Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[Na]>>[CH2:19]([O:18][C:16](=[O:17])/[C:15](/[OH:21])=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=1)=[O:10])[CH3:20]
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)/C(O)=C/C(=O)c1ccc(F)c(C(F)(F)F)c1

Procedure:
In analogy to the procedure described for example 11 a], 1-(4-fluoro-3-trifluoromethyl-phenyl)-ethanone was reacted with diethyl oxalate in the presence of metallic sodium to give (Z)-4-(4-fluoro-3-trifluoromethyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:14][CH3:15])[C:6]2[O:10][C:9]([CH2:11][OH:12])=[CH:8][C:7]=2[CH:13]=1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>C1COCC1>[C:17](=[O:18])([O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)[O:12][CH2:11][C:9]1[O:10][C:6]2[C:5]([O:14][CH3:15])=[CH:4][C:3]([O:2][CH3:1])=[CH:13][C:7]=2[CH:8]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(OC)c2oc(CO)cc2c1
Solvent: C1CCOC1
Product: COc1cc(OC)c2oc(COC(=O)Oc3ccc([N+](=O)[O-])cc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of (5,7-dimethoxybenzofuran-2-yl)methanol 6 (100 mg, 0.48 mmol) in THF (3 mL) was cooled to 0° C. TEA (69 uL, 0.48 mmol) was added dropwise followed by the portionwise addition of p-nitrophenyl chloroformate (100 mg, 0.72 mmol). The resulting solution was stirred at room temperature for 2 h. Solvent was evaporated off in vacuo and the crude residue was purified by flash chromatography, eluting with hexane:EtOAc (3:1), to give 61 (120 mg, 67%) as a white solid. H1 NMR (500 MHz, CDCl3): δ=8.29 (2H, d, J=9.0 Hz, ArH), 7.40 (2H, d, J=9.0 Hz, ArH), 6.82 (1H, s, ArH), 6.63 (1H, s, ArH), 6.52 (1H, s, ArH), 5.39 (2H, s, CH2), 4.00 (3H, s, OCH3), 3.85 (3H, s, OCH3).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]=[CH:12][CH2:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:15]([O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C(OCC=CCO)c1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCC=CCOC(=O)c1ccccc1

