Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN[O:3][CH3:4].[C:5]1([Mg]Br)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNOC
Reactant: Br[Mg]c1ccccc1
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
The benzophenone derivative 70 was prepared using chemistry outlined in Scheme 13. Weinreb amide 69, derived via coupling of the acid chloride of the corresponding acid intermediate 62 with N,O-dimethylhydroxylamine, was treated with phenylmagnesium bromide to afford 70. Subsequent reduction of compound 70 with sodium borohydride provided alcohol 71, which was further reduced in the presence of trifluoroacetic acid to give the diphenylmethane derivative 72.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.S(O)(O)(=O)=O.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:8]1([C:7]2[C:6]([CH2:5][C:4]([OH:3])=[O:23])=[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:36]([C:33]3[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=3)[N:37]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)Cc1c(-c2ccccc2)nn(-c2ccc(Cl)cc2)c1-c1ccccc1
Yield: 82.9 %

Procedure:
8.0 grams 3,3-dibenzoyl-propionic acid-ethyl ester, 5.9 grams p-chlorophenyl-hydrazine sulfate, 2.5 grams sodium acetate and 3.0 grams glacial acetic acid were reacted and the reaction product recovered by a procedure analogous to the method set out in Example (2a). 7.9 grams 3,5-diphenyl-1-(p-chlorophenyl)-pyrazol-4-acetic acid, melting at 193°-194° C. were obtained, representing a yield of 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Cl[CH2:25][C:26]([C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)=[O:27]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: Cn1cccc1C(=O)CCl
Product: COC(=O)Cc1c(C(=O)c2cccn2C)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 8 (Method B) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-chloroacetyl-1-methylpyrrole (P. D. Croce et al., Synthesis, 1990, 212).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>C(OCC)(=O)C>[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:11]=1[C:12]([NH:14][C:15]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:16])=[O:13]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)cn1
Reaction time: 6 h
Yield: 81 %

Procedure:
To a suspension of 16.7 g (0.13 mole) of 2-amino-5-chloropyridine in 250 ml of ethyl acetate was added all at once a solution of 30.0 g (0.14 mole) of 2,6-dichlorobenzoyl isocyanate in ethyl acetate. The mixture was allowed at 25° for six hours. Filtration gave 36.3 g (85%) of 1-(2,6-dichlorobenzoyl)-3-(5-chloro-2-pyridinyl)urea, m.p. 220-222°.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([C:26]([C:28]1[CH:38]=[C:37]([O:39][CH3:40])[C:31]2[O:32][C:33]([CH3:36])([CH3:35])[O:34][C:30]=2[CH:29]=1)=[O:27])[CH2:15][C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=O)(C)(C)C.ClCCl.[C:44]1(=O)[CH2:47]C[CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>FC(F)(F)C(O)=O.ClCCl.C(=O)(O)[O-].[Na+]>[CH:6]1([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][N:14]([CH2:15][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[C:26]([C:28]2[CH:38]=[C:37]([O:39][CH3:40])[C:31]3[O:32][C:33]([CH3:35])([CH3:36])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH2:47][CH2:44][CH2:45]1
Reactant: O=C1CCC1
Reactant: COc1cc(C(=O)N(Cc2cnc3ccccc3n2)C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc2c1OC(C)(C)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)N(Cc2cnc3ccccc3n2)C[C@@H]2CCCN2C2CCC2)cc2c1OC(C)(C)O2

Procedure:
73 mg of (S)-2-{[(7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl)-quinoxalin-2-ylmethyl-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester were dissolved in 3 mL 10% trifluoroacetic acid/dichloromethane and neutralized with aqueous sodium bicarbonate after 2 hours. The crude material was submitted to reductive amination reaction in dichloromethane using 53 mg (0.67 mmol) of cyclobutanone and 0.14 g (0.67 mmol) sodium triacetoxyborohydride. After overnight the reaction was quenched with aqueous sodium bicarbonate and purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 40 min. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate and evaporated in vacuum to yield 42 mg pale yellow solid as the free base. LC-MSD, m/z for C29H34N4O4 [M+H]+: 503.6. 1H NMR (400 MHz, CDCl31HCl): δ 1.7 (s, 6 H), 1.7-3.0 (m, 11 H), 3.6-4.2 (m, 8 H), 5.3-5.4 (m, 1 H), 5.8-5.9 (m, 1 H), 6.6 (s, 1 H), 6.8 (s, 1 H), 8.0 (bs, 2 H), 8.3 (bs, 1 H), 8.5-8.6 (m, 1 H), 9.1 (bs, 1 H), 12.0 (bs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:26](Br)([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[O:23][C:18]=4[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Reactant: C[C@H](Cc1ccc(O)c(O)c1)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)cc2O1

