Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[O:16][CH2:17][CH2:18][CH2:19][O:20][N:21]1C(=O)C2=CC=CC=C2C1=O)(=[O:11])=[O:10])#[N:2].[BH4-].[Na+].[OH-].[Na+]>C(O)C.O1CCCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[O:16][CH2:17][CH2:18][CH2:19][O:20][NH2:21])(=[O:11])=[O:10])#[N:2]
Reactant: Cc1cc(OCCCON2C(=O)c3ccccc3C2=O)cc(OS(=O)(=O)c2ccccc2C#N)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a solution of N-[3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide (600 mg, 1.2 mmol), as prepared in the preceding step, in 40 mL of ethanol/tetrahydrofuran/water (2:1:1) was added sodium borohydride (230 mg, 6.0 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was acidified (pH 1-2) and heated to 50° C. for 2 hours. After cooling to room temperature, the solution was adjusted to pH 8-9 with 2N NaOH. The mixture was extracted into ethyl acetate (3×50 mL), and the organic phase was washed with brine (50 mL) and dried over Na2SO4. After removing the solvent, the residue was purified by flash column chromatography (dichloromethane to 2% methanol in dichloromethane) to give the title compound as a colorless oil (370 mg, 85%). 1H-NMR (300 MHz, CDCl3) δ8.06 (m, 1H), 7.93 (m, 1H), 7.76 (m, 2H), 6.61 (s, 1H), 6.53 (s, 2H), 5.36 (br s, 2H), 3.94 (t, J=6.3 Hz, 2H), 3.78 (t, J=6.2 Hz, 2H), 2.23 (s, 3H), 1.99 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:9]=2[S:8][C:7]=1[NH2:22])=O)C.C(O)(=O)C.[CH:27](N)=[NH:28]>CN(C=O)C>[C:18]([O:17][C:15]([N:11]1[CH2:10][C:9]2[S:8][C:7]3[N:22]=[CH:27][NH:28][C:4](=[O:3])[C:6]=3[C:14]=2[CH2:13][CH2:12]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: N=CN
Reactant: CCOC(=O)c1c(N)sc2c1CCN(C(=O)OC(C)(C)C)C2
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2c(sc3nc[nH]c(=O)c23)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a 2-Amino-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 6-tert-butyl ester 3-ethyl ester (5.0 g, 15 mmol) in DMF (50 mL) solution was added formamidine acetate (2.39 g, 23 mmol, 1.5 equiv). The mixture was heated at 100° C. in an oil bath for overnight. The reaction mixture was cooled to rt and then concentrated in vacuo. Ethyl acetate (50 mL) was added to the reaction solid mixture and stirred at rt for 2 h. The mixture was then filtered, rinsed with ethyl acetate (25 mL). The solid was placed in a vacuum oven and dried for overnight to yield a white solid (4.17 g, 90.6%). 1H NMR (CD3OD-d4) δ 8.05 (s, 1H), 4.57 (s, 2H), 3.61 (t, 2H), 2.92 (t, 2H), 1.42 (s, 9H); LCMS RT=2.78 min, [M+H]+=308.0.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([CH2:23][O:24]CC2C=CC=CC=2)[O:12][C@@H:11]([N:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=3)[C@@:34]([C:46]3[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=3[O:53][CH3:54])([F:45])[C:33]2=[O:55])[C@@H:10]1[OH:56])C1C=CC=CC=1>[Pt]=O.C(OCC)(=O)C>[Cl:52][C:50]1[CH:49]=[CH:48][C:47]([O:53][CH3:54])=[C:46]([C@@:34]2([F:45])[C:35]3[C:40](=[CH:39][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:37][CH:36]=3)[N:32]([C@H:11]3[C@H:10]([OH:56])[C@@H:9]([OH:8])[C@H:14]([OH:15])[C@@H:13]([CH2:23][OH:24])[O:12]3)[C:33]2=[O:55])[CH:51]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N([C@@H]2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c2cc(C(F)(F)F)ccc21
