Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH2:10][CH2:9][C:8]1=[O:11].[CH:12]1([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:27][C:28]4[CH:33]=[CH:32][C:31](I)=[CH:30][N:29]=4)=[CH:26][C:19]=3[CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13]1.N[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[CH:12]1([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:27][C:28]4[N:29]=[CH:30][C:31]([N:7]5[CH2:10][CH2:9][C:8]5=[O:11])=[CH:32][CH:33]=4)=[CH:26][C:19]=3[CH2:18][CH2:17]2)[CH2:13][CH2:14][CH2:15]1
Reactant: O=C1CCN1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CCN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 150 °C

Procedure:
Cesium carbonate (678 mg, 1.04 mmol) was added to a solution of 2-azetidinone (308 mg, 4.3 mmol) in dioxane (1 ml). The mixture was heated in a microwave reactor at 150° C. for 1 minute then a mixture of 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (294 mg, 0.7 mmol), trans-1,2-diaminocyclohexane (0.02 ml) and copper (I) iodide (126 mg, 1.2 mmol) were added and the resulting mixture was heated in microwave reactor at 180° C. for 1 hour. The reaction mixture was cooled and applied to a SCX cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue purified by column chromatography (0.5:2.5:97.5) to afford the title compound (E219). MS (ES+) m/e 364 [M+H]+.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:12])[C:9]=1[CH2:10]2.O.Cl(O)(=O)(=O)=[O:15].C(Cl)(Cl)Cl>O1CCCC1.CCOCC.C(=O)(O)[O-].[Na+]>[C:8]1([OH:12])[C:9]2[CH2:10][C@@H:11]([OH:1])[C@H:2]([OH:15])[CH2:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: Oc1cccc2c1CC1OC1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Oc1cccc2c1C[C@@H](O)[C@H](O)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 8.0 g of 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol in 100 ml of tetrahydrofuran is cooled to 0° C. and 20 ml of water and 0.5 ml of 70% perchloric acid are added. After 4 hours, a further 1.5 ml of acid is added and the solution is stirred for 16 hours at ambient temperature and diluted with 100 ml each of ether, 10% sodium bicarbonate and saturated salt solution. The aqueous layer is separated and washed with 150 ml of 1:1 ether-tetrahydrofuran. The organic phase is washed with saturated salt solution, dried and evaporated to give an oil which solidifies on trituration with chloroform. Recrystallization gives in two crops, 4.85 g of solid which is recrystallized from ethyl acetate to give 3.84 g, melting point 179.5°-181.5° C. Two further recrystallizations of a small sample give the analytical specimen, melting point 183°-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]3[CH2:13][CH2:14][CH:15]([C:18]([O-:20])=[O:19])[CH2:16][CH2:17][CH:11]3[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:21](O)(=O)C>S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: O=C([O-])C1CCC2ON=C(c3ccc(Cl)cc3)C2CC1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: COC(=O)C1CCc2onc(-c3ccc(Cl)cc3)c2CC1
Temperature: 90 °C

Procedure:
5.3 g (0.053 mol) of chromium trioxide were added to a solution of 6.14 g (0.02 mol) of methyl 3-(4-chlorophenyl-3a,5,6,7,8,8a-hexahydro-4H-cyclohept[d]isoxazole-6-carboxylate (mixture of two diastereoisomers, prepared as described in the last paragraph of Example 1) in 110 ml of acetic acid and 0.5 ml of concentrated sulfuric acid. The mixture was heated to 90° C. for 40 minutes. Excess acetic acid was removed by evaporation, water and 2N sodium carbonate solution were added and the mixture was extracted with diethyl ether. Purification by column chromatography on silica gel using diethyl ether/hexane (1:1) for the elution gave 2.57 g or pure methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]-isoxazole-6-carboxylate of melting point 70°-71° C.
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].CC(C)=O>FC(F)(F)C(O)=O>[C:12]([C:2]([CH2:8][C:9](=[O:10])[O-:11])([CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6])[OH:1])(=[O:16])[CH:13]([CH3:15])[CH3:14]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: CC(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: CC(C)C(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Reaction time: 4 h
Yield: 57.6 %