Procedure:
More specifically, the chiral synthesis may be carried out by performing the synthetic reaction sequence outlined in Scheme III. L-DOPA 19 is treated with di-t-butyl-dicarbonate in dimethylformamide, giving (S)-N-(1-(1,1-dimethylethoxy)carbonyl)-3-hydroxy-L-tyrosine 20 which is reacted with methyl iodide and anhydrous potassium carbonate in acetone, giving (S)-N-(1,1-dimethylethoxy)carbonyl)-3,4-dimethoxy-L-phenylalanine methyl ester 21 which is reduced with lithium borohydride giving (S)-1,1-dimethylethyl-(2-(3,4-dimethoxyphenyl)-1-(hydroxymethyl)ethyl) carbonate 22, which is reacted with methanesulfonyl chloride and triethylamine in methylene chloride, giving (S)-1,1-dimethylethyl-(2-(3,4-dimethoxyphenyl)-1(((methylsulfonyl) oxy)methyl)ethyl)carbamate 23. Compound 23 is treated with trifluoroacetic acid and then is reduced using 10% Pd/C and hydrogen giving (R)-3,4-dimethoxy- -methylbenzeneethanamine 24. The compound 24 is treated with 3-chlorostyrene oxide 25 and N-(trimethylsilyl) acetamide giving a mixture of (R,S)- and (S,S)-3-chloro-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl) benzenemethanol 26. Reaction of 26 with carbonyl diimidazole and triethylamine in tetrahydrofuran, followed by chromatographic separation of the diastereomers gives cyclized derivative 27, which is reacted with boron tribromide in dichloromethane, giving (R,R)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone 28. Compound 28 is then reacted with diethyl dibromomalonate and anhydrous potassium carbonate in acetone, giving (R,R)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester 29. Compound 29 is reacted with 5N sodium hydroxide in ethanol and then isolated by reverse phase chromatography to give (R,R)-1,3-benzodioxole-2,2-dicarboxylic acid, 5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-, disodium salt 15.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:10]=2)=[CH:4][CH:3]=1.[CH:28]([Mg]Cl)([CH3:30])[CH3:29].O>O1CCCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:28]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])[CH:10]=2)=[CH:4][CH:3]=1)([CH3:30])[CH3:29]
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Cl)nc2)c2cccnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)cn1
Temperature: 20 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To 3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6, 54.0 mg, 0.000135 mol, prepared as described in Example 2) in Tetrahydrofuran (4.0 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (23.0 mg) and Isopropylmagnesium Chloride (0.15 mL, 2.0 M in Tetrahydrofuran). The reaction was stirred at 20° C. under an atmosphere of Nitrogen for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound 39 (38 mg, 70.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])=[C:28]([N:34]2[CH2:38][CH2:37][O:36][C:35]2=[O:39])[CH:29]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1N1CCOC1=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1CCOC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 3-(2-(aminomethyl)-5-fluorophenyl)oxazolidin-2-one, derived from reduction of intermediate 117, 4-fluoro-2-(2-oxooxazolidin-3-yl)benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm: 9.48 (1H, dd, J=8.6, 6.5 Hz), 7.41 (2H, m), 7.32 (3H, m), 7.22 (1H, dd, J=9.6, 2.5 Hz), 7.08 (1H, td, J=8.6, 2.7 Hz), 5.21 (2H, s), 4.57 (2H, t, J=7.7 Hz), 4.50 (2H, s), 4.07 (4H, m), 3.99 (2H, m), 1.61 (6H, s). LCMS (M+H)+ m/z 523.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]CS([O-])(=O)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OC(NC1C=CC(CCCS([O-])(=O)=O)=CC=1)=O)(C)(C)C>[CH2:22]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:14][CH:13]=2)=[CH:32][CH:33]=1)[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCS(=O)(=O)[O-])cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Yield: 99648.8 %

