Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:29])([F:30])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1)[CH2:6][CH:7]1[C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: FC(F)(F)c1cc(C=C2c3ccccc3CCc3ccccc32)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: FC(F)(F)c1cc(CC2c3ccccc3CCc3ccccc32)cc(C(F)(F)F)c1
Reaction time: 17 h

Procedure:
Add 5-(3,5-bis-trifluoromethyl-benzylidene)-10,11-dihydro-5H-dibenzo [a,d]cycloheptene (0.28 g, 0.67 mmol) to a mixture of 10% Pd/C (0.08 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (4.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite. Evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product. MS (m/e): 420 (M+); Analysis for C24H18F6: Calcd: C, 68.56 H, 4.31. Found: C, 68.55 H. 4.01.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.CN(C)CCN(C)C.CN([CH:31]=[O:32])C>CCCCCC.CCOCC>[CH3:19][O:18][C:17]1[C:8]([O:7][CH3:6])=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]=1[CH:31]=[O:32]
Reactant: COc1cc2ccccc2cc1OC
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc2ccccc2c(C=O)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
n-Butyl lithium in hexane (1.6 N, 31.3 ml) was gradually added to a solution of 2,3-dimethoxynaphthalene (9.4 g) and N,N,N′,N′-tetramethylethylenediamine (7.4 ml) in ether (150 ml) under argon at 0° C. The reaction mixture was stirred at room temperature for two hours, cooled to 0° C. and DMF (7.3 g) in ether (20 ml) added. The reaction mixture was stirred at room temperature overnight and poured in ice water. The product was extracted with ether, washed with water, dried, evaporated and recrystallized from ether. Yield: 4.2 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[CH2:9][CH2:8][C:7](=[O:11])[C:6](=O)[C:5]=2[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15].CC1(C)C2CCCC(=O)C=2C(C)(C)C1C.[CH:32]([NH2:34])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[C:10]2[CH2:9][CH2:8][C:7]3[O:11][CH:32]=[N:34][C:6]=3[C:5]=2[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15]
Reactant: CC1C(C)(C)C2=C(C(=O)C(=O)CC2)C1(C)C
Reactant: NC=O
Agent: CC1C(C)(C)C2=C(C(=O)CCC2)C1(C)C
Solvent: Cc1ccccc1
Product: CC1C(C)(C)C2=C(c3ncoc3CC2)C1(C)C
Temperature: 200 °C
Reaction time: 24 h

Procedure:
1,1,2,3,3-Pentamethyl-2,3,6,7-tetrahydro-1H-indene-4,5-dione is first prepared with 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-inden-4-one (Cashmeran®) (commercially available at IFF) via oxidation with (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) (prepared as described by Barton in Tetrahedron Letters, 1984, 25(6), pages: 603-606). A 100 mL reaction flask is charged with 1,1,2,3,3-pentamethyl-2,3,6,7-tetrahydro-1H-indene-4,5-dione (10 g, 0.04 mol) and formamide (NH2CHO) (50 mL). The reaction mixture is heated to 200° C. and stirred for 24 hours. The crude mass is diluted with toluene (50 mL) and then washed once with aqueous sodium carbonate (10%, 100 mL) followed by twice with brine (30 mL). Toluene is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product of a mixture of 6,6,7,8,8-pentamethyl-5,6,7,8-tetrahydro-4H-1-oxa-3-aza-as-indacene and 6,6,7,8,8-pentamethyl-5,6,7,8-tetrahydro-4H-indeno[4,5-d]oxazole (˜10 g) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18](=[O:34])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:12][CH:11]=1)OS(C)(=O)=O.[CH3:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40].O[C@H:44]1CC[NH:46][CH2:45]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:35])[CH:4]([C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](=[O:34])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[CH:12][CH:11]=1)[N:46]1[CH2:45][CH2:44][CH:37]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:36]1
Reactant: CCN(CC)CC
Reactant: O[C@H]1CCNC1
Reactant: COC(=O)C(OS(C)(=O)=O)c1ccc(C=CC(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: CCN(CC)C1CCN(C(C(=O)OC)c2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-methanesulfonyloxy-acetic acid methyl ester (1.89 g, 3.75 mmol) and Et3N (1.46 g, 14.4 mmol) in CH2Cl2 (30 mL) was added (S)-3-hydroxypyrrolidine (0.67 g, 4.5 mmol). This mixture was stirred overnight at room temperature, then diluted with CH2Cl2 (50 mL), washed with saturated aqueous NaHCO3 solution, water and brine, dried with Na2SO4, filtered, and evaporated to obtain a yellow solid which was directly used in the next reaction without further purification. MS: calc'd 551 (MH+), exp 551 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:27]=2)=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH2:11]2)=[CH:8][N:9]=1)(=[O:3])[NH2:2].C(Cl)Cl.C(O)(C(F)(F)F)=O>>[CH3:20][N:19]([CH3:21])[C:17](=[O:18])[NH:16][C@@H:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:7]2[N:6]=[C:5]([NH:22][C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[CH:27]=3)[C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=2)[CH2:11]1
Reactant: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3cnn(C4CCNCC4)c3)n2)C1

