Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(F)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(F)cc1)CCCC3
Temperature: 60 °C
Yield: 99.2 %

Procedure:
To a solution of methyl [2-methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.290 g; 0.7 mmol) in methanol (7 mL) was added a solution of sodium hydroxide 5 N (1.4 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.276 g (99%) of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cccc(C)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C)cccc1C(=O)O
Yield: 95 %

Procedure:
To a solution of 2 (1.19 mol) in a mixture of methanol (2 L) and water (0.5 L), potassium hydroxide pellets (100 gram, 1.5 mol) were added under cooling. The mixture was refluxed overnight and evaporated to dryness. The residue was dissolved in water (0.5 L) and acidified with HCl 6N. The product precipitated and 189 g of product was collected as white crystals. Yield 95%. 1H NMR (500 MHz, CDCl3, 25° C.) δ: 2.234 (s, 3H, CH3), 3.717 (s, 3H, OCH3), 7.062 (t, J=7.5, 1H, ArH), 7.365 (d, J=7.5, 1H, ArH), 7.496 (d, J=7.5, 1H, ArH).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[OH:23][C:16]1[C:15]([CH2:14][NH:13][C:11]([C:10]2[C:5]3[CH:4]=[N:3][C:2]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:7][C:6]=3[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:9]=2[CH3:24])=[O:12])=[C:20]([CH3:21])[CH:19]=[C:18]([CH3:22])[N:17]=1
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Product: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(N4CCOCC4)ncc23)c(O)n1
Yield: 70.5 %

