Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([Li])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][C:22]([NH:25][Si:26](Cl)([CH3:28])[CH3:27])([CH3:24])[CH3:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([Si:26]([CH3:28])([CH3:27])[NH:25][C:22]([CH3:24])([CH3:23])[CH3:21])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)N[Si](C)(C)Cl
Reactant: [Li]C1C=C(c2ccccc2)c2cc(OC)c(OC)cc21
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C([Si](C)(C)NC(C)(C)C)C=C2c1ccccc1
Reaction time: 20 h

Procedure:
(5,6-dimethoxy-3-phenyl-1H-inden-1-yl)lithium (1.24 g, 4.8 mmol) was dissolved in 20 mL of THF and added to a solution of N-(tert-butyl)-N-(1-chloro-1,1-dimethylsilyl)amine (1.035 g, 6.24 mmol) in 50 mL of THF over a 25 min period, with stirring continued for 20 h. The solution was then evaporated under reduced pressure and the residue was extracted with hexane (50 mL). After filtration, the solvent was removed under reduced pressure. To this residue, 30 mL of hexane was added and the flask was put aside into a freezer (−27° C.) for 2 days. After that time the crystallized solid was filtered off and the solvent was removed leaving 1.68 of the product as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([CH:9]3[CH2:11][CH2:10]3)[N:6]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=3[F:21])[N:5]=2)[CH2:3][CH2:2]1.[Cl:22]N1C(=O)CCC1=O>CN(C=O)C>[Cl:22][C:8]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:5][N:6]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[C:7]=1[CH:9]1[CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(-n2nc(C3CC3)cc2C2CC2)c(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2nc(C3CC3)c(Cl)c2C2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
Intermediate 10 (1.15 g, 3.40 mmol) was dissolved in DMF and to this N-Chlorosuccinimide (0.64 g, 4.8 mmol) was added at 0° C. Then reaction was allowed to stir at rt for 2 h. After completion of the reaction, work up (EtOAc) and purification afforded the title compound (0.575 g). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.18-8.09 (m, 2H), 7.64 (t, J 8.3, 1H), 1.98-1.90 (m, 1H), 1.82-1.72 (m, 1H), 0.90-0.80 (m, 4H), 0.68-0.60 (m, 4H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]#[C:28][C:29]1[C:30]([O:39][CH3:40])=[CH:31][C:32]([O:37][CH3:38])=[C:33]([CH:36]=1)[CH:34]=O.C[O-].[Li+]>CN(C=O)C.CO>[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]#[C:28][C:29]1[C:30]([O:39][CH3:40])=[CH:31][C:32]([O:37][CH3:38])=[C:33](/[CH:34]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)(=[O:12])=[O:11])=[CH:8][CH:9]=2)=[O:3])[CH:36]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)Nc3ccccn3)cc2)cc1C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
Ex-57A: A solution of 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A, 451 mg, 1.63 mmol) and 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 459 mg, 1.63 mmol) in DMF (10.0 mL) and MeOH (5.0 mL) was treated with lithium methoxide (248 mg, 6.52 mmol). The reaction mixture was stirred at room temperature for 3 h under nitrogen, quenched with water (50 mL), and extracted with (3:1) ethyl acetate/THF (4×30 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (2–5% MeOH in dichloromethane) to give 735 mg (65%) of 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-yl-benzenesulfonamide as a yellow oil. 1H-NMR (300 MHz, DMSO-d6) 8.21 (d, 2H, J=7.5), 8.18 (s, 1H), 8.00 (m, 4H), 7.81 (d, 1H, J=15.0 Hz), 7.74 (t, 2H, J=7.5 Hz), 7.17 (m, 2H), 7.05 (t, 2H, J=7.2 Hz), 6.80 (m, 3H), 6.52 (t, 1H), J=7.5 Hz), 5.43 (d, 1H, J=6.9 Hz), 3.96 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[N:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[N:24]=1>>[CH3:30][C:25]1[CH:26]=[C:27]([CH3:29])[N:28]=[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)[N:24]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-4,6-dimethyl-pyrimidine. MS (ESI) mass calcd. for C23H24N4OS, 404.53; m/z found, 405.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][C:34](O)=[O:35])[CH:27]=1.CCN=C=NCCCN(C)C.Cl.N1C=CC=CC=1>O>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][C:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:35])[CH:27]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(O)COc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(COc1cccnc1)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), pyridin-3-yloxyacetic acid hydrochloride (23 mg, 0.12 mmol), WSC.HCl (23 mg, 0.12 mmol), and dry pyridine (1 mL) were mixed, and the mixture was stirred at room temperature for 4 hours. This reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and hexane to give 5-[4-[2-[(pyridin-3-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (41 mg, yield 91%) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[C:13]([Br:29])[N:14]=1)[N:11]([CH2:15][CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])[C:10](=[O:21])[C:9]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)ncc21
Solvent: ClCCl
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)nc(Br)c21
Yield: 64.1 %

