Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1SC(C2C=C(Cl)C(S(N)(=O)=O)=C(Cl)C=2)=C(C)N=1.[Cl:20][C:21]1[CH:22]=[C:23]([C:34]2[S:38][C:37]([NH:39]C(=O)C)=[N:36][C:35]=2[CH3:43])[CH:24]=[C:25]([Cl:33])[C:26]=1[S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29]>>[NH2:39][C:37]1[S:38][C:34]([C:23]2[CH:24]=[C:25]([Cl:33])[C:26]([S:27]([N:28]([CH3:30])[CH3:29])(=[O:32])=[O:31])=[C:21]([Cl:20])[CH:22]=2)=[C:35]([CH3:43])[N:36]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(Cl)c(S(=O)(=O)N(C)C)c(Cl)c2)s1
Agent: Cc1nc(N)sc1-c1cc(Cl)c(S(N)(=O)=O)c(Cl)c1
Product: Cc1nc(N)sc1-c1cc(Cl)c(S(=O)(=O)N(C)C)c(Cl)c1

Procedure:
The title compound is prepared by the same procedure as 4-(2-amino-4-methyl-thiazol-5-yl)-2,6-dichloro-benzenesulfonamide (Example 26) by replacing N-[5-(3,5-dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 6) with N-[5-(3,5-dichloro-4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (171a).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:18]([F:19])=[CH:17][C:13](C(O)=O)=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.C([N:32]([CH2:35]C)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:44])=CC=1>CC(O)(C)C>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:11]=[C:12]4[N:20]([C@H:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH3:22])[C:35](=[O:44])[NH:32][C:13]4=[CH:17][C:18]=3[F:19])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C(=O)O)c1ccc(F)cc1
Solvent: CC(C)(C)O
Product: C[C@@H](c1ccc(F)cc1)n1c(=O)[nH]c2cc(F)c(Nc3cc(C4CC4)[nH]n3)nc21
Temperature: 83 °C
Yield: 31.5 %

Procedure:
A mixture of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinic acid (Method 40; 0.03 g, 0.08 mmol), triethylamine (0.02 g, 0.22 mmol), and DPPA (0.04 g, 0.15 mmol) in t-BuOH (2 ml) was heated to 83° C. for 5 hours. The reaction was cooled, concentrated, and then dissolved in DCM (30 ml). The organic layer was washed with water (50×2 ml), dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM:MeOH=15:1) to give the title compounds (0.01 g, 30%). NMR (400 MHz, CD3OD) 7.48-7.44 (m, 2H), 7.24 (d, J=10.3 Hz, 1H), 7.06-7.02 (m, 2H), 5.93 (br s, 1H), 5.76-5.71 (m, 1H), 1.99 (d, J=7.2 Hz, 3H), 1.90-1.84 (m, 1H), 0.96-0.94 (m, 2H), 0.64-0.63 (m, 2H). MS: Calcd.: 396. Found: [M+H]+ 397.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1[C:14](=[O:15])[C:13]2[N:16]3[C@@:20](OC)([C@H](COC(N)=O)C=2C(=O)C=1OC)[C@H:19]1[NH:29][C@H:18]1[CH2:17]3>>[NH2:29][CH2:18][CH2:17][N:16]1[CH2:13][CH2:14][O:15][CH2:19][CH2:20]1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NCCN1CCOCC1

Procedure:
This compound was prepared by the procedure described in Example 1, exept that the potassium carbonate was omitted. From 100 mg. of mitomycin A and 0.5 ml. of N-(2-aminoethyl)morpholine was obtained 70 mg. (55% yield) of the desired product having a melting point of 74°-76° C. (decomposition) and providing the following analysis:
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][OH:6].[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:13]=1[C:14]#[N:15])([O-:11])=[O:10]>>[CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][O:6][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=1[C:14]#[N:15]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: COC(C)(C)CCO
Product: COC(C)(C)CCOc1cccc([N+](=O)[O-])c1C#N
Yield: 52 %

Procedure:
Prepared as in Example 215c from 3-methoxy-3-methylbutan-1-ol and 2,6-dinitrobenzonitrile in 52% yield. MS 265 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[S:14](=[O:16])(=[O:15])[C:13]3[CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=[CH:20][C:12]=3[CH:11]=[CH:10][C:9]=2[CH:24]=1)(=[O:4])=[O:3].C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[OH:22][CH2:21][C:18]1[CH:19]=[CH:20][C:12]2[CH:11]=[CH:10][C:9]3[CH:24]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[S:14](=[O:16])(=[O:15])[C:13]=2[CH:17]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2(=O)=O
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: CS(=O)(=O)c1ccc2c(c1)C=Cc1ccc(CO)cc1S2(=O)=O

