Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:18][CH2:17][CH2:16][C@H:15]3[N:10]2[C:11](=[O:19])[CH2:12][CH:13]=[CH:14]3)[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:18][CH2:17][CH2:16][C@H:15]3[N:10]2[C:11](=[O:19])[CH2:12][CH2:13][CH2:14]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: O=C1CC=C[C@H]2CCC[C@@H](c3ccc(F)c(F)c3)N12
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@H]2CCC[C@@H](c3ccc(F)c(F)c3)N12
Yield: 71.1 %

Procedure:
Platinum oxide (48 mg) was added to a solution of (6S,9aR)-6-(3,4-difluorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (558 mg) in methanol (15 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 400 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Br[C:14]1[CH:22]=[CH:21][C:17]([N:18]([CH3:20])[CH3:19])=[CH:16][C:15]=1[O:23][CH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:14]1[CH:22]=[CH:21][C:17]([N:18]([CH3:19])[CH3:20])=[CH:16][C:15]=1[O:23][CH3:24])[OH:12]
Reactant: COc1cc(N(C)C)ccc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: COc1cc(N(C)C)ccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 42.1 %

Procedure:
With 1.97 g of 5-chloroisatin and 4.99 g of the compound obtained in Step 194-1 as starting materials, 1.52 g of the title compound (pale yellow amorphous) was obtained by a similar method to Step 21-1.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([S:19][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:17][CH:18]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: Nc1ccccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(Sc2ccccc2N)cc1
Yield: 89.7 %

Procedure:
The general procedure in example 39 was followed. 2-Iodoaniline (219 mg, 1.0 mmol), 4-tert-butylthiophenol (166 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 2-(4-tert-butylphenyl)sulfanylaniline (231 mg, 90% yield) as light yellow liquid. Column chromatographic solvent (hexane/ethyl acetate=20/1). Rf=0.4 (hexane/ethyl acetate=10/1). 1H NMR (CDCl3, 300 MHz) δ 7.42 (dd, 1 H, J=1.5 Hz, 7.5 Hz), 7.17-7.24 (m, 4 H), 7.00 (dt, 2 H, J=1.8 Hz, 8.4 Hz), 6.70-6.78 (m, 2 H), 4.28 (brs, 2 H), 1.26 (s, 9 H). 13C NMR (CDCl3, 75 MHz) δ 148.8, 148.7, 137.5, 133.3, 131.1, 126.5, 126.3, 118.9, 115.5, 115.0, 34.8, 31.7. IR (neat, cm−1) 3471, 3375, 3072, 3062, 3020, 2962, 2902, 2867. MS (EI) m/z (relative intensity) 257 (70), 242 (100). Anal. Cald. for C16H19NS, Cald. C, 74.66; H, 7.44. Found C, 74.64; H, 7.30.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:7]2[CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]([O:33]CC)=[O:32])[CH2:26][CH2:25]1)=[O:23].O.Cl>CO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:7]2[CH2:20][CH2:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][CH2:29]1)=[O:23]
Reactant: CCOC(=O)CN1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)[nH]c3ccc(Cl)cc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CN1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)[nH]c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Potassium hydroxide (320 mg) was added to a solution of ethyl 4-{3-[5-chloro-2-(4-chlorophenyl)-1H-indol-3-yl]-1-oxopropyl}piperazine-1-acetate (Example 109, 350 mg, 0.72 mmol) in methanol and the mixture was stirred at room temperature overnight. Water was added and the pH was adjusted to 7.0 with hydrochloric acid (2M). The mixture was extracted with ethyl acetate, the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was crystallised from ethyl acetate:methanol (99:1) to give the title compound as a pale solid (300 mg, 90%). 1H NMR (250 MHz, CD3OD) δ2.20-2.26 (2H, m), 2.92-2.97 (2H, m), 3.10-3.25 (4H, m), 3.55-3.60 (2H, m), 3.90-4.01 (4H, m), 7.10 (1H, dd, J 8.8, 2.0 Hz), 7.38 (1H, d, J 8.8 Hz), and 7.45-7.60 (5H, m). m/z (ES+) 460, 462 (M+1).
Reaction SMILES: C([Mg]Br)C.C1COCC1.I[C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1.C1(C)C=CC(S([C:30]#[N:31])(=O)=O)=CC=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:30]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1)#[N:31]
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CSc1nc(I)n2ccsc12
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1nc(C#N)n2ccsc12
Temperature: -5 °C
Yield: 49.1 %

