Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]#[N:27])[CH2:13][CH2:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)=[CH:10][CH2:9]2)=[CH:4][CH:3]=1.C[O-].[Na+].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]#[N:27])[CH2:9][CH2:10][CH:11]([N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][CH2:19]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(F)cc2)CC=C(N2CCN(c3cccnn3)CC2)CC1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#CC1(c2ccc(F)cc2)CCC(N2CCN(c3cccnn3)CC2)CC1
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a stirred mixture of 7.3 parts of 1-(4-fluorophenyl)-4-[4-(3-pyridazinyl)-1-piperazinyl]-3-cyclohexenecarbonitrile, 1 part of sodium methoxide solution 30% and 240 parts of methanol were added portionwise 0.8 parts of sodium borohydride. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured onto ice water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanol, yielding 4.5 parts (61.5%) of 1-(4-fluorophenyl)-4-[4-(3-pyridazinyl)-1-piperazinyl]cyclohexanecarbonitrile; mp. 188.7° C. (compound 8).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])[CH:8]=[C:9]1[C:14](=[O:15])[N:13]([CH2:16][C:17]#[N:18])[C:12]2[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=2[S:10]1)([CH3:4])([CH3:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].O>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])[CH:8]=[C:9]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[NH:33][N:32]=[N:31][N:18]=2)[C:12]2[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=2[S:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1cc(C=C2Sc3ccccc3N(CC#N)C2=O)cc(C(C)(C)C)c1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(C=C2Sc3ccccc3N(Cc3nnn[nH]3)C2=O)cc(C(C)(C)C)c1O
Temperature: 105 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 2-(3,5-di-tert.-butyl-4-hydroxybenzylidene) -4-cyanomethyl-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (compound No. 1-1, 0.335 g) in dimethylformaldehyde (5 ml), sodium azide (0.078 g) and ammonium chloride (0.064 g) were added. The mixture was stirred overnight at 105° C. under a nitrogen atmosphere. To the mixture, water was added, and the whole was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. To the oily residue, 1N aqueous sodium hydroxide solution was added. The mixture was washed with diethyl ether, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 0.21 g (56.9%) of the titled compound.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](O)=[O:9])=[CH:3][CH:2]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([N:19]([O:20][CH3:21])[CH3:18])=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A mixture of 2-(biphenyl-4-yl)acetic acid (1 g, 4.7 mmol), N,O-dimethylhydroxylamine hydrochloride (458 mg, 4.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (900 g, 4.7 mmol), hydroxybenzotriazole (635 mg, 4.7 mmol), and triethylamine (1.42 g, 14.1 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. When TLC indicated that 2-(biphenyl-4-yl)acetic acid was consumed, the reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE: EtOAc=8:1) to afford 2-(biphenyl-4-yl)-N-methoxy-N-methylacetamide (1.0 g, yield 83%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:14]=O.[C:16]([O:20][CH3:21])(=[O:19])[NH:17][NH2:18]>C(O)(=O)C.C(Cl)Cl>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:14]=[N:18][NH:17][C:16]([O:20][CH3:21])=[O:19]
Reactant: Cc1cccc(-c2nc(C=O)c(C)[nH]2)c1
Reactant: COC(=O)NN
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)NN=Cc1nc(-c2cccc(C)c2)[nH]c1C

Procedure:
A mixture of 5-methyl-2-m-tolyl-4-imidazolecarboxaldehyde (6.9 g, 0.034 mole), methyl carbazate (3.1 g, 0.034 mole). methylene chloride (70 ml) and acetic acid (1 drop) is refluxed for 1 hour. The precipitated white solid is collected by filtration to yield 7.1 g (0.026 mole), mp. 162°-164° c.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:11])=[CH:7][CH:6]=[C:5]([Cl:20])[CH:4]=1.Cl[O-].[Na+]>O.CO>[Cl:20][C:5]1[CH:4]=[CH:3][C:8]2[NH:9][C:10](=[O:11])[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:7]=2[CH:6]=1
Reactant: O=C(Nc1ccc(Cl)cc1)Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]c2ccc(Cl)cc2n1-c1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
