Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C=P(CCCC)(CCCC)CCCC)#N.[C:17]([O:21][C:22]([N:24]1[C@H:29]([CH2:30]O)[CH2:28][O:27][C@H:26]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[NH:40][C:41](=[O:61])[C@@H:42]([NH:56][C:57]([O:59][CH3:60])=[O:58])[CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].[C:62]1([SH:68])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C1(C)C=CC=CC=1>[CH3:60][O:59][C:57]([NH:56][C@H:42]([C:41]([NH:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][CH2:32][C@H:26]1[O:27][CH2:28][C@@H:29]([CH2:30][S:68][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:23])[CH2:25]1)=[O:61])[CH:43]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:58]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccccc1)c1ccccc1
Reactant: Sc1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CSc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Cyanomethylenetributylphosphorane (2 eq) was added to a stirred mixture of (2R,5R)-5-hydroxymethyl-2-{2-[2-((S)-2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-phenyl]-ethyl}-morpholine-4-carboxylic acid tert-butyl ester (1 eq) and thiophenol (1.5 eq) in toluene (0.04 M). The mixture was stirred at 90° C. for 2 h, cooled to room temperature and evaporated to dryness. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 0% to 100% of EtOAc/Hex to afford tert-butyl (2R,5S)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]-5-[(phenylsulfanyl)methyl]morpholine-4-carboxylate which was then treated with TFA following the procedure described in step 2 of Example 2 to afford the title compound.
Reaction SMILES: CC1C=CC([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=CC=1C1C=CC(C(O)=O)=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:16]1([C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:9]([NH2:8])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccnc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 251 %

Procedure:
2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol), DIPEA (52 μl), and 1-(3-aminomethyl)-4-methylpiperazine (19 mg, 0.12 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 18 h. The solvent was evaporated under vacuum and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate (1M, 5 ml). The organic phase was applied to a silica gel flash column and eluted with toluene/methanol (8:2, 7:3, 6:4), which after evaporation of the solvents under vacuum gave N-(6-methyl-4′-{[3-(4-methylpiperazin-1-yl)propylamino]carbonyl)}-1,1′-biphenyl-3-yl)-2-pyrrolidin-1-ylisonicotinamide (48 mg, 89%). NMR; δH [2H6]-DMSO 10.51,(1H, s), 8.68,(1H, t), 8.17,(1H, d), 7.93,(2H, d), 7.76,(1H, dd), 7.72,(1H, d), 7.42,(2H, d), 7.28,(1H, d), 7.00,(1H, d), 6.95,(1H, d), 3.43,(4H, m), 3.29,(2H, q), 2.49–2.32,(10H, m), 2.21–2.19,(6H, m), 1.94,(4H, m), 1.70,(2H, m). LCMS: retention time 2.13 min, MH+541.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:37]([F:38])=[CH:36][C:26]([C:27]([NH:29][C@@H:30]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31]2)=[O:28])=[C:25]([F:39])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:37]([F:38])=[CH:36][C:26]([C:27]([NH:29][C@@H:30]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31]5)=[O:28])=[C:25]([F:39])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1CC[C@@H](NC(=O)c2cc(F)c(N)cc2F)C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1CC[C@@H](NC(=O)c2cc(F)c(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)cc2F)C1
Temperature: 100 °C
Yield: 55.8 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 109 mg, 0.36 mmol), aniline (Intermediate 229; 83 mg, 0.324 mmol), and caesium carbonate (211 mg, 0.648 mmol) added to dioxane (3 mL) and the suspension bubbled with nitrogen for 10 minutes. Tris-dibenzylideneacetone dipalladium (II) (11 mg, 0.02 mmol) and XANTPHOS (17 mg, 0.03 mmol) were added and the mixture heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature filtered, and the filter cake washed with DCM and the filtrate evaporated. The residue was dissolved in DCM and purified on a silica column eluting with a gradient of 0-5% 2M ammonia in MeOH/DCM over 30 column volumes. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (95 mg, 56%).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[C:10](=[O:14])[CH:11]=[CH:12][CH3:13].C(N([CH:21]([CH3:23])[CH3:22])C(C)C)C.Cl.[CH3:25][O:26][C:27](=[O:32])[C@H:28]([CH2:30][SH:31])[NH2:29]>CO>[O:14]=[C:10]([CH:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH:6]=[CH:7][CH:2]1[CH3:1])[CH2:11][CH:12]([NH:29][CH:28]([CH2:30][S:31][CH:12]([CH2:11][C:10](=[O:14])[CH:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH:6]=[CH:23][CH:21]1[CH3:22])[CH3:13])[C:27]([O:26][CH3:25])=[O:32])[CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC=CC(=O)C1C(C)C=CCC1(C)C
Reactant: COC(=O)[C@@H](N)CS
Agent: Cl
Solvent: CO
Product: COC(=O)C(CSC(C)CC(=O)C1C(C)C=CCC1(C)C)NC(C)CC(=O)C1C(C)C=CCC1(C)C
Yield: 82 %

