Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C2C(C=C(C(O)=O)N2C)=CC=1)#[N:2].NC1C=CC(OCC(OC(C)(C)C)=O)=CC=1.[C:32]([C:34]1[CH:42]=[C:41]2[C:37]([CH:38]=[C:39]([C:44]([NH:46][C:47]3[CH:61]=[CH:60][C:50]([O:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[CH:49][CH:48]=3)=[O:45])[N:40]2[CH3:43])=[CH:36][CH:35]=1)#[N:33]>>[C:32]([C:34]1[CH:42]=[C:41]2[C:37]([CH:38]=[C:39]([C:44]([NH:46][C:47]3[CH:61]=[CH:60][C:50]([O:51][CH2:52][C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])=[CH:49][CH:48]=3)=[O:45])[N:40]2[CH3:43])=[CH:36][CH:35]=1)(=[NH:2])[NH2:33]
Reactant: Cn1c(C(=O)Nc2ccc(OCC(=O)OC(C)(C)C)cc2)cc2ccc(C#N)cc21
Reactant: Cn1c(C(=O)O)cc2ccc(C#N)cc21
Agent: CC(C)(C)OC(=O)COc1ccc(N)cc1
Product: Cn1c(C(=O)Nc2ccc(OCC(=O)OC(C)(C)C)cc2)cc2ccc(C(=N)N)cc21

Procedure:
In the same manner as in Example 1 (2), 6-cyano-1-methyl-2-indolcarboxylic acid (52 mg, 0.26 mmol) and t-butyl 4-aminophenoxyacetate (63 mg, 0.29 mmol) were condensed to quantitatively give 109 mg of t-butyl 4-[(6-cyano-1-methyl-2-indolyl)carbonylamino]phenoxyacetate as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C[O:16][C:17](OC)(N(C)C)[CH3:18]>CC(N(C)C)=O>[N+:12]([C:3]1[C:2]([CH2:1][C:17](=[O:16])[CH3:18])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])([O-:14])=[O:13]
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reactant: COC(C)(OC)N(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cccc(CC(C)=O)c1[N+](=O)[O-]
Yield: 23 %

Procedure:
A solution of methyl 3-methyl-2-nitrobenzoate (1.5 g) and N,N-dimethylacetamide dimethyl acetal (3 ml) in dimethylacetamide (5 ml) was heated at 140° C. for 3 hours. After evaporation of the solvent, the resulting brown syrup was dissolved in ethyl acetate. The solution was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give a pale brown syrup (0.42 g, 23%).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:52]([O:56][C:57](=[O:66])[NH:58][C:59]1[CH:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=1)([CH3:55])([CH3:54])[CH3:53]>CS(C)=O.O>[C:52]([O:56][C:57]([NH:58][C:59]1[CH:60]=[CH:61][C:62]([NH:65][C:13]([C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])=[O:15])=[CH:63][CH:64]=1)=[O:66])([CH3:55])([CH3:53])[CH3:54]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Carbobenzyloxy-L-proline (0.20 g, 0.80 mmol) and HATU (0.32 g, 0.84 mmol) in DMSO (6 mL) was added diisopropylethylamine (0.42 mL, 2.41 mmol) followed by tert-buty-4-aminophenylcarbamate (0.715 g, 082 mmol). The solution was stirred at ambient temperature for two hours, then diluted with water and the solid product was filtered off and purified by combi-flash 12 g column, eluting with 0-20% ethyl acetate in dichloromethane to give a sold (0.245 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([NH:16][C:17](=O)[CH3:18])[CH:14]=3)[CH:9]([CH3:20])[O:8][C:6]=2[CH:7]=1.[H-].[Na+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([N:16]([CH2:29][C:28]4[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[CH2:17][C:18]4[CH:2]=[CH:7][C:6]([O:8][CH3:9])=[CH:5][CH:4]=4)[CH:14]=3)[CH:9]([CH3:20])[O:8][C:6]=2[CH:7]=1
Reactant: CC(=O)Nc1cc2c(cn1)C(C)Oc1cc(Cl)ccc1-2
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3c(cn2)C(C)Oc2cc(Cl)ccc2-3)cc1
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
To a stirred solution of N-(8-chloro-5-methyl-5H-chromeno[3,4-c]pyridin-2-yl)acetamide (250 mg, 0.866 mmol) in DMF (25 mL) was added NaH (62.3 mg, 2.60 mmol) at room temperature and stirred for 10 min. 4-Methoxybenzyl chloride (0.236 mL, 1.732 mmol) was added dropwise and stirred at room temperature overnight. The reaction was quenched with ice and extracted with ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), brine (25 mL), dried over sodium sulphate and concentrated under reduced pressure to afford 8-chloro-N,N-bis(4-methoxybenzyl)-5-methyl-5H-chromeno[3,4-c]pyridin-2-amine (200 mg, 0.20 mmol, 24% yield) as a yellow oil. This was taken to the next step without purification. LCMS (ESI) m/e 487.2 [(M+H)+, calcd for C29H28ClN2O3 487.2]; LC/MS retention time (Method C): tR=2.52 min.
Reaction SMILES: [CH2:1]=[O:2].[CH2:3](O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[ClH:16]>ClCCCl>[Cl:16][CH2:1][O:2][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: Cl
Reactant: C=O
Reactant: CCCCCCCCCCCCO
Solvent: ClCCCl
Product: CCCCCCCCCCCCOCCl
Reaction time: 3 h

