Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)CC)C>O1CCOCC1>[Br:18][C:4]1[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCOCC3)c2)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 35.2 %

Procedure:
0.211 g (0.0005 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 10 ml of dioxane and treated with 0.217 g (0.0025 mol) of morpholine and 1 ml of triethylamine. The mixture was stirred at 40° C for 72 hrs. and the solvent was then removed. The residue was partitioned in ethyl acetate and water and the organic phase was extracted with sat. sodium chloride solution and dried over MgSO4. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1 and there was obtained 0.07 g (35%) of 4(2-bromo-6-morpholine-4-ylpyridine-4-sulphonyl)-phenylamine as white crystals; m.p.: 244-245° C.
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=[O:4].[CH3:13][C:14]([O:17][C:18](=[O:26])[NH:19][C@H:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1)([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>>[CH3:16][C:14]([O:17][C:18](=[O:26])[NH:19][C@H:20]1[CH2:24][CH2:23][C@H:22]([O:25][CH:3]=[O:4])[CH2:21]1)([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OC=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
Diethyl azodicarboxylate (0.164 ml, 1.23 mmol) was added dropwise to a stirred solution of (1S-cis)-(3-hydroxycyclopentyl)carbamic acid 1,1-dimethylethyl ester (0.124 g, 0.61 mmol), triphenylphosphine (0.323 g, 1.23 mmol) and formic acid (0.046 ml, 1.23 mmol) and the solution was stirred at room temperature for 2 h The solution was then concentrated and purified by column chromatography on flash silica eluting with 10-30% ethyl acetate in cyclohexane to give the title compound (0.07 g) as white needles from diisopropyl ether m p.84°-85° C., [α]D -12.7° (CHCl3 c=0.55%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([N:11]=[C:12](SC)SC)=[N:10][C:5]2=[CH:4][CH:3]=1.Cl.Cl.[NH2:19][CH2:20][C@@:21]1([OH:29])[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]3[O:29][C@:21]4([CH2:20][N:19]=3)[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]4)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CSC(=Nc1nc2ccc(Cl)nc2s1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Yield: 50.6 %

Procedure:
A mixture of dimethyl 5-chlorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (100 mg, 0.35 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (79 mg, 0.35 mmol) and cesium carbonate (225 mg, 0.69 mmol) in DMF (1.7 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and the solids collected by filtration. The crude solids were purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform) to afford (R)—N-(5-chlorothiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′ bicyclo[2.2.2]octan]-2-amine (62 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.13 (br. s., 1 H) 7.93 (d, J=8.53 Hz, 1 H) 7.45 (d, J=8.28 Hz, 1 H) 3.92 (d, J=10.29 Hz, 1 H) 3.67 (d, J=10.29 Hz, 1 H) 3.00-3.14 (m, 2 H) 2.77-2.93 (m, 2 H) 2.69 (t, J=7.65 Hz, 2 H) 2.12 (br. s., 1 H) 1.95 (br. s., 1 H) 1.43-1.72 (m, 3 H). MS (LC/MS) R.T.=1.10; [M+H]+=350.10.
Reaction SMILES: [F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:16].O1CCOCC1>CCOC(C)=O>[ClH:16].[F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CCNCC1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a hazy solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (52.66 g, 242 mmol) in EtOAc (1 L) was added 4M HCl/dioxane (303 mL, 1212 mmol). The mixture was allowed to stir at ambient temperature for 16 hours. The resulting precipitate was collected by filtration, washed with EtOAc and dried in vacuo to afford 37 g (99%) of desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](O)=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:36].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([F:36])=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: CC=C(CC)C1N(CC(=O)O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC=C(CC)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 74.3 %

