Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N+:3]=1[O-].C1(C)C=CC(S([Cl:22])(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:22][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc(C)[n+]([O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCl)nc1

Procedure:
Methyl 6-methylnicotinate 1-oxide (from Step 1) (6.0 g, 35.9 mmol) was added into the p-toluenesulfonyl chloride (10 g, 52.4 mmol) in 100 mL of 1,4-dioxane. The mixture was heated to reflux for 20 hours. Saturated sodium bicarbonate solution (200 ml) was added into the reaction and the mixture was transferred to separatory funnel. The compound was extracted using ethyl acetate (300 ml×2) and the combined ethyl acetate solution was dried over magnesium sulfate and evaporated to black solid (5.2 g, 78%). LC/MS, tr=1.52 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 186 (M+H). ES-HRMS m/z 186.0314 (M+H calcd for C8H9ClNO2 requires 186.0316).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C:17]1[N:25]=[C:24]2[C:20]([N:21]=[CH:22][N:23]2[C@H:26]2[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([CH2:33][O:34][CH3:35])[O:27]2)=[C:19]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:18]=1.C(O)(=O)C.[C:49]1(=O)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>>[CH:49]1([NH:15][CH2:16][C:17]2[N:25]=[C:24]3[C:20]([N:21]=[CH:22][N:23]3[C@H:26]3[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([CH2:33][O:34][CH3:35])[O:27]3)=[C:19]([NH:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:18]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: O=C1CCCCC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CNC4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
Sodium triacetoxyborohydride (154 mg, 0.72 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-[2-(aminomethyl)-6-(phenethylamino)-9H-purin-9-yl]-5-(methoxymethyl)tetrahydro-3,4-furandiol (200 mg, 0.48 mmol) (preparation 48), acetic acid (30 mg, 0.48 mmol) and cyclohexanone (45 mg, 0.46 mmol). The reaction mixture was stirred for 24 hr at room temperature and the solvent then removed under reduced pressure. The residue was then azeotroped with dichloromethane before purification by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (93:7:0.3) to give the title compound (110 mg) as a viscous oil. MS: 497 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].C(N)(=[S:13])C>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4](=[S:13])[NH2:5]
Reactant: CC(N)=S
Reactant: N#Cc1cc(F)ccc1F
Solvent: CN(C)C=O
Product: NC(=S)c1cc(F)ccc1F
Temperature: 100 °C
Reaction time: 48 h
Yield: 86.7 %

Procedure:
10 g (71.9 mmol) of 2,5-difluorobenzonitrile and 16.2 g (215.7 mmol; 3 equivalents) of thioacetamide are dissolved in 80 ml of dimethylformamide containing 10% hydrochloric acid. The reaction mixture is maintained under stirring at 100° C. for 48 hours. After returning to ambient temperature, the reaction mixture is poured onto ice and insoluble material is filtered out. The mother liquors are extracted with 3 times 80 ml of ethyl acetate and the organic phases are washed with twice 50 ml of water. The organic phases are combined, dried over sodium sulphate and the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane mixture 1:2) and 10.8 g (yield=87%) of 2,5-difluorobenzenecarbothioamide is obtained.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([C:15]2[C:24]([CH3:25])=[CH:23][C:18]([CH2:19][N:20]=[N+:21]=[N-:22])=[CH:17][C:16]=2[CH3:26])=[O:14])=[CH:11][CH:10]=1.C(O)(=O)C>C(O)C>[NH2:3][C:2]1[N:20]([CH2:19][C:18]2[CH:17]=[C:16]([CH3:26])[C:15]([C:13](=[O:14])[C:12]3[CH:27]=[CH:28][C:9]([Cl:8])=[CH:10][CH:11]=3)=[C:24]([CH3:25])[CH:23]=2)[N:21]=[N:22][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: N#CCC(N)=O
Reactant: Cc1cc(CN=[N+]=[N-])cc(C)c1C(=O)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(Cn2nnc(C(N)=O)c2N)cc(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.8 %

Procedure:
A stirred, 60° solution of sodium (105 mg, 4.55 mmol) in absolute ethanol (11.4 ml) was treated in one portion with 2-cyanoacetamide (382 mg, 4.55 mmol), kept 5 minutes, and treated in one portion with a solution of 4-(4-chlorobenzoyl)-3,5-dimethylbenzyl azide (1.05 g, 3.50 mmol) in absolute ethanol (4 ml). The mixture was refluxed 1 hour, cooled to ambient temperature, acidified with glacial acetic acid (577 μl, 605 mg, 9.10 mmol), and evaporated almost to dryness under vacuum. The residue was refluxed briefly with methanol (7 ml), cooled to ambient temperature, and filtered. The solid product was washed four times with small volumes of methanol, washed three times with water, and dried under vacuum at 40° C. to provide 870 mg (65%) 5-amino-1-(4-[4-chlorobenzoyl]-3,5-dimethylbenzyl)-1,2,3-triazole-4-carboxamide, m.p. 208°-209° C.
Reaction SMILES: [NH4+].[Br-].[C:3]1([NH2:10])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>CO>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:10]=[C:11]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ccccc1N
Agent: [Br-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(Cn2c(-c3ccc(OC)cc3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 38 %

