Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([F:13])[F:12])=[CH:4][C:3]=1[CH2:14][C:15]([OH:17])=O.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([F:13])[F:12])=[CH:4][C:3]=1[CH2:14][C:15]([Cl:21])=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(Br)c(CC(=O)O)cc1OC(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Br)c(CC(=O)Cl)cc1OC(F)F
Temperature: 25 °C

Procedure:
(2-Bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid (350 mg, 1.12 mmol) was dissolved in 6 ml dichloromethane and 0.1 ml oxalyl chloride and 0.01 ml DMF was added. The solution was stirred at room temperature until gas evolution stopped, then concentrated under reduced pressure. Dichloromethane (6 ml) was added to the residue and the solvent removed again to assure that all the oxalyl chloride was removed giving 118 mg of crude (2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid chloride.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[Si:14]([O:21][C@@H:22]1[C@@H:27]([CH3:28])[CH2:26][NH:25][CH2:24][C@H:23]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CCO>[Si:14]([O:21][C@@H:22]1[C@@H:27]([CH3:28])[CH2:26][N:25]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:24][C@H:23]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Yield: 80.1 %

Procedure:
To a mixture of 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (110.4 mg, 0.3780 mmol) and tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (from Example 28, Step 7, 100.0 mg, 0.2902 mmol) was added EtOH (2.0 mL) followed by DIPEA (163.8 mg, 1.267 mmol). The reaction mixture was heated at 100° C. for 15 h, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to afford the sub-title compound as a yellow solid (118.2 mg, 80%). LCMS calc. for C24H41N4O6Si (M+H)+: m/z=509.3. found 509.3.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([N:10]=[N+]=[N-])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[O:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([O:33][CH3:34])=[C:29]([CH:32]=2)[CH:30]=O)=[CH:21]1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:30][C:29]2[CH:32]=[C:25]([C:22]3[CH:23]=[CH:24][O:20][CH:21]=3)[CH:26]=[CH:27][C:28]=2[O:33][CH3:34])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4]
Reactant: COc1ccc(-c2ccoc2)cc1C=O
Reactant: COC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1
Product: COC(=O)C1CCC(NCc2cc(-c3ccoc3)ccc2OC)C1c1ccc(F)cc1

Procedure:
The title compound was prepared by employing the method described in Example 91, Step D with (1RS,2RS,3RS)-2-(4-fluorophenyl)-3-azidocyclopentanecarboxylic acid methyl ester (from Example 89, Step A) and the known 5-(furan-3-yl)-2-methoxybenzaldehyde (P. J. Ward, et al., J. Med. Chem. 1995, 38, 4985-92). NMR (400 MHz, CDCl3): δ 7.63-7.61 (m, 1H), 7.46 (t, 1H, J=2 Hz), 7.31 (dd, 1H, J=9,2 Hz), 7.18 (dd, 2H, J=9,5 Hz), 7.12 (d, 1H, J=2 Hz), 7.01 (t, 2H, J=9 Hz), 6.75 (d, 1H, J=9 Hz), 6.62 (dd, 1H, J=2,1 Hz), 3.73 (d, 1H, J=13 Hz), 3.61 (s, 3H), 3.54 (s, 3H), 3.53-3.38 (m, 2H), 3.45 (d, 1H, J=13 Hz), 3.27-3.22 (m, 1H), 2.41-2.29 (m, 1H), 2.02-1.87 (m, 3H), 1.69 (br, 1H). Mass spectrum (NH3 /CI): 424 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6]O.P(Br)(Br)[Br:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][Br:14]
Reactant: COc1cc(CO)cc(OC)c1
Reactant: BrP(Br)Br
Product: COc1cc(CBr)cc(OC)c1
Temperature: 80 °C

Procedure:
22 g of 3,5-dimethoxybenzyl alcohol were reacted with 50 ml of phosphorus tribromide with ice cooling and the reaction mixture was heated for 30 minutes at 80° C. For workup, the reaction mixture was poured into ice water and extracted with methyl-tert-butyl ether. The organic phases were combined, dried, and concentrated. 23 g of 3,5-dimethoxybenzyl bromide were obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:6][C:5]2=[O:18].[Cl:19][C:20]1[C:21]([CH3:30])=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>N1C=CC=CC=1>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[C:21]=3[CH3:30])(=[O:27])=[O:28])=[CH:10][CH:9]=2)[C:5](=[O:18])[NH:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)c(=O)[nH]n2Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2c(c1)c(=O)[nH]n2Cc1ccccc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 21 %

