Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:10][N:11]=[C:12]([CH3:16])[C:13](O)=[O:14])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:19])=O.N.C(ON=C(C)C(N)=O)C=CC1C=CC=CC=1>O.C(Cl)(Cl)Cl>[CH2:1]([O:10][N:11]=[C:12]([CH3:16])[C:13]([Cl:19])=[O:14])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=NOCC=Cc1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Agent: CC(=NOCC=Cc1ccccc1)C(N)=O
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=NOCC=Cc1ccccc1)C(=O)Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-(Cinnamyloxyimino)-propionyl chloride is prepared from 4.38 g. (20 mmol) 2-(cinnamyloxyimino)-propionic acid and 3.57 g. (30 mmol) thionyl chloride in the manner described in Example 6. The crude acid chloride is dissolved in 20 ml. chloroform and added, while stirring, to an ice-cooled solution of ammonia in 40 ml. chloroform. The reaction mixture is left to stand overnight at ambient temperature and then shaken up with 100 ml. water. Subsequently, the organic phase is first washed with 0.5 N hydrochloric acid, then with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous sodium sulphate and evaporated in a vacuum. The residue is recrystallized from a mixture of ethyl acetate and ligroin to give 2.9 g. (66% of theory) 2-(cinnamyloxyimino)-propionamide; m.p. 120°-121° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Cl)[C:18]=1[CH2:24][OH:25])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)=[CH:45][N:44]=2)[C:28]1=[O:56].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:31]3[CH:30]=[C:29]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([N:49]5[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH2:54]5)=[CH:45][N:44]=4)[C:28](=[O:56])[N:27]([CH3:26])[CH:32]=3)[C:18]=1[CH2:24][OH:25])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CN1CCN(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)nc2)CC1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
To a 10 mL flask were added 6-tert-butyl-2-(3-chloro-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one 101j (100 mg, 0.27 mmol), 1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (141 mg, 0.33 mmol), PCy3 (6 mg), Pd(dba)2 (6 mg) and K2CO3 (112 mg, 0.8 mmol) in order. The flask was evacuated and backfilled with nitrogen. This sequence was repeated three times. Then, 20 percent aqueous 1,4-dioxane was added to the reaction mixture. The resulting mixture was heated to 90° C. for gentle reflux and stirred for 1.5 hr under Nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth filtration agent pad (CELITE®) and concentrated to afford a residue which was purified by prep-TLC (10% MeOH in CH2Cl2) to afford 101 (80 mg, 46%) as a yellow solid. MS: [M+H]+624. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=2.0 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H), 8.36 (s, 1H), 7.87 (d, J=3.2 Hz, 2H), 7.73 (d, J=12.8 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.41 (d, J=3.2 Hz, 1H), 7.39 (d, J=3.6 Hz, 1H), 7.35 (dd, J=2.8, 9.2 Hz, 1H), 7.28 (d, J=2. Hz, 1H), 7.20 (d, J=9.2 Hz, 1H), 4.58 (t, J=4.8 Hz, 1H), 4.36 (s, 2H), 3.58 (s, 3H), 3.04 (m, 4H), 2.44 (m, 4H), 2.21 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.CS(Cl)(=O)=O.O[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C:43]([O:45][CH3:46])=[O:44].[H-].[Na+]>C(OCC)(=O)C.O.CN(C)C=O.C(N(CC)CC)C>[C:12]([O:11][C:10]([N:9]([CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:21][C:22]=1[CH3:23])[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:1][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:4][CH:5]=1)=[O:16])([CH3:13])([CH3:14])[CH3:15]
Reactant: Cc1oc(-c2ccccc2)nc1CN(C(=O)OC(C)(C)C)c1ccc(CO)cc1
Reactant: COC(=O)Cc1ccccc1O
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1OCc1ccc(N(Cc2nc(-c3ccccc3)oc2C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
To a mixture of t-butyl 4-(hydroxymethyl)phenyl[(5-methyl-2-phenyl-4-oxazolyl)methyl]carbamate (1.0 g), triethylamine (1.01 g) and ethyl acetate (50 mL) was added methanesulfonyl chloride (1.15 g) at 0° C. The reaction mixture was stirred at room temperature for 20 hrs., diluted with ethyl acetate and washed successively with a saturated aqueous sodium hydrogencarbonate and saturated brine. The mixture was dried over anhydrous magnesium sulfate and concentrated to give pale-yellow crystals. To a mixture of the obtained crystals, methyl 2-(2-hydroxyphenyl)acetate (0.55 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.14 g) at 0° C. The mixture was stirred at room temperature for 3 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give crystals (0.82 g, 60%) of methyl 2-[2-[4-[(t-butoxycarbonyl)[(5-methyl-2-phenyl-4-oxazolyl)methyl]amino]benzyloxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 85-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12]([OH:18])=[N:13][CH:14]=[CH:15][C:16]=2[Cl:17])[CH:9]=1)[C:5]#[N:6].[Cl:19]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:18])[NH:13][CH:14]=[C:15]([Cl:19])[C:16]=2[Cl:17])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccnc2O)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)c(Cl)c[nH]c2=O)c1
Temperature: 70 °C

