Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH3-]C#N.[Na+].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1>C(O)(=O)C>[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)NCC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
NaCNBH3 (11.49 g; 0.04 equiv.) was added at 0° C., over a period of 10 minutes, to a solution of methyl 1H-indole-6-carboxylate (8 g; 1 equiv.) in acetic acid (80 ml). The reaction mixture was stirred at 0° C. for 20 minutes and then warmed to room temperature and stirred for 1 hour at room temperature. When the conversion was complete, the acetic acid was distilled off under reduced pressure and the resulting residue was dissolved in dichloromethane. The resulting phases were separated. The organic phase was washed with 1N sodium hydroxide solution and dried over sodium sulfate. After removal of the solvent under reduced pressure, purification was carried out by column chromatography (silica gel, 10-15% ethyl acetate/hexane). Methyl indoline-6-carboxylate (6 g; 75%) was obtained in the form of a solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:29][C:28]1[C:23]([N:17]2[CH2:18][CH2:19][C:11]3[C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:4][CH:5]=4)=[N:15][CH:14]=[N:13][C:12]=3[CH2:16]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cn1
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cn1
Temperature: 150 °C
Yield: 27.9 %

Procedure:
N-(6-(Trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (130 mg, 0.44 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (98 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.66 mmol). The mixture was heated at 150° C. in a Personal Chemistry microwave for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate: hexane (0-100%) to give the desired compound as an off-white powder (50 mg, 28%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([SH:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:21])=[N:6][CH:7]=1.[NH2:22][C:23]1[C:24]([Cl:29])=[N:25][CH:26]=[N:27][CH:28]=1>>[ClH:29].[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20][C:24]3[C:23]([NH2:22])=[CH:28][N:27]=[CH:26][N:25]=3)=[CH:10][C:9]=2[F:21])=[N:6][CH:7]=1
Reactant: Nc1cncnc1Cl
Reactant: Nc1cnc(-c2ccc(-c3ccccc3S)cc2F)cn1
Product: Cl
Product: Nc1cnc(-c2ccc(-c3ccccc3Sc3ncncc3N)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 213 utilizing 4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and 5-amino-4-chloropyrimidine. MS (ESI): mass calcd. for C20H15FN6S, 390.11; m/z found, 391.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35-8.30 (m, 1H), 8.22 (s, 1H), 8.02 (d, J=1.4, 1H), 7.90 (s, 1H), 7.80 (m, 1H), 7.59-7.54 (m, 2H), 7.52-7.44 (m, 2H), 7.24 (dd, J=6.5, 1.6, 1H), 7.21 (m, 1H).
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:8]([NH:10][NH2:11])=[O:9])C(C)C.[CH2:16]([N:18](CC)[C:19]1[CH:20]=C(C=C(C)N=1)C(O)=O)[CH3:17]>>[CH2:16]([N:18]([CH2:19][CH3:20])[C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:8]([NH:10][NH2:11])=[O:9])[CH3:17]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: Cc1cc(C(=O)NN)cc(CC(C)C)n1
Product: CCN(CC)c1cc(C(=O)NN)cc(C)n1

Procedure:
The title compound is prepared in analogy to 2-isobutyl-6-methyl-isonicotinic acid hydrazide from 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=0.47 min, [M+1]+=223.14.
