Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:18][CH:19]([CH:27]=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:8][C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:30][NH2:31].C1COCC1>ClCCl>[C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:18][CH:19]([CH2:27][NH:31][CH3:30])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:8][C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C=O)C[C@H](NC(=O)Oc1ccccc1)C(=O)OC(C)(C)C
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCC(C[C@H](NC(=O)Oc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 78 %

Procedure:
A stirred solution of 40 (6.1 g, 14.9 mmol) in dichloromethane (50 mL) was treated with 2 N methylamine-THF solution (10 mL) at 0° C. overnight. After removal of solvents, the residual oil was dissolved in methanol (80 mL) and placed in an ice-bath. To the above solution was added sodium borohydride in small portions over 30 min. The reaction solution was kept at 0° C. for 1 hour, and solvent was then evaporated. The residue was worked up with brine and dichloromethane. After separation, the organic phase was dried over anhydrous MgSO4, rotary evaporated and dried in vacuum. The crude amine 41 (5.4 g, 78%) was obtained as a light yellow glassy solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[N:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1>>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccncc1
Reactant: Fc1ccc(Br)cn1
Product: Fc1ccc(-c2ccncc2)cn1

Procedure:
Prepared from 5-bromo-2-fluoropyridine (881 mg, 5.00 mmol) and pyridin-4-ylboronic acid (979 mg, 7.96 mmol) according to Method K, except the product was purified by silica gel chromatography (10% ethanol in ethyl acetate, Rf=0.32) instead of preparative HPLC: 1H NMR (300 MHz, chloroform-D) δ ppm 7.08 (dd, J=8.5, 3.0 Hz, 1H), 7.48-7.50 (m, 2.14), 8.01-8.07 (m, 1H), 8.51 (d, J=2.7 Hz, 1H), 8.72-8.74 (m, 2H). MS (DCI/NH3) m/z=175 (M+H)+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].CN(C=O)C.[H-].[Na+].Br[CH2:17][CH:18]([CH3:20])[CH3:19]>CCOC(C)=O>[CH2:17]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CBr
Reactant: Oc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COc1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A 1 L 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with resorcinol (20.0 g, 182 mmol) and DMF (400 mL). To the resultant solution was added NaH (4.82 g, 200 mmol) in two portions, 10 min apart. The mixture stirred at rt 30 min. 1-Bromo-2-methylpropane (37.4 g, 273 mmol) was then added, and the mixture was heated at 80° C. overnight. The mixture was cooled, diluted with EtOAc (300 mL), and washed with H2O (2×250 mL). The aqueous phases were back-extracted with EtOAc (2×100 mL). The combined organic phases were then diluted with hexanes (500 mL) and washed with half-saturated aqueous NaHCO3 (6×200 mL). The solution was filtered through phase separation paper and concentrated in vacuo to give 13.4 g of 71 as a yellow oil containing 27% dialkylated material as determined by HPLC. The substance was carried on as is. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 68% with a retention time of 3.9 min and 27% dialkylated material with a retention time of 12.0 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[O:36]1[CH2:41][CH2:40]OCC1>C(OCC)(=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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:10]1[CH:9]=[CH:14][CH:13]=[C:40]([CH:41]=[O:36])[CH:11]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cccc(C=O)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 3-formalphenylboronic acid (82.5 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(3-formyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[Cl:29])[NH2:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([Cl:29])=[C:22]([Cl:21])[CH:23]=1)=[O:10]
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cccnc1Oc1cccc(C(F)(F)F)c1

