Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].O.[C:6]([OH:10])(=[O:9])[CH:7]=[O:8]>CC(C)=O>[C:1]([NH:4][CH:7]([OH:8])[C:6]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(N)=O
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)NC(O)C(=O)O
Yield: 103.3 %

Procedure:
The titled compound 42 was prepared according to a procedure described by Williams et al.195 A solution of acetamide 34 (6.10 g, 0.10 mol) and glyoxylic acid monohydrate 41 (10.60 g, 0.14 mol) in anhydrous acetone (150 mL) was heated at reflux for 18 h. The reaction mixture was evaporated under reduced pressure to afford the desired product 42 as a viscous yellow oil (13.75 g, 100%). Spectroscopic data indicated the crude product 42 did not require purification and was used directly in the subsequent reaction (Section 7.9.2). νmax (neat): 3317bs, 2974w, 1732s, 1668s, 1538s, 1379m, 1234w, 1112w, 1048m, 880m cm−1. 1H n.m.r. (300 MHz, D6-DMSO): δ 1.84 (s, 3H, CH3CO), 5.39 (d, J=8.7 Hz, 1H, H2), (8.65, bd, J=8.4 Hz, 1H, NH), two exchangeable protons (OH) not observed. 13C n.m.r. (75 MHz, D6-DMSO): δ 22.5 (CH3CO), 70.9 (C2), 169.4 (CONH), 171.5 (C1). Mass Spectrum (ESI+, MeOH): m/z 134.2 (M+H)+, C4H8NO4 requires 134.1. Spectroscopic data were in agreement with those reported in the literature.195
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]([NH2:36])([CH3:35])[CH2:28][CH2:29][N:30]1[CH:34]=[N:33][N:32]=[CH:31]1>C(O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20]=[N:36][C:27]([CH3:35])([CH3:26])[CH2:28][CH2:29][N:30]2[CH:31]=[N:32][N:33]=[CH:34]2)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Reactant: CC(C)(N)CCn1cnnc1
Solvent: CCO
Product: COC(=O)c1cc(C(=O)C=NC(C)(C)CCn2cnnc2)ccc1OCc1ccccc1

Procedure:
16 g of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 6 g of 1,1-dimethyl-3-[1,2,4]triazol-4-yl-propylamine are heated to 70° C. for one hour in 100 mL ethanol. Then half the solvent is distilled off and the mixture remaining is cooled. The product that crystallises out is suction filtered and washed with ethanol and diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[H-].[Na+].[CH3:14]I>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:14])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
4-Bromo-2-nitrophenol (1.00 g, 4.59 mmol) was added in small portions to a suspension of sodium hydride (400 mg, 9.17 mmol) in dimethylformamide (12 ml) at room temperature under argon atmosphere, then the mixture was stirred at room temperature for 30 minutes. A solution of methyl iodide (1.30 g, 9.174 mmol) in dimethylformamide (4 ml) was added to this mixture, and stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted with diisopropyl ether. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (658 mg, 61.8%) as a pale yellow solid.