Procedure:
A mixture of 1-(2-ethyl-butyl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (200 mg, 0.53 mmol) and N-bromosuccinimide (103 mg, 0.58 mmol) in CH2Cl2 (2 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (3-15% EtOAc/hexanes+1% AcOH) to give 156 mg of the title compound as a yellow solid. MS: (+) m/z 459.31, 461.13 (M+1, 79/81Br).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH:14]=O)=[O:4].CC(O)=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH2:14][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]nc(C=O)c2c1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]nc(CN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 3-formyl-1H-indazole-5-carboxylic acid methyl ester (600 mg, 2.94 mmol) in DCM was added HOAc (0.25 mL, 4.41 mmol) followed by morpholine (0.31 mL, 3.53 mmol) and NaHB(OAc)3 (809.6 mg, 3.62 mmol) at rt. The reaction was stirred at rt overnight, and was quenched with brine. The reaction mixture was extracted with EtOAc, washed with brine, dried, and concentrated in vacuo. Purification by flash column afforded 3-(4-morpholinylmethyl)-1H-indazole-5-carboxylic acid methyl ester (800 mg, 95.7%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23].C(Cl)CCl>ClCCl>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[C:21]2[CH:29]=[CH:30][CH:31]=[C:19]([C:18]([F:17])([F:33])[F:32])[CH:20]=2)[C@H:11]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 77.5 %

Procedure:
(2S,4R)-4-(Benzyloxy)-2-isopropylpyrrolidine (0.410 g, 1.90 mmol) was dissolved in dichloromethane (30 mL) under nitrogen. (3-Trifluoromethyl-benzoylamino)-acetic acid (0.462 g; 1.90 mmol) was added followed by EDC (0.394 g, 2.06 mmol) and the mixture was stirred at room temperature-overnight. LC/MS revealed the reaction was not yet complete. More (3-Trifluoromethyl-benzoylamino)-acetic acid (0.12 g, 0.48 mmoles) and more EDC (0.30 g, 1.6 mmoles) were added and stirring continued for 3 hours at room temperature, then at reflux for 1.5 hours. The mixture was chromatographed on silica gel eluting with 30% ethyl acetate/hexane to provide 0.66 g (79%) of the coupled product as a colorless oil. LC/MS (M+H)+ m/z=449.2; 1H NMR (CDCl3) δ 8.03 (m, 1H), 7.76 (m, 1H), 7.58 (m, 2H), 7.34 (m, 5H), 4.52 (m, 2H), 4.03-4.34 (m, 4H), 3.65 (m, 1H), 3.48 (m, 1H), 2.54 (m, 1H), 2.12 (m, 1H), 1.92 (m, 1H), 0.92 (d, 3H), 0.77 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:12]1(O)[CH2:23][CH2:22]C[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].CO>[CH:1]1([O:2][C:3](=[O:11])[C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)[CH2:22][CH2:23][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: OC1CCCCCCCCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Product: O=C(OC1CCCCCCCCCCC1)c1ccc(O)cc1
Temperature: 160 °C
Reaction time: 5 h