Procedure:
30 g (1 mole) of paraformaldehyde were stirred in 100 ml 1,2-dichloroethane with 186 g (1 mole) of 1-dodecanol, and HCl gas was passed for 3 hours at 0°-5° C. The product was diluted with more solvent to give a 2M concentration.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Cl[CH2:16][C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[CH3:6][C:2]1([CH3:7])[O:1][C:17](=[O:18])[CH2:16][O:4][C:3]1=[O:5]
Reactant: CC(C)(O)C(=O)O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)COC1=O
Reaction time: 1 h
Yield: 10.4 %

Procedure:
To a flask containing two liters of chloroform, 1 mole of 2-hydroxy-isobutyric acid (104.1 gms.) and 2.2 moles of triethylamine (224 gms.), cooled in an ice bath, was slowly added 1 mole of chloroacetyl chloride (127 gms.). Addition took one hour. The chloroform was evaporated to yield a reddish semi-solid which was triturated several times with acetone followed by decantation of the reddish acetone extract. The white solid residue was triethylamine hydrochloride. The acetone extracts were combined and concentrated under vacuum to a red oil which was distilled under vacuum. The fraction distilling at 103°-110°C./0.7-0.9 torr. was collected. This fraction solidified to a green semi-solid which was recrystallized from isopropyl alcohol and then sublimed at 75°C./0.1 torr. to yield 15 grams of white solid, m.p. 82°-83°C. This was dissolved in 3000 ml. of benzene at 10°C. and extracted successively with three 300 ml. portions of 0.01 N HCl solution saturated with sodium chloride in a separatory funnel, and the benzene layer quickly dried by filtration through a bed of anhydrous sodium sulfate into a flask containing anhydrous magnesium sulfate. After the removal of the magnesium sulfate by filtration and the benzene under vacuum, the solid 3,3-dimethyl-1,4-dioxane-2,5-dione was recrystallized from isopropyl alcohol and sublimed at 75°C/0.1 torr. to yield 13 grams of solid, m.p. 85°-86°C., % C found = 50.00 vs. 50.00 calculated, % H found = 5.52 vs. 5.60 calculated.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)/[CH:21]=[C:22](\[C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C.O>C1COCC1>[Br:35][C:32]1[CH:31]=[CH:30][C:29](/[C:22](/[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:21]\[CH2:20][OH:19])=[CH:34][CH:33]=1
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC/C=C(/c1ccccc1)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A 1.2 M solution of DIBAL-H in toluene (84 ml, 100 mmol) was added dropwise, at −15° C. over 20 min, to a stirred solution of (Z)-3-(4-bromophenyl)-3-phenylacrylicacid ethyl ester (11.1 g, 33.5 mmol) in dry THF (150 ml), and the mixture stirred for 30 min. Rochelles salt and water was carefully added, and the resulting mixture extracted with ethyl acetate (x2). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give 9.3 g of (Z)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1.CS(C)=O>C(#N)C>[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH:45][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:42][CH:41]=1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: COc1ccc(CN)cc1
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1ccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(OC)c2)C3)cc1
Temperature: 80 °C
Yield: 84.7 %