Procedure:
Crude (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (277, 108 mg, 0.19 mmol) was treated with 2:1 DCM/TFA at RT for 1 hour and concentrated in vacuo to get (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide (278) TFA salt. It was dissolved in 10 mL DCE and 2 mL NMP. To it were added DIEA (330 μL, 1.9 mmol) and cyclopentanone (480 mg, 5.7 mmol). The mixture was stirred at RT for 5 hours, and to it were added HOAc (220 μL, 3.8 mmol) and NaBH(OAc)3 (240 mg, 1.14 mmol). The mixture was stirred at RT for overnight. It was diluted with 10 mL MeOH, concentrated in vacuo, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-3-(1-(1-cyclopentylpiperidin-4-yl)-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide (279) as HCl salt (45 mg, 45%). MS found for C26H40N10O2 as (M+H)+ 525.6, (M−H)− 523.3. UV: λ=254, 270, 297, 331, 374 nm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][C@H:13]([CH3:16])[CH2:14][OH:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:15][CH2:14][C@@H:13]([CH3:16])[CH2:12][O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: COC[C@H](C)CO
Reactant: ClCc1ccc(Br)cc1
Product: COC[C@H](C)COCc1ccc(Br)cc1

Procedure:
According to general method E, 1-bromo-4-chloromethyl-benzene [589-17-3] and (R)-3-methoxy-2-methyl-propan-1-ol are used to afford the title compound as a yellow oil. Rf=0.44 (EtOAc-heptane 1:6); Rt=5.29 (gradient I).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C(OCC)C>[N+:10]([C:9]1[C:5]([CH2:3][OH:2])=[N:6][N:7]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1nn(C2CCCCO2)cc1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cn(C2CCCCO2)nc1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
A stirred solution of 4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester [500 mg, Reference Example 54(a)] in tetrahydrofuran (20 ml) under nitrogen at −78° C. was treated dropwise with a solution of diisobutylaluminium hydride in tetrahydrofuran (8.82 ml, 1M). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was taken up in diethyl ether (100 ml) and quenched with water (150 ml). The resulting suspension was filtered through celite and the organic layer was collected from the filtrate, then dried over magnesium sulfate and then evaporated to yield [4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-methanol (349 mg) as a peach oil. LC-MS (Method H): RT=2.08 minutes, 250.29 (M+H+Na)+.
Reaction SMILES: C1C=CC(C(N=C=O)N=[C:9]=[O:10])=CC=1.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:14]([CH:19]([CH2:18][CH2:17][CH2:16][CH3:15])[CH2:9][OH:10])[CH3:20]
Reactant: Cc1ccccc1
Reactant: O=C=NC(N=C=O)c1ccccc1
Product: CCCCC(CC)CO

Procedure:
The batch is then diluted with 185.0 parts of toluene and a mixture of 180.0 parts of the semi-blocked toluylene diisocyanate referred to in Example 1 and 150.0 parts of a semi-blocked toluylene diisocyanate obtained from 2-ethylhexanol and an 80/20 toluylene diisocyanate isomer mixture is added in the course of 2 hours 15 minutes at 90° C. After completion of this addition, stirring is continued for 1 hour at 90° C., and the mixture is then heated to 120° C., kept at this temperature for 3.5 hours, and diluted after cooling with 81 parts of toluene. The solids content of the resulting polyether-polyol derivative containing blocked isocyanate groups, ie. of component A, is 71%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:23])[CH3:22].CS(C)=O.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22]
Reactant: CC(O)CCCCCCCCCOc1ccc2ccccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CCCCCCCCCOc1ccc2ccccc2n1