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-methylsulfonyldibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[OH-].[Na+].C1COCC1>CO>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([OH:4])=[O:2])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.091 mmol), 2 M aq. NaOH (3 mL), THF (3 mL) and MeOH (3 mL) was stirred at r.t. for 16 h. The mixture was concentrated to one-third of its original volume, and then placed in an ice bath. 1 M HCl was added with stirring until pH about 2, and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Solvent was evaporated in vacuo to give 35 mg of the title compound as a yellow solid. MS: (+) m/z 373.28 (M+1).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:27][CH2:26][N:25]([CH:24]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:21]3[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=3)[CH2:30][CH2:29]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)n(C(C)(C)C)n1

Procedure:
239 mg (97%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (130 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:4][CH:3]=1.[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43](O)=[O:44])[N:41]=1>>[NH2:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]3[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:8]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:34][CH:35]=2)=[O:44])[N:41]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: Nc1nc(CC(=O)O)cs1
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(NC(=O)Cc3csc(N)n3)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1

Procedure:
The title compound was prepared from tert-butyl (2S,5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate (i-4a) and (2-amino-1,3-thiazol-4-yl)acetic acid according to the procedure of Example 1, step A. The crude product was purified by preparative TLC plate eluting with 5% MeOH in dichloromethane to afforded the product (4.1 mg, 21%). m/z (ES) 637 (MH)+, 659 (MNa)+.
Reaction SMILES: [C:1]([S:5][S:6][CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>CC#N.O>[C:1]([S:5][S:6][CH2:7][CH:8]([NH:9][C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)SSC[C@H](N)C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)COC(=O)NC(CSSC(C)(C)C)C(=O)O
Reaction time: 0.25 h

Procedure:
To S-tert-butylmercapto-L-cysteine (10 g, 47.8 mmol) in CH3CN (40 mL) was added K2CO3 (16.5 g, 119.5 mmol) in H2O (20 mL). After stirring for 15 minutes, iso-butyl chloroformate (9.4 mL, 72 mmol) was injected slowly. The reaction was allowed to run for 3 hours. The white solid was filtered through Celite; the filtrate was concentrated to remove CH3CN. The residue was dissolved in ethyl acetate (200 mL), washed with 1N HCl (40 ml×3), brine (40×1), dried over Na2SO4. The title compound was obtained after chromatography (5% MeOH/DCM).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14]([NH2:16])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC4C=CC=CC=4)[CH:18]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C1COCC1>[C:1]1([C:7]2[C:15]3[C:14]([NH2:16])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncnc2c1c(-c1ccccc1)cn2-c1cccc(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccccc1)cn2-c1cccc(O)c1
Temperature: 25 °C

Procedure:
2.61 g of 5-phenyl-7-(3-benzyloxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine (Ex. 11) and 1.0 g of palladium on carbon 10% are stirred at 40° C. for 30 h in 100 ml of THF until the amount of hydrogen theoretically required has been consumed. After cooling to RT, the mixture is filtered and the filtrate is concentrated in an RE. The residue is slurried with ether and the crystals are filtered off. Recrystallization from methylene chloride/ethanol and from chloroform does not give a pure product. After chromatography on silica gel (methylene chloride/methanol containing NH3 (4N) 92:8), the product-containing fractions are concentrated. The residue is dissolved in hot chloroform, the solution is cooled to 0° C. and the crystals are filtered off. After filtration and drying under HV, pure 5-phenyl-7-(3-hydroxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine having a melting point of 227°-228° C. is obtained. 1H--NMR (d6 -DMSO): delta (ppm)=6.2 (br. s, 2H), 6.8 (br. d, 1H), 7.2-7.4 (m, 4H), 7.5-7.6 (m, 4H), 7.7 (s, 1H), 8.2 (s, 1H), 9.8 (s, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([O:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>ClCCl>[C:1]([O:4][C:5]1[C:13]([O:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([Cl:19])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1OC(C)=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C(=O)Cl)c1OC(C)=O

