Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:21])[C:10](=[N:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:22](=[O:27])(=[O:26])[N:23]([CH3:25])[CH3:24].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:21])[C:10](=[N:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:28](=[O:30])[CH3:29])=[CH:18][CH:19]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:22](=[O:27])(=[O:26])[N:23]([CH3:24])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccc(O)cc3)n2C)ccc1Cl
Product: CC(=O)Oc1ccc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
2.1 g (5 mmoles) of 4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(4-hydroxyphenylimino)-3-methyl-4-thiazoline (Example 2) are suspended in 25 ml of acetic anhydride and the yellow solution which results on warming, is stirred for 1 hour at 120° C. After distilling off the acetic anhydride in vacuo, the solid residue is recrystallized from isopropanol. Colorless crystals of m.p. 173°-174° C.
Reaction SMILES: [N:1]#[N:2].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:18]([NH:20][C@@H:21]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:22]([OH:36])[CH2:23][C@@:24]1([C:33]([NH2:35])=[O:34])[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:19])[CH2:15][S:16][CH3:17])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClC1C=CC=C(C(OO)=[O:52])C=1>CO>[N:1]#[N:2].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:18]([NH:20][C@@H:21]([CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C@H:22]([OH:36])[CH2:23][C@@:24]1([C:33]([NH2:35])=[O:34])[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:19])[CH2:15][S:16]([CH3:17])=[O:52])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C[C@@]1(C(N)=O)CCCN1C(C)(C)C
Agent: N#N
Solvent: CO
Product: CS(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C[C@@]1(C(N)=O)CCCN1C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
A solution of 193 mg of N2 -[3(S)-[[N-(benzyloxycarbonyl)-S-methyl-L-cysteinyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide in 2 ml of methanol was cooled to -70° C. A solution of 62 mg of 3-chloroperbenzoic acid in5 ml of methanol was added and the mixture was stirred at -70° C. for 30 minutes. The solvent was then removed by evaporation and the residue was chromatographed on silica gel using System G for the elution to give 62 mg of N2 -[3(S)-[[N-(benzyloxycarbonyl)-3-(methylsulphinyl)-L-alanyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a 1:1 mixture of diastereomers; MS: m/e 601 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[C:7]([O:36][CH2:37][CH3:38])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:44])=[O:43]>>[ClH:25].[C:1]([C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]2[N:15]([C:33]([N:50]3[CH2:49][CH2:48][N:47]([CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:52][CH2:51]3)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:18]=2)=[C:7]([O:36][CH2:37][CH3:38])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)c(OCC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)c(OCC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12f) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 729.4 [(M+H)+]
Reaction SMILES: O.[CH2:2]([CH:14]1[CH2:19][CH2:18][CH:17](O)[CH2:16][CH2:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S([O-])(O)(=O)=O.[K+]>C1(C)C(C)=CC=CC=1>[CH2:2]([CH:14]1[CH2:19][CH2:18][CH:17]=[CH:16][CH2:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC1CCC(O)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCCC1CC=CCC1
Yield: 73.3 %

