Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[N:3]=1.[OH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: Cc1coc(-c2nc(N)nc(S(C)=O)c2C#N)c1
Reactant: OCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1coc(-c2nc(N)nc(OCCc3ccccn3)c2C#N)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-(4-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: C1([N:7]2[C:11](=[O:12])[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=S)CCCCC1.SCCC[Si](OCC)(OCC)[O:23]CC>C(Cl)(Cl)Cl>[C:8]1(=[O:23])[NH:7][C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]12
Reactant: CCO[Si](CCCS)(OCC)OCC
Reactant: O=C1c2ccccc2C(=S)N1C1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)c2ccccc21
Reaction time: 8 h
Yield: 119.6 %

Procedure:
A 1-quart (0.946l) glass reactor was charged with 400 ml of chloroform, 55.4 g (0.21 mole) of N-cyclohexylthiophthalimide, and 47.6 g (0.20 mole) of 3-mercaptopropyltriethoxysilane dissolved in 400 ml of chloroform. The reaction was stirred and allowed to stand overnight to give white needles of phthalimide (35.2 g) which were separated by filtration and identified by mass spectrometry analysis. The solvent was distilled from the filtrate to give 56.9 g of an oil identified as cyclohexyl-3-dithiopropyltriethoxysilane by mass spectrometry analysis. This oil (53 g) was dissolved in 100 ml of acetone and homogeneously dispersed into N330 carbon black, with the acetone being stripped away.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][O:18][CH2:19]Cl.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][CH2:17][O:18][CH3:19])[N:12]=2)=[CH:6][CH:7]=1
Reactant: OCc1coc(-c2ccc(Cl)cc2)n1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOCc1coc(-c2ccc(Cl)cc2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1.32 g (7.54 mmol) of [2-(4-chlorophenyl)-1,3-oxazol-4-yl]methanol (Example 100A) are initially charged in 18.5 ml of dry THF and cooled to 0° C., and 0.33 g (8.29 mmol) sodium hydride (60% strength in mineral oil) are added. The mixture is stirred at 0° C. for 10 min and then at RT for 1 h. The reaction mixture is again cooled to 0° C., and 0.69 ml (9.04 mmol) of chlorodimethyl ether is added. The mixture is stirred at 0° C. for 10 min and then at RT for 2 h. 5 ml of water are then added, and the reaction mixture is extracted three times with in each case 25 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The product obtained is used without further purification in the subsequent reaction.
Reaction SMILES: [CH:1]12[CH2:7][NH:6][CH:5]1[CH2:4][N:3]([C:8]1C=N[C:15]3[C:10](=[CH:11]C=[CH:13][CH:14]=3)[N:9]=1)[CH2:2]2.ClC1N=C(C)C=C(C)[N:20]=1>>[CH3:13][C:14]1[CH:15]=[C:10]([CH3:11])[N:9]=[C:8]([N:3]2[CH2:4][CH:5]3[CH:1]([CH2:7][NH:6]3)[CH2:2]2)[N:20]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: c1ccc2nc(N3CC4CNC4C3)cnc2c1
Product: Cc1cc(C)nc(N2CC3CNC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 8, using 2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for C11H16N4, 204.27; m/z found 205.2 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[N:14][N:13]3[C@H:23]([CH2:26]OS(C)(=O)=O)[CH2:24][CH2:25][C:12]=23)=[CH:7][CH:6]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.O.C(OCC)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[N:14][N:13]3[C@H:23]([CH2:26][C:1]#[N:2])[CH2:24][CH2:25][C:12]=23)=[CH:7][CH:6]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc(F)cc2)CC[C@H]3COS(C)(=O)=O)n1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nn3c(c2-c2ccc(F)cc2)CC[C@H]3CC#N)n1
Temperature: 70 °C