Procedure:
A 1 M ethylmagnesium bromide/THF solution (2.0 ml) was added in an argon atmosphere at −40° C. to a solution of 405 mg of 5-iodo-7-methylthioimidazo[5,1-b]thiazole in 12 ml of dry THF. The mixture was stirred at the same temperature for 30 min. p-Toluenesulfonyl cyanide (372 mg) was added thereto. The temperature of the system was raised to −5° C. over a period of one hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was added thereto, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate:hexane=3:1:1) to give 131 mg of 5-cyano-7-methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:29][CH3:28])[CH:35]=3)[CH:7]=2)[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:11]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(Br)c2)c(F)c1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CSc1cccc(-c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccn2)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 27.3 %

Procedure:
5-(2-Bromo-pyridin-4-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 4 of Preparation 12, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (12.8 mg, cat.) and a 2N sodium carbonate solution (550.0 uL) were added to a mixed solvent of ethanol (550.0 uL) and 1,2-dimethoxyethane (1.2 mL). The reaction mixture was stirred at 85° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 15.0 mg of the titled compound as a white liquid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: OB(O)c1ccccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
400 mg (2.85 mmol) of ethyl 1H-pyrazole-4-carboxylate, 893 mg (5.71 mmol) of 2-chlorophenyl-boronic acid, 100 mg of 3 Å molecular sieve and 778 mg (4.28 mmol) of copper(II) acetate were initially charged in 2 ml of dichloromethane, and 461 μl (5.71 mmol) of pyridine were added. The mixture was stirred at RT for 20 h. For work-up, the mixture was filtered through a little kieselguhr, the filter residue was rinsed with about 10 ml of dichloromethane and the combined filtrates were concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 5:1). This gave 71 mg (10% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[CH:9]=[N:10][C:5]2=[C:4]([NH2:20])[CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][C:32](Cl)=[O:33].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[C:12]([CH3:19])=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])[CH:9]=[N:10][C:5]2=[C:4]([NH:20][C:32](=[O:33])[CH2:31][Cl:30])[CH:3]=1
Reactant: Cc1cc(C)c(-n2cnc3c(N)cc(C)nc32)c(C)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(C)c(-n2cnc3c(NC(=O)CCl)cc(C)nc32)c(C)c1
Temperature: 25 °C