Procedure:
4-Benzoyloxy-2-butenyl palmitate was prepared by the procedure of Example 1 from 19 gms (0.1 mole) of 4-hydroxy-2-butenyl benzoate and 26 gms (0.1 mole) of palmitoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([F:24])[C:21]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5].C([O-])([O-])=[O:33].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:23]=[C:22]([F:24])[C:21]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([NH2:19])=[O:33])[CH:8]=1)=[O:5]
Reactant: N#Cc1cc(NC(=O)c2cc(-c3ncccc3F)c(F)cc2Cl)n(-c2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(F)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of 2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)-4-fluoro-5-(3-fluoropyridin-2-yl)benzamide (Example 98, 89 mg, 0.20 mmol) in DMSO (5 mL) was added K2CO3 (56 mg, 0.41 mmol) followed by H2O2 (30% aqueous solution, 926 mg, 8.17 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was quenched by the addition of water (20 mL) and extracted into EtOAc (2×20 mL). The combined organic layers were washed with water (2×40 mL), brine (40 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting from 5-45% MeCN (with 0.1% HCO2H) in water (with 0.1% HCO2H) to afford the title compound as a white solid (70 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([NH:10][C@H:11]([C@H:27]([OH:29])[CH3:28])[C:12]([NH:14][NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].N1C=CN=C1.[CH3:36][C:37]([Si:40](Cl)([CH3:42])[CH3:41])([CH3:39])[CH3:38]>CN(C=O)C>[Si:40]([O:29][C@H:27]([CH3:28])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:30])[C:12]([NH:14][NH:15][C:16](=[O:26])[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:13])([C:37]([CH3:39])([CH3:38])[CH3:36])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
To a pre-cooled (0° C.) solution of N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-nitrobenzohydrazide (12.0 g, 27.79 mmol) in DMF (650 mL) was added imidazole (15.13 g, 222.31 mmol) then TBSCl (16.75 g, 111.15 mmol). The reaction was warmed slowly to room temperature, stirred for 72 h, cooled to 0° C. and quenched with H2O (600 mL). The solution was extracted with EtOAc (700 mL). The organic extract was washed with H2O (2×300 mL) and 5% aq. citric acid (3×250 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a light yellow oil, which was purified by flash chromatography over silica gel (30-40% EtOAc in hexanes) to provide the title compound as a colourless solid (8.50 g, 56%): 1H NMR (400 MHz, d6-DMSO, δ in ppm) 10.93 (s, 1H), 10.57 (s, 1H), 8.34 (dm, J=8.8 Hz, 2H), 8.07 (dm, J=9.0 Hz, 2H), 7.59 (d, J=8.6 Hz, 1H), 6.84 (d, J=9.0 Hz, 1H), 5.69 (d, J=8.4 Hz, 1H), 5.28 (s, 1H), 4.38 (pentet, J=6.3 Hz, 1H), 4.16 (dd, J=6.5, 8.0 Hz, 1H), 2.26 (s, 3H), 1.27 (d, J=6.3 Hz, 3H), 0.85 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H).
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:24])=[C:15](N4CCNCC4)[N:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2)[CH2:7][CH2:6]1>S(=O)(=O)(O)O>[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:24])=[C:15]([OH:2])[N:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(N3CCNCC3)c(F)cc2c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cn(C2CC2)c2nc(O)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2 ml of 70% nitric acid in 10 ml of 98% sulfuric acid was added in portions 1.0 g (3.0 mmole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, keeping the temperature between 25°-30° C. The resulting solution was stirred at room temperature for 18 hours and poured onto 40 g of ice. The mixture was stirred at room temperature for 24 hours, concentrated in vacuo, the pH adjusted to 12 with aqueous sodium hydroxide, and filtered through a fiber glass pad. The filtrate was acidified to pH 3.5 with 6.0M hydrochloric acid, the resulting precipitate removed by filtration, washed with water then ether and dried in vacuo to give 0.23 g of the title compound, mp 325°-327° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH3:21][S:22][C:23]1[N:28]=[C:27]([CH:29]=[O:30])[CH:26]=[CH:25][N:24]=1.[NH4+].[Cl-]>C1COCC1>[C:17]([O:16][C:13](=[O:15])[CH2:14][CH:29]([OH:30])[C:27]1[CH:26]=[CH:25][N:24]=[C:23]([S:22][CH3:21])[N:28]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: CSc1nccc(C=O)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1nccc(C(O)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
To a cold (0° C.) solution of diisopropylamine (5.7 mL, 40.5 mmol) in THF (130 mL) is added dropwise n-butyllithium (16.2 mL of a 2.5 M solution in hexanes, 40.5 mmol). The mixture is stirred for 45 min at 0° C., then the solution is cooled to −78° C. tert-Butyl acetate (5.5 mL, 40.5 mmol) is added dropwise to the reaction mixture. After stirring 40 min at −78° C., a solution of 2-methylsulfanyl-pyrimidine-4-carbaldehyde (5.0 g, 32.4 mmol) is added dropwise. After 30 min at −78° C., the solution is poured into aqueous saturated NH4Cl. The aqueous phase is extracted with EtOAc. The organic phase is dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (5% EtOAc/hexanes, followed by 20% EtOAc/hexanes) to afford 7.2 g (82% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J=5.1 Hz, 1H), 7.22 (d, J=5.1 Hz, 1H), 5.00 (dd, J=8.4, 3.6 Hz, 1H), 2.93 (dd, J=16.5, 3.6 Hz, 1H), 2.70 (dd, J=16.5, 7.8 Hz, 1H), 2.58 (s, 3H), 1.46 (s, 9H); ESI+ MS: m/z (rel intensity) 271.1 (85, M++H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[O:57]=[C:58]1[CH:62]([C:63](O)=[O:64])[CH2:61][CH2:60][N:59]1[C:66]1[CH:71]=[CH:70][C:69]([C:72]([F:75])([F:74])[F:73])=[CH:68][CH:67]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:63]([CH:62]1[CH2:61][CH2:60][N:59]([C:66]2[CH:67]=[CH:68][C:69]([C:72]([F:75])([F:73])[F:74])=[CH:70][CH:71]=2)[C:58]1=[O:57])=[O:64]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)cc2)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc(C(F)(F)F)cc2)C1=O
Yield: 6.4 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.200 g; 0.865 mmol), PyBOP (0.450 g; 0.865 mmol), N,N diisopropylethylamine (0.373 mL; 2.16 mmol) and 2-oxo-1-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylic acid (0.236 g; 0.865 mmol) in DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane and 1 to 7% methanol in dichloromethane) to yield 0.025 g (7%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][N:2](C)/[CH:3]=[CH:4]/[C:5](=O)[CH:6]([O:9][CH3:10])[O:7][CH3:8].C(O)(=O)C.C(N)=[NH:18]>O>[CH3:8][O:7][CH:6]([O:9][CH3:10])[C:5]1[CH:4]=[CH:3][N:2]=[CH:1][N:18]=1
Reactant: COC(OC)C(=O)/C=C/N(C)C
Reactant: N=CN
Solvent: CC(=O)O
Solvent: O
Product: COC(OC)c1ccncn1
Temperature: 120 °C
Yield: 70.3 %

