Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@H:2]1[C@@H:23]([CH2:24]C2OC3C=CC(NC)=C(C(O)=O)C=3N=2)O[C@:5]2(O[C@H:9]([C@@H:11]([C:13]([C:15]3NC=[CH:17][CH:16]=3)=O)C)[C@H:8](C)[CH2:7][C@H:6]2C)[CH2:4][CH2:3]1.[C:39]([OH:51])(=[O:50])[CH2:40][C:41]([CH2:46][C:47]([OH:49])=O)(C(O)=O)O>CS(C)=O>[CH3:17][CH2:16][CH2:15][CH2:13][CH2:11][CH:9]=[CH:8][CH2:7][CH:6]=[CH:5][CH2:4][CH:3]=[CH:2][CH:23]=[CH:24][CH:47]([OH:49])[CH2:46][CH2:41][CH2:40][C:39]([OH:51])=[O:50]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CNc1ccc2oc(C[C@H]3O[C@@]4(CC[C@H]3C)O[C@H]([C@H](C)C(=O)c3ccc[nH]3)[C@H](C)C[C@H]4C)nc2c1C(=O)O
Solvent: CS(C)=O
Product: CCCCCC=CCC=CCC=CC=CC(O)CCCC(=O)O
Reaction time: 0.08 h

Procedure:
RBL-1 cells (1.57×107 cells/tube) were preincubated for 10 minutes at 37° C. in the presence of the indicated drugs or vehicle (1% DMSO). Following the transfer of the assay tubes to an icebath, the reaction was initiated by the sequential addition of calcium ionophore A23187, an agent which increases the ability of divalent ions such as Ca++ to cross biological membranes (final concentration=1.9 μM) and 55 μM 1-14C-arachidonic acid (New England Nuclear) at a final specific activity of 3000-4000 cpm/nmole. The final volume in each tube was 1 ml. The assay tubes were incubated at 37° C. for 5 minutes, and the reaction was stopped by transferring the tubes to ice and adjusting the pH of the reaction mixture to pH 3.0-3.5 by the addition of 1M citric acid.
Reaction SMILES: [ClH:1].Cl.[CH:3]([C@H:16]1[N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[CH2:19][N:18]([CH2:25][C:26]2[CH:31]=[C:30](Br)[CH:29]=[CH:28][C:27]=2[O:33][CH3:34])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:41][N:42]1[CH:46]=[CH:45][N:44]=[CH:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[ClH:1].[ClH:1].[CH:3]([C@H:16]1[N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[CH2:19][N:18]([CH2:25][C:26]2[CH:31]=[C:30]([C:46]3[N:42]([CH3:41])[CH:43]=[N:44][CH:45]=3)[CH:29]=[CH:28][C:27]=2[O:33][CH3:34])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cn1ccnc1
Reactant: COc1ccc(Br)cc1CN1C[C@@H]2CCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2cncn2C)cc1CN1C[C@@H]2CCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 140 °C
Reaction time: 10 h
Yield: 308.7 %

Procedure:
(4R,8aS)-4-Benzhydryl-2-(2-methoxy-5-bromobenzyl)octahydropyrrolo[1,2-a]pyrazine dihydrochloride (29.8 mg) was dissolved in N,N-dimethylformamide (2.0 ml). Then potassium carbonate (85.6 mg), N-methylimidazol (43.6 mg), palladium acetate (3.98 mg) and triphenylphosphine (9.29 mg) were added to the solution at room temperature. The whole was stirred for 10 hours at 140° C. The reaction mixture was poured into aqueous sodium hydrogen carbonate. The whole mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by preparative TLC (0.5 mm) with a mixture of dichloromethane and methanol (10:1) as an eluent, and treated with 4N hydrogen chloride in ethyl acetate to give (4R,8aS)-4-benzhydryl-2-[2-methoxy-5-(3-methyl-3H-imidazol-4-yl)benzyl]octahydropyrrolo[1,2-a]pyrazine dihydrochloride (46.1 mg) as a colorless powder.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[N:15]([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[C:14]=2[CH:35]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>O>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:22][CH2:21][CH2:20][CH2:19][S:18][C:16]1[N:15]([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[C:14]2[CH:35]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: CC(C)=CCn1c(SCCCNC(=O)OC(C)(C)C)nc2ccc(NC(=O)c3ccccc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)=CCn1c(SCCCN)nc2ccc(NC(=O)c3ccccc3)cc21

