Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:18]([SH:21])[CH2:19][CH3:20].N1CCCCC1>>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH:16]([S:21][CH2:18][CH2:19][CH3:20])[CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCCCCC1=CCCC1=O
Reactant: CCCS
Solvent: C1CCNCC1
Product: CCCSC1CCC(=O)C1CCCCCCC(=O)OCC
Reaction time: 120 h

Procedure:
A mixture of 6 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone, 10 ml. of propanethiol, and 7.2 ml. of piperidine is allowed to stand for 5 days at room temperature, then diluted with 150 ml. of ether, and the ether phase is washed first with a mixture of 60 ml. of ice water and 6 ml. of concentrated HCl, and then with saturated aqueous NaCl solution, dried over NaSO4, and the solvent distilled off. After purifying the residue by chromatography (silica gel/chloroform), 2-(carbethoxyhexyl)-3-propylthio-cyclopentanone is produced as an oil.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:12])[O:9][CH2:10]Cl)([O-:3])=[O:2].[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][O:23][C:24]2[CH:37]=[CH:36][C:27]([CH2:28][CH:29]3[S:33][C:32](=[O:34])[NH:31][C:30]3=[O:35])=[CH:26][CH:25]=2)=[N:19][CH:20]=1)[CH3:14].C(N(CC)CC)C>C(Cl)Cl.O>[N+:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:12])[O:9][CH2:10][N:31]1[C:30](=[O:35])[CH:29]([CH2:28][C:27]2[CH:36]=[CH:37][C:24]([O:23][CH2:22][CH2:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:13][CH3:14])=[CH:20][N:19]=3)=[CH:25][CH:26]=2)[S:33][C:32]1=[O:34])([O-:3])=[O:2]
Reactant: O=C(NCCO[N+](=O)[O-])OCCl
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(CCOc2ccc(CC3SC(=O)N(COC(=O)NCCO[N+](=O)[O-])C3=O)cc2)nc1
Reaction time: 8 h

Procedure:
A solution of chloromethyl 2-(nitrooxy)ethylcarbamate (2, 13.37 g, 67.3 mmol) in CH2Cl2 (20 ml) is added drop-wise to a suspension of 5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)-thiazolidine-2,4-dione (pioglitazone, 12 g, 33.7 mmol) in CH2Cl2 (160 ml) and triethylamine (9.38 ml, 67.3 mmol) at 22° C. (room temperature) under an argon atmosphere. The reaction is stirred for 8 h. The reaction is diluted with CH2Cl2 and H2O and the layers separated. The organic layer is dried (MgSO4) and the solvent evaporated to give the crude product. The crude material is purified by column chromatography (silica, 40:60 ethyl acetate:heptane, product Rf 0.3 (80:20 ethyl acetate:heptane) to give the title compound (5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzyl)-2,4-dioxothiazolidin-3-yl)methyl 2-(nitrooxy)ethylcarbamate (1), 5.3 g (30%), as a white solid.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[C:28](=[O:30])[CH3:29])=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Agent: Cl
Product: CC(=O)N1C[C@H](S(=O)(=O)c2ccccc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was acylated with acetic anhydride in analogy to experiment L29 to give (2S,4R)-1-acetyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless solid. MS: 430.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>C(O)C>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:9]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:17][CH:16]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COCCNCCCNCCOC
Solvent: CCO
Product: COCCNCCCN(CCOC)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.4 %

Procedure:
To a solution of N,N'-bis(methoxyethyl)-1,3-propanediamine (4.5 g, 23.9 mmol) in ethanol (100 ml) was added under ice-cooling a solution of p-fluorobenzyl chloride (2.8 g, 19.1 mmol) in ethanol (50 ml) and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure and the resulting white oily substance was subjected to silica gel chromatography to obtain 2.3 g of the title compound as a colorless oily substance from the fraction from methylene chloride-methanol-aqueous ammonia. Yield=40%.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.Cl.[NH2:10][CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13].C>O1CCOCC1>[N:10]([CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=[C:2]=[O:1]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(N)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(N=C=O)C(=O)OC
Yield: 80 %

