (150 mg, 0.62 mmol) in MeOH (1.5 mL) was added NaHCO3 (58 mg, 0.62 mmol), followed by hydroxylamine hydrochloride (43.4 mg, 0.62 mmol). The reaction was then heated to 70° C. over night. Both TLC and MS analysis indicated complete consumption of starting material. The reaction was cooled to room temperature and concentrated under reduced pressure. Water was added and a gummy solid formed. The water was removed and the residual was taken up in MeOH and concentrated under reduced pressure to yield the title compound (50 mg, 29% yield). This material was used without further purification.
Reaction SMILES: CC1C=C(CN)C=CC=1OC(F)(F)F.FC1C=C(C=CC=1[N+]([O-])=O)OCC1C=CC(C)=CN=1.[CH3:34][C:35]1[CH:36]=[C:37]([CH:56]=[CH:57][C:58]=1[O:59][C:60]([F:63])([F:62])[F:61])[CH2:38][NH:39][C:40]1[C:41]([NH2:55])=[CH:42][CH:43]=[C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][N:49]=2)[CH:45]=1.[C:64]1(=[O:74])[C@@H:72]2[C@@H:67]([CH2:68][CH2:69][CH2:70][CH2:71]2)[C:66](=O)[O:65]1>>[CH3:54][C:51]1[CH:52]=[CH:53][C:48]([CH2:47][O:46][C:44]2[CH:43]=[CH:42][C:41]3[N:55]=[C:66]([C@H:67]4[CH2:68][CH2:69][CH2:70][CH2:71][C@H:72]4[C:64]([OH:74])=[O:65])[N:39]([CH2:38][C:37]4[CH:56]=[CH:57][C:58]([O:59][C:60]([F:62])([F:63])[F:61])=[C:35]([CH3:34])[CH:36]=4)[C:40]=3[CH:45]=2)=[N:49][CH:50]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Cc1ccc(COc2ccc(N)c(NCc3ccc(OC(F)(F)F)c(C)c3)c2)nc1
Agent: Cc1cc(CN)ccc1OC(F)(F)F
Agent: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Product: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(OC(F)(F)F)c(C)c4)c3c2)nc1

Procedure:
The title compound was prepared using analogous conditions described in Example 92 using (3-methyl-4-(trifluoromethoxy)phenyl)methanamine and 2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine in Step B and N1-(3-methyl-4-(trifluoromethoxy)benzyl)-5-((5-methylpyridin-2-yl)methoxy)benzene-1,2-diamine and cis-hexahydroisobenzofuran-1,3-dione in Step D. MS (ESI): mass calcd. for C30H30F3N3O4, 553.22; m/z found, 554.0 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.34 (d, J=1.9, 1H), 7.56 (dd, J=7.8, 2.0, 1H), 7.45 (d, J=8.7, 1H), 7.33 (d, J=7.9, 1H), 7.21-7.19 (m, 2H), 7.08-6.97 (m, 2H), 6.83 (dd, J=8.7, 2.3, 1H), 5.49-5.33 (m, 2H), 5.08 (s, 2H), 3.73-3.64 (m, 1H), 2.75-2.64 (m, 1H), 2.27 (s, 3H), 2.19 (s, 3H), 1.90-1.41 (m, 6H), 1.33 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH3:13])[C:7](=[O:21])[CH:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]=2[N:3]=1.[CH3:26][NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)=[O:29].C([O-])(O)=O.[Na+]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]([N:8]2[C:7](=[O:21])[CH:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]3[N:3]=[C:2]([C:34]4[CH:33]=[CH:32][C:31]([NH:30][C:28]([NH:27][CH3:26])=[O:29])=[CH:36][CH:35]=4)[N:11]=[CH:10][C:9]2=3)[CH3:13])=[CH:19][CH:18]=1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[C@@H](c1ccc(Cl)cc1)N1C(=O)C2COCCN2c2nc(Cl)ncc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2C(=O)N3[C@@H](C)c2ccc(Cl)cc2)cc1
Temperature: 120 °C
Yield: 16.1 %

