Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N:12]([O-])=O.[Na+].[Cl:16][Sn]Cl>O.Cl>[ClH:16].[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)[NH2:12]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.6 %

Procedure:
To a solution containing conc. HCl (76 ml) and 4-amino phenylacetic acid (10 g: 66 mmol) at 4° C. was added a solution of sodium nitrite (4.56 g; 55 mmol) in water (10 ml) dropwise, while maintaining the temperature at 0° to 4° C. The mixture was stirred for 30 minutes and added to a cold (0° C.) solution of SnCl2 (74.5 g 331 mmol) in conc. HCl (50 ml). The mixture was left to warm to room temperature overnight. The precipitate formed was filtered and washed withwater (50 ml), 50% aq. HCl (50 ml), water (50 ml) and ether (2×50 ml). The solid was dried in vacuo to give the product 13 g. M.pt. 220°-223° C. dec. MS. 166(M+) 151, 135, 121 NMR [360 Mz, 1H]ppm 3.5 (s,2H) 6.9 (d,2H) 7.1 (d, 2H), 10.7 (bs).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:23])=[N:10][CH:11]=[C:12](B3OC(C)(C)C(C)(C)O3)[N:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[C:32]([F:44])=[C:33]([CH:41]=[CH:42][CH:43]=1)[O:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>O1CCOCC1.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>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH2:23])=[N:10][CH:11]=[C:12]([C:31]3[CH:43]=[CH:42][CH:41]=[C:33]([O:34][CH:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:32]=3[F:44])[N:13]=2)=[CH:6][CH:7]=1
Reactant: Fc1c(Br)cccc1OC1CCOCC1
Reactant: CC1(C)OB(c2cnc(N)c(-c3ccc(N)cc3)n2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2nc(-c3cccc(OC4CCOCC4)c3F)cnc2N)cc1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
To a 80 mL microwave vessel containing the compound prepared in Example 15 (263.9 mg) was added Na2CO3 (181.7 mg) and Pd(PPh3)4 (48.8 mg). The 4-(3-bromo-2-fluorophenoxy)tetrahydro-2H-pyran (253.6 mg) was added by dissolving in 3:1 1,4-dioxane:H2O then adding via pipet and using the remainder of the solvent to wash over any remaining material (total volume: 8.5 mL). The mixture was stirred and sparged with argon for 5 minutes. The vial was placed in the microwave then heated to 150° C. After 15 minutes at 150° C., the mixture was allowed to cool. The dark brown mixture was diluted with EtOAc and washed with H2O two times. The aqueous layers were back extracted with EtOAc. The combined organic layers were washed with brine then dried over Na2SO4, filtered and solvent was removed in vacuo. The material was absorbed onto silica and purified on the Isolera (50 g silica column; 0-15% MeOH in EtOAc) followed by purification via reverse phase on the Isolera (60 g C18 column; 5-95% ACN with 0.1% trifluoroacetic acid (TFA) in H2O with 0.1% TFA). Fractions containing product were combined and solvent was removed in vacuo. The material was taken up in MeOH and desalted by passing through a StratoSphere 200 mg PL-HCO3 MP SPE cartridge. Resin was washed with MeOH and 20% MeOH in DCM. Solvent was removed in vacuo to give the title compound (94.9 mg) having the following data as a dark amber solid/film solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C(Cl)CCl.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[C:40]1([NH:39][C:20](=[O:22])[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: Nc1ccccc1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Nα -Benzyloxycarbonyl-L-phenylalanine (4.95 g, 16.5 mmol) was dissolved in dichloromethane (70 ml) and the solution was cooled to 0° C. and stirred during the addition of pentafluorophenol (3.35 g, 18.2 mmol), followed by EDC (3.49 g, 18.2 mmol). The mixture was allowed to warm to room temperature, stirred for a further 1 hour then cooled back to 0° C. Aniline (3.85 g, 41.4 mmol) was added dropwise and the mixture was warmed to room temperature then stirred overnight. The solution was washed twice with 1M sodium carbonate, twice with 1M hydrochloric acid and finally with brine before drying over anhydrous magnesium sulphate. The solution was filtered and evaporated to a white solid which was recrystallised from ethyl acetate-hexane. Yield: 2.57 g (41%). 1H-NMR; δ (CDCl3), 7.87 (1H, brs), 7.43-7.03 (15H, br m), 5.62 (1H, m), 5.08 (2H, s), 4.59 (1H, s) and 3.15 (2H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[NH:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C(O)(=O)C.O.O.[ClH:25].[C:26]([N:34]1[CH2:39][CH2:38][O:37][C:36]([C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([F:65])[CH:59]=2)([CH2:40][CH2:41]N2CCC(C3C=CC=CC=3)(NC(N)=O)CC2)[CH2:35]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>CO>[ClH:25].[ClH:25].[C:26]([N:34]1[CH2:39][CH2:38][O:37][C:36]([C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([F:65])[CH:59]=2)([CH2:40][CH2:41][N:9]2[CH2:8][CH2:7][C:6]([C:4](=[O:5])[NH:3][N:2]([CH3:18])[CH3:1])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10]2)[CH2:35]1)(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Reactant: CN(C)NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)NC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Yield: 145 %

