Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:40])[F:41])[CH:34]=3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1ccc(Cl)c(Nc2nc3cc(C(=O)O)c4c(c3[nH]2)CC(C)(C)O4)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)c(Nc2nc3cc(C(=O)Nc4cccc(C(F)(F)F)c4)c4c(c3[nH]2)CC(C)(C)O4)c1
Yield: 16.5 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-5-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-27, 0.175 g, 0.471 mmol), thionyl chloride (2.0 mL), 3-trifluoromethyl phenyl amine (0.114 g, 0.707 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.9% MeOH:DCM to afford 0.040 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 2.33 (s, 3H), 3.16 (d, J=5.4 Hz, 2H), 6.87-6.88 (m, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.44 (d, J=7.2 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.73 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 8.34 (s, 2H), 9.00 (s, 1H), 10.01 (s, 1H), 10.05 (s, 1H); MS [M+H]+: 515.22.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.C1(C2(CC(O)(C)C)OC(=O)N([C@H](C3C=CC(C4C=CN(C)C(=O)C=4)=CC=3)C)CC2)CC1>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]=[C:13]=[O:15])[CH3:9])=[CH:4][C:3]=1[CH3:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc([C@H](C)N)ccc1Br
Agent: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC(CC(C)(C)O)(C2CC2)OC1=O
Solvent: CO
Product: Cc1cc([C@H](C)N=C=O)ccc1Br

Procedure:
The title compound was prepared from (S)-1-(4-bromo-3-methyl-phenyl)-ethylamine and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 1. Mass spectrum (ESI+): m/z=272/274 (Br) [M+H+MeOH]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Oc1ccccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cccc(Oc2ccccc2Cl)c1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
To a mixture of 3-cyanophenyl boronic acid (2.84 g, 19.3 mmol), 2-chlorophenol (1.24 g, 9.64 mmol), copper (II) acetate (1.75 g, 9.64 mmol) and 4 Å molecular sieves is added CH2Cl2 (30 mL). While stirring at 25° C., pyridine (3.89 mL, 48.2 mmol) of is added and the reaction mixture stirred at 25° C. for 48 hours. Once complete, the reaction is filtered, and the resulting filtrate is concentrated to afford a crude oil which is purified by column chromatography (5% ethyl acetate in hexanes) to provide 1.92 g of 3-(2-chlorophenoxy)benzonitrile.
Reaction SMILES: C(O[C:4]1[N:14](CC2C=CC3NC4C=CC=CC=4CCC=3C=2)[C:7]2=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)C.[CH2:31](OC1NC2=NC(C)=CC(C)=C2N=1)[CH3:32]>>[CH2:31]([C:4]1[NH:14][C:7]2=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH3:32]
Reactant: CCOc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1N2
Reactant: CCOc1nc2c(C)cc(C)nc2[nH]1
Product: CCc1nc2c(C)cc(C)nc2[nH]1

Procedure:
[step 1] 2-(2-Ethoxy-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (324 mg, 33%) was obtained in the same manner as in step 1 of Example 1, using 2-ethoxy-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (478 mg, 2.50 mmol), obtained in Reference Example 2, instead of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(=O)(O)[O-].[Na+].[C:27]([O:36][CH3:37])(=[O:35])[C:28]1[C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)[OH:30].[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C.C(OCC)C>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][O:7][C:6]1[CH:5]=[C:4]([CH:21]=[CH:20][CH:19]=1)[CH2:3][O:30][C:29]1[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=1[C:27]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)c1ccccc1O
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
The free base of 2-(3-chloromethyl-phenoxymethyl)-quinoline hydrochloride (540 mg, 1.7 mmol, example 49) is prepard by partioning the material between ethyl ether and sodium bicarbonate and drying the organic phase with magnesium sulfate. This material is then dissolved with methyl salicylate (260 mg, 1.7 mmol) in DMF (10 mL) at 0° C. and sodium hydride (60%, 65 mg 1.7 mmol) is added. The reaction is brought to room temperature for 15 min. and is then heated at 60° C. for 6 h. The reaction is cooled and partioned between ethyl acetate and a saturated ammonium chloride solution. The organic phase is dried over magnesium sulfate, filtered, concentrated in vacuo and purified by column chromatography (silica, 50 to 80% ether in hexanes) to provide the title compound; MS (ESI) 400 (M+H)+.
Reaction SMILES: [CH:1]12[N:7]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[N+]([O-])([O-])=O.[NH4+].[CH3:23][S-:24].[Na+].C1OCCOCCOCCOCCOC1>C1COCC1>[CH3:23][S:24][C@@H:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C@H:1]1[NH:7][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[S-]
Reactant: O=C(OCc1ccccc1)N1C2CCCCC21
Agent: C1COCCOCCOCCOCCO1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CS[C@@H]1CCCC[C@H]1NC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 7-azabicyclo[4.1.0]heptane-7-carboxylate (see Example 13, 0.273 g, 1.18 mmol) in 3 mL of THF was added eerie ammonium nitrate (0.065 g, 0.12 mmol) and sodium thiomethoxide (0.165 g, 2.36 mmol). After 30 min, 15-crown-5 (0.520 g, 2.36 mmol) was added. After 110 h, the reaction was concentrated in vacuo, diluted with water, and extracted 3× with diethyl ether. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-15% ethyl acetate in hexanes to provide benzyl rac-[(1R,2R)-2-(methylthio)cyclohexyl]carbamate that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 280.1 for [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[CH2:20]([O:22][C:23](=[O:33])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:21].C(N(CC)CC)C>C(#N)C>[CH2:20]([O:22][C:23](=[O:33])[CH2:24][N:25]([CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:21]
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Reactant: CCOC(=O)CNCc1ccccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN(Cc1ccccn1)Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12