Procedure:
A mixture of potassium cyanide (44 mg, 0.67 mmol), tetrabutylammonium iodide (catalytic), and (S)-methanesulfonic acid 3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-ylmethyl ester (54 mg, 0.135 mmol) in N,N-dimethylformamide (0.35 mL) and water (0.13 mL) is heated at 70° C. for 4 h. The mixture is cooled, taken up in ethyl acetate (20 mL), washed with water and brine, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (2% methanol/chloroform) to yield the title compound, 25 mg (56%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1([C:28](Cl)=[O:29])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>>[CH2:1]([NH:9][C:28]([C:15]1([CH2:14][CH2:13][CH2:12][CH2:11][Br:10])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:29])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NCCc1ccccc1
Product: O=C(NCCc1ccccc1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from phenethylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2(O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:25](N(CC)CC)[CH3:26].S(Cl)(Cl)=O.C([Mg]Br)C>C1COCC1>[CH2:25]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:7](=[O:12])[N:6]1[CH2:13][C:14]([F:17])([F:16])[F:15])[CH3:26]
Reactant: CCN(CC)CC
Reactant: O=C1Nc2ccc(Cl)cc2C(O)(c2ccccc2)N1CC(F)(F)F
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCC1(c2ccccc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a −20° C. solution of 6-chloro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (5.5 g, 15 mmol) in THF (50 mL) was added triethylamine (10.7 mL, 77 mmol) and then thionyl chloride (1.2 mL, 17 mmol) was added dropwise. After 20 min, 1M ethylmagnesium bromide in THF (46 mL, 46 mmol) was added over 10 min. and the reaction mixture warmed to 0° C. After an additional 30 min at 0° C., the reaction was quenched by pouring into a well stirred mixture of 300 mL EtOAc and 200 mL water which was acidified with 1N HCl solution. The layers were mixed and separated and the organic layer washed with 200 mL brine and filtered to remove unreacted starting material. The filtrate was concentrated in vacuo. Purification by normal phase chromatography (120 g silica gel cartridge, 10-75% EtOAc/hexanes) provided 4-ethyl-6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) δ 8.73 (s, NH); 7.39 (m, 3H); 7.35 (m, 2H); 7.09 (dd, 1H, J=8.43 and 2.2 Hz); 6.70 (d, 1H, J=8.43 Hz); 6.49 (d, 1H, J=2.38 Hz); 3.92 (dq, 1H, J=9.52 and 15.9 Hz); 3.47 (dq, 1H, J=8.61 and 17 Hz); 2.41 (dq, 1H, J=7.14 and 14.29 Hz); 2.28 (dq, 1H, J=7.14 and 14.28 Hz); 0.91 (t, J=7.14 Hz, 3H); MS (Electrospray): m/z 369.2 (M+H)
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][O:13][N:12]=1)([O-:3])=[O:2].C(N)C>>[N+:1]([CH2:4][CH2:5][NH2:6])([O-:3])=[O:2].[O:13]1[CH:14]=[CH:15][C:11]([CH2:10][S:9][CH2:8][CH2:7][NH:6][CH:5]=[CH2:4])=[N:12]1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccon1
Agent: CCN
Product: C=CNCCSCc1ccon1
Product: NCC[N+](=O)[O-]

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene (seeExample 31 (ii)) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH:7](=O)[CH2:8][CH:9]([CH3:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(NCC)C>ClCCl>[CH2:8]([CH:7]1[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(O)CCS
Reactant: CC(C)CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCNCC
Solvent: ClCCl
Product: CC(C)CC1OC(C)CCS1

Procedure:
75 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 4.74 grams (0.055 moles) of isovaleraldehyde is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with diethyl amine to a pH of about 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 8.8 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 3 fractions:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:17][NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[C:34](#[N:36])C>>[C:34]([C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:18]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH3:17])#[N:36]
Reactant: CC#N
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: CNCCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(CCc1ccc(F)cc1)CCC(C#N)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 3-bromo-1,1-diphenylpropane (1.5 g-see Preparation 4), N-methyl-4-fluorophenethylamine (0.766 g-see CA 80:PIZ0985y), anhydrous potassium carbonate (1.38 g) and acetonitrile (50 ml) was heated under reflux for 24 hours then concentrated in vacuo. The residue was dissolved in water (40 ml) and extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with hexane containing dichloromethane (25% up to 100%) and then with dichloromethane containing methanol (0% up to 3%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield, 0.51 g.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:32])([F:33])[F:19])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Product: CC(=O)c1csc(Cn2ccc(NC(=O)/C=C/c3ccccc3C(F)(F)F)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05: tR=0.85 min; [M+H]+=420.84.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O.O.[NH2:23][NH2:24].CCOC(C)=O.Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:3]3[C:2](=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=3)[NH:24][N:23]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
(2-Fluoro-3-trifluoromethyl-phenyl)-(4-methoxy-phenyl)-methanone (59.6 mg, 0.2 mmol) was dissolved in 1 ml of pyridine. Hydrazine hydrate (97 μl, 2 mmol) and 4-(dimethylamino)-pyridine (24.4 mg, 0.2 mmol) were added. The reaction mixture was stirred overnight at 100° C. After cooling to room temperature, EtOAc and 1M HCl were added. The organic phase was washed three times with brine, dried over MgSO4 and concentrated under vacuum. Purification of the crude product by flash column chromatography on silica gel (n-heptane/ethyl acetate, 85:15) afforded 56 mg of the analytically pure product.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[N:7]2)(=[O:32])=[O:33])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc2c(C3CCCC3)n[nH]c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)n2nc(C3CCCC3)c3ccccc32)cc1
Reaction time: 12 h
Yield: 45.7 %

