Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][OH:16])[CH3:12].[H-].[Na+].O>CN(C=O)C>[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][O:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCN(CC)CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To the solution of 8.0 g (51 mMol) of 1-chloro-4-nitrobenzene and 6.0 g (6.8 mL; 51 mMol) of 2-diethylamino-ethanol in 50 mL of DMF at 0° C. is added 2.7 g of NaH portionwise over 2 h. After stirring another hour at rt, the reaction mixture is poured onto 300 mL of water and stirred. After filtering off some crystalline product, the aqeous layers are extracted with ethyl acetate. The combined organic layers are dried and evaporated to obtain diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine. Title compound: ES-MS: 239 [M+H]+; single peak at tR=5.1 min (System 2).
Reaction SMILES: C(OC([N:11]1[CH:16]2[CH2:17][NH:18][CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=O)C1C=CC=CC=1.[CH2:20]=O.[BH4-].[Na+]>CO>[CH3:20][N:18]1[CH2:17][CH:16]2[NH:11][CH:12]([CH2:13][O:14][CH2:15]2)[CH2:19]1
Reactant: C=O
Reactant: O=C(OCc1ccccc1)N1C2CNCC1COC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CC2COCC(C1)N2
Temperature: 25 °C
Yield: 80.4 %

Procedure:
To a solution of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound X) (84 mg, 0.28 mmol) in MeOH (5 mL) was added paraformaldehyde (41 mg, 1.38 mmol) and NaBH4 (21 mg, 0.56 mmol). The reaction mixture was refluxed for 16 hours under argon atmosphere, and then quenched with sat. NaHCO3, then extracted with EtOAc (20 mL) three times. The combined organic layer was washed successively with sat. NH4Cl, NaHCO3 and brine, and then dried over Na2SO4. The solvent was concentrated under reduced pressure. The residue was dissolved in MeOH (20 mL). To the solution was added 10% Pd on carbon (20 mg). The mixture was stirred under one atmosphere pressure of hydrogen at room temperature. After the reaction was completed, the mixture was filtered and concentrated to give the crude 7-methyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (Compound Z) (32 mg, 81%) which was directly used for next step. MS: calc'd (MH+) 143, measured (MH+) 143.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH3:37][S:38]([CH2:41][CH2:42][NH2:43])(=[O:40])=[O:39].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:43][CH2:42][CH2:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: CS(=O)(=O)CCN
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCS(C)(=O)=O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and 2-(methylsulfonyl)ethylamine using diethyl cyanophosphonate as a coupling reagent. Mass: 614.00 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=O.C[Si]([N:22]=[C:23]=[N:24][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[N:24][C:23]#[N:22]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (379 mg, 1.28 mmol) in anhydrous DCM (10 mL) was added TiCl4 (1 M solution in DCM, 2.6 mL, 2.6 mmol) dropwise within 15 min at rt. The mixture was stirred for another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (0.525 g, 0.63 mL, 2.82 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give N-(6-bromospiro[chroman-2,1′-cyclohexane]-4-ylidene)cyanamide as a light brown solid (410 mg), which was used in the next step without further purification. MS ESI +ve m/z 319 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]([S:21]Cl)=[O:20]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][C:19](=[O:20])[S:21][N:15]=2)=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: c1ccccc1
Product: O=c1oc(-c2ccc(OCc3ccccc3)cc2)ns1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
4-benzyloxybenzamide (0.66 g, 2.98 mmol) and 0.26 ml of chlorocarbonyl sulfenyl chloride were dissolved in 10 ml of benzene, refluxed for 3 hours, and stirred at 50° C. for 12 hours. The organic solvent was distilled off under reduced pressure, and the resulting solid was washed with n-hexane to obtain 0.78 g of 5-(4-benzyloxy-phenyl)-[1,3,4]oxathiazol-2-one.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][CH:7]=[C:8]([C:14](=[O:28])[C:15]2[CH:20]=[C:19]([F:21])[C:18]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)=[CH:17][C:16]=2F)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.O>O1CCOCC1>[F:21][C:19]1[CH:20]=[C:15]2[C:16](=[CH:17][C:18]=1[N:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1)[N:6]([CH:3]1[CH2:5][CH2:4]1)[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]2=[O:28]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(-n2cccc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 80 °C
Yield: 77.3 %