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask containing 1-(4-(S),5-(S)-Bis-benzyloxy-6-(R)-benzyloxymethyl-3-(R)-hydroxy-tetrahydro-pyran-2-(R)-yl)-3-(S)-(5-chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-VIII) (0.144 g, 0.18 mmol) was added ethyl acetate (1 mL). Platinum oxide (0.020 g, 0.09 mmol) was added to the reaction mixture which was then placed under a hydrogen atmosphere. The reaction was allowed to stir at room temperature overnight. The crude reaction mixture was purified via reverse phase column chromatography (C18, 1:1 water:acetonitrile). The title product was obtained as a white solid (0.040 g, 42%). 1H NMR (MeOH-D4, 400 MHz): δ 7.73 (dd, 1H, J=1.6 Hz, 0.9 Hz), 7.52 (s, 1H), 7.39 (m, 2H), 7.30 (dd, 1H, J=5.5 Hz, 2.0 Hz), 6.94 (dd, 1H, J=7.5 Hz, 1.2 Hz), 5.43 (d, 1H, J=9.5 Hz), 4.04 (t, 1H, J=9.1 Hz), 3.95 (dd, 1H, J=10.5 Hz, 1.4 Hz), 3.75 (dd, 1H, J=6.8 Hz, 5.3 Hz), 3.57 (s, 3H), 3.53 (m, 2H); 19F NMR (MeOH-D4, 376 MHz): δ−64.6, −161.7; LRMS: 519 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][CH:13]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][CH:13]=[C:12]2[O:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(C=O)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)cc3C=O)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
2-Hydroxy-5-methyl-benzaldehyde (344 mg), 4-chloro-6,7-dimethoxyquinoline (113 mg), and 4-dimethylaminopyridine (313 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with aqueous sodium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give 2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methyl-benzaldehyde (157 mg, yield 96%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:24][C:25]1[C:26]([C:35](O)=[O:36])=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:35]([C:26]3[C:25]([Cl:24])=[CH:30][C:29]([C:31]([F:33])([F:32])[F:34])=[CH:28][N:27]=3)=[O:36])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Product: C[C@@]1(c2cc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R1=Me) and 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=431.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10](=[O:12])[O-:11])([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])O.[N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[C:14]=[O:15]>>[O:22]([C:18]1[CH:17]=[C:16]([NH:13][C:14](=[O:15])[NH:1][C@@H:2]([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])[CH2:9][C:10]([O-:11])=[O:12])[CH:21]=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[N+](C)(C)CC(N)(O)CC(=O)[O-]
Reactant: O=C=Nc1cccc(Oc2ccccc2)c1
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1cccc(Oc2ccccc2)c1
Yield: 58 %

Procedure:
According to the method described in example S11, aminocamitine (1.28 HBr salt, 68 mg, 0.31 mmol) was reacted with 1-isocyanato-3-phenoxybenzene to yield the title compound as a white solid (69 mg, 58%). 1H NMR (400 MHz, CD3OD) 7.34 (t, J=7.96 Hz, 2 H), 7.17-7.23 (m, 2 H), 7.04-7.12 (m, 2 H), 6.95-7.00 (m, 1 H), 6.59 (dd, J=7.83, 2.02 Hz, 1 H), 4.57 (br. s, 1 H), 3.72 (dd, J=13.64, 9.09 Hz, 1 H), 3.46-3.56 (m, 1 H), 3.20 (s, 9 H), 2.42-2.56 (m, 2 H). MS ESI [M]+, calcd for [C20H24N3O4+H]+: 371.43 found m/z 371.7 (100).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[CH:15])[CH:8]=2)[S:3]1.I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.C(Cl)Cl>C(N(CC)CC)C>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:17]([C:15]#[C:14][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[S:3][CH:2]([CH3:1])[CH2:11][C:10]3([CH3:12])[CH3:13])=[CH:18][CH:19]=1)[CH3:25]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)S2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)S3)cc1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
