Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[C:12]([CH:14]=[C:15]3[CH2:20][C@@H:19]([OH:21])[CH2:18][CH2:17][C@:16]3([CH3:22])[C@H:5]1[CH2:4][CH2:3]2)=[O:13].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:40]1[CH:45]=[CH:44][CH2:43][CH2:42][CH2:41]1>>[O:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]1[O:21][C@H:19]1[CH2:18][CH2:17][C@@:16]2([CH3:22])[C:15](=[CH:14][C:12](=[O:13])[C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:20]1
Reactant: C[C@]12CC[C@H](O)CC1=CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: C[C@]12CC[C@H](OC3CCCCO3)CC1=CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3β-hydroxyandrost-5-ene-7,17-dione (2) (0.5 g, 1.65 mmol) was placed in a dried, argon-flushed flask where it was dissolved in dry dichloromethane (20.0 mL). Pyridinium toluene-p-sulfonate (0.043 g. 0.17 mmol) was added followed by 3,4-dihydro-2H-pyran (0.23 mL, 2.5 mmol) and the solution was stirred at room temperature, under an atmosphere of argon, for 2-3 h. The reaction was quenched by adding water and the product was extracted thrice with ether (3×20 mL). The combined ether extracts were washed with dilute acetic acid, water and bicarbonate solution and dried (MgSO4). Solvent was removed and the crude product was purified using chromatography on silica gel (ethyl acetate-hexane, 15:85, v/v). The compound first eluted was identified as androsta-3,5-diene-7,17-dione (0.150 g), m.p. 167-8° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]3[C:11]([C:12]=2[CH2:13][C:14]([NH2:16])=[O:15])=[CH:10][C:9]([OH:17])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].[CH3:32][O:33][P:34]([CH2:38][CH2:39][CH2:40]Br)(=[O:37])[O:35][CH3:36]>C1COCC1.O.C(OCC)(=O)C>[CH3:32][O:33][P:34]([CH2:38][CH2:39][CH2:40][O:17][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:4]([CH:1]1[CH2:2][CH2:3]1)=[C:12]2[CH2:13][C:14]([NH2:16])=[O:15])(=[O:37])[O:35][CH3:36]
Reactant: COP(=O)(CCCBr)OC
Reactant: NC(=O)Cc1c(C2CC2)n(Cc2ccccc2)c2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COP(=O)(CCCOc1ccc2c(c1)c(CC(N)=O)c(C1CC1)n2Cc1ccccc1)OC
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
2-Cyclopropyl-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (295 mg. 0.9 mmol) was dissolved in 10 mL of THF and 40 mL of DMF and 45 mg (1.1 mmol) of 60% NaH/mineral oil added. After 0.17 hours, 250 mg (1.1 mmol) of (3-bromopropyl)phosphonic acid dimethyl ester was added and stirring maintained for 6.5 hours. The mixture was diluted with water and ethyl acetate, the organic layer separated, washed with water, brine and dried (Na2SO4). The solution was evaporated at reduced pressure and the residue chromatographed on silica gel eluting with a gradient, 1% MeOH/methylene chloride→5% MeOH/methylene chloride, to give 280 mg (71% yield) of [3-[[3-(2-amino-2-oxoethyl)-2-cyclopropyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[N:5][NH:4][C:3]1=[S:10].C[O-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[N:5][N:4]=[C:3]1[S:10][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: Cc1n[nH]c(=S)n(N)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nnc(SCc2ccccc2)n(N)c1=O
Temperature: 25 °C

Procedure:
6.5 Parts by weight of 4-amino-2,3-dihydro-6-methyl-3-thiono-as-triazin-5(4H)-one is added to a solution of 2.3 parts by weight of sodium methoxide in 50 parts by volume of methanol. After a few minutes 5.2 parts by weight of benzylchloride is added and the resulting mixture is stirred over night at room temperature. The solvent is removed under vacuum and the residue is washed with water to give 4.5 parts of 4-amino-3-benzylthio-6-methyl-as-triazin-5(4H)-one.
Reaction SMILES: [N+]([CH2:4][C:5](C)([OH:13])[CH2:6][CH2:7][CH:8]([N+:10]([O-:12])=[O:11])[CH3:9])([O-])=O>C1C=CC=CC=1>[N+:10]([CH:8]([CH3:9])[CH2:7][CH2:6][C:5](=[O:13])[CH3:4])([O-:12])=[O:11]
Reactant: CC(CCC(C)(O)C[N+](=O)[O-])[N+](=O)[O-]
Solvent: c1ccccc1
Product: CC(=O)CCC(C)[N+](=O)[O-]
Reaction time: 24 h
Yield: 45.3 %