Procedure:
To a 2 mL microwave vial were added 2-chloro-5-((S)-1-(4-chlorophenyl)ethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x51, 100 mg, 0.264 mmol), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (146 mg, 0.527 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (10.85 mg, 0.013 mmol). After the vial was sealed, dioxane (1.5 mL) and aqueous saturated NaHCO3 (0.38 mL) were added, and the mixture was degassed by bubbling nitrogen through a syringe needle for 10 minutes. The mixture was then heated in a microwave to 120° C. for 30 minutes. The reaction mixture was partitioned between brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by normal phase column chromatography (SiO2, 50-100% EtOAc/hexanes in 20 minutes) to give the title compound (single diastereomer, 21 mg, 16%). 1H NMR (400 MHz, DMSO-d6) δ 1.75 (d, J=7.1 Hz, 1H), 1.83 (d, J=7.1 Hz, 3H), 2.65 (d, J=4.5 Hz, 3H), 2.95-3.07 (m, 1H), 3.55-3.73 (m, 2H), 4.02 (dd, J=11.6, 3.0 Hz, 1H), 4.25 (dd, J=11.2, 3.7 Hz, 1H), 4.40 (dd, J=10.6, 3.8 Hz, 1H), 4.45-4.54 (m, 1H), 6.02-6.09 (m, 1H), 6.14 (d, J=7.1 Hz, 1H), 7.33-7.50 (m, 7H), 7.60 (s, 1H), 7.76 (s, 1H), 8.07-8.16 (m, 2H), 8.70 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C25H25ClN6O3, 493.17. found 493.4.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1/[CH:17]=[CH:18]/[C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22](OC)=[O:23]>O1CCCC1.[OH-].[Na+]>[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1/[CH:17]=[CH:18]/[C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[CH2:22][OH:23]
Reactant: COC(=O)c1cccc(/C=C/c2ccc3ccccc3n2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(/C=C/c2ccc3ccccc3n2)c1
Reaction time: 0.5 h

Procedure:
Solid lithium aluminum hydride (025 g) is added in portions to a stirred solution of methyl 3-[2(E)-(quinolin-2-yl)ethenyl]benzoate (2.1 g, 7.3 mmol) in tetrahydrofuran (50 ml). The mixture is stirred for 30 minutes, diluted with sodium hydroxide solution and extracted with ethyl acetate. The extract is dried and evaporated and the residue chromatographed on silica in ethyl acetate-hexane.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH:19]=O)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I:21][C:22]1[CH:27]=[CH:26][NH:25]/[C:24](=[N:28]\[NH2:29])/[CH:23]=1>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](/[CH:19]=[N:29]/[N:28]=[C:24]1\[NH:25][CH:26]=[CH:27][C:22]([I:21])=[CH:23]\1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Reactant: N/N=c1/cc(I)cc[nH]1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(/C=N/N=c3/cc(I)cc[nH]3)nc12
Reaction time: 1 h

Procedure:
To 8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde (3.21 g, 11.2 mmol) in DCM (30 mL) was added (Z)-1-(4-iodopyridin-2(1H)-ylidene)hydrazine (3.15 g, 13.4 mmol). The reaction was stirred for 1 hour, affording a yellow precipitate, which was collected by filtration and used without further purification in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.C>O1CCOCC1.[OH-].[Na+]>[F:17][C:14]1[CH:13]=[CH:12][C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cn(-c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Crude 1-(4-fluoro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (175 mmol) was dissolved in 450 mL dioxane and 450 mL 2N sodium hydroxide solution. The reaction mixture was refluxed for 2 h. Charcoal (1 g, Norit SA II) was added and reflux was continued for another 20 min. The mixture was filtered hot and washed with 50 mL 2N sodium hydroxide solution. The filtrate was treated with 550 mL 2N HCl and stirred at RT overnight. The solid material was filtered off and dried at 50° C. and 15 mbar. The desired compound was obtained as an off-white solid (28 g, 78%), MS: m/e=205.1 (M−H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([N:13]2[N:17]=[N:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14]2)[CH2:10][CH:9]1[C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]#[N:39])[CH2:28][CH2:27]1)=[O:25])=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[C:18]1([C:15]2[N:16]=[N:17][N:13]([CH:11]3[CH2:12][NH:8][CH:9]([C:24]([N:26]4[CH2:31][CH2:30][N:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:38]#[N:39])[CH2:28][CH2:27]4)=[O:25])[CH2:10]3)[N:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(n2nnc(-c3ccccc3)n2)CC1C(=O)N1CCN(c2ccccc2C#N)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccccc4)n3)CN2)CC1
Reaction time: 5 h

Procedure:
2-[4-(2-Cyano-phenyl)-piperazine-1-carbonyl]-4-[5-(phenyl)-tetrazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (6) is added to CF3COOH, and the reaction mixture is stirred for about 5 h. After removal of CF3COOH, the residue is dissolved in DCM, washed, dried and concentrated to give 2-(4-{4-[5-(phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (2).