Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([C:14]2[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=2)=[O:13])[CH2:8][CH2:7]1)C.O[Li].O>>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:12]([CH:9]3[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:23])=[O:3])[CH2:11][CH2:10]3)=[O:13])=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccc3c(c2)OCO3)CC1
Agent: [Li]O
Solvent: O
Product: O=C(O)CN1CCC(C(=O)c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
To a solution of [4-(benzo[1,3]dioxole-5-carbonyl)-piperidin-1-yl]-acetic acid ethyl ester (0.35 g, 1.1 mmol in 6 mL of THF and 2 mL of methanol) was added LiOH.H2O (0.23 g, 5.5 mmol in 3 mL of water) and the reaction mixture was stirred at ambient temperature for 1.5 hours. The solvent was removed in vacuo then diluted with 20 mL of water (pH 14). The residue was treated with 12 mL of 1 N HCl (pH 4), frozen at −78° C. and lyophilized for 24 hours to yield the title compound (0.30 g, 0.98 mmol). MS (ESI) m/z 292.9 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.12 min.
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].Br[CH2:27][Cl:28]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:28][CH2:27][S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: ClCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: O=S(=O)(CCl)c1cccc2ccccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A mixture of 1-naphthalene sulfonyl chloride (20.2 g, 89.1 mmol), sodium sulfite (22.5 g, 178 mmol) and sodium bicarbonate (15.1 g, 180 mmol) in water was stirred at 100° C. for one hour, allowed to cool to ambient temperatures for 40 minutes, treated with bromochloromethane (90 mL, 1.4 mol) and tetrabutylammonium bromide (2.87 g, 8.91 mmol), stirred at 75° C. for 14.5 hours and cooled to ambient temperatures. The phases were separated and the organic phase was concentrated in vacuo. The resultant residue was purified by flash chromatography with 100% ethyl acetate to give 1-chloromethanesulfonyl-naphthalene as a pale yellow solid, 19.0 g (88.8% yield), mp 103-5° C., Mass Spectrum (+EI, M+) m/z 240. 1HNMR (500 MHz, DMSO-d6): δ8.64-5 (m, 1H), 8.41 (d, 1H, J=8.23 Hz), 8.27 (dd, 1H, J=7.33 Hz and 1.22 Hz), 8.16-8.18 (m, 1H), 7.71-7.81 (m, 3H), 5.40 ppm, (s, 2H). Elemental Analysis for C11H9ClO2S: Calcd: C, 54.89; H, 3.77; N, 0.00; Found: C, 54.98; H, 3.81; N, 0.00.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:36][CH2:37][CH3:38])=[C:11]([CH:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:18]=2)[OH:16])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH2:37]([O:36][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[CH:12][C:11]=1[C:15]([C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([Si:26]([CH:30]([CH3:31])[CH3:32])([CH:27]([CH3:29])[CH3:28])[CH:33]([CH3:34])[CH3:35])[CH:18]=1)=[O:16])[CH3:38]
Reactant: CCOc1c(OCc2ccccc2)cccc1C(O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1c(O)cccc1C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Yield: 38.8 %

Procedure:
To a solution of (3-benzyloxy-2-ethoxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (664,195 mg, 0.37 mmol) in a mixture of methanol (20 mL) and tetrahydrofuran (50 mL) was added palladium on carbon (50 mg, 10% wt., 0.2 mmol). The mixture was stirred under hydrogenation for seventeen hours. After removal of solvent, the residue was washed with a mixture of ethyl ether and hexanes to provide the compound as a white solid (665, 63 mg, 95%). MS (ESI) [M+H+]+=439.37.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:12][C:13]1[S:17][C:16]2=[N:18][C:19]([C:21](O)=[O:22])=[CH:20][N:15]2[CH:14]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:21]([C:19]3[N:18]=[C:16]4[N:15]([CH:20]=3)[CH:14]=[C:13]([Br:12])[S:17]4)=[O:22])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(NCc1ccc2c(c1)OCO2)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using benzo[d][1,3]dioxol-5-ylmethanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].[OH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12]CC)=[O:11].C(=O)([O-])[O-].[K+].[K+].C(OC1C=C(C=CC=1)C(O)=O)CC>>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CC(C)CBr
Agent: CCCOc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)COc1cccc(C(=O)O)c1