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13](=[O:35])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=O)[CH3:22])=[C:16]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[CH:15]=1>C(O)C>[CH3:22][C:21]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C:16]2[CH:15]=[C:14]([C:13](=[O:35])[NH:12][CH2:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=3)[CH:19]=[CH:18][C:17]=2[N:20]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc2c(c1)OCO2
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Acetic acid (2 ml) and ethanol (5 ml) are added to an N-(2-pyridylmethyl)-4-acetylamino-3-(3,4-methylenedioxybenzylamino)benzamide (0.490 g) and the solution is stirred for eight hours at 70° C. The residue obtained by reduced pressure condensation is purified using silica gel column chromatography (eluate: ethyl acetate/methanol=9/1), and crystallization is performed in ethyl acetate. The crystals are separated through filtration, dried and thus, 2-methyl-1-(3,4-methylenedioxybenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.270 g) is obtained. 1H-NMR (CDCl3, δ): 2.59 (3H, s), 4.78 (2H, d, J=4.8 Hz), 5.28 (2H, s), 5.93 (2H, s), 6.51 (1H, d, J=1.6 Hz), 6.55 (1H, dd, J=1.4 and 7.9 Hz), 6.72 (2H, d, J=8.0 Hz), 7.22 (1H, dd, J=6.7 and 5.0 Hz), 7.34 (1H, d, J=7.7 Hz), 7.62 (1H, br t), 7.67-7.75 (3H, m), 7.96 (1H, d, J=1.1 Hz), 8.58 (1H, d, J=4.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:21]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:19])[N:10]=1.C(N)CCC.O>CO>[NH2:21][C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([O:8][C:9]2[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[N:10]=2)=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)nn(C)c1=O
Solvent: CCCCN
Solvent: O
Solvent: CO
Product: CC(C)c1cc(Oc2c(Cl)cc(N)cc2Cl)nn(C)c1=O
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A mixture of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-isoindole-1,3-dione (66) (64 g, 139.6 mmol) in methanol (500 mL) was treated with butylamine (34.67 mL, 349 mmol). The mixture was heated to reflux for 1.5 h. At this time, the reaction was cooled to room temperature and treated dropwise with water (384 mL). The resulting solids were collected by filtration, washed with a 1:1 solution of methanol/water (180 mL) followed by water (250 mL) and dried under vacuum to afford 6-(4-amino-2,6-dichloro-phenoxy)-4-isopropyl-2-methyl-2H-pyridazin-3-one (67) (34.12 g, 74.4%) as an off-white solid; ES(+)-LRMS for C14H15Cl2N3O2 (M+H)+ at m/z=328. Exact Mass=327.0541; Molecular Weight=328.20.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([S:10][CH3:11])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12](Cl)(Cl)=[O:13].[CH3:16][NH:17][CH3:18]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:18])[C:12]([N:7]1[C:8]([S:10][CH3:11])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:13]
Reactant: CNC
Reactant: O=C(Cl)Cl
Reactant: CSc1nnc(C(C)(C)C)[nH]1
Solvent: Cc1ccccc1
Product: CSc1nc(C(C)(C)C)nn1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 5.0 g (0.029 m) of 3-tert.butyl-5-methylthio-1,2,4-4H-triazole in toluene (100 ml) was added 50 ml of a toluene solution of phosgene (12%) and the reaction was heated to reflux for 2 hrs. After cooling, an excess of aqueous dimethyl amine was added and, after stirring at room temperature for 1 hr. the organic phase was washed with dilute hydrochloric acid, then with water and was then dried over anhydrous sodium sulfate. The toluene was evaporated to near dryness at reduced pressure and the residue was crystallized from hexane. Filtration gave 6.1 g (87%) of 1-dimethylcarbamyl-3-tert.butyl-5-methylthio-1,2,4-1H-triazole, MP 51°-53° C. Spectral properties agree with the structure as represented above:
Reaction SMILES: [C:1]1(OC(=O)CCC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:13].[K+].[O:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>CO>[C:1]1([CH:18]([CH2:17][CH3:16])[C:19]([OH:15])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: CCCC(=O)Oc1ccccc1
Agent: [K+]
Solvent: CO
Product: CCC(C(=O)O)c1ccccc1

Procedure:
