Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(N(C)C)=O.O>[CH3:11][O:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=[CH:8][CH:7]=1
Reactant: Oc1ccccc1
Reactant: COc1ccnc(Cl)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccnc(Oc2ccccc2)c1C#N
Temperature: 75 °C
Yield: 70.4 %

Procedure:
A solution of 2-chloro-4-methoxynicotinonitrile (1.02 g) in dimethylacetamide (30 mL) was treated with cesium carbonate (2.96 g) followed by phenol (0.683 g) at room temperature. The mixture was heated to 75° C. overnight. The mixture was cooled to room temperature, diluted with water (100 mL) and the precipitated solids collected by filtration, to provide the title compound (0.964 g) with the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:22](I)[CH3:23].O>CS(C)=O>[CH2:22]([N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1)[CH3:23]
Reactant: CCI
Reactant: COc1ccc(NC(=O)c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
A mixture composed of 600 mg of 4-methoxy-N-(4-methoxy-phenyl)benzamide and 150 mg of 60% sodium hydride was stirred in 7.5 ml of dimethyl sulfoxide at 50° C. for 10 minutes. Then, 1.05 ml of ethyl iodide was added, and the reaction mixture was stirred for 30 minutes. After water was added to the reaction mixture, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 80:1 mixture of chloroform and acetone as the developing solvent) to obtain 591 mg of N-ethyl-4-methoxy-N-(4-methoxyphenyl)benzamide.
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([S:6][CH2:5][C:4]([CH3:15])([CH3:14])[C:3](=[O:16])[CH2:2][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:8][CH:9]=1
Reactant: CC(C)(CSc1ccc(Cl)cc1)C(=O)CBr
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CSc1ccc(Cl)cc1)C(=O)Cn1ccnc1
Yield: 81.7 %

Procedure:
199 g (0.618 mol) of 1-bromo-4-(4-chlorophenylsulphenyl)-3,3-dimethylbutan-2-one, 120 g (1.76 mols) of imidazole and 243.5 g (1.76 mols) of potassium carbonate in 3 liters of acetone are stirred under reflux for 5 hours. The mixture is then allowed to cool, the inorganic salts are filtered off with suction, and the filtrate is concentrated. The residue is taken up in methylene chloride, washed three times with water, dried over sodium sulphate, and concentrated. Recrystallizing from diisopropyl ether produces 156 g (82% of theory) of 4-(4-chlorophenylsulphenyl)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one having a melting point of 50° C. ##STR118##
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)C2C(=C(C)C(OC)=CC=2)N=1)[CH3:12]>>[Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:14]([O:13][CH2:11][CH3:12])[CH:23]=[C:22]2[O:24][CH:25]1[CH2:42][CH:41]2[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]3[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]2=[O:43])[CH2:37]3)[CH2:26]1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Reactant: COc1cccc(N)c1Br
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(Br)c2n1

Procedure:
The title compound (6) was prepared from 2-bromo-3-methoxyaniline following the procedure (Steps A-J) reported for synthesis of 17-[2-ethoxy-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (2): m/z=631 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[NH2:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([Cl:20])[N:14]=1.[OH-].[Na+]>O.CC(C)=O>[Cl:20][C:15]1[CH:16]=[C:17]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)[N:18]=[C:13]([NH2:12])[N:14]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Nc1nc(Cl)cc(Oc2ccc3ncccc3c2)n1