Procedure:
0.07 g (0.00115 mol) of a 60% suspension of sodium hydride in mineral oil is added to a solution of 0.41 g (0.00114 mol) of ethyl 3-cyclopropylamino-2-(2,5-difluoro-4-pyrrol-1-ylbenzoyl)acrylate in 10 ml of anhydrous dioxane. The mixture is heated at 80° C. for 2 hours under a nitrogen atmosphere and left to cool, 30 ml of water are added and the precipitate is filtered off and washed with water to give 0.3 g of a product melting at 216°-9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:15][C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][C:21]=3[C:22]=2[N:23]=1.[Cl-].[NH4+:32]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:15][C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:25]([C:28]([NH2:32])=[O:30])=[CH:24][C:21]=3[C:22]=2[N:23]=1
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3nncn3-c3ccc(F)cc3F)sc1CCO2
Reactant: [NH4+]
Agent: [Cl-]
Product: NC(=O)c1ccc2c(c1)-c1nc(-c3nncn3-c3ccc(F)cc3F)sc1CCO2

Procedure:
2-[4-(2,4-Difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carboxylic acid and ammonium chloride were reacted in the general amide coupling procedure to give 407. NMR: (CDCl3): 3.32-3.35 (2H, m), 4.32-4.30 (2H, m), 6.96-6.99 (1H, m, Ar), 7.09-7.14 (1H, m, Ar), 7.48-7.50 (1H, m, Ar), 7.54-7.58 (1H, m, Ar), 8.09-8.11 (1H, m, Ar) and 8.35 (1H, s, Ar). MS: (ESI+) MH+=425.95
Reaction SMILES: [CH:1]([S:4]([CH2:7][C@H:8]1[C@@H:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:15]2=[O:32])[CH2:12][CH2:11][NH:10][CH2:9]1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:33][C:34]([CH3:36])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:34]([N:10]1[CH2:11][CH2:12][C@H:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:22]=3)[C:15]2=[O:32])[C@H:8]([CH2:7][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:5])=[O:6])[CH2:9]1)([CH3:36])[CH3:33]
Reactant: CC(C)S(=O)(=O)C[C@@H]1CNCC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)N1CC[C@H](N2CC[C@H](NC(=O)c3cccc(C(F)(F)F)c3)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
A sample of N—((S)-1-((3R,4S)-3-(isopropylsulfonylmethyl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide (0.05 g) was dissolved in 1,2-dichloroethane (3 mL) prior to the addition of acetone (0.38 mL, 0.525 mMol). After stirring at rt for 1 h, sodium triacetoxyborohydride (0.445 g, 0.21 mMol) was added to the reaction. Stirring was continued for 2 h when the reaction was quenched with saturated NaHCO3. Partitioned between EtOAc and water. Organic layer was washed with brine and dried (MgSO4). Filtered, concentrated and chromatographed. The desired product, N—((S)-1-((3R,4S)-1-isopropyl-3-(isopropylsulfonylmethyl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide (0.0086 g, yield=16%) was obtained as a white solid. MS found: (M+H)+=518.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)[CH:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)[CH:38]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)no2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)no3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (565 mg, 1.77 mmol) and (RS)-3-oxo-3-{3-[3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propionic acid tert.-butyl ester (Example K12) (710 mg, 1.77 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (721 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH2:27]([O:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH3:28]>>[CH2:27]([O:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])[CH3:28]
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: CCOCn1ccnc1
Product: CCOCn1ccnc1C(=O)c1cn(-c2cccc(-c3cc(F)ccc3OC)c2)cn1

Procedure:
This compound is prepared by method C using compound 12b and 1-(ethoxymethyl)imidazole.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:20])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=2)=[C:5]2[CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24][C:4]=12)[CH3:2].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)(C)C.[OH-].[Na+].C(#N)C>[CH3:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:24][C:23]([CH3:25])([CH3:26])[CH2:22][CH2:21][C:5]=23)=[O:20])[CH:16]=[C:15]([CH3:17])[C:14]=1[O:18][CH2:27][CH:29]1[CH2:30][O:31]1
Reactant: ClCC1CO1
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)c2c1CC(C)(C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC#N
Product: CCc1sc(C(=O)CCc2cc(C)c(OCC3CO3)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (75 mg, 0.20 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1.7 mL) is treated with epichlorohydrine (75 mg, 0.60 mmol) and the mixture is stirred at rt for 1 h. The mixture is diluted with acetonitrile (1 mL) and separated by prep. HPLC (Phenomenex Aqua, 75×30 mm ID, 10 μm, 10-95% acetonitrile in water containing 0.5% formic acid) to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (50 mg) as a colourless resin; LC-MS: tR=1.21 min, [M+1]=427.41.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10]O.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>ClCCl>[Br:13][CH2:10][C:3]1[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: BrP(Br)Br
Reactant: COc1cccc(C)c1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(C)c1CBr
Temperature: -10 °C
Reaction time: 8 h