Procedure:
150 ml (0.46 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline, 98 mg (1.1 equiv.) of N-(2-pyridylmethyl)-glycine ethyl ester and 0.076 ml (1.2 equiv.) of triethylamine are stirred at reflux in 5 ml of acetonitrile for 20 hours. The mixture is concentrated by evaporation and the residue is suspended in diethyl ether and filtered. After drying, the title compound is obtained in the form of a white powder.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C@H:10]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:11][CH2:12][N:13]1[CH2:16][CH:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:14]1)C)(C)(C)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[F:29][C:26]1[CH:27]=[CH:28][C:23]([C@H:10]([CH2:11][CH2:12][N:13]2[CH2:14][CH:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:16]2)[CH2:9][NH:7][CH3:6])=[CH:24][CH:25]=1
Reactant: CN(C[C@@H](CCN1CC(N2CCOCC2)C1)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC[C@@H](CCN1CC(N2CCOCC2)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl[(2S)-2-(4-fluorophenyl)-4-(3-morpholin-4-ylazetidin-1-yl)butyl]-methylcarbamate (0.44 g, 1.04 mmol) was dissolved in a HCl-saturated solution of ethyl acetate. The mixture was stirred at room temperature for 1 h and then the solvent was removed by evaporation. There was obtained 450 mg of [(2S)-2-(4-fluorophenyl)-4-(3-morpholin-4-ylazetidin-1-yl)butyl]methylamine dihydrochloride as a foam. 1H NMR (500 MHz, CD3OD): 2.0 (m, 1H), 2.2 (m, 1H), 2.7 (s, 3H), 3.0-5.0 (cm, 18H), 7.2 (t, 2H), 7.5 (t, 2H); LCMS: m/z 322 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:12]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.C1(C)C=CC=CC=1.O.CS(C)=O>[ClH:1].[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:20]3[CH2:21][CH2:22][N:17]([CH:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)[CH2:18][CH2:19]3)[S:3][C:4]=2[CH:10]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: C1CCC(N2CCNCC2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCO
Product: Clc1ccc2nc(N3CCN(C4CCCC4)CC3)sc2c1
Temperature: 130 °C
Reaction time: 23 h