Procedure:
In the manner as in Example 1, 2.75 grams (0.009 mole) of 2(3-trifluoromethylphenoxy)nicotinoyl chloride, 1.5 grams (0.009 mole) 3,4-dichloroaniline, 0.9 grams (0.009 mole) triethylamine and 125 milliliters toluene were combined to yield 2.3 grams (59.8% of theoretical yield) of the desired product, a waxy solid. The structure was confirmed by mass spectrometry.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C=O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:10][CH2:11][N:12]([CH3:28])[CH2:13][CH2:14]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(NC(=O)OCc2ccccc2)ccc1C1CCNCC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COc1cc(NC(=O)OCc2ccccc2)ccc1C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a mixture of benzyl (3-methoxy-4-piperidin-4-ylphenyl)carbamate (Preparation Example 455) (1.52 g) and 1,2-dichloroethane (70 mL), formalin (3.62 mL) and sodium triacetoxyborohydride (1.42 g) were added and stirred overnight at room temperature. After addition of water and saturated aqueous sodium hydrogen carbonate, the reaction liquid was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=100:0:0 to 10:1:0.1) to give benzyl [3-methoxy-4-(1-methylpiperidin-4-yl)phenyl]carbamate (1.26 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[S:17][C:15]=2[N:16]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d ]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:7][CH2:6][CH:5]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][CH2:3]1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.ClCCl>[N:21]([CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:20])([F:1])[CH2:3][CH2:4]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(F)(F)CC2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CCC(F)(F)CC1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of toluene-4-sulfonic acid 4,4-difluorocyclohexylmethyl ester (100 mg, 0.33 mmol)) in N,N-Dimethylformamide (0.5 mL) was added sodium azide (32 mg, 0.49 mmol). The reaction mixture was stirred at 90° C. for 90 min, cooled to room temperature and diluted with dichloromethane (5 mL). The organic layer was washed with water (2×5 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[CH:11]1([C:14]2[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:8][C:7]1[C:2]([NH:19][C:16]2[CH:15]=[C:14]([CH:11]3[CH2:13][CH2:12]3)[NH:18][N:17]=2)=[N:3][C:4]([Cl:10])=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Clc1cc(Cl)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Temperature: 25 °C
Yield: 12.8 %

Procedure:
A solution of 2,3,5,6-tetrachloropyridine (0.20 g, 0.9 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (0.20 g, 1.8 mmol), and triethylamine (0.10 g, 1.4 mmol) in NMP (2 ml) was heated in a microwave at 200° C. for 30 min. The reaction was cooled to 25° C., quenched with water (10 ml), and extracted with MTBE (4×30 ml). The combined organic fractions were then dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=50:1) to give the title compound (0.035 g, 12%). MS: Calcd.: 303. Found: [M+H]+ 303.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.Br[CH2:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][CH2:26][O:25]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][CH2:26][O:25]1
Reactant: BrCCC1OCCCO1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CCC1OCCCO1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 2-(2-bromoethyl)-1,3-dioxane according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(2-(1,3-dioxan-2-yl)ethyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[C:12]([OH:17])(=[O:16])[C:13]([CH3:15])=[CH2:14].C(N(CC)CC)C>C(Cl)Cl>[C:12]([O:17][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: C=C(C)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC(O)COc1ccccc1
Temperature: 60 °C
Yield: 85 %

Procedure:
In a two neck flask equipped with a condenser under nitrogen atmosphere were placed 15.017 g (0.1 mol) of 1,2-epoxy-3-phenoxypropane, 9.039 g (0.105 mol) of methacrylic acid, 1.35 g (0.013 mol) of triethylamine and 30 mg of BHT. The reaction mixture was stirred at 60° C. 1H NMR showed reaction completion at 24 hours. Reaction mixtures was dissolved in methylene chloride and extracted with saturated solution of sodium hydroxide (NaOH) 3×25 ml, diluted solution of acid chloride (HCl) 2×25 ml, 2×25 ml of saturated solution of sodium bicarbonate (NaHCO3) and finally with brine 1×25 ml. Organic layer was dried over sodium sulfate (Na2SO4), filtered and vacuum dried. 20.14 grams (yield: 85%) of low viscosity (η=0.0891 Pa*s) amber material was obtained.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:9]=1)=[O:3].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[CH:9]=[C:4]([C:2]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:3])[CH:5]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cc(C(=O)Cl)cc(-c2ccc(C)cc2)c1
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl 5-(chlorocarbonyl)-4′-methylbiphenyl-3-carboxylate (5.5 g, 18 mmol) in methylene chloride (100 mL) at 0° C. were slowly added pyrrolidine (2.6 g, 36 mmol) and triethylamine (7.6 mL, 54 mmol). The mixture was stirred at room temperature for 2 h, and then washed with brine, aq. Na2CO3 solution and water. The separated organic phase was dried (Na2SO4), and concentrated. The residue was purified by silica gel column (30-100% EtOAc/hexane) to afford the desired compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:3]1[CH3:18].[CH2:19]([O:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[C:23]([CH3:25])([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([CH3:18])=[C:4]2[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH3:24])[CH3:20]
Reactant: Cc1c(-c2ccncc2)c2cc(O)ccc2n1C
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c(C)n2C

