Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CN=C1.[C:20](O)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[OH:23][C:22]1[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=1[C:20]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:28]
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: O=C(O)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: O=C(NCCNC(=O)c1ccccc1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
To a mixture of benzyl 2-aminoethylcarbamate (1.65 g, 8.5 mmol), imidazole (0.58 g, 8.5 mmol), salicylic acid (1.73 g, 8.5 mmol) in ethyl acetate (30 mL) was added a solution of DCC (1.75 g, 8.5 mmol) in ethyl acetate (50 mL). The mixture was stirred (RT, 16 h) and filtered. The solution was concentrated under reduced pressure and the crude product was purified by silica chromatography (EtOAc:PE, 0-50%) to afford benzyl 2-(2-hydroxybenzamido)ethylcarbamate as a white solid (1.84 g, 66%). Mass calculated for C17H18N2O4=314.34. found: [M+H]+=315.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:16])([CH3:15])[CH:9]=[C:8]2[CH3:17])=[O:4].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:18](=[O:20])[CH3:19])[C:10]([CH3:16])([CH3:15])[CH:9]=[C:8]2[CH3:17])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(C)=CC(C)(C)N2
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1ccc2c(c1)C(C)=CC(C)(C)N2C(C)=O

Procedure:
A mixture of 1,2-dihydro-2,2,4-trimethylquinoline-6-carboxylic acid methyl ester (2.3 g) and a catalytic amount of N,N-dimethylaminopyridine in acetic anhydride (60 ml) was stirred at 100° C. for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/11/9 (v/v) as eluent.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][N:9]([CH3:12])[C:8](=[O:13])[CH:7]=1.[F:14][C:15]1[CH:29]=[CH:28][C:18]2[C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][O:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:14][C:15]1[CH:29]=[CH:28][C:18]2[C:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH2:3][CH2:4][NH:5][C:6]4[CH:11]=[N:10][N:9]([CH3:12])[C:8](=[O:13])[CH:7]=4)[CH2:26][CH2:27]3)=[N:20][O:21][C:17]=2[CH:16]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cn1ncc(NCCCl)cc1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cn1ncc(NCCN2CCC(c3noc4cc(F)ccc34)CC2)cc1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.8 %

Procedure:
3.67 g (16.4 millimoles) of 5-(2-chloroethylamino)-2-methyl-2H-pyridazine-3-one-hydrochloride, 90 ml of acetonitrile, 4.05 g (18.4 millimoles) of 6-fluoro-3-piperidine-4-yl-1,2-benzisoxazole, 6.84 g of potassium carbonate and 0.37 g of potassium iodide are admixed. The reaction mixture is stirred under heating to boiling for 24 hours, cooled to room temperature and filtered. To the product 100 ml of water are added and the aqueous phase is extracted five times with 50.0 ml of dichloro methane each. The united organic phases are washed with water, dried over anhydrous magnesium sulfate, filtered and the organic phase is evaporated in vacuo. The residue is suspended in diethyl ether and filtered. The crude product is recrystallized from acetonitrile. Thus 3.4 g of the desired compound are obtained. Yield 55.9%.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CCO.[Pd]>[CH3:1][NH:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN(Cc1ccccc1)c1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1ncccc1N
Yield: 92.2 %

Procedure:
A mixture of N-benzyl-N-methyl-3-nitropyridin-2-amine (15 g) and 10% Pd—C (6.56 g) in EtOH (300 mL) was hydrogenated under balloon pressure at room temperature over weekend. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give N2-methylpyridine-2,3-diamine (7.00 g) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.O[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22]([O:14][CH2:13][CH:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4][O:5]3)=[CH:10][CH:9]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCC(CO)c1ccc2c(c1)OCCC2(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)OCCC2(C)C
Yield: 87.5 %

Procedure:
A solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.366 g, 1.32 mmole) in 27 mL of THF was treated with 0.222 g of methyl 4-hydroxybenzoate, 0.382 g of triphenylphosphine and 0.23 mL of diethyl azodicarboxylate (DEAD). The reaction mixture was heated at reflux for two hours, diluted with 50 mL of ether and then washed with two 25 mL portions of water and 25 mL of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 7% ethyl acetate in hexanes) to yield 0.474 g of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptyloxy]-benzoic acid methyl ester, as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:14])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:15]([O:17][C:18]([C:20]#[C:21][C:22](OCC)=[O:23])=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[N:6]2[C:5]([C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=3)=[C:4]([CH3:14])[S:3][C:2]2=[N:1][C:22](=[O:23])[CH:21]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Cc1sc(N)nc1-c1ccc(Br)cc1
Product: CCOC(=O)c1cc(=O)nc2sc(C)c(-c3ccc(Br)cc3)n12