Procedure:
In a glass tube was weighed 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 (0.32 mmol), acetonitrile (2.5 mL), 4-methoxybenzylamine (0.66 mmol), and dimethylsulfoxide (1.11 mmol). The stirred solution was heated at 80° C. for 20 hours. The solvent was evaporated and the residue was dissolved in dichloromethane (5 mL), washed twice with water, dried over anhydrous sodium sulfate, and evaporated. Flash chromatography on silica gel using hexane/ethyl acetate/dichloromethane (3:1:1) provided 0.155 g (86%) of the title compound as a white solid, which was recrystallized from ethyl acetate/hexane, m.p. 178-179° C. MS [(+)ESI, m/z]: 570 [M+H]+Anal. Calcd for C36H33N3O4: C, 75.64; H, 5.82; N, 7.35. Found: C, 75.31; H, 5.83; N, 7.27.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[CH2:37]([C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:25]=2)=[CH:32][CH:33]=1)[CH3:38]
Reactant: CCc1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CCO)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl ]butyl]phenol (260 mg) in DMF (4 ml), 60% oily sodium hydride (44 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, (E)-4-chloromethyl-2-[2-(4-ethylphenyl)ethenyl]oxazole (272 mg) was added under ice cooling. After stirring overnight at room temperature, water was added under ice cooling. The precipitate was collected by filtration and washed with water. The precipitate was dissolved in ethyl acetate and dried (magnesium sulfate), after which it was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the titled compound (297 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=S)[N:10]=2)=[CH:5][CH:4]=1.[OH-:24].[Na+].OO>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:24])[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c(=S)nc2-c2ccc(OC)cc2)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2n[nH]c(=O)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A slurry of 9.6 g of 5,6-bis-(4-methoxyphenyl)-1,2,4-triazin-3-thione (29.5 mmol) in 100 mL of water was treated with 2.64 g of 50% aqueous sodium hydroxide (33 mmol). Most of the solids dissolved. The reaction mixture was cooled in an ice bath and 3.8 g of 30% hydrogen peroxide (33 mmol) was added slowly. An additional 4 mL of hydrogen peroxide solution was added, and the reaction mixture was stirred overnight at room temperature. The solids were filtered, washed with water, and dried under vacuum to give 8.6 g of product, mp 238–242° C.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][C:11]=1[CH3:19].C(N(CC)CC)C.Cl>O1CCCC1.O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])=[CH:12][C:11]=1[CH3:19]
Reactant: COc1ccc(CCN)cc1C
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCNC(=O)C2CCC2)cc1C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Cyclobutanecarbonyl chloride (7 g) was added dropwise to a solution of 2-(4-methoxy-3-methylphenyl)ethylamine (11.36 g) and triethylamine (13 ml) in tetrahydrofuran (150 ml) and the resulting suspension stirred for 16 hours. The mixture was poured into water (150 ml), acidified with dilute hydrochloric acid and extracted with ethyl acetate (4×50 ml). The combined organic extracts were washed with brine then dried over magnesium sulphate and the solvent removed in vacuo. The residue was washed with petroleum ether (bp 40°-60° C.) to give crude N-[2-(4-methoxy-3-methylphenyl)ethyl]cyclobutanecarboxamide (12 g). A sample recrystallised from acetonitrile had mp 103°-104° C.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][C@@:7]1([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1O)([O-:3])=[O:2].N1C=CC=CC=1.C(N(CC)CC)C>O>[N+:1]([C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][C@@:7]1([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:8]1)([O-:3])=[O:2]
Reactant: Nc1ncnc2c1ncn2[C@]1(Cc2ccccc2[N+](=O)[O-])O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Nc1ncnc2c1ncn2[C@@]1(Cc2ccccc2[N+](=O)[O-])C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.5 %

