Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][CH2:10][CH2:11][N:12]([CH3:40])[C:13]([C:15]1[C:19](=[O:20])[N:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[N:17]([CH3:29])[C:16]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=1)=[O:14])=[O:7])(C)(C)[CH3:2]>S(=O)(=O)(O)O.C(O)C>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:16]2[N:17]([CH3:29])[N:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[C:19](=[O:20])[C:15]=2[C:13]([N:12]([CH2:11][CH2:10][O:9][CH2:8][C:6]([O:5][CH2:1][CH3:2])=[O:7])[CH3:40])=[O:14])=[CH:35][CH:34]=1)([CH3:37])([CH3:38])[CH3:39]
Reactant: CN(CCOCC(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(C(C)(C)C)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)COCCN(C)C(=O)c1c(-c2ccc(C(C)(C)C)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Yield: 51.5 %

Procedure:
To a mixture of 900 mg of 4-(N-t-butyloxycarbonylmethyloxyethyl-N-methyl-aminocarbonyl)-3-(4-t-butylphenyl)-1-(4-cyanophenyl)-2-methyl- 2H-pyrazol-5-one and 10 ml of ethanol, 4 drops of concentrated sulfuric acid was added, and the resulting reaction solution was refluxed under heating for 2.5 hours. After the ethanol was removed by evaporation under reduced pressure, water was added, and the reaction solution was extracted with chloroform. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The insolubles were filtered off, and the filtrate was concentrated. The resulting residue was recrystallized in chloroform-ether-hexane to give 440 mg of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([C:12]1[N:13]=[C:14]3[C:20]([CH:21]=[O:22])=[CH:19][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]3=[N:16][CH:17]=1)=[N:5][NH:6]2.[H-].[Na+].I[CH3:34]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([C:12]1[N:13]=[C:14]3[C:20]([CH:21]=[O:22])=[CH:19][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]3=[N:16][CH:17]=1)=[N:5][N:6]2[CH3:34]
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(F)cc(F)c34)cnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2c(F)cc(F)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
To a solution of 2-(4,6-difluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (890 mg, 2.1 mmol) in DMF (9 ml) at 0° C. was added sodium hydride (60% in mineral oil, 279 mg, 2.49 mmol). The reaction mixture was stirred at 0° C. for 10 min then iodomethane (0.18 ml, 2.9 mmol) was slowly added. The mixture was stirred at 0° C. for 30 min then at room temperature for 30 min. The reaction was quenched with sat'd NH4Cl, diluted with water and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 20% to 100% EtOAc/heptane to provide 226 mg (22%) of 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow solid.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[F:9][C:10]([F:28])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH2:22][CH2:23][CH2:24][SH:25])[N:16]=1.C[O-].[Na+].I[CH2:33][C:34]([NH2:36])=[O:35]>CO>[F:28][C:10]([F:9])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH2:22][CH2:23][CH2:24][S:25][CH2:33][C:34]([NH2:36])=[O:35])[N:16]=1
Reactant: NC(=O)CI
Reactant: NC(=NCC(F)(F)F)Nc1ccnc(SCCCS)n1
Agent: C[O-]
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Solvent: CO
Product: NC(=O)CSCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]propanethiol hydrogen maleate (147 mg.) and sodium methoxide (70 mg.) in MeOH was treated with 2-iodoacetamide (123 mg.) and the solution stirred at room temperature for 24 hours and then evaporated to dryness. The residue was partitioned between water and EtOAc, and the EtOAc phase was dried and evaporated to dryness. The residue was purified by preparative tlc on silica gel using EtOAc/MeOH/concentrated aqueous ammonia (s.g. 0.880) 6:1:0.5 v/v/v as developing solvent to give 2-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-ylthio)propylthio]acetamide as a gum (50 mg.) which was crystallised as the hydrogen maleate salt (m.p. 168°-170°) from EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]([CH3:20])[C:5]([O:6][C:7]2[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:16])[N:10]=[C:9](Cl)[N:8]=2)=[C:4]([CH3:21])[CH:3]=1.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.N1C=CC=CC=1>C1COCC1.CO>[Br:1][C:2]1[CH:19]=[C:18]([CH3:20])[C:5]([O:6][C:7]2[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:16])[N:10]=[C:9]([NH:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[N:8]=2)=[C:4]([CH3:21])[CH:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(Br)cc(C)c1Oc1nc(Cl)nc(C)c1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cc(Br)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(C)c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 84.3 %

