Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]=[C:27]([NH2:29])[S:28][C:24]=2[CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[F:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]=[C:27]([NH:29][C:15]([CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[O:17])[S:28][C:24]=2[CH:23]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)Nc2nc3ccc(F)cc3s2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 6-fluoro-benzothiazol-2-ylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C19H17FN2O5S [M+H]+: 405.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]([NH:14][CH3:15])=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:12][NH:14][CH3:15])[CH3:2]
Reactant: CCc1c(C(=O)NC)[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCc1c(CNC)[nH]c2ccccc12
Temperature: 0 °C
Yield: 60.9 %

Procedure:
A solution of 3-ethyl-N-methyl-1H-indole-2-carboxamide (970 mg, 4.80 mmol) in dioxane was added slowly to an ice-cooled solution of lithium aluminium hydride (273 mg, 72 mmol) in dioxane (10 mL). The mixture was stirred at reflux overnight. Excess lithium aluminium hydride was quenched with 15% NaOH (2 mL) and the mixture separated. The aqueous phase was washed twice with ethyl acetate and the combined organic phases dried to afford the title compound (550 mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.42 (d, J=8 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.00 (t, J=7.2 Hz, 1H), 6.89 (t, J=7.2 Hz, 1H), 3.75 (s, 2H), 2.66 (q, J=7.5 Hz, 2H), 2.27 (s, 3H), 1.14 (t, J=7.6 Hz, 3H).
Reaction SMILES: CI.[C:3]([O-])(O)=O.[Na+].Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([C:23]3([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24]3)[NH:16][CH2:15][CH2:14][C:13]2=1>C(O)C>[ClH:9].[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([C:23]3([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:25][CH2:26]3)[N:16]([CH3:3])[CH2:15][CH2:14][C:13]2=1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CCOC(=O)C1(C2c3[nH]c4ccc(Cl)cc4c3CCN2C)CCC1

Procedure:
0.3 ml of methyl iodide and 0.8 g of NaHCO3 are added to a solution of 1 g of the compound of Example 1 in 25 ml of ethanol. After reaction for 24 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure and then the residue is taken up in a mixture of water and dichloromethane. After extraction, drying and filtration, the organic phase is concentrated under reduced pressure. Crystallisation from a solution of ethanol and ethereal hydrogen chloride enables the expected product to be obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].S(=O)(=O)(O)O.[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>C1COCC1.C(OCC)C.O>[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1
Reactant: N#CCc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: NCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution of 2M LAH (31 mL) in THF (37 mL) at 0° C. was added sulfuric acid (1.6 mL) dropwise. This mixture was allowed to stir for 30 min and then (3-bromophenyl)-acetonitrile (30.6 mmol) in THF (7.5 mL) was slowly added. The reaction mixture was allowed to warm to rt and stir for 1 hr. The reaction was cooled to 0° C. and then a 1:1 v:v mixture of THF:water (20 mL) was added, followed by diethyl ether (40 mL). A precipitate formed. 4N NaOH was added until the solution reached pH=9. The mixture was filtered and the solid was washed with ether. The solution was dried over Na2SO4 and concentrated to give 2-(3-bromophenyl)ethanamine (28.1 mmol, 92%) as an oil, which was used without further purification.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].I[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][NH:12][C:11]2=[O:18].[CH:19]([C:21]1[O:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[O:18]=[C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:24]3[O:25][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)[CH:9]=2)[N:14]=[CH:13][NH:12]1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a 40° C. solution of Na2CO3 (3.9 g, 36 mmol) in inert gas (nitrogen or argon) degassed aqueous dioxane (100 mL, 2:1 dioxane: H2O) was added [HP(t-Bu)3]BF4 (0.52 g, 1.8 mmol) and Pd(OAc)2 (0.4 g, 0.18 mmol). The mixture was stirred at 30° C. (internal temperature) under an atmosphere nitrogen for 30 min, and then 6-iodoquinazolin-4(3H)-one ((Va); 5 g, 18 mmol) and 5-formylfuran-2-ylboronic acid ((VIa); 4.1 g, 29 mmol) were added. The mixture was heated to 80° C. (internal temperature) and stirred until TLC analysis showed completion of the reaction. The reaction product mixture was cooled to ambient temperature and filtered through celite (1 g), and the filter cake was washed with n-BuOH (200 mL). The combined filtrates were separated and the organic layer was washed twice with a saturated aqueous solution of NaCl (100 mL each). The organic phase was concentrated down to about 50 mL under vacuum and the residue was cooled to ambient temperature with stirring to precipitate the product. The slurry was filtered and the filter cake was washed with n-BuOH (40 mL) and then dried at 60° C. under vacuum to give crude compound of formula (IX) (4.5 g, 91% HPLC, 16.5 mmol). 1H NMR (300 MHz, d6-DMSO, 1347-126-19): δ 7.47 (d, J=3.6 Hz, 1H), 7.68 (d, J=3.6 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H), 8.28 (dd, J=8.7 Hz, J=2.1 Hz, 1H), 8.53 (d, J=2.1 Hz, 1H), 9.64 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:65]1([CH2:71][C:72]([NH2:74])=[O:73])[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@H:9]2[C:28]([N:68]2[CH2:69][CH2:70][N:65]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:66][CH2:67]2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCN(CC(N)=O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.138 mmol) in methylene chloride (5 mL), HATU (Aldrich, 79 mg, 0.21 mmol) was added followed by the addition of DIPEA (0.145 mL, 0.83 mmol) and 2-piperazin-1-yl-acetamide (Chembridge, 45 mg, 0.21 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a ISCO machine (12 g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 87 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:27])=[C:5]([C:18]([O:25][CH3:26])=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:27])=[C:5]([C:18]([O:25][CH3:26])=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OCC(=O)OC(C)(C)C
Yield: 52.6 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-hydroxybenzoate (1.09 g, 2.53 mmol) was dissolved in acetone (50 ml) and after adding thereto anhydrous sodium carbonate (0.420 g, 3.03 mmol) and tert-butyl bromoacetate (0.592 g, 3.03 mmol), the solution was refluxed under heating for 3 hours. The reaction solution was filtered, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (0.650 g, 1.33 mmol, 53%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)=[S:4].[N-:13]=[N+:14]=[N-:15].[Na+]>O1CCCC1.O>[N:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)=[S:4])=[N+:14]=[N-:15]
Reactant: Cc1cc(C(=S)CBr)ccc1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=S)CN=[N+]=[N-])ccc1O
Reaction time: 5 h