Procedure:
24 g of 2,3-bis(acetyloxy)benzoic acid was suspended in 100 ml of dichloromethane and, at -10° C., 23 g of phosphorous pentachloride was added. The hydrogen chloride gas that formed was removed The resulting clear solution was then evaporated in an oil-pump vacuum yielding a brown honey. This was dissolved in 300 ml of petroleum ether and filtered over active carbon. After distilling off the solvent, the title compound was obtained in the form of white crystals (25.1 g); melting point 97°-99° C. (dec.)
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)=[CH:17][C:16]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][O:27][C:2]3[CH:12]=[C:6]4[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]4[C:4](=[O:13])[N:3]=3)=[CH:24][CH:25]=2)=[CH:17][C:16]=1[C:30]([F:31])([F:32])[F:33]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methanol.
Reaction SMILES: [Cl:1][C:2]1[C:8]([N:9]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:16]([O-])=O)[CH:3]=1>[Pd].C1COCC1>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:6])=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10]1
Reactant: Nc1cc(N2CCC(F)(F)C2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cl
Product: Nc1cc(Cl)c(N2CCC(F)(F)C2)cc1N
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 4-chloro-5-(3,3-difluoropyrrolidin-1-yl)-2-nitroaniline (300 mg, 1.1 mmol), THF (10 mL) and Pd/C (20 mg) was stirred for 1.5 days at RT under a hydrogen atmosphere (3.0 bar). The catalyst was removed by filtration. To the filtrate was added 4 M HCl in dioxane (10 mL). The mixture was concentrated and used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[O:5]1)#[N:2]>N.CO.[Ni]>[NH2:2][CH2:1][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[O:5]1
Reactant: COc1ccc(F)cc1CCC1CCC(CC#N)O1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc(F)cc1CCC1CCC(CCN)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
To a round bottom flask under an atmosphere of Ar was added Raney Ni that was washed with methanol. Compound 12 (80 mg, 0.3 mmol), dissolved in 2 M NH3 in methanol was added to the flask. The flask was evacuated and purged with H2 once. A balloon containing H2 gas was then attached to the flask and the reaction was allowed to stir for 4 h at room temperature. The reaction mixture was filtered through a plug of Celite and the crude product obtained after the removal of the solvent was purified by preparative TLC and eluted with (MeOH/CH2Cl2, 10:90, v:v, Rf=0.1) to give the product (55 mg, 70%) as a 2:1 mixture of trans/cis diastereomers; 1H NMR: (CDCl3, 500 MHz): δ 6.87 (m, 1 H), 6.82 (dd, J=3.0, 8.5 Hz, 1 H), 6.72 (m, 1 H), 4.03 (m, 0.65 H), 3.96 (m, 0.65 H), 3.89 (m, 0.35 H), 3.82 (m, 0.35 H), 3.78 (s, 3 H), 2.68 (m, 1 H), 2.58 (m, 1 H), 2.03 (m, 2 H), 1.83 (bs, 2 H), 1.86-1.6 (m, 4 H), 1.54 (m, 2 H); HRMS (ESI) [M+H]+ calcd for C15H23FNO2 268.1713, found 268.1701; HPLC>96% pure (tR=4.66 min, 40(A):55(B):5(C):0.01(D); tR=5.05 min, 10(A):85(B):5(C):0.01(D)).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:8]([S:12]([NH:15]C(C)(C)C)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:8]([S:12]([NH2:15])(=[O:13])=[O:14])[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c(COC(C)=O)cccc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(COC(C)=O)cccc1S(N)(=O)=O
Yield: 92 %

Procedure:
A solution of 2.58 g of 3-acetoxymethyl-2-carboethoxy-N-(1,1-dimethylethyl)benzenesulfonamide in 25 mL of trifluoroacetic acid was stirred at room temperature overnight. Removal of the solvent on the rotovap followed by trituration with n-butyl chloride provided 2.0 g of a white solid, m.p. 98°-100° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Ag]=O.CC(C)=O>[CH2:17]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: FC(F)(F)c1cccc(C2CCCNC2)c1
Agent: O=[Ag]
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(C2CCCN(Cc3ccccc3)C2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
2.2 g of silver oxide were added to a mixture of 4.6 g of 3-(m-trifluoromethylphenyl)-piperidine and 22 ml of acetone and the mixture was cooled on an ice water bath while 2.55 ml (≃3.6 g) of benzyl bromide was added dropwise over 10 minutes at a temperature less than 10° C. The mixture was stirred at 0° C. for one hour and was filtered. The filtrate was evaporated to dryness under reduced presssure to obtain 7 g of raw product which was chromatographed over silica gel. Elution with an 85-10-5 cyclohexane-chloroformtriethylamine mixture and evaporation to dryness under reduced pressure yielded 4.99 g of N-benzyl-3-(m-trifluoromethylphenyl)-piperidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.[CH2:17](S)C.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([S:8][CH2:10][CH3:17])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCS
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCSc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, ethanethiol and DBU in dioxane. EI-MS m/e (%): 301 (M{81Br}+, 28), 299 (M{79Br}+, 27), 220 ([M—Br]+, 100), 160 (30), 118 (24).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]3[O:30][CH2:29]3)=[C:22]([CH3:31])[CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]([OH:30])[CH2:29][NH:36][CH2:32][CH2:33][CH2:34][CH3:35])=[C:22]([CH3:31])[CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: CCCCN
Reactant: COc1ccc(C(c2ccc(OCC3CO3)c(C)c2)C2CCCc3ccccc32)cc1
Solvent: CCO
Product: CCCCNCC(O)COc1ccc(C(c2ccc(OC)cc2)C2CCCc3ccccc32)cc1C