Procedure:
A mixture of 4-(4-bromo-2,6-dimethylphenoxy)-2-chloro-6-methyl-5-nitropyrimidine (22.0 g, 59.3 mmol), 4-aminobenzonitrile (7.7 g. 65.2 mmol) and pyridine (4.8 ml, 59.3 mmol) in THF (300 ml) was heated to 80° C. for 10 hours. The reaction mixture was dissolved in methanol, washed with brine and extracted with ethyl acetate. The organic layer was washed twice with brine, dried over MgSO4 and concentrated to dryness. The solid was washed with a mixture of hexane:ethyl acetate (80:20) before filtration. After filtration, the solid was washed again with methanol. The filtrate was concentrated again until dryness. The second round of precipitation was collected following the same procedure. The operation was repeated until total product was recovered. The combined solids were recrystallized from acetone to obtain the title compound (22.72 g, 50 mmol, 84%). 1H NMR (CDCl3, 400 MHz) δ 2.14 (s, 6H), 2.60 (s, 3H), 7.22 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.9, 2H), 7.27 (s, 2H), 12.75 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:19])[C:11]=1[O:12][CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[O:8][CH:7]([C:20]([F:23])([F:22])[F:21])[C:6]([C:24]([O:26]C)=[O:25])=[CH:5]2.[OH-].[Na+].Cl>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:19])[C:11]=1[O:12][CH2:13][CH:14]([CH2:15][CH3:16])[CH2:17][CH3:18])[O:8][CH:7]([C:20]([F:23])([F:21])[F:22])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2
Reactant: CCC(CC)COc1c(Cl)cc2c(c1C)OC(C(F)(F)F)C(C(=O)OC)=C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)COc1c(Cl)cc2c(c1C)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
The ester from Step 3 (0.55 g, 1.35 mmole) was dissolved in 3.5 mL methanol and 3.5 mL THF. Sodium hydroxide (2.5 N) (1.6 mL, 4 mmole) was added to above solution and stirred at room temperature overnight. The reaction mixture was acidified with 1.5 N HCl. The compound was extracted with EtOAc. The organic layer was washed with water and dried over anhydrous MgSO4. The filtrate was evaporated and dried in vacuo, after recrystalization with EtOH and water to afford a yellow solid (0.31 g, 59%): ESHRMS m/z391.0884 (M−H, C18H19O4F3Cl, Calc'd 391.0918). 1H NMR (acetone-d6/400 MHz) 7.84 (s, 1H), 7.45 (s, 1H), 5.88 (q, 1H, J=7.0 Hz), 3.92 (m, 2H), 2.17 (s, 3H), 1.71 (m, 1H), 1.61 (m, 2H), 1.53 (m, 2H), 0.971 (t, 6H, J=7.2 Hz).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:22])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[S:25].[Cl-].[NH4+].N>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[C:29]1[S:23][C:24](=[S:25])[N:26]([CH2:15][C:16]([OH:18])=[O:17])[C:27]1=[O:28])[C:13]1[N:14]=[C:10]([NH:9][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:22])[S:11][CH:12]=1)=[O:17])[CH3:20]
Reactant: O=C1CSC(=S)N1
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 3 g of ethyl 2-(3-phenylureido)thiazol-4-ylglyoxylate, 1.25 g of rhodanine, 1 g of ammonium chloride 1 ml of 28% v/v aqueous ammonia and 10 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Cl[C:20]1[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]=1.O>CC(N(C)C)=O>[NH2:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:25]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1ccnc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 90 °C

Procedure:
760 mg (3.25 mmol) 2,2,2-Trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 3 mL dry dimethylacetamide under argon atmosphere, and 273 mg (8.15 mmol) NaH is added over 5 min. 211 mg (1.63 mmol) 2-Chloropyrimidin-4-amine is then added and the solution stirred at 90° C. over night. 1 mL Water is added carefully to quench all excess NaH, and the mixture poured into 50 ml of 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (gradient ethyl acetate:cyclohexane from 1:1 to 3:1). Yield: 350 mg (52%). ESI-MS m/z 327 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=O)[CH:10]=[CH:9][C:7](=O)[C:5]=2[CH:6]=1.C1(=O)OC(=O)C2=CC=CC=C12.C1(=O)OC(=O)C=C1.S(=O)(=O)=O>>[CH:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:7]=2)[CH:3]=[CH:2][CH:1]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: O=C1C=CC(=O)O1
Agent: O=C1OC(=O)c2ccccc21
Agent: O=S(=O)=O
Product: c1ccc2ccccc2c1

Procedure:
The gas containing naphthoquinone, phthalic anhydride, maleic anhydride, sulfur trioxide and the unreacted naphthalene which is obtained by the catalytic gas phase oxidation of naphthalene is cooled to about 180° to 300° C. and is fed into a scrubber water washing type collector such as a spraying tower or a bubbling tower and is usually contacted with a collecting water at 30° to 70° C. so as to collect them as an aqueous slurry of phthalic acid and naphthoquinone, each at concentration of 1 to 30 wt.%. A constant quantity of the aqueous slurry is held at the bottom of the collector tower. A part of the aqueous slurry is discharged and treated by the conventional separation of naphthoquinone and phthalic acid, for example, the process for extracting naphthoquinone with an organic solvent such as toluene and xylene by heating the discharged aqueous slurry to separate naphthoquinone from the water phase containing phthalic acid and crystallizing phthalic acid by cooling the water phase and filtering it. The filtrate is recycled as the collecting water. Before the recycling, it is preferable to neutralize sulfuric acid and maleic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[C:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:22]3[CH2:23][CH2:24][CH:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: C1CCOC1
Product: Clc1ccc2nc(CN3CCC(c4ccccc4)CC3)cn2c1
Yield: 34 %