Procedure:
A 1 L four-necked flask equipped with a mechanical stirrer, a thermometer, and a Dean-Stark water separator was charged with 4-n-dodecylcyclohexanol (0.372 mol), potassium hydrogen sulfate (0.187 mol), and xylene (100 g), and they were heated and refluxed for 16 hours. After completion of the reaction, the reaction mixture was filtered with a glass filter, the solvent was removed by vacuum distillation, and purification was carried out by silica gel column chromatography (silica gel 60 (70-230 mesh), manufactured by Merck Ltd., elution solvent: n-hexane). The reaction product thus obtained was subjected to vacuum distillation using a kugelrohr distillation apparatus at 130° C./30 Pa to give 68.32 g (73% yield) of 4-dodecyl-1-cyclohexene (Formula (12) below). The results of 1H-NMR of this product are shown below.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][N+:13]([O-:16])=[C:12]([CH3:17])[C:11]=1[CH3:18]>CS(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:10]1[CH:15]=[CH:14][N+:13]([O-:16])=[C:12]([CH3:17])[C:11]=1[CH3:18]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: COCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
2.0 g (22 mmol) of 3-methoxypropanol was dissolved in 50 ml of dimethyl sulfoxide to obtain a solution. 2.7 g (66 mmol) of sodium hydride was added to this solution at a room temperature. The obtained mixture was stirred at 60° C. for one hour and cooled to a room temperature by allowing to stand, followed by the addition of 3.0 g (19 mmol) of 4-chloro-2,3-dimethylpyridine N-oxide. The obtained mixture was stirred at 40° C. for one hour. After the completion of the reaction, the reaction mixture was distilled to remove the dimethyl sulfoxide. The obtained residue was purified by silica gel column chromatography to obtain 760 mg of 4-(3-methoxypropoxy)-2,3-dimethylpyridine N-oxide.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1>CO.CN(C=O)C.[Pd]>[NH2:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCNC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
Same procedure as above with Z-Trp-NH(CH2)4NHBoc (1.16 g, 2.28 mmol), 10% Pd/C (242 mg) in MeOH/DMF (10 mL, 1/1). After purification by flash chromatography on silica gel (4-25% MeOH/CH2Cl2), Trp-NH(CH2)4NHBoc was isolated as a white foam (701 mg, 82%). 1H NMR (300 MHz, CDCl3) δ 1.39 (m, 4H, 2 CH2), 1.46 (s, 9H, (CH3)3), 3-3.35 (m, 6H, CH2 Trp, 2 CH2N), 3.7 (m, 1H, CHα), 4.71 (m, 1H, NHBoc), 7.05 (d, J=2 Hz, 1 aromatic H), 7.1 (t, J=7.7 Hz, 1 aromatic H), 7.2 (m, 2H, 1 aromatic H, NH amide), 7.38 (d, J=7.9 Hz, 1 aromatic H), 7.65 (d, J=7.9 Hz, 1 aromatic H), 8.94 (broad s, 1H, NH indole). 13C NMR (75 MHz, CDCl3) δ 26.9, 27.6, 30.8 (2 CH2, CH2 Trp), 28.5 ((CH3)3), 38.7, 40.3 (CH2NHCO, CH2NHBoc), 55.6 (CHα), 79.3 (C(CH3)3), 111.3, 111.4, 118.9, 119.5, 122, 123.3, 127.6, 136.4 (8 aromatic C), 156.2 (CO carbamate), 174.8 (CO amide).
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][O:4][CH2:3]1.[NH:30]1[C:38]2[C:33](=[CH:34][C:35](B(O)O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([C:9]3[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=4)[N:10]=3)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCOC[C@@H]3C)nc2c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCOC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To a solution of (S)-methyl 3-(3-methylmorpholino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (250 mg, crude) in dioxane (5 mL) was added Pd(PPh3)4 (33 mg, 0.03 mmol), 1H-indol-5-ylboronic acid (230 mg, 1.43 mmol), K3PO4 (361 mg, 1.71 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90° C. under an inert atmosphere of nitrogen and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1%-10% ethyl acetate in petroleum ether to afford (S)-methyl 2-(1H-indol-5-yl)-3-(3-methylmorpholino)quinoxaline-6-carboxylate as a yellow solid (110 mg).
Reaction SMILES: [F:1][C:2]([F:27])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[CH2:28]([NH2:31])[CH2:29][NH2:30]>CS(C)=O>[F:1][C:2]([F:27])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:30][CH2:29][CH2:28][NH2:31])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Reactant: NCCN
Solvent: CS(C)=O
Product: NCCNc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Reaction time: 22 h

Procedure:
100 mg (0.25 mmol) of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine are dissolved in 1 ml of dimethyl sulfoxide, and 0.2 ml of ethylenediamine is added. After stirring for 22 h at 100°, the reaction mixture is concentrated and chromatographed (methylene chloride:methanol:concentrated ammonia solution=90:10:1). N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(2-amino-ethyl-amino)-4-pyridyl]-2-pyrimidineamine is obtained; FAB-MS: 423 (M+ +H), Rf =0.1 (methylene chloride:methanol:concentrated ammonia solution=90:10:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=1[NH2:21].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Yield: 25.8 %

Procedure:
A mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (1 g, 3.90 mmol), 2-methyl-5-nitroaniline (890 mg, 5.90 mmol), and 2N HCl (3 ml) in water:ethanol (1:1, 200 ml) was refluxed for 48 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10-12. The mixture was extracted with ethyl acetate (200 ml), washed with water (2×100 ml), with aqueous saturated NaCl (1×100 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness to give a tan solid (377 mg, 30%). 1H NMR (CDCl3): 8.90 (s, 1H), 8.80 (dd, J=1.8, 4.8 Hz, 2H), 8.30 (dd, J=1.5, 4.5 Hz, 2H), 8.09 (dd, J=2.4, 8.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:5]1.C(N(C(C)C)CC)(C)C.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>C(#N)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:6]2[CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:8][N:4]([CH2:3][CH2:2][NH:1][S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:43])[F:44])[CH:34]=3)(=[O:41])=[O:40])[N:5]=2)=[CH:20][CH:19]=1
Reactant: NCCN1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=S(=O)(NCCN1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.3 %

