Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCCCCOc1ccc(-c2ccccc2)cc1
Yield: 94.7 %

Procedure:
To a 4 L three-necked round bottom flask fitted with a mechanical stirrer and a condenser were added 125.0 g of 4-hydroxybiphenyl (0.734 mol), 154.5 g of 6-bromo-1-hexanol (0.853 mol), 690 g of potassium carbonate, and 2500 ml of acetone. The reaction mixture was stirred and heated at reflux for 4 days and then filtered. The acetone was removed on a rotary evaporator, the residue was recrystallized from a mixture of ethyl acetate and hexanes to afford 188 g of white crystals (95%): mp 92–94° C.; 1H-NMR (CDCl3) δ (ppm) 1.30–1.84 (m, 8H), 3.65 (t, 2H), 3.99 (t, 2H), 6.98 (d, 2H), 7.32–7.56 (m, 7H).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH2:8][CH2:9][N:10]2[C:14](=[CH:15][C:16](SC3C=CC=CC=3)=[O:17])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:3])[CH3:2].[CH3:25][NH:26][CH3:27]>>[CH3:25][N:26]([CH3:27])[C:16](=[O:17])[CH:15]=[C:14]1[CH2:13][S:12][C:11]2=[C:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:8][CH2:9][N:10]12
Reactant: CC(C)OC(=O)C1=C2SCC(=CC(=O)Sc3ccccc3)N2CC1
Reactant: CNC
Product: CC(C)OC(=O)C1=C2SCC(=CC(=O)N(C)C)N2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 g of S-phenyl (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo[2,1-b]thiazol-3-ylidene)thioacetate was suspended in 10 ml of a 40% aqueous solution of dimethylamine and stirred at room temperature for 1 hour. After distilling off the excessive dimethylamine, the obtained crude crystals were recrystallized from isopropyl alcohol. Thus 0.7 g of the title compound was obtained as crystals.
Reaction SMILES: [C:1]1([P:7](Cl)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([Cl:26])([Cl:25])[Cl:24])[CH:20]=[CH:19][N:18]=1.Cl>>[C:1]1([P:7]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([Cl:25])([Cl:24])[Cl:26])[CH:20]=[CH:19][N:18]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: Nc1cc(C(Cl)(Cl)Cl)ccn1
Agent: Cl
Product: O=P(Nc1cc(C(Cl)(Cl)Cl)ccn1)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 56.7 %

Procedure:
6.2 ml (0.03 mol) of diphenylphosphoryl chloride were added to 6.3 g (0.03 mol) of 2-amino -4trichloromethylpyridine and 60 ml of pryidine at 0° C. After 12 hours at 25° C., the reaction mixture was added to 200 ml of 5% strength hydrochloric acid. The colorless precipitate formed was isolated. 7.0 g (53%) of the desired product were obtained. Mp.: 134°-136° C.; Active Ingredient Example 1.016
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[OH-].[NH4+:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH2:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a rapidly stirred solution of saturated aqueous ammonium hydroxide (50 mL) and ice in a 0 deg. C. bath was added 2,4-dichloro-5-nitropyrimidine (6.0 g, 31 mmol) in portions. The resulting yellow foamy mixture was allowed to stir for 30 min, at which point the precipitate was isolated by filtration. The solid was rinsed several times with ice-cold water and once with ice cold ethanol to give a peach-colored solid. The crude solid was purified by adsorption onto 18 g silica gel, followed by silica gel chromatography, eluting with 0-20% MeOH/dichloromethane to give 2-chloro-5-nitropyrimidin-4-amine as an off-white solid. MS (ES+): 175 (M+H)+; Calc. for C4H3ClN4O2=174.55.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:22]=[CH:21][C:15]([C:16](OCC)=[O:17])=[CH:14][CH:13]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:22]=[CH:21][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(OCc2cc3ccccc3o2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(OCc2cc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
Compound 93 (300 mg, 1.01 mmol) was dissolved in THF (15 mL) and LiAlH4 (38 mg, 1.01 mmol) was added portionwise, with vigorous stirring. The suspension was stirred at room temperature for 1 h. THF was evaporated off in-vacuo. The crude residue was taken up in EtOAc and washed with water, brine and dried (MgSO4). EtOAc was evaporated off in-vacuo to obtain (4-(benzofuran-2-ylmethoxy)phenyl)methanol (150 mg, 0.59 mmol), as a crude product. This was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2C=O)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([OH:25])=[CH:11][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1Oc1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
The crude aldehyde from step 1 (23.3 g, 0.10 mmol) was dissolved in dichloromethane (500 mL), and m-chloroperbenzoic acid (70%, 50.0 g, 0.20 mmol) and sodium bicarbonate (25.2 g, 0.30 mmol) were added. The resulting heterogeneous mixture was stirred and heated under reflux for 2 h and then quenched with an aqueous solution of sodium sulfite (0.5 M, 500 mL). After stirring at 25° C. for 30 min, the organic phase was separated and the aqueouse phase was extracted with dichloromethane (2×200 mL). The combined organic phases were washed with a saturated solution of sodium bicarbonate (2×200 mL), dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel, eluting with an 8:2 mixture of hexane and ethyl acetate to give the title phenol.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=[S:32]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(NNc1ccccc1C(F)(F)F)c1c(F)cccc1F
Product: Fc1cccc(F)c1C(=S)NNc1ccccc1C(F)(F)F

