Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:23][C:24]4[S:25][CH:26]=[N:27][N:28]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl>[C:8]([C:7]1[CH:6]=[C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:23][C:24]4[S:25][CH:26]=[N:27][N:28]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)[C:4]([O:29][CH3:30])=[CH:3][C:2]=1[C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=1)#[N:9]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc(-c2cccc(C(F)(F)F)c2)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Temperature: 120 °C

Procedure:
A vial was charged with 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (EXAMPLE 337, 69.8 mg, 0.152 mmol) (3-(trifluoromethyl)phenyl)boronic acid (57.9 mg, 0.305 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (3.13 mg, 7.62 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (11.55 mg, 0.015 mmol) and potassium phosphate (162 mg, 0.762 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (693 μl) and water (69.3 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. The mixture was extracted with EtOAc, MeOH-EtOAc, and MeOH-DCM. The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7.5% MeOH/DCM) to give an off-white solid. The solid was taken up in DCM and filtered. The collected solid was washed with DCM (2×), dried under a stream of N2 (g), and dried under vacuum to give 1-(2-cyano-5-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.80 (s, 1H), 8.73 (d, J=5.7 Hz, 1H), 8.62-8.55 (m, 1H), 8.17 (d, J=5.6 Hz, 1H), 8.11-8.04 (m, 2H), 7.98 (s, 1H), 7.96-7.78 (m, 3H), 7.51 (s, 1H), 7.19 (br. s., 1H), 3.83 (s, 3H). m/z (ESI) 567.9 (M+H)+.
Reaction SMILES: [H][H].[O:3]1[CH:9]2[CH:4]1[C:5]([O:7][C:8]2([CH3:11])[CH3:10])=[O:6]>[Pd].O1CCCC1>[OH:3][CH:9]1[C:8]([CH3:11])([CH3:10])[O:7][C:5](=[O:6])[CH2:4]1
Reactant: CC1(C)OC(=O)C2OC21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1(C)OC(=O)CC1O
Yield: 63 %

Procedure:
In dioxane, 2-hydroxy-4,4-dimethyl-γ-butyrolactone prepared in the same manner as in Production Example 10 was subjected to a reaction (dehydration reaction) with equivalent P2O5 at room temperature to yield a corresponding α,β-unsaturated-γ-butyrolactone in a yield of 30%. The prepared α,β-unsaturated-γ-butyrolactone was then allowed to react with m-chloroperbenzoic acid (MCPBA) in methylene chloride at room temperature to yield 2,3-epoxy-4,4-dimethyl-γ-butyrolactone in a yield of 85%. Hydrogen was bubbled in a mixture of 10 mmole of the above-prepared 2,3-epoxy-4,4-dimethyl-γ-butyrolactone, 1 g of a 5% by weight Pd-C, and 20 ml of tetrahydrofuran at room temperature for 11 hours. The reaction mixture was filtrated and was concentrated, and the concentrate was subjected to column chromatography on a silica gel to yield 3-hydroxy-4,4-dimethyl-γ-butyrolactone in a yield of 63%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][C:8]2([CH3:18])[CH3:17])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][C:8]2([CH3:18])[CH3:17]
Reactant: [H][H]
Reactant: CC1(C)Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Nc2ccccc2-c2c(N)cnn21
Yield: 75.3 %