Methyl 3,3-bis(ethoxycarbonyl)-4-[2',5'-dimethoxy-4'-(4"-methoxy-3"-phthalido)] phenylbutyrate III) (25 g., 0.046 mole) is taken up in tetrahydrofuran (200 ml.) and methanol (200 ml.); an aqueous solution of potassium hydroxide (3.35 g., 0.060 mole, 200 ml.) is added thereto. The mixture is heated under reflux for 4 days and the solvent substantially removed thereafter by evaporation under reduced pressure. The residue is acidified with dilute aqueous hydrochloric acid (1 N, 100 ml.) and extracted with methylenechloride (300 ml.) the organic phase is washed with water (100 ml.), dried over anhydrous magnesium sulfate, filtered, and the solvent removed from the filtrate under reduced pressure to yield 3,3-Bis(ethoxycarbonyl)-4-[2',5'-dimethoxy-4'-(4"-methoxy-3"-phthalido)] phenylbutyric acid, (IV) m.p. 105°-109° C., I.R. (Nujol), 2600, 2800 (broad for CO2H), 1750 (CO of the lactone), 1730 (CO of the ester), 1698 (CO of the CO2H) cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[C:18]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[CH2:19]1>O1CCCC1>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:18]([CH2:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[O:29])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2ccc(NC(=O)Cc3ccccc3C(=O)O)cc2Cl)C1=O
Yield: 58.5 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step C, using 4.0 grams (0.016 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 2.6 grams (0.016 mole) of homophthalic anhydride in 150 mL of tetrahydrofuran. The reaction mixture was concentrated under reduced pressure to a residual oil. The oil was dissolved in acetone, and petroleum ether was added. The resultant solid was collected by filtration and was recrystallized from acetone/water to yield 3.9 grams of 2-[[2-chloro-4-[(2-carboxyphenylmethyl)carbonylamino]phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 194°-196° C.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.O.[F:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>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.O>[F:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccncc1F
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: O
Solvent: COCCOC
Product: CN(Cc1cc(-c2ccncc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (215 mg), (3-fluoropyridin-4-yl)boronic acid hydrate (120 mg), sodium hydrogencarbonate (126 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 80° C. for 3 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow oil (yield 60 mg, 27%).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:15]([Sn:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11].[CH2:24]([Sn+2:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: O=C(O)CCCCCCCCC(=O)O
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Product: CCCCCCCC[Sn+2]CCCCCCCC
Product: O=C([O-])CCCCCCCCC(=O)[O-]

Procedure:
Sebacic acid and dioctyltin oxide are introduced into a screw drier in accordance with Example 4b. At the exit, dioctyltin sebacate (compound 7) is obtained as a white free-flowing powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:16]([F:31])([O:20][C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[C:17]([F:19])[F:18]>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:19][C:17]([F:18])([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:16]([F:31])[O:20][C:21]([F:29])([F:30])[C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)cc(C(=O)OC)c1
Temperature: 66 °C
Yield: 85.1 %

Procedure:
In a nitrogen purged dry box, THF (500 mL) and dimethyl 5-hydroxy-isophthalate (42 g, 0.20 mol) were added to an oven-dried round bottom reaction flask equipped with a stirrer and addition funnel. Potassium carbonate catalyst (6.955 g, 0.0504 mol) was added via the addition funnel to form a reaction mixture. Subsequently PPVE (79.8 g, 0.30 mol) was added via the addition funnel and the thus formed reaction mixture was heated to reflux at 66° C. for 16 hours. The catalyst was then removed from the resulting mixture via filtration through a bed of silica gel. The filtrate thus produced was concentrated under vacuum using a rotary evaporator, followed by vacuum distillation to give 81.04 g (85.12% yield) of the desired dimethyl 5-(1,1,2-trifluoro-2-(perfluoropropoxy)ethoxy)isophthalate (F10-iso) collected as the distillate.