Procedure:
To a solution of carnitine (3 grams; 0.015 mole) in trifluoroacetic acid (5 cc), isobutyryl chloride (10 cc; 0.096 moles) was added dropwise. The resulting mixture was kept at 45° C. for 4 hours, acetone was added thereto and the residual carnitine was filtered off. Anhydrous ethyl ether was added to the solution and the desired product (2 grams; yield 66%) was obtained by precipitation.
Reaction SMILES: CO[C:3](=[O:5])[O-:4].[CH3:6][N+:7]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8]1.C1(=O)[O:18][C:16](=[O:17])[CH:15]=[CH:14]1>O>[C:3]([O-:4])(=[O:5])/[CH:14]=[CH:15]\[C:16]([O-:18])=[O:17].[CH3:6][N+:7]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:6][N+:7]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1C=CC(=O)O1
Reactant: COC(=O)[O-]
Agent: C[N+]1(C)CCCC1
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]
Yield: 136.3 %

Procedure:
By following the same procedure as Example 20 (2nd step) except that 17.5 g of N,N-dimethylpyrrolidinium methyl carbonate, 17.5 g of water, and 9.8 g of maleic anhydride were used, 21.4 g (yield of 99.6%) of N,N-dimethylpyrrolidinium maleate was obtained. The content of mono-maleate was less than 0.1% and the contents of impurity ions were less than 1 ppm.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[N:10]>[OH-].[Na+]>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[N:10]
Reactant: CNC
Reactant: N#CCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCCCC#N
Reaction time: 24 h

Procedure:
A mixture of dimethylamine (4 mL, 40% in water) and 5-bromo-pentanenitrile (2.3 mL, 20 mmol) is stirred for 24 h. The resulting reaction mixture is diluted with sodium hydroxide solution (10 mL, 5M) and extracted with ether. The ether extract is dried over K2CO3 and concentrated under reduced pressure to give an oil (1.5 g) which is used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:14][CH2:15][C@@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C:18]([OH:20])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:29](I)[CH3:30]>O.CO>[CH2:7]([O:14][CH2:15][C@@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C:18]([O:20][CH2:29][CH3:30])=[O:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)CC(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of cesium carbonate (3.53 g, 10.9 mmol) in water (22 ml) was added to an ice-cooled solution of (3S)-4-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]butanoic acid (3.36 g, 10.9 mmol) in methanol (70 ml) and water (7 ml), and the reaction stirred for 20 minutes. The mixture was concentrated under reduced pressure and azeotroped with N,N-dimethylformamide and dichloromethane. The residual oil was dissolved in N,N-dimethylformamide (70 ml), ethyl iodide (1.64 g, 10.9 mmol) added, and the reaction stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, suspended in ethyl acetate (300 ml), washed with water (4×), brine, then dried (MgSO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using hexane:ethyl acetate (85:15) to afford the title compound as a pale yellow oil, 2.86 g; 1H NMR (CDCl3, 400 MHz) δ: 1.26 (t, 3H), 1.45 (s, 9H), 2.65 (d, 2H), 3.58 (m, 2H), 4.17 (m, 3H), 4.55 (s, 2H), 5.20 (bs, 1H), 7.36 (m, 5H).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:26])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCCl.C(N(CC)CC)C.[C:42]([O:46][CH3:47])(=[O:45])[CH:43]=[CH2:44]>[I-].OCCC1SC=[N+](C)C=1C.CCO>[O:26]=[C:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:14]1=[N:15][O:16][C:12]([C:9]3[C:8]([C:27]([F:28])([F:29])[F:30])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:11][N:10]=3)=[C:13]1[CH2:24][CH2:23]2)[CH2:44][CH2:43][C:42]([O:46][CH3:47])=[O:45]
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: Cc1c(CCO)sc[n+]1C
Agent: [I-]
Solvent: ClCCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 75 °C
Reaction time: 7 h
Yield: 23.6 %