Procedure:
To a solution of 0.91 gram of 1,5-dinitro-2-methyl-2-hexanol in 25 milliliters of benzene there was added 4.2 grams of alumina. The mixture was stirred for 24 hours, and the alumina was removed by filtration. After evaporation of the filtrate there was obtained 0.29 gram of 5-nitro-2-hexanone which was identified by infrared and proton magnetic resonance.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=1.[C:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(O)C.C(OCC)(=O)C>[CH3:17][C:14]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=2)=[CH:24][CH:25]=1)([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Reactant: CC(C)(C)c1ccc(CN)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)cnc1NCc1ccc(C(C)(C)C)cc1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A solution of ethyl 2-chloro-5-fluoro-3-pyridinecarboxylate (0.490 g, 2.41 mmol) in ethanol (10.0 mL) was treated with 4-tert-butylbenzylamine (0.450 mL, 2.55 mmol). The mixture was heated to 150° C. for 0.5 h and then to 160° C. for 20 min. in a Biotage Initiator microwave synthesizer. The solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organic portions were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (20-40% ethyl acetate in hexanes) afforded a mixture of the title compound and starting material as a clear yellow oil (0.326 g, 41%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.39 (d, J=3.0 Hz, 1H), 8.20 (d, J=3.3 Hz, 1H), 8.14 (t, J=5.1 Hz, 1H), 7.91 (dd, J=6.9, 3.2 Hz, 2H), 7.89 (dd, J=8.1, 3.0 Hz, 2H), 4.69 (d, J=5.3 Hz, 2H), 4.44 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.32 (s, 9H). MS(ES+) m/e 331 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[N:12]=2)=[CH:6][CH:5]=1)([O-])=O.C(=O)=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[N:12]=2)=[CH:8][CH:9]=1
Reactant: Nc1cccc(Nc2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Agent: O=C=O
Solvent: CO
Product: Nc1ccc(Nc2cccc(N)n2)cc1
Reaction time: 3 h

Procedure:
2,6-Diaminopyridine (9.2 mmol, 1.0 g) and 1-fluoro-4-nitrobenzene (9.2 mmol, 1.3 g) were dissolved in 10 mL anhydrous DMF. The solution was stirred at ambient temperature while 95% sodium hydride (18.3 mmol, 440 mg) was added. The solution turned reddish black in 30 min. The reaction mixture was stirred for an additional 20 hours at room temperature. The reaction mixture was poured slowly into 25 mL 10% aqueous NH4Cl solution mixed with ice (25 g). The resulted aqueous solution was extracted with EtOAc (4×30 mL). The combined organic phase was dried over MgSO4 and evaporated to dryness. The residual oil was purified by flash column chromatography on silica gel (EtOAc:Hexane 1:2) to provide N2-(4-nitrophenyl)pyridine-2,6-diamine (1.6 g, 76%), a reddish orange crystal: 1H NMR (500 MHz, CDCl3) δ 8.19 (d, 2H, J=9.0 Hz), 7.51 (d, 2H, J=9.0 Hz), 7.42 (t, 1H, J=8.0 Hz), 6.85 (s, 1H), 6.30 (d, 1H, J=8.0 Hz), 6.16 (d, 1H, J=8.0 Hz), 4.51 (s, 2H); MS m/z (relative intensity) 231 (M+1, 100), 184 (100). N2-(4-nitrophenyl)pyridine-2,6-diamine (2.6 mmol, 0.6 g) and 10% Pd/C (30 mg) were added to a 20 mL test tube equipped with a stir bar and then dry ice (0.5 g, CO2) was added to the mixture just before MeOH (8 mL) was added. The suspension was then put into a pressure vessel under 80 psi H2. The reaction mixture was stirred for 3 hours. The solution turned from yellow to colorless. The reaction mixture was transferred into a 10 mL syringe and filtered through an Acrodisc syringe Filter into a 100 mL round bottom flask containing 37% aqueous HCl (4 mL). The solvent was then evaporated and azeotroped to dryness with toluene and absolute ethanol (3×30 mL of 1:1 mixture). The product was obtained as an off-white powder in quantitative yield: 1H NMR (500 MHz, D2O) δ 7.48 (t, 1H, J=14.0 Hz), 7.25 (m, 4H), 6.13 (d, 1H, J=14.0 Hz), 6.09 (d, 1H, J=14.0 Hz); Ms m/z (relative intensity) 201 (M+1, 100).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:38][CH:37]=4)(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 88 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-(trifluoromethyl)benzenesulfonamide (26 mg, 0.040 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 19 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4-(trifluoromethyl)benzenesulfonamide (percentage yield: 88%), was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([NH:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([NH2:22])=O)[CH2:16][CH2:15]2)[N:4]=1.Cl>C1COCC1.CCOC(C)=O.CO>[NH2:22][CH2:20][C@@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:5]2[N:4]=[C:3]([N:2]([CH3:23])[CH3:1])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=2)[CH2:19][CH2:18]1
Reactant: CN(C)c1nc(N[C@H]2CC[C@@H](C(N)=O)CC2)nc2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1nc(N[C@H]2CC[C@@H](CN)CC2)nc2ccccc12
Temperature: 0 °C