Procedure:
To a solution of 5-amino-1-benzyl-1,2-dihydro-indazol-3-one (0.04 g) in pyridine (1 mL) was added 3-chloro-2-methylbenzenesulfonylchoride (0.038 g) in one go. The solution was stirred at 60° C. for 24 hours. The pyridine was then removed in vacuo and the residue was dissolved in EtOAc/water and separated. The aqueous phase was extracted a further two times with EtOAc and the combined organic phases were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the volatiles were removed in vacuo to afford a crude residue. The crude material was purified via flash column chromatography eluting with EtOAc/nHeptane/1% AcOH) to afford the desired N-(1-benzyl-3-oxo-2,3-dihydro-1H-indazol-5-yl)-3-chloro-2-methyl-benzenesulfonamide (0.015 g) as a pale yellow powder. MS (ESI+): 428.4 ([M+H]+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[CH:33][C:7]=2[N+:6]=1[O-])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>[Ni].C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([S:34]([N:37]([CH3:39])[CH3:38])(=[O:35])=[O:36])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(S(=O)(=O)N(C)C)cc2[n+]1[O-]
Agent: [Ni]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2cc(S(=O)(=O)N(C)C)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-dimethylaminosulphonyl-3-N-oxido-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate by catalytic hydrogenation in the presence of Raney nickel and subsequent reaction with trifluoroacetic acid in methylene chloride.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:20])[C:7]([S:18][CH3:19])=[C:8]2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH3:3].[OH:21]O>C(O)C.C(Cl)Cl>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:20])[C:7]([S:18]([CH3:19])=[O:21])=[C:8]2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH3:3]
Reactant: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: OO
Solvent: ClCCl
Solvent: CCO
Product: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 18 h

Procedure:
To a solution of allyl (4R,5S,6S)-6-((1R)-1-hydroxyethyl)-4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (100 mg) in ethanol (1.0 ml) was added a 30% aqueous solution of hydrogen peroxide (0.5 ml) and the mixture was allowed to stand at the ambient temperature for 18 hours. The solution was diluted with methylene dichloride and washed with water, 5% aqueous sodium thiosulfate solution and brine successively. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford allyl (4R,5S,6S)-6-((1R)-1-hydroxyethyl)-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50.0 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([N:11]1[C@H:12]([C:17](=[O:19])[NH:39][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][CH2:14][C:15]1=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccccc1
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Temperature: 2.5 °C

Procedure:
(S)-5-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (14.9 g, 57 mmol) is suspended in dichloromethane (100 mL) and added DMAP (7.1 g, 58 mmol) while cooling on ice (0-5° C.). The suspension immediately clarified. EDCI (11.1 g, 58 mmol) is added resulting in precipitation which quickly clarified again. Phenethylamine (6.8 mL, 54 mmol) is added slowly via syringe. The reaction is complete in one half hour. The dichloromethane layer is washed with aqueous 10% citric acid, water and saturated bicarb, then dried over anhydrous sodium sulfate, filtered and concentrated to a white solid. LCMS characterization ES+367.1 (m+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH2:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].C(N[C@@H](C(O)=O)CC(C)C)(=O)C>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([NH2:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CCC2N
Agent: CC(=O)N[C@H](CC(C)C)C(=O)O
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CC[C@@H]2N
Temperature: 65 °C

Procedure:
5-tert-Butyl-2,3-dihydro-1H-inden-1-ylamine (11.70 g, 44.4% ee), N-acetyl-(D)-leucine (11.78 g), and methanol (120 mL) were combined and heated at 65° C. for 1 hour. The solution was allowed to cool to ambient temperature. The solids were filtered and washed with toluene. The solid was then resuspended in methanol (125 mL) and brought to reflux. The solution was allowed to cool to ambient temperature and the solids were filtered. The solid was dried at 40° C. under reduced pressure to provide the title compound (98.7% ee).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4](C=O)[CH2:3][CH2:2]1.[CH3:9][O:10][C:11](=[O:17])[CH2:12][C:13]([CH2:15][Cl:16])=[O:14].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C.N1CCCCC1.C(O)(=O)C>[S:1]1[CH2:6][CH2:5][C:4](=[C:12]([C:13](=[O:14])[CH2:15][Cl:16])[C:11]([O:10][CH3:9])=[O:17])[CH2:3][CH2:2]1
Reactant: O=CC1CCSCC1
Reactant: COC(=O)CC(=O)CCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COC(=O)C(C(=O)CCl)=C1CCSCC1
Reaction time: 0.75 h