Procedure:
Treat a solution of 5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-ylamine (0.05 g, 1.9 mmol), and N,N-diisopropylethylamine, (0.04 mL, 0.21 mmol) in 1,2-dichloroethane (5 mL) with chloroacetyl chloride (0.017 mL, 0.21 mmol). Heat the solution to reflux for 3 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate. Purify by preparative TLC (5% MeOH in CH2Cl2) to obtain the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(=O)(O)[O-].[Na+]>ClCCl>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:14](=[O:15])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1nccs1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)Oc1ccccc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred mixture of 2-aminothiazole (2 g, 20 mmol), pyridine (10 mL), and anhydrous dichloromethane (20 mL) was added phenyl chloroformate (3 mL, 24 mmol) under argon at 0° C. The mixture was stirred at the same temperature for 5 min and at rt overnight before saturated aqueous sodium bicarbonate solution (30 mL) was added slowly. After mixed with heptanes (30 mL), the mixture was stirred for 30 min. The solid was filtered, washed with water (3×3 mL) and then diethylether (3×3 mL), and dried to give phenyl thiazol-2-ylcarbamate (3.4 g, 15 mmol, 75% yield) as an off-white solid.
Reaction SMILES: C(OC([CH:11]([NH:21][CH3:22])[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=O)C1C=CC=CC=1>CO.[C].[Pd]>[CH3:22][NH:21][CH2:11][CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CNC(CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
In methanol (70 ml) was dissolved tert-butyl 4-[(benzyloxy)carbonyl]-4-methylaminobutyrate (6.06 g), and to the mixture was added 10% palladium-carbon (580 mg). Under hydrogen atmosphere, the mixture was stirred at room temperature for 3 hours, and 10% palladium-carbon was removed. The solvent was evaporated under reduced pressure to give tert-butyl 4-methylaminobutyrate (3.35 g, 98%).
Reaction SMILES: C([O:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([P:18]([O:22][CH3:23])([O:20][CH3:21])=[O:19])[F:17])=[CH:12][CH:11]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:21][O:20][P:18]([CH:16]([F:17])[C:13]1[CH:14]=[CH:15][C:10]([C:9]([OH:24])=[O:8])=[CH:11][CH:12]=1)([O:22][CH3:23])=[O:19]
Reactant: COP(=O)(OC)C(F)c1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COP(=O)(OC)C(F)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 4-[(dimethoxy-phosphoryl)-fluoro-methyl]-benzoic acid benzyl ester (76 mg, 0.216 mmol) in MeOH (0.21M) was added 20 mol % Pd on Carbon (0.043 mmol). The resulting mixture was degassed with alternating vacuum and hydrogen gas (4×), then stirred under a hydrogen atmosphere (1 atm) at ambient temperature for 18 hours. The reaction mixture was filtered through a nylon syringe filter and concentrated in vacuo to give the title compound: MS: cal'd 263 (MH+), exp 263 (MH+)
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]1[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]#[N:23])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:10]1[CH2:11][CH2:12]1)[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]#[N:23])[CH2:18][CH2:17]1)=[O:15])([CH3:1])([CH3:3])[CH3:4]
Reactant: N#CC1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
In a round-bottomed flask, Boc-D-cyclopropylglycine (1.80 g, 8.36 mmol) and piperidine-4-carbonitrile (1.2 g, 10.9 mmol) were dissolved in DMF (30 ml). HATU (3.5 g, 9.2 mmol) and N,N-diisopropylethylamine (2.3 ml, 13.2 mmol) were added and the yellow solution was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 2.72 g (95%) of [(R)-2-(4-cyanopiperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a light yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16]O)[C:11]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][Cl:21])[C:11]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1ccnc(CCl)c1C
Yield: 187.7 %

Procedure:
11.8 g (0.047 mol, 1.0 eq.) of 4-octyloxy-2-hydroxymethyl-3-methylpyridine was dissolved in 600 mL of chloroform, and 28.6 g (0.240 mol, 5.1 eq.) of thionyl chloride was added dropwise at 19 to 27° C. Subsequently, the mixture was heated to reflux for one hour and then concentrated, to obtain 23.8 g of 4-octyloxy-2-chloromethyl-3-methylpyridine as a black oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([CH3:29])[C:5]2[N:6]=[C:7]([C:11]3[N:12]([C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=4)[N:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=3)[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33]>C1COCC1>[Cl:1][C:2]1[CH:28]=[C:27]([CH3:29])[C:5]([NH:6][C:7]([C:11]2[N:12]([C:20]3[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[N:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)=[O:8])=[C:4]([C:9](=[O:10])[NH:30][CH2:31][CH:32]([OH:34])[CH3:33])[CH:3]=1
Reactant: CC(O)CN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NCC(C)O)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Yield: 89.5 %

Procedure:
A solution of 3.5 g (7.9 mmol) 6-chloro-2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-8-methylbenzo[d][1,3]oxazin-4-one and 2.5 g 1-amino-2-propanol in 50 ml THF is heated to a temperature of 60° C. for 2 hours. The solvent is then evaporated and the residue is treated with 50 ml hexane. After decantation of the hexane phase, the residue is crystallised in 10 ml isopropanol to give 3.65 g (89%) white crystals (m.p. 193-197° C.).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:35][NH:36][CH3:37].C1COCC1.O>C1COCC1>[CH:11]1([C:9]2[N:10]=[C:3]3[C:2]([N:36]([CH3:37])[CH3:35])=[N:7][CH:6]=[CH:5][N:4]3[C:8]=2[CH2:14][C:15]2[CH:34]=[CH:33][C:18]3/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=4[O:22][CH2:23][C:17]=3[CH:16]=2)[CH2:12][CH2:13]1
Reactant: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(Cl)nccn34)cc2COc2cc(F)ccc21
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(N(C)C)nccn34)cc2COc2cc(F)ccc21
Temperature: 100 °C
Yield: 87.3 %