Procedure:
Following the general procedure of Example 39, Step 2 and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.307 g), 4-phenylpiperidine (Aldrich or Chart J; 0.2955 g), and THF (2 mL) are converted to product, which is chromatographed on silica gel using methanol/dichlormethane (4/96), followed by crystallization from ethyl acetate, to give 0.169 g of the title compound; mp 132-133° C.; MS m/z 325; IR (mineral oil) 1073, 801, 696, 1324, 1501 cm-1 ; 1H NMR (CDCl3) δ1.83, 2.20, 2.51, 3.14, 3.75, 7.11, 7.24, 7.52, 7.54, 8.13.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.Cl.[N:11]1([CH2:16][CH2:17][C:18](O)=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:18](=[O:19])[CH2:17][CH2:16][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: O=C(O)CCN1CCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(CCN1CCCC1)NNc1ccc(F)cn1
Reaction time: 18 h

Procedure:
5-fluoro-2-hydrazinopyridine (285 mg, 2.24 mmol) and 3-(pyrrolidin-1-yl)propanoic acid hydrochloride (400 mg, 2.24 mmol) were dissolved in DMF (15 mL). EDC (516 mg, 2.69 mmol), HOBt (30.0 mg, 0.22 mmol) and triethylamine (374 μL, 2.69 mmol) were added and the reaction stirred for 18 h. The mixture was loaded onto an SCX-2 cartridge, which was washed with MeOH then with 2M NH3 in MeOH. The basic fractions were evaporated in vacuo then purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound contaminated with several impurities (400 mg). The product was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:33])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=2)=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1nc(CO)cs1)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.8 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (100 mg, 0.22 mmol) in diethyl ether (10 mL) was cooled to 0° C. and then treated with lithium aluminum hydride (13 mg, 0.32 mmol). The reaction mixture was slowly warmed to 25° C. where it was stirred for 16 h. After this time, the reaction mixture was slowly diluted with water (5 mL) and then extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-phenoxy-phenyl)-propionamide (50 mg, 55%) as a white solid: mp 83.7-87° C.; EI-HRMS m/e calcd for C24H26N2O3S (M+) 422.1664, found 422.1674.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][O:14][C:15]([NH:17][CH2:18][C@@H:19]([C:21]([OH:23])=[O:22])[OH:20])=[O:16])=[CH:11][CH:10]=1.CI.CCOC(C)=O.CCCCCC>CO>[CH3:1][O:22][C:21](=[O:23])[C@@H:19]([OH:20])[CH2:18][NH:17][C:15]([O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:25][CH:24]=1)=[O:16]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(COC(=O)NC[C@H](O)C(=O)O)cc1
Agent: [Cs+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)[C@@H](O)CNC(=O)OCc1ccc(OC)cc1
Reaction time: 18 h

Procedure:
Stir cesium carbonate (6.2 g) and N-(4-methoxybenzyloxycarbonyl-(S)-isoserine (10 g) in dimethyl formamide(DMF) (50 ml) for 1 hr. then add methyl iodide (5.4 g). Stir the resulting mixture for 18 h and concentrate in vacuo. Partition the residue between EtOAc/water and then brine. Concentrate the dried (MgSO4) EtOAc solution in vacuo to give an amber oil. Chromatograph this oil on a column of flash silica gel (1100 ml) using EtOAc:hexane (9:1) as eluant to give an amber oil, [α]D26 =+16.9° (MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[CH:4][C:3]=1[CH2:17][NH:18][CH2:19][CH2:20][CH3:21].[N:22]#[C:23]Br>C(O)C>[NH2:22][C:23]1[N:18]([CH2:19][CH2:20][CH3:21])[CH2:17][C:3]2[C:2](=[CH:16][CH:15]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=3)[C:10]#[N:11])[CH:4]=2)[N:1]=1
Reactant: N#CBr
Reactant: CCCNCc1cc(Oc2cccc(C#N)c2)ccc1N
Solvent: CCO
Product: CCCN1Cc2cc(Oc3cccc(C#N)c3)ccc2N=C1N
Temperature: 25 °C