Procedure:
To a solution of cis-4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexanecarboxylic acid amide (18.78 g, 60 mmol) in THF (200 mL) was added a solution of 1 M BH3 in THF (300 mL, 300 mmol). The mixture was stirred at reflux for 2 hr. After cooling the reaction mixture to 0° C., 4 M HCl in EtOAc (100 mL) and MeOH (200 mL) were added. The mixture was concentrated. The mixture was treated with 1 M aqueous sodium hydroxide and the aqueous layer was extracted with CH2Cl2. The organic layer was dried over sodium sulfate, concentrated, and purified by column chromatography (silica gel, 10% 2 M NH3/MeOH in CH2Cl2) to give cis-N2-(4-aminomethyl-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine as a white solid (10.6 g, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: Brc1ccc(-c2nsc3cc(OCCCN4CCCC4)ccc23)cc1

Procedure:
According to the method in example 4, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and pyrrolidine were converted to yield 3-(4-Bromo-phenyl)-6-(3-pyrrolidin-1-yl-propoxy)-benzo[d]isothiazole, MS: 418 (MH+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][O:9][CH2:8][C:7]=2[CH:6]=[C:5]([CH:13]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]=C(C)O[N:34]=3)=[CH:29][CH:28]=2)[C:14]2[NH:15][C:16](=[O:25])[N:17]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:18]=2)[CH:4]=1.O.[C:40]([OH:43])(=[O:42])[CH3:41]>CO.[Fe]>[C:40]([OH:43])(=[O:42])[CH3:41].[CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][O:9][CH2:8][C:7]=2[CH:6]=[C:5]([CH:13]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH2:37])=[NH:34])=[CH:29][CH:28]=2)[C:14]2[NH:15][C:16](=[O:25])[N:17]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[N:18]=2)[CH:4]=1
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 814 mg of 5-{(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one in 15 ml of a methanol:water:acetic acid=1:1:1 mixed solvent there was added 1 g of iron powder, and the mixture was stirred overnight at 60° C. under a nitrogen atmosphere. After adding 7.5 ml of a methanol:water:acetic acid=1:1:1 mixed solvent to the reaction mixture, the mixture was further stirred at 60° C. for 5 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (476 mg).
Reaction SMILES: [NH3:1].[CH:2]1([C:5]2([C:12]3[CH:13]=[C:14]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=4)=[O:21])[CH:15]=[CH:16][C:17]=3[F:18])[CH2:10][O:9][CH2:8][C:7](=S)[NH:6]2)[CH2:4][CH2:3]1.C(OO)CCC>CO>[NH2:1][C:7]1[CH2:8][O:9][CH2:10][C:5]([C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[F:18])([CH:2]2[CH2:4][CH2:3]2)[N:6]=1
Reactant: N
Reactant: O=C(Nc1ccc(F)c(C2(C3CC3)COCC(=S)N2)c1)c1ccc(Cl)cn1
Agent: CCCCOO
Solvent: CO
Product: NC1=NC(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)(C2CC2)COC1
Reaction time: 16 h