A solution of 55 mg (0.26 mmol) of 2,4,4-trimethyl-6-ethynyl-thiochroman (Compound 55) and 70.5 mg (0.26 mmol) of ethyl 4-iodo benzoate (29) in 1.5 ml of distilled triethylamine was placed in a heavy walled tube. Argon was bubbled through the mixture for 20 minutes under slightly reduced pressure. To the mixture was added 18 mg (0.051 mmol) of bis triphenylphosphine palladium (II) chloride and 9.7 mg (0.051 mmol) of cuprous iodide. The tube was then sealed and the mixture was stirred at 55 degrees C. for 72 hours. The mixture was then cooled to room temperature. The reaction mixture was diluted wth CH2Cl2 and treated with a small amount of silica. The solvent was then removed in-vacuo and the residue was subjected to flash chromatography (silica; 1.5% EtOAc/Hexanes) to give the title compound as a white crystalline solid. PMR(CdCl3): 1.25 (3H, s), 1.35 (3H, d, J=6.6 Hz), 1.37-1.44 (6H, m), 1.75 (1H, t, J=13 Hz), 1.88 (1H, dd, J=13 Hz, 3.5 Hz), 3.40-3.50 (1H, m), 4.38 (2H, q, J=7Hz), 7.17 (1H, dd, J=8.1 Hz, 1.8 Hz), 7.26 (1H, d, J=1.5 Hz), 7.33 (1H, J=8.1 Hz), 7.55 (2H, d, J=8.4 Hz, 8.01 (2H, d, J=8.4 Hz).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5]C)=[O:4].BrC1C=CC(C(C)(C)C(OCC)=O)=CC=1>>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)c1ccc(Oc2ccccc2)cc1
Agent: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)(C(=O)O)c1ccc(Oc2ccccc2)cc1

Procedure:
The title compound was prepared according to the method of Example 22B, substituting the product of Example 48B for the product of Example 22A.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:16]1[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 3,4-difluoronitrobenzene (12.00 g, 75.4 mmol) (Aldrich) and N-methylpiperazine (18.89 g, 188.6 mmol) in acetonitrile (150 mL) was heated at reflux for 3 h. The reaction mixture was allowed to stand overnight at room temperature, then the solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate (200 mL each). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined organic layers were then washed with water and brine (200 mL each), dried (MgSO4), filtered, and evaporated under reduced pressure to give 1-(2-fluoro-4-nitrophenyl)-4-methylpiperazine as a pale brown solid (17.5 g, 97%, mp 68–70° C.).
Reaction SMILES: CN1CCN(C([O:10][CH:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=O)CC1.C(O)(=O)C.Cl.Br>O.C(O)=O>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([N:20]2[CH:18]([OH:19])[C:13]3[C:12](=[N:17][CH:16]=[CH:15][N:14]=3)[C:11]2=[O:10])=[N:26][CH:25]=1
Reactant: CN1CCN(C(=O)OC2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Agent: Br
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: O=CO
Product: O=C1c2nccnc2C(O)N1c1ccc(Cl)cn1

Procedure:
According to the present invention, (R) or (S) Zopiclone is treated with acid selected from acetic acid, formic acid, hydrochloric acid, hydrobromic acid or mixtures thereof; the resulting solution is heated between 50° to 70° C. followed by cooling and diluting with water to give 6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydro pyrrolo-[3,4-b]-pyrazine. This intermediate is used for the preparation of Zopiclone by conventional method.