Procedure:
A solution of (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (70 mg, 0.15 mmol) in morpholine (1.0 mL) was stirred at 150° C. for 30 minutes under microwave (pressure: 10.5 bar, equipment power: 150 W). The mixture was concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford (R)—N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-2-morpholino-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (55 mg, 70.5%). LRMS (M+H+) m/z: calcd 500.25. found 500. HPLC purity (214 nm): 98.6%. 1H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 7.28 (dt, J=11.9, 7.7 Hz, 5H), 6.10 (dd, J=13.7, 6.5 Hz, 2H), 4.51 (s, 2H), 3.78-3.65 (m, 8H), 2.47 (s, 3H), 2.41 (s, 3H), 2.26 (s, 3H), 2.03 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[I:21][C:22]1[CH:23]=[C:24]([CH2:28][NH2:29])[CH:25]=[CH:26][CH:27]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:29][CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([I:21])[CH:23]=2)[N:3]=1
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCc1cccc(I)c1
Solvent: CCCCO
Solvent: CC(C)O
Product: CCC(C)n1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.128 ml of 3-iodo-benzenemethanamine in place of the benzylamine. The reaction medium is taken to a temperature of 80 to 85° C. for approximately 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol and placed for two days at a temperature of approximately 0° C., followed by separating, washing with 10 ml of isopropanol and drying at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 290 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccc(Nc2ccc3[nH]ccc3c2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 2-amino-4,6-dichloropyrimidine (1.64 g, 10 mmol), 5-aminoindole (1.32 g, 10 mmol), diisopropylethylamine (5.23 ml, 30 mmol) and N,N-dimethylformamide (30 ml) was heated at 60° C. and stirred overnight under nitrogen atmosphere. The reaction mixture was partitioned between ethyl acetate and water after cooled to room temperature; and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off; the obtained residue was dissolved in tetrahydrofuran (100 ml); 10% Palladium on carbon (50% wet, 1.0 g) was added thereto under nitrogen atmosphere; and the reaction mixture was stirred for 4 days under hydrogen atmosphere at atmospheric pressure. The reaction system was purged with nitrogen; the catalyst was filtered off; the filtrate was concentrated under reduced pressure; the residue was purified by NH silica gel column chromatography (eluent; ethyl acetate:methanol=95:5); diethyl ether was added to the residue to crystallize; and the crystals were filtered off, and dried under aeration to yield the title compound (852 mg, 3.8 mmol, 38%) as pale brown crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:9]=3[N:17]=2)[CH:19]=1)(=[O:35])=[O:34]
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 2,4-dichlorobenzene-1-sulfonyl chloride (0.0460 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 2,4-dichloro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.0340, 41%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.02-2.11 (2H, m), 2.24-2.29 (2H, m), 3.70-3.75 (2H, m), 4.10-4.16 (2H, m), 5.65-5.71 (1H, m), 7.33 (1H, dd, J=1.8, 8.6 Hz), 7.54 (1H, d, J=2.0 Hz), 8.05 (1H, d, J=8.8 Hz), 8.20 (1H, d, J=9.2 Hz), 8.36 (1H, d, J=8.8 Hz), 8.48-8.55 (2H, m), 8.84 (1H, s), 9.15 (1H, d, J=1.6 Hz). m/z=532.0 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].C(O)(=O)C.C(O)(=O)C.[CH3:24][N:25]([CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1)[CH3:26]>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([CH2:27][N:25]([CH3:26])[CH3:24])[CH2:29][CH2:30]1
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Solvent: CC(=O)O
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (360 mg, 1.5 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexanamine diacetic acid salt (500 mg, 1.8 mmol) to afford the desired product (340 mg, 63%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.89 (s, 1H), 8.93 (s, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 5.16-4.96 (m, 1H), 2.67 (s, 3H), 2.34-2.24 (m, 2H), 2.22 (s, 6H), 2.14 (d, J=7.1 Hz, 2H), 1.98-1.89 (m, 2H), 1.56-1.47 (m, 1H), 1.41-1.32 (m, 2H), 1.28-1.10 (m, 2H); ESI MS m/z 361 [M+H]+; HPLC 98.8% (AUC), tR=8.42 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:5]=1[CH2:6][CH2:7][NH2:8])[CH3:2].Cl.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>O>[N+:17]([C:11]1[C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[C:4]([O:3][CH2:1][CH3:2])[CH:12]=1)([O-:19])=[O:18]
Reactant: CCOc1ccc(OCC)c(CCN)c1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc([N+](=O)[O-])c(OCC)cc1CCN
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
5.23 g (25 mmol) 2,5-diethoxyphenethylamine N5 was mixed with 10 ml water and cooled to 0° C. while 3 ml conc. HCl was added slowly. The resultant milky emulsion was to cooled 0 to 5° C. and 13.5 ml conc. HNO3 was added slowly and carefully within about 2 hours. The temperature was kept below 10° C. The mixture solidified when about half of the HNO3 had been added. 50 ml icy water was added to render the mixture stirrable. Then the rest of the HNO3 was added. The mixture was warmed up to room temperature and stirred at room temperature for 3 hours, basified to pH>12 with 40% NaOH and then extracted with 2×100 ml CHCl3. The CHCl3 extraction was back washed with 3×100 ml 0.5 M NaOH and dried over 10 g K2CO3. The solvent was evaporated to afford 3.22 g orange oil (yield: 52%), which crystallized when cool.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[OH:17][C@@H:18]1[CH2:22][NH:21][CH2:20][C@@H:19]1[CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[OH:17][C@@H:18]1[CH2:22][N:21]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:16])[CH2:20][C@@H:19]1[CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.654 g, 3.0 mmol) in 1:1 (MeOH/CHCl3) (50 mL) were added phenylmethyl {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (0.750 g, 3.0 mmol) and Na2SO4 (0.100 g) and the resulting solution stirred at ambient temperature for 18 hours. Na(OAc)3BH (1.91 g, 9.0 mmol) was added and the solution stirred an additional 2 hours. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column [0-100% CHCl3/(90:10:1) CHCl3/MeOH/NH4OH)] to yield a colorless oil. (0.897 g, 66%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.Br[CH:16]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH3:21]
Reactant: Oc1ccccc1-n1cccc1
Reactant: CCOC(=O)C(Br)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Oc1ccccc1-n1cccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
Sodium hydride (90 mg, 3.9 mmol) was added to a solution of 1-(2-hydroxyphenyl)pyrrole (0.4 g, 2.5 mmol) in anhydrous THF (5 mL) at rt. The reaction mixture was stirred for 1 h at rt, and then a solution of ethyl α-bromo-α-(1-naphtyl)acetate (1.0 g, 4.0 mmol) in anhydrous THF (5 mL) was added dropwise. After 12 h at rt, the solvent was removed in vacuo, and the residue was taken up in dichloromethane. The organic layers were washed with brine, dried, and evaporated. The residue was purified by chromatography (toluene) to give 0.46 g of the title compound as a colorless oil; IR (neat): 1734 cm−1; 1H NMR (CDCl3) δ 1.10 (t, 3 H, J=7.0 Hz), 4.10 (m, 2 H,), 6.15 (s, 1 H), 6.30 (m, 2 H), 6.35-8.25 (m, 13 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=3[CH:18]=[N:17]2)=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:25][C:20]2[C:19]3[CH:18]=[N:17][N:16]([CH2:15][C:14]4[CH:26]=[CH:27][C:11]([O:10][CH3:9])=[CH:12][CH:13]=4)[C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc(Cn2ncc3c(N)cccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(Cn2ncc3c(Nc4ccnc(Cl)n4)cccc32)cc1
Temperature: 90 °C
Reaction time: 65 h
Yield: 63.8 %