Procedure:
3.8 g (0.015 mole) of 1-nitro-5,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline is reduced with hydrogen in ethanol in the presence of palladium/carbon. When the hydrogen consumption ceases, the catalyst is removed and the solvent is evaporated. Thus, 2.42 g (76%) of 1-amino-5,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline are obtained. M.p.: 181°-183° C. The hydrochloride can be precipitated by treating the free amine in ethanol with anhydrous hydrogen chloride dissolved in ethyl acetate. M.p.: 244°-245° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br>>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH2:26][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(=O)[nH]c1=O
Yield: 56.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-bis(trifluoromethyl)benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (280 mg, yield: 56.2%).
Reaction SMILES: [CH2:1]([C:5]1[C:10](=[O:11])[NH:9][N:8]([CH3:12])[C:7]2=[N:13][C:14]([NH2:18])=[N:15][C:16](=[O:17])[C:6]=12)C(C)=O>COCCO>[NH2:18][C:14]1[NH:15][C:16](=[O:17])[C:6]2[CH:5]([CH3:1])[C:10](=[O:11])[NH:9][N:8]([CH3:12])[C:7]=2[N:13]=1
Reactant: CC(=O)Cc1c2c(=O)nc(N)nc-2n(C)[nH]c1=O
Solvent: COCCO
Product: CC1C(=O)NN(C)c2nc(N)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
4-Acetonyl-7-amino-1-methylpyrimido{4,5-c}-pyridazine-3,5-(1H, 2H)-dione (0.054 g) was dissolved in boiling methyl cellosolve (1 l), and the solution was concentrated to 40 ml when precipitated solid was noticed to be present. The mixture was allowed to cool to room temperature and stand overnight. Yellowish-green solid was collected, washed with methyl cellosolve (10 ml) methanol (2 ml), and dried under vacuum at 75° C. to yield 0.018 g (35%) of product: nmr (CF3COOH) δ3.03(s, 3H), 4.26(s, 3H),6.83(br s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]2[C:21]([C:22]3[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]4[C:34]5[N:35]=[C:36]([NH2:38])[S:37][C:33]=5[CH:32]=[CH:31][CH:30]=4)[CH:23]=3)=[CH:20][CH:19]=[C:18]([C:39]([F:42])([F:41])[F:40])[N:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]2[C:21]([C:22]3[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]4[C:34]5[N:35]=[C:36]([NH:38][C:43](=[O:45])[CH3:44])[S:37][C:33]=5[CH:32]=[CH:31][CH:30]=4)[CH:23]=3)=[CH:20][CH:19]=[C:18]([C:39]([F:41])([F:42])[F:40])[N:17]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NCC4CN(Cc5ccccc5)CCO4)ncn3)cccc2s1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NCC4CN(Cc5ccccc5)CCO4)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(6-(2((4-benzylmorpholin-2-yl)methylamino)-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine, Example 1(c), (110 mg, 0.18 mmol) and DMAP (10 mg, 0.08 mmol, Aldrich) in DCM (8 mL) was added acetic anhydride (90 μL, 0.9 mmol, Aldrich). The mixture was stirred at room temperature for 18 h and evaporated under reduced pressure. The residue was dissolved in EtOAc and the solution was washed with a sat. aqueous solution of NaHCO3, H2O and brine, dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography [2% (2N NH3 in MeOH)/DCM] to give the title compound as a light-yellow solid. MS (ESI, pos. ion.) m/z: 636 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[H][H].[C:11]([N:15]1[C:20](=[O:21])[C:19](Cl)=[C:18]([Cl:23])[CH:17]=[N:16]1)([CH3:14])([CH3:13])[CH3:12]>O1CCCC1>[C:11]([N:15]1[C:20](=[O:21])[C:19]([O:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])=[C:18]([Cl:23])[CH:17]=[N:16]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CC(C)CCO
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CCOc1c(Cl)cnn(C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred, room temperature solution of 3-methyl-1-butanol (0.5 mL, 4.52 mmol) in tetrahydrofuran (10 mL) was treated with a 60% oil suspension of sodium hydride (0.24 g, 5.88 mmol). After 5 minutes, hydrogen gas evolution had subsided, so the dichloro-intermediate from Example 330A (1.0 g, 4.52 mmol) was added and the reaction mixture was stirred at room temperature for 20 hours. The reaction was quenched with 10% aqueous citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, 100% hexanes). The title compound was obtained as a pale yellow oil (yield: 0.7 g, 56.7%). 1H NMR (300 MHz, CDCl3) δ 0.95 (d, J=6 Hz, 6H), 1.63 (s, 9H), 1.64 (q, J=6 Hz, 2H), 1.85 (nonet, J=6 Hz, 1H), 4.49 (t, J=6 Hz, 2H), 7.64 (s, 1H). MS (DCI/NH3) m/z 273 (M+H)+, 290 (M+NH4)+.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][OH:19])[CH:13]=[C:12]([CH2:20]N(CC)CC)[C:11]=2[OH:26])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[N:27]1[N:28]([C:36]2[CH:41]=[C:40]([CH2:42][CH2:43][CH2:44][OH:45])[CH:39]=[CH:38][C:37]=2[OH:46])[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=12.CO.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:20]([C:12]1[CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][OH:19])[CH:15]=[C:10]([N:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1]2)[C:11]=1[OH:26])[C:38]1[CH:39]=[C:40]([CH2:42][CH2:43][CH2:44][OH:45])[CH:41]=[C:36]([N:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]3=[N:27]2)[C:37]=1[OH:46]
Reactant: CCN(CC)Cc1cc(CCCO)cc(-n2nc3ccccc3n2)c1O
Reactant: OCCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: OCCCc1cc(Cc2cc(CCCO)cc(-n3nc4ccccc4n3)c2O)c(O)c(-n2nc3ccccc3n2)c1
Yield: 61.2 %