Procedure:
33 mg (0.07 mmol) of tert-butyl {3-[6-benzoylamino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-ylsulfanyl]propyl}carbamate were dissolved in 102 μl of trifluoroacetic acid and 100 μl of water and stirred at room temperature for 6 hours. The reaction mixture was diluted with water and freeze-dried. 34 mg of the desired product were obtained in quantitative yield.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][O:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccoc12
Product: Clc1ncnc2ccoc12
Temperature: 25 °C
Yield: 78 %

Procedure:
Furo[3,2-d]pyrimidin-4(3H)-one (Intermediate 83) (1.49 g) and phosphorus oxychloride (15 mL) were heated to 120° C. for 45 minutes, cooled to ambient temperature, and evaporated under high vacuum. The residue was added to 50% saturated sodium carbonate (100 mL) and extracted into DCM (3×100 mL). The combined organics were dried and the solvent removed to afford the title compound as an orange solid (1.32 g, 78%);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23]#[C:24][C:25]2(O)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[CH2:16]([O:15][C:14]1[N:13]=[N:12][C:11]([C:23]#[C:24][C:25]2[CH2:30][CH2:29][O:28][CH2:27][CH:26]=2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC1(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)CCOCC1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)C1=CCOCC1
Temperature: 25 °C
Yield: 52.3 %

Procedure:
4-{2-[5,6-bis(Benzyloxy)pyridazin-3-yl]ethynyl}oxan-4-ol (Intermediate 59; 2.0 g, 4.8 mmol) was dissolved in dichloromethane (20 ml). Triethylamine (2.94 g, 28.82 mmol, 6.0 equiv.) was added to the clear solution followed by the addition of methanesulfonyl chloride (1.64 g, 14.42 mmol, 3.0 equiv.) at room temperature. The reaction mixture was stirred for an hour at room temperature before the reaction mass was poured into water (200 ml) and product was extracted into ethyl acetate (100 ml×2). The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo to get the crude title compound (1.0 g, 52% yield) which was used as such for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C@H:11]([OH:24])[CH2:12][C:13](=[N:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH:14]([CH3:16])[CH3:15])[S:9][CH:10]=1)=[O:5])[CH3:2].[BH4-].[Na+].C1COCC1.CC(O)=O.CCO>C1COCC1.CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C@H:11]([OH:24])[CH2:12][C@@H:13]([NH:17][S@:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[O:19])[CH:14]([CH3:15])[CH3:16])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc([C@H](O)CC(=N[S@@](=O)C(C)(C)C)C(C)C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc([C@H](O)C[C@@H](N[S@@](=O)C(C)(C)C)C(C)C)n1
Temperature: -78 °C
Reaction time: 12 h