Procedure:
9.7 mL diphosgene is added dropwise over 50 minutes to a mixture of 12.85 g dimethyl aminomalonate hydrochloride and 0.1 g activated charcoal in 25 mL dioxane under N2. The reaction mixture is warmed to 75°-80° C. during this time. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is purified by fractional distillation (bp 80°-85° C., <1 mm Hg) to give pure dimethyl isocyanatomalonate in >80% yield.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C@H:8]([OH:19])[C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C@H:8]([O:19][S:30]([CH3:29])(=[O:32])=[O:31])[C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](c1ccc(Cl)c(Cl)c1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)c(Cl)c1)[C@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of (2R,3R)-1-(tert-butyl-dimethyl-silyloxy)-3-(3,4-dichloro-phenyl)-butan-2-ol (4.63 g, 13.2 mmol) in DCM (44 mL) at 0° C. were added Et3N (4.6 mL, 33.0 mmol), DMAP (81.0 mg, 0.7 mmol), and MsCl (2.2 ml, 28.4 mmol). The mixture was stirred overnight at rt. The reaction was quenched with water (100 mL) and extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to yield an orange oil. The product was purified by flash chromatography (Et2O/hexanes) to afford 4.99 g (88%) of the desired product as a colorless liquid. 1H NMR (400 MHz, CDCl3): 7.39 (d, J=8.3, 1H), 7.35 (d, J=2.1, 1H), 7.12 (dd, J=8.3, 2.1, 1H), 4.72-4.69 (m, 1H), 3.71 (dd, J=11.4, 5.7, 1H), 3.64 (dd, J=11.4, 4.3, 1H), 3.24-3.18 (m, 1H), 2.81 (s, 3H), 1.36 (d, J=7.2, 3H), 0.90 (s, 9H), 0.06 (s, 3H), 0.06 (s, 3H).
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[C:12](Cl)(=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O.CCOCC.CCOC(C)=O>[CH2:14]([O:13][C:12]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1)=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 5 °C
Yield: 111.4 %

Procedure:
A 500-mL 4-necked round-bottom flask was charged with a solution of NaOH (8 g, 198.00 mmol, 1.00 equiv, 99%) in H2O (200 mL). To this was added piperidine-3-carboxylic acid (25.8 g, 197.75 mmol, 1.00 equiv, 99%), in small portions at 0° C. Then, a solution of benzyl carbonochloridate (39.2 g, 227.48 mmol, 1.15 equiv, 99%) in Et2O (50 mL) was added at 0° C. over 40 minutes. Then a solution of NaOH (12 g, 1.50 equiv) in H2O (300 mL) was added drop wise with stirring at 0-10° C. The resulting solution was allowed to stir overnight at room temperature. The reaction progress was monitored by TLC (EtOAc/PE=1/1). The pH adjusted to 3 with 10% aqueous HCl. The resulting solution was extracted with ethyl acetate (3×500 mL). Combined organic layers were dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator to afford 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid (58 g) as white solid.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C([O-])([O-])=O.[K+].[K+].[CH3:11][O:12][C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]34[CH2:38][CH:33]5[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]5)[CH2:30]3)[CH2:36]4)[CH:23]=2)=[CH:18][CH:17]=1.O>CN(C=O)C>[CH3:11][O:12][C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:2][C:3]#[N:4])=[C:24]([C:29]34[CH2:38][CH:33]5[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]5)[CH2:30]3)[CH2:36]4)[CH:23]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(-c2ccc(OCC#N)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
Bromoacetonitrile (84 mg, 0.7 mmol), K2CO3 (166 mg, 1.2 mmol) and KI (53 mg, 0.32 mmol) were added to a solution of (E)-3-(3′-adamantan-1-yl-4′-hydroxybiphenyl-4-yl)-acrylic acid methyl ester (250 mg, 0.64 mmol) in DMF (2 ml). The mixture was stirred at RT for 3 h. Cold water was added and the solution was extracted with EtOAc. The organic layer was washed with a saturated solution of NaHCO3, water and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to obtain (E)-3-(3′-adamantan-1-yl-4′-cyanomethoxybiphenyl-4-yl)-acrylic acid methyl ester (240 mg, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:23]I.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[N:13]=2)[CH3:23])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CI
Reactant: COc1ccc(Nc2nc(C)nc3ccccc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(C)nc3ccccc23)cc1OC