Procedure:
A solution of ammonia in methanol (7 M) (5.1 ml, 35 mmol) was added to a suspension of (RS)-5-chloro-pyridine-2-carboxylic acid [3-(3-cyclopropyl-5-thioxo-morpholin-3-yl)-4-fluoro-phenyl]-amide (=5-chloro-pyridine-2-carboxylic acid [3-((RS)-3-cyclopropyl-5-thioxo-morpholin-3-yl)-4-fluoro-phenyl]-amide) (0.240 g, 0.59 mmol) in methanol (18 ml). Thereafter, tent-butyl hydroperoxide (70% in water) (0.81 ml, 5.9 mmol) was added at room temperature and the mixture stirred for 16 hours. For the workup, the clear solution was evaporated at reduced pressure. The residue was purified by chromatography on silica gel using a 80:10:1-mixture of ethyl acetate, methanol, and ammoniumhydroxide as the eluent. The pure fractions were combined and evaporated, then the residue was treated with a mixture of dichloromethane and water. After evaporation of the organic layer, the 5-chloro-pyridine-2-carboxylic acid [3-((RS)-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide (22) was obtained as a white solid (99 mg, 43% of theory). Mass (calculated) C19H18ClFN4O2S [388.828]; (found) [M+H]+=389.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:31]([NH:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=4)=[O:32])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cccc(N=C=O)c1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: COc1cccc(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)c1

Procedure:
The title compound, MS: m/e=425.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 3-methoxyphenyl-isocyanate.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[CH2:17]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
A 100-mL round-bottomed flask was charged with a solution of 9H-carbazole (1.67 g, 9.90 mmol, 1.00 equiv, 99%) in DMF (20 mL) followed by addition of NaH (400 mg, 16.50 mmol, 1.00 equiv, 99%) in small portions at 0° C. over 5 minutes. 1-(Bromomethyl)benzene (1.7 g, 9.90 mmol, 1.00 equiv, 99%) was then added drop wise at 0° C. over 5 minutes. The resulting mixture was stirred at room temperature for 16 hours. The progress was monitored by TLC (EtOAc:PE=1:5). Upon completion, the reaction was then quenched by the addition of water/ice (100 mL). The solids were collected by filtration and dried in an oven under reduced pressure to afford 9-benzyl-9H-carbazole as white solid (2.3 g, 90%). LCMS: [M+H]+: 258.
Reaction SMILES: Br[CH2:2][CH:3]([Br:8])[CH2:4][CH2:5][CH2:6][CH3:7].[S:9]([O-:12])([O-:11])=[O:10].[Na+:13].[Na+].O>C(O)C>[Br:8][CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2][S:9]([O-:12])(=[O:11])=[O:10].[Na+:13]
Reactant: O=S([O-])[O-]
Reactant: CCCCC(Br)CBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCC(Br)CS(=O)(=O)[O-]
Yield: 50 %

Procedure:
1,2-Dibromohexane (1.22 g, 5.0 mmol) was added to a solution of 0.6 g (5 mmol) of sodium sulfite in 20 mL of a 1:1 mixture of water and ethanol, and the resulting mixture was refluxed for 24 hours with vigorous stirring. The ethanol was then removed by distillation and the residual solution was allowed to stand at room temperature, whereupon white crystals precipitated. The crystals were filtered off under reduced pressure, washed with ether and dried to give 0.67 g (2.5 mmol) of the desired substance, namely sodium 2-bromohexylsulfonate (yield 50%).
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[NH:30][C:29]([C:31]5[N:36]=[CH:35][CH:34]=[CH:33][N:32]=5)=[N:28][N:27]=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].C1C=CC2N(O)N=NC=2C=1.[CH3:53][N:54]1[CH:58]=[C:57]([C:59](O)=O)[N:56]=[CH:55]1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C.C(O)(=O)C>[CH3:53][N:54]1[CH:58]=[C:57]([C:59]2[N:12]3[C:3]([C:4]4[CH:5]=[C:6]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[C:7]([C:13]5[CH:18]=[CH:17][C:16]([CH2:19][N:20]6[CH2:21][CH2:22][CH:23]([C:26]7[NH:30][C:29]([C:31]8[N:36]=[CH:35][CH:34]=[CH:33][N:32]=8)=[N:28][N:27]=7)[CH2:24][CH2:25]6)=[CH:15][CH:14]=5)=[N:8][C:9]=4[CH:10]=[CH:11]3)=[N:1][N:2]=2)[N:56]=[CH:55]1
Reactant: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ncccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: Cn1cnc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(CN6CCC(c7nnc(-c8ncccn8)[nH]7)CC6)cc5)nc4ccn23)c1
Temperature: 80 °C

