Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.CN1C(=O)CCC1.Cl[C:14]1[CH:21]=[C:20]([CH3:22])[C:17]([C:18]#[N:19])=[C:16]([O:23][CH3:24])[N:15]=1.C([Mg]Br)CC.Cl>C(OC(=O)C)C>[CH3:24][O:23][C:16]1[N:15]=[C:14]([CH2:2][CH2:1][CH3:5])[CH:21]=[C:20]([CH3:22])[C:17]=1[C:18]#[N:19]
Reactant: C1CCOC1
Reactant: COc1nc(Cl)cc(C)c1C#N
Agent: CCC[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCc1cc(C)c(C#N)c(OC)n1
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A transparent red-colored THF/NMP(50 mL/5 mL) solution of 6-chloro-2-methoxy-4-methyl-nicotinonitrile (2.00 g, 11.0 mmol) and Fe (acac)3 (387 mg, 1.1 mmol) was slowly added with 11 mL of n-propylmagnesium bromide (2M solution in diethyl ether) and then stirred for about 20 minutes. The mixture was then added with 10 mL of 1M HCl solution 10 mL and diluted with 300 mL of ethylacetate. The resulting organic layer was washed with water and a saturated solution of sodium chloride, dried with anhydrous sodium sulfate and then filtered. A silica gel column chromatography (10% EtOAc/Hexane) was performed on the residue obtained by concentrating the above filtrate under reduced pressure and obtained 2.23 g (88%) of 2-methoxy4-methyl-6-propyl-nicotinonitrile in colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([N:13]2[C:21](=[O:22])[C:20]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[CH:18]=[N:17][C:16]=3[N:15]([CH3:31])[C:14]2=[O:32])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:40])C(=O)C1>CN(C=O)C>[CH2:1]([O:8][CH:9]1[CH2:10][CH:11]([N:13]2[C:21](=[O:22])[C:20]3[N:19]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[C:18]([Cl:40])=[N:17][C:16]=3[N:15]([CH3:31])[C:14]2=[O:32])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(C2CC(OCc3ccccc3)C2)c(=O)c2c1ncn2Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C2CC(OCc3ccccc3)C2)c(=O)c2c1nc(Cl)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
To a solution of 1-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (220 mg, 0.49 mmol) in DMF (3 mL) was added NCS (71.7 mg, 0.54 mmol) in portions at 0° C. The reaction was stirred at room temperature for 4 h. The reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM/methanol (60:1) to give 1-(3-(benzyloxy)cyclobutyl)-8-chloro-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (170 mg, 71.8% yield) as yellow solid. LCMS retention time 2.079 min; LCMS MH+ 485.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7](I)[CH3:8].Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[CH2:20][NH:21][CH2:22][CH2:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.CN(C)C=O>O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[CH2:20][N:21]([CH2:7][CH3:8])[CH2:22][CH2:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(C2=CCCNC2)c1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC=C(c2cccc(OC)c2)C1
Reaction time: 16 h

Procedure:
9.8 g of sodium carbonate and 2.6 ml of ethyl iodide were added to a suspension of 7 g of 3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine hydrochloride and 70 ml of dimethylformamide and the mixture was stirred for 16 hours and was diluted with water. The mixture was extracted with ethyl acetate and the organic extract was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-1-1 cyclohexane-chloroform-triethylamine mixture to obtain 5.3 g of 3-(3-methoxyphenyl)-1-ethyl-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]([C:8](=O)[CH:9]([CH3:11])[CH3:10])[CH:7]=1.[NH2:14]O.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CCO.CC(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:13][N:14]=[C:8]([CH:9]([CH3:11])[CH3:10])[C:6]=2[CH:7]=1
Reactant: NO
Reactant: CC(C)C(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1noc2ccc(Br)cc12
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 14.8 %

