Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH3:12].O>CN>[NH2:12][C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=[C:2]([Br:1])[N:3]=1
Reactant: N
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: CN
Solvent: O
Product: Nc1nc(Br)cn2ccnc12
Temperature: 85 °C

Procedure:
Procedure 1: A mixture of 1.00 eq. of 6,8-imidazo[1,2-a]pyrazine 3 in 28% ammonia/water solution or 40% aqueous methyl amine is heated to between 80 to 90° C. for 24 hr. The resulting mixture is partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 and the combined organic extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is crystallized from ethanol to yield 4.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:25])=[C:4]([C:21]([Cl:24])=[CH:22][CH:23]=1)[C:5]([NH:7][C:8]1[C:16]2[O:15][C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].C=O.[C:28]([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C>[Cl:25][C:3]1[C:2]([NH:1][CH3:28])=[CH:23][CH:22]=[C:21]([Cl:24])[C:4]=1[C:5]([NH:7][C:8]1[C:16]2[O:15][C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: [BH3-]C#N
Reactant: Nc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CNc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
A mixture of 6-(3-amino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (100 mg), aqueous 37% formaldehyde, sodium cyanoborohydride (70 mg) and acetic acid (5 drops) in acetonitrile (2 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was partitioned between dichloromethane and aqueous saturated sodium bicarbonte. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC on silica gel and the obtained oil was crystallized from diisopropyl ether to give 6-(2,6-dichloro-3-methylaminobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (21 mg).
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH:15]1([Mg]Br)[CH2:17][CH2:16]1>O1CCCC1>[CH:15]1([CH:11]([C:10]2[CH:13]=[CH:14][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=2)[OH:12])[CH2:17][CH2:16]1
Reactant: Br[Mg]C1CC1
Reactant: CCCS(=O)(=O)c1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CCCS(=O)(=O)c1ccc(C(O)C2CC2)cc1
Temperature: 25 °C

Procedure:
To 4-(propylsulphonyl)benzaldehyde (0.58 g) in dry tetrahydrofuran (5 mL), at −78° C. under nitrogen, was added a 0.5 M solution of cyclopropylmagnesium bromide in tetrahydrofuran (6.0 mL), slowly with stirring. The mixture was stirred for 1.75 h, quenched by addition of acetic acid (0.5 mL), then warmed to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine, solvent stripped, and the residue chromatographed on silica gel, eluent 35% to 50% ethyl acetate in isohexane, to give the title compound as a white solid. 1H NMR (360 MHz, CDCl3) δ 7.88 (2H, d, J=8.3 Hz), 7.63 (2H, d, J=8.4 Hz), 4.10 (1H, m), 3.06 (2K, m), 2.14 (1H, d, J=2.9 Hz), 1.75 (2H, m), 1.18 (1H, m), 0.99 (3H, t, J=7.4 Hz), 0.66 (2H, m), 0.49 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1cc(NCc2ccccc2)ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
A solution of the product of Example 84A (0.63 g, 2.4 mmol), benzaldehyde (0.24 g, 2.3 mmol) and sodium cyanoborohydride (0.15 g, 2.4 mmol) in methanol (10 mL) containing 1% acetic acid was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (20 mL) and the resultant solution was concentrated under vacuum to a yellow solid. The solid was dissolved in ethyl acetate (50 mL), and washed with water, 10% sodium bicarbonate and 10% sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and solvent removed under vacuum leaving a light yellow oil. The oil was purified by silica gel chromatography eluting with 1% methanol in methylene chloride to provide the title compound (0.63 g, 77%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:5]=1[C:6]([NH:8][OH:9])=[O:7])[CH3:2].CO>CCO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:10]=1)[C:6]([NH:8][OH:9])=[O:7]
Reactant: CCOc1ccc([N+](=O)[O-])cc1C(=O)NO
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCOc1ccc(N)cc1C(=O)NO
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 726 %

Procedure:
2-Ethoxy-5-nitro-N-hydroxybenzamide (2.39 g, 1.06 mmol) was suspended in EtOH (50 ml) and 10% Pd on carbon (wet basis) (240 mg) was added. The mixture was hydrogenated at 50 psi for 1.5 hrs. MeOH (50 ml) was added and the mixture was filtered through celite. The volatiles were removed in vacuo and the residue was taken up in IPA (50 ml). The mixture was heated at 60° C. for 0.5 hr then stood at RT overnight. The precipitated solid was collected by filtration, washed with MTBE and dried in vacuo to give 1.51 g of 5-amino-2-ethoxy-N-hydroxybenzamide (73%) as an off-white solid.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:27][Cl:28].[ClH:36]>C1(C)C=CC=CC=1>[ClH:28].[ClH:36].[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:27][C:26]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:14][CH2:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Yield: 80.6 %