Procedure:
In 100 ml of xylene were dissolved 35.9 g (97.0 mmols) of crude 2-(2H-benzotriazole-2-yl)-4-(3-hydroxypropyl)-6-(N,N-diethylaminomethyl)phenol synthesized in Example 11 and 26.1 g (97.0 mmols) of the purified product of 2-(2H-benzotriazole-2-yl)-4-(3-hydroxypropyl)phenol synthesized in Example 6. 5 ml of a methanol solution of 28% sodium methylate was added, and the mixture was refluxed in a nitrogen stream for 10 hours. The subsequent treatment was carried out in the same manner as in Example 12, giving 33.0 g of 2,2'-methylenebis[6-(2H-benzotriazole-2-yl)-4-(3-hydroxypropyl)phenol] as white crystals (yield 61.2%, purity 99.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C@H:11]2[NH2:19])[CH:6]=[CH:7][C:8]=1[Cl:9].C(OC(OCC)CBr)C.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]2[NH2:19])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: COc1cc([C@@H]2c3ccccc3C[C@H]2N)ccc1Cl
Agent: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(C2c3ccccc3CC2N)ccc1Cl
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A mixture of 1.0 grams(3.65 mmol) of Compound L from step B, 0.55 mL (3.65 mmol) 2-bromoacetaldehyde diethyl acetal, and 1.0 grams (7.3 mmol) anhydrous potassium carbonate in 35 mL dry DMF was stirred at 150° C. for 4 hours. After cooling to room temperature, the mixture was poured into 300 mL ether, washed with three 50 mL portions of water, dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting with 1:1 hexane-ethyl acetate to give 1.1 grams (77%) of N-(2,2-diethoxyethyl)-trans-1-(3-methoxy-4-chlorophenyl-2-indanamine (Compound M) as an oil, 200 MHz NMR(CDCl3) d 1.15(tr,6H,J=7 Hz), 2.70-290(m,3H), 3.20-3.70(m,6H), 4.09(d,1H,J=8 Hz), 4.55(tr,1H,J=5 Hz), 6.70-6.90(m,3H), 7.10-7.30(m,4H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[N+:24]([O-])=O)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CO>[Pt].C1(C)C=CC=CC=1>[NH2:24][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:13][CH2:12][C:2]([CH3:27])([CH3:1])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(CNC(=O)OC(C)(C)C)CNc1c(N)cnc2ccccc12

