Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][C:14]1[CH:15]=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1>>[Br:13][C:14]1[C:15]([C:10]2[S:9][C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12][CH:11]=2)=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1
Reactant: Clc1ncc(Br)cn1
Reactant: c1ccc(Sc2nccs2)cc1
Product: Clc1ncc(Br)c(-c2cnc(Sc3ccccc3)s2)n1

Procedure:
The title compound was prepared from 2-Phenylthiothiazole and 5-bromo-2-chloro-pyrimidine in a manner analogous to Example 249, Step 1. MS (M+H)+ 386.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Cl.[NH+]1C=CC=CC=1.O>C(OC)(C)(C)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(F)c1C#N
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)C
Solvent: O
Product: N#Cc1c(O)cccc1F
Temperature: 190 °C
Reaction time: 5 h

Procedure:
151 g (1 mol) of 2-fluoro-6-methoxybenzonitrile and 346.5 g (3 mol) of pyridinium hydrochloride were introduced into a 2 l flask and then slowly heated to 190° C. under a protective gas atmosphere and then stirred at this temperature for 5 h. The mixture was cooled by slowly stirring to room temperature overnight. Then 1000 ml of water were added, and the mixture was heated to 80° C. After adding 1000 ml of methyl tert.-butyl ether, the phases were separated and the aqueous phase was back-extracted twice with 500 ml of methyl tert.-butyl ether. The combined methyl tert.-butyl ether phases were washed once with 800 ml of 10% strength aqueous sodium hydroxide solution and once with 400 ml of water. The two aqueous phases were combined, adjusted to pH 2 with concentrated hydrochloric acid and washed three times with 500 ml of methylene chloride. Then, the combined organic phases were washed once with 10% strength hydrochloric acid. The organic phase was dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 120 g (87% of theory) of the desired product of purity >99% according to GC.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)(OCC)=[O:2].[CH:16]1[C:17](/[CH:32]=[N:33]/[OH:34])=[CH:18][CH:19]=[N+:20]([CH2:22][N+:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[N:30]/[OH:31])=[CH:25][CH:24]=2)[CH:21]=1.[Br-:35].[Br-].[H-].[K+].[Br-]>>[OH:2][CH2:1][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1.[CH:18]1[C:17](/[CH:32]=[N:33]/[OH:34])=[CH:16][CH:21]=[N+:20]([CH2:22][N+:23]2[CH:24]=[CH:25][C:26](/[CH:29]=[N:30]/[OH:31])=[CH:27][CH:28]=2)[CH:19]=1.[Br-:35].[Br-:35]
Reactant: CCOC(=O)CCCCC1=CCCC1=O
Agent: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: [Br-]
Agent: [H-]
Product: O=C1CCC=C1CCCCCO

Procedure:
Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenomethoxime (Example 24) with diisobutyl alumium hydride in the manner described in Example 17 gives crystals, m.p. 33°-35° C. IR (KBr) 3420, 1630, 1050, 886 cm-1. 243 maxMeOH 243 (12,020).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:14][C:15]#[N:16]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:14][C:15]#[N:16])[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: N#CCBr
Product: N#CCN1CCN(c2ccccn2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Pyridin-2-yl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=203.2: 1HNMR(DMSO-d6) 8.05 (dd, 1H), 7.50 (dd, 1H), 6.80 (d, 1H), 6.60 (dd, 1H), 3.80 (s, 1H), 3.50 (t, 4H), 2.50 (t, 4H).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]=[N:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21])([O-])=[O:4].C1(C=CC(O)=CC=1)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.N(C1C=CC=CC=1)=NC1C=CC=CC=1.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[OH:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[N:13]1[N+:3]([O-:4])=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=[N:12]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Example 5 of EP 0,257,151 is duplicated. Water (70 ml), 97% sodium hydroxide (5.2 g), 2-nitro-2'-hydroxy-5'-methylazobenzene (12.9 g) and toluene (10 ml) are mixed and heated to 60° C. After stirring, hydroquinone (0.6 g) is added, and glucose (5.0 g) is added to the mixture over one hour at 40° to 45° C. The mixture is further stirred two hours, and the azobenzene disappears. The reaction liquor is neutralized with 62% sulfuric acid (5.8 g), and is cooled to 20° C. to precipitate a crystal. The crystal thus precipitated is separated filtration to obtain a wet product 12 g of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole-N-oxide (dry weight 10.8 g, yield: 90.0%, and melting point: 138° to 140° C.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[CH:40]=[CH:39][C:15]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23](=[O:29])[CH:22]=[C:21]3[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[O:17])=[CH:14][CH:13]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Cl:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][CH2:30][C:21]1[C:20]2[C:25](=[CH:26][CH:27]=[C:18]([C:16]([C:15]3[CH:39]=[CH:40][C:12]([Cl:11])=[CH:13][CH:14]=3)([OH:17])[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:19]=2)[N:24]([CH3:28])[C:23](=[O:29])[CH:22]=1