Procedure:
[2-Methyl-6-(methyloxy)phenyl]methanol (for a preparation see Intermediate 56)(300 mg, 1.971 mmol) in dichloromethane (4.5 ml) under nitrogen was stirred and cooled to −10° C. A solution of phosphorus tribromide (186 μl, 1.97 mmol) in DCM (4 ml) was then added dropwise over about 15 min and the solution stirred for a further 30 min at this temperature. The solution was allowed to warm up to ambient temperature. After a few hours, saturated aqueous sodium bicarbonate (approximately 5 ml) was added and the mixture stirred vigorously. The suspension was stored in freezer overnight. The phases were separated and the aqueous phase extracted further with chloroform. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give the title compound as yellow solid (424 mg); LCMS: (System 4) No MH+, tRET=3.01 min.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH:11]C(=O)OCC3C=CC=CC=3)[C:4]2=[N:3][CH:2]=1.C(O)C>[Pd].C1(C)C=CC=CC=1>[CH:1]1[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1
Reactant: O=C(N[C@@H]1CCc2ccccc2-n2ccnc21)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N[C@@H]1CCc2ccccc2-n2ccnc21
Reaction time: 64 h
Yield: 83.7 %

Procedure:
Combine benzyl N-[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamate (120.0 g, 359.9 mmol) and ethanol (2.0 L) in a Büchi hydrogenator and add 10% palladium on carbon (Pd/C) (10.0 g, 9.4 mmol) slurried in toluene (200 ml). Hydrogenate (60 psi, ambient temperature) the mixture for approximately 64 hours. Filter the mixture through diatomaceous earth and wash the cake with THF (300 ml). Concentrate the filtrate under reduced pressure to give the title compound (60 g, 84%) as a white foam: MS (m/z): 200 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1.[CH3:13][N:14]=[C:15]=[S:16]>C(#N)C>[CH3:13][NH:14][C:15](=[S:16])[NH:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1
Reactant: CN=C=S
Reactant: N#CCCCCn1ncc(N)n1
Solvent: CC#N
Product: CNC(=S)Nc1cnn(CCCCC#N)n1

Procedure:
A solution of 5-(4-amino-1,2,3-triazol-2-yl)valeronitrile (1.65 g.) in acetonitrile (5 ml.) and methylisothiocyanate (0.73 g.) was stirred for 18 hours at ambient temperature and then heated under reflux for 6 hours. The solvent was evaporated and the residue was triturated with ether/EtOH to give 5-[4-(3-methylthioureido)-1,2,3-triazol-2-yl]valeronitrile as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C:50]1[S:51][CH:52]=[C:53]([C:55]2[CH:66]=[CH:65][C:58]([C:59]([NH:61][CH:62]3[CH2:64][CH2:63]3)=[O:60])=[CH:57][CH:56]=2)[N:54]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][C@H:9]1[C:13](=[O:15])[NH:49][C:50]1[S:51][CH:52]=[C:53]([C:55]2[CH:56]=[CH:57][C:58]([C:59](=[O:60])[NH:61][CH:62]3[CH2:64][CH2:63]3)=[CH:65][CH:66]=2)[N:54]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reactant: CC(C)(C)OC(=O)N1CCS[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCS[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-Thiazolidine-2,3-dicarboxylic acid 3-tert-butyl ester (49.4 mg, 0.21 mmol) was dissolved in DMF (2 mL). DIEA (74 μL, 0.42 mmol) was added followed by HATU (80.7 mg, 0.21 mmol). The reaction was stirred at ambient temperature for 15 minutes. Then 4-(2-Amino-thiazol-4-yl)-N-cyclopropyl-benzamide (54.6 mg, 0.21 mmol) was added. The reaction was stirred at ambient temperature overnight and then heated to 50° C. for 7 hours. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 30.5 mg. MS: 475.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 0.54-0.75 (m, 4H), 1.22-1.47 (m, 9H), 2.79-2.90 (m, 1H), 3.05-3.25 (m, 2H), 3.55-3.75 (m, 1H), 5.33-5.50 (m, 2H), 7.78-7.98 (m, 5H), 8.40-8.48 (d, 1H), 12.50-12.59 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[C:19]2[C:14]=1[CH2:15][CH2:16][C:17](=[O:31])[NH:18]2.C(O)C.[ClH:41]>CO.[C].[Pd]>[ClH:41].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:14]=1[CH2:15][CH2:16][C:17](=[O:31])[NH:18]2
Reactant: COc1ccc(CCNCC(O)COc2ccc(OCc3ccccc3)c3c2CCC(=O)N3)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COc1ccc(CCNCC(O)COc2ccc(O)c3c2CCC(=O)N3)cc1OC
Temperature: 25 °C