Procedure:
The procedure is as in Example 1, except that 9.4 g of 2-amino-4-(p-bromophenyl)-5-methyl thiazole and 5.95 g of acetylene dicarboxylic acid diethyl ester are used. 2-methyl-3-(p-Bromophenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 217° to 220° C. (decomposition) is obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][NH2:5].C(N(CC)CC)C.[Cl:36][CH2:37][CH2:38][CH2:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[Cl:36][CH2:37][CH2:38][CH2:39][S:40]([NH:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 1.2 g (3 mM) of 2-methoxy-3-octadecylcarbamoyloxypropylamine IVa1 (described in JP Kokai No. 60-243047) in 24 ml of dichloromethane and 0.54 ml (3.9 mM) of triethylamine is added 0.401 ml (3.3 mM) of 3-chloropropanesulfonyl chloride with ice-cooling and the mixture is stirred at room temperature overnight. The product is isolated by dichloromethane extraction and dichloromethane layer is washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (3:2) mixture as an eluent. The product is recrystallized from chloroform-n-hexane mixture to give 1.386 g (2.56 mM) of 3-(3-chloropropylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane IIIa1 as colorless crystals in 85% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.C1COCC1.[CH3:25][NH2:26]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:26][CH3:25])=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CN
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CNCc1sc2c(N3CCOCC3)nc(Cl)nc2c1C
Reaction time: 24 h
Yield: 70 %

Procedure:
2-Chloro-7-methyl-4-morpholinothieno-[3,2-d]pyrimidine-6-carbaldehyde 36 was dissolved in 20 mL toluene and 20 mL THF followed by the addition of 15 mL 40% methylamine in H2O and the reaction was stirred for 24 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in 30 mL methanol and 30 mL THF followed by the addition of NaBH4. The reaction was stirred at room temp for at least 24 hours and product formation was confirmed by LCMS. The solvents were removed in vacuo and the crude product purified by flash chromatography to give 2.53 g (2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine 37 (70% yield) MS (Q1) 314 (M)+
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:26]=1)C1C=CC=CC=1.C.[H][H]>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:26]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(C=CCCCCCCCCCCCCCCOCc3ccccc3)c3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)n2cc(CCCCCCCCCCCCCCCCO)c3ccccc32)cc1
Yield: 91.9 %

Procedure:
3-(16-benzyloxyhexadecenyl)-1-(4-methoxybenzen-sulfonyl)indole (530 mg, 0.86 mmol) was dissolved in 25 mL of ethanol and added to palladium supported on activated charcoal (5%, 50 mg). The resulting mixture was allowed to stand at room temperature for 3 hours under 1 atmospheric pressure of hydrogen. After filtration, the reaction mixture was extracted with ethyl ether. The organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography to give 3-(16-hydroxyhexadecyl)-1-(4-methoxybenzenesulfonyl)indole as a white solid (417 mg, 92%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=O)[O:22]C(C)(C)C)[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1.[C:28](O)([C:30](F)(F)F)=O.C(Cl)(=O)C=C>C(Cl)Cl>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:22])[CH:28]=[CH2:30])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CSc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Agent: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(SC)nc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of tert-butyl (3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (51) (651 mg, 1.69 mmol) in 10 mL of DCM at RT was added 3 mL of TFA. The resulting homogeneous solution was stirred at RT for 1 h. It was concentrated under reduced pressure. The residue was in dissolved in 20 mL of DCM and cooled with an ice bath, then treated with DEIA (1.47 mL, 8.47 mmol) followed by acryloyl chloride (0.16 mL, 2.03 mmol). After 20 min at 0° C., additional acryloyl chloride (80 μL) was added in. The resulting mixture was stirred for 5 min, then quenched with 0.5 N NaOH (10 mL). The layers were separated and the water layer was extracted with 50 mL of DCM. The combined DCM extracts were washed with 2×5 mL of brine, dried over Na2SO4 and concentrated. The residue was stirred in 25 mL of EtOAc. The insoluble solid was filtered and dried to give 310 mg of N-(3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (11a). The filtrate was concentrated and purified on a silica gel column (35-100% EtOAc in hexanes) to give 140 mg of N-(3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (11a). m/z (ESI, +ve ion) 338.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.40 (1H, s), 8.95 (1H, s), 8.05 (1H, d, J=9.6 Hz), 7.68 (2H, m), 7.49 (1H, t, J=7.8 Hz), 7.04 (1H, d, J=8.2 Hz), 6.72 (1H, d, J=9.6 Hz), 6.46 (1H, dd, J=17.0, 10.2 Hz), 6.26 (1H, d, J=16.8 Hz), 5.78 (1H, d, J=9.6 Hz), 2.20 (3H, s).
Reaction SMILES: C(C[CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH3:11])(=[O:9])=[O:8])#N.Cl.[C:13]([OH:16])(=[O:15])[CH3:14]>>[CH3:11][NH:10][S:7]([CH2:6][CH2:5][CH2:4][CH2:14][C:13]([OH:16])=[O:15])(=[O:9])=[O:8]
Reactant: CC(=O)O
Reactant: CNS(=O)(=O)CCCCC#N
Agent: Cl
Product: CNS(=O)(=O)CCCCC(=O)O
Yield: 58 %