Procedure:
A mixture of 3-(4-amino-3-propylaminomethyl-phenoxy)-benzonitrile (0.032 mol) in ethanol (400 mL) was stirred at room temperature, and cyanogen bromide (0.038 mol) was added, and then the reaction mixture was stirred and refluxed for 2 hours. After cooling, the precipitate was filtered off, washed with diisopropyl ether and dried to yield crude product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=C/N(C)C)[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][N:3]=1.I([O-])(=O)(=O)=[O:17].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:5]([N+:13]([O-:15])=[O:14])=[CH:4][N:3]=1)[CH:8]=[O:17]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)/C=C/c1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a solution of (E)-2-(2-chloro-5-nitropyridin-4-yl)-N,N-dimethylethenamine (1.0 equiv) in 1:1 THF/H2O (0.1 M) was added sodium periodate (3.0 equiv) portionwise. The resulting solution was stirred at rt for 6 hours, at which time the white solid was filtered and rinsed with ethyl acetate. The entire filtrate was washed with NaHCO3(sat.), with NaCl(sat.), dried over MgSO4, filtered and concentrated. Purification by column chromatography (20% ethyl acetate/hexanes, Rf=0.3) yielded 2-chloro-5-nitroisonicotinaldehyde (71%). 1H NMR (CDCl3): δ 10.51 (s, 1H), 9.25 (s, 1H), 7.75 (s, 1H).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:66]=[CH:65][CH:64]=[C:63]([F:67])[C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([O:58]C)=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]>>[F:33][C:34]1[CH:66]=[CH:65][CH:64]=[C:63]([F:67])[C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([OH:58])=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4c(F)cccc4F)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4c(F)cccc4F)cc3)cc2C1=O
Yield: 77 %

Procedure:
The compound of example 138 was prepared analogous to compound of example 98 by hydrolysis of compound of example 137.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[CH2:16][CH2:15][N:14]([CH3:17])[C:13](=[O:18])[C:9]3=[C:10]([O:11]C)[C:6]=2[C:5](=[O:19])[N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=2)[N:3]=1.[CH3:29][C:30](=O)[CH2:31][CH2:32][C:33](=O)[CH3:34].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[CH2:20][N:4]1[C:5](=[O:19])[C:6]2[C:10]([OH:11])=[C:9]3[C:13](=[O:18])[N:14]([CH3:17])[CH2:15][CH2:16][N:8]3[C:7]=2[C:2]([N:1]2[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]2[CH3:29])=[N:3]1
Reactant: COc1c2n(c3c(N)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1nn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 120 °C

Procedure:
A mixture of 4-amino-2-(3-chloro-4-fluorobenzyl)-10-methoxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (100 mg, 246 μmol), hexan-2,5-dione (34 mg, 296 μmol), and toluenesulfonic acid (catalytic amount) in toluene (2 mL) was heated in a sealed tube in an oil bath at 120° C. for one hour. The product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0-30% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][CH3:9])(=[O:7])[CH2:5][SH:6].Cl[C:11]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[CH:12][C:13]#[N:14]>CO>[NH2:14][C:13]1[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[S:6][C:5]=1[C:4]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CS
Reactant: N#CC=C(Cl)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc(-c2ccncc2)cc1N
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
To a stirred solution of sodium methoxide (2.12 g, 39.3 mmol) in methanol (59 mL) was added methyl thioglycolate (3.51 mL, 39.3 mmol). After 10 min, 3-chloro-3-(pyridin-4-yl)acrylonitrile (6.47 g, 39.3 mmol) was added, and the mixture was heated at 50° C. After 1 h, the mixture was concentrated to about a half volume at reduced pressure and poured into water (500 mL). Extraction with ethyl acetate/tetrahydrofuran (4:1, 500 mL), washing with brine, drying over magnesium sulfate, filtration and concentration at reduced pressure gave the title compound (8.81 g, 96%) as a yellow solid:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39]O>C(Cl)Cl.O>[I:25][CH2:39][CH:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[O:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][O:27]1
Reactant: OCC1CCCC1OC1CCCCO1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: ICC1CCCC1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
A solution of triphenylphosphine (1.70 g, 6.49 mmol) and imidazole (884 mg, 12.98 mmol) in methylene chloride (8.32 mL) cooled to 0° C. was treated with iodine (1.64 g, 6.49 mmol). After the iodine was completely dissolved, a solution of [2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-methanol (1.0 g, 4.99 mmol) was added to the reaction mixture. The reaction was stirred at 0° C. for 1 h and at 25° C. for 2 h. At this time, the reaction was poured into water (100 mL) and extracted with methylene chloride (1×30 mL). The organics were washed with a saturated aqueous sodium thiosulfate solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo at 25° C. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(2-iodomethyl-cyclopentyloxy)-tetrahydropyran (1.17 g, 75.8%) as a clear liquid: EI-HRMS m/e calcd for C11H19IO2 (M+) 309.0352 found 309.0348.