Procedure:
A mixture of (4-methoxyphenyl)-(3-methyl-4-(2,3-epoxypropyloxy)phenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (300 mg, 0.001 mol), n-butyl amine (1.0 m, 0.01 mol) and ethanol (15 ml) was refluxed for 8 hrs. Ethanol was distilled off and the residue was passed through a basic alumina column using hexane:ethyl acetate as the eluent. Solvent was distilled off to give the title compound. Yield 212 mg, (60.05%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[CH3:5][N:6]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[CH3:5][N:6]([CH:17]1[CH2:18][CH2:19][N:20]([C:3](=[S:4])[NH:2][CH3:1])[CH2:21][CH2:22]1)[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)N1CCC(N(C)C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
A solution of methyl isothiocyanate (500 mg, 6.8493 mmol, 1 eq) in dichloromethane (4 ml) was added dropwise over a period of 5 min to a solution of benzyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-52) (1.7 g, 6.8493 mmol, 1 eq). When the addition was complete, the reaction mixture was stirred for 20 hours at room temperature. Concentration under reduced pressure was then carried out and the crude product was purified by column chromatography (silica gel, 2% methanol in dichloromethane). Yield: 45% (1 g, 3.115 mmol)
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:15][N:16]([CH3:21])[S:17](Cl)(=[O:19])=[O:18].O>C(Cl)(Cl)Cl>[CH3:15][N:16]([CH3:21])[S:17]([N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[CH2:1][CH3:2])(=[O:19])=[O:18]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCc1ncc[nH]1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1nccn1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a stirred solution of 2-ethylimidazole (100 g) and triethylamine (115 g) in chloroform (800 ml) at 0° C. is added a solution of dimethylsulfamoyl chloride (153 g) in chloroform (200 ml). The mixture is stirred overnight at room temperature. Water (1.5 liter) is added to the reaction mixture after which the organic layer is separated and concentrated. The residue is dissolved in ethyl acetate (1 liter) and washed with water, and then dried over sodium sulfate and concentrated. Distillation gives 1-dimethylsulfamoyl-2 -ethylimidazole (182 g) as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])[CH:6]=1)([CH3:4])[CH3:3].[Cl:20][CH2:21][C:22]([NH:24][CH2:25]O)=[O:23]>S(=O)(=O)(O)O>[Cl:20][CH2:21][C:22]([NH:24][CH2:25][C:9]1[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=[C:7]([S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:13])=[O:14])[C:8]=1[OH:11])=[O:23]
Reactant: CN(C)C=NS(=O)(=O)c1cc(C(C)(C)C)ccc1O
Reactant: O=C(CCl)NCO
Agent: O=S(=O)(O)O
Product: CN(C)C=NS(=O)(=O)c1cc(C(C)(C)C)cc(CNC(=O)CCl)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3 g (0.01 mole) of 4-(1,1-dimethylethyl)-2-dimethylaminomethyleneaminosulfonylphenol are dissolved in 30 ml of sulfuric acid, and 1.1 g (0.009 mole) of 2-chloro-N-hydroxymethylacetamide are added. The mixture is stirred for 30 minutes at room temperature and poured into ice water. The product is filtered off with suction and recrystallized from methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH:22]=[O:23])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CCO)cc2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
A solution of 4-[4-(2-hydroxyethyl)-phenoxy]piperidine-1-carboxylic acid tert-butyl ester (8.10 g, 25.2 mmol) in 90 mL of CH2Cl2 was cooled to 0° C. as Dess-Martin periodinane (11.2 g, 26.5 mmol) was added in portions. After stirred at rt overnight, the reaction was diluted with 100 mL of CH2Cl2, and washed with saturated NaHCO3 (5×100 mL), water, and dried over Na2SO4. Flash chromatography with 60% Et2O in hexane gave 2.83 g (35%) of 4-[4-(2-oxo-ethyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester: MS m/z 220 (M-Boc+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH:14]=[CH:13][NH:12][CH2:11][CH2:10]1)[NH:8][C:7]2=[O:16]>CC(O)=O.O=[Pt]=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)[NH:8][C:7]2=[O:16]
Reactant: O=C1NC2(C=CNCC2)c2c(Br)cccc21
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C1NC2(CCNCC2)c2c(Br)cccc21
Yield: 98.8 %

Procedure:
A solution of 7-bromo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridin]-3-one (2 g, 0.0072 mol) in CH3COOH was hydrogenated in the presence of PtO2 for 1.5 h. The catalyst was removed by filtration and the filtrate was concentrated to give the crude product which was washed with saturated aq Na2CO3. The solvent was removed to give the 7-bromospiro[isoindoline-1,4′-piperidin]-3-one (2 g, 100%).