Procedure:
1-(5-Bromo-2-hydroxyphenyl)-2-methylpropan-1-one (0.82 g, 3.37 mmol) was dissolved in EtOH (10 mL) then hydroxylamine (50% solution in water, 0.267 g, 4.05 mmol) was added followed by HOAc (1 drop). The mixture was heated to about 80° C. for about 2 h. The mixture was cooled then evaporated under reduced pressure to give an oil. Acetic anhydride (2 mL, 20 mmol) was added and the mixture was stirred for about 45 min at ambient temperature. The mixture was concentrated under reduced pressure then pyridine (7 mL) was added and then the mixture was heated to about 145° C. for about 3 h. The mixture was cooled, treated with 1 N HCl, and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and evaporated to a residue that was then dissolved in DME (4 mL). Cesium carbonate (1.09 g, 3.35 mmol) was added and the mixture was heated at about 150° C. for about 30 min in the microwave. The mixture was evaporated and then purified by flash chromatography with 9:1 heptane/EtOAc to give the title compound (0.12 g, 15%): LC/MS (Table 1, Method a) Rt=3.33 min; MS m/z: 340.1 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13](Br)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Li].C1(C)C=CC=CC=1.Br[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH3:34])=[N:30][CH:31]=1>[Zn+2].[Br-].[Br-].C1COCC1>[CH2:33]([O:32][C:29]1[CH:28]=[CH:27][C:26]([C@H:13]2[CH2:14][CH2:15][C@H:10]([C@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)[CH2:11][CH2:12]2)=[CH:31][N:30]=1)[CH3:34]
Reactant: CCOc1ccc(Br)cn1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](Br)CC2)CC1
Agent: [Br-]
Agent: [Li]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(OCC)nc3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.02 m of trans-4-(trans-4-propylcyclohexyl)-cyclohexylbromide, 0.04 m of lithium, 0.01 m of ZnBr2, 40 ml of toluene and 12 ml of THF are stirred at 0°-10° for 2 hours under ultrasonic. The 0.02 m of 5-bromo-2-ethoxy-pyridine and 0.5 g Pd (Ph3P)4 as the catalyst are added, and the mixture is stirred for further 4 hours at room temperature. Customary work-up yields 2-ethoxy-5-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-pyridine.
Reaction SMILES: C[Si](Cl)(C)C.[Na+].[I-].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:20]=[C:19]([O:21]C)[C:18](=[O:23])[C:17]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:26][CH:25]=2)=[N:16]1.O>CC#N>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:20]=[C:19]([OH:21])[C:18](=[O:23])[C:17]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:26][CH:25]=2)=[N:16]1
Reactant: COc1cn(-c2ccccc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1c(O)cn(-c2ccccc2F)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
TMSCl (1.27 mL, 10 mmol) was added at room temperature to a solution of NaI (1.50 g, 10 mmol) in CH3CN (60 mL). After stirring for 30 min, 1-(2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (0.725 g, 2 mmol) was added to the resulting suspension. The mixture was stirred for 30 min at room temperature and then refluxed for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (1/1) and recrystallized from MeOH/H2O to give the title compound (0.648 g, 93% yield) as off-white prisms: mp 218-220° C.; NMR (300 MHz, DMSO-d6): δ ppm 6.99 (1H, d, =1.9 Hz), 7.10 (1H, dt, J=1.5, 7.9 Hz), 7.21-7.26 (1H, m), 7.32-7.54 (7H, m), 7.80 (1H, d, J=1.9 Hz), 8.44 (1H, d, J=2.6 Hz). Anal. Calcd for C19H13FN4O2: C, 65.51; H, 3.76; N, 16.08. Found: C, 65.73; H, 3.88; N, 16.24.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4].C(N(CC)CC)C.[S:40](Cl)([CH3:43])(=[O:42])=[O:41]>ClCCl>[Cl:32][C:8]1[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][S:40]([CH3:43])(=[O:42])=[O:41])[CH3:6])=[CH:30][CH:29]=[C:28]([Cl:31])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNS(C)(=O)=O)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a stirred solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (80 mg) and triethylamine (22.4 mg) in dichloromethane (1 ml) was dropwise added mesyl chloride (21.4 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. The mixture was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 8-[2,6-dichloro-3-[N-(mesylglycyl)-N-methylamino]benzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (70 mg) as colorless amorphous.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]#[N:21])=[O:5])C.O.[OH-].[Li+].CO>O>[C:20]([C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([C@@H:7]3[CH2:8][CH2:9][CH2:10][C@H:6]3[C:4]([OH:5])=[O:3])[CH:12]=2)[NH:16][CH:15]=1)#[N:21]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1c1ccc2[nH]cc(C#N)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1c[nH]c2ccc([C@@H]3CCC[C@H]3C(=O)O)cc12

Procedure:
A solution of cis-2-(3-Cyano-1H-indol-5-yl)-cyclopentanecarboxylic acid ethyl ester (0.95 g, 3.36 mMol), lithium hydroxide monohydrate (0.71 g, 16.8 mMol), methanol (20 mL), and water (5 mL) was heated at reflux for 6 h. The solution was concentrated in vacuo and the residue dissolved in water and washed once with dichloromethane. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3×20 mL). The pooled organic extracts were washed once with brine, dried over sodium sulfate, and concentrated in vacuo to give the product as a light brown oil which solidified upon standing (0.66 g, 77%). LC-MS: 1.33 min (2 min gradient); 277.07 (MNa)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12].C(P(O)(=O)O)CC.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH:11]([CH3:13])[CH3:12])=[O:8])=[CH:4][N:3]=1
Reactant: CC(C)N
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCCP(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 7.7 %