Procedure:
To a mixture containing 7.25 g (0.05 mol) 6-hydroxy-quinoline, 8.25 g (0.05 mol) 2-amino-4,6-dichloropyrimidine in 300 mL of water/acetone 1:1 are added 2.0 g (0.05 mol) sodium hydroxide. On heating a clear solution is first obtained from which a thick precipitate separates. Stirring under reflux is continued for a total of 6 h. The mixture is cooled, filtered and the solid washed with acetone/water 1.1 and dried. The title compound is obtained as a solid: map. 248-250° C.; MS: [M+1]+=273; HPLC: CtRet=1.30; TLC (dichloromethane/methanol 95:5): Rf=0.46.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[P:9](Cl)([Cl:12])([Cl:11])=[O:10]>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][P:9]([Cl:12])([Cl:11])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCCCCCCBr
Solvent: ClCCl
Product: O=P(Cl)(Cl)OCCCCCCBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Bromohexan-1-ol was added dropwise to phosphorusoxy chloride (equimolar) in dichloromethane over 30 minutes under nitrogen. The mixture was stirred at room temperature under nitrogen for 16 hours. The mixture was evaporated, dried under vacuum, then distilled under vacuum, to give the pure 6-bromohexyldichlorophosphate compound. Triethylamine and dichlorophosphate (equimolar) were added dropwise over 2 minutes under nitrogen to 1,3-dihexadecyloxy-2-(hydroxymethyl)-2-methyl propane (0.3×molar amount of dichlorophosphate) in dry diethyl ether. The mixture was heated at 60° C. under nitrogen for 16 hours before triethylamine (same molar amount as dichlorophosphate) and water were added and heating maintained for a further two hours. After cooling, the aqueous layer was removed and the residue evaporated to dryness and azeotroped with benzene (×3). The residue was dissolved in diethylether, filtered and evaporated to give a crude product, which was at least partially purified by silica gel chromatography using chloroform:methanol:25% ammonia (690:270:64). Triphenylphosphine was added to the intermediate thus prepared in dry chloroform. The mixture was heated at 60° C. for 16 hours before it was cooled and the solvents evaporated under reduced pressure. The residue was purified by silica gel chromatography, elusing with chloroform:methanol (3:1) to chloroform:methanol:water (65:25:4). Fractions containing the desired compound were combined and evaporated under reduced pressure to give the desired final compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]3[C:23]([C:14]=2[S:13][C:12]1=O)=[CH:22][CH:21]=[CH:20][CH:19]=3.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]3[C:23]([C:14]=2[S:13][C:12]1=[S:34])=[CH:22][CH:21]=[CH:20][CH:19]=3
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCCOCCOCCn1c(=O)sc2c3ccccc3ccc21
Solvent: Cc1ccccc1
Product: COCCOCCOCCn1c(=S)sc2c3ccccc3ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.7 g of 3-methoxyethoxyethoxyethylnaphtho[2,1-d]thiazoline-2-on, 2.4 g of Lawesson's reagent and 10 ml of toluene were fed into a 50 ml short-neck flask provided with a reflux condenser. The resultant mixture was heated under reflux and stirring for 2 hours. After cooling to room temperature followed by purification by column chromatography (hexane:ethyl acetate=3:1), the intended compound was obtained.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].C(O)C.[H][H]>O1CCCC1>[CH3:3][C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[C:1]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](CC(=O)O)C(=O)O

Procedure:
A solution of an itaconic acid (40.9 mg, 0.314 mmol) dissolved in tetrahydrofuran (THF) (0.3 mL) and ethanol (EtOH) (0.3 mL) is added to an autoclave in which the catalyst obtained in Preparation Example 7 was added. After replacing the atmosphere to hydrogen gas, it was stirred for 18 hours at reaction temperature of 50° C. under 3 atm pressure of hydrogen. After the reaction, it was cooled down to be room temperature, and the catalyst was filtered in the atmosphere to recover thereof and washed with THF (1 mL) three times. The solvent was concentrated from the filtrate, and the desired (S)-2-methylsuccinic acid was obtained. The yield thereof measured by NMR was >99%, and the optical purity thereof was >90% ee.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1.N>CO.[Ni]>[CH3:1][O:2][CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH2:13][NH2:14])[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: COCc1cnc2ccc(C#N)cn12
Agent: [Ni]
Agent: N
Solvent: CO
Product: COCc1cnc2ccc(CN)cn12
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 3-(methoxymethyl)imidazo[1,2-a]pyridine-6-carbonitrile (7-3) (300 mg, 1.6 mmol) in methanol (30 mL) were added Raney nickel (slurry in water, 150 mg) and 1N ammonia. The reaction mixture was stirred under H2 for 2 h. The mixture was filtered. The filtrate was concentrated to afford the title compound (300 mg). MS (m/z): 192.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1Cl.C(O)(=[O:17])C>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[OH:17]
Reactant: CC(=O)O
Reactant: Clc1cc(-c2ccccc2)nnc1Cl
Product: Oc1cc(-c2ccccc2)nnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 19 (158 g, 0.7 mol) and acetic acid (700 mL) was heated under reflux for 5 hrs. The reaction mixture was cooled to room temperature, the precipitate filtered and the bright yellow filter cake washed with water (5×500 mL). The filter cake was recrystallized from ethyl acetate (200 mL), filtered and dried over a medium frit sintered glass funnel in vacuo to give the desired product 20 in 32% yields. HPLC (tr/purity): 15.37 min, >95%. ESI m/z (MeOH): 2073 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:22]([O:24]CC)=[O:23])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1.O.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:22]([OH:24])=[O:23])=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:13]=1
Reactant: CCOC(=O)c1oc(-c2c(F)cccc2F)nc1-c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(-c3c(F)cccc3F)oc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a stirred solution of ethyl 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylate (0.030 g, 0.08 mmol) in THF and H2O (1:1, 3 mL) was added lithium hydroxide hydrate (0.008 g, 0.33 mmol) and the reaction mixture stirred at room temperature for 2.5 hours. The THF was removed in vacuo and 1N aqueous HCl was added and the resultant precipitate collected by filtration to afford 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylic acid (0.027 g, 0.08 mmol, 98%) as a white solid which was used without further purification. LCMS (1) Rt: 1.24 min; m/z (ES+) 332.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:23])[N:14]([CH3:22])[N:15]=[C:16]([CH3:21])[C:17]=1S(C)=O)[CH3:2].CS(C)=[O:26].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:23])[N:14]([CH3:22])[N:15]=[C:16]([CH3:21])[C:17]=1[OH:26])[CH3:2]
Reactant: CS(C)=O
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)=O)c(C)nn(C)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a 50 ml volume three-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfinyl-2,3-dihydro-3-pyridazinone ((2-19)-(1)-39) (0.60 g), DMSO (2.73 ml), and 10% of aqueous tetra-n-butylammonium hydroxide solution (9.4 g) were added under a nitrogen atmosphere, and stirred at 90° C. for 2 hours. The reaction mixture was added to water and hydrochloric acid was added to adjust pH to less than 2. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform) to give 0.33 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH2:14]2)=[O:10].O>CN(C)C=O>[N:1]1([CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2cc(C(=O)CBr)ccc2N1
Reactant: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Cc2cc(C(=O)CN3CCCCC3)ccc2N1
Yield: 49.1 %