Procedure:
A solution of the product mixture containing β-hydroxy imine 31 (˜0.943 mmol) and imine 26 (˜0.178 mmol) in THF (3.50 mL) was cooled to −78° C. Ti(OEt)4 (0.469 mL, 2.24 mmol) was added, followed by NaBH4 (0.0847 g, 2.24 mmol), and the solution was stirred at −78° C. for 12 h. The solution was acidified using a 4:1 (v/v) solution of THF/AcOH (3.2 mL) followed by addition of EtOH (2 mL) and H2O (10 mL). The solution was warmed to rt and diluted with EtOAc. The mixture was washed once with brine, and the aqueous fraction was extracted once with EtOAc. The combined organic fractions were dried with Na2SO4, filtered, and concentrated. NMR analysis on the unpurified material established a 92:8 ratio of diastereomers. HPFC purification (100% EtOAc) produced 0.332 g (74%, over two steps) of the pure major diastereomer 32 as a colorless oil. [α]25D=+103.2 (c=1.0, CHCl3). IR (film): 1474, 1718, 2868, 2929, 2960, 3283 cm−1. 1H NMR (500 MHz, CDCl3): δ 0.90 (d, 3H, J=6.8 Hz), 0.93 (d, 3H, J=6.8 Hz), 1.29 (s, 9H), 1.40 (t, 3H, J=7.1 Hz), 1.70 (doublet of septets, 1H, J=2.3, 6.8 Hz), 1.91 (ddd, 1H, J=3.6, 11.5, 14.7 Hz), 2.30 (ddd, 1H, J=3.0, 11.8, 14.7 Hz), 3.30 (d, 1H, J=8.5 Hz), 3.40-3.47 (m, 1H), 4.38-4.45 (m, 2H), 5.18 (ddd, 1H, J=3.1, 6.7, 11.6 Hz), 5.48 (d, 1H, J=6.7 Hz), 8.11 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 14.4, 17.3, 19.7, 23.0, 33.9, 40.6, 56.3, 58.5, 61.3, 67.8, 127.4, 147.0, 161.6, 177.6. HRMS (FAB) calcd. for C16H28N2O4NaS2 (M+Na): 399.1388. Found 399.1389.
Reaction SMILES: [NH2:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[C:16]([F:22])[CH:15]=1)#[N:13]>>[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[C:16]([F:22])[CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Product: CC(C)(C)OC(=O)C(C)(C)NCc1ccc(C#N)cc1F

Procedure:
The title compound was prepared following general procedure 10 starting from tert-butyl 2-amino-2-methylpropanoate and 4-cyano-2-fluoro benzyl bromide. The title compound was isolated as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.78-7.75 (d, J=10.0 Hz, 1H), 7.71-7.65 (m, 2H), 3.70-3.68 (d, J=6.9 Hz, 2H), 2.55 (s, 1H), 1.44 (s, 9H), 1.19 (s, 6H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:14]([OH:16])=O.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:14]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:16]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
Diisopropylethylamine (0.65 mL, 3.7 mmol) was added to a mixture of 3-chloro-4-nitro-benzoic acid (0.2 g, 0.992 mmol), aniline (0.1 mL, 1.1 mmol) and HBTU (0.42 g, 1.1 mmol) in acetonitrile (20 mL) and the reaction mixture was stirred at 80° C. for 8 hours and then at room temperature for 62 hours. The resulting mixture was then partitioned between water and ethyl acetate, the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified on a silica gel plug (hexane/EtOAc, 80/20) to afford 135 mg (49% yield) of 3-chloro-4-nitro-N-phenyl-benzamide as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1/[CH:11]=[C:12](\[CH3:18])/[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[NH4+]>O1CCCC1.CO.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1/[CH:11]=[C:12](\[CH3:18])/[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)/C(C)=C/c1ccc(N)cc1F
Yield: 85.2 %