Reaction SMILES: [C:1]([SH:3])#N.N.C(Cl)(=O)C1C=CC=CC=1.[F:14][C:15]1[CH:31]=[CH:30][CH:29]=[CH:28][C:16]=1[O:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:21]=2[N:22]=1>CC(C)=O>[F:14][C:15]1[CH:31]=[CH:30][CH:29]=[CH:28][C:16]=1[O:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([N:27]=[C:1]=[S:3])[CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: Nc1ccc2nc(Oc3ccccc3F)sc2c1
Reactant: N#CS
Agent: N
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: Fc1ccccc1Oc1nc2ccc(N=C=S)cc2s1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
An amount of 17 g of ammonium rhodanide is dissolved in 200 ml of absolute acetone; an addition is then made to the solution, with stirring, of 31 g of benzoyl chloride. The reaction mixture is allowed to boil with refluxing for 5 minutes; a solution is then added of 57 g of 2-(2'-fluorophenoxy)-6-aminobenzothiazole (obtained from 2-(2'-fluorophenoxy)-6-nitrobenzothiazole by catalytic hydrogenation, cp. Example 6) in 400 ml of acetone. Stirring is continued for 2 minutes at the boiling temperature, and the mixture then poured, with stirring, into 5000 ml of ice water. Filtration is performed, the filter residue washed with water, and suspended in 350 ml of 10% sodium hydroxide solution. The suspension is quickly brought to boiling temperature and allowed to boil for a further 2 minutes. Cooling is then rapidly carried out in an ice bath; the suspension is neutralised with 2-n hydrochloric acid, and the pH-value adjusted with 2-n ammonia to 8. Filtration is again performed, the filter residue washed wth water until neutral, and dried at 80° in vacuo. The finely powdered material is suspended in 500 ml of anhydrous chlorobenzene and refluxed for 14 hours. After the solvent has been evaporated off, the residue is chromatographed through aluminium oxide with methylene chloride as the eluant. The obtained 2-(2'-fluorophenoxy)-6-isothiocyanobenzothiazole melts at 115° - 117°.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.[NH2:19][C:20]([CH:24]1[CH2:26][CH2:25]1)([CH3:23])[C:21]#[N:22]>ClCCl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:19][C:20]([C:21]#[N:22])([CH:24]1[CH2:26][CH2:25]1)[CH3:23])=[O:7]
Reactant: CC(N)(C#N)C1CC1
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C#N)(NC(=O)c1cccc(CCl)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
3-(Chloromethyl)benzoyl chloride (9.08 mmol, 1.290 ml, 1.716 g) and triethylamine (27.2 mmol, 3.79 mL, 2.76 g) were stirred in dichloromethane (10 mL) at 0° C. 2-Amino-2-cyclopropylpropanenitrile (9.08 mmol, 1 g) was added dropwise and the reaction allowed to warm to room temperature and stir for 1 hour. The reaction mixture was washed with water and the organic phase concentrated under vacuum to afford the title compound (1.451 g). MS (ESI) m/z 263.1 [M+H]+
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:28])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:27])[CH2:25][CH3:26])=[CH:14]CO>ClCCl>[Cl:1][CH2:26]/[CH:25]=[C:24](\[CH3:27])/[CH2:23][CH2:22]/[CH:21]=[C:20](\[CH3:28])/[CH2:19][CH2:18][CH:17]=[C:13]([CH3:14])[CH3:12]
Reactant: CCC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
(Note: all temperatures indicated are for the contents of the reaction flask). To a stirred solution of 299 mg (2.24 mmol) of N-chlorosuccinimide in 15 mL of dichloromethane at -30° C. under argon was added 0.18 mL (2.45 mmol) of distilled dimethyl sulfide over 5 minutes. After 10 minutes at -30° C., the reaction was allowed to warm to 0° C. for 10 minutes, followed by cooling to -40° C. A solution of 441.4 mg (1.99 mmol) of 3,7,11-trimethyl-2,6,10-tridecatrien-1-ol in 5 mL of dichloromethane was added dropwise over 10 minutes. The reaction was allowed to warm gradually to 0° C. over 1 hour, and then maintained for 1 hour. After quenching with cold water, the mixture was extracted with hexane and the hexane extract was washed with cold water and cold brine, dried (MgSO4) and evaporated to afford 483 mg of a crude product. Rapid flash chromatography on 20 g of silica gel eluted with 3:97 ethyl acetate:petroleum ether provided 406.5 mg (85%) of a colorless liquid. 13C NMR indicated that this material contained a trace (3%) impurity.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.C(O)C.C(OCC)(=O)C.[C:23](#[N:25])C>>[NH:7]1[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:5]([CH2:4][C:23]#[N:25])=[CH:6]1