Procedure:
A mixture of 2,6-dichlorobenzothiazole (0.39 g, 1.9 mmol), 1-cyclopentylpiperazine (0.22 g, 1.4 mmol) and dimethylsulfoxide (2.0 mL) was stirred at 130° C. for 23 h. The reaction mixture was allowed to cool and water (50 mL) and potassium carbonate (1 g) was added. The resulting mixture was extracted with a mixture of ethyl acetate and dichloromethane and filtered. The filtrate was separated and the organic extract was washed with brine (2×) and dried (MgSO4). The volatiles were evaporated to give a solid residue which was dissolved into a mixture of ethanol (30 mL) and 1 N hydrochloric acid (2.5 mL). Toluene was added and the mixture was concentrated. Ethanol and toluene was added and the mixture was concentrated again. This afforded a solid which was treated with ethanol (50 mL) and heated to reflux temperature. The resulting mixture was left overnight for crystallization. This afforded after filtration and drying 0.35 g (69%) of 6-chloro-2-(4-cyclopentylpiperazin-1-yl)benzothiazole, hydrochloride.
Reaction SMILES: [CH:1](=[C:8]1/[C:9]([O:11][C:12](=[O:14])[CH2:13]/1)=[O:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1[C@@H:23]2[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][NH:16]1.[OH-].[Na+]>ClCCl>[CH:1](=[C:8](/[CH2:13][C:12]([N:16]1[CH2:17][C@H:18]2[C@H:23]([CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:15]1)=[O:14])\[C:9]([OH:11])=[O:10])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C/C(=C/c2ccccc2)C(=O)O1
Reactant: C1CC[C@H]2CNC[C@H]2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)/C(=C\c1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a suspension of (Z)-benzylidenesuccinic anhydride (139 mg) in dichloromethane (30 ml) was added cis-hexahydroisoindoline (120 mg) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 2N sodium hydroxide solution and the mixture was extracted with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was crystallized from ethyl acetate to give 190 mg of (Z)-2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:45]1[CH2:53][CH2:52][CH2:51][C@H:46]1[C:47]([O:49][CH3:50])=[O:48].Cl.C(N1CCOCC1)C>CN(C)C=O>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:45]1[CH2:53][CH2:52][CH2:51][C@H:46]1[C:47]([O:49][CH3:50])=[O:48])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of Boc-D-Phe-OH (5 g) in N,N-dimethyl formamide (200 ml) were successively added 1-hydroxy benzotriazole (4.29 g), dicyclohexyl carbodimide (4.29 g), H-Pro-OMe.HCl (3.1 g) and N-ethylmorpholine (3 ml). The mixture was stirred at 0° C. for 1 hour and then kept at room temperature for 2 days. The mixture was cooled to −20° C. and dicyclohexylurea was removed by filtration. The filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed successively with 5% sodium hydrogen carbonate, 0.1M hydrogen chloride-solution, saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel in heptane/ethyl acetate=6/4 (v/v) as eluent. The fractions containing Boc-D-Phe-Pro-OMe were pooled and evaporated. Yield: 1.5 g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])=[O:9].C(N(CC)CC)C.[C:27](=[O:35])([O:32][CH2:33][CH3:34])[O:28][CH:29](Cl)[CH3:30].[I-].[Na+]>CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH:29]([O:28][C:27]([O:32][CH2:33][CH3:34])=[O:35])[CH3:30])=[O:14])=[O:9]
Reactant: O=C(C=Cc1cccs1)Nc1ccccc1C(=O)O
Reactant: CCOC(=O)OC(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)OC(C)OC(=O)c1ccccc1NC(=O)C=Cc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
A mixture of 2-[3-(2-thienyl)acrylamido]benzoic acid (273 mg, 1 mmol) and triethylamine (0.2 ml, 1.4 mmol) in dry acetone (10 ml) was stirred at room temperature for 30 minutes. To the solution, 1-chloroethyl ethyl carbonate (214 mg, 1.4 mmol) and sodium iodide (210 mg, 1.4 mmol) were added under ice cooling, and the mixture was heated under reflux for 19 hours. The reaction mixture was filtered by suction and the solvent was removed from the filtrate. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate, then with saturated aqueous sodium chloride, and dried over magnesium sulfate. After removing the solvent, the residue was purified by silica gel column chromatography (developing solvent:benzene:ether=49:1). The second eluate was collected. After removing the solvent, the resulted oily product was crystallized with isopropyl ether to give the desired compound (98 mg, yield, 25%). m.p., 154°-156° C. (white crystals, recrystallized from methanol/tetrahydrofuran/water).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=[O:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[CH3:20]S(C)=O>>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3]2([C:2]([F:1])([F:18])[F:19])[CH2:20][O:17]2)[CH:13]=1
Reactant: COc1ccc(Br)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: CS(C)=O
Product: COc1ccc(Br)cc1C(C)(C)CC1(C(F)(F)F)CO1

Procedure:
To a solution of 1,1,1-trifluoro-4-(5-bromo-2-methoxyphenyl)-4-methylpentan-2-one (5 g, 14.7 mmol) in 5 mL of anhydrous DMSO at room temperature was added 14.6 mL of the ylide stock solution (17.3 mmol) over 5 minutes. The reaction was quenched after 2 hours with water and diethyl ether. The aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-[2-(5-bromo-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane as a dark yellow oil.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:7](Cl)=[S+:6][S:5][N:4]=1.[NH2:9][C:10]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>C(Cl)Cl>[Br:20][C:18]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10](/[N:9]=[C:7]2\[C:3]([Cl:2])=[N:4][S:5][S:6]\2)[CH:19]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: Clc1ns[s+]c1Cl
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)cc1/N=c1/ssnc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.3 %

Procedure:
A mixture of 4,5-dichloro-1,2,3-dithiazol-1-ium chloride (1.9 g, 9.1 mmol) and methyl 2-amino-4-bromobenzoate (1.0 g, 4.3 mmol) in DCM (10 mL) was stirred for 48 h at room temperature. The solvent was evaporated to give the crude compound, which was purified by column chromatography on silica gel to give 350 mg of the desired product. MS (ESI): 367 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[C:23]([F:30])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:32].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:32])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([F:30])[C:24]([O:28][CH3:29])=[C:25]([F:27])[CH:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(OC)c(F)c1
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(OC)c(F)c1

