Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]12[O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]2>O>[N:1]1([C@@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: C1CCC2OC2C1
Solvent: O
Product: O[C@@H]1CCCC[C@H]1N1CCCC1
Temperature: 90 °C
Yield: 98 %

Procedure:
Pyrrolidine (4.26 g, 60 mmol) was added to a solution of cyclohexene oxide (1.96 g, 20 mmol) in H2O (6 mL), and the resulting mixture was heated at 90° C. for 16 hours. After cooling, the solvent was removed under reduced pressure and the resulting residue was extracted with DCM (10 mL×3). The organic phasew were combined and dried with anhydrous Na2SO4. After removing the Na2SO4 by filtration, the solvent was evaporated and the material dried under vacuum to afford the desired compound (+/−)-1 (3.3 g, 19.5 mmol, yield 98%). 1H NMR (CDCl3) δ 4.06 (s, 1H), 3.45-3.30 (m, 1H), 2.75-2.63 (m, 2H), 2.62-2.50 (m, 2H), 2.51-2.42 (m, 1H), 1.90-1.58 (m, 8H), 1.45-1.15 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:33][NH:34][CH3:35].C(O)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9]([N:34]([CH3:35])[CH3:33])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
5-Cyano-2-{(4S)-5-cyano-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (40 mg, 83 μmol) was dissolved in THF (5 ml), a 33% strength solution of dimethylamine in ethanol (37 μl, 208 μmol; 2.5 eq.) was added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (13.8 mg, 34% of theory).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24](=O)[CH2:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18]2)=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) according to the general procedure M. Obtained as a light yellow solid (140 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[CH:6]=[C:7]([C:9]3[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=3)[N:8]=[C:2]12.[Br:17]Br>C(O)(=O)C>[Br:17][C:6]1[N:3]2[C:2]([S:1][CH:5]=[CH:4]2)=[N:8][C:7]=1[C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[O:14])=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(-c2cn3ccsc3n2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=Cc1ccc(-c2nc3sccn3c2Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Imidazo[2,1-b]thiazol-6-yl-benzaldehyde (3.8 g, 14.9 mM) is dissolved in 30 mL acetic acid. A solution of bromine (1.1 eq) in acetic acid (15 mL) is added to the reaction mixture. The reaction mixture is stirred for 3 h at room temperature. The solid obtained is collected by filtration and re-dissolved in water (100 ml) and the solution neutralized by aqueous ammonia. The solid obtained is collected by filtration and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([O:10]C)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(O)cc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
To a solution of (35) (15.0 g, 69.0 mmol) in CH2Cl2 (40 mL), cooled to 0° C., a 1 M BBr3 solution in CH2Cl2 (140 mL, 140 mmol) was added dropwise. The ice bath was removed and the reaction was stirred at room temperature for 18 h. The reaction was quenched with MeOH and concentrated. The residue was dissolved in EtOAc (500 mL) and washed with water (300 mL). The organic layer was separated, dried (Na2SO4) and concentrated to give 5-bromobenzene-1,3-diol (45) (13.03 g, >99%) as an orange oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH3:9][C:10]1([CH3:26])[C:14]([CH3:16])([CH3:15])[O:13][B:12]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=2)[O:11]1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[CH3:15][C:14]1([CH3:16])[C:10]([CH3:9])([CH3:26])[O:11][B:12]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[CH:19][CH:18]=2)[O:13]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC1(C)OB(c2ccc(CCN)cc2)OC1(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2ccc(CCNS(=O)(=O)CCCCl)cc2)OC1(C)C
Temperature: 23 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
Add 3-chloropropanesulfonyl chloride (0.285 g, 1.6 mmol) to a suspension of 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethylamine (0.383 g, 1.3 mmol) in dichloromethane (10 mL) at 0° C. Then slowly add DBU (0.457 g, 3.0 mmol) and allow the mixture to warm up to 23° C. Stir 2 h at 23° C. and add more dichloromethane and 1M HCl. Separate layers and wash organic phase with more HCl (×2). Back-extract aqueous phase with dichloromethane (×2). Combine organic phases and wash them with brine, dry over sodium sulfate, concentrate over Celite® and purify by flash chromatography (silica gel), eluting with hexanes-ethyl acetate 3:1 to give 0.333 g of the desired compound as a thick oil. Mass spectrum ESI positive (m/z): 388 (M+1), 410 (M+23).
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:4]=2[N:3]=1
Reactant: COCCOCCl
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2COCCOC
Reaction time: 66 h
Yield: 24 %