Procedure:
This compound is prepared by the procedure described in step B of EXAMPLE 68 from 1.55 g of 4-(3,3- dimethylcarbazoyl)-4-phenylpiperidine (free base) and 0.38 ml of acetic acid in 26 ml of MeOH, and then 2.4 g of the compound obtained in step A of EXAMPLE 68 in 26 ml of MeOH and 0.47 g of sodium cyanoborohydride in 26 ml of MeOH. This gives 1.82 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 4-chlorosalicylic acid (75 g, 435.6 mmol) in anhydrous DMF (871 mL) was added Cs2CO3 (70.7 g, 217.8 mmol) and MeI (27.5 mL, 439.9 mmol) sequentially. The reaction mixture was stirred at room temperature overnight. Ice cold water (3 L) was added to the reaction mixture and the precipitated solid was filtered and dried to provide VII-1-I (75 g, 92% yield).
Reaction SMILES: [CH2:1](OC(C1(CCCCSC)CCC1)=O)[CH3:2].[CH2:16]([O:18][C:19]([C:21]1([CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:24][CH2:23][CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH2:24][CH2:23][CH:22]1[CH2:1][CH3:2])=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(CCCCS(C)(=O)=O)CCC1
Reactant: CCOC(=O)C1(CCCCSC)CCC1
Product: CCOC(=O)C1(CCCCS(C)(=O)=O)CCC1CC
Yield: 92 %

Procedure:
Using the general procedure described in example 46, starting with 1-[4-(methylthio)butyl]cyclobutanecarboxylic acid ethyl ester, 1-[4-(methylsulfonyl)-butyl]cyclobutanecarboxylic acid ethyl ester was prepared in 92% yield as a colorless oil. HR MS: Obs. mass, 262.1231. Calcd. mass, 262.1238, M+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:23]([CH3:34])=[CH:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:12]=[C:13]([O:15]CC2C=CC=CC=2)[CH:14]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>[Pd].C(OCC)(=O)C>[OH:15][C:13]1[CH:12]=[C:11]([CH:23]([CH3:34])[CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:10]=[C:9]([OH:8])[CH:14]=1
Reactant: [H][H]
Reactant: CC(=CCCOc1ccccc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(CCCOc1ccccc1)c1cc(O)cc(O)c1
Reaction time: 12 h

Procedure:
A solution of 4-(3,5-dibenzyloxyphenyl)-1-phenoxypent-3-ene (51 g., 0.113 M) in a mixture of absolute ethanol (160 ml.), ethyl acetate (160 ml.) and concentrated hydrochloric acid (0.2 ml.) is hydrogenated for 12 hours under 55 lbs. hydrogen in the presence of 10% Pd/C. Removal of the catalyst by filtration and concentration of the filtrate under vacuum yields 30.8 g. (100%) of product as a viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]([C:46]1[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1)([CH3:45])([CH3:44])[CH3:43]>C(#N)C>[C:42]([C:46]1[CH:51]=[CH:50][C:49]([S:52]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:54])=[O:53])=[CH:48][CH:47]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(C(C)(C)C)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 43 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0294 g, 0.0637 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0530 mL, 0.382 mmol) and 4-tert-butylbenzenesulfonyl chloride (0.0440 g, 0.191 mmol) to obtain 4-(4-tert-butylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0180 g, yield 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:16]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Br:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(-c2ccc(Br)cc2)cc1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: BrCc1ccc(-c2ccc(Br)cc2)cc1

