Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:48])[CH:7]([NH:12][C:13](=[O:47])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[S:22][S:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[C:32](=[O:46])[NH:33][CH:34]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[C:39]([CH:34]([NH:33][C:32]([C:25]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=1[S:23][S:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:48])=[O:5])=[O:47])=[O:46])[CH2:35][CH:36]([CH3:38])[CH3:37])([OH:41])=[O:40]
Reactant: COc1ccc(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(SSc2cc(OC)ccc2C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)NC(CC(C)C)C(=O)O)c(SSc2cc(OC)ccc2C(=O)NC(CC(C)C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
A solution of [S-(R*,R*)-2[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-5-methoxyphenyldisulfanyl]-4-methoxybenzoylamino]-4-methyl-pentanoic acid tert-butyl ester (1.2 g, 1.7 mmol) and anisole (1 mL) in 10 mL dichloromethane, cooled to about 0° C., was treated dropwise with 10 mL of trifluoroacetic acid. The mixture was allowed to warm to ambient temperature. After 4 hours, 5 mL toluene was added, and the solvents were removed in vacuo. The crude product was recrystallized from methanol/water to yield 0.7 g of the title compound.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=2[N:24]=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2nc(C)sc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2nc(CBr)sc2c1
Temperature: 25 °C
Yield: 47 %

Procedure:
17.4 mg of dibenzoyl peroxide were added to a solution of 0.8 ml of 2-methyl-6-methoxybenzothiazole and 1.05 g of N-bromosuccinimide in 20 ml of carbon tetrachloride at room temperature and the resulting mixture was stirred under reflux for 5 hours. At the end of this time, the mixture was allowed to cool to room temperature and then extracted with methylene chloride. The resulting extract was washed consecutively with a saturated aqueous sodium sulfite solution, water and an aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using an 8:1 by volume mixture of hexane and ethyl acetate, to give 649.3 mg (yield 47%) of the title compound as a solid having a melting point of 78° to 81° C.
Reaction SMILES: C(O[CH:5]([C:22]1[N:23]=[CH:24][N:25]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]=1[CH3:27])[CH:6]1[C:20](=[O:21])[N:10]2[C:11]3[C:16]([C:17]([CH2:18][CH3:19])=[C:9]2[CH2:8][CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=O)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.O>[CH2:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]2[C:20](=[O:21])[C:6](=[CH:5][C:22]3[N:23]=[CH:24][N:25]([C:28]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:26]=3[CH3:27])[CH2:7][CH2:8][C:9]=12)[CH3:19]
Reactant: CCc1c2n(c3ccccc13)C(=O)C(C(OC(C)=O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCc1c2n(c3ccccc13)C(=O)C(=Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Temperature: 75 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-ethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (2.06 g) in toluene (30 ml) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 ml). After being stirred at 75° C. for 3 hours, the solution was diluted with chilled water. The organic layer separated was washed with aqueous oxalic acid solution, water, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was triturated with methanol and filtered to give 10-ethyl-8,9-dihydro-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (1.41 g).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][NH:16][C:15]2=O)([CH3:9])([CH3:8])[CH3:7].N>C1(C)C=CC=CC=1.CN(C)C1C=CC=CC=1>[Cl:3][C:15]1[C:14]2[C:19](=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=[CH:12][CH:13]=2)[N:18]=[CH:17][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cccc2c(=O)[nH]cnc12
Agent: N
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)c1cccc2c(Cl)ncnc12
Temperature: 0 °C

Procedure:
18.6 ml (200 mmol) of phosphoryl chloride are added dropwise at room temperature to a suspension of 10.2 g (50 mmol) of 8-tert-butyl-4(3H)-quinazolinone in 100 ml of toluene. After addition of 5 drops of N,N-dimethylaniline, the reaction mixture is heated under reflux for 5 h. After cooling, the reaction mixture is diluted with 300 ml of toluene, poured onto 1000 g of ice and rendered alkaline (pH about 9) by addition of conc. ammonia solution. The organic phase is separated off, washed once with 300 ml of sat. sodium chloride solution, dried over magnesium sulfat e, and the toluene is removed in vacuo. The residue is chromatographed on silica gel (n-heptane:ethyl acetate 3:1 v:v). Yield: 9.3 g (42 mmol), 84%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[C:4]([F:12])[CH:3]=1.[CH:13]1([C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:16]2[CH2:17][CH2:18][C@H:13]([C:20]3[CH:29]=[CH:28][C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[CH2:14][CH2:15]2)=[C:4]([F:12])[CH:3]=1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: NCCCc1ccc(Cl)cc1F
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(Cl)cc4F)CC3)cc2o1