Procedure:
In a methanol (5 mL) solvent in the presence of NH4Br (362.3 mg, 3.70 mmol), a solution including 1,2-phenylenediamine (100 mg, 0.92 mmol) and p-anisaldehyde (0.11 mL, 0.82 mmol) was stirred at room temperature for 6 hours, and methanol was evaporated therefrom. The residual was distributed between ethyl acetate and water. An organic layer was dried by using MgSO4, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (3:1) to obtain a solid Compound 116.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>C1COCC1>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH:22][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CN(C)CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
To a stirred solution of commercially available 5-bromo-thiophene-2-sulfonyl chloride (3.0 g, 11.5 mmol) in THF (22 ml) was added at room temperature triethylamine (1.76 ml, 12.6 mmol), the mixture was cooled (ice-water) and a solution of commercially available N,N-dimethyl-ethylenediamine (3.76 ml, 34.4 mmol) in THF (22 ml) was added drop wise. The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by column chromatography (dichloromethane/methanol/NH4OH 16:1:0.1) to yield the title compound (3.49 g, 97%) as a light yellow oil. MS (ISN) 310.9 [(M−H)−].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]2)[CH2:20][CH2:19]1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([Cl:47])[C:33]=1[OH:48]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]4)[CH2:20][CH2:19]2)=[CH:3][C:2]([C:36]2[CH:37]=[C:32]([Cl:31])[C:33]([OH:48])=[C:34]([Cl:47])[CH:35]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCC(O)C2)CC1)C1CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCC(O)C2)CC1)C1CC1

Procedure:
Following general procedure M, (6-bromo-4-((trans-4-((3-hydroxypyrrolidin-1-yl)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclo propyl)methanone (47 mg, 0.10 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) to afford the desired product (34 mg, 61%) as an off-white solid. 1H NMR (500 MHz, MeOD) δ 9.13 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 7.98 (dd, J=8.7, 2.0 Hz, 1H), 7.92-7.87 (m, 1H), 7.63 (s, 2H), 4.59-4.54 (m, 1H), 4.53-4.47 (m, 1H), 4.17-4.11 (m, 1H), 3.16-3.10 (m, 2H), 2.94 (d, J=7.0 Hz, 2H), 2.88-2.79 (m, 1H), 2.33 (d, J=12.9 Hz, 2H), 2.28-2.17 (m, 1H), 2.06-1.96 (m, 3H), 1.84 (br s, 1H), 1.59 (q, J=12.2 Hz, 2H), 1.31-1.06 (m, 6H). ESI MS m/z 554 [C30H33Cl2N3O3+H]+; HPLC>99% (AUC), tR=11.11 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH:21][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(CN)N2CCOCC2)cc1
Reactant: Cc1ccccc1C(=O)O
Product: COc1ccc(C(CNC(=O)c2ccccc2C)N2CCOCC2)cc1

Procedure:
From 2-methylbenzoic acid and 2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH3:24][O:25][CH:26]([O:30][CH3:31])[CH2:27][NH:28][CH3:29]>ClCCl>[CH3:24][O:25][CH:26]([O:30][CH3:31])[CH2:27][N:28]([CH3:29])[C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[S:3]
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Reactant: CNCC(OC)OC
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(NC(=S)N(C)CC(OC)OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 15 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 6.5 parts of 2,2-dimethoxy-N-methyl-ethanamine and 195 parts of dichloromethane was stirred for 1 hour at room temperature. The reaction mixture was evaporated and the residue was triturated in 4-methyl-2-pentanone. The product was filtered off and dried, yielding 19.4 parts (95%) of N-(2,2-dimethoxyethyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-N-methylthiourea; mp. 155.0° C. (40).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CCO>[Cl:10][C:4]1[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: C1CCNC1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Solvent: CCO
Product: N#Cc1cc(Cl)nc(N2CCCC2)c1
Temperature: 70 °C
Yield: 85.1 %