Procedure:
A solution of (4′-bromo-biphenyl-4-yl)-methanol, 7.01 g (27.9 mmol) and dibromo-triphenylphosphorane 11.8 g (27.9 mmol) in 150 mL of methylene chloride stirred at room temperature for 2 h. The solution was diluted with 100 mL of water and extracted with 2×200 mL portions of diethyl ether. The organic layers were combined, washed with sat. aq. NaCl, and dried (MgSO4). After the solution was concentrated, the residue was purified through a short plug of silica gel (eluted with 50% EtOAc-Heptane) to afford the desired product in 9.1 g (100%) as a white solid. The material was taken to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]#[N:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:34][O:35][CH:36](OC)OC>>[C:20]([C:3]1[C:4]([CH3:19])=[N:5][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[C:2]=1[N:1]=[CH:34][O:35][CH3:36])#[N:21]
Reactant: COC(OC)OC
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC=Nc1c(C#N)c(C)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A mixture of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylpyrazole (5 g) and p-toluenesulphonic acid hydrate (0.1 g) in trimethylorthoformate (20 ml) was heated at reflux for 4.5 hours. After cooling, the reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in diethyl ether and left to crystallize at 0° C. The dark colored solid was recrystallized from a mixture of ethanol and water to give 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methyl-5-methoxymethyleneaminopyrazole (4.67 g), m.p. 75°-78° C., in the form of buff crystals.
Reaction SMILES: C([O:4][C@H:5]1[C@H:11]([O:12]C(=O)C)[C@@H:10]([O:16]C(=O)C)[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37](=[N:39][O:40][CH3:41])[CH3:38])=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:42][O:43]C(=O)C)[CH2:7][O:8]2)(=O)C.O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:41][O:40][N:39]=[C:37]([CH3:38])[CH2:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:23]2[CH:22]=[C:21]([C@@:9]34[O:20][C@@:6]([CH2:42][OH:43])([CH2:7][O:8]3)[C@@H:5]([OH:4])[C@H:11]([OH:12])[C@H:10]4[OH:16])[CH:26]=[CH:25][C:24]=2[Cl:27])=[CH:34][CH:33]=1
Reactant: CON=C(C)COc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C)COc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-(2-(methoxy imino)propoxy)benzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (120 mg, 0.18 mmol) in THF (0.8 mL), methanol (1.2 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (15.2 mg, 0.36 mmol) at 0° C. The reaction mixture was stirred at r.t. for 1 h. Volatiles were evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 1:9 MeOH:DCM) to provide the title compound (60 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[CH3:12][N:13]([CH3:27])[CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=2)=[CH:16][CH2:15]1>>[ClH:6].[ClH:6].[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([C:17]2[CH2:18][CH2:19][CH:14]([N:13]([CH3:27])[CH3:12])[CH2:15][CH:16]=2)[N:25]=1)=[O:5]
Reactant: CN(C)C1CC=C(c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1F
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3ccc(F)cc3F)n2)CC1
Product: Cl
Yield: 45.7 %

Procedure:
Using a method similar to example 1, using 2,4-difluoro-benzoyl chloride (106 mg, 0.60 mmol) and 6-(4-dimethylamino-cyclohex-1-enyl)-pyridin-2-ylamine (preparation 10, 100 mg, 0.46 mmol) provides the free amine of the title compound as a colorless oil (59 mg, 36%): MS (ES): m/z=358.2 (M+H)+; 1H NMR (CDCl3): δ 8.94 (d, 1H), 8.21 (m, 2H), 7.72 (t, 1H), 7.19 (d, 1H), 7.04 (m, 2H), 6.71 (m, 1H), 2.78 (m, 1H), 2.49 (m, 3H), 2.38 (s, 6H), 2.17 (m, 2H), 1.59 (m, 1H). Using a salt formation method similar to that in example 1 gives the dihydrochloride salt: Di-hydrochloride salt: Anal cal'd for C20H21F2N3O.2HCl: C, 55.82; H, 5.39; N, 9.76. Found: C, 56.15; H, 5.49; N, 9.73.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:9][S:10](Cl)(=[O:12])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.[F:14][C:15]([F:33])([F:32])[C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][C@:2]1([CH2:9][S:10]([N:27]2[CH2:26][CH2:25][C:24]3[C:29](=[CH:30][CH:31]=[C:22]([C:19]4[CH:20]=[N:21][C:16]([C:15]([F:33])([F:14])[F:32])=[N:17][CH:18]=4)[CH:23]=3)[CH2:28]2)(=[O:12])=[O:11])[NH:3][C:4](=[O:8])[NH:5][C:6]1=[O:7]
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: FC(F)(F)c1ncc(-c2ccc3c(c2)CCNC3)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(-c4cnc(C(F)(F)F)nc4)ccc3C2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
[(4S)-4-Methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.0295 g, 0.13 mmol) in dry THF (0.60 mL) was added dropwise to a stirred solution of 6-[2-(trifluoromethyl)pyrimidin-5-yl]-1,2,3,4-tetrahydroisoquinoline (0.039 g, 0.14 mmol), DIPEA (0.034 mL, 0.20 mmol) and dry THF (0.60 mL) at ice-bath temperature. After the addition was complete the solution was stirred at RT for 2 h and then taken up in water-brine and extracted twice with EtOAc. The combined organic phases were washed with brine, dried, filtered and concentrated to give a crude product. Purification by preparative HPLC afforded 0.050 g (76%) of the title compound as a white solid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C.O>C(#N)C>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: OCCCCCBr
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: OCCCCCSc1nc2ccccc2[nH]1
Yield: 75 %