Procedure:
Compound 14c (17.3 g) was dissolved in tetrahydrofuran (180 ml) and methanol (180 ml), and iron powder (19.1 g) was added thereto. An ammonium chloride aqueous solution (1.67 mol/l, 110 ml) was added to the reaction mixture while refluxing under heating. The obtained mixture was refluxed under heating for 1 hour. After the mixture was allowed to cool, the iron powder was removed by Cerite filtration. Ethyl acetate and purified water were added to the filtrate, and extraction and washing were carried out. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized with n-heptane to obtain Compound 14d (13.0 g, 85%) as an opalescent solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)([O-])=O.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>CO.C(Cl)Cl.[Pd]>[C:21]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)(=[O:24])[CH:22]=[CH2:23]
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C=CC(=O)Cl
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(OC(C)=O)cc1
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
H2 is bubbled through a solution of 1 (280 mg, 1.54 mmol) and 10 mg of 10% Pd on carbon in 20 ml of MeOH for 1 hr. The catalyst is removed by filtration. Triethylamine (410 μl, 3.08 mmol) is added to the filtrate which was chilled on ice, then acryloyl chloride (250 μl, 3.08 mmol, Aldrich) in 10 ml of dry CH2Cl2 is added dropwise with stirring over 0.5 hr under Ar. The reaction is then allowed to return to ambient temperature, followed by 2 hr of stirring. Anion exchange resin (Bio-Rad, AG-MP1, OH−) (4 equivalents based on acryloyl chloride) is added, the mixture is filtered, and the filtrate is treated with sufficient cation exchange resin (Dowex, 50W×8, H+) to bring the mixture to neutrality (moist pH paper). The resin is removed by filtration, and the solvent is removed by rotary evaporation to yield an off-white solid (268 mg, 85%). ESI-MS (M+H)+: 206.1. 1H-NMR (acetone-d6) δ 9.15 (1H, br, NH), 7.78 (2H, d, J=9.0 Hz, NHCCH), 7.08 (2H, d, J=9.0 Hz, NHCCHCH), 6.55˜6.37 (2H, m, COCHCHH (anti to each other)), 5.75 (1H, dd, J=9.8 and 2.2 Hz, COCHCHH (syn to COCH)), 2.25 (3H, s, CH3).
Reaction SMILES: ClC1N=C([NH:8][CH2:9][CH2:10][S:11]([OH:14])(=[O:13])=[O:12])C=C(Cl)N=1.Cl[C:17]1[CH:22]=[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:20]=[C:19]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[N:18]=1>>[N:28]1([C:19]2[N:18]=[C:17]([NH:8][CH2:9][CH2:10][S:11]([OH:14])(=[O:13])=[O:12])[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:20]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=S(=O)(O)CCNc1cc(Cl)nc(Cl)n1
Reactant: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Product: O=S(=O)(O)CCNc1cc(N2CCCC2)nc(N2CCCC2)n1

Procedure:
The 2-(2,6-dichloropyrimidin-4-ylamino)ethanesulfonic acid (III, EXAMPLE 97, 3.0 g) is dissolved in pyrrolidine (IV, 125 ml) and heated to reflux. Solvent evaporation gives a semisolid which is chromatographed on 155 g of silica gel eluting with chloroform/3.9M ammonia in methanol (7/3). An initial fraction of 150 ml is collected followed by 15 ml fractions. Fractions 8-18 contained the desired product. Solvent evaporation and drying under high vacuum gives a solid (a portion of which) is rechromatographed on 155 g silica gel and eluting with the same solvent system as described above. The appropriate fractions are pooled and concentrated to give the title compound, which is used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]([N:4]1[C:8](O)([C:9]([F:12])([F:11])[F:10])[CH:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[N:5]1)=[S:3].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])=O>C(O)C>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[N:1]=[C:2]([N:4]2[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[N:5]2)[S:3][CH:20]=1
Reactant: CCOC(=O)C1C=NN(C(N)=S)C1(O)C(F)(F)F
Reactant: COc1ccccc1C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc(-c3ccccc3OC)cs2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 1-(aminocarbonothioyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-carboxylate (470 mg, 1.65 mmol, prepared according to J. Comb. Chem. 2002, 4, 23-32) and 2-bromo-2′-methoxyacetophenone (377 mg, 1.65 mmol) in ethanol (8 mL) was heated at 80° C. After 1 h, the mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 55% EtOAc in hexanes) provided the title compound as an off-white solid: LCMS m/z 398.5 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.26 (dd, J=7.6, 1.6 Hz, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.37 (ddd, J=8.9, 6.5, 1.8 Hz, 1H), 7.12-7.01 (m, 2H), 4.42 (q, J=7.0 Hz, 2H), 4.02 (s, 3H), 1.42 (tr=7.0 Hz, 3H).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:43])[CH2:7][C:8]1[CH:42]=[CH:41][CH:40]=[CH:39][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:13]=1>C1COCC1.O.CO>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:39]=[CH:40][CH:41]=[CH:42][C:8]=4[CH2:7][C:6]([OH:43])=[O:5])[C:17]([CH3:18])=[CH:16][N:15]=3)=[CH:25][CH:24]=2)[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cnc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
LiOH.H2O (24 mg, 0.56 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (A8) (44 mg, 0.081 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL) and the resulting mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the resulting residue was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound A9 as brown oily residue (36 mg, 84%); LCMS-A: rt 5.737 min; m/z 532.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=S)[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:36](O)[CH3:37]>[Ni]>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[CH2:24][N:23]([CH2:36][CH3:37])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=S)NCC4)cc2)CCC1
Agent: [Ni]
Product: CCN1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of tert-butyl(1-(4-(3-phenyl-5-thioxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (41 mg, 0.08 mmol) in dry ethanol (1 mL) was added Raney Nickel (1 mL) under nitrogen. The resulting mixture was heated under reflux for 4 h. After cooled down to room temperature, the mixture was filtered on celite (rinse few times with ethanol) and concentrated to dryness under reduced pressure to give the title compound (28 mg, 74%). 1H NMR (500 MHz, CDCl3): 7.29 (1H, s), 7.22-7.18 (4H, m), 7.15-7.14 (3H, m), 7.07-7.06 (2H, m), 4.98 (1H, br s), 3.64 (2H, S), 3.09 (2H, t), 2.83 (2H, t), 2.58 (2H, q), 2.50-2.20 (4H, m), 2.00-1.91 (1H, m), 1.74-1.66 (1H, m), 1.40-1.10 (9H, br), 1.15 (3H, t).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([NH:27][C:28](=[O:41])[CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:21]=1[Cl:42])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43]N(C)C=O.[H-].[Na+].CI>O>[Si:1]([O:18][CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([N:27]([CH3:43])[C:28](=[O:41])[CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:21]=1[Cl:42])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(NC(=O)CN2C(=O)c3ccccc3C2=O)c1Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1Cl
Reaction time: 0.83 h