Procedure:
Tetrahydrothiapyran-4-carboxaldehyde (1.5g) in ethyl acetate (10 ml) was treated with methyl-4-chloroacetoacetate (1.5g), 4A sieve (3g) and the mixture cooled in an ice-bath. Piperidine (3 drops) and acetic acid (3 drops) were now added and the mixture stirred at 0-5° for 45 min. Excess ethyl acetate was added and the organic solution washed with 1M hydrochloric acid. After washing the extracts with water they were dried over anhydrous magnesium sulphate and evaporated to give a colourless oil. Chromatography o silica gel using ethyl acetate-hexane mixtures gave the title compound mixture Z/E (1:2)) as a colourless oil (2g). νmax (CHCl3) 1720 and 1630 cm-1 ; δ(CDCl3) inter alia 3.82(s) and 3.87(s), 6.84 (d, J=10Hz) and 6.94 (d, J™10Hz) m/e 262 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[N:15][C:16](=S)[C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].C(N(CC)CC)C.Cl>C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[N:15][C:16](=[N:23][OH:24])[C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1
Reactant: NO
Reactant: FC(F)(F)C(=S)N=c1ccccn1Cc1ccc(Cl)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: ON=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 21.5 h
Yield: 63 %

Procedure:
25 ml of ethanol was added to 1.00 g (3.00 mmol) of the N-[1-((6-chloropyridin-3-yl)methyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroethanethioamide (1-20) 1 synthesized by the method in Synthetic Example 4, 1.04 g (15.0 mmol) of hydroxylamine hydrochloride and 2.00 ml (1.50 g, 15.0 mmol) of triethylamine were added thereto in sequence, and the resulting mixture was stirred at 50° C. for 21.5 hours. After the reaction was completed, ethyl acetate and 1% hydrochloric acid were added to the reaction solution to perform liquid separation, and the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The organic layer was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the subject material. Amount obtained 625 mg (yield 63%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[CH:17]([NH2:20])([CH3:19])[CH3:18].Cl>C(O)(C)C>[CH:17]([NH:20][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4])([CH3:19])[CH3:18]
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CC(C)N
Agent: Cl
Solvent: CC(C)O
Product: CC(C)NCC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Yield: 47.1 %

Procedure:
12.6 g of the 5-chloroacetyl-8-hydroxycarbostyril (IV) obtained in Example 4 or 8 was suspended in 130 ml of isopropanol, and 2515 g of isopropylamine (III) was added dropwise to the resulting suspension while stirring. The reaction mixture was then stirred at 55° to 60° C. for 3 hours. After cooling, concentrated hydrochloric acid was added to the mixture to adjust the mixture to a pH of 2 to 3, and the precipitated crystals were filtered, washed with acetone and recrystallized from methanol-dimethylformamide (1:1 by volume) to obtain 6.5 g of 5-isopropylaminoacetyl-8-hydroxycarbostyril (II) hydrochloride having a melting point of 286° - 288° C. (with decomposition as pale yellow crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6])[CH3:2].CN(C=O)C.[NH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([Cl:28])=[CH:20][C:19]=1[OH:29].C(N(CC)CC)C>O>[Cl:28][C:21]1[C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]([NH:17][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][N:10]=[CH:11][C:3]=2[CH2:1][CH3:2])=[C:19]([OH:29])[CH:20]=1
Reactant: CCc1cnccc1C(=O)Cl
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cnccc1C(=O)Nc1cc(C(F)(F)F)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.62 g of 3-ethyl isonicotinic acid 4 ml of thionyl chloride was heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give 3-ethyl isonicotinic acid chloride. A mixture of the resultant 3-ethyl isonicotinic acid chloride and 3 ml of DMF was added dropwise to a mixture of 0.87 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.83 g of triethylamine and 3 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for two hours, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.23 g of N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]-3-ethyl isonicotinamide.
Reaction SMILES: [C:1]([CH:4]1[CH:9]([CH3:10])[CH:8]=[CH:7][CH2:6][C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]1([CH3:11])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)C1C(C)C=CCC1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)[C@H]1[C@@H](C)CCCC1(C)C

Procedure:
464 g 1-acetyl-2,2,6-trimethyl-4-cyclohexene (V, prepared according to K. S. Ayyar Chem. Comm. 1973, 161) (2.8 moles) in 800 ml of ethanol and 3 g 10% palladium on charcoal are hydrogenated in an autoclave under a pressure of 50 atm and at 50° C. After the uptake ceases, the reaction mixture is filtered and concentrated by distillation under reduced pressure. The product cis-1-acetyl-2,2,6-trimethylcyclohexane (VI, containing about 10% of the trans isomer) is collected at 83°-88° c./12 mm; yield 420 g (90%).
Reaction SMILES: Cl.Cl.[N:3]1[C:11]2[CH2:10][C@@H:9]([C:12]([O:14][CH3:15])=[O:13])[NH:8][CH2:7][C:6]=2[NH:5][CH:4]=1.C(N(CC)CC)C.[Se](=O)=O.CCOCC>C(Cl)(Cl)(Cl)Cl>[N:3]1[C:11]2[CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[N:8]=[CH:7][C:6]=2[NH:5][CH:4]=1
Reactant: COC(=O)[C@@H]1Cc2nc[nH]c2CN1
Agent: Cl
Agent: O=[Se]=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1cc2nc[nH]c2cn1
Temperature: 25 °C
Yield: 47 %