Procedure:
A mixture of 4-cyano-N-methylbutane-1-sulfonamide (Example 9; 100 mmol), acetic acid (100 ml) and concentrated hydrochloric acid (100 ml) was refluxed for 5 hours and then concentrated in vacuo. The residue was taken on THF and then filtered off. The filtrate was concentrated and the residue was washed with dichloromethane to give the pure product (11 g; 58% yield).
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[C:20]3[C:21]4([CH2:24][O:25][CH2:26][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:23][CH2:22]4)=[CH:12][CH:13]=1)=[O:6])([CH3:4])[NH2:3].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:4][C:2]1([CH3:1])[NH:3][C:28](=[O:30])[N:7]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[C:20]4[C:21]5([CH2:24][O:25][CH2:26][C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23]5)=[CH:12][CH:13]=2)[C:5]1=[O:6]
Reactant: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)COC3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc4c3C3(CC3)COC4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 214.5 %

Procedure:
To a solution of 2-methyl-N1-[6-(1H-spiro[2-benzopyran-4,1′-cyclopropan]-5-yloxy)-3-pyridinyl]alaninamide (34 mg, 0.096 mmol) in dry Dichloromethane (DCM) (5 mL) TEA (0.067 mL, 0.481 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (12.85 mg, 0.043 mmol) in dry Dichloromethane (DCM) (2 mL) was slowly added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with water (5 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a column SNAP 10 g and Dichloromethane/methanol 99:1 to Dichloromethane/methanol 95:5 as eluents affording the title compound (35 mg) as a white solid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([C:18]3[N:19]=[N:20][N:21]([CH2:23][C:24](=[O:26])[CH3:25])[N:22]=3)[CH2:17][C@@:11]1([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:12]([O:27][CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.C1COCC1>[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([C:18]3[N:19]=[N:20][N:21]([CH2:23][CH:24]([OH:26])[CH3:25])[N:22]=3)[CH2:17][C@@:11]1([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:12]([O:27][CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:41])([F:42])[F:40])[CH:30]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
Sodium borohydride (13 mg, 0.34 mmol) was added to a solution of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-[2-(2-oxopropyl)-2H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Compound 3i in Table 3; 0.2 g, 0.31 mmol) in methanol (10 ml) and THF (2 ml). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel eluting with 25 and 35% ethyl acetate/iso-hexanes to yield the title compound (189 mg, 95%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C.[Br:28][C:29]1[CH:30]=[CH:31][C:32]2=[C:33]([CH:50]=1)[N:34]=[C:35]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:36][C:37]([C:39](O)=[O:40])=[CH:38]2.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCOCC>[Br:28][C:29]1[CH:30]=[CH:31][C:32]2=[C:33]([CH:50]=1)[N:34]=[C:35]([NH:42][C:43](=[O:44])[O:45][C:46]([CH3:47])([CH3:49])[CH3:48])[CH2:36][C:37]([C:39](=[O:40])[N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:38]2
Reactant: CCCNCCC
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(Br)ccc2C=C(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: -15 °C
Reaction time: 0.67 h
Yield: 76.3 %