Procedure:
22.82 g (0.15 mol) p-hydroxybenzoic acid methyl ester, 55.30 g (0.30 mol) cyclododecanol and 28 mg (0.1 mmol) tetraisopropyl orthotitanate are placed under argon in a round-bottom flask with distillation bridge. The mixture is stirred and heated to 160° C. within one hour. On reaching this temperature the pressure is reduced to 900 mbar and during the further course of the reaction to 800 mbar, during which time methanol is removed by distillation. Stirring is continued for 5 hours at this temperature. A further 0.05 ml tetraisopropyl orthotitanate are added and the reaction mixture is stirred for a further 20 hours at 170° C. under normal pressure. The residue undergoes column chromatography (silica gel 60, 0040-0.063 mm, Merck). An n-hexane/acetone mixture (5:1) is used as eluent. The product obtained in this way is freed from adhering cyclododecanol under high vacuum at 140° C. The residue is recrystallised in acetone. 5.9 g (13%) in the form of colourless crystals are obtained:
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]3[CH:21]([N:27]([CH:29]4[CH2:31][CH2:30]4)[CH3:28])[CH2:20][CH2:19][C:18]([CH3:33])([CH3:32])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[K+].Cl>CO.O1CCCC1>[CH:29]1([N:27]([CH3:28])[CH:21]2[CH2:20][CH2:19][C:18]([CH3:32])([CH3:33])[C:17]3[CH:16]=[C:15]([C:14]#[C:13][C:10]4[CH:9]=[CH:8][C:7]([C:4]([CH3:5])([CH3:6])[C:3]([OH:34])=[O:2])=[CH:12][CH:11]=4)[CH:24]=[C:23]([O:25][CH3:26])[C:22]2=3)[CH2:30][CH2:31]1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C#Cc2ccc(C(C)(C)C(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.3 %

Procedure:
A solution of 2-{4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionic acid methyl ester (Intermediate 85, 0.09 g, 0.196 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was treated with a 3M solution of potassium hydroxide (1.5 mL, 4.5 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% methanol in ethyl acetate as the eluent to afford the title product as a yellow solid (0.057 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([I:21])=[CH:16][C:3]=1[C:4](/[C:6](=[CH:12]/N(C)C)/[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[NH2:22][C@@H:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][OH:25]>C1COCC1>[F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([I:21])=[CH:16][C:3]=1[C:4](/[C:6](=[CH:12]/[NH:22][C@@H:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][OH:25])/[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CC(C)[C@H](N)CO
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)c(F)cc1F
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C\N[C@H](CO)C(C)C)C(=O)c1cc(I)c(F)cc1F

Procedure:
A solution of 13 (14.6 g, 35.6 mmol) and (S)-2-amino-3-methylbutan-1-ol (14) (3.95 g, 36.7 mmol) in THF (35 mL) was stirred at rt for 30 minutes (min). The mixture was concentrated under reduced pressure to give crude 15 as a yellow oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH2:6][C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]>C(O)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C@:8]12[CH2:9][CH2:10][CH2:11][C@H:7]1[CH2:6][S:3][C:2]([NH2:4])=[N:1]2
Reactant: Fc1ccccc1C1=C(CCl)CCC1
Reactant: NC(N)=S
Solvent: CCO
Product: NC1=N[C@@]2(c3ccccc3F)CCC[C@H]2CS1
Temperature: 25 °C

Procedure:
Thiourea (2.60 g) was added to a solution of 1-(2-chloromethylcyclopent-1-enyl)-2-fluorobenzene obtained in Preparation Example 3-(4) (7.20 g) in ethanol (100 mL), and the mixture was stirred with heating under reflux for five hours. The reaction solution was cooled to room temperature and the solvent was evaporated under reduced pressure. The residual syrup was washed with heptane, followed by drying under reduced pressure. Trifluoroacetic acid (50.0 mL) and trifluoromethanesulfonic acid (10.0 mL) were added to the residue in an ice bath. Then, the reaction mixture was warmed to room temperature and stirred for four days. The reaction solution was poured into ice, diluted with ether and then neutralized with sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by NH-silica gel column chromatography to obtain the title compound (4.98 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]=[C:6](Cl)[S:5][N:4]=1.[CH2:9]1[O:13][CH2:12][O:11][CH:10]1[CH2:14][OH:15].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[O:13]1[CH2:9][CH:10]([CH2:14][O:15][C:6]2[S:5][N:4]=[C:3]([S:2][CH3:1])[N:7]=2)[O:11][CH2:12]1
Reactant: OCC1COCO1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCC2COCO2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To 10 ml of N,N-dimethylformamide, 835 mg of 3-methylthio-5-chloro-1,2,4-thiadiazole and 520 mg of glycerol formal were dissolved, and added 204 mg of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 20 minutes and at room temperature for 30 minutes. Then, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with tert-butylmethylether. After the organic layer was dried by anhyrous sodium salfate, the organic layer was concentrated, and the residue obtaind was subjected to silica gel column chromatography (hexane:ethyl acetate=20:1), followed preparative HPLC to obtain 250 mg of 5-(1,3-dioxolane-4-yl)methoxy-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[S:26]([CH3:29])(=[O:28])=[O:27].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][N:25]([C:30]1[CH:36]=[CH:35][C:33]([NH:34]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:32][CH:31]=1)[S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: CN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-methyl-N-methylsulphonyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: ClCc1ccccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
The whole of the 2-benzyloxybenzyl alcohol thus obtained was dissolved in 500 ml of tetrahydrofuran, and 85 ml of thionyl chloride were added dropwise, whilst ice-cooling, to the resulting solution. The reaction mixture was then allowed to stand overnight at room temperature, after which it was concentrated by evaporation under reduced pressure to give a dark colored oil. This product was dissolved in toluene, and the solution was decolorized by treating it with silica gel for chromatography followed by filtration. The filtrate was concentrated by evaporation under reduced pressure to give 2-benzyloxybenzyl chloride as a yellow oil, which was used in the following reaction without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[CH3:26]O>>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([O:14][CH3:26])=[O:13])=[CH:6][CH:5]=1
Reactant: Nc1ccc(CC(C(=O)O)c2cn(C3CCCCC3)cn2)cn1
Reactant: CO
Agent: Cl
Product: COC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3 ml of an HCl-saturated ether solution were added to a solution of 50.0 mg (0.16 mmol) of the compound from example 1i in 8 ml of methanol and stirred at room temperature for 6 h. The solution was then concentrated to dryness, and the resulting residue was dried under high vacuum. 51 mg of the title compound resulted as bishydrochloride in the form of an amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:19]=[C:18]([NH2:20])[S:17][N:16]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[C:26]1([C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N+]=[N-])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:19]=[C:18]([NH2:20])[S:17][N:16]=1)[C:12]([O:14][CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1nsc(N)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1nsc(N)n1