Reactant: Cn1c(=O)cc(CCc2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cn1c(=O)cc(CCc2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazole (195 mg, 2.292 mmol, 2.00 equip) in THF (10 mL) at −78° C. was added n-butyllithium (1.6 M in hexanes, 1.447 mL, 2.315 mmol, 2.02 equip) dropwise. After 30 minutes, a solution of 6-(4-chlorobenzoyl)-4-(3-chlorophenethyl)-1-methylquinolin-2(1H)-one (500 mg, 1.146 mmol, 1 equip, prepared as described in ANGIBAUD, P. R., et al., PCT Publication WO2002/051835 A1, published 4 Jul. 2002) in HMPA (8 mL) was added dropwise and the reaction mixture was warmed to room temperature. The reaction was stirred overnight, then quenched with water and the resulting mixture extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by MPLC using methanol-dichloromethane as the eluent to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)-1-methylquinolin-2(1H)-one as a tan solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27].N1CCC[C@H]1C(O)=O.CCOC(C)=O>CS(C)=O.[Cu]I>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:5]3[N:6]=[CH:7][C:2]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[CH3:23])=[N:3][CH:4]=3)[C:9]([C:19]([F:22])([F:21])[F:20])=[N:10][C:11]=2[CH:16]=1
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(Br)cn1
Reactant: Cc1ccccc1CN
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NCc2ccccc2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
Into a 50 mL roundbottom flask, was placed a solution of 1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) (50 mg, 0.13 mmol) in DMSO (5 mL) (1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) was prepared as described for Compound 1 above). To this was added 2-methyl-benzylamine (40 mg, 0.33 mmol) followed by CuI (10 mg, 0.05 mmol). To the mixture was added L-proline (20 mg, 0.17 mmol). The resulting solution was held at 50° C. for 1 hr while the reaction progress was monitored by TLC (EtOAc/PE=1:2). After completion, the reaction mixture was allowed to cool to room temperature, then washed twice with H2O (30 mL each). After removal of the volatile components under vacuum, the residue was purified by eluting through a silica gel column with a 1:10 EtOAc/PE solvent system. This resulted in 25 mg (44%) of the product [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-benzyl)-amine as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:11]2[CH2:16][CH2:15][C:14]([CH2:23][C:24]3([CH3:27])[CH2:26][O:25]3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:28])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.OO.[CH2:31]1COCC1>CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:11]2[CH2:16][CH2:15][C:14]([CH2:23][C:24]([OH:25])([CH2:26][CH3:31])[CH3:27])([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:13][C:12]2=[O:28])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC1(CC2(c3ccccc3)CCN(C(C)(C)c3ccc(Br)cc3)C(=O)O2)CO1
Agent: OO
Solvent: COC(C)(C)C
Product: CCC(C)(O)CC1(c2ccccc2)CCN(C(C)(C)c2ccc(Br)cc2)C(=O)O1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2-(4-bromophenyl)propan-2-yl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one (57 mg, 128.4 μmol) in THF (10 mL) was added dropwise LiBEt3H (642 mL, 642 μmol) at 0° C. under nitrogen. The resulting mixture was stirred at 10° C. for 2 h. The reaction solution was cooled to 0° C. Hydrogen peroxide (10 mL) was added dropwise while maintain the temperature below 25° C. The resulting mixture was diluted with MTBE (50 mL), washed with water (50 mL) and 30 wt % aqueous sodium thiosulfate (50 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to afford 3-(2-(4-bromophenyl) propan-2-yl)-6-(2-hyroxy-2-ethylpropyl)-6-phenyl-1,3-oxazinan-2-one. 1H NMR: (CDCl3) δ 7.45-7.26 (m, 7H), 6.94-6.92 (d, 2H), 3.27-3.24 (m, 1H), 2.85-2.78 (m, 1H), 2.41-2.30 (m, 2H), 2.22 (m, 3H), 1.65 (s, 3H), 1.47 (s, 3H), 1.15 (s, 3H), 1.03 (s, 3H); LC-MS Method 2 tR=1.35 min, m/z=448, 446.