A solution of sodium hydroxide (4 grams (g)) in water (15 milliliters (ml)) was added to a solution of 4,4'-dichlorocarbanilide (14.1 g, 0.05 mole) in methanol (300 ml). Sodium hypochlorite solution (100 ml, 1 N in 0.1 molar sodium hydroxide) was then added dropwise over 30 minutes to the vigorously stirred reaction mixture, maintaining the temperature below 35° C. by means of an ice bath. Stirring was continued at room temperature for 5 hours after which the small amount of solid present was removed by filtration. The filtrate was evaporated to a volume of about 50 ml, diluted with water (500 ml), and subsequently acidified to a pH of 3 with hydrochloric acid. The product was then filtered, washed with water, dried at 80° C. and identified as 6-chloro-1-(4-chlorophenyl)-2-benzimidazolinone by infrared spectra. The product recovery was 66 percent of theoretical and the product melted at 239° C. (recrystallized from toluene).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[CH2:13]([O:15][C:16](=[O:34])[C@H:17]([NH2:33])[CH2:18][CH:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]OS(C)(=O)=O)[CH3:14].O>CN(C)C=O>[CH2:13]([O:15][C:16](=[O:34])[C@H:17]([NH2:33])[CH2:18][CH:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][S:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[CH3:14]
Reactant: COc1ccc(CS)cc1
Reactant: CCOC(=O)[C@H](N)CC(COS(C)(=O)=O)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](N)CC(CSCc1ccc(OC)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (5.5 g, 137.8 mmol) and 4-methoxybenzylmercaptan (15.4 mL, 110.2 mmol) were dissolved in N,N-dimethylformamide (150 mL), and the mixture was stirred for 10 min at 0° C. To the resulting solution was added in drops (R)-4-BOC-amino-5-methanesulfonyloxy-pentanoic acid ethyl ester (46.7 g, 137.8 mmol) prepared in Step B, and the mixture was stirred for 4 h at 0° C. Water was added thereto to quench the reaction, and the reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound.
Reaction SMILES: [F-].[Cs+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH:12]1[CH2:16][CH2:15][O:14][C:13]1=[O:17].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])=[CH:6][CH:5]=1
Reactant: O=C1OCCC1Br
Reactant: Oc1ccc(Cl)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OCCC1Oc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 54.8 %

Procedure:
Cesium fluoride (7.6 g) was added to a solution of 4-chlorophenol (1.29 g) in dimethylformamide (35 mL) and the mixture was stirred at 100° C. for 5 min. 3-bromodihydrofuran-2(3H)-one (3.3 g) was added and the reaction mixture was heated to 120° C. for 1.5 h. The reaction mixture was poured into water and extracted with EtOAc. The aqueous layer was extracted with ethylacetate. The organic layers were washed with water, dried over sodium sulfate and filtered. The crude mixture was concentrated to dryness and purified by chromatography on silica gel to yield the title compound as a colorless oil (1.17 g; 55%). MS (ESI): m/z=212 [M]+.
Reaction SMILES: Br[C:2]1[N:3]([CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[C:8]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[CH3:20])[CH:7]=[CH:6][CH:5]=2.[CH3:28]B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10](=[O:12])[C:11]([CH3:28])=[CH:2][N:3]2[CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC(CCC)n1c(Br)cc(=O)c2c(-c3ccc(C)cc3C)cccc21
Reactant: CB(O)O
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CCC)n1cc(C)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
3 Bromo-5-(2,4-dimethylphenyl)-1-(1-propylbutyl)quinolin-4(1H)-one was then charged with methylboronic acid (0.19 g, 3.2 mmol), potassium carbonate (0.22 g, 1.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol) and diluted with dioxane (8 mL) under nitrogen gas. Water (29 μL, 1.6 mmol) was added last. The reaction was stirred at 90° C. overnight. The solution was cooled and concentrated. Flash chromatography (40% ethyl acetate/hexanes) gave 0.049 g (43% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9][C:10]([OH:14])([C:12]#[CH:13])[CH3:11].[Cl-].[NH4+].[OH2:19].O=O>C(O)C>[CH3:16][C:2](=[CH:3][CH2:4][CH2:5][C:6]([CH3:15])=[CH:7][CH2:8][CH2:9][C:10]([CH3:11])([OH:19])[C:12]#[C:13][C:13]#[C:12][C:10]([CH3:11])([OH:14])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:15])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])[CH3:1]
Reactant: O
Reactant: C#CC(C)(O)CC/C=C(\C)CCC=C(C)C
