Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:4])(=O)=[O:2].[N:5]1[CH:10]=CC=[CH:7][C:6]=1[CH3:11].CNC(C)C.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>ClCCCl>[CH3:10][N:5]([CH:6]([CH3:11])[CH3:7])[S:1]([Cl:18])(=[O:4])=[O:2]
Reactant: O=S(=O)=O
Reactant: Cc1ccccn1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: CNC(C)C
Solvent: ClCCCl
Product: CC(C)N(C)S(=O)(=O)Cl
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
63.2 g (0.41 mol) of sulfur trioxide as a 52% solution in 1,2-dichloroethane were added with stirring at from 0 to 5° C. within 15 min to a solution of 70.0 g (0.752 mol) of α-picoline in 250 ml of 1,2-dichloroethane, followed by washing with 50 ml of 1,2-dichloroethane and stirring for 15 min until the temperature rose to 25° C. 26.3 g (0.342 mol) of 95% pure N-methyl-N-[1-methylethyl]amine were then added within 15 min with stirring at from 20 to 35° C., followed by washing with 50 ml of 1,2-dichloroethane and stirring at 55° C. for 15 min. After cooling to 20° C., 42.7 g (0.205 mol) of phosphorus pentachloride were added with stirring at from 20 to 32° C. within 15 min with external cooling, followed by washing with 150 ml of 1,2-dichloroethane. After stirring at 70° C. for 2 h, the reaction mixture was concentrated under reduced pressure and distilled via a Normag column head having a 10 cm column. 35 g (59.6% of theory) of the title compound having a boiling point of 110-115° C./30 mbar were obtained. Refractive index nD23=1.4620.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH2:11])[C:4]=2[CH:5]=[N:6][CH:7]=1.[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>>[Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: NC1CCc2c(Br)cncc21
Product: CCS(=O)(=O)NC1CCc2c(Br)cncc21
Yield: 94 %

Procedure:
In analogy to the procedure described for the preparation of example 2, (rac)-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine (intermediate A-4 [C]) and ethanesulfonyl chloride gave the title compound as a grey solid in 94% yield. MS: 304.99 (M+H+, 1 Br).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[CH:7][CH:6]=2)[CH3:2].N[C:24]1[CH:25]=C2C(=C[CH:32]=1)NC(CCC(C)C)=C2>>[CH3:32][CH:24]([CH3:25])[CH2:2][CH2:1][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[CH:7][CH:6]=2
Reactant: CC(C)CCc1cc2cc(N)ccc2[nH]1
Reactant: CCc1cc2cc(NS(=O)(=O)c3ccc(C)cc3)ccc2[nH]1
Product: Cc1ccc(S(=O)(=O)Nc2ccc3[nH]c(CCC(C)C)cc3c2)cc1

Procedure:
Refer to 45a) using 5-amino-2-(3-methyl-n-butyl) indole.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:33][CH3:34])=[C:30]([OH:32])[CH:31]=1>C(OCCO)C>[OH:32][C:30]1[CH:31]=[C:26]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:27]=[CH:28][C:29]=1[O:33][CH3:34]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: COc1ccc(N)cc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)cc1O
Yield: 89.2 %