Procedure:
The above alcohol was oxidised under Swern conditions (dimethyl sulphoxide, 0.615 g; oxalyl chloride, 0.38 ml; triethylamine, 2.74 ml) to give after column chromatography 11-(2-quinolinyloxy)undecan-2-one (0.96 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][Mg]Cl>C1COCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:14]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 2-bromo-5-(trifluoromethyl)benzaldehyde (10 g, 39.6 mmol) in THF (40 mL), methyl magnesium chloride (3 M in THF) (26.4 mL, 79.3 mmol) was added at −78° C. dropwise. The reaction was warmed to 25° C. and stirred at this temperature for 1 h under a nitrogen atmosphere. Then the reaction mixture was diluted with water (200 mL) extracted with ethyl acetate (2×200 mL). Organic part was dried over sodium sulfate, filtered and concentrated in vacuum to give the crude compound which was further purified by column chromatography using silica gel (100 to 200 mesh) eluting with 0% to 10% ethyl acetate in hexanes to afford 1-(2-bromo-5-(trifluoromethyl)phenyl)ethanol (10.4 g, 98%) as a clear liquid. MS (ESI, Negative ion) m/z (M−1): 267.0. 1H NMR (400 MHz, DMSO) δ 7.87 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 5.68 (d, J=4.2 Hz, 1H), 5.03-4.94 (m, 1H), 1.32 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[OH-].[K+:32].O>C(O)(C)C.CCCCCCC>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][N-:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[K+:32]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCCCCCC
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
To 40.81 g losartan (chromatographic purity 98.73%) in 153 ml i-propanol, a mixture of 10 g potassium hydroxide, 5.1 ml water, and 100 ml i-propanol was added at a temperature of 38-40° C. to a pH of 10-11 during half an hour. Approximately 140 ml of the solvent (i-propanol/water mixture) were removed by distillation, and 92 ml n-heptane were added. It was stirred at room temperature until a white precipitate was formed. The precipitate was diluted with 54 ml n-heptane, filtered, washed with 70 ml n-heptane, and dried in vacuo at 50° C. to yield 38.4 g losartan potassium (yield: 86%, chromatographic purity: 99.67%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][C:23]=1[C:37]([OH:40])([CH3:39])[CH3:38].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:5]=[C:6]([O:8][CH3:9])[N:7]=2)=[CH:24][C:23]=1[C:37]([OH:40])([CH3:38])[CH3:39]
Reactant: CC(C)(O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2ccc(Cl)c(C(C)(C)O)c2)n1
Yield: 19.9 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (0.58 g), 2-[2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propan-2-ol (0.63 g), Cs2CO3 (1.36 g) and tetrakis(triphenylphosphine)palladium (0) (50 mg) in water (8 mL)/DME (32 mL) is heated at 90° C. for 16 h. The solution is poured into water and extracted with EtOAc (2×200 mL). The organic layer is dried over sodium sulfate, filtered, evaporated in vacuo. The residue is chromatographed on silica gel eluting with EtOAc to afford 2-(2-chloro-5-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-propan-2-ol (162 mg, Example 98). MS: 466 (M+H); 1H NMR (300 MHz, DMSO) □8.2 (m, 1H); 7.8, (d, 1H, J=0.3 Hz); 7.5-7.7 (m, 2H); 7.4 (d, 2H, J=0.4 Hz); 7.3 (m, 1H); 7.3 (s, 1H); 6.6 (s, 1H); 4.2 (s, 3H); 4 (s,3H); 3.8 (m, 2H); 3.05 (t, 2H); 1.55 (s, 6H). IC50=110 nM
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[F:17]>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[C:13]([C:2]2[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1cnc(N)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cnc(N)c(-c2ccc(F)c(F)c2)c1
Temperature: 100 °C

Procedure:
3-Bromo-5-methylpyridin-2-amine (0.5 g, 2.7 mmol), 3,4-difluorophenylboronic acid (0.5 g, 3.2 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (0.1 g, 0.1 mmol) were dissolved in a mixture of dioxane (10 mL) and 1M aqueous sodium carbonate solution (8 mL) under argon and the mixture was heated to 100° C. for 1 hour. The reaction was diluted with ethyl acetate, separated and the organic layer was washed with brine, dried with sodium sulfate, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 1:1) as eluent. The title compound was obtained as a light brown crystalline solid (0.6 g, quant.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1.CCN(CC)CC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[NH:17][CH2:18][CH2:19]2
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Nc1ccc2c(c1)CCN2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc2c(c1)CCN2

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (250 mg, 0.89 mmol), 2,3-dihydro-1H-indol-5-ylamine×2HCl (184 mg, 0.89 mmol) and Et3N (0.37 mL, 2.67 mmol) in N,N-dimethylformamide (DMF) (10 mL) is stirred for 4 days. The reaction mixture is concentrated in vacuo and the residue is triturated in H2O for 24 hours. The precipitate is filtered, washed with H2O and dried in vacuo to give 370 mg of the title compound as a brown solid. HRMS (ESI) m/z calcd for C18H14BrN3O2 (M+H)+1 384.03422. found: 384.03553. The compound is contains 29% of 4-(5-amino-2,3-dihydro-indol-1-ylmethylene)-6-bromo-4H-isoquinoline-1,3-dione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1.CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O>C1CCCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:27])=[O:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:16]=1
Reactant: OCc1cc(F)c(-c2ccc(OCc3ccccc3)cc2)c(F)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: O=C(O)c1cc(F)c(-c2ccc(OCc3ccccc3)cc2)c(F)c1