Procedure:
To a suspension of 3-chloro-5-[(4-chloro-2-hydroxypyridin-3-yl)oxy]benzonitrile (50 mg, 0.178 mmol) in acetic acid (1 mL) was added N-chlorosuccinimide (35.6 mg, 0.267 mmol) and the resulting mixture heated to 70° C. for 2 hours. This mixture was allowed to cool to room temperature and the resulting white solid was filtered and washed with methanol (1 mL) to provide the title compound. LRMS (M+1): 314.6.
Reaction SMILES: Br.[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:10]=2[CH2:9][O:8]1.[CH2:26]([NH2:28])[CH3:27]>>[CH2:26]([NH:28][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH2:6][CH2:5][CH2:4][N:3]([CH3:25])[CH3:2])([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[O:8][CH2:9][C:10]=2[CH:15]=1)=[NH:17])[CH3:27]
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Reactant: CCN
Agent: Br
Product: CCNC(=N)c1ccc2c(c1)COC2(CCCN(C)C)c1ccc(F)cc1
Temperature: 80 °C
Yield: 19 %

Procedure:
Using 250 mg of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile hydrobromide (citalopram HBr, 1.0 equiv) and ethylamine (1.3 equiv) gave, after heating at 80° C. for 15 h, the title product (65 mg, 19% yield) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][N:7]3[C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][CH:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CO>[OH:12][CH:11]1[C:10]2[CH:9]=[CH:8][N:7]3[C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][CH:3]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]1[OH:1]
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)C(O)C(c1ccccc1)N3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c3c(ccn2c1C)C(O)C(O)C(c1ccccc1)N3
Temperature: 0 °C
Yield: 71 %

Procedure:
700 mg of 8-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]-naphthyridin-7-one are suspended in 15 ml of methanol and treated with 200 mg of sodium borohydride in portions at room temperature with stirring. After stirring for 2 hours, the mixture is poured onto 100 ml of ice water. The precipitate which is deposited is filtered off, briefly dried in vacuo and recrystallized from a little 2-propanol. 500 mg of the title compound of melting point 150-2° C. are obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCc2ccc(S(=O)(=O)N3CCCCC3)cc2C1

Procedure:
21.1 g (77 mmol) of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (prepared as described in G. Grunewald et al. J. Med. Chem 1999, 42, 118-134) in 50 ml of THF were added dropwise to a solution of 6.0 g (70 mmol) of piperidine and 10.9 g (84 mmol) of diisopropylethylamine in 230 ml of THF, and the mixture was heated under reflux for two hours. After the reaction was complete, the solvent was removed in vacuo, the residue was taken up in dichloromethane/water and, after making alkaline with 10% strength sodium hydroxide solution and separating the phases, the organic phase was dried over sodium sulfate. The crude product remaining after filtration and removal of the solvent was purified by column chromatography on silica gel (mobile phase: methylene chloride with 3% methanol).
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2NN=[N:26][N:25]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].N1C=CC=CC=1>O>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:3][C:2]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)=[N:26][N:25]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(-c2nnn[nH]2)cc1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(C)(C)C)cc3)o2)cc1
Yield: 92 %

Procedure:
A mixture of methyl 4-chloroformylbenzoate (1.17 g), 5-(4-t-butylphenyl)-1H-tetrazole (1.00 g) and pyridine (10 ml) was heated under reflux for 1 hr. After cooling, water was added to the mixture. The crystals were collected by filtration and dissolved in ethyl acetate. This solution was washed with 1 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with cold hexane to give methyl 4-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (1.51, yield 92%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: 210–211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([OH:22])(=[O:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].Cl.[CH2:39]([O:41][NH2:42])[CH3:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:42][O:41][CH2:39][CH3:40])(=[O:21])=[O:22])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: CCON
Reactant: O=C(c1cnc2c(S(=O)(=O)O)cnn2c1Nc1cc(Cl)ccc1Cl)N1CCC(c2ccc(F)cc2)CC1
Agent: Cl
Product: CCONS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 21.9 %