Procedure:
A solution of 1-(2,6,6-trimethylcyclohex-3-enyl)but-2-en-1-one (19.28 g, 100 mmol, 2 equiv.), ethyl diisopropylamine (6.45 g, 50 mmol, 1 equiv.) and L-Cystein methyl ester hydrochloride (8.60 g, 50 mmol, 1 equiv.) in MeOH (120 ml) is heated to reflux during 28 h. The solvent is removed in vacuo and the residue dissolved in methyl t-butyl ether. The solution is washed with dilute aq. NaCl, dried over MgSO4 and concentrated. The residue is purified by chromatography on SiO2 to yield 21.3 g (82%) of the title compound as yellowish, viscous oil.
Reaction SMILES: O=S(Cl)[Cl:3].O[CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[Cl:3][CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cccc(CO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1cccc(CCl)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
SOCl2 (57 g, 0.48 mol) was added to a solution of methyl 6-(hydroxymethyl)picolinate 66 (40.0 g, 0.239 mol) (Chem. Eur. J. 2006, 12, 6393-6402) in dichloromethane (500 mL) at room temperature. The mixture was stirred at 40° C. for 1 h and sat. aq K2CO3 was added to adjust the pH to 9. The mixture was extracted with CH2Cl2 and the combined organics were washed with brine, dried (Na2SO4), and concentrated in vacuo to give 67 (45 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:30]([OH:32])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[C:24](=[O:29])[CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][C@H:44]([CH3:46])[CH2:43][C@H:42]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:41]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>CN(C=O)C>[C:50]([O:49][C:48]([NH:47][C@H:42]1[CH2:43][C@@H:44]([CH3:46])[CH2:45][N:40]([C:39]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[NH:33][C:30]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24](=[O:29])[CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:32])[CH2:41]1)=[O:54])([CH3:51])([CH3:52])[CH3:53]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Reactant: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(4-methyl-3-oxopiperazin-1-yl)quinoline-2-carboxylic acid (0.012 g, 0.028 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.013 g, 0.043 mmol) and HATU (0.034 g, 0.089 mmol) in DMF (0.30 mL), DIPEA (0.019 mL, 0.11 mmol) was added. The resulting mixture was stirred at room temperature for 2 h, then quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, then purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound as a yellow solid (0.005 g, 20%). LCMS calc. for C39H46N8O6 [M+H]+: m/z=723.4. found: 723.4.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1.C(O)C>O>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13](=[O:14])[CH2:12][C:11]([CH3:10])=[O:15]
Reactant: C=C1CC(=O)O1
Reactant: Cc1ccc(N)c(C)c1
Solvent: O
Solvent: CCO
Product: CC(=O)CC(=O)Nc1ccc(C)cc1C
Temperature: 85 °C
Yield: 95 %

Procedure:
2.48 kg/h (20.5 mol/h) of 2,4-dimethylaniline, 1.83 kg/h (21.3 mol/h) of diketene (purity 98%) and 8 kg/h of a mixture of 2.4 kg/h of ethanol and 5.6 kg/h of water are metered separately but simultaneously into a reactor which has been preheated to about 80° C. The reactor consists of a double-shell glass vessel of about 0.6 l capacity and is equipped with a stirrer, thermometer, reflux condenser and, at the bottom, with a run-off. Immediately the metering has started, the heat evolved by the reaction causes the reactor contents to reflux at about 85° C. The heating of the reactor is discontinued and the reaction is continued by limiting the reactor contents to about 0.3 1 by continuous pumping out. The reactor discharge is cooled to about 15° C. with stirring, and the light-colored crystals which are formed are separated from about 7 kg/h of the pale yellow mother liquor by filtration. The moist product, which is obtained at about 5 kg/h, is washed with about 4 kg/h of cold aqueous 30% strength ethanol and dried, leaving 4 kg/h (19.5 mol/h) of 2',4'-dimethylacetoacetanilide (melting point about 89° C.) corresponding to a yield of 95% based on amine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([CH:15]([NH2:18])[CH2:16][CH3:17])[CH3:14]>CS(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: CCC(N)CC
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.8 %

Procedure:
A mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine (250 mg, 1.21 mmol) and 1-ethyl-propyl amine (105 mg, 1.21 mmol) in DMSO (4 ml) was stirred at room temperature for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentratd to give 280 mg of yellow oil. The oil was purified through silical gel column chromatography using 65% chloroform in hexane as eluent to give 110 mg (35%) of the title compound as a yellow crystal, mp 82–84° C. 1H NMR (CDCl3) δ 6.57 (d, 1H), 6.46 (s, 1H), 3.39 (m, 1H), 2.42 (s, 3H), 1.4–1.8 (m, 4H), 0.94 (t, 6H) ppm
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C([O-])([O-])=O.[K+].[K+].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C=O)C>[CH2:2]([N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18])[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 87.9 %