Procedure:
The title compound was prepared from (3,4-dimethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (288 mg, 0.98 mmol), methyl iodide (0.094 ml, 1.47 mmol), sodium hydride (60 mg, 1.5 mmol) in DMF similar to example 21 to give 70 mg (23%) of off white solids. 1H NMR (CDCl3): 7.75-7.72 (m, 1H), 7.56-7.50 (m, 1H), 7.05-6.94 (m, 2H), 6.85 (d, J=7.5 Hz, 1H), 6.76-6.71 (m, 2H), 3.92 (s, 3H)), 3.78 (s, 3H), 3.61 (s, 3H), 2.73 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35][C:36](N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12]([N:14]3[CH2:36][CH2:35][C@H:16]([OH:17])[CH2:15]3)=[O:13])[CH:19]=[CH:20][C:21]=2[CH3:22])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: Cc1ccc(C(=O)N2CC[C@H](O)C2)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (S)-3-hydroxypyrrolidine for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.31 (d, 1H, J=7.6 Hz), 7.62 (m, 2H), 7.52 (m, 2H), 7.01 (m, 2H), 5.59 (m, 2H), 4.42 .(m, 1H), 3.64 (m, 4H), 2.19 (s, 3H), 2.00 (m, 2H). ESHRMS m/z 476.1147 (M+H calculated for C23H21ClF2N3O4 requires 476.1183).
Reaction SMILES: ICI.C([Zn]CC)C.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(C1[C:18]([C:23]([O:25][CH3:26])=[O:24])=[N:19][CH:20]=CC=1)=C>C(Cl)Cl.[Cl-].[NH4+]>[CH:11]1([C:12]2[C:18]([C:23]([O:25][CH3:26])=[O:24])=[N:19][CH:20]=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: CCCCCC
Reactant: C=Cc1cccnc1C(=O)OC
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: ICI
Product: COC(=O)c1ncccc1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diiodomethane (2.46 g, 9.20 mmol) in dry DCM (5 ml) at −10° C. was added diethyl zinc in hexane (1 M, 9.2 ml, 9.20 mmol). The reaction was stirred for 30 minutes under nitrogen. To this was then added methyl 3-ethenylpyridine-2-carboxylate (0.30 g, 1.84 mmol) as a solution in DCM (5 ml) over a 15 minute period. The reaction was then allowed to warm to room temperature and was stirred at room temperature for 15 hours. The reaction mixture was diluted with a saturated solution of ammonium chloride (25 ml) and the organics were extracted with ethyl acetate (3×30 ml). The combined organics were washed with water (25 ml), brine (25 ml), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-15% ethyl acetate/n-hexane to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C@@:22]2([CH3:25])[CH2:24][O:23]2)=[O:21])=[CH:15][C:14]=1[CH3:26])#[N:12].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:25][C@@:22]([OH:23])([CH3:24])[C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[C:14]([CH3:26])[CH:15]=2)=[O:21])=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: Cc1cc(NC(=O)[C@@]2(C)CO2)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)[C@@](C)(O)COc2ccc(C#N)c(F)c2)ccc1C#N
Temperature: 50 °C
Reaction time: 25.5 h
Yield: 70.8 %