Procedure:
Using an analogous procedure to that described in EXAMPLE 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 167.0 mg (1.2 mmol) of 5-amino-2-methoxyphenol to give 313.3 mg (89.3%) of the product as a gray solid, m.p. 254-256° C., mass (electrospray, m/e): M+H 351.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.Cl.[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1)[CH3:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:41][CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:30]([CH3:31])[CH3:29])=[CH:34][CH:35]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: CN(C)Cc1ccc(CCN)cc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(CN(C)C)cc4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred suspension of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.10 g, 0.28 mmol), 2-(4-((dimethylamino)methyl)phenyl)ethanamine dihydrochloride (0.056 g, 0.31 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.13 g, 0.34 mmol) in N,N-dimethylformamide (1.4 mL) at ambient temperature was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The resulting solution was stirred at ambient temperature for 60 minutes, then partitioned between water (15 mL) and ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 90/10 chloroform/(90/10 methanol/concentrated ammonium hydroxide), to afford methyl 6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless film (0.083 g, 57% yield).
Reaction SMILES: [CH:1](/[C:14]1[C:19]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:18][C:17]([NH2:24])=[CH:16][CH:15]=1)=[CH:2]\[C:3]1[C:8]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:7][C:6]([NH2:13])=[CH:5][CH:4]=1.[OH-:25].[Na+:26].[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH:1](/[C:14]1[C:19]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:18][C:17]([NH:24][C:34]([NH:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])=[CH:16][CH:15]=1)=[CH:2]\[C:3]1[C:8]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:7][C:6]([NH:13][C:34]([NH:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])=[CH:5][CH:4]=1.[Na+:26].[Na+:26]
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(/C=C/c2ccc(N)cc2S(=O)(=O)O)c(S(=O)(=O)O)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccccc1)Nc1ccc(/C=C/c2ccc(NC(=O)Nc3ccccc3)cc2S(=O)(=O)[O-])c(S(=O)(=O)[O-])c1
Reaction time: 8 h
Yield: 78 %

Procedure:
(E)-6,6′-(Ethene-1,2-diyl)bis(3-aminobenzenesulfonic acid) (18.5 g, 0.05 mol) was dissolved in water (800 ml) by adjusting to pH 7 with 2N sodium hydroxide. Phenyl isocyanate (11.9 g, 0.10 mol) was added over a period of 90 minutes then stirred overnight. Further phenyl isocyanate (0.6 g, 0.005 mol) was added with a second overnight stir. The resultant suspended solid was filtered off, re-suspended in acetone, filtered off and dried for 24 h at 40° C. to give the title compound as a beige solid (31.7 g, 78%); C28H22N4Na2O8S2 requires C, 51.5%, N, 8.6%. found C, 44.8%, N, 6.9%, sample strength determined as 80% based on N content.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(O)C.[Sn](Cl)[Cl:32].[OH-].[Na+]>Cl.C(OCC)(=O)C>[ClH:32].[NH2:25][C:21]1[CH:20]=[C:19]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cl[Sn]Cl
Reactant: COc1ccc(C(NC(=O)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(NC(=O)c2ccccc2)c2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]benzamide (3.24 g) [prepared as described in step (c) above] was added in small portions to a 1:1 by volume mixture of ethanol and concentrated hydrochloric acid at ambient temperature. Tin (II) chloride (6.78 g) was then added in small portions to the mixture in an ice bath. The mixture was stirred at ambient temperature for 20 minutes and then heated under reflux for 2 hours. After cooling, the reaction mixture was neutralized with aqueous solution of sodium hydroxide and the insoluble material was removed by filtration using a Celite (trade mark) filter aid. The filtrate was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column using a 2:1 by volume mixture of hexane and ethyl acetate as the eluant, to afford a colorless oil. This oil was dissolved in a solution of hydrogen chloride in ethyl acetate (4N) and the solvent was evaporated to dryness. The residual solid was suspended in diethyl ether and filtered, to afford the title compound (2.68 g) as a white solid.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][CH2:10]2)[CH2:7][CH2:6]3.S(=O)(=O)(O)O.[C:29](=O)(O)[O-:30].[K+].O>CO>[OH:1][C@@H:3]1[C@@H:2]([O:30][CH3:29])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1
Reactant: O=C([O-])O
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2α,3α-Epoxy-5α-pregn-16-en-20-one (500 mg.) in methanol (30 ml.) was treated with concentrated sulphuric acid (0.1 ml.). The reaction solution was stirred at room temperature for 10 minutes, and then potassium bicarbonate solution (10%, 6 ml.) and water were added and the precipitate was extracted into chloroform. The chloroform solution was evaporated to an oil which was purified by preparative TLC in ethyl acetate/petrol (1/2), to give, as the major product title compound (255 mg) as colourless plates (from ethyl acetate/petrol), m.p. 186°-189°, [α]D (c, 0.82) + 62° , λmax (EtOH) 239 nm (ε 8370).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][OH:21])[C:10]=2[C:9]2[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=2[S:7]1)=[O:5])[CH3:2].[C:28]1(C)[C:29]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1.N1C=CC=C[CH:40]=1>ClCCl>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][O:21][S:34]([C:29]3[CH:28]=[CH:33][C:32]([CH3:40])=[CH:31][CH:30]=3)(=[O:35])=[O:36])[C:10]=2[C:9]2[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=2[S:7]1)=[O:5])[CH3:27]
Reactant: CCN(CC)C(=O)C1Sc2ccccc2-c2c1c1ccccc1n2CCO
Reactant: c1ccncc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)C1Sc2ccccc2-c2c1c1ccccc1n2CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.5 %