Procedure:
To a solution of the product of Step A (150.5 g, 0.576 mole) in tetrahydrofuran (1 liter) cooled to 20° C., add dropwise sodium azide (37.4 g, 0.576 mole) in water (450 ml) and stir for five hours. Partially evaporate the solvent and extract the concentrated reaction mixture with chloroform. Dry the organic phase and evaporate in vacuo to obtain 2-azido-4'-hydroxy-3'-methylthioacetophenone, mp. 124°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13](NC2C=CN(C)N=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][O:43][C:44](=[O:61])[C:45]1[CH:50]=[CH:49][C:48]([CH:51]([N:55]2[CH:59]=[CH:58][C:57]([NH2:60])=[N:56]2)[CH2:52][CH2:53][CH3:54])=[CH:47][CH:46]=1>C(Cl)Cl>[CH3:42][O:43][C:44](=[O:61])[C:45]1[CH:46]=[CH:47][C:48]([CH:51]([N:55]2[CH:59]=[CH:58][C:57]([NH:60][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:56]2)[CH2:52][CH2:53][CH3:54])=[CH:49][CH:50]=1
Reactant: CCCC(c1ccc(C(=O)OC)cc1)n1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCCC(c1ccc(C(=O)OC)cc1)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 131 mg, 0.40 mmol) was dissolved in methylene chloride (2 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (200 μL, 0.40 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (92 μL, 0.79 mmol) was added. The reaction continued to stir at 0° C. for 15 min. 4-[1-(3-Amino-pyrazol-1-yl)-butyl]-benzoic acid methyl ester (108 mg, 0.40 mmol) was dissolved in methylene chloride (2 mL) and added dropwise to the reaction. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was diluted with ethyl acetate (50 mL), washed with water (2×15 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to an orange foam. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 4-(1-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-butyl)-benzoic acid methyl ester (110 mg, 47%) as a white foam: ESI-LRMS m/e calcd for C30H36ClN3O5S [M+] 585.2, found 586.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.93-1.02 (m, 3H, CH3), 1.05-1.22 (m, 2H, CH2), 1.22-1.40 (m, 2H, CH2), 1.42-2.00 (m, 8H, 4×CH2), 2.02-2.45 (m, 3H, CH2 and CH), 3.26 (s, 3H, SO2CH3), 3.52 (t, J=7.5 Hz, 1H, CH), 3.91 (s, 3H, OCH3), 5.11 (m, 1H, NCH), 6.74 (d, J=2.2 Hz, 1H, Ar), 7.27 (d, Jo=8.2 Hz, 2H, Ar), 7.40 (d, J=2.2 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.6 Hz, 1H, Ar), 7.58 (d, Jm=1.6 Hz, 1H, Ar), 7.98 (d, Jo=8.2 Hz, 2H, Ar), 8.04 (brs, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][C:13]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>[NH4+].[Cl-].O.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][C:13]([CH2:26][N:27]3[CH2:28][CH2:29][N:30]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:31][CH2:32]3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Nc2ncc(CN3CCNCC3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
The crude residue from Step 1 was taken up in DCM (3 mL, 46.6 mmol), cooled to 0° C. and then DIEA (0.132 mL, 0.755 mmol) and methanesulfonyl chloride (0.029 mL, 0.378 mmol) were added. The mixture was stirred at the same temperature for 1 h and then diluted with NH4Cl(aq) and water (10 mL each) and diluted with DCM (10 mL). The separated aqueous layer was extracted with DCM (2×15 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and chromatographed through a Redi-Sep pre-packed silica gel column (DCM to 10% MeOH in DCM) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amine (21 mg, 16%) as a yellow solid. LCMS (API-ES) m/z 510 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 13.58 (br. s., 1H) 12.62 (br. s., 1H) 9.73 (br. s., 1H) 8.62 (s, 1H) 8.54 (d, J=2.54 Hz, 1H) 8.22 (d, J=1.56 Hz, 1H) 8.18 (dd, J=8.90, 2.45 Hz, 1H) 6.85 (d, J=8.80 Hz, 1H) 3.85 (s, 3H) 3.56 (s, 2H) 3.01-3.18 (m, 4H) 2.86 (s, 3H) 2.86 (s, 3H) 2.53 (br. s., 4H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[N:4][C:3]=1[Cl:16].C([O-])([O-])=O.[Na+].[Na+].[Cl:23][C:24]1[C:25](B(O)O)=[CH:26][C:27]([F:30])=[N:28][CH:29]=1.C(Cl)Cl>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:16][C:3]1[N:4]=[CH:5][C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:7][C:2]=1[C:25]1[C:24]([Cl:23])=[CH:29][N:28]=[C:27]([F:30])[CH:26]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: Clc1ncc(NCC2CCOCC2)nc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1cc(-c2nc(NCC3CCOCC3)cnc2Cl)c(Cl)cn1
Temperature: 100 °C
Yield: 43.1 %