Procedure:
Methyl (6S)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylate dihydrochloride (156.5 g, 0.62 mol), triethylamine (445.0 g, 4.4 mol, 7.0 mol eqv.), selenium dioxide (158.2 g, 1.43 mol, 2.3 mol eqv.), and polyphosphatesilyl ether (PPSE) (15.0 g) were added to CCl4 (1.5 L). The mixture was refluxed for 6 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was suspended in methanol (1.5 L), and triethylamine was added to adjust to pH 8. The brown solid was filtered and washed well with methanol. This brown solid (117.0 g) was recrystallized from hot DMF (2 L, 140° C.). The solution was filtered hot to remove black side products. Upon cooling to room temperature, the desired product crystallized out as a yellow solid (51.3 g, 47% yield, 95% pure). 1H NMR (DMSO-d6): δ 13.20 (br s, 1H), 9.02 (s, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 3.89 (s, 3H); LCMS: Rt=1.33 min, and M+1=178.1 u/e.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[Li+].CC1(C)CCCC(C)(C)N1[Mg][Cl:48].ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:48][C:11]1[C:12]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][C@@H:19]4[CH2:23][CH2:24][CH2:25][C@@H:18]34)[N:14]([CH2:26][C@H:27]3[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]=2[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:9][C:10]=1[C:34]#[N:35]
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CC1(C)CCCC(C)(C)N1[Mg]Cl
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a −78° C. solution of 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 3.2, Step 3; 250 mg, 0.509 mmol) in THF (7 mL) was added 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (Aldrich, 1M in THF/toluene) (1.02 mL, 1.02 mmol). The resulting solution was stirred at −78° C. for 45 minutes, and then hexachloroethane (301 mg, 1.273 mmol) was added as a solid in one portion. The reaction was allowed to warm slowly to 10° C. over 2 hours and then quenched with saturated NH4Cl (10 mL). EtOAc (75 ml) was added, and the organic layer was washed with water and brine (25 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column eluting with 0 to 50% EtOAc/DCM afforded 7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C27H30Cl2N6O [M+H]+=525. found=525.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:12]=[C:11](Cl)[C:10]2[C:5](=[C:6]([O:16][CH3:17])[C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=1>O1CCCC1>[Cl:2][C:3]1[N:12]=[C:11]([NH2:1])[C:10]2[C:5](=[C:6]([O:16][CH3:17])[C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc2c(Cl)nc(Cl)nc2c1OC
Reactant: N
Solvent: C1CCOC1
Product: COc1ccc2c(N)nc(Cl)nc2c1OC

Procedure:
Ammonia was passed into a solution of 2,4-dichloro-7,8-dimethoxyquinazoline (287 g., 1.11 moles) in tetrahydrofuran (6 liters) for five hours at room temperature. After stirring an additional hour the suspension was concentrated in vacuo to 2 liters and filtered. The solid was suspended in 2 liters of water, filtered, washed with water and cold methanol. Recrystallization from dimethylformamide/water yielded 164 g. (62%) of pure product, M.P. 300°. (dec.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-]>O.C(O)C.C(O)(=O)C.[Zn]>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 96.7 %

Procedure:
4-(4-Benzyl-1-piperazinyl)-1-nitrobenzene (2.6 g; 8.9 mmol) synthesized by the above process and zinc powder (3.2 g; 48 mmol) were added to a solution of calcium chloride (665 mg; 6.0 mmol) in water-ethanol-acetic acid (12 ml-55 ml-1.2 ml), and the mixture was stirred under reflux for 15 minutes in a bath controlled at 110° C. Insoluble substances were removed from the reaction mixture by suction filtration through Celite, and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the resultant concentrated residue to conduct extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The thus-obtained crude crystals were recrystallized from benzene-n-hexane to obtain 2.3 g (yield: 96%) of 4-(4-benzyl-1-piperazinyl)aniline as pale brown needles (melting point: 137-138° C.).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[O:29]1[CH2:34]CCOO1.[Cl-].[NH4+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([CH2:34][OH:29])[CH:16]([CH3:17])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COOOC1
Reactant: CC(C)CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](CO)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 0.5 h
Yield: 124.2 %

Procedure:
Titanium tetrachloride (18 ml) was added dropwise to a solution of 4(R)-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (41.5 g) in dichloromethane (300 ml) at 0° C. Diisopropylethylamine (28 ml) was added dropwise and the resulting purple suspension was stirred for 30 min, then a solution of trioxane (11.2 g) was added, followed by titanium tetrachloride (18 ml) and the mixture was stirred for two hours, during which time the solution changed in colour from purple to amber. Ammonium chloride (400 ml saturated aqueous solution) was added and the mixture was stirred for 10 min, then the phases separated and the organic layer washed with water and saturated brine, dried (NaSO4) and evaporated to give the title compound as a colourless solid (45 g).