Reaction SMILES: O1CCOC1[C:6]1[CH:7]=[C:8]([C:15]([OH:17])=[O:16])[C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1.[C:18]([O:21][C:22](=O)[CH3:23])(=[O:20])C>N1C=CC=CC=1>[O:21]1[CH2:22][CH2:23][O:20][CH:18]1[C:7]1[CH:6]=[CH:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc(C2OCCO2)cnc1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C(O)c1nccc(C2OCCO2)c1C(=O)O
Yield: 92 %

Procedure:
A solution of 5-(1,3-dioxolan-2-yl)-2,3-pyridinedicarboxylic acid (2.86 g, 0.012 mol), acetic anhydride (11.3 mL, 0.12 mol) and pyridine is stirred at room temperature for 1 hour and 45 minutes, then at reflux temperature for 4 hours. The reaction mixture is concentrated in vacuo to give the title compound as an oil (2.64 g, 100%), identified by IR spectra analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][C:31](Cl)=[O:32]>C1COCC1>[CH3:28][N:29]([CH3:34])[CH2:30][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:6][CH:7]=1)=[O:32]
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: CN(C)CC(=O)Cl
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)CN(C)C)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 2-(dimethylamino)acetyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71 (t, J=7.33 Hz, 3H) 1.28-1.38 (m, 2H) 2.24 (bs, 2H) 2.90 (s, 6H) 4.21 (s, 2H) 6.79 (s, 1H) 7.58 (t, J=7.58 Hz, 1H) 7.76 (d, J=8.59 Hz, 2H) 7.79-7.90 (m, 4H) 8.10 (d, J=8.34 Hz, 1H) 9.89 (s, 1H) 10.94 (s, 1H); ESI-MS: m/z calc'd for C25H27N5O2S 461.58. found 462.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][CH:8]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:30][C@@H:31]1[CH2:40][CH2:39][C:38]2[C:33](=[C:34]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)[CH:35]=[CH:36][CH:37]=2)[CH2:32]1>CN(C)C=O>[CH3:47][N:44]1[CH2:45][CH2:46][N:41]([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:33]=2[CH2:32][C@H:31]([NH:30][C:1]([C:4]2[N:5]=[C:6]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[S:7][CH:8]=2)=[O:3])[CH2:40][CH2:39]3)[CH2:42][CH2:43]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2csc(-c4ccccc4)n2)CC3)CC1
Temperature: 75 °C
Reaction time: 17 h
Yield: 55.8 %

Procedure:
To a solution of 4-carboxy-2-phenylthiazole (88 mg, 0.43 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added 1,1′-carbonyldiimidazole (73 mg, 0.45 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 17 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent gave 99 mg (56% yield) of the title compound as white crystals: mp 175-176° C.; [α]21D '85° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 432 (6, M+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:26]=[C:27]([C:31]2[O:35][C:34]([CH3:36])=[N:33][N:32]=2)[CH:28]=[CH:29][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.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>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[O:35][C:34]([CH3:36])=[N:33][N:32]=5)[CH:28]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nnc(-c2cccc(I)c2)o1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nnc(C)o4)c3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 45.2 %

Procedure:
A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.100 g, 0.32 mmol) and 5-(3-iodophenyl)-2-methyl-[1,3,4]oxadiazole (0.0915 g, 0.32 mmol) in dry triethylamine (3.5 mL) was treated under argon with a mixture of tetrakis(triphenylphosphine)palladium (0.016 g, 0.013 mmol), cuprous iodide (0.0033 g, 0.017 mmol), and triphenylphosphine (a small crystal) at 75° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue was extracted into methylene chloride and the organic phase was washed with cold dilute hydrochloric acid, water, brine and was dried (sodium sulfate). Purification by chromatography (silica, 10 to 20% ethyl acetate in methylene chloride) followed by drying at 50° C. in vacuo afforded the titled compound as a white powder (0.068 g, 45%), mp 139°-141° C. Anal. (C29H30N2O4.1/3H2O) calcd: C 73.09, H 6.49, N 5.88, found: C 73.07, H 6.35, N 5.79. 1H-NMR (400 MHz, CDCl3) δ 8.15 (t, J=1.6 Hz, 1H), 8.01 (d-t, J=1.4 Hz, J=7.9 Hz, 1H), 7.62 (d-d, J=1.5 Hz, J=7.8 Hz, 1H), 7.49 (t, J=7.9 Hz), 7.21 (d, J=2.3, 1H), 7.14 (d-d, J=8.5 Hz, J=2.4 Hz, 1H), 6.88 (d, J=8.5, 1H), 4.82 (p, J=4.2 Hz, 1H), 3.86 (s, 3H), 3.04 (d-t, J=6.1 Hz, J=14.2, 2H), 2.64 (s, 3H), 2.51 (d,br, J=15.0, 2H), 2.42-2.32 (m, 2H), 2.27 (d-t, J=2.8 Hz, J=14.2 Hz, 2H), 2.00-1.5 (m, 9H with H2O).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[H][H]>[Pd].CO>[CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCc1ccc2cccnc2c1O