Procedure:
A pressure bottle was charged with platinum on carbon (5%, 0.70 g) followed by tert-butyl 2,2-dimethyl-3-[(3-nitroquinolin-4-yl)amino]propylcarbamate dissolved in 250 mL of toluene. The reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). The next day, the reaction mixture was carefully charged with 25 mL of MeOH and filtered through a pad of CELITE filter agent. The pad was rinsed with 1:1 CH2Cl2/methanol. The solvent was removed under reduced pressure to give tert-butyl 3-[(3-aminoquinolin-4-yl)amino]-2,2-dimethylpropylcarbamate as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].C1N=C(N)C2N=CN([C@@H]3[O:41][C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:1][C:2]([F:27])([F:26])[C:3]([OH:41])=[O:5].[F:27][C:2]([F:1])([F:26])[C@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)(=[O:20])=[O:19])[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3nccs3)CC2)cc1)C(F)(F)F
Product: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3nccs3)CC2)cc1)C(F)(F)F
Product: O=C(O)C(F)(F)F

Procedure:
(2R)-1,1,1-trifluoro-2-(4-(4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=3.1 Hz, 1H), 7.67 (d, J=3.1 Hz, 1H), 7.48 (d, J=8.8 Hz, 2H), 6.94 (d, J=9.0 Hz, 2H), 3.48-3.58 (m, 4H), 3.27-3.38 (m, 4H), 1.76 (s, 3H). m/z (ESI, +ve ion) 421.8 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=1.18 μM; GK-GKRP EC50 (LC MS/MS)=4.75 μM.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH3:9])[O:6][CH:7]=1.[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[Cl-:1].[CH2:8]([C:5]1[O:6][CH:7]=[C:3]([CH2:2][P+:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:4]=1)[CH3:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCc1nc(CCl)co1
Solvent: CC#N
Product: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)co1
Product: [Cl-]
Yield: 81.7 %

Procedure:
A mixture of 4-chloromethyl-2-ethyl-1,3-oxazole (4.87 g), triphenylphosphine (7.89 g) and acetonitrile (100 mL) was heated under reflux for 15 hrs. The reaction mixture was concentrated, and the obtained crystals were washed with diethyl ether to give [(2-ethyl-1,3-oxazol-4-yl)methyl]triphenylphosphonium chloride as colorless crystals (10.02 g, yield 79%). Recrystallization thereof from acetonitrile-diethyl ether gave colorless prism crystals. melting point: 222-223° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].Cl[Sn]Cl>Cl.CO>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccnc2c([N+](=O)[O-])cccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: COC(=O)c1ccnc2c(N)cccc12
Yield: 85.1 %

Procedure:
In a similar fashion using route 19 general procedure 29, 8-nitro-quinoline-4-carboxylic acid methyl ester 474 (0.5 g, 2.15 mmol), SnCl2 (1.6 g, 8.6 mmol), 6N HCl (2 drops) and MeOH (10 ml) at 70° C. for 3 h gave the title compound (370 mg, 65%) which was used in the next step without further purification.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.S1C=CC=C1>[Pd].C(OC(C)C)(C)C.CO>[N:13]1([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: c1ccc2c(c1)CCN2
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: c1ccsc1
Solvent: CO
Product: CCOC(=O)N1CCC(N2CCc3ccccc32)CC1
Yield: 58.7 %

Procedure:
A mixture of ethyl 4-oxo-1-piperidinecarboxylate (85 g) and 2,3-dihydro-1H-indole (60 g), palladium on activated carbon (10%) (4 g) and a solution of thiophene in isopropyl ether (4%) (2 ml) in methanol (700 ml) was reacted in a Parr Pressure Vessel at 50° C. overnight. After completion, the mixture was filtered and the filtrate was evaporated, yielding 80 g (58%) of ethyl 4-(2,3-dihydro-1Hindol-1-yl)-1-piperidine-carboxylate (intermediate 6)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]2.Cl.[N:18]([O-])=[O:19].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:18]=[O:19])[CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]2
Reactant: O=N[O-]
Reactant: Cc1ccc2c(c1)CC(c1ccccc1)N2
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)CC(c1ccccc1)N2N=O
Reaction time: 0.08 h
Yield: 100.5 %