Procedure:
Using 7-(2,5-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.15 g, 0.27 mmol) obtained in Example 27 step 1 and O-ethylhydroxylamine hydrochloride (0.104 g, 1.06 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (0.036 g, 22%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[CH:9]=[C:10]([F:15])[C:11](OC)=[O:12])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:17])([CH3:16])[CH:9]=[C:10]([F:15])[CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: COC(=O)C(F)=CC(C)(C)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C=C(F)CO)c1ccc(Cl)cc1
Yield: 70.2 %

Procedure:
The method of Example 6 was repeated using methyl 4-(4-chlorophenyl)-2-fluoro-4-methylpent-2-enoate (Example 3) (0.56 g), diethyl ether (20 ml) and lithium aluminium hydride (0.21 g) to yield the title compound (0.35 g, 92%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([SH:36])[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([S:36][C:2]2[CH:3]=[CH:4][N:5]3[C:10]=2[C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]3)[CH:33]=[CH:34][CH:35]=1
Reactant: COc1cccc(S)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(I)c2c(=O)n1-c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(Sc2ccn3nc([C@H](C)NC(=O)OC(C)(C)C)n(-c4ccccc4)c(=O)c23)c1
Yield: 30 %

Procedure:
(S)-tert-Butyl (1-(5-iodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (500 mg, 1.04 mmol) was treated with 3-methoxybenzenethiol (219 mg, 1.56 mmol), potassium carbonate (216 mg, 1.56 mmol) and copper(I) iodide (297 mg, 1.56 mmol) according to the method described in Preparation 44. The residue was purified by reverse phase using Isolera® Purification System to give 154 mg (30% yield) to the title compound. Purity 100%.
Reaction SMILES: C(O[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5][C:6]1[CH2:10][CH2:9][CH2:8][N:7]=1)C.F[B-](F)(F)F.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[C:11]1([C:4](=[N:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:5]=[C:6]2[CH2:10][CH2:9][CH2:8][NH:7]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)N
Reactant: CCOC(=CC1=NCCC1)c1ccccc1
Agent: F[B-](F)(F)F
Product: CC(C)(C)N=C(C=C1CCCN1)c1ccccc1

Procedure:
By heating the solution of 9.1 g (0.03 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-1-pyrroline-tetrafluoroborate in 50 ml of tert.-butylamine in a closed tube at 105° for 18 hours and processing analogously to Example 1, there is obtained crude 2-[2-phenyl-2-(tert.-butylimino)-ethylidene]-pyrrolidine. The crude base is dissolved in ether, and 2.8 g of methanesulphonic acid is added, whereupon 2-[2-phenyl-2-(tert.-butylimino)-ethylidene]-pyrrolidine-(1:1)-methanesulphonate crystallises out. It melts at 208°-209° (decomposition) after recrystallisation from ethyl acetate.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([Cl:14])[CH:6]=1.C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.O1CCCC1>[N:4]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([Cl:14])[CH:6]=1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Agent: Cl
Agent: II
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(N=C=S)cc1Cl
Temperature: 25 °C
Reaction time: 24.5 h
Yield: 62 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 4-amino-2-chlorobenzoic acid (0.26 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 24.5 hours. To the obtained reaction mixture, a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) was dropwise added over a period of 5 minutes at 0° C., followed by stirring at 0° C. for further two hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and stirred. Then, ethyl acetate (6 mL) was added, and the organic layer was separated and concentrated under reduced pressure to dryness. To the residue, water (4 mL) and sodium hydrogencarbonate (0.14 g, 1.7 mmol) were added, and the insoluble matter was removed by filtration. To the filtrate, 1M hydrochloric acid (1.5 mL) and water (2.0 mL) were added, and the precipitated solid was collected by filtration. To this solid, ethyl acetate (6 mL), water (2.0 mL) and sodium hydrogencarbonate (25 mg, 1.7 mmol) were added, and the organic layer was concentrated under reduced pressure to dryness to obtain 4-isothiocyanato-2-chlorobenzoic acid as a white solid (0.20 g, yield: 62%, HPLC purity: 91%, HPLC retention time: 3.9 min). LC-MS ES-212, 214 (retention time: 4.2 min, condition 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][O:31]C5CCCCO5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:38]C(=O)C)[CH:10]=1.C(Cl)(=O)C>CO>[NH2:38][C:11]1[CH:12]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(CCOC5CCCCO5)c4)ccc32)c1
Solvent: CC(=O)Cl
Solvent: CO
Product: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(CCO)c4)ccc32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
To a solution of N-(2′,4′-difluoro-5-(5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)-ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)acetamide (0.12 g, 0.125 mmol) in methanol (5 ml) was added (1 ml) acetyl chloride at 0° C. The mixture was stirred at RT for 16 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 28% yield (0.026 g). 1H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 1H), 8.20 (s, 1H), 7.97-7.95 (d, 2H), 7.69-7.64 (m, 2H), 7.59-7.56 (dd, 1H), 7.39-7.36 (m, 1H), 6.88 (s, 2H), 6.82 (d, 1H), 5.70 (s, 2H), 4.95 (s, 1H), 4.19-4.16 (t, 2H), 3.81-3.78 (t, 2H); LC-MS (ESI): Calculated mass: 431.44; Observed mass: 432.2 [M+H]+ (rt: 0.4 min).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C@@H:24]([OH:35])[CH2:25][C@@H:26]2[OH:34])[CH:21]=[CH:20]3)[CH2:17][CH2:16]1)[CH3:14])[CH3:9].CO>CCOCC>[OH:34][C@@H:26]1[C@@:27]2([CH3:28])[C:22](=[CH:21][CH2:20][C@@H:19]3[C@@H:29]2[CH2:30][CH2:31][C@@:32]2([CH3:33])[C@H:18]3[CH2:17][CH2:16][C@@H:15]2[C@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:8]([CH3:9])[CH3:7])[CH2:23][C@@H:24]([OH:35])[CH2:25]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 72 %