Procedure:
To a solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (6 g, 26.5 mmol) in anhydrous DMF (30 ml) was added sodium carbonate (3.09 g, 29.15 mmol). After 10 minutes stirring at room temperature methoxyethoxymethylchloride (3.03 ml, 26.5 mmol) was added and stirring continued under nitrogen at room temperature for 66 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (100 ml) and washed with brine (100 ml), the aqueous extract was extracted with DCM (100 ml) and the organic extracts dried (MgSO4) combined and concentrated in vacuo. The residue was triturated with EtOAc and the solid filtered off. Concentration of the filtrate afforded a light brown oil that was absorbed onto silica and purified by SPE (Si, 50 g) eluting with a gradient of 1:1 EtOAc/cyclohexane-EtOAc to afford the title compound as a white solid (2 g, 24%), m/z 315.2[MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>ClCCl>[F:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:42])=[CH:36][CH:35]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (33.6 mg, 0.33 mmol) (Aldrich), followed by the addition of 1-fluoro-4-isocyanato-benzene (39.7 mg, 0.22 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-fluoro-phenyl)-amide as a white solid (Yield 40 mg, 59%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:27][CH2:28][CH3:29])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl[CH2:31][O:32][CH2:33][CH3:34].C1C=CC=CC=1>CCCCCC>[CH2:33]([O:32][CH2:31][N:3]1[C:4]([CH2:27][CH2:28][CH3:29])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]1[CH3:1])[CH3:34]
Reactant: CCCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(C)N1
Reactant: CCOCCl
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(C)N1COCC

Procedure:
By following the same procedure as in Example 25 except that 0.5 g. of diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.5 g. of chloromethoxyethane were used as the starting materials, benzene was used as the eluant, and hexane was used as the solvent for recrystallization, 0.35 g. of colorless acicular crystals of diethyl 1-ethoxymethyl-2-methyl-4-(3-nitrophenyl)-6-propyl-1,4-dihydropyridine-3,5-dicarboxylate melting at 97° C. were obtained.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Br:15]CCCCCCCCCCCCBr>Br>[Br:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCCCCCCCCCCCO
Reactant: BrCCCCCCCCCCCCBr
Agent: Br
Product: OCCCCCCCCCCCCBr

Procedure:
1,12-Dodecanediol (50 g, 0.25 mol) in hydrogen bromide 48% (220 ml) was continuously extracted with petroleum ether (b.p. 80-100° C.) (300 ml) for 18 hours. The solvent was evaporated under reduced pressure and the crude oil obtained was filtered through a pad of silica gel. Elution with petroleum ether (b.p. 40-60° C.) gave a colourless fraction containing 1,12-dibromododecane. The silica gel was then eluted with acetone to give the title compound as a pale yellow oil after evaporation of the solvent. The title compound crystallised upon cooling and was recrystallised from petroleum ether (b.p. 40-60° C.).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[CH:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>>[CH:18]1([C:24]([O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)C3CCCCC3)CC2)cc1