Procedure:
N-3,3-Diphenylpropylpiperazine in the amount of 2.8 g (0.01 mole) and 2.2 g (0.01 mole) of 3,4,5-trimethoxybenzyl chloride were dissolved in 20 ml of toluene, and heated at the refluxing temperature for 4.5 hours. After the reaction liquid was left to cool, dry hydrogen chloride gas was passed through the reaction liquid while cooling the liquid to precipitate crystals of 1-(3,3-diphenylpropyl)-4-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride, which were recrystallized from an ethanol and ether mixed solvent to obtain 4.3 g of pure crystals (80.6% yield) with a melting point of 178°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)[C:5]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:4]=2[O:3]1.[C:23]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][C:2]1([CH3:22])[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]([CH3:23])[C:11](=[O:15])[CH:10]=2)[C:5]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:4]=2[O:3]1
Reactant: CC1(C)N=C(Oc2cc[nH]c(=O)c2)c2cc(C#N)ccc2O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cn1ccc(OC2=NC(C)(C)Oc3ccc(C#N)cc32)cc1=O
Reaction time: 2 h

Procedure:
A mixture of 295 mg of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-4-pyridyloxy)-6-cyano-2H-1,3-benzoxazine, 20 ml of acetone, 400 mg of K2CO3 and 0.2 ml of dimethyl sulfate is boiled for 2 hours. The mixture is filtered and subjected to customary work-up to give 2,2-dimethyl-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridyloxy)-6-cyano-2H-1,3-benzoxazine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:18][CH2:19][N:20]([C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([CH3:32])=[CH:24][CH:25]=3)=[O:31])[CH2:21][CH2:22]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a suspension of 5-amino-7-(piperazin-1-yl)-2-(pyridine-3-yl)thiazolo[5,4-d]pyrimidine (150 mg, 0.48 mmol) in dioxane (10 ml) was added 4-tolyl isocyanate (63 μl, 0.5 mmol). The resulting reaction mixture was stirred at room temperature for 30 minutes. The solvents were evaporated in vacuo and the residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/25), yielding the pure title compound as a yellowish solid (170 mg, 79%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:13]=1[C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][NH:24][O:25][CH3:26].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>[Cl-]>[CH3:23][N:24]([O:25][CH3:26])[C:14](=[O:16])[C:13]1[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:12]=1[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CNOC
Reactant: O=C(Nc1ccc(O)cc1C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(O)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Benzyloxycarbonylamino-5-hydroxybenzoic acid (6.0 g) and N,O-dimethylhydroxylamine hydrochloride (2.5 g) were dissolved in methylenb chloride (80 ml). To the solution were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (4.6 g) and triethylamine (5 ml). The mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, which was subjected to extraction with ethyl acetate (200 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give N-methyl-N-methyloxy-2-benzyloxycarbonylamino-5-hydroxybenzamide as a yellow oily product (5.0 g).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=O.[CH3:14][O:15][C:16]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[C:17]=1[NH2:18].[Cl-].[NH4+]>S(Cl)(Cl)=O.N1C=CC=CC=1>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([NH:18][C:17]1[C:19]([O:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=1[O:15][CH3:14])=[O:5]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCC(Br)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCC(Br)C(=O)Nc1c(OC)cc(OC)cc1OC
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
2-Bromodecanoic acid (1 g, 3.8 mmol) was heated under reflux in thionyl chloride (10 ml) for 1 hour. The thionyl chloride was evaporated and the residue was dissolved in dry ether (10 ml) and added dropwise to a solution of 2,4,6-trimethoxyaniline (0.7 g, 3.8 mmol) in pyridine (20 ml) at 0° C. and the mixture was stirred for 1.5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted three times with ethyl acetate (60 ml). The combined organics were extracted with water and brine and dried and concentrated. Recrystallization from isopropyl ether afforded 1.1 g (65%) of the title compound, m.p. 109°-110° C. This material was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:19])[N:12]([CH3:18])[NH:13]2.[H-].[Na+].Br[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:19])[N:12]([CH3:18])[N:13]2[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25]
Reactant: CCC(Br)CC