Procedure:
A suspension of 2,4-dichloropyrimidine (3.71 g, 24.87 mmol), 1-(4-methoxybenzyl)-1H-indazol-4-amine (6 g, 23.69 mmol) and N,N-diisopropylethylamine (4.54 mL, 26.06 mmol) in ethanol (60 mL) was stirred at 90° C. for 65 hours. The reaction mixture was concentrated to dryness, diluted with ethyl acetate (100 ml), washed with water (100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 5 to 70% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford N-(2-chloropyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-indazol-4-amine (5.53 g, 64%) as a pink solid. NMR Spectrum: (DMSOd6) 3.70 (s, 3H), 5.57 (s, 2H), 6.86 (d, 2H), 6.93 (d, 1H), 7.22 (d, 2H), 7.37 (dd, 1H), 7.48 (d, 1H), 7.59 (d, 1H), 8.22 (d, 1H), 8.23 (s, 1H), 10.13 (s, 1H); Mass spectrum: MH+ 366
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[CH:17]OC(C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:23]([NH2:33])(=[O:32])([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)=[O:24]>Cl.C(O)C>[O:16]=[C:11]1[C:10](=[CH:17][NH:31][C:28]2[CH:29]=[CH:30][C:25]([S:23]([NH2:33])(=[O:24])=[O:32])=[CH:26][CH:27]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:12]1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC=C1C(=O)Nc2ccc(-c3ccccc3)cc21
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc(-c4ccccc4)cc32)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of 0.09 g (0.31 mmol) of 5-phenyl-3-tert-butoxymethylene-1,3-dihydro-indol-2-one, 0.053 g (0.31 mmol) of sulfanilamide, and 2 drops of conc. HCl in 15 mL of ethanol was refluxed for 1 h and cooled to rt. The resulting yellow solid was isolated by filtration, washed with ethanol and dried to give 0.068 g (56%) of the title compound: 1H NMR (DMSO-d6): δ 6.90 (d, J=8.2 Hz, 1H), 7.25 (s, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.34 (dd, J=1.6, 8.2Hz, 1H), 7.43 (d, J=7.5 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 7.64 (d, J=7.5 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.99 (d, J=1.6 Hz, 1H), 8.74 (d, J=12.5 Hz, 1H), 10.62 (s, 1H), 10.76 (d, J=12.5 Hz,1H); APCI−MS m/z 390 (M−H)−.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:28][C:29](=O)[CH2:30][C:31]1[O:35][CH:34]=[N:33][CH:32]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[O:35][CH:34]=[N:33][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cnco1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3cnco3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 17 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and oxazol-5-yl-acetic acid methyl ester with heating for 5 days to afford the title compound as tan solid (22 mg, 17%). LC/MS (Method B) 3.59 min, [M+1]+ 462.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[Na+].[Br:16][C:17]1[S:18][C:19](C2C=CC=CC=2)=[N:20][N:21]=1>CN(C)C=O>[Br:16][C:17]1[S:18][C:19]([O:13][CH2:12][CH:9]2[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)=[N:20][N:21]=1
Reactant: CCCCCC1CCC(CO)CC1
Reactant: Brc1nnc(-c2ccccc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC1CCC(COc2nnc(Br)s2)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 42.4 %

Procedure:
4-Pentylcyclohexylcarbinol (1.5 g, 8.15 mmol) are dissolved in dimethylformamide (40 ml), and sodium hydride (0.3 g, 12.23 mmol) is added at room temperature over a period of about 15 minutes. When the gas evolution is complete, 2-bromo-5-phenyl-1,3,4-thiadiazole (2.95 g, 12.23 mmol) is added to the resultant alkoxide, and the mixture is subsequently stirred at 50° C. for 6 hours, poured onto an ice/water mixture, filtered with suction and extracted. Separation by column chromatography (SiO2, CH2Cl2) gives 1.2 g (43% of theory) of 2-bromo-5-(4-pentylcyclohexylmethoxy)-1,3,4-thiadiazole.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[CH3:15][C@H:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[C:17]1([C@@H:16]([N:23]2[C:10](=[O:11])[C:5]3[C:6](=[CH:12][CH:13]=[CH:14][C:4]=3[N+:1]([O-:3])=[O:2])[C:7]2=[O:9])[CH3:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: C[C@@H](c1ccccc1)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 180 °C
Yield: 74.9 %