Procedure:
from trans-4-(4-dimethylaminomethylphenyl)-cyclohexanol and cyclohexane carboxylic acid chloride/triethylamine. White crystals.
Reaction SMILES: Cl[C:2]([CH3:17])([CH3:16])[CH:3]([N:14]=[O:15])[CH2:4][N:5]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]1[N+:11]([O-:13])=[O:12].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([CH3:30])([CH3:29])[C:24](=[N:27][OH:28])[CH2:25]C.CCN(C(C)C)C(C)C>C(#N)C>[CH3:16][C:2]([CH3:17])([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([CH3:30])([CH3:29])[C:24](=[N:27][OH:28])[CH3:25])[C:3](=[N:14][OH:15])[CH2:4][N:5]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]1[N+:11]([O-:13])=[O:12]
Reactant: CCC(=NO)C(C)(C)NCCCN
Reactant: Cc1cn(CC(N=O)C(C)(C)Cl)c([N+](=O)[O-])n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=NO)C(C)(C)NCCCNC(C)(C)C(Cn1cc(C)nc1[N+](=O)[O-])=NO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3-Chloro-3-methyl-2-nitroso-1-(4-methyl-2-nitro-1H-imidazol-1-yl)butane (3.41 g, 13.09 mmol) was added in portions to a stirred solution of N-(3-aminopropyl)-1-amino-1,1-dimethyl-2-butanone oxime (2.0 g, 11.56 mmol, Example 1) and (i-Pr)2NEt (1.64 g, 13.09 mmol) in dry acetonitrile (20 mL) at 50° C. under a nitrogen atmosphere. After the addition the reaction mixture was stirred for an additional 2 hours at 50° C. and cooled to room temperature. The solid which formed was filtered and recrystallized from acetonitrile to provide the title product as a light yellow colored solid. Yield: 3.08 g (59.4%); mp. 140-141° C.; 1H NMR (DMSO-d6) δ1.12 & 1.19[2s, 6H, C(CH3)2], 1.33(m, 2H, CH2CH2CH2), 1.70[s, 3H, C(═N)CH3], 1.79(bs, 2H, NH), 2.15(s, 3H, imi-CH3), 2,19(m, 4H, NHCH2), 5.19[s, 2H, NCH2C(═N)], 7.05(s, 1H, imi-CH) and 10.33 & 11.36(2s, 2H, NOH). Ms m/e 398 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([C:33]#[N:34])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([C:33]#[N:34])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncc(C#N)n4cc3-c3ccccc3)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-9 (46 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 4-10.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH2:17])[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH:17][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc2ccc3c(c2o1)C(CCN)CC3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2ccc3c(c2o1)C(CCNC(=O)c1ccccc1)CC3
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethanamine hydrochloride (100 mg, 0.396 mmol) and triethylamine (111 μL, 0.792 mmol) were dissolved in tetrahydrofuran (4 mL), benzoyl chloride (55.1 μL, 0.475 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→60/40) to give the title compound (55.6 mg, yield 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:7]2=[O:24].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])[N:8]([CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:7]2=[O:24]
Reactant: CC(C)(C)[Si](C)(C)OCCCn1c(Cl)nc2c(Br)cccc2c1=O
Reactant: CC(C)(C)N
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1CCCO[Si](C)(C)C(C)(C)C
Temperature: 130 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of 8-bromo-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloroquinazolin-4(3H)-one (500a; 0.080 g, 0.185 mmol) in tert-butylamine (Aldrich; 0.584 mL, 5.56 mmol) was sealed and heated in a biotage initiator microwave at 100° C. for 30 min, 130° C. for 30 min, and 150° C. for 60 min. The reaction was partitioned between satd aq sodium bicarbonate and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-2-(tert-butylamino)-3-(3-((tert-butyldimethylsilyl)oxy)propyl)quinazolin-4(3H)-one (0.077 g, 0.164 mmol, 89% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (1H, dd, J=8.0, 1.4 Hz), 7.85 (1H, dd, J=7.6, 1.4 Hz), 6.97 (1H, t, J=7.8 Hz), 5.24 (1H, s), 4.10 (2H, t, J=7.1 Hz), 3.75 (2H, t, J=5.4 Hz), 1.85-1.99 (2H, m), 1.62 (9H, s), 0.95 (9H, s), 0.12 (6H, br. s.). m/z (ESI, +ve ion) 468.0/470.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:3]1=2.S(=O)(=O)(O)O.[CH2:27]([OH:29])[CH3:28]>>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([O:29][CH2:27][CH3:28])=[O:19])=[CH:16][C:3]1=2
Reactant: CCO
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1ccccc1S2
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc2c(c1)C(=O)Cc1ccccc1S2
Reaction time: 1 h