Procedure:
To a solution of 11-(2-Hydroxy-ethyl)-6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid diethylamide (iv) (100 mg, 0.26 mmol) in anhydrous dichloromethane 3 ml was added toluenesulfonyl chloride (100 mg, 0.52 mmol) and pyridine (0.2 ml, 2.6 mmol) at 0° C. under nitrogen. The reaction mixture was then stirred at room temperature for 48 hours. After quenched with 20 ml water, the mixture was extracted with dichloromethane 2×20 ml. The organic was dried (MgSO4) and removed in vacuo. The residue was purified by flash column chromatography over silica using a gradient 20% mixture of ethyl acetate and hexane to 40% ethyl acetate as eluant. Appropriate fractions were combined and the solvent was removed in vacuo to give the product 11-(2-Tosyloxy-ethyl)-6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid diethylamide (Compound 10P) as a white solid 98 mg. Yield 48%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[C:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[CH2:6]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([C:19]1[C:7]2[CH2:6][C:5](=[CH:4][CH2:3][CH2:2][Br:1])[C:15]3[C:10]([O:9][C:8]=2[CH:16]=[CH:17][CH:18]=1)=[N:11][CH:12]=[CH:13][CH:14]=3)(=[O:26])[CH3:25]
Reactant: BrCCC=C1Cc2ccccc2Oc2ncccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cccc2c1CC(=CCCBr)c1cccnc1O2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of example 53, step 1 (7.2 g) in dichloromethane (70 ml) was added aluminum chloride (9.1 g) and acetyl chloride (3.2 ml), and the mixture stirred at 0° C. for 10 minutes. The reaction mixture was poured into ice. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The Residue was purified by silica gel chromatography, eluting with ethyl acetate-hexane (1:2) to give 7-acetyl-5-(3-bromopropylidene)-5,11-dihydro[1]benzoxepino[2,3-b]pyridine (7.9 g).
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:26][C@@H:25]([F:28])[C@@H:24]3[C@H:20]2[CH2:21][NH:22][CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:35]1([CH2:40][CH:41]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[CH2:50][C:51](O)=[O:52])[CH3:42])[CH2:39][CH2:38][CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[N:35]1([CH2:40][CH:41]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[CH2:50][C:51]([N:22]2[CH2:21][C@@H:20]3[C@@H:24]([C@H:25]([F:28])[CH2:26][CH2:27][C:19]3([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:23]2)=[O:52])[CH3:42])[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CC(CN1CCCC1)Oc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(CN1CCCC1)Oc1ccccc1CC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 41.7 %