Reactant: CC#N
Reactant: CN(C)Cc1c[nH]c2ccncc12
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CCc1c[nH]c2ccncc12
Yield: 26 %

Procedure:
Using essentially the same procedure described in Example 1, Step 5, hereinabove and employing N,N-dimethyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)methylamine as substrate and 1:2 ethanol:ethyl acetate as the chromatography eluent affords the title acetonitrile as a yellow solid, 0.160 g (26% yield), identified by NMR analysis.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13](=O)[CH2:14]Br)[CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23]([NH2:25])=[S:24])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:24][CH:14]=[C:13]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([NH:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[N:12]=3)[N:25]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: O=C(O)CCNc1cccc(C(=O)CBr)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cccc(NCCC(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(2-carboxyethylamino)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(2-carboxyethylamino)-2-pyridyl]thiazole.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:6][CH:5]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH2:22][CH2:21]1.CCN(CC)CC>CC#N>[N:17]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[S:10][C:9]=1[O:8][C:7]1[CH:18]=[CH:19][C:4]([CH2:3][N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])[CH2:24][CH2:25]2)=[CH:5][CH:6]=1
Reactant: O=C1CCCN1C1CCNCC1
Reactant: ClCc1ccc(Oc2nc3cccnc3s2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCCN1C1CCN(Cc2ccc(Oc3nc4cccnc4s3)cc2)CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 57.1 %

Procedure:
To a solution of 2-[4-(chloromethyl)phenoxy][1,3]thiazolo[5,4-b]pyridine hydrochloride (70 mg, 0.223 mmol) and 1-piperidin-4-yl-pyrrolidin-2-one (64 mg, 0.379 mmol, 1.7 equiv.) in CH3CN (1.3 mL) was added Et3N (110 μL, 0.759 mmol, 3.4 equiv.). The reaction was allowed to stir at 60° C. for 6 h. The solution was cooled to rt, filtered and purified using preparative reverse phase HPLC to afford the desired product as a cream-colored solid (52 mg, 57%). 1H NMR (600 MHz, DMSO-d6): 8.45 (dd, J=4.7, 1.5, 1H), 8.09 (dd, J=8.1, 1.5, 1H), 7.50 (dd, J=8.2, 4.8, 1H), 7.47-7.40 (m, 4H), 3.80-3.69 (m, 1H), 3.52 (s, 2H), 3.35-3.29 (m, 2H), 2.91-2.85 (m, 2H), 2.20 (t, J=8.1, 2H), 2.07-2.00 (m, 2H), 1.94-1.85 (m, 2H), 1.73-1.62 (m, 2H), 1.54-1.48 (m, 2H). MS (ESI): mass calcd. for C22H24N4O2S, 408.16; m/z found, 409.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:31]([CH3:33])[CH3:32])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:30])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([OH:28])=[O:27])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(O)C.C(=O)([O-])O.[Na+:41]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:31]([CH3:33])[CH3:32])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:30])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([O-:28])=[O:27])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.[Na+:41]
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-]
Temperature: 25 °C
Yield: 104.5 %

Procedure:
A suspension of (3R,5S,E)-7-[4,5-bis-(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3,5-dihydroxy-6-heptenoic acid (200 mg) in sodium hydrogen carbonate (36.8 mg) and water (80 ml) was stirred at room temperature. After 19 h ethanol (20 ml) was added and the resulting clear solution stirred at room temperature. After 15 min the mixture was evaporated to dryness, the residue was dissolved in water (50 ml), filtered and then freeze dried to give the title compound (219 mg) as a white fluffy solid, [α]D +22.6° (C 0.53, H2O), δ(D2O) 1.20-1.55, 1.55-1.78 (m, 2H, CH(OH)CH2CH(OH)), 1.33 (d, J 7 Hz, 6H, CH(CH3)2), 2.26 (d, J 7 Hz, 2H, CH2CO2Na), 3.28 (septet, J 7 Hz, 1H, --CH(CH3)2, 3.67 (m, 1H, =CHCH(OH)CH2CH(OH)). 4.35 (m, 1H, CH=CHCH(OH)), 5.49 (dd, J 14 Hz and 7 Hz, 1H, NCH=CH), 6.72 (d, J 14 Hz, 1H, NCH=CH), 6.97 (t, 9 Hz, 2H, C-3 and C-5 protons of 4-fluorophenyl), 6.90-7.40 (m, 6H, aromatics).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[C:14]([CH3:21])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:22][O-:23].[Na+]>CC(N(C)C)=O>[CH3:22][O:23][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[C:14]([CH3:21])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: C[O-]
Reactant: Cc1cc(-c2cc3ncccc3c(Cl)n2)ccc1N(C)C
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1nc(-c2ccc(N(C)C)c(C)c2)cc2ncccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
100 mg (0.31 mmol) of 6.1 was placed in 0.5 ml dimethylacetamide and then 60 mg (1.1 mmol) sodium methoxide were added. The reaction mixture was stirred for 1 h at 50° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][C@H:13]([N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:28][N:29]1[C:33]([CH3:34])=[C:32](B2OC(C)(C)C(C)(C)O2)[C:31]([CH3:44])=[N:30]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([N:17]([CH3:18])[C@H:13]1[CH2:14][CH2:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:32]2[C:31]([CH3:44])=[N:30][N:29]([CH3:28])[C:33]=2[CH3:34])[CH2:12]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CN(Cc1ccccc1)[C@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N(C)Cc1ccccc1)C2
Reaction time: 3 h

Procedure:
(6S)-6-[Benzyl(methyl)amino]-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (5.0 g, 12.517 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (3.60 g, 15.246 mmol) and Pd(PPh3)4 (1.70 g, 1.471 mmol) were added to a solution of K2CO3 (3.31 g, 23.95 mmol) in a mixture of 1,2,-dimethoxyethane (120 mL) and H2O (15 mL). The reaction mixture was purged with N2 (g) for 10 min, and warmed up to reflux. The reaction was completed in 3 h (TLC analysis). It was allowed to reach room temperature, diluted with H2O (150 mL) and extracted with AcOEt (300 mL). The organic layer was filtered through Celite (washing with AcOEt), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-10-20% Et3N/AcOEt) to afford the desired product as a brown-colored oil. The material was dissolved in CH2Cl2 (100 mL) and acidified with HCl aqueous solution (6 N). The organic layer was discarded, and the aqueous layer was taken to pH>13 with NaOH aqueous solution (6 N). It was extracted with CH2Cl2 (3×200 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated, to give 3.67 g of the coupling product (Rf=0.3 (AcOEt), pale yellow oil, 81% yield).
Reaction SMILES: O.[N+:2]([C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:14]>O1CCCC1>[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([S:11][C:7]1[CH:6]=[C:5]([N+:2]([O-:4])=[O:3])[CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: O=[N+]([O-])c1cccc(S)c1
Reactant: C=C(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Sc1cccc([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a mixed solution of water (1.6 mL)-concentrated sulfuric acid (1.6 mL) was added 3-nitrothiophenol (0.5 g), and the mixture was stirred at room temperature for 1 hour. To the mixture was added a solution of α-methylstyrene (0.38 g) in tetrahydrofuran (1.6 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/2) to give 3-(1-methyl-1-phenylethylthio)nitrobenzene (0.88 g). This material was dissolved in tetrahydrofuran (10 mL). To the solution were added methanol (10 mL), nickel (II) bromide (35 mg) and sodium borohydride (0.37 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/2) to give the title compound (0.69 g).