Procedure:
To a mixture of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 88A, 80 mg, 0.195 mmol), 5-(2-hydroxyethyl)-3,4-dimethylthiazolium iodide (11.12 mg, 0.039 mmol), 1,2-dichloroethane (1 mL), EtOH (1.000 mL), triethylamine (0.082 mL, 0.585 mmol) and methyl acrylate (0.053 mL, 0.585 mmol) was bubbled with nitrogen for 1 min. and then sealed in a 1-dram vial. The mixture was heated at 75° C. for 15 h. Additional 5-(2-hydroxyethyl)-3,4-dimethylthiazolium iodide (30 mg) and methyl acrylate (0.053 mL, 0.585 mmol) were added and the mixture was stirred at 75° C. for 7 h. The solvents were removed under reduced pressure. The residue was treated with water (2 mL) and extracted with dichloromethane. The combined dichloromethane extracts were dried (sodium sulfate) and concentrated. Flash chromatography purification (4 g silica gel column, 20→100% dichloromethane in heptanes) afforded methyl 4-oxo-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (23 mg, 0.046 mmol, 23.76% yield) as a glassy solid.
Reaction SMILES: [C:1]([C@@H:5]([C@H:7]([C:9]([O:11]C)=O)[OH:8])[OH:6])([O:3]C)=O.[OH:13][CH2:14][C:15]([CH2:19][OH:20])([CH2:17][OH:18])[NH2:16]>CO>[OH:13][CH2:14][C:15]([NH:16][C:1](=[O:3])[C@@H:5]([C@H:7]([C:9]([NH:16][C:15]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:14][OH:13])=[O:11])[OH:8])[OH:6])([CH2:19][OH:20])[CH2:17][OH:18]
Reactant: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Reactant: NC(CO)(CO)CO
Solvent: CO
Product: O=C(NC(CO)(CO)CO)[C@H](O)[C@@H](O)C(=O)NC(CO)(CO)CO

Procedure:
A suspension of 1.78 g of dimethyl L-tartrate and 4.85 g of tris-hydroxymethyl-methylamine in 50 ml of methanol was heated under reflux for 6 days and then concentrated. The residue was purified by chromatography over silica gel with ethyl acetate/methanol/water as the eluent and gave N,N'-bis-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-L-tartaramide, [a]+101.00 (c 0.4; dimethyl sulfoxide), MS: m/z 357.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:37][C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:39](=[O:40])[C:38]([CH3:43])([CH3:42])[CH3:37])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CN2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.220 g, 0.57 mmol) and triethylamine (0.12 mL, 0.86 mmol) in CH2Cl2 was added trimethylacetyl chloride (0.11 mL, 0.86 mmol), and the reaction was stirred for 1 hour at room temperature. The mixture was concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C([O-])(=O)C.[Na+].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1cccc(Br)c1
Temperature: 25 °C

Procedure:
10 g (49.5 mmol) of 2-bromonitrobenzene, 13 g (163 mmol) of sodium acetate, and 10 g (59 mmol) of 3-bromoaniline were stirred at 180° C. for 8 hours in an argon atmosphere. After cooling the reaction solution to room temperature, the reaction solution was diluted with ethyl acetate, and filtered. After concentrating the filtrate, the residue was washed with methanol to obtain (3-bromophenyl)-(2-nitrophenyl)amine.
Reaction SMILES: [C:1]([C:3]1([NH:12]C(=O)C(O)CC(C)C)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:4]1)#[N:2].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.CN1CCOCC1.C(N)C1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:12][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:4]1
Reactant: CCCN1CCC(C#N)(NC(=O)C(O)CC(C)C)CC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: NCc1ccccc1
Solvent: CN1CCOCC1
Product: CCCN1CCC(N)(C#N)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 108.7 %

Procedure:
To a solution of 2-hydroxy-4-methyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide (0.316 g, 1.1 mmol) in CH2Cl2 (30 mL) was added DMAP (0.192 g, 1.6 mmol), p-nitrophenyl chloroformate (0.249 g, 1.2 mmol), and N-methylmorpholine (0.136 mL, 1.2 mmol). The resulting mixture was allowed to stir overnight (20 h) under argon at room temperature, then treated with benzylamine (1.68 g, 16 mmol) and allowed to stir overnight (20 h). When the reaction was complete the mixture was diluted with CH2Cl2 (50 mL), then washed with saturated aq. NaHCO3 (50 mL), water and brine, dried over Na2SO4, filtered and evaporated in vacuo to give 0.200 g (50% yield) of the desired product after purification by prep-HPLC;
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([O:19][CH3:20])[C:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[C:12]3[Cl:32])([OH:8])[C:6]#[CH:7])[CH2:2]1.CCN(CC)CC.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[Cl:32][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:5]([CH:3]3[CH2:4][N:1]([C:40](=[O:42])[CH3:41])[CH2:2]3)([OH:8])[C:6]#[CH:7])[CH:10]=2)[N:15]=[C:14]([O:19][CH3:20])[C:13]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: C#CC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)C1CNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)C1CN(C(C)=O)C1
Temperature: 40 °C