Procedure:
Analogously to the procedure described in Example 58, by treating 2,6-difluoro-N'-(α,α,α-trifluoro-o-tolyl)-benzhydrazide (see Examples 35 and 36) with Lawesson reagent there is produced 2,6-difluoro-N'-(α,α,α-trifluoro-o-tolyl)-thiobenzhydrazide which is required as the starting material in Example 18.
Reaction SMILES: Cl.[S:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:4]=[N:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26].Cl>CN(C)C=O.O>[CH3:26][O:25][CH:24]([O:27][CH3:28])[CH2:23][CH2:22][N:11]1[CH:12]=[C:7]([C:5]2[CH:4]=[N:3][S:2][CH:6]=2)[C:8](=[O:14])[NH:9][C:10]1=[O:13]
Reactant: O=c1[nH]cc(-c2cnsc2)c(=O)[nH]1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2cnsc2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.44 %

Procedure:
5-(4-isothiazolyl)-2,4(1H,3H)-pyrimidinedione hydrochloride (Prep23, 300 mg, 1.036 mmol) was dissolved in N,N-Dimethylformamide (DMF) (4 ml) to give a pale yellow suspension. K2CO3 (215 mg, 1.554 mmol) was added ant the reaction mixture was stirred at room temperature for 1 h. 3-bromo-1,1-bis(methyloxy)propane (0.173 ml, 1.140 mmol) was added. Mixture was stirred at room temperature for 3 days, then diluted with water, acidified with diluted HCl until pH ˜5, and extracted with EtOAc. The organic phase was washed with water (3 times), brine, dried over Na2SO4, filtered and the solvent evaporated. The obtained residue was purified by flash chromatography eluting with cyclohexane/EtOAc 1:1. Obtained 60 mg (13.44% yield) of a 9:1 mixture of the title compound and the corresponding bis alkylated derivative.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:18](OS(C(F)(F)F)(=O)=O)[CH3:19])[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].N12CCCN=C1CCCCC2>ClCCl>[CH3:1][O:2][C:3]([C:5]1([CH:18]=[CH2:19])[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(C)OS(=O)(=O)C(F)(F)F)CN(C(=O)OC(C)(C)C)CCO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CC1(C(=O)OC)CN(C(=O)OC(C)(C)C)CCO1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
A warm (35° C.) solution of 2-(1-trifluoromethanesulfonyloxy-ethyl)-morpholine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (1.384 g, 3.284 mmol) in dichloromethane (40 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (2.5 mL, 16.422 mmol). After stirring at 35° C. for 2 h, the reaction was cooled to 0° C. and quenched with hydrochloric acid (1 M, 50 mL). The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo to provide the title compound as an orange oil which was used without further purification in the next step. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 3.13-3.29 (m, 2H), 3.60-3.73 (m, 1H), 3.79 (s, 3H), 3.83-3.92 (m, 2H), 4.24 (d, J=13.1 Hz, 1H), 5.37 (d, J=10.9 Hz, 1H), 5.55 (d, J=17.4 Hz, 1H), 5.84 (dd, J=17.4, 10.9 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O=O>[CH2:12]([S:6][C:3]([CH3:5])([CH3:4])[C@H:2]([C:7]([OH:9])=[O:8])[NH2:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(SCc1ccccc1)[C@@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
D-Penicillamine (5)(140 9: 938 mmol) and sodium hydroxide (43 g; 938 mmol) were dissolved in a mixture of oxygen-free water (670 ml) and oxygen-free isopropanol (830 ml) at 0° C. To the resultant solution, benzyl bromide (208.6 g; 1219 mmol) was dropwise added, and the mixture was stirred at room temperature overnight. The reaction mixture was made neutral with 2N aqueous sodium hydroxide, stirred at -20° C. to precipitate crystals, which were collected by filtration to give Compound (6) (157.3 g; yield 70%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH:16]([CH3:18])[CH3:17]>O>[CH:3]1([CH2:2][O:1][CH:16]([CH3:18])[CH3:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CC(C)Br
Reactant: OCC1CCCCCCCCCCC1
Solvent: O
Product: CC(C)OCC1CCCCCCCCCCC1