Reactant: Cc1ccc(-c2cccc3[nH]n(C)c(=O)c23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)n1c2cccc(-c3ccc(C)cc3C)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
To a solution containing 0.008 g (0.03 mmol) of 4-(2,4-dimethylphenyl)-2-methyl-1,2-dihydro-3H-indazol-3-one in 2 ml of N,N-dimethylformamide under a nitrogen atmosphere was added 0.001 g (0.038 mmol) of sodium hydride followed by 0.007 g (0.048 mmol) of 3-bromopentane. The reaction was allowed to stir at room temperature for 48 h, quenched with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 25% ethyl acetate/dichloromethane gave 0.003 g (30%) of compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.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>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:3]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2ccccc21
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: COCCOC
Product: COc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
3-bromo-1-(phenylsulfonyl)-1H-indole (500 mg, 1.49 mmol) and 5 mol % tetrakis(triphenylphosphine)palladium were mixed in 9 ml degassed DME. The mixture was stirred for 5 min under nitrogen and was then heated to 85° C. 4-Methoxyphenyl boronic acid (1.2 eq) dissolved in 3 ml DME and 5.95 ml sodium hydrogen carbonate (1 M) were simultaneously added drop wise at 85° C. over 5 min. The reaction was stirred at 85° C. for 10 min and then cooled to room temperature. DME was concentrated, water was added and the remaining aqueous mixture was extracted with DCM. The combined organic layers were concentrated and the crude product was purified on silica using EtOAc/n-heptane (1:9 to 2:8) as eluents. 363 mg 3-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-indole was obtained as white crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13]1[NH:18][CH2:17][CH2:16][N:15]2[CH2:19][CH2:20][CH2:21][CH:14]12.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]3[CH2:19][CH2:20][CH2:21][CH:14]3[CH2:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C1CC2CNCCN2C1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CCN3CCCC3C2)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (342 mg, 2 mmol), octahydropyrrolo[1,2-a]pyrazine (252 mg, 2 mmol) and potassium carbonate (552 mg, 4 mmol) in dimethylacetamide (10 mL) was heated at 100° C. for 16 hours. After cooling to ambient temperature, the mixture was poured into water and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 98/2 dichloromethane/methanol to give the title compound. MS: 278 (M+H+).
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.[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]([OH:21])=[O:20])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a cooled (−78° C.) solution of 2,4-dichloro-5-nitropyrimidine (0.53 g, 2.75 mmol) in THF (2 mL) was added a solution of anthranilic acid (0.37 g, 2.50 mmol) and N,N-diisopropylethylamine (0.5 mL, 3.0 mmol) in THF (2.0 mL). The reaction was stirred for 2.0 hours. The reaction was then poured onto ice and allowed to warm to room temperature then was filtered. The isolated solid was dried under vacuum, then recrystallized from hot ethyl acetate and cold hexane to give 2-[(2-chloro-5-nitropyrimidin-4-yl)amino]benzoic acid (307 mg, 42%) as a yellow solid. 1H NMR (DMSO-d6/D2O): δ 9.20 (s, 1H), 8.36 (d, 1H), 8.07 (d, 1 H), 7.70 (t, 1 H), 7.37 (t, 1 H). MS m/z 294 (M+1).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6])(=O)[CH3:2].[OH-].[Na+].O.[CH:13]1(C=O)[CH2:18][CH2:17]C[CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[CH:2]1([CH:1]=[C:4]2[CH2:9][CH2:8][O:7][C:5]2=[O:6])[CH2:17][CH2:18][CH2:13][CH2:14][CH2:15]1
Reactant: O=CC1CCCCC1
Reactant: CC(=O)C1CCOC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OCCC1=CC1CCCCC1
Temperature: 25 °C
Yield: 21 %

Procedure:
A solution of 2-acetyl-γ-butyrolactone (15.4 g) in toluene (100 mL) was treated portionwise with sodium hydroxide (4.8 g) during 10 min and then refluxed with a Dean & Stark moisture receiver until the formation of water had stopped (about 1 h). After that the reaction mixture was treated dropwise with cyclohexanecarbaldehyde (15.0 g) during 1 h. Upon completion of the addition, the mixture was refluxed for 4 h, then cooled to room temperature and washed with water. After drying over magnesium sulfate, the obtained organic phase was filtered, concentrated on a rotary evaporator and distilled in vacuum to give 4.54 g (21%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[BH4-].[Na+].CC(O)=O>CO>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([OH:12])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: O=C1CCCc2c(Br)cncc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC1CCCc2c(Br)cncc21
Temperature: 0 °C
Yield: 92 %