Procedure:
To a solution of dipropylamine (2.16 ml, 15.7 mmol) in CH2Cl2 (50 mL) at −10° C. was added EDCI (3.02 g, 15.7 mmol) followed by diisopropylethylamine (2.97 ml, 17.1 mmol) over 5 min. The resulting mixture was stirred for 40 min at −15° C. To the reaction mixture was added (1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylic acid (5.00 g, 13.1 mmol) followed by HOBt (2.13 g, 15.7 mmol) over 5 min maintaining the reaction temperature between −15 to −12° C. The resulting mixture was warmed to room temperature and stirred for 19 h. The reaction mixture was poured onto water (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were washed with sat'd aq NH4Cl (75 mL). The organic layer was separated. The sat'd aq NH4Cl solution was extracted with CH2Cl2 (50 mL) again. The combined organic layers were washed with sat'd aq NaHCO3 (2×75 mL) followed by brine (2×100 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was taken into ether (50 mL) and kept in the freezer for 16 h. The precipitates were filtered off and the filtrate was concentrated under reduced pressure to afford 4.64 g (76%) of tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate. MS APCI(+) m/z 464, 466 (M+1, Br pattern) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:21][C:22]([F:34])([F:33])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C>O1CCCC1.O>[CH:18]([O:17][CH:11]([CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][C:30](=[O:31])[CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:33])([F:21])[F:34])=[CH:28][CH:27]=2)[CH:3]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(N)c1)OC(C)C
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OC)c(NC(=O)Cc2ccc(C(F)(F)F)cc2)c1)OC(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
0.3 g of ethyl 3-(3-amino-4-methoxyphenyl)-2-isopropoxypropanoate and 0.218 g of (α,α,α-trifluoro-p-tolyl)acetic acid were dissolved in 7 ml tetrahydrofuran, and 0.22 g of carbonyldiimidazole and 0.23 ml triethylamine were added thereto, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was ice-cooled, and water was added followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (6:1), 0.34 g of ethyl 2-isopropoxy-3-[4-methoxy-3-(4-trifluoromethylphenylacetylamino)phenyl]propanoate was obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:12](=O)[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)(C)(C)C.O.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][CH3:12])[CH2:15][CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a suspension of LAH (0.5 g, 5 eq) in THF (10 mL), was added 7a and the mixture was refluxed for 72 h. After allowing the reaction mix to cool down to room temperature, 0.5 mL of water, 1 mL of 1 M sodium hydroxide and 1.5 mL of water were added slowly and sequentially. Ethyl acetate was added and the mixture was filtered. Removal of the solvent gave 0.36 g (66% on both steps) of 7b as an oil which was used without further purification on the next step.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Br[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([C:17]2[CH:18]=[C:19]([NH2:20])[CH:21]=[CH:22][CH:23]=2)[CH:4]=[N:3]1
Reactant: Nc1cccc(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(N)c2)cn1
Temperature: 25 °C
Yield: 94 %

Procedure:
1-methyl-1H-pyrazole-4-boronic acid pinacol ester (0.098 g, 0.639 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (0-10% MeOH/CH2Cl2). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.095 g in 94% yield.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C1COCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]2[O:8][C:22](=[O:23])[NH:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2ccc(C(F)(F)F)cc2)o1
Temperature: 24 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
4-(Trifluoromethyl)benzoic acid hydrazide (commercially available from Maybridge Chemicals) (5 g, 24.5 mmol) was taken up in THF (250 ml)/triethylamine (2.7 ml, 26 mmol) under N2 and 1,1'-carbonyl-diimidazole (4.2 g, 26 mmol) added. The solution was stirred for 18 h at 24° C., concentrated, and the residue was taken up in ethyl acetate, washed with 1N HCl solution, sat'd NaHCO3 solution, and brine prior to drying (MgSO4). Concentration gave 5 g (89%) of the title compound from which a sample was recrystallized from diethyl ether/hexanes: mp 214-216° C. MS m/z: 231 (MH+).