Procedure:
To a solution of 2-tert-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer (20 g) in ethyl acetate (200 ml) and tetrahydrofuran (100 ml) was added dropwise a solution of diphenyldiazomethane in ethyl acetate (0.9 m mole/ml, 80 ml) at ambient temperature, and the mixture was stirred for an hour. The reaction mixture was washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, and then dried over magnesium sulfate. The solution was evaporated to give benzhydryl 2-tert-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (15.0 g), mp 164° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH:24]1[CH:28]=[C:27]([CH2:29][N:30]2[C:34](=[O:35])[CH2:33][S:32][C:31]2=[O:36])[N:26]=[N:25]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14](/[CH:16]=[C:33]4/[C:34](=[O:35])[N:30]([CH2:29][C:27]5[N:26]=[N:25][NH:24][CH:28]=5)[C:31](=[O:36])[S:32]/4)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:21])([F:23])[F:22])[CH:3]=1
Reactant: O=Cc1ccc2c(c1)nnn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: O=C1CSC(=O)N1Cc1c[nH]nn1
Product: O=C1S/C(=C\c2ccc3c(c2)nnn3Cc2ccc(Cl)cc2C(F)(F)F)C(=O)N1Cc1c[nH]nn1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-benzotriazol-5-yl}methylidene)-3-(1H-1,2,3-triazol-4-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from 1-(4-chloro-2-trifluoromethylbenzyl)-1H-benzotriazole-5-carbaldehyde (from Example 258) and 3-(1H-[1,2,3]triazol-4-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 85) following General Procedure F.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH2:7][OH:8])[N+:4]([O-:6])=[O:5].[CH2:11](OC=C)[CH3:12]>Cl.C(#N)C>[CH3:11][CH:12]1[O:8][CH2:7][C:3]([CH2:9][OH:10])([N+:4]([O-:6])=[O:5])[CH2:2][O:1]1
Reactant: C=COCC
Reactant: O=[N+]([O-])C(CO)(CO)CO
Agent: Cl
Solvent: CC#N
Product: CC1OCC(CO)([N+](=O)[O-])CO1
Temperature: 25 °C
Yield: 86 %

Procedure:
Following the procedure 2(A) described in this application, to a 100 ml round bottom flask equipped with a stir bar and reflux condenser topped with a nitrogen inlet was added 5 g (0.03 mol) tris(hydroxymethyl)nitromethane, 2.86 g (0.04 mol) ethylvinyl ether, 50 ml acetonitrile and 5 drops concentrated HCl. The reaction was heated to 35°-40° C. for 4 hours. After cooling to room temperature the volatiles were removed to give the product, 2-methyl-5-hydroxymethyl-5-nitro-1,3-dioxane, in 86% yield. 1H NMR in CD3OD confirmed the structure.