Procedure:
According to the disclosure of Example 1, 99 g of hydroxymethylcyclododecane was first converted into the sodium alcoholate. 74 g (0.6 mol) of 2-bromopropane was added dropwise to the boiling suspension, and then the mixture was heated for 30 hours under reflux. The reaction mixture was poured into water, the organic phase was washed with water, dried over Na2SO4, and then distilled.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=1)#[N:18]>>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Reactant: N#Cc1ccc(CO)cc1
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C#N)cc2)c1

Procedure:
The title compound was prepared from methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and (4-cyanophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C18H14N4O3, 335; Found, 335.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([C:16]1[O:17][C:18]2[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=2[C:20]=1[CH:21]([OH:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:13][CH2:14][CH3:15].ClCCl>C(OCC)C>[CH2:12]([C:16]1[O:17][C:18]2[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=2[C:20]=1[C:21]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)=[O:35])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1oc2ccccc2c1C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(-c2ccc(O)cc2)cc1
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Pyridinium chlorochromate (1.74 g, 8.06 mmol), was added into a mixture of 4'-[(2-butyl-benzofuran-3-yl)-hydroxy-methyl]-biphenyl-4-ol (2.0 g, 5.37 mmol), and dichloromethane (20 mL). The reaction mixture was stirred for 1 hour, diluted with ethyl ether and filtered through a florisil pad. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexanes/EtOAc 3:1) gave a yellow solid(1.1 g): MS m/e 370 (M+);
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:14][C:11]2[CH:10]=[CH:9][C:8]([C@H:5]3[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)=[CH:18][CH:19]=1
Reactant: Oc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc([C@H]3CC[C@H](O)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a suspension of p-(trans-4-hydroxycyclohexyl)phenol (67.62 mmol, 13.00 g) in acetone (400 mL) is added 1-bromomethyl-4-methoxybenzene (74.38 mmol, 10.57 mL) and potassium carbonate (81.14 mmol, 11.33 g). The mixture is stirred for 64 h at room temperature and filtered. The filtrate is concentrated and recrystallized from CH2Cl2 (100 mL) to give the title compound (15.1 g, 71%) as a white solid. 1H NMR (400 MHz, CDCl3): 1.34-1.49 (m, 4H), 1.87-1.90 (m, 2H), 2.02-2.07 (m, 2H), 2.38-2.45 (m, 1H), 3.61-3.68 (m, 1H), 3.79 (s, 3H), 4.93 (s, 2H), 6.88 (d, 2H, J=8.8 Hz), 6.89 (d, 2H, J=8.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 7.32 (d, 2H, J=8.8 Hz).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCOC(=O)Cl
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: CCCCCOC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)-phenyl)urea hydrochloride and pentyl chloroformate by using the same method as in Example 107.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(O)(=O)C.[CH3:25][C:26]1[N:27]=[CH:28][S:29][C:30]=1[CH2:31][NH:32][CH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:32]([CH2:31][C:30]3[S:29][CH:28]=[N:27][C:26]=3[CH3:25])[CH2:33][CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Reactant: Cc1ncsc1CNCCc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)Cc3scnc3C)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.423 g) and acetic acid (0.14 g) were added to a 1,2-dichloroethane solution (10 ml) of N-(4-methylthiazol-5-ylmethyl)-N-(2-pyridin-3-ylethyl)amine (0.36 g). The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.48 g) was added, and the mixture was stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→50:50). The purified product was condensed under reduced pressure. The residue was washed with diethyl ether, and dried to give the title compound (0.37 g) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCCCCCOc1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 77.9 %