Procedure:
2-[4-(tert-Butoxycarbonylamino)phenyl]ethylmethanesulfonate (described in Example40a) (52.9 g; 0.168 mmole), (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 40h) (40 g; 0.168 mmole) and potassium carbonate (69.5 g; 0.503 mmole) were mixed in acetonitrile (1200 ml) and refluxed over night. Another portion of 2-[4-(tert-butoxycarbonylamino)phenyl]ethylmethanesulfonate (2.5 g; 7.9 mmole) was added. The reaction mixture was refluxed for 8 more hours then filtered. Evaporation of the filtrate gave 76.6 g 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]#[C:14][Si](C)(C)C.CO.[F-].[Cs+]>O1CCCC1>[C:13]([C:3]1[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[F:12])#[CH:14]
Reactant: COc1cc(OC)c(F)c(C#C[Si](C)(C)C)c1F
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1c(F)c(OC)cc(OC)c1F
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a stirred solution of [(2,6-difluoro-3,5-dimethoxyphenyl)ethynyl](trimethyl)-silane (630 mg, 2.33 mmol) in tetrahydrofuran (2 mL)/methanol (2 mL), cesium fluoride (354 mg, 2.33 mmol) was added at room temperature. After 1 hour, the reaction was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, concentrated to give the desired product (440 mg, 95%). 1H NMR (300 MHz, CDCl3): δ 6.62 (t, J=7.8 Hz, 1H), 3.89 (s, 7H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Br)=[N:6][CH:7]=1.[CH3:10][NH:11][CH3:12]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:11]([CH3:12])[CH3:10])=[N:6][CH:7]=1
Reactant: BrCc1ccc(Br)cn1
Reactant: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Place 5-bromo-2-bromomethyl-pyridine (1.7 g, 6.7 mmol, 1 eq) (Bioorg. Med. Chem. Lett. 1994, 4(1), 99) in a 250 mL round bottom short neck flask, dissolve in 100 mL of THF, cool to 0° C. and treat with a 2 M N,N-dimethylamine solution in THF (9 mL, 18 mmol, 2.7 eq). After 2 hours, concentrate the reaction, dilute with 50 mL of CH2Cl2, and wash with 20 mL of water. Dry the organics and concentrate to give 0.90 g (64%) of the title compound as a brown oil. MS (ES), m/z 217 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:20]2[C:24]([CH3:25])=[N:23][N:22]=[N:21]2)=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17])(=[O:9])[CH3:8].I[CH2:27][CH3:28]>CC(C)=O>[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:20]2[C:24]([CH3:25])=[N:23][N:22]=[N:21]2)=[C:15]([CH:19]=1)[C:16]([O:18][CH2:27][CH3:28])=[O:17])(=[O:9])[CH3:8]
Reactant: CCI
Reactant: CC(=O)Oc1ccc(-n2nnnc2C)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OC(C)=O)ccc1-n1nnnc1C
Yield: 92.2 %

Procedure:
Cesium carbonate (176 g, 1.13 mol) was added to a solution of 5-acetoxy-2-(5-methyltetrazol-1-yl)benzoic acid (164 g, 0.620 mol) in 1.8 L of acetone. The mixture was stirred vigorously and iodoethane (116 g, 0.682 mol) diluted with 100 mL of acetone was added dropwise over a one-hour period. The reaction was stirred overnight at ambient temperature and was then concentrated under reduced pressure. The resulting solid was partitioned between dichloromethane and water. The aqueous fraction was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated to give 166 g of ethyl 5-acetoxy-2-(5-methyltetrazol-1-yl)benzoate as a brown oil.
Reaction SMILES: [OH2:1].Br[CH2:3][C:4]1[C:12]2[C:7](=[N:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[S:6][N:5]=1>CS(C)=O>[Cl:13][C:9]1[N:8]=[C:7]2[S:6][N:5]=[C:4]([CH2:3][OH:1])[C:12]2=[CH:11][CH:10]=1
Reactant: Clc1ccc2c(CBr)nsc2n1
Reactant: O
Solvent: CS(C)=O
Product: OCc1nsc2nc(Cl)ccc12
Temperature: 80 °C

Procedure:
Water (8 mL) was added to a solution of 3-(bromomethyl)-6-chloroisothiazolo[5,4-b]pyridine (19.0 mmol) in dimethylsulfoxide (40 mL) and the reaction mixture was heated at 80° C. for 1.5 h. The reaction mixture was then quenched with water (50 mL) and the resulting solution was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the crude (6-chloroisothiazolo[5,4-b]pyridin-3-yl) methanol as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH:20]([N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])=[CH2:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C>[OH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:21]=[CH:20][N:22]2[C:23](=[O:32])[C:24]3[C:25](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:27])=[CH:3][CH:4]=1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Reactant: OCCc1ccc(Br)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1C=Cc1ccc(CCO)cc1
Temperature: 90 °C
Reaction time: 21 h