Procedure:
A solution of 2,6-dichloropyridine-4-carbonitrile 24 (4 g, 23.5 mmol) in abs. EtOH (10 mL) was added with pyrrolidine (1.15 mL, 1 mol eq) and the mixture was heated at 70° C. for 6 h. The solvent was removed under reduced pressure, water was added to the residue and the aqueous phase was extracted with EtOAc (3×40 mL). The combined organic phase was washed with brine (1×60 mL), dried over Na2SO4 and evaporated to afford 25A as a pale yellow deliquescent solid (4.2 g, 20 mmol, 87% Yield). 1HNMR (DMSO, 400 MHz) δ 2.00 (m, 4H), 3.42 (m, 4H), 6.39 (s, 1H), 6.61 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH2:27]([OH:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:33][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:7]=1
Reactant: CCCCCCO
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CCCCCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and hexan-1-ol (100 μl; 0.781 mmol), example 46 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [C:1]([O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([O:4][C:5]1[C:12]([O:13][CH3:14])=[C:11]([N+:20]([O-:22])=[O:21])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(C=O)c1OC(C)=O
Agent: O=S(=O)(O)O
Product: COc1c([N+](=O)[O-])ccc(C=O)c1OC(C)=O
Temperature: -15 °C
Reaction time: 0.67 h

Procedure:
42 (42.0 g, 0.22 mol) was added portionwise as a finely ground powder over 1 h to a solution of concentrated sulphuric acid (28 mL) in 100% nitric acid (140 mL) at −20° C. During the addition, the reaction temperature was maintained at around −15° C. The reaction mixture was stirred at −5° C. for a further 40 min, then poured into to ice/water (1 L) and extracted rapidly with toluene (2×). The organic phase was washed successively with 0.25 M NaHCO3 aq. water and brine, dried (Na2SO4) and evaporated to dryness to give crude product (19.8 g) as a yellow oil, which was shown by NMR to contain ˜60% nitro-compounds. Purification of 8 g of this material by column chromatography (three times, SiO2, first eluting with 1:9 EtOAc:cyclohexane, then with 3:7 EtOAc:cyclohexane and finally with 1:1 EtOAc:cyclohexane) gave 43 (2.53 g) in (˜80% purity) together with 2-hydroxy-3-methoxy-4-nitrobenzaldehyde (˜10%). The product was used as such in the next step.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([C:28]3[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=3)=[N:25][CH:24]=2)=[CH:19][CH:18]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:36]([O:40][C:41]([NH:43][CH:44](P(OC)(OC)=O)[C:45]([O:47][CH3:48])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>C1COCC1.C(Cl)Cl>[C:36]([O:40][C:41]([NH:43][C:44](=[CH:32][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[S:27][C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=3)=[CH:24][N:25]=2)=[CH:35][CH:34]=1)[C:45]([O:47][CH3:48])=[O:46])=[O:42])([CH3:37])([CH3:38])[CH3:39]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C=O)cc3)s2)cc1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C=C(NC(=O)OC(C)(C)C)C(=O)OC)cc3)s2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A stirring mixture of 1,1,3,3-tetramethylguanidine (86 μl, 0.69 mmol) was added to a suspension of 4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde (260 mg, 0.685 mmol) and methyl 2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate (185 mg, 0.62 mmol) in anhydrous THF (10 mL) under nitrogen, at −70° C. The reaction mixture was stirred at −70° C. for 1 h then at RT for 18 h. The reaction mixture was diluted with DCM (50 mL), washed with water (50 mL), passed through a phase separation cartridge and the organic phase concentrated in vacuo to afford a yellow solid. The solid was triturated with EA/EtOH (20 mL) and the collected solid washed with EtOH (10 mL) and Et2O to afford 284 mg (79%) of methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)acrylate as a yellow solid. LCMS-ESI (m/z) calculated for C31H38N2O5S: 550.7. found 551.0 [M+H]+, tR=3.11 min. (Method 8).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([CH:9]=[O:10])[CH2:5][CH2:4]1.Cl>C(OCC)(=O)C>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]([C:6]3([CH:9]=[O:10])[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]3)[CH:16]=[CH:15][C:14]=2[O:17][CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccc(C2(C=O)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C2(C=O)CCC(=O)CC2)cc1OC1CCCC1
Yield: 112.9 %

Procedure:
4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one dimethyl ketal (0.1 g, 0.28 mmol) in ethyl acetate (2 mL) was treated with 3N hydrochloric acid (5 mL) and the mixture was stirred vigorously and gently heated for 10 min. The mixture was extracted twice with ethyl acetate, the combined organic extracts were washed with 5% aqueous sodium carbonate, dried (potassium carbonate) and the solvent was removed in vacuo. This material, combined with that obtained from an identical reaction, was purified by flash chromatography, eluting with 2% ethyl acetate/chloroform, to provide a white solid (0.1 g, 57%): m.p. 55°-57° C. Analysis Calc. for C19H24O4 : C 72.13, H 7.65; found: C 72.09, H 7.57.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:15]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[C:22]([NH:21][CH2:20][C:19]([N:16]1[CH2:17][CH2:18][CH:14]([N:11]2[CH2:10][CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:13][CH2:12]2)[CH2:15]1)=[O:32])=[O:31]
Reactant: Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.9 %