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 1,2-dimethyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][NH:16][C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]1.ClC(Cl)(Cl)S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O>CN(C)C=O>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]([CH2:33][C:34]([F:37])([F:36])[F:35])[C:15](=[O:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:13][CH2:12]1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 70.7 mg, 1.06 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (301 mg, 0.884 mmol) in N,N-dimethylformamide (7 mL) at −35° C. After 15 min, 2,2,2-trifluoroethyl trichloromethanesulfonate (0.314 mL, 1.91 mmol) was added and the reaction was stirred at −35° C. After 30 min, an additional amount of sodium hydride (27 mg, 0.40 mmol) and 2,2,2-trifluoroethyl trichloromethanesulfonate (0.140 mL, 0.85 mmol) were added. After 2 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (306 mg). MS 423 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14](O)=O.CCN(C(C)C)C(C)C.[NH2:26][C:27]1[C:28](=[O:40])[N:29]([CH3:39])[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=1[NH2:33]>C(#N)C>[CH2:34]([N:31]1[C:32]2[N:33]=[C:14]([CH2:13][C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=[N:8][CH:7]=3)[NH:26][C:27]=2[C:28](=[O:40])[N:29]([CH3:39])[C:30]1=[O:38])[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1ccc2cncc(CC(=O)O)c2c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Temperature: 25 °C

Procedure:
A suspension of (6-methoxy-isoquinolin4-yl)-acetic acid (3.5 g, 13.82 mmol) in acetonitrile (70 ml) is treated sequentially with Hunig's base (6.15 ml, 36 mmol), O-(7-benzotriazo-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.29 g, 16.6 mmol) and 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (3.22 g, 15.2 at mmol) while the solution is stirred at room temperature. The reaction is stirred at ambient temperature for 2 h, prior to evaporation of the solvent. The residue is tritruated with ethyl acetate (50 ml) filtered and washed with ethyl acetate and then dried at 50° C. under reduced pressure. The resulting intermediate is suspended in a mixture of methanol (30 ml) and 4M aqueous sodium hydroxide (60 ml) and heated at 80° C. for 45 minutes. This suspension is neutralized with acetic acid and cooled to 0-5° C. overnight. The resultant solid is collected by filtration, and washed with methanol/water 1:9 (30 ml) followed by methanol (30 ml). Drying under high vacuum at 50° C. affords 3-isobutyl-8-(6-methoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 394.5.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:17]([CH3:19])([CH3:18])[C:16]([CH3:20])=[N:15][C:5]2=[N+:6]([CH2:8][CH2:9][CH2:10][S:11]([O-:14])(=[O:13])=[O:12])[CH:7]=1.[Br:21]C1C=C2C(C)(C)C(C)=NC2=NC=1>>[Br:21][C:2]1[CH:3]=[C:4]2[C:17]([CH3:19])([CH3:18])[C:16]([CH3:20])=[N:15][C:5]2=[N+:6]([CH2:8][CH2:9][CH2:10][S:11]([O-:14])(=[O:13])=[O:12])[CH:7]=1
Reactant: CC1=Nc2c(cc(Cl)c[n+]2CCCS(=O)(=O)[O-])C1(C)C
Reactant: CC1=Nc2ncc(Br)cc2C1(C)C
Product: CC1=Nc2c(cc(Br)c[n+]2CCCS(=O)(=O)[O-])C1(C)C