Procedure:
1-Bromo-3-chloro-4-hydroxybenzene (0.50 g, 2.41 mmol) was dissolved in acetonitrile (20 mL) and stirred at rt. Potassium carbonate (0.47 g, 3.37 mmol) and iodooctane (0.57 mL, 3.13 mmol) were added and the reaction was heated to 80° C. for 4 h. The reaction was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. Silica gel chromatography eluting with 1% ethyl acetate/hexane yielded 0.6 g of product: ESI-MS 317.0 (M+H).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9]1(C)[CH:14]=CC(S(O)(=O)=O)=C[CH:10]=1.COC(OC)(C)C>>[CH3:10][C:9]1([CH3:14])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Oc1ccccc1O
Solvent: COC(C)(C)OC
Product: CC1(C)Oc2ccccc2O1

Procedure:
The preparation of the 2-substituted-1,3-benzodioxole starting compounds is known to the art. For example, catechol is subjected to dehydration and the resulting mixture is treated with para-toluenesulfonic acid. Thereafter, dimethoxypropane or another dialkoxyalkane within the ambit of this invention is added to this mixture and the final reaction mix is heated to distill off methanol and drive to reaction to completion. The resulting product is isolated as 2,2-dimethyl-1,3-benzodioxole. It is also possible to condense catechol with a ketone, using P2O5, directly, employing a dehydrating agent to drive off water and to thereby form the desired dioxole starting product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 80.6 %

Procedure:
Following the general method as outlined in Example 89, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 370 mg; 0.80 mmol) and propionyl chloride (179 mg; 1.93 mmol), 310 mg (80%) of the title compound was obtained as a yellow oil, which was used directly without further purification.
Reaction SMILES: [C:1]([CH:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)#[N:2].[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[C:1]([C:3]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)([C:12]#[N:13])[CH3:16])#[N:2]
Reactant: COc1ccc(C(C#N)C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(C#N)C#N)cc1
Reaction time: 22 h
Yield: 268.5 %

Procedure:
To a mixture of Compound 35 (1.0 g, 6.0 mmol) and NaH (280 mg, 7.0 mmol) in DMF (12 ml) was added MeI (1.0 g, 7.0 mmol) at room temperature. After the mixture was stirred for 22 hours, the mixture was poured into H2O (30 ml), and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated to give a yellow oil (3 g), which was purified by a column chromatography on silica gel to give Compound 35 as a colorless solid (900 mg, 81%).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[Cl:19][CH2:20][C:21]1[C:22]([NH:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:19].[ClH:18].[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:33][CH2:34][C:35]([F:38])([F:36])[F:37])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: COc1ccc2nc(NCC(F)(F)F)c(CCl)cc2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCC(F)(F)F)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 24 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (342 mg, 1.47 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride SLA 41070 (500 mg, 1.47 mmol) at RT followed by a 2 N aq. LiOH solution (1.47 mL, 2.94 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 97:3) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation and drying, 233 mg of 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (3.05 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 45 as a yellow solid (200 mg, 24% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5]([O:10]C)[N:4]=1.[CH3:12]COCC>>[NH2:9][C:7]1[NH:8][CH:3]([S:2][CH3:1])[N:4]([CH3:12])[C:5](=[O:10])[CH:6]=1
Reactant: COc1cc(N)nc(SC)n1
Reactant: CCOCC
Product: CSC1NC(N)=CC(=O)N1C
Yield: 60 %

Procedure:
The compound soluble in ether was 2-methylmercapto-4-amino-6-methoxypyrimidine. This compound was removed from the solid residue by repeated washings with ether and filtering out of the solid residue. The solid residue was then recrystallized from alcohol to give 43 as slender prisms (yield=60%, m.p. 255° C.).