Procedure:
[step 6] (E)-2-{8-[(8-chloro-2-cyclopropylimidazo[1,2-a]pyrazin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (0.2 g, 0.43 mmol) obtained in step 5 was dissolved in THF (1.4 mL), and 2 mol/L dimethylamine THF solution (1.7 mL, 3.4 mmol) was added. The mixture was stirred with heating at 100° C. for 1.5 hr in an Emrys Optimizer microwave synthesizer. Water was added to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0 v/v-50/50 v/v) to give the title compound (0.18 g, 87%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([OH:11])=[CH:5][C:4]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].O>CN(C)C=O>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][O:11][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([C:1]#[N:2])=[C:4]([N:12]=[CH:13][N:14]([CH3:15])[CH3:16])[CH:5]=1
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1O
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C#N)c(N=CN(C)C)cc1OCCCCCl
Yield: 796.2 %

Procedure:
A solution of N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide (3.29 g, 1.5 mmol) in dimethylformamide (33 ml) and potassium carbonate (4.14 g, 30 mmol) was reacted with 1-bromo 4-chorobutane (3.86 g, 2.5 mmol) at 60° C. for 2 hours. Water was added to the reaction mixture which was then extracted with ethyl acetate. The organic phase was dried (magnesium sulphate), concentrated and the residue was purified by chromatography on silica gel. Elution with dichloromethane:ethyl acetate (8:2) then increased polarity to (6:4) yielded N′-[5-(4-chlorobutoxy)-2-cyano-4-methoxyphenyl]-N,N-dimethylimidoformamide as a white solid (3.7 g, 80% yield):
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.[Cl:28][CH2:29][C:30]#[N:31]>O>[Cl:28][CH2:29][C:30]1[N:31]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[C:7]2[C:6](=[CH:23][C:22]([O:24][CH3:25])=[C:21]([O:26][CH3:27])[CH:20]=2)[N:5]=1
Reactant: N#CCCl
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Powdered aluminium chloride (6.7 g) was added to a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (8.0 g) and chloroacetonitrile (25 ml), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate. The solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (=10/1, v/v) gave 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinazoline (4.9 g, 52%) which was then recrystallized from acetone.
Reaction SMILES: II.[CH3:3][C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6]Br.[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)#[N:11]>C1COCC1>[CH3:3][C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][C:16]([C:15]1[CH:18]=[CH:19][C:12]([C:10]#[N:11])=[CH:13][CH:14]=1)=[O:17]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(C)(C)CCBr
Agent: II
Solvent: C1CCOC1
Product: CC(C)(C)CCC(=O)c1ccc(C#N)cc1
Temperature: -10 °C
Yield: 62.5 %

Procedure:
Keep Mg turnings (402 mg, 15.251 mmol) in vacuo in a two-neck round bottom flask for 2 h. Purge the flask with nitrogen/vacuo several times. Add a couple crystals of iodine, anhydrous THF (60 mL) and 3,3-dimethyl-bromobutane (0.8 mL, 5.59 mmol) slowly (exothermic reaction observed). Add dropwise the remaining 3,3-dimethyl-bromobutane (1.6 mL, 11.18 mmol) and reflux the mixture overnight. Add some additional 3,3-dimethyl-bromobutane (0.24 mL, 1.67 mmol) and reflux for 30 min. Cool the mixture to −10° C. and add a solution of 4-cyanobenzaldehyde (4 g, 30.502 mmol) in anhydrous THF (40 mL). Warm the flask gradually to room temperature overnight. Quench the mixture with 0.1M aqueous HCl (100 mL) and extract twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1) to give the desired intermediate as an oil (0.752 g, 23%).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]4[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=4)=[N:13][N:14]=[C:6]3[N:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]=2[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)=[N:13][N:14]=[C:6]3[N:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]=2[N:3]=1
Reactant: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCNC(=O)c3ccc(OC)cc3)nnc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCNC(=O)c3ccc(O)cc3)nnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]-4-methoxybenzamide (63.0 mg, 0.125 mmol) in CH2Cl2 (5 mL) at 0° C. was added a solution of Boron tribromide in CH2Cl2 (1.0 M, 1.3 mL, 1.3 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and then concentrated and purified by preparative LCMS to give the desired product. LCMS calculated for C20H23BrN7O3 (M+H): m/z=488.1, 490.1. Found: 488.0, 489.9.