Procedure:
Part C: To a solution of 1-(2-aminoethyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (0.56 gram, 1.87 mmol) and diisopropylethylamine in acetonitrile (20 ml) was added 3-(trifluoromethyl)phenylsulfonyl chloride (0.35 ml, 2.18 mmol) and the resulting solution was stirred at room temperature for 20 minutes. After concentration in vacuo the residue was dissolved in ethylacetate and washed with 2 N sodium hydroxide solution. The ethylacetate layer was concentrated in vacuo. The resulting oil was crystallised from a small amount of diisopropyl ether to afford crystalline N-[2-(3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazol-1-yl)ethyl]-3-(trifluoromethyl)benzenesulfonamide (0.44 gram, 46% yield). Melting point: 94-96° C.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:26][C:12]2([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)[N:13]=[C:14]([NH:17]C(=O)C3C=CC=CC=3)[S:15][CH2:16][CH:11]2[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].NN>C(O)C.C(OCC)(=O)C>[Si:1]([O:8][CH:9]1[CH2:26][C:12]2([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)[N:13]=[C:14]([NH2:17])[S:15][CH2:16][CH:11]2[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1cccc(-c2cccc(C34CC(O[Si](C)(C)C(C)(C)C)CC3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cccc(C34CC(O[Si](C)(C)C(C)(C)C)CC3CSC(N)=N4)c2)c1
Temperature: 120 °C
Yield: 100.3 %

Procedure:
A mixture of N-(6-(tert-butyldimethylsilyloxy)-7a-(3′-methoxybiphenyl-3-yl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (0.200 g, 0.349 mmol) and hydrazine (0.559 g, 1.75 mmol) in ethanol (4 mL) is stirred at 120° C. over night. The mixture is cooled, diluted with ethyl acetate and is washed with water. The organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure to give the title compound (0.164 g, 100%). ES/MS m/e: 469 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:22].[NH2:23][CH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.CN1CCCC1=O.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:23][CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:22]
Reactant: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1ccccc1Cl)C2
Reactant: NC1CCC(CO)CC1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1Nc2nc(NC3CCC(CO)CC3)ncc2CN1c1ccccc1Cl
Temperature: 25 °C

Procedure:
Sulfone 11.1 (350 mg, 104 mmol) was combined with 4-aminocyclohexylmethanol 1:1 cis/trans) (400 mg, 3.3 mmol) (prepared as described in Chem.Ber.; GE; 96; 1963; 2377-2386) with 0.3 mL of 1-methyl-2-pyrrolidinone. The mixture was heated at 1000 for 2 hours at which time it was cooled to room temperature. The reaction mixture was added to water and extracted with ethyl acetate, washed with water, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 10:90 methanol/dichloromethane as eluant The column fractions containing the product were concentrated to a foam which was resuspended in methanol. Addition of hydrochloric acid (1.0M/Et2O, 1.0 equivalent) gave a salt which was filtered to give the hydrochloride salt of 3-(2-chlorophenyl)-7-(4-hydroxymethylcyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([NH2:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](OC(OCC)CBr)[CH3:19]>CN(C=O)C.O>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[O:16][CH:18]=[CH:19][N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)Cc1ccccc1Oc1ccccc1
Reactant: CCOC(CBr)OCC
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(Oc2ccccc2Cc2ncco2)cc1
Yield: 41 %

Procedure:
A mixture of (2-phenoxyphenyl)acetamide (3.9 g) and bromoacetaldehyde diethyl acetal (3.1 ml) in DMF (100 ml) was heated for 2 hours. After cooling, the resulting mixture was diluted with water and extracted with ether. The extracts were washed with water then dried, concentrated and chromatographed using ethyl acetate: hexane (50:50) as eluant to give 2-(2-phenoxyphenylmethyl)oxazole (1.77 g, 41%) as a brown oil, 1H NMR (CDCl3): delta 4.20 (2H,s), 7.01 (1H,s) and 7.54 (1H,s) ppm.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=O)=[CH:33]1)(=[O:31])[CH3:30]>>[C:29]([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH2:41][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]3[C:16]4[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=2)=[CH:33]1)(=[O:31])[CH3:30]
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CC(=O)n1cc(C=O)c2ccccc21
Product: CC(=O)n1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c2ccccc21