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:11]([O:26][CH3:27])[CH:10]=1.COCCCOC1C=CC(C(CCCCC)CC(O)=O)=C(OC)C=1>CO.C(OCC)(=O)C>[CH3:1][S:2][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:11]([O:26][CH3:27])[CH:10]=1
Reactant: CCCCCC(CC(=O)OC)c1ccc(OCCCBr)cc1OC
Reactant: C[S-]
Agent: CCCCCC(CC(=O)O)c1ccc(OCCCOC)cc1OC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCC(CC(=O)OC)c1ccc(OCCCSC)cc1OC
Yield: 83 %

Procedure:
200 mg (2.85 mmol) of sodium thiomethoxide were added to a solution of 278 mg (0.69 mmol) of methyl 3-[4-(3-bromopropoxy)-2-methoxyphenyl]octanoate, which was a synthetic intermediate of the compound of Preparation 50A, in 6 ml of methanol, and the resulting mixture was stirred for 1 hour. The reaction mixture was then diluted with ethyl acetate, and the diluted solution was washed several times with water and once with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel, using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent, to give methyl 3-[4-(3-methylthiopropoxy)-2-methoxyphenyl]octanoate containing a small amount of impurities. Oxidation of the product and subsequent treatment of the reaction mixture were conducted in a similar manner to that described in Example 21 to give 230 mg of the sulfone derivative as an oily substance in a 83% yield over the two steps. This product was hydrolyzed in a similar manner to that described in Preparation 7 to give the title compound as an oily substance.
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12][OH:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22].CCOCC>C1C=CC=CC=1>[C:20]([O:13][CH2:12][CH2:11][O:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:23])[CH:21]=[CH2:22]
Reactant: CCCCCCCC(=O)OCCO
Reactant: C=CC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=CC(=O)OCCOC(=O)CCCCCCC
Reaction time: 2 h

Procedure:
A solution of 2-hydroxyethyl caprylate (HEC) (1 mol; 188.3 g) in pyridine (1.25 mol; 98.9 g; 100.7 ml) was added under continuous stirring at 5°-10° C. into a solution of freshly distilled acryloyl chloride (1.12 mol; 101.4 g) in benzene (300 ml). The mixture was further stirred for 2 hours at the reaction temperature, extracted with 800 ml of 2% hydrochloric acid, the emulsion formed was broken by addition of ether and the aqueous layer was repeatedly extracted with ether until the reaction on capryloyloxyethyl acrylate was negative. The combined ether extracts were washed with water, solution of potassium hydrogencarbonate (KHCO3), and water and dried with magnesium sulfate (MgSO4). Ether was removed by distillation under normal pressure and the product was distilled after addition of octylpyrocatechol as an inhibitor. The overall yield of raw product was 74.9%. The obtained fractions contained 60 to 93% of capryloyloxyethyl acrylate. The product with purity 99.8% was obtained by redistillation; b.p. 111° C./66.7 Pa. Elemental analysis for C13H22O4 theory: 64.44% C, 9.15% H; found 64.23% C; 9.41% H. The infrared and 13C-NMR spectra proved the expected structure.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](=[O:17])[CH3:16])=[CH:14][C:9]=2[N:8]=[C:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)[CH:3]([CH3:5])[CH3:4].[Br:26]Br.C(OCC)C>C(O)(=O)C>[ClH:1].[Br:26][CH2:16][C:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH2:2][CH:3]([CH3:4])[CH3:5])[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[N:8][C:9]=2[CH:14]=1)=[O:17]
Reactant: BrBr
Reactant: COc1cccc(-c2nc3cc(C(C)=O)ccc3n2CC(C)C)c1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cccc(-c2nc3cc(C(=O)CBr)ccc3n2CC(C)C)c1
Yield: 63.2 %

Procedure:
To a solution of 32.7 g (91.3 mM) of 1-[1-isobutyl-2-(3-methoxy phenyl)-1H-benzimidazol-5-yl]ethanone hydrochloride in 330 ml of acetic acid are added dropwise 4.7 ml (91.4 mM) of bromine. 100 ml of diethyl ether are then added and the crystalline product is filtered off. It is washed with diethyl ether and dried under vacuum to give 35 g of 2-bromo-1-[1-isobutyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]ethanone hydrochloride.