Procedure:
A mixture of (E)-4-dimethylamino-1,1-dimethoxy-but-3-en-2-one (49.6 g, 286 mmol) and formamidine acetate (44.7 g, 429 mmol) was heated at 120° C. for 4 h. After cooling to room temperature the mixture was poured into water and extracted with dichloromethane. The combined organic extracts were then dried over sodium sulfate, filtered and evaporated. Purification by distillation afforded the title product (31 g, 70%) as a colourless liquid. Bp 59-60° C. at 1.3 mbar. MS: m/e=155.0 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.O.[Cl:16][CH2:17][C:18]([CH3:20])=[CH2:19]>ClCCl>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([C:18]([CH3:20])([CH3:19])[CH2:17][Cl:16])[CH:8]=1
Reactant: C=C(C)CCl
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Br)cc1C(C)(C)CCl

Procedure:
Sulfuric acid (2 mL, 0.033 mol) was added dropwise under argon to 4-bromoanisole (14.6 mL, 0.117 mol). The mixture was warmed to 40–43° C. (warm water bath) and 3-chloro-2-methyl propene was added dropwise in 4 equal portions over 2 hrs. After 2 hrs at 40–43° C. the solution was diluted with dichloromethane and washed successively with water, saturated aqueous NaHCO3, water and brine, dried (Mg2SO4), filtered and evaporated. The residue was crystallized from hexanes to give 14.1 g of 4-bromo-2-(2-chloro-1,1-dimethyl-ethyl)-1-methoxy-benzene. The mother liquor was further purified on silica gel (10% ethyl acetate in hexane) to afford additional 4.8 g of product. 58% yield. 1H NMR (300 MHz; CDCl3): δ 1.43 (s, 6 H), 3.82 (s, 3 H), 3.93 (s, 2 H), 6.75 (dd, J=2.4 Hz and 7.2 Hz, 1 H), 7.32 (m, 2 H).
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([F:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[F:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:2]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(Cl)nc1
Reactant: C1COCCN1
Product: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(N2CCOCC2)nc1

Procedure:
N-[7-Fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-6-morpholin-4-yl-nicotinamide was prepared starting from 6-chloro-N-[7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-yl-methyl]-nicotinamide (Example I-105) and morpholine. 1H MS calcd. for C26H22F2N4O3 [(M+H)+] 477.2, obsd. 477.0.
Reaction SMILES: [OH:1][C:2]1[C:3]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.I[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:17]([O:1][C:2]1[C:3]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:18][CH3:19]
Reactant: CC(=O)Nc1cc2ccccc2cc1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1cc2ccccc2cc1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
N-(3-Hydroxynaphthalen-2-yl)acetamide (4.87 g, 24.2 mmol) was suspended in acetonitrile (50 ml). A 1-iodopropane (4.52 g, 26.6 mmol) acetonitrile solution (40 ml) and potassium carbonate (4.35 g, 31.5 mmol) were added thereto, and the resulting mixture was stirred for 3 hours while heating under reflux. The mixture was then cooled to room temperature and concentrated to dryness under reduced pressure. Water was added to the residue, followed by extraction using dichloromethane. The thus-obtained organic layer was concentrated to dryness under reduced pressure, and the residue was then purified using silica gel column chromatography (dichloromethane:ethyl acetate=20:1). The purified product was concentrated to dryness under reduced pressure, giving a white powder of N-(3-propoxynaphthalen-2-yl)acetamide (5.64 g, yield: 96%).
Reaction SMILES: CCN(CC)CC.C([SiH](CC)CC)C.C([O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][N:29]=[C:30]2[C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)=[CH:25][N:24]=1)C1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:38][N:36]1[CH:37]=[C:33]([C:30]2[N:29]=[CH:28][CH:27]=[C:26]3[C:31]=2[CH:32]=[C:23]([OH:22])[N:24]=[CH:25]3)[CH:34]=[N:35]1
Reactant: Cn1cc(-c2nccc3cnc(OCc4ccccc4)cc23)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2nccc3cnc(O)cc23)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.2 %

Procedure:
A solution of Pd(OAc)2 (4 mg, 0.019 mmol), Et3N (7.5 uL, 0.053 mmol), triethylsilane (0.085 mL, 0.531 mmol) in DCM (8 mL) was stirred at room temperature for 10 minutes. A solution of 7-(benzyloxy)-1-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridine (Preparation 88, 120 mg, 0.379 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with aqueous saturated ammonium chloride (20 mL) and extracted with ether (2×30 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give the title compound (13 mg, 15%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)P(=O)(N(C)C)N(C)C.CCOCC>[CH2:18]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCBr
Reactant: Oc1cccc2c1NCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCN1CCCc2cccc(O)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.3 %