Procedure:
To a stirring solution of 5-bromo-pentene (6.0 g, 0.040 mol) in DMF (30 mL) was added K2CO3 (4.7 g, 0.034 mol) and potassium phthalimide (6.21 g, 0.033 mmol) and the reaction mixture was heated at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The aqueous layer was then extracted with ethyl acetate (2×50 mL), and the combined organic layers were washed with 5% aq. NaHCO3 (2×20 mL), brine (30 mL) and dried over Na2SO4. Filtration and solvent evaporation gave an oil, which was purified by flash chromatography (silica gel/hexanes:ethyl acetate 0-35%) to yield the desired 2-(pent-4-enyl)-isoindoline-1,3-dione as a solid (6.36 g, 0.029 mmol, 72.5% yield): MS m/e calcd 216.1. found 216.1; NMR (250 MHz, DMSO-d6) δ 7.79-7.95 (m, 4H), 5.70-5.91 (m, 1H), 4.90-5.11 (m, 2H), 3.58 (t, 2H), 1.98-2.10 (m, 2H), 1.59-1.78 (m, 2H).
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:16][N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:19][C:18]2([CH3:30])[CH3:29])=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1(C)C=CC=CC=1>[C:38]([N:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:8]([O:16][N:17]1[C:18]([CH3:30])([CH3:29])[CH2:19][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:21][C:22]1([CH3:24])[CH3:23])=[N:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)NC2CCCCC2)C(C)(C)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)N(C(=O)c2ccccc2)C2CCCCC2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.6 %

Procedure:
To a solution of compound 1 (4.21 g, 10 mmol) [prepared according to Example 1] in toluene (25 ml) is added triethylamine (1.55 ml, 11 mmol) and benzoyl chloride (1.55 g, 11 mmol). The mixture is stirred at room temperature for 24 hours, then washed with water (2×10 ml), dried over MgSO4 and evaporated. The residue is chromatographed over silica gel with hexane-ethyl acetate (4:1) and the pure fractions are recristallized from acetonitrile to afford 0.98 g of the title compound as a white solid, mp. 147-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:16]=O)=[CH:4][CH:3]=1.[N:18]1([C:24]2[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH2:16][N:21]2[CH2:20][CH2:19][N:18]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=3)[CH2:23][CH2:22]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(C)(C)C3)CC2)cc1

Procedure:
reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde, ethyl 4-piperazin-1-ylbenzoate and sodium triacetoxyborohydride and isolating or not isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate;
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N+:7]([C:10]1[CH:11]=[C:12]([CH2:16][SH:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].CS(O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:25]=1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[N+:7]([C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][S:17][CH2:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:32])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH:27]=[CH:28][CH:29]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc(CS)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(CSCc2cccc([N+](=O)[O-])c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
A solution of cesium carbonate (0.57 g, 1.8 mmol) in N,N-dimethylformamide (1.8 mL) at 0° C. was treated with (3-nitrophenyl)methanethiol (0.22 mL, 1.6 mmol) dropwise and stirred at 0° C. for 10 min. The reaction mixture was treated with a solution of 3-[(tert-butoxycarbonyl)amino]benzyl methanesulfonate (0.41 g, 1.3 mmol) in N,N-dimethylformamide (2.4 mL) dropwise and stirred at 0° C. for 30 min. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (40 mL) and brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to a crude brown oil. This material was purified by flash column chromatography to give the desired product (0.42 g, 84% for 2 steps) as a yellow oil. LCMS for C19H22N2O4SNa (M+Na)+: m/z=396.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]1[N:14]=[CH:15][N:16]=[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:6]2=1.N1C=CC=CC=1.[Cl-].[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([CH2:40][NH:41][CH:42]=[S:43])=[CH:39][C:34]=2[O:33][CH2:32]1.CO>ClCCl>[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([CH2:40][NH:41][C:42]([N:21]3[CH2:20][CH2:19][N:18]([C:17]4[C:6]5[C:5]6[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=6)[NH:8][C:7]=5[N:14]=[CH:15][N:16]=4)[CH2:23][CH2:22]3)=[S:43])=[CH:39][C:34]=2[O:33][CH2:32]1
Reactant: S=CNCc1ccc2c(c1)OCO2
Reactant: COc1cc2[nH]c3ncnc(N4CCNCC4)c3c2cc1OC
Agent: [Cl-]
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2[nH]c3ncnc(N4CCN(C(=S)NCc5ccc6c(c5)OCO6)CC4)c3c2cc1OC
Reaction time: 8 h