Procedure:
A suspension of 4-bromo-6,7-dihydroisoquinolin-8(5H)-one (intermediate A-2 [C]) (2.135 g, 9.44 mmol) in MeOH (18.9 mL) was cooled to 0° C. and treated with NaBH4 (357 mg, 9.44 mmol) in 5 portions over 30 min. The reaction was stirred for ¾ h at 0° C., then AcOH was added dropwise until a pH ˜5-6 was obtained and the reaction mixture was evaporated. The residue was diluted with water and poured into aq. sat. NaHCO3-solution, then extracted with EtOAc (3×). The organic layers are washed once with aq. sat. NaHCO3 and aq. 10% NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was precipitated with CH2Cl2/n-pentane to afford the title compound (1.98 g, 92%) as dark brown viscous oil. MS: 227 (M+, 1Br).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([C:10](Cl)([Cl:12])[Cl:11])[CH:7]=[C:6]([O:14][CH3:15])[N:5]=1>CC(C)=O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH:10]([Cl:12])[Cl:11])[CH:7]=[C:6]([O:14][CH3:15])[N:5]=1
Reactant: COc1cc(C(Cl)(Cl)Cl)cc(OC)n1
Agent: Cl
Solvent: CC(C)=O
Product: COc1cc(C(Cl)Cl)cc(OC)n1
Temperature: 60 °C

Procedure:
A solution was prepared by dissolving 19.63 grams (0.087 mole) of stannous chloride, dihydrate in 100 ml of acetone. To this mixture was added 7.3 ml of concentrated hydrochloric acid. The mixture was stirred for ~10 minutes. To this mixture was added a solution prepared by dissolving 12.8 grams (0.05 mole) of 2,6-dimethoxy-4-(trichloromethyl)pyridine in 40 ml of acetone at 30° C. The mixture was heated to reflux (60° C.) and refluxed for ~31/2 hours. The reaction mixture was cooled to ~15° C. and the acetone was removed at this temperature. The residual material was mixed with ~250 ml of water and raised to a pH of ~12 with ~20-30 ml of a 50 percent sodium hydroxide solution. The mixture was extracted twice with 250 ml portions of warm (60°-100° C.) petroleum ether and the petroleum ether extract washed twice with water. The petroleum ether extract was dried over sodium sulfate, filtered and the ether removed by evaporation. The desired 2,6-dimethoxy-4-(dichloromethyl)pyridine product was recovered from the residue by crystallization from hexane. The product melted at 59°-62° C. and was recovered in a yield of 7.3 grams (65.8 percent of theoretical). Upon analysis, the product was found to have carbon, hydrogen, nitrogen and chlorine contents of 43.44, 4.08, 6.32 and 31.68 percent, respectively, as compared to the theoretical contents of 43.26, 4.08, 6.30 and 31.93 percent, respectively, as calculated for the above-named compound. The structure of the compounds was confirmed by NMR.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:27]([O:26][C:22](=[O:25])[CH:23]=[CH:24][C:2]1[CH:14]=[CH:13][CH:12]=[C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH:3]=1)[CH3:28]
Reactant: C=CC(=O)OCC
Reactant: Ic1cccc(CN2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cccc(CN2CCOCC2)c1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
To a solution of 4-(3-iodo-benzyl)-morpholine (3.44 g, 11.4 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (1.7 mL, 12.5 mmol), ethyl acrylate (4.1 mL, 45.4 mmol), tri-o-tolylphosphine (346 mg, 1.14 mmol) and palladium (II) acetate (127 mg, 0.57 mmol). The mixture was heated at 80° C. overnight. After concentration, the mixture was chromatographed on silica gel to afford Intermediate 172(a) as a colorless oil (2.37 g, 9.1 mmol) in 80% yield.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13]O)[CH2:7]1>>[Cl:3][CH2:13][CH2:12][CH2:11][N:8]1[CH2:9][CH2:10][C@H:6]([F:5])[CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: OCCCN1CC[C@H](F)C1
Product: F[C@H]1CCN(CCCCl)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
0.143 g (1.2 mmol) of thionyl chloride was added to a solution (ice bath) of 0.143 g (1.0 mmol) of 3-[(3S)-3-fluoropyrrolidin-1-yl]propan-1-ol. The reaction mixture was stirred for 2 h at 50° C. and concentrated in vacuo to give 0.103 g (50%, 3 steps) of (3S)-1-(3-chloropropyl)-3-fluoropyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH2:17]([O:21][C:22]1[CH:32]=[CH:31][C:25]([CH:26]=[CH:27][C:28](O)=O)=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([O:21][C:22]1[CH:23]=[CH:24][C:25](/[CH:26]=[CH:27]/[C:28]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[CH:31][CH:32]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1ccc(C=CC(=O)O)cc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCCOc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(CCC)c(=O)n3CCC)cc1
Yield: 63.6 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.21 g (14.6 mmol) of 4-butoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.47 g (yield 64%) of Compound 51 as white needles.