Procedure:
2-Fluoro-4-hydroxy benzonitrile (0.81 g, 5.9 mmol) and (2R)-2-methyl-oxirane-2-carboxylicacid-(4-cyano-3-methylphenyl)amide (0.905 g, 4.2 mmol) were dissolved in 17.6 ml of EtOAc. Anhydrous K2CO3 (0.29 g; 2.1 mmol) was added and the mixture heated to 50° C. and stirred for 25.5 hours. The mixture was cooled to room temperature, 30 ml of EtOAc added and washed first with 2×24 ml of 1M Na2CO3 and then 2×24 ml of water. Organic layer was dried over Na2SO4, filtered and evaporated to give 1.05 g of crude product.
Reaction SMILES: [Cl-].[OH-].[OH-].C([Sn+3])CCC.[CH:9]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.COC1C=CC(O)=CC=1.C1(C=CC(O)=CC=1)O.[C:39](OC)(=[O:43])[C:40]([CH3:42])=[CH2:41]>CCCCCCC>[C:39]([O:21][CH:9]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:43])[C:40]([CH3:42])=[CH2:41]
Reactant: OC1CCCCCCCCCCC1
Reactant: C=C(C)C(=O)OC
Agent: CCCC[Sn+3]
Agent: COc1ccc(O)cc1
Agent: Oc1ccc(O)cc1
Solvent: CCCCCCC
Product: C=C(C)C(=O)OC1CCCCCCCCCCC1

Procedure:
Monobutyltin dihydroxide monochloride (6.0 parts) was heated under vacuum to oligomerize it. To the oligomerized catalyst was added cyclododecanol (184 parts), 4-methoxyphenol (0.5 parts), hydroquinone (0.5 parts), heptane (50 parts) and methyl methacrylate (300 parts) and the reaction mixture was heated as in Example 1. Methanol, heptane, and excess methyl methacrylate were removed from the crude product. To remove the tin catalyst and polymerization inhibitors, the crude product containing approximately 50% solvent was washed three times with 159 sodium hydroxide at 20% of batch weight. After reducing alkalinity by washing the product with a 15% sodium chloride brine solution, the organic layer was concentrated to yield 228 parts (90% based on cyclododecanol) yield of cyclododecyl methacrylate. The purity was greater than 98%. Analysis for residual tin was 740 ppm.
Reaction SMILES: [O:1]1[C:5]2([CH2:16][CH2:15][CH2:14][C:7]3([CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8]3)[CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:1]1[C:5]2([CH2:16][CH2:15][CH2:14][C:7]3([CH2:11][CH2:10][CH:9]([CH2:12][O:13][S:23]([C:20]4[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=4)(=[O:25])=[O:24])[CH2:8]3)[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCC2(CCCC3(C2)OCCO3)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC3(CCCC4(C3)OCCO4)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (1,4-dioxa-dispiro[4.1.4.3]tetradec-9-yl)methanol (14a) (1.20 g, 5.3 mmol) in dry pyridine (12 mL) at 0° C. was added 4-dimethylamino-pyridine (catalytic amount) and p-toluenesulfonyl chloride (2.04 g, 10.6 mmol). The reaction mixture was stirred at room temperature for 24 hours and then poured into a 2 M HCl solution (50 mL). The aqueous solution was extracted with CH2Cl2 and the combined organic layers were washed with a 2 M HCl solution and then with a saturated K2CO3 solution. After drying over anhydrous MgSO4, the solvent was removed in vacuo to afford the desired product as a colorless oil which was used without further purification in the next step.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19](Cl)=[O:20].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[O:12][CH2:11][CH2:10][N:9]([C:19](=[O:20])[CH2:18][C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cccs1)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.9 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and thiophen-2-yl-acetyl chloride (401.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:3). The fractions containing 1-(2-phenylmorpholin-4-yl)-2-(thiophen-2-yl)ethan-1-one are collected and the solvent is removed in vacuo to give 511 mg of colorless oil.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].BrBr.[CH3:7][O:8][C:9]([C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)=[O:10]>CO>[C:2]([S:1][C:14]1[CH:15]=[C:11]([C:9]([O:8][CH3:7])=[O:10])[N:12]([CH3:16])[CH:13]=1)#[N:3]
Reactant: N#C[S-]
Reactant: COC(=O)c1cccn1C
Agent: BrBr
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(SC#N)cn1C
Temperature: 25 °C
Yield: 47.6 %