Procedure:
To a suspension of 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (20 mg, 0.065 mmol), Na2CO3 (17.98 mg, 0.170 mmol) and 5-chloro-2-fluoropyridin-4-ylboronic acid (17.16 mg, 0.098 mmol) in DME (1 ml) was added PdCl2(dppf).CH2Cl2 adduct (4.26 mg, 5.22 μmol). The reaction mixture was capped in a flask and heated to 100° C. for 4 hr an oil bath. The reaction mixture was diluted with EtOAc and washed with H2O sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude was purified by column chromatography on silica gel (50% EtOAc/Hexane) to yield 5-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (10 mg, 0.028 mmol, 42.9% yield). LCMS (m/z): 357.0 (MH+), retention time=0.95 min.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][C:14]([O:16]CC)=[O:15])[C@H:8]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23][C@H:7]3[C:6]=2[C:5]=1[Cl:31].Cl>O.C1COCC1>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C@@H:7]2[C@@H:8]([N:9]([CH2:13][C:14]([OH:16])=[O:15])[C:10]3[CH:11]=[CH:12][C:4]([Cl:3])=[C:5]([Cl:31])[C:6]=32)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)CN1c2ccc(Cl)c(Cl)c2[C@@H]2CCN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]2c3c(ccc(Cl)c3Cl)N(CC(=O)O)[C@H]2CC1
Temperature: 60 °C
Yield: 99.9 %

Procedure:
A solution of KOH (0.16 g, 2.8 mmol) in H2O (10 mL) was added to a solution of tert-butyl (5aS*,10bS*)-9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.96 g, 2.17 mmol) in THF (15 mL). The mixture was heated at 60° C. for 2 h. The reaction was then cooled to rt, acidified with 10% aqueous HCl, and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated to give crude white foam (0.90 g): 1H NMR (300 MHz, CDCl3) δ 67.14 (d, J=8.3 Hz, 1H), 6.21 (d, J=8.4Hz, 1H), 4.08 (m, 1H), 3.93 (d, J=18.3 Hz, 1H), 3.76 (d, J=18.3 Hz, 1H), 3.47 (m, 5H), 2.04 (m, 4H), 1.44 (s, 9H); HRMS (FAB) calcd for C19H24CL2N2O4+H 415.1191, found 415.1198.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:5]([NH:13][CH:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:19]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(Nc2c(N)cnc3ccsc23)CC1