Reaction SMILES: I.[NH:2]=[C:3]1[NH:7][CH2:6][CH2:5][NH:4]1.[H-].[Li+].[H][H].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[N:20]=[C:21]=[O:22]>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[NH:20][C:21]([N:2]=[C:3]1[NH:7][CH2:6][CH2:5][NH:4]1)=[O:22]
Reactant: [H][H]
Reactant: Cc1cccc(Cl)c1N=C=O
Reactant: N=C1NCCN1
Agent: I
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1NC(=O)N=C1NCCN1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A solution of 10.65 grams (0.05 mole) of 2-iminoimidazolidine hydroiodide in dimethylformamide is added dropwise with stirring over a 15 minute period to a cooled to 5° C. suspension of 397.5 milligrams (0.05 mole) of lithium hydride in 50 milliliters of dry dimethylformamide under nitrogen whereupon hydrogen evolution is observed. While stirring is continued, the mixture is allowed to gradually warm to room temperature. Thereafter, the reaction mixture is cooled to 0°-5° C. and a solution of 5.0 grams (0.03 mole) of 2-chloro-6-methylphenyl isocyanate in 25 milliliters of dry dimethylformamide is added dropwise over a two hour period. After completion of the addition, the mixture is allowed to warm gradually to room temperature while the stirring under nitrogen atmosphere is continued overnight to obtain the desired N-(2-chloro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea product which remains in solution. The product is recovered from the reaction mixture by (a) adding the mixture to 300 milliliters of ice water with stirring, (b) lowering the pH below 2 with aqueous 10 percent hydrochloric acid to precipitate acid insoluble material (c) filtering, (d) basifying the filtrate to pH 8-9 with solid potassium carbonate, and (e) saturating the solution with solid sodium chloride to precipitate the desired N-(2-chloro-6-methylphenyl)-N'-(2-imidazolidinylidene)urea free base as a white solid. The product after washing thoroughly with water has a melting point of 169°-171° C.
Reaction SMILES: O1CCCC1.[C:6]1([CH3:23])[CH:11]=[CH:10][C:9]([O:12][C:13]2[S:17][C:16]([CH2:18][C:19](Cl)=[N:20][OH:21])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[C:6]1([CH3:23])[CH:11]=[CH:10][C:9]([O:12][C:13]2[S:17][C:16]([CH2:18][C:19]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=4)[O:21][N:20]=3)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: Cc1ccc(Oc2ccc(CC(Cl)=NO)s2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)s2)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 14 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (5-p-tolyloxy-thiophen-2-yl)acetohydroximoyl chloride (130 mg, 0.461 mmol) described in Manufacturing Example 48-1-5 and 3-ethynyl-pyridin-2,6-diamine (30.0 mg, 0.226 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (126 μL, 0.903 mmol), which was stirred for 7 hours at 60° C. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (12.0 mg, 14.0%).
Reaction SMILES: [H][H].[N:3]1[C:8]2[NH:9][CH:10]=[CH:11][C:7]=2[C:6]([N:12]2[CH2:16][CH2:15][C@@H:14]([N:17]([CH3:25])[C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH2:13]2)=[N:5][CH:4]=1>CO.[Pd]>[N:3]1[C:8]2[NH:9][CH:10]=[CH:11][C:7]=2[C:6]([N:12]2[CH2:16][CH2:15][C@@H:14]([N:17]([CH3:25])[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)[CH2:13]2)=[N:5][CH:4]=1
Reactant: [H][H]
Reactant: CN(c1ccnc(Cl)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: [Pd]
Solvent: CO
Product: CN(c1ccncn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
Under the atmosphere of hydrogen, a mixture of (R)—N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-chloro-N-methylpyrimidin-4-amine (30 mg, 0.09 mmol), Pd/C (10 wt. %, 20.0 mg) was stirred in 3.0 mL methanol at ambient temperature for 4 h. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by preparative TLC (DCM/MeOH=15/1) to give the title compound. MS (m/z): 296 (M+H)+.