Procedure:
Condensation of 3-(4-chloro-2-fluorophenyl)-1-propylamine (1.5 g, 6.5 mmol) and ketone 5 (1.5 g, 6.5 mmol), following the procedure described in Example 1, gave 6-{trans-4-[3-(4-chloro-2-fluorophenyl)-propylamino]cyclohexyl}-3H-benzoxazol-2-one (479 mg, 18%), as a white solid: 1H NMR (500 MHz, DMSO-d6): δ 7.36-7.32 (m, 2H), 7.22-7.20 (m, 1H), 7.13 (d, J=1 Hz, 1H), 6.99-6.94 (m, 2H), 3.70-3.00 (br s, 2H), 2.64 (t, J=8 Hz, 2H), 2.57 (t, J=8 Hz, 2H), 2.47-2.38 (m, 2H), 1.94 (br d, J=10 Hz, 2H), 1.77 (br d, J=10 Hz, 2H), 1.70-1.64 (m, 2H), 1.44 (dddd, J=13, 13, 13, 3 Hz, 2H), 1.13 (dddd, J=13, 13, 13, 3 Hz, 2H).
Reaction SMILES: [Na].[CH3:2][C@@:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4]1.[I-].[K+].Cl[CH2:26][C:27]([O:29][CH3:30])=[O:28]>CO>[CH3:2][C@@:3]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:14][CH:15]=2)[C:7](=[O:8])[N:6]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:5](=[O:9])[NH:4]1
Reactant: C[C@]1(c2ccc(O[C@H]3CCCCO3)cc2)NC(=O)NC1=O
Reactant: COC(=O)CCl
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CN1C(=O)N[C@](C)(c2ccc(O[C@H]3CCCCO3)cc2)C1=O
Reaction time: 2 h
Yield: 70.6 %

Procedure:
230 mg (10 mmol) of sodium were dissolved in 25 ml of anhydrous methanol under argon. 2.9 h (10 mmol) of 10.2 were added. The mixture was heated to reflux with stirring for 2 hours. 1.66 g (10 mmol) of potassium iodide were then added and a solution of 0.975 ml (10 mmol) of methyl chloroacetate in 1.1 ml of anhydrous methanol was added dropwise in the course of 15 minutes. The mixture was heated to reflux for 4 hours and then allowed to stand at room temperature overnight. A further 0.195 ml (2 mmol) of methyl chloroacetate in 0.22 ml of anhydrous methanol were added and the batch was stirred under reflux for 4 hours. The precipitate was filtered off with suction and the filtrate was concentrated. The residue was dissolved in methylene chloride, insoluble matter was filtered off and the filtrate was chromatographed on silica gel using methylene chloride/ethyl acetate (9:1). 2.56 g (71%) of 10.3 were obtained.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8]([C:27](=[O:34])[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:7]=1)([OH:3])=[O:2].[BH4-].[Na+].C(O)(=O)C.ClCCl>O1CCOCC1.O>[C:1]([CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[CH:10][CH:9]=[C:8]([CH:27]([OH:34])[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:7]=1)([OH:3])=[O:2]
Reactant: COc1ccc(/C=C/CCCCOc2ccc(C(=O)CCCC(=O)O)nc2CCC(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(/C=C/CCCCOc2ccc(C(O)CCCC(=O)O)nc2CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of 20 mg of 5-{2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-pyridyl}-5-oxopentanoic acid in 0.9 ml of dioxane and 0.1 ml of water is mixed with 6.5 mg of sodium borohydride and stirred for 2 hours at room temperature. The reaction mixture is mixed with ice water, acidified with glacial acetic acid, shaken out with dichloromethane, the organic phase is dried on sodium sulfate and concentrated by evaporation. The crude product is dissolved in 0.6 ml of methanol, 0.3 ml of 2n sodium hydroxide solution is added, and the mixture is stirred for 48 hours at room temperature. The reaction mixture is concentrated by evaporation, acidified to pH 3 with 2n sulfuric acid, shaken out with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. 15 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.C(Cl)Cl>[C:10]1([S:16]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Reaction time: 4 h
Yield: 89 %