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 1-acetyl-1H-indole-3-carbaldehyde according to the procedure of Example 66. MS (ES) m/z 550.0.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.CC(C)([O-:34])C.[K+]>C(O)(C)(C)C.COCCOC>[OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C:17](=[O:21])[C:18]([OH:34])([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: C[C@H](CCC(=O)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 40 °C

Procedure:
248 mg (0.6 m mol) of 1α,3β-dihydroxy-24-oxo cholesta-5,7-dien and 101 mg (0.9 m mol) of potassium-t-butoxide was dissolved in a mixture of t-butyl alcohol and ethyleneglycol dimethyl ether (1:1 V/V) warming at 40° C., and while cooling the solution with icewater to about 0° C. and stirring violently.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].C[O-].[Na+].[CH:16](OC)=[O:17].C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.O>[OH:17][CH:16]=[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(=CO)c1ccccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a three neck flask (1000 mL), 50 g of methyl 2-o-tolylacetate and 600 mg of toluene were added, and then 54.3 g of sodium methoxide was further added with stiffing. The mixture was cooled with an ice-water bath to less than 10° C., and then a mixture of methyl formate (65 mL) and toluene (50 mL) was dripped. After that, the ice-water bath was removed and the temperature was raised slowly to room temperature. The solution was allowed to react with stirring for 12 hrs, and then dumped into 1000 mL of water, shaken, standed for demix. The organic layer was extracted with 500 mL of water twice. The water layer was combined, acidized with 6M hydrochloric acid to pH value of 4-5, extracted with ethyl acetate, dried with anhydrous magnesium sulfate, and distilled under vacuum condition to yield 55.9 g of light red oily product with a yield of 95%.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:30][CH2:29]4)[CH:27]=3)=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][C@H:17]([CH3:35])[N:18]3[C:31]([O:33][CH3:34])=[O:32])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:29][CH2:30]4)[CH:27]=3)=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][C@H:17]([CH3:35])[N:18]3[C:31]([O:33][CH3:34])=[O:32])[CH2:11]1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CN(C(=O)OC(C)(C)C)C3)c2CC[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CNC3)c2CC[C@@H]1C

Procedure:
(S)-Methyl 5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was prepared by treating a solution of (S)-methyl 5-(1-(tert-butoxycarbonyl)azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate in dichloromethane with trifluoroacetic acid according to the procedure outlined in Example 5-1, Step 3. 1H NMR (300 MHz, CD3OD) δ ppm 1.01-1.15 (m, 7H), 1.40-1.58 (m, 1H), 2.15-2.25 (m, 1H), 2.35-2.50 (m, 1H), 2.80-2.92 (m, 1H), 3.40-3.59 (m, 2H), 3.60-3.81 (m, 6H), 4.43-4.62 (m, 2H), 7.21-7.32 (m, 2H), 7.75 (s, 1H), 7.95 (s, 1H). MS (ESI, pos. ion) m/z 383 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.CS([Cl:21])(=O)=O>C1C=CC=CC=1>[Cl:21][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncccc1CO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ncccc1CCl
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxymethy-2-methylpyridine (0.65 g, 5.3 mmol) in dry benzene (5 ml) was added triethylamine (1.0 ml, 7.4 mmol) followed by methanesulfonyl chloride (0.78 ml, 10.1 mmol) dropwise over 5 min. The heterogeneous dark gummy mixture was stirred at room temp. overnight. The reaction was filtered through Celite and washed with benzene (2×). The combined filtrates were washed with brine, dried (Na2SO4), and concentrated in vacuo to the crude product as a yellow oil which was used as is.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S(Cl)([Cl:17])=O>>[OH:1][C:2]1[CH:11]=[C:10]([C:12]([Cl:17])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1cc(O)nc2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(O)nc2ccccc12

Procedure:
A mixture of 2-hydroxyquinoline-4-carboxylic acid (V, 2.89 g) and of thionyl chloride (25 ml) is stirred at 80° for 12 hr and then allowed to cool. Excess thionyl chloride is removed under reduced pressure and dichloromethane is added to the residue. The dichloromethane is then removed and the process repeated to remove traces of thionyl chloride. The residue is dried under reduced pressure to give 2-hydroxyquinolin-4-oyl chloride (V-A) as a solid, which is used without further purification, mp: shrinkage and melting from approximately 260-275°.