Procedure:
Subsequent chlorination (70° C.; 3h30) of 8-[2-(3,5-difluoro-4-methoxy-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.330 g; 3.156 mmol), and purification by FC (DCM/MeOH=25/1) afforded 1-chloro-8-[2-(3,5-difluoro-4-methoxy-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (0.730 g; 51%). LC-MS: tR=1.04 min.; [M+H]+=456.05 g/mol.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]1[CH2:14][C@H:13]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:12][CH2:11][C@@H:10]1[N:20]1[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)OCC2C=CC=CC=2)[C:21]1=[O:36])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].CCOCC>Br.CC(O)=O.CCOC(C)=O>[NH2:25][C@H:22]1[CH2:23][CH2:24][N:20]([C@H:10]2[CH2:11][CH2:12][C@@H:13]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:14][C@H:9]2[CH2:8][S:5]([C:1]([CH3:2])([CH3:4])[CH3:3])(=[O:7])=[O:6])[C:21]1=[O:36]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)(C)C)C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)(C)C)C1
Yield: 33.7 %

Procedure:
The material from above benzyl (S)-1-((1S,2R,4R)-2-(tert-butylsulfonylmethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (1.0 g) was dissolved in 33% HBr/AcOH (5 mL) at rt. The solution was stirred for 30 min before Et2O was added. This resulted in a precipitate which was isolated. The solid was dissolved in EtOAc and was washed with sat. Na2CO3 solution. The organic phase was dried (MgSO4), filtered, and concentrated to afford (S)-3-amino-1-((1S,2R,4R)-2-(tert-butylsulfonylmethyl)-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (250 mg). MS found: (M+H)+=388.4.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:43]/[OH:44])/[C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:46]1([C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=2)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:43]/[O:44][C:46]2([C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=3)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)/[C:27]([O:29][CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1(Br)CCCCC1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\OC1(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCCCC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 61 %

Procedure:
Benzhydryl 2-(2-tritylaminothiazol-4-yl)-(Z)-2(hydroxyimino)acetate (3.44 g) was treated with 4-nitrobenzyl 1-bromocyclohexanecarboxylate as described in Example 5a to give the title compound (3.0 g, 61%) as a foam. δH (CDCl3) 1.26-2.30 (10H, m), 5.22 (2H, s), 6.39 (1H, s), 6.77 (1H, br s), 7.14 (1H, s), 7.28 (25H, s), 7.46 (2H, d), and 8.01 (2H, d).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([OH:16])[N:10]=1)[CH2:2]2.[CH:17]([NH2:20])([CH3:19])[CH3:18]>>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13]([NH:20][CH:17]([CH3:19])[CH3:18])[N:12]=[C:11]([OH:16])[N:10]=1)[CH2:2]2
Reactant: Oc1nc(Cl)cc(N2CC3CCC(C2)O3)n1
Reactant: CC(C)N
Product: CC(C)Nc1cc(N2CC3CCC(C2)O3)nc(O)n1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
In a 2-5 mL microwave vial was placed 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-ol (26, 30 mg, 0.124 mmol) in iPrNH2 (2.5 ml) to give a yellow solution. The reaction was heated under microwave irradiation at 140° C. for 30 min followed by 30 min of heating under microwave irradiation at 160° C. The solvents were removed under reduced pressure. The residue was dissolved in dichloromethane, and purified by silica gel chromatography, using gradient (0-10%) of MeOH in dichloromethane. The title compound was isolated as a yellow solid (20 mg, 61%)
Reaction SMILES: I.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([Cl:20])=[C:8]([C:13]3[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=3)[CH:9]=2)[CH2:4]1.[CH2:21]([S:25](Cl)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([S:25]([NH:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([Cl:20])=[C:8]([C:13]3[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=3)[CH:9]=2)[CH2:4]1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]
Reactant: NC1CCc2cc(C3=NNC(=O)CC3)c(Cl)cc2C1
Reactant: CCCCS(=O)(=O)Cl
Agent: I
Product: CCCCS(=O)(=O)NC1CCc2cc(C3=NNC(=O)CC3)c(Cl)cc2C1

Procedure:
2-Amino-6-[4,5-dihydropyridazin-3(2H)-on-6-yl]-7-chloro-1,2,3,4-tetrahydronaphthalene.hydroiodide and butanesulfonyl chloride were treated in the same manner as in Example 111 to obtain 2-n-butylsulfonylamino-6-[4,5-dihydropyridazin-3(2H)-on-6-yl]-7-chloro-1,2,3,4-tetrahydronaphthalene.