Procedure:
5-Methyl-2-phenylindoline (0.7 g, 0.00334 mol) was dissolved in ethanol (5 mL), and 1N hydrochloric acid solution (3.5 mL) was added at 0° C. The resulting reaction mixture was stirred for 5 min, and then a solution of sodium nitrite (0.462 g, 0.00668 mol) in water (8.5 mL) was added at 0° C. The mixture was stirred for 1 h at RT, and after completion of reaction (monitored by TLC), the solvent was removed under reduced pressure to obtain product as a brown colored oil (0.8 g).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:33])[C:9]2[CH:14]=[C:13]([CH2:15][C:16]3[C:17](=[O:28])[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20](=[O:23])[C:21]=3[CH3:22])[CH:12]=[CH:11][C:10]=2[O:29]C(=O)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>CO.O>[CH:1]1([NH:7][C:8](=[O:33])[C:9]2[CH:14]=[C:13]([CH2:15][C:16]3[C:17](=[O:28])[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20](=[O:23])[C:21]=3[CH3:22])[CH:12]=[CH:11][C:10]=2[OH:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)NC3CCCCC3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)NC3CCCCC3)c2)=C(C)C1=O
Yield: 54.9 %

Procedure:
N-Cyclohexyl-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.070 g, 0.154 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.035 g, 0.0846 mmol, 55%).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C@H:4]1[O:14][CH2:15][CH3:16])#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][C@@H:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C@H:4]1[O:14][CH2:15][CH3:16]
Reactant: [H][H]
Reactant: CCOC(=O)N1CC[C@@H](C#N)[C@H](OCC)C1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOC(=O)N1CC[C@@H](CN)[C@H](OCC)C1
Yield: 27.4 %

Procedure:
A mixture of intermediate (13) (0.19 mol) in methanol saturated with NH3 (500 ml) was hydrogenated at 14° C. with Raney nickel as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The desired fractions were collected and the solvent was evaporated, yielding 12 g of ethyl (trans)-4-(aminomethyl)-3-ethoxy-1-piperidinecarboxylate (intermediate 14).
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[C@@H:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C@@H:25]([CH2:31][CH3:32])[CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:5]1=[O:33])C=C.O.I([O-])(=O)(=O)=O.[Na+].CC[O:44][C:45]([CH3:47])=[O:46]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:6]([C@@H:25]([CH2:31][CH3:32])[CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:5](=[O:33])[C@:4]([CH2:47][C:45]([OH:44])=[O:46])([CH3:1])[CH2:9]2)[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: CCOC(C)=O
Reactant: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CS(C)(=O)=O)C1=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC[C@@H](CS(C)(=O)=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cc(F)cc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonyl)butan-2-yl)piperidin-2-one (Example 395, Step B, 58 mg, 0.110 mmol) in acetonitrile (1.0 mL), EtOAc (1.0 mL), and water (1.5 mL) was added ruthenium(III) chloride hydrate (0.55 mg, 2.42 μmol) and sodium periodate (144 mg, 0.672 mmol). After 2 hours, the mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography on silica gel (eluent: 10% MeOH/DCM) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.ClC[C@@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:18][C:15]1([CH3:19])[O:16][C@H:17]([CH2:1][O:2][C:3]2[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=2)[CH2:13][O:14]1
Reactant: COc1ccc(C=O)cc1
Reactant: CC1(C)OC[C@@H](CCl)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2ccc(C=O)cc2)O1

Procedure:
2 g (16.38 mmol) of p-methoxybenzaldehyde together with 3.7 g (24.57 mmol) of (4S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane and 15.8 g (114.64 mmol) of potassium carbonate are stirred in 10 ml of DMF at 130° C. overnight. The mixture is then added to water and extracted with methylene chloride. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 5:1). This gives 2.42 g (61% of theory) of the target compound.