Procedure:
A mixture of 499.2 mg (3.35 mmol) of 1,2,3,4-tetrahydro-8-quinolinol (see Example 7A), 425 mg (5.05 mmol, 1.5 eq.) of sodium bicarbonate, and 780 μl (3.69 mmol, 1.1 eq.) of 98% 1-bromodecane in 10 ml of hexamethylphosphoric triamide under argon was stirred for three hours at room temperature, followed by 44 hours at 50° C. The reaction was diluted with 80 ml of 1:1 ether:petroleum ether and the organic layer was washed with five 40 ml portions of water and 40 ml of brine, dried over sodium sulfate and evaporated to yield 1.04 g of a brown oil. Purification by flash chromatography on 110 g of silica, eluted with 5:95 ethyl acetate:petroleum ether afforded 624.4 mg of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH:18]=[CH:17][N:16]=1>>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[CH:18]=[CH:17][N:16]=[C:15]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][S:10]([NH2:13])(=[O:11])=[O:12])[CH:5]=[CH:6][CH:7]=2)[CH:20]=1
Reactant: Nc1cccc(CCS(N)(=O)=O)c1
Reactant: COc1ccccc1-c1ccnc(Cl)c1
Product: COc1ccccc1-c1ccnc(Nc2cccc(CCS(N)(=O)=O)c2)c1
Yield: 2.3 %

Procedure:
H1 was prepared from A6 (92 mg, 0.46 mmol) and A1 (100 mg, 0.46 mmol) following the procedure reported for G1 and obtained as a pale yellow amorphous solid (4 mg, 2%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.95-3.03 (m, 2H), 3.21-3.29 (m, 2H), 3.81 (s, 3H), 6.87 (bs, 2H), 6.93-7.01 (m, 2H), 7.07 (t, J=7.5 Hz, 1H), 7.10-7.14 (m, 1H), 7.16 (d, J=8.5 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.36-7.47 (m, 4H), 8.07 (d, J=5.4 Hz, 1H), 9.67 (bs, 1H). MS (ES) C20H21N3O3S requires: 383. found: 384 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=1[S:31]([CH3:34])(=[O:33])=[O:32]>C(#N)C.C(N(CC)C(C)C)(C)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH:30][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=4[C:14]#[N:15])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:29])=[CH:24][C:23]=1[S:31]([CH3:34])(=[O:32])=[O:33]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: CC(N)c1ccc(Cl)c(S(C)(=O)=O)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NC(C)c4ccc(Cl)c(S(C)(=O)=O)c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (250 mg, 0.88 mmol) and 1-(4-chloro-3-(methylsulfonyl)phenyl)ethanamine (300 mg, 1.28 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (700 μL) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.O1CCN(CCN[S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])CC1>>[O:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH2:6][CH2:7]1
Reactant: NCCCN1CCOCC1
Reactant: O=S(=O)(NCCN1CCOCC1)C(F)(F)F
Product: O=S(=O)(NCCCN1CCOCC1)C(F)(F)F

Procedure:
In the manner described above, substituting N-(3-aminopropyl)morpholine (41.35 grams; 0.286 mole) for the N-(2-aminoethyl)morpholine and recrystallizing the crude product from methylcyclohexane, N-(3-morpholinopropyl)trifluoromethanesulfonamide is obtained, m.p. 95°-97° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][NH:28][C:29]2=[O:34]>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][NH:28][C:29]3=[O:34])=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22]
Reactant: Nc1cccc2c(=O)[nH]ccc12
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(C)c1OC
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2c(=O)[nH]ccc12)C(F)(F)F)c1ccc(F)c(C)c1OC

Procedure:
In the same way as in Example 130, 200 mg (0.62 mmol) of (2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 100 mg (0.62 mmol) of 5-aminoisoquinolin-1(2H)-one and 0.39 ml (1.25 mmol) of titanium tert-butoxide are reacted to give 5-{[(2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}isoquinolin-1 (2H)-one. 460 mg of crude imine are cyclized in the same way as in Example 130 at −30° C. with 7.9 ml (7.9 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50-100%) yields 223 mg of desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:27]=[C:28]1[O:32][C:30](=[O:31])[CH2:29]1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:30](=[O:31])[CH2:29][C:28]([CH3:27])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1CC(=O)O1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
2-({4-[2-(Heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (3.41 g) synthesized in Example 303-2 was dissolved in N,N-dimethylformamide (43 mL), and diketene (0.75 g) was added dropwise under ice-cooling. After warming to room temperature, the mixture was stirred for one hour. The mixture was diluted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2-[(4-{2-[acetoacetyl(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (3.4 g) as a colorless oil. The present compound was used in the next step without particular purification. The present compound (1.0 g) was dissolved in ethanol (10 mL), hydrazine monohydrate (0.103 g) was added thereto at room temperature, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL), diphosphorus pentasulfide (0.459 g) and sodium carbonate (0.437 g) were added thereto, and the mixture was heated under reflux for 2 hr. The solvent was evaporated, and the residue was directly purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 1:2) to give the title compound (0.54 g) as a colorless oil.