Procedure:
1-(phenylsulphonyl)indole is prepared according to the procedures described in S. Roy, G. W. Gribble Tetrahedron Lett. 2005, 46, 1325-1328, by reaction of indole with phenylsulphonyl chloride (PhSO2C1) in a basic medium (NaOH) in the presence of a catalytic quantity of (n-Bu)4NHSO4 in CH2Cl2 at 0° C. for 1 hour then at ambient temperature for 4 hours (yield: 89%).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2Br)[CH2:3]1.[F:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(Cl)Cl.CCCCCC>[NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2[C:34]2[CH:33]=[N:32][CH:31]=[C:30]([F:29])[CH:35]=2)[CH2:3]1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2Br)C[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Solvent: ClCCl
Product: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncc(F)c2)C[C@@H]1O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
4-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide (Stage 245.1, 60 mg, 0.122 mmol), 3-fluoropyridine-5-boronic acid pinacol ester and Na2CO3 (0.183 mL, 0.366 mmol) were added to a vial containing DME (1 mL) under an argon atmosphere. PdCl2(dppf)-(CH2Cl2) (5.98 mg, 7.33 μmol) was added and the RM was stirred at 80° C. for 1.5 h. The RM was filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, DCM/MeOH, from 98:2 to 8:2). Fractions containing product were combined and the solvent was evaporated off under reduced pressure to give a residue which was suspended in DCM/n-hexane, filtered, washed with n-hexane and were purified by preparative HPLC (Condition 14). Fractions containing pure product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure. The aq. residue was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a residue which was suspended in DCM/n-hexane 1:5 and filtered to afford the title product as a white solid. HPLC (Condition 10) tR=6.01 min, UPLC-MS (Condition 3) tR=0.84 min, m/z=493.1/495.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.61 (br. s, 2H) 2.63-2.74 (m, 2H) 3.12 (br. s, 1H) 3.22-3.31 (m, 2H) 3.74 (br. s, 1H) 4.98 (d, J=3.52 Hz, 1H) 6.93 (d, J=8.60 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.78 (d, J=9.77 Hz, 1H) 7.86 (m, J=9.00 Hz, 3H) 7.92 (dd, J=8.80, 2.15 Hz, 1H) 8.50 (s, 1H) 8.56 (d, J=2.74 Hz, 1H) 10.10 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4](NS(C1C=CC=CC=1)(=O)=O)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].F[P-](F)(F)(F)(F)F.[N:29]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.CC#N>C(OCC)(=O)C>[C:8]([O:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][NH2:29])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCNN

Procedure:
A solution of acid 2-7 (380 mg, 1.19 mmole), amine 1-4 (362 mg, 1.19 mmole), BOP (789 mg, 1.79 mmole), NMM (521 μl, 4.76 mmole) and CH3CN (6 ml) was stirred at ambient temperature for 20 h. The reaction was diluted with ethyl acetate and then washed with H2O, sat. NaHCO3, 10% KHSO4, brine, dried (MgSO4) and concentrated. Flash chromotography (silica, EtOAc) gave the ester 2-8 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cccc2ccccc12
Product: O=C(Nc1cccc2ccccc12)c1cc(Cl)ccc1O
Yield: 66 %

Procedure:
Using 5-chlorosalicylic acid and 1-naphthylamine as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=O)=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH3:42][N:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH2:48][S:49][C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=1>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:54][C:53]4[CH:55]=[CH:56][C:50]([S:49][CH2:48][C:44]5[N:43]([CH3:42])[CH:47]=[CH:46][N:45]=5)=[CH:51][CH:52]=4)=[O:31])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Reactant: Cn1ccnc1CSc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4C)cc2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml): was added one droplet of DMF. Then, thionyl chloride (0.15 ml) was added to the mixture at 0° C., and the mixture was allowed to be at room temperature and stirred for 1 hour under nitrogen atmosphere. This solution was added to a solution of 4-[[(1-methylimidazol-2-yl)methyl]sulfanyl]aniline (456 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15 ml) at 0° C. The mixture was stirred overnight at room temperature under nitrogen atmosphere, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (576 mg) (Compound 322) as yellow amorphous.
Reaction SMILES: C([O:8][CH2:9][CH:10]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[Si:20]([O:19][CH:10]([CH2:9][OH:8])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CC(COCc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(CO)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl 4-(benzyloxy)-3-(tert-butyldimethylsilyloxy) butanoate XXXVI (3.1 g, 8.15 mmol) in EtOAc (200 mL) under a nitrogen atmosphere was added 10% palladium on carbon (600 mg). The reaction flask was evacuated and then charged with a balloon of hydrogen. The reaction mixture was then stirred at room temperature for 16 h before being filtered through Celite. The filtrate was then concentrated under reduced pressure. Purification of the crude product by column chromatography (100% DCM→50% EtOAc/DCM) afforded tert-butyl 3-(tert-butyldimethylsilyloxy)-4-hydroxybutanoate XXXVII (2.1 g, 7.22 mmol, 88.7% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.CC(OC)(C)C.Cl[Pd]Cl>[ClH:1].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
Methyl 2-chloroisonicotinate (4.5 g, 26.23 mmol), 4-fluorophenylboronic acid (4.51 g, 32.26 mmol), potassium carbonate (2.247 g, 16.26 mmol) and PdCl2 (dppf) (0.380 g, 0.52 mmol) were mixed in methanol (30 mL) in two 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The solids were removed by filtration and the filtrate evaporated to yield a dark red slurry. To the residue was added HCl (1.25 M in methanol, 100 mL). The mixture was stirred at 45° C. for 4 h, then concentrated. Satd NaHCO3 (100 mL) was added under ice cooling and extracted with DCM (3×100 mL) The combined organic phases were washed with brine, passed through a phase separator and evaporated to yield a brown solid. The crude was dissolved in MTBE (180 mL) and some solids were filtered off. Cooled with ice-water, hydrogen chloride (4 M in dioxane, 10 mL, 40 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at 0° C. for 10 min. The solid was collected by filtration and washed with MTBE to yield methyl 2-(4-fluorophenyl)isonicotinate hydrochloride (6.4 g, 91%) as a beige solid. 1H NMR (400 MHz, cd3od) d 4.07 (s, 3H), 7.37-7.51 (m, 2H), 8.02-8.13 (m, 2H), 8.37 (dd, 1H), 8.71 (d, 1H), 8.97 (dd, 1H). MS m/z 232 (M+H)+
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][C:13]=3[N:14]=2)[CH:7]=[CH:6][C:5]=1[OH:19])[CH2:2][CH3:3].Br[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:28]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:4]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][C:13]=3[N:14]=2)[CH:7]=[CH:6][C:5]=1[O:19][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:28]2)[CH2:2][CH3:3]
Reactant: COC(=O)Cn1ccc2cc(OCCCBr)ccc21
Reactant: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67.1 %