Procedure:
To 2'-deoxy-N -bis-ortho-nitrobenzyladenosine (200 mg, 0.518 mmol) was added anhydrous pyridine (10 ml) and evaporated to dryness. Pyridine (10 ml) was added followed by 4-4'-dimethoxytrityl chloride (900 mg, 2.3 mmol, 4.5 equiv.) and triethylamine (280 mg, 2.76 mmol, 4.0 equiv.) and stirred at room temperature under an argon atmosphere for 5 hours. Water (0.5 ml) was added and stirred for 20 minutes. The mixture was partitioned between ether and water (20 ml each) and the aqueous phase was re-extracted with ether (20 ml). The extracts were combined and washed with water (20 ml) and dried over anhydrous sodium sulfate, filtered and evaporated. The material was purified by chromatography on silica gel (4 g, using 0.7-2.5% methanol in methylene chloride) to yield 5'-O-DMT- N6 -bis-ortho-nitrobenzyl-2'-deoxyadenosine, (121 mg, 33%).
Reaction SMILES: [N-:1]=[C:2]=[S:3].[Na+].N1C=CC=CC=1.CS(O[N:16]=[C:17](Cl)[C@H:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:19]1)(=O)=O.[CH3:29][C:30]1[C:31]([S:36][C:37]2[CH:38]=[C:39]([O:44][C:45]3[C:46]([CH3:51])=[N:47][CH:48]=[CH:49][CH:50]=3)[C:40]([NH2:43])=[N:41][CH:42]=2)=[N:32][CH:33]=[CH:34][CH:35]=1>C(#N)C>[CH3:29][C:30]1[C:31]([S:36][C:37]2[CH:38]=[C:39]([O:44][C:45]3[C:46]([CH3:51])=[N:47][CH:48]=[CH:49][CH:50]=3)[C:40]([NH:43][C:2]3[S:3][N:16]=[C:17]([C@H:18]4[CH2:22][O:21][C:20]5([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)[O:19]4)[N:1]=3)=[N:41][CH:42]=2)=[N:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cccnc1Sc1cnc(N)c(Oc2cccnc2C)c1
Reactant: [N-]=C=S
Reactant: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cccnc1Sc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To acetonitrile (50 mL) was added sodium isothiocyanate (0.1749 g, 2.158 mmol), pyridine (0.3740 ml, 4.624 mmol), followed by (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (0.5507 g, 1.850 mmol), and the resulting mixture was heated to 60° C. for 30 minutes. 5-(3-Methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (0.500 g, 1.541 mmol) was added and the reaction was stirred overnight at 60° C. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and 1N NaOH. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was dried over silica gel (100% ethyl acetate). Concentration of the major UV active fraction with an Rf of 0.5 afforded (S)-N-(5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.565 g, 1.030 mmol, 66.8% yield) as an off white powder/crystals.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].CN(/[CH:12]=[N:13]/[C:14]1[C:15]([C:26]([O:28]C)=O)=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:24][CH3:25])=[CH:19][CH:18]=2)C.C(O)(=O)C>O1CCCC1>[CH3:25][O:24][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]=[C:15]3[C:14](=[CH:23][C:22]=2[CH:21]=1)[NH:13][CH:12]=[C:7]([C:6]#[N:8])[C:26]3=[O:28]
Reactant: CC#N
Reactant: COC(=O)c1cc2ccc(OC)cc2cc1/N=C/N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2cc3c(=O)c(C#N)c[nH]c3cc2c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.81 mL (7.03 mmol) of n-butyllithium (2.5M in hexane) in 2.0 mL of tetrahydrofuran at −78° C. is added dropwise a solution of 0.448 mL (8.44 mmol) of acetonitrile in 4.4 mL of tetrahydrofuran. After completion of addition, the suspension is stirred for 10 minutes. To this is added 804.5 mg (2.81 mmol) of methyl 3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate in 18 mL of tetrahydrofuran dropwise. The resulting reaction mixture is stirred at −78° C. for 1 hour and at −5° C. for 1 hour. The reaction mixture is again cooled to −78° C. and 4.0 mL (69.9 mmol) of acetic acid is added dropwise. The reaction mixture is warmed up to room temperature and stirred overnight. The precipitate is collected by filtration and washed sequentially with water, acetonitrile and methanol. After drying in vacuo, this yields 468.6 mg (67%) of 8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a yellow solid, mp>265° C.
Reaction SMILES: [C:1]([Br:4])(=O)[CH3:2].[N+](C1C=[C:12]([CH2:14][C:15]([F:18])([F:17])[F:16])[N+:11]([O-:19])=[C:10]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH:9]=1)([O-])=O.[OH-].[Na+]>CC(O)=O>[Br:4][C:1]1[CH:9]=[C:10]([CH2:20][C:21]([F:22])([F:23])[F:24])[N+:11]([O-:19])=[C:12]([CH2:14][C:15]([F:16])([F:17])[F:18])[CH:2]=1
Reactant: O=[N+]([O-])c1cc(CC(F)(F)F)[n+]([O-])c(CC(F)(F)F)c1
Reactant: CC(=O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: [O-][n+]1c(CC(F)(F)F)cc(Br)cc1CC(F)(F)F
Temperature: 90 °C
Yield: 72 %