Procedure:
In a manner similar to the method described in example 34a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1-hydroxycarbonyl-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.16 g, 0.33 mmol) prepared in example 81c was reacted with cyanuric fluoride (0.044 mL, 1.64 mmol) (Alfa) and pyridine (0.13 g, 1.64 mmol) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-fluorocarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (yield: 0.12 g, 75%).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22]C(=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:29][CH2:30][CH2:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34](C(C)=C)[C:33]1=[O:44]>CO>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:29][CH2:30][CH2:31][N:32]3[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[NH:34][C:33]3=[O:44])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: C=C(C)n1c(=O)n(CCCBr)c2ccccc21
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCn3c(=O)[nH]c4ccccc43)c2CC1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
Add potassium hydroxide (933 mg, 16.6 mmol) in one portion to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.52 mmol) in methanol (10 mL). Heat the reaction at reflux under nitrogen 4 h. Then cool to room temperature and add 1-(3-bromo-propyl)-3-isopropenyl-1,3-dihydro-benzoimidazol-2-one (142 mg, 0.52 mmol). Stir the reaction at room temperature overnight. Remove solvents in vacuo, extract into diethyl ether (2×50 mL), wash with water (2×50 mL) and brine (50 mL). Dry over MgSO4, filtrate and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (209 mg, 76%). MS (ES+) m/z: 550 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([F:17])[CH:19]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1c(Cl)cnn1C
Yield: 36.4 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (30 mg, 0.13 mmol) was treated with 3,4-Difluorophenyl isocyanate (17 μL, 0.14 mmol) in a similar manner to Example 1.53, providing 18.6 mg (34%) of Compound 92: LCMS m/z (%)=393 (M+H35Cl, 100), 395 (M+H37Cl, 38). 1H NMR (400 MHz, acetone-d6) δ: 8.18 (s, 1H), 8.05 (s, 1H), 7.65 (m, 1H), 7.57 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J=2 Hz, 1H), 7.09 (d, J=4 Hz, 1H), 7.06 (d, J=2 Hz, 1H), 7.04 (d, J=8 Hz, 1H), 3.72 (s, 3H), 3.55 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:27]4[O:26][C:25]([CH3:29])([CH3:28])[CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[N:32]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:27]4[O:26][C:25]([CH3:28])([CH3:29])[CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:30][C:31]2[CH:35]=[CH:34][N:33]([CH2:36][C:37]([OH:39])([CH3:38])[CH3:40])[N:32]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CC1(C)Cc2cccc(Oc3cnn(C(CC4CCCC4)C(=O)O)c(=O)c3)c2O1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc4c3OC(C)(C)C4)cc2=O)n1
Yield: 84 %

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 67) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (1.13 g, 84%); ES+-HRMS m/e calcd for C29H37N5O5 [M+H+] 536.2868 found 536.2866. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (br. s., 3H), 1.06 (br. s., 3H), 1.06-1.16 (m, 1H), 1.24-1.74 (m, 8H), 1.40 (s, 6H), 1.91 (br. s., 1H), 2.20-2.35 (m, 1H), 3.09 (s, 2H), 3.89 (s, 2H), 4.68 (s, 1H), 5.46 (dd, J=11.0, 4.1 Hz, 1H), 5.69 (d, J=2.7 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 6.90 t, 7.5 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 8.11 (d, J=2.7 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:37]2([CH3:38])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:32])[C@H:18]([OH:31])[C:19]#[C:20][C:21]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:40][C:41](=[O:43])[CH3:42])[CH2:6]1)(=[O:3])[CH3:2].[K].[CH3:45]I>CS(C)=O.C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@@:37]2([CH3:38])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:32])[C@H:18]([O:31][CH3:45])[C:19]#[C:20][C:21]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:40][C:41](=[O:43])[CH3:42])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)[C@H](O)C#CC(C)(C)OC5CCCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CO[C@H](C#CC(C)(C)OC1CCCCO1)[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 90 %

Procedure:
100 mg of (22S)-1α,3β-diacetoxy-25-tetrahydropyranyloxy-cholest-5-en-23-yn-22-ol (IIIa1) obtained in Example 1 (1) was dissolved in 1.5 ml of dimethylsulfoxide, and after adding thereto 13.2 mg of powderous potassium hydroxyde and 31 μl of methyl iodide, the mixture was stirred for 3.5 hours at room temperature. The reaction solution was diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatgraphy (solvent; n-hexane:ethyl acetate=7:1) for purification to give 92 mg of (22S)-1α,3β-diacetoxy-22-methoxy-25-tetrahydropyranyloxy-cholest-5-en-23-yn (IVb1) (yield: 90%).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[CH2:21]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)[C:11]([S:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:29])=[O:2])=[C:12]1[CH3:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Br)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Sc2cccc(C(=O)O)c2)c2ccc(Br)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1-Benzyl-6-bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.040 g, 0.086 mmol) was dissolved in THF:MeOH (1:1) then LiOH (1M aq.) was added and the reaction stirred at room temperature overnight. Acid-base extraction afforded the title compound.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][CH:25]([CH2:30][CH:31]3[O:33][CH2:32]3)[C:26]([O:28]C)=[O:27])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH:24][CH:25]([CH2:30][CH:31]([OH:33])[CH2:32][S:1][C:2]3[NH:3][CH:4]=[CH:5][N:6]=3)[C:26]([OH:28])=[O:27])(=[O:22])=[O:23])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Sc1ncc[nH]1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3ncc[nH]3)C(=O)O)cc2)cc1