Procedure:
To 200 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]thiepin-2-yl)-propionamide in 4 ml of ethanol was added 0.4 ml of conc. sulfuric acid and the mixture was refluxed with stirring for 1 hour. The solvent was distilled off to obtain the residue, to which was added pieces of ice, and the mixture was extracted with ethyl acetate and the extract was washed with saturated sodium hydrogen carbonate, then saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain brown oil, which was chromatographed over silica gel, and eluted with benzene-chloroform. There was obtained 141 mg of ethyl 2-(10,11-dihydro-11-oxo dibenzo[b,f]-thiepin-2-yl)-propionate as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[C:17]1([CH2:23][S:24](Cl)(=[O:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:24]([CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:26])=[O:25])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)Cc3ccccc3)c2)cc1Cl
Yield: 42.8 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, leg) in anhydrous pyridine (500 μl) was added alpha-toluenesulfonyl chloride (18.3 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-1-phenyl-methanesulfonamide (14.3 mg, >95% purity, yield: 42.8%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 2): ESI-MS m/z: 384 [M+H]+, retention time=2.22 min, 1H NMR (400 MHz, DMSO-d6) δ ppm 4.65 (s, 2H) 7.29-7.32 (m, 5H) 7.63 (t, J=2.21 Hz, 1H) 7.76 (dd, J=8.15, 1.71 Hz, 1H) 8.00 (d, J=1.64 Hz, 1H) 8.09 (d, J=8.21 Hz, 1H) 8.35 (d, J=2.53 Hz, 1H) 8.61 (d, J=2.02 Hz, 1H) 10.24 (br. s., 1H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:22](O)(=[O:25])[CH2:23][OH:24]>O1CCCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH2:6][C:7]([O:9][C:23](=[O:24])[CH2:22][OH:25])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)O
Reactant: O=C(O)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)SCCC(=O)OC(=O)CO
Reaction time: 8 h

Procedure:
3-(Acetylthio)propanoic acid (2.96 g.) and 1,1'-carbonyldiimidazole (3.24 g.) are dissolved in 20 ml. of dry tetrahydrofuran with stirring at room temperature. After twenty minutes, a solution of glycolic acid (1.52 g.) and 2.80 ml. of triethylamine in 15 ml. of tetrahydrofuran are added. The reaction mixture is stored overnight at room temperature. The tetrahydrofuran is removed in vacuo, the crude residue taken up into ethyl acetate, washed with 1 N hydrochloric acid and three times with water, dried over magnesium sulfate and the O-(3-acetylthiopropanoyl)glycolic acid is concentrated to dryness in vacuo, yield 3.9 g. This is dissolved in ether and dicyclohexylamine is added. The dicyclohexylamine salt precipitates, yield 2.85 g., m.p. 150°-157°. The salt is converted to the free acid by adding to ethyl acetate and adding 10% potassium bisulfate solution, yield 1.5 g.
Reaction SMILES: [NH2:1][C:2](=[N:38][OH:39])[CH2:3][O:4][NH:5][C:6]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37])=[O:7].N1C=CC=CC=1.Cl[C:47](=O)[C:48]([O:50][CH3:51])=[O:49]>ClC(Cl)C>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[CH:9]1[CH:8]([C:6]([NH:5][O:4][CH2:3][C:2]2[N:1]=[C:47]([C:48]([O:50][CH3:51])=[O:49])[O:39][N:38]=2)=[O:7])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[NH:25][S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(N)=NO)C1c1ccc(Cl)cc1Cl
Reactant: COC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1nc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)no1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1000 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 26 ml of dichloroethane was added dropwise 0.4 ml of pyridine, and then 0.23 ml of methyl chloro(oxo)acetate was added dropwise thereto under ice-cooling, followed by stirring at 0° C. for 10 minutes, at room temperature for 20 minutes, and at 80° C. for 2 hours. The reaction solution was cooled to room temperature, washed with 0.1 M hydrochloric acid and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 670 mg of methyl 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazole-5-carboxylate as a white amorphous substance.