Procedure:
Combine 3-Cyclopentyl-1H-indazole (2.168 g 11.640 mmole) with triethylamine (3.526 g, 34.92 mmoles) in 50 mls of dichloromethane. Dissolve 4-Chlorosulfonyl-benzoic acid methyl ester (4.085 g, 17.460 mmole) in dichloromethane 50 ml and add drop wise to solution at 0° C. Stir the reaction is for 12 hrs. Dilute the reaction and wash with NaHCO3. Dry organic layer over MgSO4 and concentrate. Purify the residue via column chromatography with a mixture of ethyl acetate and hexanes to isolate 2.046 g (Yield=48.5%) of the title compound: MS ES+385.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl>[Si:14]([O:9][CH2:8][C:6]1[N:7]=[C:2]([NH2:1])[CH:3]=[CH:4][CH:5]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: Nc1cccc(CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N)n1
Reaction time: 24 h
Yield: 76.7 %

Procedure:
To a solution of dichloromethane (15 mL) was added (6-aminopyridin-2-yl)methanol (0.72 g, 5.8 mmol), tert-butyl(chloro)dimethylsilane (1.05 g, 6.95 mmol) and triethylamine (1.05 mL, 7.53 mmol). The mixture was stirred for 24 h and washed with saturated sodium bicarbonate (2×30 mL) and aqueous hydrochloric acid (2×30 mL, 0.1 N). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification was done using silica gel chromatography eluting with hexane: ethyl acetate (1:1) and fractions were combined and concentrated to afford the titled product as a white solid (1.06 g, 70%). HPLC: Rt 2.58 min. (96.5% area). 1H NMR (400 MHz, CDCl3), δ: 7.34 (t, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.25 (d, J=8.1 Hz, 1H), 4.54 (s, 2H), 4.27 (bs, 2H), 0.84 (s, 9H), 0.11 (s, 6H); LRMS (ESI): m/z: 239.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[CH:10]([S:12]([OH:15])(=[O:14])=[O:13])[CH3:11].Cl.[NH2:17][CH2:18][CH:19]([SH:24])[CH2:20][C:21]([OH:23])=[O:22]>O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[CH:10]([S:12]([OH:15])(=[O:14])=[O:13])[CH3:11].[NH2:17][CH2:18][C@H:19]([SH:24])[CH2:20][C:21]([OH:23])=[O:22]
Reactant: NCC(S)CC(=O)O
Agent: CC(c1ccc(Cl)c(Cl)c1Cl)S(=O)(=O)O
Agent: Cl
Solvent: O
Product: NC[C@H](S)CC(=O)O

Procedure:
(-)-1-(2,3,4-Trichlorophenyl)ethanesulfonic acid (3.18 g) is dissolved in water (17.4 ml), and thereto is added aqueous solution of racemic 4-amino-3-mercaptobutyric acid hydrochloride (3.77 g) in water (24.6 ml). The mixture is dissolved at 70° C.-80° C., and allowed to cool. After cooling, the mixture is stirred under ice-cooling for one hour, and the precipitated crystals are collected by filtration, washed, and dried to give (3R)-4-amino-3-mercaptobutyric acid (-)-1-(2,3,4-trichlorophenyl)ethanesulfonate (3.81 g).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([O:13][C:14](=[O:35])[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:34])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][CH3:30])=[C:25]([N+:31]([O-])=O)[CH:24]=2)[CH2:17]1)([CH3:12])([CH3:11])[CH3:10].[CH2:36]([N:38]1[C:42]2=[N:43][CH:44]=[CH:45][CH:46]=[C:41]2[CH:40]=[C:39]1[CH:47]=O)[CH3:37]>O.C(O)C.C(Cl)Cl.[O-]S([O-])(=O)=O.[Na+].[Na+]>[C:9]([O:13][C:14](=[O:35])[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([C:23]2[CH:28]=[CH:27][C:26]3[N:29]([CH3:30])[C:47]([C:39]4[N:38]([CH2:36][CH3:37])[C:42]5=[N:43][CH:44]=[CH:45][CH:46]=[C:41]5[CH:40]=4)=[N:31][C:25]=3[CH:24]=2)=[O:34])[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CCn1c(C=O)cc2cccnc21
Reactant: CNc1ccc(C(=O)N2CCCC(NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCn1c(-c2nc3cc(C(=O)N4CCCC(NC(=O)OC(C)(C)C)C4)ccc3n2C)cc2cccnc21
Temperature: 100 °C
Yield: 54 %