Procedure:
An oxidation was carried out with 107 mg of the product of Stage B, with Jones' reagent under the conditions as described in Example 2, Stage C to obtain 86 mg of the expected product with a Rf=0.06 cyclohexane/ethyl acetate 7/3).
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1.[NH:16]([CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[NH2:17].ClCC1C=NC=CC=1>C(O)C>[CH3:15][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:9])=[O:10])[N:16]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:17]=1
Reactant: NNCc1cccnc1
Reactant: CC(=O)Cc1nc2ccccc2c(=O)o1
Agent: ClCc1cccnc1
Solvent: CCO
Product: Cc1cc(Nc2ccccc2C(=O)O)n(Cc2cccnc2)n1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A solution in ethanol (50 mL) of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (11.2 g, 55.1 mmol) and 3-hydrazinomethylpyridine (7.44 g, 60.4 mmol) which was prepared from 3-chloromethylpyridine following the method described in Reference Example 2-2, was heated under reflux for 1 hour. The solution was cooled to room temperature, and the resulting crude crystals were collected by filtration. The crystals were washed with ethanol and air dried to give the title compound (11.3 g, 67% yield). mp: 180-183° C. (recrystallized from ethanol).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1>C(O)C.[Ni]>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: [Ni]
Solvent: CCO
Product: NCc1ccc(F)cc1C(F)(F)F
Reaction time: 2.5 h
Yield: 19.6 %

Procedure:
To a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (2.0 g) in ethanol (10.0 mL) was added Raney Ni (catalytic amount). The reaction mixture was subjected for hydrogenation in Parr apparatus under 50 psi for 2-3 h. The reaction mass filtered through celite and concentrated the filtrate to afford 0.400 g of the desired product. 1HNMR (CDCl3): δ 3.98 (s, 2H), 7.24 (t, J=9.0 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H); MS [M+H]+: 194.03.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.CS(O[CH2:16][CH2:17][CH2:18][N:19]1[C:27]([O:28]C)=[N:26][C:25]2[C:20]1=[N:21][C:22]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[N:23][C:24]=2[NH2:30])(=O)=O.[Cl-:36].[Na+].O>>[ClH:36].[ClH:36].[ClH:36].[NH2:30][C:24]1[N:23]=[C:22]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])[N:21]=[C:20]2[C:25]=1[NH:26][C:27](=[O:28])[N:19]2[CH2:18][CH2:17][CH2:16][NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: NCCCN1CCOCC1
Reactant: [Cl-]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCOS(C)(=O)=O)c2n1
Agent: [Na+]
Solvent: O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCCN3CCOCC3)c2n1
Product: Cl
Temperature: 28 °C
Reaction time: 10 h

Procedure:
To N-(3-aminopropyl)morpholine (86.90 g, 602.52 mmol) which was cooled to 3° C. was in several times added 3-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl methanesulfonate (amount corresponding to dried weight 15.00 g (40.17 mmol)) not to exceed to 20° C. After stirring at 28° C. for 10 hours, thereto was added 15% brine (160.00 g), and the mixture was extracted with a mixture of toluene (194.08 g) and THF (199.8 g). After removal of the organic solvent, concentrated hydrochloric acid (41.84 g) was added thereto, and the mixture was stirred at 25° C. for 3 hours. After removal by distillation of the solvent, to the residue was added methanol (118.65 g), followed by raising to 55° C. Isopropanol (353.25 g) was dropped thereto and the mixture was crystallized and further raised to 70° C. After one hour, the mixture was cooled to 20° C. The resulting crystal was filtered, washed and dried to give the subject compound (16.80 g, 77.5% by 2 steps). Purity: 99.70% (HPLC)
Reaction SMILES: CC(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:10]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:9]=1)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:23]([O:22][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OC(C)(C)C)cc(OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(OCc2ccccc2)c1
Yield: 88.5 %

Procedure:
A solution of 28 g of 3-(octadecyloxy)-5-(phenylmethoxy)phenylcarbamic aciddimethylethyl ester and 76 ml of trifluoroacetic acid in 700 ml of methylene chloride was kept at room temperature for 2 hours. The solution was concentrated at reduced pressure and the residue was extracted with methylene chloride. The extract was washed with NaHCO3 solution, dried and concentrated to a solid which was dissolved in 1000 ml of ether.The solution was treated with 21 ml of 3N HCl in ethanol. The hydrochloridesalt which precipitated was filtered and treated with excess NaHCO3 toliberate the free base which was extracted with methylene chloride. The dried extract was concentrated at reduced pressure to give 20.4 g (89% yield, mp 57°-59°) of 3-(octadecyloxy)-5-(phenylmethoxy)benzenamine.