Reaction SMILES: [C:1](=[N:9][NH:10]C(N)=O)([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[S:14](Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[S:14]1[CH:2]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:9]=[N:10]1
Reactant: CC(=NNC(N)=O)c1ccncc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: c1cc(-c2csnn2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.8 g of 4-acetylpyridine semicarbazone was added to 47 ml of thionyl chloride under ice-cooling, and, after allowing to warm to room temperature, the mixture was stirred for 1 hour. 200 ml of chloroform was added to the reaction mixture, and the resulting mixture was added dropwise to an aqueous solution of sodium carbonate cooled with ice. The chloroform layer was separated, washed with water, dried and concentrated to obtain 3.4 g of 4-(1,2,3-thiadiazol-4-yl)pyridine. Melting point: 121°-123° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])[NH2:5].N1C=CC=CC=1.Cl[C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]1[N:5]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:7][N:6]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(=NO)c1ccc(F)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2ccc(F)cc2F)no1
Yield: 77.3 %

Procedure:
To a solution of 2,4-difluoro-N′-hydroxybenzimidamide 5.2 (3.52 g, 33% purity, max. 7.2 mmol) and pyridine (2.32 mL, 28.7 mmol) in anhydrous CH2Cl2 under N2 was added ethyl chlorooxoacetate (1.27 g, 9.32 mmol) dropwise over 5 min at RT. The mixture was stirred under reflux. After 1 h30, the rxn mixt. was concentrated and purified on silica gel using CH2Cl2, furnishing 1.414 g of title product 5a as colorless oil. Yield: 1.414 g (78%). LCMS: P=94%, rt=4.21 nm, m/z=255, 277 (M+Na).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[C:39]3([CH2:44][CH2:43][CH2:42][NH:41][CH2:40]3)[C:38](=[O:45])[N:37]([CH3:46])[CH2:36]2)=[CH:31][CH:30]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC#N.C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:18])[CH3:17])[C:11]([N:41]1[CH2:42][CH2:43][CH2:44][C:39]2([C:38](=[O:45])[N:37]([CH3:46])[CH2:36][CH:35]2[C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)[CH2:40]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CC(c2ccc(F)cc2)C2(CCCNC2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CN1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Reaction time: 20 h
Yield: 96.7 %

Procedure:
To a stirred solution of (R)-3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methylpropionylamino)-propionic acid (Intermediate 3A) (344 mg, 0.904 mmol) and 4-(4-fluorophenyl)-2-methyl-2,7-diazaspiro[4.5]decan-1-one (270 mg, 0.904 mmol) in MeCN (4 mL) was added dropwise a solution of ®T3P (50% in EtOAc) (1.055 ml, 1.807 mmol) at room temperature. The resulting colourless solution was stirred for 20 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL). The aqueous phase was separated and extracted using DCM (3×10 mL), the combined organic fractions were washed with 10% citric acid (10 mL), dried (MgSO4) and then concentrated under reduced pressure to afford tert-butyl 1-((2R)-3-(benzyloxy)-1-(4-(4-fluorophenyl)-2-methyl-1-oxo-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (546 mg, 97%) as a white amorphous solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1.[CH:15]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[O:4][CH:3]([CH2:2][NH:1][C:22]([CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:23])[CH2:12][CH2:11]2
Reactant: O=C(Cl)C1CCCCCC1
Reactant: COc1cccc2c1OC(CN)CC2
Product: COc1cccc2c1OC(CNC(=O)C1CCCCCC1)CC2

Procedure:
The title compound is prepared analogously to the instructions of Example XII from 2-aminomethyl-8-methoxy-chroman and cycloheptanecarbonyl chloride, and is further reacted directly.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO.[NH4+].[Cl-]>CN(C=O)C.O>[CH3:27][O:26][C:22](=[O:25])[CH2:23][CH2:24][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:7][CH:8]=2)[C:13]1=[O:21]