Reaction SMILES: COC1C(OC)=NS(=O)N=1.[CH3:11][N:12](CC1SC=C(CSCCN)N=1)[CH3:13].[CH3:25][N:26]([CH2:28][C:29]1[S:30][CH:31]=[C:32]([CH2:34][S:35][CH2:36][CH2:37][NH:38][C:39]2[C:43](OC)=[N:42][S:41](=[O:46])[N:40]=2)[N:33]=1)[CH3:27].CNC>>[CH3:25][N:26]([CH2:28][C:29]1[S:30][CH:31]=[C:32]([CH2:34][S:35][CH2:36][CH2:37][NH:38][C:39]2[C:43]([N:12]([CH3:13])[CH3:11])=[N:42][S:41](=[O:46])[N:40]=2)[N:33]=1)[CH3:27]
Reactant: COC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Agent: CNC
Agent: COC1=NS(=O)N=C1OC
Product: CN(C)Cc1nc(CSCCNC2=NS(=O)N=C2N(C)C)cs1

Procedure:
When a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, Step A] is reacted with one equivalent of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine [prepared in Example 33, Step E] and the resultant 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide is treated with an excess of dimethylamine according to the procedure described in Example 28, the title compound is thereby produced.
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22]C(Cl)=O>>[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][C:4](=[O:9])[CH2:5][C:6]([O:7][CH2:2][CH3:10])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Product: CCOC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared in a manner analogous to Intermediate 123 starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[NH2:11][OH:12].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[N:11]\[OH:12]
Reactant: NO
Reactant: O=Cc1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O/N=C\c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a suspension of 3-fluorobenzaldehyde (6.75 g, 54 mmol) and hydroxylamine hydrochloride (4.16 g, 60 mmol) in ethanol (4.3 mL) and water (13 mL) was added ice (25 g). Then a solution of sodium hydroxide (5.5 g, 138 mmol) in water (6.5 mL) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 30 min stirring at room temperature a white solid precipitated and the resulting mixture was then diluted with water and acidified with HCl (4 N). The white precipitate was then filtered off, washed with water and dried under high vacuum to afford the title compound (7.0 g, 93%) which was obtained as a white solid. MS m/e (EI): 139.1 [M].
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:7][CH2:6][C:5](=[O:8])[NH:4][CH:3]1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>C1COCC1>[CH3:1][C:2]1([CH3:17])[O:7][CH2:6][C:5](=[O:8])[N:4]([C:29]([O:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=2)=[O:30])[CH:3]1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)OCC(=O)NC1c1ccc(F)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)OCC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of (±)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine (240 mg, 0.996 mmol) in THF (10 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1.10 mL, 1.0 M in THF). The mixture was stirred for 30 min at 0° C. and then cooled back to −78° C. The mixture was transferred via a cannula to a precooled solution of 4-nitrophenyl chloroformate (605 mg, 3.0 mmol) in THF (10 mL) at −78° C. The resulting mixture was stirred while warmed to room temperature over 3 hours. The reaction was quenched with water (2 mL) and extracted with EtOAc (2×100 mL). The organic layer was dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography (SiO2, 40:60 EtOAc/Hexanes) to afford 0.328 g (81%) of the product as a pale oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][CH:7]=4)=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: CC(C)n1nccc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)n1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A dry flask was charged with 2-Isopropyl-2H-pyrazole-3-carboxylic acid (0.159 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (101 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 2-Isopropyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.328 g, 0.84 mmol, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([OH:17])([CH3:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1.[CH2:18](Cl)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.FC1C=CC(OC2C=CC=CC=2)=C(C(O)(C)CN2C=CN=C2)C=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([C:9]([OH:17])([CH3:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1
Reactant: ClCCc1ccccc1
Reactant: CC(O)(Cn1ccnc1)c1cc(F)ccc1O
Agent: CC(O)(Cn1ccnc1)c1cc(F)ccc1Oc1ccccc1
Product: CC(O)(Cn1ccnc1)c1cc(F)ccc1OCCc1ccccc1
Yield: 13.4 %

Procedure:
The general procedure of Example 6 was repeated using 4-fluoro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol [compound (2-4)] and phenethyl chloride, to thereby yield 2-(5-fluoro-2-(phenyloxy)phenyl)-1-(1H-1-imidazolyl)-2-propanol as a colorless oily product (yield: 13.4%).