Procedure:
2.0 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-benzyloxy-3,4-dihydrocarbostyril was suspended in 50 ml of methanol, and ethanol containing hydrogen chloride was added to the suspension until the suspension showed acidity to form a homogeneous solution. 0.7 g of 10% palladium carbon was added to the resulting solution, and the mixture was stirred at room temperature and at atmospheric pressure to absorb hydrogen. The reaction completed at the point when the absorption of hydrogen ceased. The catalyst was removed by filtration, and the methanol evaporated. To the residue was added a small amount of ethanol to crystallized followed by recrystallization from ethanol to obtain 1.5 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-hydroxy-3,4-dihydrocarbostyril hydrochloride as colorless powdery crystals having a melting point of 171°-173° C.
Reaction SMILES: [CH2:1]([C@@:4]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([F:22])[F:21])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH2:30]>C1COCC1.C(Cl)Cl>[F:21][CH:20]([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)([CH2:1][CH2:2][CH2:3][OH:30])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(OC(F)F)cc2)C(=O)O1
Reactant: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(OC(F)F)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: -9 °C
Reaction time: 21 h
Yield: 80 %

Procedure:
A solution of (R)-6-allyl-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (0.2780 g, 0.686 mmol, 1.0 equiv) in THF (20 mL) was degassed and then cooled with an ice-salt bath (−9° C.). To this solution was added a solution of 1.0 M BH3.THF complex in THF (1.5 mL, 1.5 mmol, 2.2 equiv). The resulting mixture was allowed to slowly warm to rt while stirring overnight (21 h) and then quenched with H2O (3 mL) and NaBO3.H2O (0.680 g, 6.8 mmol, 10 equiv). The mixture was vigorously stirred at rt overnight and then diluted with CH2Cl2, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to give 0.2337 g (80%) of (R)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.59 min, m/z 446 (MNa+), 380, 210, 171; 1H NMR (400 MHz, CD3OD) δ 7.27-7.23 (m, 2H), 7.04 (t, J=8.8 Hz, 2H), 6.94 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.67 (t, J=74.1 Hz, 1H), 5.48 (q, J=7.1 Hz, 1H), 3.43-3.39 (m, 2H), 3.07-3.02 (m, 1H), 2.42-2.37 (m, 1H), 2.26-2.10 (m, 2H), 1.91-1.85 (m, 2H), 1.58-1.50 (m, 1H), 1.46 (d, J=7.0 Hz, 3H), 1.29-1.20 (m, 1H); 19F NMR (376 MHz, CD3OD) δ −83.95 (d, J=73.8 Hz), −117.51 (m).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1([CH:18]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:20][C:19](=[O:21])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CC=Cc1cccc(Cl)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)C(CC=Cc1cccc(Cl)c1)c1ccccc1

Procedure:
A sodium hydroxide solution (7.5 ml., 20%) is added to a solution of p-chlorobenzaldehyde (17.86 g., 0.127 mole) and 3-phenyl-6-(m-chlorophenyl)-5-hexen-2-one (36.11 g., 0.127 mole) in ethanol (360 ml.) with stirring. The gum that separates on continued stirring is chromatographed (benzene) through a silica gel column to obtain the product as a very viscous oil (opaque).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[N:56]1[CH:61]=[CH:60][N:59]=[CH:58][C:57]=1[C:62](Cl)=[O:63]>>[CH3:3][O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][N:26]1[C:62]([C:57]1[CH:58]=[N:59][CH:60]=[CH:61][N:56]=1)=[O:63])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: O=C(Cl)c1cnccn1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1cnccn1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (25 mg) was reacted with pyrazine-2-carbonyl chloride according to General Procedure F. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+4% MeOH). to give (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(pyrazine-2-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (12 mg). LCMS (m/z): 847.