Reactant: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COC(=O)CCn1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of 1-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (560 mg, 1.9 mmol) in DMF (9.0 mL) are added methyl acrylate (0.19 mL, 2.1 mmol) and 40% benzyltrimethyl ammonium hydroxide in MeOH (0.09 mL, 0.19 mmol). The resulting mixture is stirred at room temperature for 3 hr. Then Sat. NH4Cl (5 mL) and water (50 mL) are added and the mixture is extracted with EtOAc (3×50 mL). The organic layers are combined, washed with water (3×75 mL), dried over MgSO4 and concentrated to give crude product. Purification by flash column chromatography using 30% EtOAc in hexanes affords 600 mg (83%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid methyl ester.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)C.C[O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][C:14]=2[CH:23]=1.Cl>ClCCl.O>[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][C:14]=2[CH:23]=1
Reactant: CCOC(=O)c1cc2cc(OC)ccc2o1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)ccc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a mixture of aluminum chloride (6.3 g, 47.7 mmol) and ethanethiol (4.5 g, 72.9 mmol) in dichloromethane (81 mL) at 0° C. was added ethyl 5-methoxybenzofuran-2-carboxylate (3.0 g, 13.6 mmol). After stirring for 16 h at room temperature, the mixture was poured into water, acidified with 3N HCl and extracted with dichloromethane (2x). The organic layers were combined, washed with brine, collected, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a white solid (2.16 g, 77%). 1H NMR (400 MHz, CDCl3) δ 7.45 (m, 2H), 7.08 (m, 1H), 7.02 (m, 1H), 5.35 (s b, 1H), 4.44 (q, 2H), 1.42 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[C:7]([Cl:13])[C:6]=1[F:14])[CH3:2].C(N(CC)CC)C.[C:23]([O:27][C:28](=[O:35])[NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:32]2[CH2:33][CH2:34][CH:30]([NH:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:35])[CH2:31]2)=[C:7]([Cl:13])[C:6]=1[F:14])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(N2CCC(NC(=O)OC(C)(C)C)C2)c(Cl)c1F
Reaction time: 48 h
Yield: 98.6 %

Procedure:
To a solution of 3-chloro-2,4,5-tri-fluorobenzoic acid ethyl ester (Example 1c, 5.50 g, 23.05 mmol) in acetonitrile (25 mL) is added triethylamine (6.43 mL, 46.1 mmol) and pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.72 g, 25.4 mmol). After 48 hours, the mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound (9.2 g). MS CI: m/z 405 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19](=[O:32])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[CH3:17][O:18][C:19](=[O:32])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](=[O:29])(=[O:30])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9](=[O:10])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-phenyl-methanone and 131 mg of 3-(4-chlorosulfonyl-phenyl)-propionic acid methyl ester. 1H-NMR (400 MHz, CDCl3): δ 2.50 (t, 2H, J=8.0 Hz), 2.83 (t, 2H, J=8.0 Hz), 3.64 (s, 3H), 7.08 (d, 2H, J=8.8 Hz), 7.33 (d, 1H, J=2.8 Hz), 7.36–7.42 (m, 4H), 7.47 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.58 (m, 3H), 7.75 (d, 1H, J=8.8 Hz), 9.78 (s, 1H). MS: m/z 458.9 (M++1).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](I)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[F:15][C:16]([F:20])([F:19])[CH:17]=[CH2:18].C(OP(Cl)(=O)[O-])C.N12CCN(CC1)CC2>CC(C)=O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:18]=[CH:17][C:16]([F:20])([F:19])[F:15])(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)I)cc1
Reactant: C=CC(F)(F)F
Agent: C1CN2CCN1CC2