Procedure:
To a flask containing crude 1-(azetidin-3-yl)-1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)-benzyl)quinolin-6-yl)prop-2-yn-1-ol (130 mg, 0.28 mmol, Example 16) was added DCM (10 mL) followed by Et3N (0.2 mL, 1.44 mmol) and acetic anhydride (0.1 mL, 1.06 mmol) at room temperature. The mixture was heated to 40° C. for 2 hours and then quenched with a solution of saturated aqueous NaHCO3. The aqueous portion was extracted with DCM (3×35 mL) and the combined organics were dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel using (5% MeOH-DCM) provided the title compound as an off white amorphous solid. 1H NMR (500 MHz, CD3OD) δ 8.44 (d, J=1.9 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.91-7.82 (m, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 4.40 (s, 2H), 4.36-4.18 (m, 1H), 4.16-4.01 (m, 4H containing a singlet at 4.07), 4.05-3.98 (m, 1H), 3.93-3.80 (m, 1H), 3.28 (s, 1H), 3.24-3.09 (m, 1H), 1.85 (d, J=3.3 Hz, 3H); MS (ESI): mass calcd. for C26H22ClF3N2O3, 502.1, m/z found 503.2 [M+H]+. 1-(3-(1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-hydroxyprop-2-yn-1-yl)azetidin-1-yl)ethanone was purified by chiral SFC: (Stationary phase: CHIRALPAK AD-H, 5 μm, 250×20 mm), Mobile phase: 70% CO2, 30% MeOH), to give 2 enantiomers. The first eluting enantiomer was Example 7b and the second eluting enantiomer was Example 7c.
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Br:12])[CH:3]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.OOS([O-])=O.[K+]>CN(C=O)C.O>[Br:12][C:4]1[C:5]([C:6]#[N:7])=[CH:8][C:9]2[N:10]([CH3:11])[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: CNc1cc(C#N)c(Br)cc1N
Reactant: O=Cc1cccnc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2cccnc2)nc2cc(Br)c(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To solution of 4-amino-2-bromo-5-(methylamino)benzonitrile (0.2 g, 0.0008 mol) and nicotinaldehyde (0.094 g, 0.0008 mol) in DMF (5 ml) and H2O (2 ml) was added OXONE® monopersulphate (0.43 g, 0.0007 mol). Reaction mass was stirred at room temperature for 3 h. The reaction mixture was quenched with 10% K2CO3 solution to PH˜8-10 and extracted with EtOAc (3×20 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford the crude compound, which was purified by column chromatography to obtain title compound 5-bromo-1-methyl-2-(pyridin-3-yl)-1H-benzimidazole-6-carbonitrile. (3971H NMR (400 MHz, DMSO-d6), δ: 9.08 (s, 1H), 8.80-8.79 (d, J=4 Hz, 1H), 8.53 (s, 1H), 8.34-8.32 (d, J=7.2 Hz, 1H), 8.23 (s, 1H), 7.67-7.63 (m, 1H), 3.96 (s, 3H). MS (M+1): 313.12, Purity 93.84%.
Reaction SMILES: Br[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>C(NC(C)C)(C)C>[CH3:36][Si:37]([C:40]#[C:41][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH:3]=1)([CH3:39])[CH3:38]
Reactant: C#C[Si](C)(C)C
Reactant: BrC1=Cc2ccccc2Cc2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#CC1=Cc2ccccc2Cc2ccccc21
Yield: 53.6 %