Procedure:
To a stirred solution of 11-3 (0.23 g, 0.4 mMol), HOBT (0.06 g, 0.45 mMol), and 1-methyl-1H-imidazole-4-carboxylic acid (0.06 g, 0.45 mMol) in anhydrous DMF (2 mL) was added DIEA (0.13 mL, 0.8 mMol) followed by EDC (0.09 g, 0.5 mMol). The solution was heated in the microwave reactor for 15 minutes at 80° C. Solution was then treated with 0.2 mL of acetic acid and was heated to 80° C. in the microwave reactor for 20 minutes. Upon cooling to room temperature, the solution was passed through a syringe filter and purified on a C18 reverse phase HPLC to give 12-1 as a solid. Mass (M+1) calculated: 632.2742 observed: 632.274
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C([S-])C.[Na+].O.Cl>CN(C)C=O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=Cc2ccc(N(c3ccc(C)cc3)c3ccc(C)cc3)cc2)cc1
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccc(O)cc3)cc2)cc1

Procedure:
The above-prepared 4-methoxy-4′-(di-p-tolylamino)stilbene and twice equimolar amount of sodium ethanethiolate are dissolved in N,N-dimethylformamide, and reacted for 5 hours at 130° C. The mixture is cooled down, and then poured into water and neutralized with hydrochloric acid. The objective material is extracted therefrom using acetic acid. The extracted liquid is washed with water, and then dried. The crude objective material is prepared by removing the solvent (i.e., N,N-dimethylformamide) therefrom. Further, the crude objective material is purified with a column chromatography using silica gel. Thus, 4-hydroxy-4′-(di-p-tolylamino)stilbene (i.e., objective material) is prepared.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Cl:14]Cl.Cl>>[Cl:14][C:7]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[NH2:6]
Reactant: ClCl
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Product: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 95 %

Procedure:
Once the total amount of 2,4-dinitroaniline and the corresponding amount of chlorine gas--an equimolar amount and c. 10 % excess of this latter--have been added to the hydrochloric acid, the batch is allowed to react for half an hour to 1 hour and then excess chlorine is expelled with nitrogen. The product is isolated by filtration, washed until neutral and dried. The 2-chloro-4,6-dinitroaniline is obtained by this process in a yield of 95 % with a content of less than 0.5 % by weight of unreacted starting material (dinitroaniline).
Reaction SMILES: [F:1][C:2]([F:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11]([OH:13])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[F:51][C:52]1[CH:59]=[CH:58][C:55]([CH2:56][NH2:57])=[CH:54][CH:53]=1>CN(C=O)C>[F:21][C:2]([F:1])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11]([NH:57][CH2:56][C:55]1[CH:58]=[CH:59][C:52]([F:51])=[CH:53][CH:54]=1)=[O:13]
Reactant: NCc1ccc(F)cc1
Reactant: O=C(O)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
To a solution of 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-thiazole-5-carboxylic acid (0.15 g, 0.45 mmol) in DMF (3 ml) are added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (216 mg, 0.68 mmol) and N-methylmorpholine (0.01 ml, 0.9 mmol) at 0° C. followed by the addition of 4-fluorobenzyl amine (67 mg, 0.54 mmol). The reaction mixture is stirred at RT for 3 h. After completion of the reaction, the mixture is poured onto ice-water, extracted with EtOAc (3×50 ml). The combined organic layers are washed with brine (50 ml), dried over sodium sulfate and evaporated to dryness to yield the crude product, which is purified by column chromatography (silica gel, 15% acetone/hexane) affording 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-thiazole-5-carboxylic acid amide (example 14) (93 mg, 0.21 mmol, 47%). [M+H]+ 441.1.