Procedure:
Compound 6 was prepared analogously to compound 5 (Example 5), except that 5-bromo-2,3,3-trimethyl-3H-pyrrolo[2,3-b]pyridine (50) was used as a starting material.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(N(CC)C(C)C)(C)C.O1CCCC1.[C:42](O)(=[O:46])[C@H:43]([CH3:45])[OH:44].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[OH:44][C@@H:43]([CH3:45])[C:42]([N:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1)=[O:46]
Reactant: C[C@H](O)C(=O)O
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(C(=O)[C@H](C)O)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of 8-Azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.811 g, 0.000786 mol) and N,N-diisopropylethylamine (0.274 mL, 0.00157 mol) in tetrahydrofuran (5.0 mL, 0.062 mol) was added simultaneously L-lactic acid (0.0708 g, 0.000786 mol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.329 g, 0.000865 mol). The reaction was stirred at room temperature overnight. The mixture was partitioned between saturated sodium bicarbonate and methylene chloride and extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 490 (191.2 mg) as a colorless solid. MS(ESI+) 454.2. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.2, 1H), 7.22 (m, 1H), 7.06 (s, 1H), 5.84-5.66 (m, 1H), 5.09 (dd, J=11.1, 5.8, 1H), 4.65 (m, 1H), 4.37 (t, J=5.0, 2H), 4.28 (m, 2H), 4.16 (quin, J=6.5, 1H), 3.94-3.78 (m, 2H), 3.43 (t, J=5.0, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6, 6H), 1.21 (d, J=6.7, 3H)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][OH:14])([O-:3])=[O:2]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCCO)c1
Temperature: 70 °C
Yield: 74.1 %

Procedure:
A solution of m-nitrophenol (2.0 g, 14 mmol), 2-bromoethanol (1.4 mL, 20 mmol), and potassium carbonate (3.0 g, 22 mmol) in N,N-dimethylformamide (10 mL) was heated at 70° C. for 7 h. The reaction mixture was treated with additional 2-bromoethanol (0.5 mL, 7.2 mmol) and potassium carbonate (1.0 g, 7.2 mmol) and heated at 70° C. for 20 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (150 mL). The organic layer was separated and washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to a crude residue. This material was purified by flash column chromatography to give the desired product (1.9 g, 70%) as a white solid. LCMS for C8H10NO4 (M+H)+: m/z=183.9.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[C:6]([NH:8][CH:9]1[C:19]2[C:20]3[C:12](=[C:13]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[NH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10]1)=[O:7])([O-])=O.C(OCC)(=O)C>CO.[C].[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[C:6]([NH:8][CH:9]1[C:19]2[C:20]3[C:12](=[C:13]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccccc1C(=O)NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58 %

Procedure:
A portion (250 mg) of the compound obtained in Example 128 was suspended in methanol (50 ml) and to the suspension was added 10% palladium-carbon (25 mg). The mixture was stirred for 3.5 hours at room temperature under a hydrogen atmosphere. Ethyl acetate was added to the reaction mixture, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was crystallized from ether to yield 134 mg (58%) of the titled compound.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH3:15])[CH2:10][CH2:9]1.Cl[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[N:14]([C@H:11]1[CH2:12][CH2:13][C@H:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][Br:2])[CH2:9][CH2:10]1)[CH3:15])[CH:21]([CH3:23])[CH3:22]
Reactant: CN[C@H]1CC[C@H](OCCCCBr)CC1
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Product: CC(C)COC(=O)N(C)[C@H]1CC[C@H](OCCCCBr)CC1

Procedure:
In analogy to example 11.4, trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-amine hydrochloride and isobutyl chloroformate (with 2.1 eq N,N-diisopropylethylamine) were reacted to yield trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-carbamic acid isobutyl ester which was used directly in the next steps see Example 12.45-12.54.