Procedure:
The reaction of isobutyl bromide and ethyl 3-hydroxybenzoate in the presence of potassium carbonate was performed as described for Compound 24 to give 3-isobutoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.94 (s, COOH); 7.48 (m, 1 arom. H); 7.40 (m, 2 arom. H); 7.12 (m, 1 arom. H); 3.76 (d, J=6.4, (CH3)2CHCH2O); 2.00 (m, (CH3)2CHCH2O); 0.96 (d, J=6.4, (CH3)2CHCH2O). 13C-NMR (100 MHz, d6-DMSO): 167.11 (—C═O); 158.73; 132.12; 129.68; 121.42; 119.35; 114.46; 73.46; 27.66; 18.98 (2 C).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1>>[C:15]([C:7]1[C:8]([C:11]([F:12])([F:14])[F:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1)[C:2]([CH3:1])=[CH:10]2)#[N:16]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: CC(=O)Nc1ccc(OCCBr)cc1
Product: CC(=O)Nc1ccc(OCCn2c(C)cc3c(C(F)(F)F)c(C#N)ccc32)cc1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and N-{4-[(2-bromoethyl)oxy]phenyl}acetamide: 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.39 (d, J=9.0 Hz, 2H), 6.72 (d, J=9.0 Hz, 2H), 6.55 (s, 1H), 4.65 (t, J=5.0 Hz, 2H), 4.21 (t, J=5.0 Hz, 2H), 2.55 (s, 3H), 1.95 (s, 3H); MS (ES) m/z 402 (M+1).
Reaction SMILES: I[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][CH2:37][O:38]2.C(OCC)(=O)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:42]2[C:33]([Cl:32])=[C:34]3[C:39](=[CH:40][CH:41]=2)[O:38][CH2:37][CH2:36][CH2:35]3)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC1(C)OB(c2ccc3c(c2Cl)CCCO3)OC1(C)C
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc2c(c1Cl)CCCO2)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
To a solution of methyl 2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.075 g; 0.158 mmol) in a mixture of DME-water (3:1) (0.480 mL) were added potassium carbonate (0.066 g; 0.475 mmol), tetrakis(triphenylphosphine) palladium(0) (0.018 g; 0.016 mmol) and 2-(5-chlorochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.070 g; 0.238 mmol). The solution was stirred for 30 min at 140° C. under microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (0-40%) in heptane furnished 0.027 g (34%) of the title compound as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:31])[C:5]2=[C:6]([CH2:8][C@H:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3Br)[NH:10]/[C:11]/2=[N:12]\[O:13][C@H:14]([CH2:20][CH2:21][OH:22])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:7]=1.[CH3:32][O:33][C:34]1[N:39]=[C:38](B2OCCN(C3C=CC=CC=3)CCO2)[CH:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(N(C)C)=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:31])[C:5]2=[C:6]([CH2:8][C@H:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([O:33][CH3:32])[N:39]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][C@H:14]([CH2:20][CH2:21][OH:22])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:7]=1
Reactant: Cc1nc(N)nc2c1/C(=N/O[C@H](CCO)C(=O)N(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: COc1cccc(B2OCCN(c3ccccc3)CCO2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/O[C@H](CCO)C(=O)N(C)C)N2)n1
Temperature: 85 °C
Yield: 43.7 %

Procedure:
A mixture of (R)-2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide (31 mg, 0.063 mmol), 2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (93 mg, 0.313 mmol), Pd(dppf)2Cl2 (9.16 mg, 0.013 mmol), 2N aq Na2CO3 (0.156 mL, 0.313 mmol) and DMA (2.0 mL) was degassed with N2 and heated at 85° C. for 4 h. Cooled to r.t., filtered trough celite and purified by prep LCMS to afford (R)-2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene) aminooxy)-4-hydroxy-N,N-dimethylbutanamide (92, 14.4 mg, 43.9%) as off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.08-2.16 (m, 2H) 2.60 (s, 3H) 2.98 (s, 3H) 3.02 (d, J=9.85 Hz, 1H) 3.10 (s, 3H) 3.16-3.33 (m, 1H) 3.62-3.81 (m, 2H) 3.89 (s, 3H) 4.94 (ddd, J=10.04, 3.98, 0.88 Hz, 1H) 5.03 (t, J=6.19 Hz, 1H) 5.27 (br. s., 2H) 5.79 (s, 1H) 6.74 (dd, J=8.34, 0.76 Hz, 1H) 7.01 (dd, J=7.33, 0.76 Hz, 1H) 7.07-7.23 (m, 2H) 7.65 (dd, J=8.34, 7.33 Hz, 2H). MS (ES) [M+H] calculated for C26H31FN7O4, 524.56. found 524.40.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:28])[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[C:21](=[O:28])[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[O:17]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Cc1cccc(N)c(=O)c1
Solvent: Cc1ccccc1C
Product: Cc1cccc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)c(=O)c1
Reaction time: 48 h
Yield: 48.2 %