Procedure:
386 mg of 3-nitrophthalic anhydride and 242 mg of (S)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 1.5 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 443 mg of the desired product as a light yellow powder. Yield: 75%. m.p. 115-117° C.; MS(EI+) 296(M)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18].N1C=CC=CC=1.[CH2:25]([CH:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28](Cl)=[O:29])[CH3:26]>C(Cl)(Cl)Cl>[CH2:25]([CH:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28]([O:18][C:10]1[CH2:11][C:12]([CH3:16])([CH3:17])[CH2:13][C:14](=[O:15])[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:29])[CH3:26]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)c(C)c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCC(CC)C(=O)OC1=C(c2ccc(C)cc2C)C(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
A solution of 1.50 g (6.14 mmol) of 2-(2',4'-dimethylphenyl)-5,5-dimethyl-1,3-cyclohexanedione in 10 ml of chloroform was cooled in ice and 1.94 g (24.56 mmol) of pyridine added followed by 2.00 g (12.28 mmol) of 2-ethylhexanoyl chloride. The mixture was stirred for 2 hrs. at room temperature, then refluxed for 12 hrs. The mixture was worked up exactly as described in Example I above to give 1.58 g of a slightly yellow, viscous oil. This material was chromatographed through 75 g of silica gel (0.063-0.2 mm) using a gradient ranging from 98:2 to 90:10 hexane-ethyl acetate. The chromatography gave 1.15 g (51%) of 3-(2-ethylhexanoyloxy)-5,5-dimethyl-2-(2',4'-dimethylphenyl)-2-cyclohexenone as a clear colorless oil which showed one spot on a thin layer chromatogram (70:30 hexane-ethyl acetate) at Rf=0.52.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1)(=[O:4])=[O:3].[CH2:19](OC1C=C(OC)N=C(CCCO)N=1)C>>[CH3:1][S:2]([O:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][CH3:19])[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1)(=[O:3])=[O:4]
Reactant: COc1cc(OC)nc(CCCOS(C)(=O)=O)n1
Reactant: CCOc1cc(OC)nc(CCCO)n1
Product: CCOc1cc(OC)nc(CCCOS(C)(=O)=O)n1

Procedure:
The title compound was synthesized according to the procedure described for 3-(4,6-dimethoxypyrimidin-2-yl)propyl methanesulfonate (step 4), starting from 3-(4-ethoxy-6-methoxypyrimidin-2-yl)propan-1-ol. LC-MS conditions B: tR=0.68 min, [M+H]+=291.08.
Reaction SMILES: C(O)(=O)C.Cl.[O:6]1[CH2:10][CH2:9][CH:8]([NH:11][NH2:12])[CH2:7]1.[CH:13](=O)[C:14]([CH3:16])=[O:15].[Na+].[Cl-]>O>[O:6]1[CH2:10][CH2:9][CH:8]([NH:11][N:12]=[CH:13][C:14](=[O:15])[CH3:16])[CH2:7]1
Reactant: CC(=O)C=O
Reactant: NNC1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C=NNC1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
Acetic acid (1.7 mL) was slowly added to a solution of tetrahydrofuran-3-ylhydrazine hydrochloride (2.50 g, 18.0 mmol) (prepared as described by Bacon, E. R.; Singh, B.; and Lesher, G. Y. in U.S. Pat. No. 5,294,612) in water (30 mL). This mixture was then added dropwise to a solution of pyruvaldehyde (2.59 g, 2.34 mL, 14.4 mmol) in water (240 mL). The mixture was stirred overnight at room temperature. The mixture was poured into a seperatory funnel, NaCl was added and dissolved in the aqueous phase and then extracted with CH2Cl2 (6-times). The combined organic extracts were dried over Na2SO4, filtered and concentrated to provide crude material, which was purified by preadsorbing the oil on SiO2 followed by chromatography (Isco, 80 g RediSep column) eluting with a 0-80% EtOAc/heptane gradient over 80 minutes. Analysis of fractions resulted in isolation of 2-oxopropanal tetrahydrofuran-3-ylhydrazone (1.19 g, 53%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][CH3:16])[C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:15][CH3:16])[C:12]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([C:18]#[N:17])=[CH:20][CH:21]=2)=[O:14])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(C(=O)O)c1ccc(NC(C)=O)cc1
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(NC(C)=O)cc1

Procedure:
(RS)-(4-Acetylamino-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-2-(4-acetylamino-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Off-white, amorphous solid. MS 338.3([M+H]+)