Procedure:
0.04 g of hydroxybenzotriazole hydrate is added to a solution, cooled to +5° C., of 1 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride and 0.924 g of 2-{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetic acid in 40 cm3 of dry dichloromethane, followed by 0.79 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.51 cm3 of diisopropylethylamine. After stirring for 2.5 hours at +5° C. and for 20 hours at 20° C., the reaction mixture is washed twice with 50 cm3 of water, dried over magnesium sulphate and then concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 31 cm), eluting under a nitrogen pressure of 0.5 bar with an ethyl acetate, acetic acid and water mixture (60/10/10 by volume) and collecting fractions of 25 cm3. Fractions 11 to 31 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 20 cm3 of dichloromethane, the solution is washed with 20 cm3 of a 1N aqueous solution of sodium hydroxide and then dried over magnesium sulphate and concentrated to dryness. This wash with a basic solution is repeated again. 0.68 g of (3aR, 7R,7aR)-2-{{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetyl}-4,4-diphenyl-7-fluoroperhydroisoindole is obtained in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[N:10]=1.C(=O)([O-])[O-].[K+].[K+].N1C=NC=NC=1.Br[CH2:49][CH2:50][CH2:51][CH3:52]>O.CN(C)C=O>[CH2:49]([O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:7][CH2:2][CH2:3][CH3:4])=[CH:17][C:16]=3[OH:22])[N:12]=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[N:10]=2)=[C:2]([OH:1])[CH:7]=1)[CH2:50][CH2:51][CH3:52]
Reactant: CCCCBr
Reactant: Oc1ccc(-c2nc(-c3ccc(Sc4ccccc4)cc3)nc(-c3ccc(O)cc3O)n2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ncncn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc(-c2nc(-c3ccc(Sc4ccccc4)cc3)nc(-c3ccc(OCCCC)cc3O)n2)c(O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a 500 mL round bottomed flask equipped with a magnetic stirrer, condenser and nitrogen atmosphere are charged 2.0 g (4.2 mmol) of 2,4-bis-(2,4-dihydroxyphenyl)-6-[4-(phenylthio)phenyl]-s-triazine, 0.58 g (4.2 mmol) of potassium carbonate and 30 mL of N,N-dimethylformamide. The mixture is heated to 90° C., and the s-triazine compound dissolves readily. Bromobutane (4.5 mL, 42.0 mmol) is added all at once. The reaction mixture is heated at 90° C. for 2.5 hours and then stirred at room temperature overnight yielding a yellow precipitate. Chilled water is added and the yellow precipitate is isolated by vacuum filtration to give 2.74 g of crude product. The crude product is purified by flash chromatography with 1:1 heptane:ethyl acetate to afford 0.26 g (10%) yield of the title compound as a yellow solid; mp>250°.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6](C(O)=O)[CH2:5][CH2:4]1.CN(C)CCCN=C=NCC.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:41][C:42]1[C:50]([NH2:51])=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([NH2:46])=[O:45]>O1CCCC1.O>[NH2:41][C:42]1[C:50]([NH:51][CH:6]2[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]2)=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([NH2:46])=[O:45]
Reactant: COC1CCC(C(=O)O)CC1
Reactant: NC(=O)c1cccc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC1CCC(Nc2cccc(C(N)=O)c2N)CC1
Reaction time: 1 h
Yield: 64 %