Procedure:
To a stirred mixture of 10-bromo-5H-dibenzo[a,d]cycloheptene (9.70 g, 0.036 mol) (J. Med. Chem. 1995 38(4), 708-714), palladium(II)chloride bistriphenylphosphine (1.25 g, 0.018 mol), triphenyl phosphine (0.942 g, 0.0036 mol), copper(ll)acetate hydrate (0.327 g, 0.002 mol) in 20 ml of diisopropyl amine was added (trimethylsilyl)acetylene (3.88 g, 0.040 mol) and refluxed for an hour. The resulting mixture was concentrated, diluted with hexane (25 ml) and filtered through a pad of silica gel. The filtrate was concentrated to yield 5.57 g of 10-(trimethylsilyl)ethynyl-5H-dibenzo[a,d]cycloheptene.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[C:4]([S:10]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]2=3)(=[O:12])=[O:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C=O)C>[C:37]([O:36][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][O:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Br:1])=[CH:3][C:4]=1[S:10]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]1=2)(=[O:12])=[O:11])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: O=S(=O)(c1cc(Br)c(Cl)cc1O)N1CCCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(Br)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 62 °C
Yield: 93.9 %

Procedure:
To 4-bromo-5-chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenol (0.83 g, 2 mmol) in dry DMF (8 mL), was added K2CO3 (0.69 g, 5 mmol), followed by the addition of t-butyl 4-bromobutyrate (0.58 g, 2.6 mmol). The mixture was heated at 62° C. for 15 hrs and partitioned between ethyl acetate (50 mL) and water (25 mL). The organic layer was separated, washed with brine (2×25 mL), and dried over MgSO4. After filtration, the solution was concentrated and purified by silica gel column chromatography eluting with ethyl acetate in hexanes (1/8) yielding 4-[4-bromo-5-chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid tert-butyl ester as a pale yellow foam (1.05 g). MS: 501.8 (M+H-tBu)+; tR=11.2 min (method 2). NMR (CDCl3), δ, 8.060 (1H, s), 7.133-7.205 (3H, m), 7.011-7.067 (1H, m), 6.789 (1H, d, J=8.1 Hz), 4.086 (2H, t), 3.742 (2H, t), 2.826 (2H, m), 2.346 (2H, t), 1.827-1.959 (4H, m), 1.617-1.641 (2H, m), 1.431 (9H, s).
Reaction SMILES: [CH2:1]([N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6](Cl)=[O:7])[CH2:2][CH2:3][CH3:4].[S:13]1[CH:17]=[CH:16][C:15]2[CH:18]([NH2:22])[CH2:19][CH2:20][CH2:21][C:14]1=2>>[CH2:1]([N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([NH:22][CH:18]1[C:15]2[CH:16]=[CH:17][S:13][C:14]=2[CH2:21][CH2:20][CH2:19]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NC1CCCc2sccc21
Reactant: CCCCN(CCCC)C(=O)Cl
Product: CCCCN(CCCC)C(=O)NC1CCCc2sccc21

Procedure:
Similarly, diethyl-, dipropyl-, and dibutylcarbamoyl chloride are reacted with 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine to afford 1,1-diethyl-, 1,1-dipropyl-, and 1,1-dibutyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, respectively. Substitution of the above-mentioned carbamoyl chlorides with the corresponding thiocarbamoyl chlorides affords the corresponding thioureas.
Reaction SMILES: [CH2:1]([C:3]1[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:20]1)[CH3:2].Br[C:32]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH:44]([CH3:46])[CH3:45])=[C:39]([Cl:47])[CH:38]=2)[S:34][N:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:47][C:39]1[CH:38]=[C:37]([C:35]2[S:34][N:33]=[C:32]([C:8]3[C:3]([CH2:1][CH3:2])=[C:4]([CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:24]4)[CH:5]=[CH:6][CH:7]=3)[N:36]=2)[CH:42]=[CH:41][C:40]=1[O:43][CH:44]([CH3:45])[CH3:46]
Reactant: CCOC(=O)CN1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)CC1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CN1CCC(Cc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2CC)CC1
Yield: 30.7 %

Procedure:
A solution of ethyl (4-{[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinyl)acetate (D144) (200 mg, 0.481 mmol), 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (161 mg, 0.481 mmol), tripotassium phosphate (307 mg, 1.444 mmol) and Pd(Ph3P)4 (55.6 mg, 0.048 mmol) in N,N-Dimethylformamide (DMF) (6 mL) and Water (1.500 mL) was heated by Biotage Initiator to 120° C. for 15 min. The reaction solution was diluted with ethyl acetate, washed with water, dried over sodium sulphate, concentrated and purified by ISCO column chromatography to afford ethyl (4-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-1-piperidinyl)acetate (D145) (80 mg). MS (ES): C29H36ClN3O3S requires 541.2. found 542.2 (M+H+).