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (48.3 g) in acetonitrile (480 mL) was added diisopropylethylamine (46.6 g), N-vinylphthalimide (43.7 g) and tri-o-tolylphosphine (7.31 g) and the mixture was purged with nitrogen gas three times. Palladium acetate (2.7 g) was added and the mixture was stirred at 90° C. for 21 hr under nitrogen. The reaction was cooled and the precipitated product collected by filtration. The resulting solid was re-dissolved in dichloromethane and ethyl acetate and filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound, 24 g.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O)(=O)[CH2:52][C:53]([CH2:58][C:59](O)=O)([C:55]([OH:57])=O)[OH:54]>ClCCl>[C:11]([O:10][C:8]([N:1]1[CH2:7][CH2:6][CH2:5][N:4]([C:55]([C:53]2([OH:54])[CH2:52][CH2:59][CH2:58]2)=[O:57])[CH2:3][CH2:2]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)C2(O)CCC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product of example 10a (340 mg), tert-butyl 1,4-diazepane-1-carboxylate (694 μl), DIPEA (2.4 ml) and BOP (1.9 g) in dichloromethane (15 ml) was stirred for 18 h at room temperature. The reaction mixture was poured into an aqueous citric acid solution (5%) and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in toluene/acetone [1/0→7/3 (v/v)] as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([OH:15])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCCc2c1[nH]c1ccc(Br)cc21
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (500 mg, 1.9 mmol) in methanol (20 mL) was added sodium borohydride (144 mg, 3.8 mmol) portionwise. The reaction mixture was stirred for one hour and quenched with water (5 mL). The reaction was concentrated, diluted with methylene chloride and washed with water. The organic phase was concentrated and the crude alcohol purified by flash chromatography on silica (5% to 30% ethyl acetate/hexanes gradient) to provide 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ol (255 mg, 50%) as a light brown solid: 1H-NMR (DMSO-d6): δ 10.99 (s, 1H), 7.54 (d, 1H), 7.25 (d, 1H), 7.12 (dd, 1H), 5.18 (d, 1H), 4.75-4.70 (m, 1H), 2.64-2.53 (m, 2H), 2.02-1.91 (m, 2H), 1.77-1.66 (m, 2H); MS m/z (M−1) 339, 341.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[NH:13][CH3:14].[CH2:15]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O)[CH3:16].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Br:1][C:2]1[C:3]2[N:13]([CH3:14])[C:20]([C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[S:17][CH2:15][CH3:16])=[N:12][C:4]=2[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CCSc1ccccc1C(=O)O
Reactant: CNc1c(N)cc(C(F)(F)F)cc1Br
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cc(Br)c2n1C
Temperature: 115 °C
Yield: 43.2 %

Procedure:
A mixture of 3-bromo-N2-methyl-5-trifluoromethylbenzene-1,2-diamine (2.22 g), 2-ethylsulfanylbenzoic acid (1.80 g), WSC (1.40 g), and pyridine (10 ml) was stirred under reflux at 115° C. for 6 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.48 g of 7-bromo-2-(2-ethylsulfanylphenyl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter referred to as Present Compound 74).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)#[N:7].C([O-])([O-])=O.[Na+].[Na+].O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:11]1[CH2:12][CH2:13][CH:8]([C:6]#[N:7])[CH2:9][CH2:10]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: N#CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CC1CCN(C(=O)CCl)CC1
Reaction time: 0.5 h

Procedure:
Chloroacetyl chloride (0.43 mL) was added to a mixture of a solution of 4-cyanopiperidine (500 mg) in CH2Cl2 (5 mL) and an aqueous 2 M Na2CO3 solution (5.7 mL) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. After the reaction mixture was further stirred at room temperature for 4 hours, CH2Cl2 and water were added thereto, then, extraction was performed on the mixture using CH2Cl2, and the extract was washed with saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure, whereby 1-(chloroacetyl)piperidine-4-carbonitrile (845 mg) was obtained as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([S:8]([O-:10])=[O:9])[CH:7]=1.[Na+].I[CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([S:8]([CH3:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Br)cc1S(=O)[O-]
Reactant: CI
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium 5-bromo-2-methoxybenzenesulfinate (1.99 g) in DMF (873 ml) was added iodomethane (32 ml). The reaction mixture turned yellow and was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (ca. 5 ml). The mixture was diluted with EtOAc and extracted with 5% LiCl (3×) and brine (1×). The organic layer was dried (Na2SO4/MgSO4) and filtered. The filtrate was concentrated and purified by silica gel column chromatography to give 1.62 g 4-bromo-1-methoxy-2-(methylsulfonyl)benzene as a white crystalline solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].C([N:13]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21](S(NC3C=CC=CC=3C(C3C=CC(F)=CN=3)=O)(=O)=O)=[CH:20][CH:19]=2)[C:14]1=[O:43])C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[O:43]=[C:14]1[NH:13][CH2:17][CH2:16][N:15]1[C:18]1[CH:23]=[CH:22][C:21]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:20][CH:19]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(c1ccc(F)cn1)c1ccccc1NS(=O)(=O)c1ccc(N2CCN(Cc3ccccc3)C2=O)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1NCCN1c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1.5 mL (23.1 mmol) of chlorosulfonic acid in 3 mL of carbon tetrachloride at 0° C. was added slowly 500 mg (3.1 mmol) of the compound of Step 1. The reaction was almost completed after 2 h at 0° C. The reaction mixture was poured into ice water slowly, then filtered to collect the solids formed. The aqueous layer was extracted with chloroform (3×100 ml), and the combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo. The filtered solid and the crude material from the extraction were combined to provide the title compound (LC/MS found: 261.1)