Procedure:
A solution of piperidine (0.39 ml, 3.9 mmole) and 5-(2-bromoacetyl)-2-indolinone (500 mg, 1.97 mmole) in N,N-dimethylformamide (15 ml) was stirred at room temperature 4 h then was poured into water (50 ml) and washed with dichloromethane (250 ml), the organic solution was washed with water several times and dried over sodium sulfate. After evaporation of the solvent the residue was chromatographed on siiica-gel using ethyl acetate as eluant to give 5-(2-piperidin-1-yl-acetyl)-2-indolinone (250 mg).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:25][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: CC(C)(C)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
In 15 ml of N,N-dimethylformamide was dissolved 2.0 g (0.0092 mol) of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone. The resulting solution was added with 1.3 g (0.0123 mol) of anhydrous sodium carbonate and 1.6 g (0.0088 mol) of 4-t-butylbenzyl chloride, and then heated under stirring at 80°~110° C. for two hours. The resulting mixture was cooled to room temperature, and then added with 100 ml of water and stirred. The solid thus precipitated was filtered off, washed with water, dried, and recrystallized from ethanol to obtain 2.9 g of 2 -t-butyl-5-(p-t-butylbenzylthio)-4-chloro-3(2H)-pyridazinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36](=[O:37])[CH2:35][O:34][CH2:33][CH2:32][O:31][CH3:30])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COCCOCC(=O)Cl
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COCCOCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (50 mg, 0.13 mmol) and 2-(2-methoxyethoxy)acetyl chloride (0.039 mL, 0.38 mmol). Yield 52 mg (80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5]1.[H-].[Na+].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1COCC1>[CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:20][C:19]1[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
(S)-Pyroglutamic acid methyl ester (0.200 g, 1.40 mmol) was dissolved in dry THF (5 ml) and NaH (0.061 g, 1.5 mmol) was added. After gas evolution ceased, 4-nitrobenzyl bromide (0.332 g, 1.54 mmol) was added and the mixture stirred for 1 h. The reaction was quenched with saturated NaHCO3 solution (40 mL) and extracted with EtOAc (2×50 ml). The organic layers were washed with water, brine, dried (MgSO4), filtered, and concentrated to give the title compound as a solid. 1H NMR (CDCl3) δ 8.19 (d, 2H, J=8.6 Hz), 7.40 (d, 2H, J=8.6 Hz), 5.29 (d, 1H, J=15 Hz), 4.19 (d, 1H, J=15 Hz), 4.02 (dd, 1H, J=3,9 Hz), 3.79 (s, 3H), 2.54-2.67 (m, 1H), 2.42-2.51 (m, 1H), 2.27-2.39 (m, 1H), 2.11-2.21 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].S(=O)(=O)(O)O.[Na]>S(=O)(=O)(O)O>[O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([C:16]([O:18][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[O:17])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)c1ccc2oc3ccccc3c(=O)c2c1
Reactant: CCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CCCCCCCCCCCCOC(=O)c1ccc2oc3ccccc3c(=O)c2c1
Reaction time: 6 h
Yield: 81.8 %