Procedure:
Example 22 is prepared from 2-mercaptoimidazole and 1d using the procedure described for compound 20.
Reaction SMILES: [CH:1]1([C:7]2([OH:19])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]2[CH2:13][C:14]([O:16]CC)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[Na+]>[CH:1]1([C:7]2([OH:19])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]2[CH2:13][C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CC1C=CC=CC1(O)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC1C=CC=CC1(O)C1CCCCC1
Yield: 79 %

Procedure:
A dissolved solution of ethyl 2-cyclohexyl-2-hydroxy- phenylacetate (Compound (4), 8.0 g) in methanol (150 ml) and 1N aqueous sodium hydroxide solution (60 ml) was refluxed for 3 hours and then, methanol was then removed under pressure. The residual solution was acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate. The solvent was removed under pressure. The residue was recrystallized from hexane-ether to obtain the title compound (5.65 g, 80.3%) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1.[CH:23]([O-])([O-])OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:23]=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1
Reactant: CCOC([O-])[O-]
Reactant: COc1ccc(C2=NCC(NN)=Nc3ccc(Cl)cc32)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C2=NCc3nncn3-c3ccc(Cl)cc32)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 1.6 parts of 7-chloro-2-hydrazino-5-(4-methoxyphenyl)-3H-1,4-benzodiazepine in 50 parts by volume of ethanol is added 3 parts of ethyl orthoformate. To the mixture is added 0.5 part by volume of concentrated sulfuric acid with stirring. After 5 minutes, the reaction mixture is neutralized with a saturated aqueous sodium bicarbonate solution, followed by removal of the solvent. To the residue is added water, whereupon 8-chloro-6-(4-methoxyphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is obtained as crystals. Recrystallization from acetone-ethyl acetate gives pale yellow flakes melting at 216°-217° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][C:9]([OH:11])=[O:10].[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[CH2:13]([O:10][C:9](=[O:11])[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]([CH3:7])[C:2]1([CH3:12])[CH3:1])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=CCC(CC(=O)O)C1(C)C
Solvent: CCO
Product: CCOC(=O)CC1CC=C(C)C1(C)C
Temperature: 78 °C
Yield: 3289.9 %

Procedure:
A solution of α-campholenic acid (100 g) and p-toluene-sulfonic acid (2 g) in ethanol (3 liters) was kept at reflux (78° C.) for 3 hours. The alcohol was then removed, the residue taken up in CH2Cl2 (1.5 liters) and the solution extracted with ice cold 5% aqueous sodium hydroxide (2×500 ml) and water (500 ml). Concentration of the CH2Cl2 solution gave a crude product (81 g) which was distilled through a 9" glass packed column to give 75 g of a colorless liquid; bp 90° C. @ 4,8 mm Hg; analysis: 97% (CW 20M fused silica column, 120° C.) ethyl α-campholenate.
Reaction SMILES: C(C1[C:12]2[C:7](=[CH:8][C:9](C)=[CH:10][CH:11]=2)[C:6](C)(C)C1C)(C)C.[CH2:17]([Cl:21])[C:18](=[CH2:20])[CH3:19].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:20][C:18]([C:10]1[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=1)([CH3:19])[CH2:17][Cl:21]
Reactant: C=C(C)CCl
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2C(C)C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(C)(C)CCl)cc1
Temperature: 40 °C