Procedure:
A solution of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (1.2 g) and 2-amino-6-methyl-2,4,6-cycloheptatrien-1-one (0.7 g) in xylene (21 ml) is refluxed for 8 hours. The reaction mixture is then allowed to stand at room temperature for 2 days. The crystals that have separated out are collected by filtration, washed with toluene and recrystallized from dimethylformamide to give 4-hydroxy-2-methyl-N-(6-methyl-1-oxo-2,4,6-cycloheptatrien-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.8 g), m.p. 276°-280° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:37])=[C:5]([C@@H:10]2[CH2:15][N:14]3[CH2:16][CH2:17][N:18](C(OCC4C=CC=CC=4)=O)[CH2:19][C@H:13]3[CH2:12][N:11]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]>CO.[Pd]>[C:1]([C:3]1[C:4]([CH3:37])=[C:5]([C@@H:10]2[CH2:15][N:14]3[CH2:16][CH2:17][NH:18][CH2:19][C@H:13]3[CH2:12][N:11]2[C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1c([C@@H]2CN3CCN(C(=O)OCc4ccccc4)C[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Agent: [Pd]
Solvent: CO
Product: Cc1c([C@@H]2CN3CCNC[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Reaction time: 8 h

Procedure:
To a solution of (3R,9aS)-8-benzyl 2-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)tetrahydro-1H-pyrazino[1,2-a]pyrazine-2,8(9H,9aH)-dicarboxylate (600 mg, 1.180 mmol) in MeOH (100 mL) was added Palladium on carbon (10%, 126 mg, 0.118 mmol) and the resulting mixture was subjected to hydrogenation at rt overnight. The reaction mixture was filtered through Celite, washed with mixture of methanol and methylene chloride (1:1) and the filtrate was concentrated to give the title compound: LC/MS: (M+1)+: 375.28.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[C@H:31]([CH2:32][OH:33])[CH2:30][O:29][C:28]5=[O:34])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:36][CH2:37][O:38][CH3:39]>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[C@H:31]([CH2:32][O:33][CH2:36][CH2:37][O:38][CH3:39])[CH2:30][O:29][C:28]5=[O:34])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: COCCBr
Reactant: O=C(c1ccc(N2C(=O)OC[C@H]2CO)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: COCCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 40.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{4-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (694 mg) described in Example 280 and 1-bromo-2-methoxyethane (250 mg), the title compound (318 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(#N)C.CN(C)C=O.[I:20]N1C(=O)CCC1=O>>[OH:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][C:5]([I:20])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ncccc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: Oc1ncc(I)cc1C(F)(F)F
Temperature: 80 °C
Yield: 80 %