Procedure:
Potassium thiocyanate (6.44 g, 66 mmol) is suspended in 18 ml of methanol and cooled to -78° under nitrogen. A solution of 1.75 ml of bromine (33 mmol) in 10 ml methanol is added dropwise. The resulting light yellow suspension is stirred for an additional 5 minutes at -78° before 4.17 g (30 mmole) of 2-methoxycarbonyl-1-methylpyrrole in 5 ml methanol is added all at once. After stirring and gradual warming to room temperature, the reaction mixture is poured into 250 ml of ice water, stirred vigorously and filtered. The solid is washed with water, dissolved in methylene chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a white solid which after recrystallization from hexane-ethyl acetate gives 2.8 g of pure 4-cyanothio-2-methoxycarbonyl-1-methylpyrrole.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](OC)=[O:17])[N:11]=2)[N:9]=1)[NH2:3].[BH4-].[Na+].CO.Cl>O1CCCC1.O.C(OCC)(=O)C>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[N:11]=2)[N:9]=1)[NH2:3]
Reactant: COC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(N)=Nc1nc(-c2cccc(CO)n2)cs1
Reaction time: 1.6 h
Yield: 90.6 %

Procedure:
To a mixture of 2-(diaminomethyleneamino)-4-(6-methoxycarbonylpyridin-2-yl)thiazole (0.7 g) and sodium borohydride (0.3 g) in tetrahydrofuran (10 ml) was added a methanol (1.5 ml) at 50°-55° C. and the mixture was stirred for 1.6 hours at the same temperature. The reaction mixture was added to a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 6N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 2-(diaminomethyleneamino)-4-(6-hydroxymethylpyridin-2-yl)thiazole (0.57 g).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].C(N(CC)CC)C.[CH3:14][O:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:5][C:2]([NH:1][S:18]([CH2:17][CH2:16][O:15][CH3:14])(=[O:20])=[O:19])([CH3:6])[C:3]#[N:4]
Reactant: CC(C)(N)C#N
Reactant: COCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCS(=O)(=O)NC(C)(C)C#N
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To a stirred mixture of 10 g (0.12 mole) 2-amino-2-methyl-propionitrile and 12.1 g (0.12 mole) triethylamine in about 200 ml methylene chloride cooled by an ice bath, 18.8 g (0.12 moles) 2-methoxyethane sulfonyl chloride (the product of Example 19) in 15 ml methylene chloride were added dropwise. The reaction mixture was then stirred at room temperature over the weekend. The reaction mixture was washed three times with equal amounts (about 200 ml) water, dried over magnesium sulfate, filtered and stripped to give an oil. The oil was recrystallized from ethyl ether/petroleum ether to give 15.0 g of the above-identified product, melting point 58°-60° C.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[S:58][CH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C=O)C.O>[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[S:58][CH:59]1[CH2:64][CH2:63][N:62]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:61][CH2:60]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Brc1ccccc1SC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Sc2ccccc2Br)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.15 g, 0.000533 mol) in DMF (3 mL) was added DIPEA (0.206 g, 0.00160 mol), HOBt (0.0864 g, 0.00064 mol) and EDCI.HCl (0.122 g, 0.00064 mol) at ambient temperature. After 2 minutes 4-(2-bromo-phenylsulfanyl)-piperidine hydrochloride (0.197 g, 0.00064 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried. Purification by column chromatography using silica gel 60-120 mesh (40% ethyl acetate in hexane) afforded 0.097 g (36%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-bromo-phenylsulfanyl)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 499.07 (M+1)+, 95.7%, 1H NMR (DMSO-d6): δ 13.8 (d, 1H), 8.1 (t, 1H), 7.8 (d, 2H), 7.6 (dd, 1H), 7.58-7.3 (m, 6H), 7.22-7.06 (m, 2H), 4.3-4.1 (m, 3H), 3.9-3.6 (m, 2H), 3.0 (m, 1H), 2.0 (m, 2H), 1.7-1.4 (m, 3H).