Procedure:
To prepare the 1-isopropyl-2,3,3,5-tetramethylindane, the procedures of Traas et al., U.S. Pat. No. 4,352,748 are substantially followed. Specifically, methallyl chloride (24 g) is added to a mixture of toluene (92 g) and concentrated sulfuric acid (49 g), while maintaining the temperature at about 40° C. The reaction mixture is stirred for half an hour, after which time the layers are separated. The organic layer is washed neutral with soda solution, dried on magnesium sulfate and evaporated. The residue is distilled under diminished pressure to obtain 2-methyl-2 (para-tolyl)propyl chloride. A mixture of 2 methyl-2-(para-tolyl)propyl chloride (18 g) and tert-amyl chloride (10 g) is added to aluminum chloride (10 g) dissolved in nitromethane (50 ml), at a temperature of between about 5° C. and 10 ° C. The reaction mixture is allowed to warm to room temperature, with stirring, over a period of about one hour. The reaction mixture is then poured over ice, and extracted three times with ether. The solution in ether is washed to neutrality, dried on magnesium sulfate and evaporated. The residue is distilled under diminished pressure to yield 1-isopropyl-2,3,3,5-tetramethylindane.
Reaction SMILES: [OH:1][CH:2]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1.C(N(CC)CC)C.Cl[C:33]([O:35][CH3:36])=[O:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:36][O:35][C:33]([O:1][CH:2]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)=[O:34]
Reactant: COC(=O)Cl
Reactant: Cc1cccc(C#CC(O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)OC(C#Cc1cccc(C)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the Compound of Example 39 (50 mg, 0.15 mmol), triethylamine (65 μL, 0.45 mmol) and 4-dimethylaminopyridine (10 mg, 0.07 mmol) in 3 mL of CH2Cl2 cooled at 0-5° C., methyl chloroformate (23 μL, 0.30 mmol) was added dropwise. The reaction mixture was stirred at r.t. overnight. Afterwards, it was evaporated to dryness and purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 8:2 affording the title product (0.28 g) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14](O)[CH2:15]C=C)=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1.CSC.[CH3:31][OH:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[CH:15][CH:31]=[O:32])=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1
Reactant: C=CCC(O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Reactant: CO
Solvent: CSC
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C=CC=O
Reaction time: 2 h

Procedure:
N-[4-(4-fluorophenyl)-5-(1-hydroxybut-3-enyl)-6-isopropyl-pyrimidin-2-yl]-N-methylmethanesulfonamide (4 g, 10.2 mmol) is diluted in 102 mL methanol. O3 gas is bubbled through the solution at −15° C. to −10° C. for 60 min. Reaction solution is bubbled with Argon for 2 min to remove the excess of O3. Dimethylsulfide (1.5 ml, 20.3 mmol) is added to the solution, maintaining stirring for 2 hours. Upon completion of the reaction, the solution is distilled under reduced pressure to remove the excess of dimethylsulfide and solvent. The residue is diluted in 200 mL dichloromethane, washed with DM water (50 mL), brine (50 mL) and dried over magnesium sulfate (1 g). The solvent is removed by distillation under reduced pressure to afford 4.1 g of N-[4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl]-N-methylmethanesulfonamide.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=[O:16])#[N:2].[OH-:20].[K+]>O>[C:15]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:20])([OH:17])=[O:16]
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2ccc(C)cc2)c1C#N
Agent: [K+]
Solvent: O
Product: Cc1ccc(-n2ncc(C(=O)O)c2C(N)=O)cc1
Reaction time: 72 h

Procedure:
To 10 g. of ethyl 5-cyano-1-(4-methylphenyl)-4 pyrazolecarboxylate was added 5.6 g. of potassium hydroxide and 200 ml. of water followed by enough water to cause solution. The mixture was stirred under reflux for 8 hours and allowed to stand for 3 days. It was then poured over ice, made acid and filtered. The solids from the filtration were heated in 100 ml. of ethyl acetate, and the undissolved solid was separated, dried and identified as 4.25 g. of the desired product, m.p. 260° dec. The product was identified by nuclear magnetic resonance analysis in DMSOd6. δ2.36 (s,3), methyl; 7.32 (d,2), aromatic; 7.45 (d,2), aromatic; 8.01 (s,1), pyrazole; 7.91 (s,1), carboxamide; 8.33 (s,1), carboxamide.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:13]1[CH:18]=[C:17](C=O)[C:16]([CH:21]=O)=[CH:15][CH:14]=1.C(Cl)Cl>CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:21][C:16]3[C:15](=[CH:14][CH:13]=[CH:18][CH:17]=3)[C:11]2=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: O=Cc1ccccc1C=O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 42.6 %

Procedure:
A mixture of 4-acetylphenylisocyanate (27.5 g, 0.17 mol) and o-phthalicdicarboxaldehyde (25.0 g, 0.186 mol) is heated in an oil bath at 170°-175° C. for 4.0 hours under nitrogen atmosphere. On cooling the melt solidified which is pulverized and refluxed with CH2Cl2 and CH3OH and filtered to give 18.2 g (41.4%) of the desired 2-(4-acetylphenyl)-2,3-dihydro-1H-isoindole-1-one, mp 235°-237° C. The residue is recrystallized from DMF (1800 ml). Yield 13.0 g (29.6%), mp 236°-239° C. (Jap. patent J5 7050-960; mp 243°-244° C. for the nonsolvated compound, prepared by a different route).