Procedure:
Sodium hydrosulfite (235 mg, 1.150 mmol) dissolved in water (1.500 mL) was added to a solution of tert-butyl(1-(4-(methylamino)-3-nitrobenzoyl)piperidin-3-yl)carbamate (145 mg, 0.383 mmol) and 1-ethyl-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (66.7 mg, 0.383 mmol) in ethanol (3 mL) at RT under nitrogen. The reaction mixture was heated to 100° C. in a microwave for 5 h. The reaction mixture was diluted with DCM (20 mL), Na2SO4 was added and the resultant suspension filtered and concentrated in vacuo to yield the crude product as a yellow oil. The crude product was purified by Biotage SP4 on a SNAP 25 g silica cartridge using a gradient of 0% (20% MeOH/DCM)/DCM→100% (20% MeOH/DCM)/DCM. Appropriate fractions were combined and evaporated under vacuum to give the title compound as a yellow solid (104 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:30](O)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)C(=O)O
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)C(C)(C)C)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
99 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 20 mg (0.20 mmol, 1.0 eq.) of pivalic acid were reacted according to General Method 1. Yield: 56 mg (73% of theory)
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[C:11]1([CH2:17][CH2:18][CH2:19][NH:20][S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:24](/[S:21]([NH:20][CH2:19][CH2:18][CH2:17][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:23])=[O:22])\[C:25]#[N:26])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCS(=O)(=O)NCCCc1ccccc1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)NCCCc1ccccc1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and (3-phenyl-n-propyl)aminosulfonylacetonitrile as in Example 1 gave (E)-3-(2-nitrothien-5-yl)-2-[(3-phenyl-n-propyl)aminosulfonyl]acrylonitrile
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O1CCCC1.CO.C[Si]([C:18]#[C:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)(C)C>O>[C:19]([C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1)#[CH:18]
Reactant: C[Si](C)(C)C#Cc1cccc(S(N)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#Cc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.6 %

Procedure:
Under cooling in an ice bath, potassium carbonate (610 mg) was added to a tetrahydrofuran (30 mL) and methanol (70 mL) solution of 3-[(trimethylsilyl)ethynyl]benzenesulfonamide (11.1 g), and the obtained solution was then stirred at a room temperature for 12 hours. Thereafter, water was added to the reaction solution, and the solvent was then distilled away under a reduced pressure. Then, the residue was extracted with diethyl ether. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel 60N, hexane:ethyl acetate=2:1 to 1:1), so as to obtain the title compound (5.84 g) in the form of a light brown solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH:19]=[O:20])=[N+:2]=[N-:3].[CH2:28](O)[CH2:29][OH:30].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]2[O:30][CH2:29][CH2:28][O:20]2)[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])=[N+:2]=[N-:3]
Reactant: OCCO
Reactant: COc1cc(C=O)cc(OCCOCCOCCOCCN=[N+]=[N-])c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C2OCCO2)cc(OCCOCCOCCOCCN=[N+]=[N-])c1OC
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A mixture of 4.95 g (12.91 mmol) 3-{2-[2-(2-{2-azidoethoxy}ethoxy)ethoxy]ethoxy}-4,5-dimethoxybenzaidehyde 8, 5 ml (5.57 g, 90 mmol) ethylene glycol and 200 mg (1.0 mmol) p-toluene sulfonic acid monohydrate was refluxed in 120 ml of toluene for 8 hrs using a Dean-Stark trap. After cooling to room temperature the rection mixture was poured into 200 ml of diluted sodium bicarbonate solution, washed with water and brine and dried over magnesium sulfate. After removal of the solvent the residue was purified by silica gel column chromatography (cyclohexane/ethyl acetate 1/1), giving 4.43 g (10.8 mmol, 80%) of the product as a clear oil. 1H-NMR (CDCl3) δ=6.73 (dd, 2H, J=5.0 Hz, J=1.8 Hz), 5.72 (s, 1H), 4.19 (m, 2H), 4.11 (m, 2H), 4.03 (m, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.76-3.71 (m, 4H), 3.70-3.64 (m, 8H), 3.37 (m, 2H) ppm. 13C-NMR δ=153.3, 152.4, 139.2, 133.1, 105.4, 103.6, 103.4, 70.7, 70.6, 70.5 (2 peaks), 69.9, 69.6, 68.7, 65.1, 60.6, 56.0, 50.6 ppm. MS: m/z=427 [M]+. Anal. calcd for C19H29N3O8: C, 53.39, H, 6.84, N, 9.83. Found C, 52.30, H, 6.89, N, 9.72.