Procedure:
To N-(2-(3-(4-(2-aminophenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dichlorobenzamide (Example #4.149, 0.063 g, 0.13 mmol) in DCM (1 mL) was added triethylamine (0.037 mL, 0.26 mmol) and methanesulfonyl chloride (0.011 mL, 0.14 mmol). The reaction mixture was stirred at room temperature for about 16 h. The solvent was removed in vacuo and the residue was purified by RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5 for 3 min., 5% to 60% acetonitrile/0.05M aqueous ammonium acetate over 6 min at 22.5 mL/min with 2.5 mL/min. acetonitrile at-column dilution; APCI positive mode detection; Xterra prep. MS C18. 19×50 mm column) to afford 3,4-dichloro-N-(2-(3-(4-(2-(methylsulfonamido)phenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)benzamide (0.0052 g, 0.009 mmol). RP-HPLC (Table 1, Method a) Rt 2.07 min; m/z: (M+H)+ 553.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C@@H:19]3[C@@H:14]([C:15]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[C:16]=4[CH2:17][CH2:18]3)[CH2:13][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>Br>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C@@H:19]3[C@@H:14]([C:15]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:16]=4[CH2:17][CH2:18]3)[CH2:13][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCC1CCCCC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCC1CCCCC1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
5.0 g (0.0146 mol) of rac-cis-3-(4-cyclohexyl-butyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole were dissolved in 0.171 of 48% aqueous HBr and boiled under reflux for 5 hours. The mixture was poured onto ~200 g of ice and treated with 200 ml of 28% aqueous NaOH solution. The mixture was extracted three times with ethyl acetate, whereupon the organic phase was washed with saturated sodium chloride solution, dried with MgSO4, filtered and concentrated. By chromatography of the residue over silica gel with n-hexane/ethyl acetate 1:1 there were obtained 4.3 g (90%) of oily rac-cis-3-(4-cyclohexyl-butyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([O:18][CH2:19][CH2:20][NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:15]=[N:16][CH:17]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:27].[H-].[Na+].[CH3:30]I>CN(C=O)C>[CH3:30][N:21]([CH2:20][CH2:19][O:18][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:27])[CH2:4][CH2:5]3)[CH:13]=1)[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23]
Reactant: CI
Reactant: CCS(=O)(=O)NCCOc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)CCOc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
To a solution of ethanesulfonic acid {2-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-yloxy]-ethyl}-amide (example 151, 0.06 g, 0.154 mmol) in DMF (1.5 mL) cooled at 0° C. with an ice bath was added 60% NaH in mineral oil (0.008 g, 0.2 mmol) and the reaction mixture was stirred for 15 min. Then, MeI (0.026 g, 0.185 mmol) was added and the reaction mixture was stirred at 0° C. for another 30 min. The mixture was quenched with aq. ammonia (1 mL), diluted with brine (5 mL) and then extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.050 g, 80%) as a light yellow amorphous solid. MS: 404.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=3[C:11]=2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[CH2:28]([N:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33]Cl)[CH3:29]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=3[C:11]=2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:33][CH2:32][CH2:31][N:30]([CH2:35][CH3:36])[CH2:28][CH3:29])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCCl
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(Cc2ccc(Cl)cc2)oc2ccccc12
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(Cc3ccc(Cl)cc3)oc3ccccc23)cc1

Procedure:
Reaction of 2-(4-chlorobenzyl)-3-(4-hydroxyphenylsulfonyl)benzofuran with 3-diethylaminopropyl chloride by procedures described hereinabove gives the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH:18]=3)=[CH:9][CH:8]=2)[CH:2]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:39][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[CH:18]=3)=[CH:11][CH:12]=2)[CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4cccnc4)cc3)c2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4ccc[n+]([O-])c4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a solution of (E)-N-[4-(3-pyridyl)phenyl]-3-(4-methylphenyl)cinnamamide (250 mg) in tetrahydrofuran (20 ml) was added 3-chloroperbenzoic acid (70%, 0.24 g) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was recrystallized from ethanol-tetrahydrofuran-acetone to give (E)-N-[4-(1-oxidopyridin-3-yl)phenyl]-3-(4-methylphenyl)cinnamamide (Compound 193) (208 mg) as pale yellow crystals. 1H-NMR (200 MHz, DMSO-d6) δ 2.38 (3H, s), 6.95 (1H, d, J=15.7 Hz), 7.31 (2H, d, J=8.1 Hz), 7.45-7.57 (2H, m), 7.59-7.94 (12H, m), 8.19 (1H, d, J=6.5 Hz), 8.58 (1H, s). IR (KBr) 3423, 1672, 1597, 1531, 1477, 1340, 1201, 901, 835, 793 cm-1 ;