Procedure:
Acetyl bromide (14 mL) was added to a solution of 4-nitro-2,6-bis-(2,2,2-trifluoro-ethyl)-pyridine 1-oxide (2.7 g, 8.9 mmol) dissolved in AcOH (25 mL). The reaction mixture was heated to 90 ° C. for 5 hours. The reaction was cooled to room temperature, poured into ice, made basic with NaOH pellets and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 30% EtOAc in hexanes) gave the product as a yellow oil (2.18 g, 72%). 1H NMR (400 MHz, CDCl3): δ 3.92 (t, J=10.1 Hz, 4 H), 7.59 (s, 2 H).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C:4]1[NH:8][CH:7]=[N:6][CH:5]=1.[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:13]([N:12]([CH3:17])[CH3:11])(=[O:15])=[O:14])[CH:5]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)(C)Cc1cnc[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1cnc(CC(C)(C)C)c1

Procedure:
A solution of 5-(2,2-dimethylpropyl)-1H-imidazole, dimethylsulfamoyl chloride (25 mL), Et3N (45 mL) in CH2Cl2 (300 mL) was added DMAP (0.8 g). The reaction mixture was refluxed overnight. The solvent was evaporated and the residue was purified by silica gel chromatography to give the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[F:24][C:25]([F:29])([F:28])[C:26]#[CH:27]>>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:23])([C:19]([F:21])([F:22])[F:20])[C:27]#[C:26][C:25]([F:29])([F:28])[F:24])=[CH:14][CH:13]=1)[S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: CN(c1ccc(C(=O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Reactant: C#CC(F)(F)F
Product: CN(c1ccc(C(O)(C#CC(F)(F)F)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1

Procedure:
The compound was prepared from N-methyl-N-(4-trifluoroacetyl-phenyl)-benzenesulfonamide (Example 22, Step A) and 3,3,3-trifluoroprop-1-yne following the procedure described in Example 29. 1H NMR (CDCl3) δ 3.19 (s, 3H), 4.30 (br s, 1H), 7.11–7.63 (m, 9H). Mass Spectrum (CI+) m/e=438 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5]C=CC=1.[CH2:8]1[O:10][C@H:9]1[CH2:11]Cl.C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-:27].[Na+]>CN(C)C=O>[CH2:11]([O:7][CH2:1][CH:6]1[O:27][CH2:5]1)[CH:9]1[O:10][CH2:8]1
Reactant: [OH-]
Reactant: Oc1ccccc1
Reactant: ClC[C@H]1CO1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(OCC1CO1)C1CO1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2.50 g of a phenol derivative represented by the following formula: ##STR17## 4.25 g of R-(-)-epichlorohydrin (chemical purity: 98.5% or more, optical purity: 99% or more) and 20 mg of benzyltriethylammonium chrolide were dissolved in 3 ml of dimethylformamide. To the solution was added dropwise 24% by weight sodium hydroxide aqueous solution (1.2 equivalents) at 60° C. The reaction was conducted for 40 minutes at the same temperature, and then the reaction mixture was cooled to room temperature followed by extraction with ether. After evaporating the solvent at reduced pressure, the residue was purified by a silica gel column chromatography to obtain 1.62 g of a S-isomer of glycidyl ether represented by the following formula (Intermediate 1). ##STR18##