Agent: [Pd]
Solvent: CO
Product: CCCc1ccc2cccnc2c1O
Yield: 84.5 %

Procedure:
Into a stainless steel autoclave, one introduces 93 g of 7-allyl-8-hydroxyquinoline (i.e. 0.5 mole), 250 ml of methanol, and 3 g of 5% palladium on charcoal. The hydrogenation is carried out under a 4 kg/cm2 hydrogen pressure. After absorption of a sufficient quantity of hydrogen and cooling, one filters off the catalyst, removes the solvent by distillation under normal pressure, and then distills the residue under high vacuum. The 7-propyl-8-hydroxyquinoline distills at 105°-106°C at a pressure of 0.25 mm Hg. One collects 78 g of a light yellow liquid. Yield = 84.5%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]2[N:11]=[CH:12][NH:13][C:9]=2[CH:8]=1.C(N(CC)CC)C.Cl.C(N(CC)CC)C>CC(C)=O.O>[Cl:16][C:15]1[C:7]([Cl:6])=[CH:8][C:9]2[N:13]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[N:11][C:10]=2[CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1cc2nc[nH]c2cc1Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)n1cnc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of methanesulphonyl chloride (60 parts) in acetone (800 parts) was added dropwise to a suspension of 5,6-dichloro-benzimidazole (94 parts) in acetone (240 parts) containing triethylamine (50 parts). A precipitate of triethylamine hydrochloride was observed and the temperature rose to 40° C. The mixture was heated under reflux for 10 minutes and then stirred at room temperature for 20 hours. On pouring into cold water (4000 parts) a solid product precipitated out, which was filtered off, washed with water, dried and recrystallised from acetone (charcoal) to give 5,6-dichloro-1-(methylsulphonyl)-benzimidazole (61 parts) as pale yellow needles, melting point 191°-193° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][NH:29][CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:15])[F:14])[C:5]=12.C(N(CC)CC)C.[CH3:40][C@H:41]1[CH2:43][O:42]1>C(O)(C)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][N:29]([CH2:40][C@@H:41]([OH:42])[CH3:43])[CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:14])[F:15])[C:5]=12
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a mixture of 5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitrile dihydrochloride (20 mg, 0.04 mmol, racemic intermediate from Example 129, Step 2) and triethylamine (18 μL, 0.13 mmol) in isopropyl alcohol (0.1 mL) was added (S)-(−)-methyloxirane (9.1 μL, 0.13 mmol). The resulting mixture was stirred at 90° C. for 5 h. The crude mixture was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to 2.5 mg (10%) of give the desired product. The product was isolated as a mixture of diastereomers. LCMS calculated for C23H28F2N7O2 (M+H)+: m/z=472.2; Found: 472.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:19]([O-])=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:7]=[CH:6]2.CO>[Pd]>[NH2:19][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[C:9]2=[O:13]
Reactant: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1N
Reaction time: 3 h

Procedure:
A mixture of (R)-2-(6-methoxy-5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (200 mg, 0.0007 mol), methanol (20 mL, 0.5 mol) and palladium, 10% weight on charcoal (21 mg, 0.00017 mol) was stirred under hydrogen (1 atm) for 3 h. The reaction mixture was filtered over celite and the solvent was removed to afford the product as a brown solid.