Procedure:
1.5 g of 2-mercaptobenzimidazole and 1.7 g of 5-bromopentanol were refluxed for 5 hours in an acetonitrile solvent containing 1.2 g of triethylamine. The reaction mixture was cooled, then added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 1.77 g of the title compound (yield: 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[O:12][C:11]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][CH:21]=4)=[O:19])=[CH:16][C:10]=3[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[O:12][C:11]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:21]=4)=[O:19])=[CH:16][C:10]=3[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc2c(c1)OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)O2)c1c[nH]c2ccccc12
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)Cc2ccc3c(c2)OC(c2ccc(Cl)cc2)(c2ccc(Cl)cc2)O3)c2ccccc21
Yield: 88.6 %

Procedure:
A suspension of 3-[(2,2-di[4-chlorophenyl]-1,3-benzodioxolan-5-yl)methylcarbonyl]-1H-indole (8.9 g) (see Preparation 10) in 2-butanone (200 ml) was treated with anhydrous potassium carbonate (12.2 g) and ethyl 4-bromobutanoate (5.2 g). The mixture was heated under reflux for 16 hours, filtered and evaporated. Flash chromatography (silica, eluant=dichloromethane) gave the title compound as a crystalline solid (9.68 g).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11].[N+:19]([O-])([O:21]C(C)C)=[O:20]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[OH:6][C:7]1[C:8]([N+:19]([O-:21])=[O:20])=[C:9]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: CC(C)O[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Sulfuric acid (3.0 mL, 56 mmol) was added dropwise over 2 min to a solution of methyl 3-hydroxy-4-methoxybenzoate (3.64 g, 20 mmol), tetrabutylammonium hydrogensulfate (340 mg, 1.0 mmol), isopropyl nitrate (5.0 mL, 50 mmol), and dichloromethane (CH2Cl2) (40 mL) at 0° C. The reaction was allowed to warm to room temperature, maintained for 45 min, and then quenched with ice water (100 mL). This mixture was extracted with dichloromethane (250 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (4:1→3:7; hexanes:ethyl acetate) to give methyl 3-hydroxy-4-methoxy-2-nitrobenzoate: MS (ESI): 228.4.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH2:25][CH2:26][CH2:27][C:28]#N.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:28][CH2:27][C:26]#[N:25])[N:8]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Reactant: N#CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(CCC#N)n1
Temperature: 90 °C
Yield: 77.1 %

Procedure:
A mixture of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (I-1a, step 5, 3.50 g, 8.14 mmol), 3-aminopropionitrile (1.79 mL, 24.4 mmol), diisopropylethylamine (2.84 ml, 16.3 mmol) and Na2CO3 (1.73 g, 16.3 mmol) in dry NMP (4 mL) was heated at 90° C. for 8 hours. The reaction was cooled to room temperature, and then partitioned between EtOAc (100 mL) and water (100 mL), and the layers separated. The organic portion was washed with water (100 mL), saturated aqueous NaHCO3 solution (100 ml), brine (100 mL), dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (SiO2, 0-50% EtOAc in heptane) to furnish 3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propanenitrile as a pale yellow foam (2.91 g, 6.28 mmol). LCMS (m/z) 463.1 (MH+), tR=0.98 minute, 1H NMR (CDCl3) δ ppm −0.09 (s, 9H) 0.73-0.85 (m, 2H) 0.99-1.11 (m, 2H) 1.12-1.21 (m, 2H) 1.90-2.05 (m, 1H) 2.75 (t, J=6.7 Hz, 2H) 3.36-3.48 (m, 2H) 3.76 (q, J=6.5 Hz, 3H) 5.50 (br s, 1H) 5.85 (s, 2H) 7.20 (d, J=5.1 Hz, 1H) 8.37 (d, J=5.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:16][NH2:17]>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([NH:17][CH3:16])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CN
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Product: CNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., to a stirred ice-water suspension (˜200 mL) of 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoic acid was slowly added a precooled 40% methylamine (13 mL). The reaction mixture was then stirred for 2 hours before being acidified to pH˜2. The desired product was precipitated and filtered out. After being dried overnight, the pure 2-chloro-4-fluoro-5-[(methylamino)sulfonyl]benzoic acid was obtained as white solid (9.8 g, 100%).