Procedure:
A solution of 1α-hydroxycholesteryl tosylate (7, R' is 4-methylphenyl, 1.35 g) in anhydrous ether (80 ml) was heated under reflux with lithium aluminum hydride (0.098 g, 23.9 mmoles) under anhydrous conditions for 5 hours. Work-up of the reaction mixture as described in the above procedure for the preparation of 4,6-cholestadien-1α,3β-diol 4 followed by chromategraphy of the crude carbinol on silica gel (25 g) using low boiling petroleum ether-benzene as the eluent gave 705 mg (72% yield based on 1α-hydroxycholesterol 6) of 5.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[C:12]([O:15][C:16](=[O:18])[CH3:17])(=O)[CH3:13]>[Cl-].[Cl-].[Zn+2]>[C:16]([O:15][C:12]1[CH:1]=[C:2]([CH:11]=[CH:10][CH:13]=1)/[CH:3]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:2]([CH3:1])[CH:3]=[N:4][C:5]\1=2)(=[O:18])[CH3:17]
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)Oc1cccc(/C=C2\CCCc3cc(C)cnc32)c1

Procedure:
A mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 ml), m-hydroxybenzaldehyde (20 g), acetic anhydride (50 ml) and ZnCl2 (1 g) was heated at reflux for 31/2 hours. The solvent was removed by evaporation and the residue dissolved in ethyl acetate (300 ml). The solution was extracted with 2N HCl, and the acidic phase was washed once with ethyl acetate. It was then basified (Na2CO3) and the product extracted into a mixture of diethyl ether and ethyl acetate. The solvent was removed by evaporation and the residue crystallised from di-isopropyl ether, washed twice with hexane and then dried to give the title compound as the hemihydrate (7.4 g). m.p. 66°-8° C.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].C(N(CC)CC)(C)C.[C:41]1([SH:47])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH3:3]
Reactant: Sc1ccccc1
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Agent: CCN(CC)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(Sc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirring solution of benzyl 6-(1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (46 mg) in anhydrous DMF (1 ml) is added N-isopropyl-N,N-diethylamine (13 mg) and thiophenol (11 mg). The resulting solution is stirred in the cold for 15 mins. and at room temperature for 45 mins, then diluted with ethyl acetate (10 ml). The mixture is thoroughly washed with water (5×2 ml) and brine, dried with MgSO4, filtered, and evaporated to dryness. The residue is purified on a silica gel GF plate to yield benzyl 6-(1-hydroxyethyl)-3-phenylthio-1-azabicyclo[3.2.0]hept-b 2-en-7-one-2-carboxylate.
Reaction SMILES: CS[C:3]([N:7]([CH3:9])[NH2:8])=[N:4][C:5]#[N:6].[NH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1>>[CH3:9][N:7]1[C:3]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:23])[CH3:24])[CH:16]=2)=[N:4][C:5]([NH2:6])=[N:8]1
Reactant: CSC(=NC#N)N(C)N
Reactant: CN(C)Cc1cccc(OCCCN)c1
Product: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Yield: 58.3 %

Procedure:
A mixture of N-cyano-1-methylhydrazinecarboximidothioic acid methyl ester (200 mg) and 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (289 mg) was heated at 40° under a reduced pressure of 20 mm of mercury for 4 hours. The reaction mixture was cooled, triturated with ether and the resulting solid recrystallised from ethyl acetate to give the title compound as colourless crystals (246 mg) m.p. 95°-96.5°.