Procedure:
To a solution of 300 mg (2.17 mmol) of 6-aminonicotinic acid in 50 mL of chloroform were added 370 μL (4.34 mmol) of isopropylamine, 4 mL of anhydrous propanephosphonic acid (25 wt % solution in ethyl acetate) and 1.4 mL (10 mmol) of triethylamine, and the mixture was stirred for 6 hours at room temperature. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1 to 5/1) to give 30 mg (8%) of the title compound.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.CO>[C:16]([Si:13]([CH3:15])([CH3:14])[O:12][CH:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCC(C(=O)O)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of Example 45A (6.6 g, 23.0 mmol) in tetrahydrofuran (31 mL) and methanol (20 mL) was added lithium hydroxide monohydrate (1.93 g, 46.1 mmol). The resulting mixture was heated at 60° C. for 2 hours. The heat was removed and the reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the solution was neutralized with 1M HCl. Ethyl acetate (200 mL) was added and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the titled compound (4.5 g). MS (CI) m/z 259 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:28])[C:3]=1[CH2:29][C:30]([OH:32])=O.[NH:33]1[CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:63][P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([F:28])[C:3]=1[CH2:29][C:30]([N:33]1[CH2:36][CH:35]([F:63])[CH2:34]1)=[O:32])[O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=2)[CH2:16][CH2:15]1
Reactant: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)n1
Reactant: C1CNC1
Reactant: F[P-](F)(F)(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N4CC(F)C4)c(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2,6-difluoro-4-{2-[(1S,2R)-2-{1-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetic acid (100 mg, 0.230 mmol) (from example 1, step C) in 1 ml anhydrous DMF at RT was added azetidine (13.2 mg, 0.230 mmol) and N,N-diisopropylethylamine (0.201 ml, 1.15 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (175 mg, 0.461 mmol) was added into the solution and stirred at RT for 4 hrs. The reaction mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-100% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 509.4.2 (M+H)+. GPR119 Human EC50:1.4 nM.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH:7]([CH3:14])[CH2:6]2)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl.O>[CH3:14][CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH:1]3[CH2:2][O:23]3)[CH:4]=2)[C:9](=[O:13])[O:8]1
Reactant: C=Cc1ccc2c(c1)CC(C)OC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CC1Cc2cc(C3CO3)ccc2C(=O)O1

Procedure:
A solution of 6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one (1.69 g, 8.98 mmol) in DCM (60 mL) was treated with m-CPBA (3.10 g, 17.96 mmol) overnight at room temperature. The reaction was then diluted with water (50 mL) and DCM (50 mL). The organic layer was further washed successively with saturated aqueous sodium bicarbonate (30 mL), water (30 mL), and brine (30 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated. The residue was purified via MPLC (15-40% EtOAc/Hex) to give 3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9]C(C#N)CC[C:5]2=1.[O:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[CH3:22][Mg]I.Cl>O.CCOCC>[C:21]([CH:20]1[CH2:9][CH2:10][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([Cl:1])[CH:3]=3)[NH:11][C:18]=2[CH2:19]1)(=[O:17])[CH3:22]
Reactant: C[Mg]I
Reactant: C1CCOC1
Reactant: N#CC1CCc2c([nH]c3ccc(Cl)cc23)C1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(=O)C1CCc2c([nH]c3ccc(Cl)cc23)C1
Temperature: 10 °C