Procedure:
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80% yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130° C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55%). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II)acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40%). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1′-bis(diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92%). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95%). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25° C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74% to 95%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15]O)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>N1C=CC=CC=1.CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][N:29]=[N+:30]=[N-:31])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CO)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of trans-(4-hydroxymethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (123 g, 505 mmol) in pyridine (1 L) was cooled at 4° C. and a solution of p-toluenesulfonyl chloride (125 g, 657 mmol) in pyridine (200 ml) was added below 10° C. The mixture was stirred at ambient temperature for 15 hr and concentrated. After dissolution with EtOAc and H2O, the organic layer was separated. The aqueous layer was extracted with EtOAc (three times), the combined organic layer was washed with H2O, dried over MgSO4, filtered, and concentrated to give a pale yellow oil. To a solution of the above oil in DMF (1.6 L) was added NaN3 (98.8 g, 1.52 mol). The reaction mixture was stirred at ambient temperature for 14 hr and concentrated. After dissolution with CHCl3 and saturated aqueous NaHCO3, the organic layer was separated. The aqueous layer was extracted with CHCl3 (three times), the combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 17% EtOAc in hexane) to give trans-(4-azidomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (124 g, 91%) as a colorless oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH3:12])=[C:10]([C:13]3[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH:18]=3)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:26]>>[ClH:26].[CH3:12][C:11]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[N:9][C:10]=1[C:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=1
Reactant: Cc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1ccccc1
Agent: Cl
Product: Cc1c(C2=CCNCC2)nnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-[1-phenyl-5-methyl-1H-[1,2,3]-triazol-4-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (7.4 mg) prepared in Example 7 was dissolved in 2.0 ml of 10% methanolic hydrochloric acid solution and stirred at room temperature for 10 minutes. The solvent was evaporated in vacuo to give the title compound as a brown solid crude product.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[CH:20]([CH:22]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH:23]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=O.C(O)(=O)C>O1CCCC1>[OH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:23]1[CH:22]([CH:20]=[CH:3][C:2](=[O:1])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:30][CH2:29][C:24]21[O:25][CH2:26][CH2:27][O:28]2
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(C=CC1CCC2(OCCO2)C1CCCCCCCO)CCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
A solution of dimethyl 2-oxo-4-phenylbutylphosphonate [2.5 g; prepared as described hereinafter in Example 9(iv)] in anhydrous tetrahydrofuran (50 ml.) was added to a stirred suspension of sodium hydride (0.24 g.) in tetrahydrofuran (20 ml.). The mixture was stirred at room temperature in an atmosphere of nitrogen for 24 hours, then treated dropwise with a solution of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [2.7 g; prepared as described hereinbefore in Example 1(iv)] in tetrahydrofuran (30 ml.) and stirred for a further 2 hours in an atmosphere of nitrogen. The mixture was acidified to pH 4 by the addition of glacial acetic acid, the solvents were removed in vacuo and the residue was extracted with diethyl ether. The ethereal solution was washed with aqueous sodium bicarbonate solution (10% w/v) and then with water and dried over anhydrous magnesium sulphate. Evaporation of the solution gave 6-(7-hydroxyheptyl)-7-(3-oxo-5-phenylpent-1-enyl)-1,4-dioxaspiro[4,4] nonane (3.9 g.), in the form of a yellow oil (νmax 955 cm-1, 990 cm-1, 1625 cm-1, 1665 cm-1, 1690 cm-1).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Li+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Product: N#Cc1ccc(N=c2sc3ncccc3c(=O)n2Cc2ccccc2)cc1
Yield: 70.1 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.21 mmol) of 2-(4-cyanoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 28 mg of lithium hydride and 604 mg of benzyl bromide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 834 mg of 3-benzyl-2-[(4-cyanophenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one (70%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 103 mg of 2-[N-benzyl-N-(4-cyanophenyl)-N-propylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (10%, recrystallized from ether) as a high polarity substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>>[C:24]1([C:22]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[CH:3]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:19])[F:20])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: BrCc1ccc2ccccc2n1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromomethyl-quinoline following the procedure of Example 478: MS (ES) m/z 535.3.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OCC1C=CC=CC=1)=O.[CH3:44][C:45]([OH:47])=[O:46]>[Pd]>[C:45]([OH:47])(=[O:46])[CH3:44].[C:19]1([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([NH:16][C@@H:15]([C:32]([NH:34][C@@H:35]([C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[CH3:36])=[O:33])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)[C@@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(O)cc1

Procedure:
Prepared analogously to the method described in Example 1(e) above from (R)-N5 -(Cbz)-N2 -(diphenylacetyl)-(R)-N-[1-(4-hydroxyphenyl)ethyl]-ornithine amide (26.8 g; 46.23 mmol; from step (d) above), 10% Pd/C (2.5 g) and HOAc (1L; as opposed to HCl/MeOH) yielding 24.3 g of the sub-title compound (after azeotroping with toluene).