Procedure:
2-Propyl-4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenol (Example 36, 0.75 g, 2.76 mmol) was combined with [5-(3-bromo-propoxy)-indol-1-yl]-acetic acid methyl ester (Example 47, 0.75 g, 2.30 mmol) in 12 mL DMF (containing 1 v/v % of water). To this mixture was added Cs2CO3 (1.50 g, 4.60 mmol), and the resulting mixture was allowed to stir at rt for 14 h. At this time, the reaction mixture was diluted with EtOAc (50 mL) and then washed three times with water (75 mL total). The water layers were extracted with EtOAc (25 mL) and the combined organic extracts were dried over MgSO4, filtered, and then concentrated under reduced pressure. Purification via flash silica gel chromatography (1:1 hexane/EtOAc) gave the title compound (800 mg, 64%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.75-7.70 (m, 2H), 7.18-7.10 (m, 2H), 7.05 (d, 1H), 6.92-6.85 (m, 2H), 6.48 (d, 1H), 4.84 (s, 2H), 4.30-4.20 (m, 4H), 3.75 (s, 3H), 2.90-2.75 (m, 4H) 2.70-2.60 (m, 2H), 2.40-2.30 (m, 2H), 1.95-1.85 (m, 4H), 1.70-1.58 (m, 2H), 0.95 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[C:4]([C:3]=1[CH3:12])=[N+:9]([O-:11])[O:10][N:6]=2
Reactant: Cc1c(Br)ccc(N)c1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(Br)ccc2no[n+]([O-])c12
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
4-bromo-3-methyl-2-nitroaniline (8.2 g, 36 mmol) was stirred in 150 mL ethanol, treated with potassium hydroxide solution (4.4 g, 45 wt. %, 36 mmol) to produce an orange solution. After cooling to 0-5° C., this solution was treated dropwise with commercial bleach solution (100 g, 5 wt. %, 67 mmol) over 30 min to produce a tan slurry. The cooling bath was removed and the mixture was stirred for 30 min more, treated with 600 mL water and the solid product was collected by filtration and washed well with water. The wet solid was taken up in 350 mL ethyl acetate and 150 mL water and filtered to remove a small amount of orange solids. The organic phase was washed with 75 mL saturated NaCl, dried (Na2SO4) and evaporated to give the title compound which was carried on to the deoxygenation step without further purification (7 g, 85%): EIMS m/z 228.
Reaction SMILES: [CH:1](/[S:9](Cl)(=[O:11])=[O:10])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[CH:1](/[S:9]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=1)(=[O:11])=[O:10])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: Nc1ccc(F)cc1
Product: O=S(=O)(/C=C/c1ccccc1)Nc1ccc(F)cc1
Yield: 58.7 %

Procedure:
A solution of (E)-styrylsulfonyl chloride (10 mmol) and 4-fluoroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 83-85° C., was obtained 58.7% yield.