Procedure:
A solution of 1.0 g. of 6-chloro-2-cyano-1,2,3,4-tetrahydrocarbazole in 15 ml. of tetrahydrofuran was added dropwise to a cooled (10° C. ), stirred solution of 9.6 g. of methyl magnesium iodide in 20 ml. of ether. The reaction mixture was refluxed and stirred under an atmosphere of dry nitrogen for 24 hours. Thereafter, it was cooled to 5° C. in an ice bath and 50 ml. of cold water was carefully added followed by 3 ml. of concentrated hydrochloric acid. The mixture was heated for 3 hours on a steam bath. After the mixture had been cooled by adding ice, it was extracted with ether. The ether solution was washed by extraction with dilute sodium bicarbonate and water. When the ether solution had dried over anhydrous magnesium sulfate, the desiccant was removed by filtration and the ether was removed by distillation, yielding 0.8 g.of product. Following crystallization from a mixture of hexane and ethyl acetate, 0.4 g. of 2-acetyl-6-chloro-1,2,3,4-tetrahydrocarbazole was obtained, m.p. 159° -161°.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:10])=[O:9])=[CH:6][CH:5]=1.[N:15]1[CH:20]=CC=[CH:17][CH:16]=1.C(OCC)(=[O:23])C>>[ClH:10].[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:23][CH2:17][CH2:16][NH:15][CH3:20])=[O:9])=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: c1ccncc1
Product: CNCCOC(=O)c1ccc(OC(F)(F)F)cc1
Product: Cl
Temperature: 60 °C
Reaction time: 25 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl (methyl)carbamate (1.30 g) obtained in Reference Example 1 and ethyl acetate (10 mL) were added 4-trifluoromethoxybenzoyl chloride (1.83 g) and pyridine (0.72 mL). The mixture was stirred at 60° C. for 25 hrs. Ethyl acetate (60 mL) was added to the reaction mixture, and the mixture was washed with water (30 mL), a saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride—ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 14.5 hrs., the mixture was concentrated under reduced pressure. The residue was washed twice with ethyl acetate (15 mL), and dried under reduced pressure at 60° C. to give the title compound (1.83 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH:7]([CH3:25])[N:8]([C:21](=[O:24])[CH2:22][CH3:23])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([CH3:20])[CH:12]=3)[C:4]=2[CH:3]=1.O.NN>CO.ClCCl.[Ni]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=3[CH2:6][CH:7]([CH3:25])[N:8]([C:21](=[O:24])[CH2:22][CH3:23])[N:9]=2)=[CH:12][C:13]=1[CH3:20]
Reactant: CCC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2CC1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCC(=O)N1N=C(c2ccc(N)c(C)c2)c2cc(Cl)ccc2CC1C
Reaction time: 0.75 h
Yield: 55.9 %

Procedure:
3.86 g (10 mmoles) of (±)-4,5-dihydro-8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3-propionyl-3H-2,3-benzodiazepine are dissolved in a mixture of 80 cm3 of methanol and 13 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is purified by chromatography over a column containing silica gel and using a mixture of ethyl acetate and hexane, then the product is recrystallized from acetonitrile. Thus, 1.99 g (56%) of the title compound are obtained in the form of cream coloured solids melting at 152–154° C.
Reaction SMILES: Br[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)[OH:4].[Na+].[I-:25]>CC(C)=O>[I:25][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)[OH:4]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CI)ccc1OCc1ccccc1
Yield: 91.7 %

Procedure:
A mixture of (R)-2-bromo-1-[4-phenylmethoxy-3-[(methylsulfonyl)amino]phenyl]ethanol (12.4 g, 31 mmol) and NaI (52 g, 346 mmol) were refluxed in acetone (190 mL) for 1.75 hours. After filtration, the filtrate was concentrated to a pasty red-brown solid which was partitioned between CH2Cl2 (150 mL) and H2O (190 mL). The organic phase was washed with 150 mL ~23.5% w/w aq. sodium bisulfite and with H2O (150 mL), dried over Na2SO4 and concentrated to give the title compound (12.72 g, 91%).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH:10]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCn1nc(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CCn1nc(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 9.9 %

Procedure:
Using cyclohexyl{1-ethyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}methanol, (0.39 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.32 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.06 g, 11%) was obtained as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([O:29][CH3:30])[O:17][C@H:16]1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][OH:48])=[CH:41][CH:40]=2)[CH:32]=1)(=[O:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([O:29][CH3:30])[O:17][C@H:16]1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH:47]=[O:48])=[CH:41][CH:40]=2)[CH:32]=1)(=[O:13])[CH3:12]
Reactant: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.08 h

Procedure:
Oxalyl chloride (0.068 mL, 0.80 mmol) was added to a solution of DMSO (0.113 mL, 1.60 mmol) in dry DCM (1 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred for 5 min. at the same temperature and then a solution of (2S,3S,4R,5S,6S)-2-(4-chloro-3-(4-(2-hydroxyethoxy)benzyl)phenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (220 mg, 0.403 mmol), in dry DCM (3 mL) was added. The reaction mixture was stirred at the same temperature for 1 h. NEt3 (0.334 mL, 2.40 mmol) was added and the reaction mixture was allowed to come to r.t. The crude compound was extracted with DCM (30 mL). The organic layer was separated, washed with water (15 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the title compound, which was used as such in next step.