Procedure:
To a solution of 6,7-dimethoxy-4-piperazino-9H-pyrimido[4,5-b]indole (200 mg, 0.64 mmol) and pyridine (0.5 mL, 6.4 mmol) in dichloromethane (20 mL) was added the solution of product 1c in dichloromethane (20 mL) and the mixture was stirred overnight. Methanol was added to quench excess thiophosgene, and the residue after removal of solvent was purified by silica gel column chromatography eluting with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 130 mg (40%).
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([CH3:13])[CH:8]=[CH:7][CH:6]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:4]=1>C(O)C.CCOC(C)=O.O>[CH3:1][NH:2][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:13])[CH:4]=1)(=[O:11])=[O:10]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNS(=O)(=O)c1cccc(C)c1
Temperature: 0 °C
Yield: 90 %

Procedure:
A RBF was charged with methylamine (0.9 mL, 40%, 28 mmol) in ethanol (2 mL). The mixture was chilled to 0° C. in an ice bath while stirred under an inert atmosphere. Then, m-toluenesulfonyl chloride (0.8 mL, 6 mmol) was added dropwise into the mixture. The resulting mixture was allowed to stir at 0° C. under an inert atmosphere for 30 minutes. The mixture was diluted with EtOAc and water and then the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give N,3-dimethylbenzenesulfonamide (1.0 g, 98% yield) as a colorless oil. MS (ESI pos. ion) m/z: 173 (MH+). Calculated exact mass for C7H10NO2S: 172.
Reaction SMILES: CI.[C:3](#N)C.[I:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:24])[NH:14][CH:15]([C:20]([NH:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[I:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:24])[NH:14][C:15]([CH3:3])([C:20]([NH:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=1
Reactant: CC#N
Reactant: CNC(=O)C(NC(=O)c1ccc(I)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)C(C)(NC(=O)c1ccc(I)cc1)C(=O)OC
Yield: 82 %

Procedure:
Methyl iodide (0.35 mL) was added to an acetonitrile (40 mL)-DMF (16 mL) suspension of 1-iodo-4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl]carbamoyl}benzene (1.5 g) as obtained in Example 15-(1) and potassium carbonate (0.81 g), and the mixture was stirred for 4 days at room temperature under closed conditions. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the desiccant was filtered out, whereafter the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=45/55→14/86) to obtain 1-iodo-4-{[1-methoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl]carbamoyl}benzene (colorless oil) (1.3 g, 82%).
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[CH:31][NH:32]3)=[CH:24][CH:23]=1.[OH2:37]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)=[CH:24][CH:23]=1
Reactant: O
Reactant: c1cc(-c2ccncc2)c2cc[nH]c2c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccncc2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Pyridinium tribromide (90% (Aldrich), 24.70 g, 69.50 mmol) was added portion-wise over 10 minutes to a suspension of 4-pyridin-4-yl-1H-indole (4.50 g, 23.17 mmol) in 2-methyl-2-propanol (135 mL), ethanol (90 mL) and acetic acid (45 mL). The mixture was stirred at room temperature for one hour and then acetic acid (180 mL) was added. After stirring for an additional hour, water (1 mL) and zinc dust (15.06 g, 232 mmol) were added and stirring was continued for another hour. Residual zinc dust was removed by filtration and washed with methanol. The filtrate was concentrated and the syrupy residue was stirred in water (500 mL) overnight. The solid that formed was filtered, washed with water to remove zinc and pyridine salts and dried under high vacuum dry to give 5.85 g (99%) of 4-pyridin-4-yl-1,3-dihydroindol-2-one as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:16])=[C:7]([Cl:15])[CH:8]2[S:12][C:11]([SH:13])=[N:10][CH:9]2[CH:14]=1)=[O:4].CI.[CH3:19]CN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:16])=[C:7]([Cl:15])[CH:8]2[S:12][C:11]([S:13][CH3:19])=[N:10][CH:9]2[CH:14]=1)=[O:4]
Reactant: COC(=O)C1=CC2N=C(S)SC2C(Cl)=C1N
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1=CC2N=C(SC)SC2C(Cl)=C1N

Procedure:
This compound is prepared as described in Acta. Chim. Slov. 2002, 49, 871 using the crude 6-amino-7-chloro-2-mercapto-3a,7a-dihydro-benzothiazole-5-carboxylic acid methyl ester as starting material. Methylation is performed with MeI and Et3N in DMF. The 6-amino-7-chloro-2-methylsulfanyl-3a,7a-dihydro-benzothiazole-5-carboxylic acid methyl ester is obtained, after column chromatography purification over silica gel, in 59% over 3 steps from 2,5-diamino-3-chloro-4-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester (step d in example H17); LC/MS: 289/291 (M+1)+.