Agent: CCOP(=O)([O-])Cl
Solvent: CC(C)=O
Product: Nc1ccc(S(=O)(=O)C=CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-trifluoromethylvinyl 4-aminophenyl sulfone is prepared by the addition of 4-acetamidobenzenesulfonyl iodide to 1,1,1-trifluoropropene followed by dehydrohalogenation and removal of the N-acetyl protective group by hydrolysis in a hydrochloric acid-ethanol mixture. The product is dissolved in acetone (25.1 g or 0.1 mol), an acetone solution of 0.1 mol (17.3 g) of ethylphosphorochloridate in acetone added, followed by 11.2 g of 1,4-diazabicyclo[2.2.2]octane in 10% acetone solution. The reaction mixture is stirred for one hour at room temperature, filtered, most of the acetone evaporated, and the residue is mixed with chloroform, washed and worked up. There is thus obtained 4-diethoxyphosphoramidophenyl 2-trifluoromethylvinyl sulfone: ##SPC59##
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([Mg]Cl)(C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[CH:27][N:28]3[C:37]=2[CH:36]=[C:35]2[C@@:30]([CH3:40])([C@@H:31]([CH:38]=[O:39])[CH2:32][CH2:33][CH2:34]2)[CH2:29]3)=[CH:21][CH:20]=1>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[CH:27][N:28]3[C:37]=2[CH:36]=[C:35]2[C@@:30]([CH3:40])([C@@H:31]([CH:38]([OH:39])[C:2]4[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=4)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:32][CH2:33][CH2:34]2)[CH2:29]3)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(C(O)[C@H]2CCCC3=Cc4c(-c5ccc(F)cc5)ncn4C[C@@]32C)c1
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 3-iodobenzoate (0.17 mL, 1 mmol) in anhydrous THF (2 mL) cooled in an acetonitrile-dry ice bath was added isopropylmagnesium chloride solution (2M in THF, 0.5 mL, 1 mmol) dropwise under nitrogen. The reaction mixture was stirred at the same temperature for 30 min before (5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinoline-6-carbaldehyde (Example 1g, 55 mg, 0.18 mmol) was added. The mixture was stirred in an acetonitrile-dry ice bath for 1 hr before being quenched by the addition of saturated aqueous ammonium chloride solution (3 mL) at the same temperature. The reaction mixture was extracted with ethyl acetate (3×3 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (25-100% ethyl acetate in heptanes, then 0-10% methanol in ethyl acetate) gave ethyl 3-(((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)(hydroxy)methyl)benzoate as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](=O)[CH2:6]2.[NH2:12]O.Cl.CCO>O>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][CH:5]([NH2:12])[CH2:6]2
Reactant: CN1C2CCCC1CC(=O)C2
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C2CCCC1CC(N)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a 250 mL RB flask were added 9-methyl-9-azabicyclo[3.3.1]nonan-3-one (10 g), NH2OH.HCl (5.26 g), NaOAc.3H2O (10.26 g), EtOH (56 mL), and H2O (26 mL). The mixture was refluxed for 1.5 h and cooled to RT. Solvents were removed and the residue was partitioned between aqueous K2CO3 (3M) and CHCl3. The organic phase was separated and the aqueous phase extracted twice with CHCl3. The combined CHCl3 solution was washed once with brine, dried over Na2SO4, filtered, and evaporated to a brownish oil, which solidified upon standing. The solid was transferred to a 500 mL Parr flask. To this were added Raney-Ni (6.2 g, wet) and NH3 solution in MeOH (150 mL), made by bubbling NH3 into MeOH for 20 min. This mixture was hydrogenated under a pressure of 40-45 psi of H2 at RT for 18 h. The mixture was filtered through a pad of Celite. All volatiles were removed on a rotary evaporator. EtOH (50 mL) was added to the residue and then evaporated to give an I-1 as an oil (9.5 g, 94%). This crude product contained two isomers, and was used without further purification.