Procedure:
1.4 g (8.9 mmol) of 4-methoxycyclohexanecarboxylic acid were dissolved in 30 ml of tetrahydrofuran and, at 0° C., successively 1.9 g (1.8 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×hydrochloride, 1.8 g (11.6 mmol) of N-hydroxybenzotriazole and 1.95 g (19.2 mmol) of triethylamine were added. The mixture was stirred for 1 hour. Then 2.0 g (8.9 mmol) of 2,3-diaminobenzamide×2 hydrochloride and 1.95 g (19.2 mmol) of triethylamine were added. The mixture was then stirred at 0° C. for 1 hour and at room temperature for 16 hours. The mixture was diluted with a large amount of water and extracted several times with ethyl acetate. The organic phases were combined, dried and concentrated in vacuo. 1.5 g of the product were obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:15])[CH3:14].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:25])[CH3:24].[Cl-].[NH4+]>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([OH:25])([CH3:24])[CH2:14][C:13]#[N:15]
Reactant: CC#N
Reactant: CC(=O)c1ccccc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(CC#N)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
To a stirring solution of diisopropylamine (0.97 mL, 6.83 mmol) in tetrahydrofuran (15 mL) at −78° C. under nitrogen was added a solution of n-butyllithium (2.86 mL, 7.14 mmol, 2.5 M in hexane). After the addition was complete, the mixture was stirred at −78° C. for 10 minutes and removed cooling bath for 5 minutes. The mixture was cooled back to −78° C., acetonitrile (0.33 mL, 6.21 mmol) was added and the reaction mixture was then stirred at −78° C. for 30 minutes. 1-(2-Chloro-phenyl)-ethanone (1 mL, 7.45 mmol) was added and the resulting solution was allowed to warm to ambient temperature. After 18 hours at ambient temperature, saturated aqueous ammonium chloride (5 mL) was added to the reaction mixture and it was concentrated at reduced pressure. The resulting crude product was diluted with ethyl acetate (30 mL), washed with water (15 mL) followed by saturated aqueous sodium chloride (10 mL). The organic layer was concentrated and purified by column chromatography (40 g silica gel cartridge) eluting with ethyl acetate/hexane (0%-15%) to give the product as a colorless oil (1.1 g, 90%).
Reaction SMILES: CC(O[C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]2[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:23]([OH:25])=[O:24])=[O:7])(C)C.[NH2:26][C:27]1[CH:38]=[CH:37][C:30]([C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])=[CH:29][CH:28]=1.[Cl:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:50]([OH:52])=O)[C:47]=2[F:49])[N:42]([CH3:53])[CH:41]=1>[Pd]>[Cl:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:6]([N:8]3[CH2:12][C@@H:11]([CH:13]4[CH2:14][CH2:15][N:16]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:17][CH2:18]4)[CH2:10][C@H:9]3[C:23]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])=[CH:37][CH:38]=3)=[O:25])=[O:7])[C:47]=2[F:49])[N:42]([CH3:53])[CH:41]=1.[Cl:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:50]([N:8]3[CH2:12][C@@H:11]([CH:13]4[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]4)[CH2:10][C@H:9]3[C:23]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:37][CH:38]=3)=[O:24])=[O:52])[C:47]=2[F:49])[N:42]([CH3:53])[CH:41]=1
Reactant: C=CCOC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C2CCN(S(C)(=O)=O)CC2)C[C@H]1C(=O)O
Reactant: Cn1cc(Cl)c2c(F)c(C(=O)O)ccc21
Agent: [Pd]
Product: C=CCOC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](C3CCN(S(C)(=O)=O)CC3)CN2C(=O)c2ccc3c(c(Cl)cn3C)c2F)cc1
Product: Cn1cc(Cl)c2c(F)c(C(=O)N3C[C@@H](C4CCN(S(C)(=O)=O)CC4)C[C@H]3C(=O)Nc3ccc(C(=O)O)cc3)ccc21

Procedure:
Allyl 4-[({(2S,4R)-1-[(3-chloro-4-fluoro-1-methyl-1H-indol-5-yl)carbonyl]-4-[1-(methylsulfonyl)-4-piperidinyl]-2-pyrrolidinyl}carbonyl)amino]benzoate was prepared from the compound prepared in Example 63 following the procedures described in Example 5, 9 and 8. (Note: in the step corresponding to Example 5, allyl 4-aminobenzoate was used in place of tert-butyl 4-aminobenzoate. In the step corresponding to Example 8, the acid prepared in Example 92 was used in place of 1-(N,N′-bis(tert-butoxycarbonyl)carbamimidoyl)piperidine-4-carboxylic acid). After that, the crude allyl ester was treated with palladium(0) following the procedure described in Example 91 to give the title compound as an off-white solid.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[CH2:6]([C:9]1[C:14]([CH:15]=O)=[CH:13][C:12]2[O:17][CH2:18][O:19][C:11]=2[CH:10]=1)[CH2:7][CH3:8]>O.C(O)C>[CH2:6]([C:9]1[C:14]([CH:15]=[N:4][OH:1])=[CH:13][C:12]2[O:17][CH2:18][O:19][C:11]=2[CH:10]=1)[CH2:7][CH3:8]
Reactant: CCCc1cc2c(cc1C=O)OCO2
Reactant: [OH-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1cc2c(cc1C=NO)OCO2
Reaction time: 4 h

Procedure:
21.3 g (0.533 mol) of sodium hydroxide in 27 ml of water were added to a suspension of 37.1 g (0.533 mol) of hydroxylamine hydrochloride in 500 ml of ethanol and a solution of 77.0 (0.4 mol) of 6-n-propyl-3,4-methylenedioxybenzaldehyde in 150 ml of ethanol was then added. After stirring for four hours under reflux, the reaction mixture was cooled, the solvent was stripped off and the residue was treated with water. The mixture was filtered and the residue was triturated with a mixture of petroleum ether and ether (6:1), again filtered off and dried in air. 72 g (87% of theory) of crystals of melting point 83° C. were obtained.