Procedure:
A mixture of 12.01 g (50 mmol) of the above 9-oxo-9H-xanthene-2-carboxylic acid, 77.4 g (420 mmol) of n-dodecanol and 0.2 g (2 mmol) of concentrated sulfuric acid is kept at 140° C. for 6 hours. The sulfuric acid is neutralized with 0.33 g (4 mmol) of sodium acetam and the excess n-dodecanol is removed by distillation (98° C./0.1 mbar). The brown residue is taken up in isopropanol and the product which has precipitated is filtered off and dried uider a high vacuum. 16.7 g (82%) of n-dodecyl 9-oxo-9H-xanthene-2-carboxylate, melting point 79°-81° C., result as a beige powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:31]([C:29]3[NH:28][N:27]=[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)[CH:30]=3)=[O:32])[N:5]=2)=[CH:10][C:11]=1[N+:17]([O-:19])=[O:18])#[N:14]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Reactant: O=C(O)c1cc(-c2ccccn2)n[nH]1
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(-c4ccccn4)n[nH]3)n2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (300 mg) and 3-(pyridine-2-yl)-1H-pyrazole-5-carboxylic acid (161 mg) using the method of Example 34(d). Yield 166 mg. 1H-NMR (400 MHz; d6-DMSO): δ 3.75 (q, 2H), 4.43 (t, 2H), 7.09 (d, 1H), 7.31 (br. s, 1H), 7.39 (m, HA), 7.88-7.96 (m, 3H), 8.20 (d, 1H), 8.37 (dd, 1H), 8.47-8.57 (m, 1H), 8.64 (m, 1H), 8.71 (d, 1H), 13.90 (m, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][NH2:13])[C:6]=2[S:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1>C(O)C>[CH3:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][N:13]=[CH:20][C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)[C:6]=2[S:5][CH:4]=1
Reactant: Cc1csc2c(NN)ncnc12
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CCO
Product: Cc1csc2c(NN=Cc3cccnc3)ncnc12
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A suspension of (7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazine hydrochloride (5, 1.7 g, 7.9 mmol) and 3-pyridinecarboxaldehyde(1.1 g, 10.3 mmol) in ethanol (30 mL) was heated at reflux for 4 hours. After cooling to room temperature, the solid product was collected by vacuum filtration and recrystallized from methanol to yield 3-pyridinecarboxaldehyde(7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazone (1.5 g, 71% yield) as white needles.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[S:24][C:23]([S:25]([NH:18][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:27])=[O:26])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1ccc(Cl)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was reacted with 5-chlorothiophene-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.38 (dd, J=1.5 & 10.2 Hz, 1H), 7.32 (ddd, J=2.1, 5.1 & 9.3 Hz, 1H), 7.25 (d, J=3.9 Hz, 1H), 7.10 (dd, J=9.0 & 18.6 Hz, 3H), 6.84 (d, J=4.2 Hz, 1H), 5.86 (dt, J=1.8, 8.7 & 17.4 Hz, 1H), 5.49 (br s, D2O exchangeable, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:17][CH:16]3[N:18](CC4C=CC=CC=4)[CH:12]([CH2:13][O:14][CH2:15]3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:1]1([S:7]([N:10]2[CH2:11][CH:12]3[NH:18][CH:16]([CH2:15][O:14][CH2:13]3)[CH2:17]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2
Temperature: 23 °C

Procedure:
A mixture of 7-benzenesulfonyl-9-benzyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (CAS 335620-96-7) (2.074 g, 5.66 mmol) and 10% palladium on carbon (780 mg, 10 mol %) in ethanol (130 mL) was hydrogenated at atmospheric hydrogen pressure at 50° C. for 1.5 days. Cooled to 23° C., filtered the catalyst off, washed with ethanol, the solvent was removed in vacuum to the title compound as a light yellow solid (1.253 g, 83%), MS (ISP) m/e=269.2 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2Br)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>COCCO.O.[Cu]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:17]3[S:18][CH:19]=[CH:20][C:21]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=NO)c2sccc2Br)CC1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: CC(C)(C)OC(=O)N1CCC(c2noc3ccsc23)CC1
Temperature: 65 °C
Reaction time: 6 h
Yield: 49.5 %

Procedure:
Add to a stirring solution of 4-[(3-bromo-thiophen-2-yl)-hydroxyimino-methyl]piperidine-1-carboxylic acid tert-butyl ester (Example 21b)(25 g., 64.2 mmol) in 2-methoxyethanol (200 mL), a solution of potassium hydroxide (7.2 g, 128.4 mmol) in water (20 mL). Heat the reaction to 60° C. and then add copper powder (1.25 g). Stir at 60-70° C. for 6 h and then at ambient temperature overnight. Pour the reaction mixture into water (500 mL) and extract with EtOAc (3 times). Concentrate to a dark residue and purify by column chromatography over silica gel (heptane/EtOAc, 4:1) to provide 9.8 g (50%) of a white solid.