Procedure:
To a mixture of 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-(phthalimidoacetylamino)benzene (453 mg) and N,N-dimethylformamide (2.2 ml) was added sodium hydride (60% in oil, 31 mg) under ice-cooling, and the mixture was stirred for 50 minutes. To the mixture was added methyl iodide (0.055 ml), and the mixture was stirred for 2.5 hours at ambient temperature. Water (88 ml) was added to the mixture under ice-cooling, and the resulting precipitates were collected by vacuum filtration and washed with water and ethyl acetate to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (236 mg) as powder.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH:22]1([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:14]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
Add to a stirring solution of 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid methyl ester (2.0 g, 5.22 mmol) in THF (50 mL) and MeOH (25 mL), 5N NaOH (3 mL, 2.9 eq.). Stir the solution for 2 h at room temperature and the remove solvents to give a paste. Treat the paste with 1N HCl (25 mL) and a solid results. Dilute further with water (50 mL). Filter the solid, back-wash with water, and dry (20 mm Hg, 60° C.) to provide the pure title compound (1.63 g, 84%); 1H NMR (DMSO-d6) δ 8.06 (m, 4H), 7.93 (d, J=8.2 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.53 (s, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.28 (t, J=7.7 Hz, 1H), 3.17 (m, 1H), 2.08 (m, 2H), 1.69 (m, 6H); MS (ESI) m/z 368 (m−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:14][CH3:15].CCN(CC)CC.[Cl:23][CH2:24][C:25](Cl)=[O:26].C(Cl)Cl>CCCCCC.C(OCC)(=O)C>[Cl:23][CH2:24][C:25]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:14][CH3:15])[CH:4]=2)[CH2:13][CH2:12]1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: COc1cc(N2CCNCC2)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl

Procedure:
Protocol S was followed using 1-(4-chloro-3-methoxyphenyl) piperazine, Et3N, chloroacetyl chloride and methylene chloride. Column chromatography using a solvent mixture (hexane/ethyl acetate=1.5/1) afforded the title compounds as a white solid
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][O:22][CH2:21][CH2:20][O:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36]>C(Cl)(Cl)Cl>[CH2:35]([N:37]([CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][O:22][CH2:21][CH2:20][O:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7])[CH2:38][CH3:39])[CH3:36]
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Product: CCN(CC)Cc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccn1

Procedure:
From (+)-2-chloromethyl-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and diethylamine. [α]D20=+48.9° (c=1.02, CHCl3), ES-MS m/e (%): 457 (M+H+, 100).