Procedure:
tert-Butyl {4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}carbamate (216 mg, 0.550 mmol) and 10% Pd/C (20 mg) in methanol (5 mL) was subjected to balloon pressure of H2 at room temperature for 2 h. The mixture was filtered, concentrated and purified on silica gel column (eluting with 0-10% MeOH in methylene chloride) to give the desired product. LCMS calculated for C18H27N4O2S (M+H)+: m/z=363.2. Found: 363.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CS(C)=O>[O:12]=[C:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Temperature: 10 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A 5 L-3-neck flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen inlet was charged with Py-SO3 (277 g, 1.74 mol) and DMSO (900 mL) and cooled to 10° C. in ice-bath. TEA (177 g/244 mL, 1.74 mol) was added. A solution of tert-butyl-3 hydroxyazetidine-1-carboxylate (Preparation 1, 100.8 g, 0.58 mol) in DMSO (500 mL) was added slowly via addition funnel at 10° C. The reaction was stirred at ambient temperature overnight. GC/MS analysis of the reaction mixture reveals that the reaction was completed. The reaction was quenched with brine (1 L). Solids were filtered and the aqueous was extracted with ethyl acetate (3×1 L). The combined organics were washed with saturated aqueous NaHCO3 (1.5 L), brine (1.5 L), dried over sodium sulfate, filtered, and concentrated to give the desired product (94 g, 95% yield). 1H NMR (CDCl3) δ 4.6 (s, 4H), 1.4 (s, 9H).
Reaction SMILES: [NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:10]=1.S(=O)(=O)(O)[OH:25].[OH-].[Na+]>CO>[NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:9][CH:10]=1
Reactant: C[C@H](CCc1ccc(C#CCCCC2CCCCC2)s1)C(N)O
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](CCc1ccc(C(=O)CCCCC2CCCCC2)s1)C(N)O
Yield: 91 %

Procedure:
(2R)-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol (26 mg, 0.41 mmol) obtained in Example 1 was dissolved in methanol (2 ml), and 6N sulfuric acid (2 ml) was added thereto followed by heating under reflux for 4 hours. After the reaction solution was made alkaline with a 1N aqueous sodium hydroxide solution, the resulting solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (130 mg, 91% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=O)[C:7](=[O:13])[NH:8]2.IC1C=CC=C2C=1C(=O)C(=O)N2.CC(=C)C.[CH:32]1[C:37]([NH:38][NH2:39])=[CH:36][CH:35]=[C:34]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:33]=1.Cl>>[CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:39][NH:38][C:37]1[CH:36]=[CH:35][C:34]([S:40]([NH2:43])(=[O:41])=[O:42])=[CH:33][CH:32]=1)[C:7](=[O:13])[NH:8]2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)=Cc1cccc2c1C(=O)C(=O)N2
Agent: C=C(C)C
Agent: Cl
Agent: O=C1Nc2cccc(I)c2C1=O
Product: CC(C)=Cc1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 51 %

Procedure:
By methods described in Procedure L, 4-(2-methyl-propenyl)-1H-indole-2,3-dione was prepared from 4-iodo-1H-indole-2,3-dione and isobutylene in 34% yield: 1H NMR (DMSO-d6): δ 1.82 (s, 3H), 1.90 (s, 3H), 6.79 (d, J=7.9 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 10.97 (s, 1H); APCI−MS m/z 200 (M−1)−. Condensation of 4-(2-methyl-propenyl)-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound as a yellow solid (51% yield): 1H NMR (DMSO-d6): δ 1.84 (s, 3H), 2.04 (s, 3H), 6.78 (s, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.24 (s, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 11.11 (s, 1H), 12.91 (s, 1H); APCI−MS m/z 369 (M−1)−. Anal. Calcd for C18H18N4O3S: C, 58.36, H, 4.90; N, 15.12; S, 8.66. Found C, 58.41, H, 4.87; N, 15.18; S, 8.56.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].Cl.[CH3:14]O>>[CH3:14][O:11][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: O=C(O)Cc1cc(O)ccc1Br
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1cc(O)ccc1Br
Temperature: 70 °C

Procedure:
To (2-bromo-5-hydroxy-phenyl)-acetic acid (1.5 g, 6.5 mmol) in MeOH (15 mL) was added HCl (4N in 1,4-dioxane; 3 mL), and the solution was heated to 70° C. for 8 hours. The mixture was concentrated to give the desired product as a white solid (1.2 g).