Agent: O=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)=CCCC(C)=CCCC(C)(O)C#CC#CC(C)(O)CCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 5 l-capacity, 3-neck, round-bottom flask was charged with 114.7 g of dehydronerolidol, 305.9 g of ammonium chloride, 191.2 g of cuprous chloride, 765 ml of water and 765 ml of ethyl alcohol, and the mixture was agitated at room temperature for 18 hours while blowing oxygen thereinto. After completion of the reaction, none of the starting reactants were left. The reaction mixture was separated with a centrifuge, and the mother solution was extracted with benzene. Benzene and ethyl alcohol were removed from the organic layer by distillation, and the residue was dissolved in benzene and washed with water. The resulting benzene solution was dried with anhydrous calcium sulfate and the solids were removed from the dried solution by filtration. Distillation of benzene from the benzene solution gave 107.8 g of a viscous liquid of 2,6,10,15,19,23-hexamethyltetracosa-2,6,18,22-tetraene-11,13-diyne-10,15-diol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[N:19]=[C:20]=[O:21]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[NH:19][C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)=[O:21]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2[nH]ncc2c1)Nc1c(Cl)cccc1Cl
Temperature: 110 °C
Reaction time: 4 h

Procedure:
5-Aminoindazole (100 mg, 0.75 mmol) and 2,6-dichlorophenyl isocyanate (155.3 mg, 0.83 mmol, 1.1 eq) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]1[C:30]1[C:31]([O:36]CC2C=CC=CC=2)=[N:32][CH:33]=[CH:34][CH:35]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH:24]1([C:13]2[C:14]3[C:19](=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[N:11]([CH2:10][CH2:9][OH:8])[C:12]=2[C:30]2[C:31]([OH:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccnc3OCc3ccccc3)n(CCOCc3ccccc3)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccnc3O)n(CCO)c2c1
Reaction time: 72 h
Yield: 89.6 %

Procedure:
To a solution of methyl 1-(2-(benzyloxy)ethyl)-2-(2-(benzyloxy)pyridin-3-yl)-3-cyclohexyl-1H-indole-6-carboxylate (57 mg, 0.099 mmol) in ethyl acetate (10 mL), 10% Pd on carbon (10 mg) was added. The reaction mixture was stirred under an hydrogen atmosphere (1 atmos.) for three days. It was filtered through celite, and the filtrate concentrated to give the title compounds as an off-white solid, (35 mg, 90% yield). MS m/z 395(MH+); 1H NMR (300 MHz, CD3OD) δ ppm 1.24-1.40 (m, 3 H) 1.70-1.98 (m, 7 H) 2.58 (m, 1 H) 3.71 (t, J=6.04 Hz, 2 H) 3.94 (s, 3 H) 4.11 (m, 1 H) 4.22 (m, 1 H) 6.58 (t, J=6.59 Hz, 1 H) 7.58-7.76 (m, 3 H) 7.82 (d, J=8.78 Hz 1 H) 8.19 (s, 1 H).
Reaction SMILES: [O:1]=[O+][O-].C1(C=[CH:11][C@@H:12]2[N:15]([Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:14](=[O:23])[C@H:13]2[CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=[N:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])C=CC=CC=1>C(Cl)Cl>[CH:11]([C@@H:12]1[N:15]([Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:17])[CH3:18])[C:14](=[O:23])[C@H:13]1[CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[N:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:1]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ozone was passed through a -78° C. CH2Cl2 (650 mL) solution of compound 4a (55 g, 84 mmol) until a blue color was maintained. Excess ozone was purged with N2. Dimethyl sulfide (60 mL) was added. The solution was allowed to warm to room temperature and to stand for 48 h. The solution was concentrated to afford the title compound which was not further purified but used directly in step B.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=4)=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(F)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-fluorobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA to yield the title compound.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Si:23]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([NH2:47])=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1C=CC=CC=1>[Si:23]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](=[S:10])[NH2:47])([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)[Si](OCCCCC(N)=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(C)(C)[Si](OCCCCC(N)=S)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lawesson's reagent (8.19 g, 20.25 mmol) was heated to reflux in benzene (100 mL) for 1 hr. Cool to just below reflux temperature, and add a solution of 5-{[tert-butyl(diphenyl)silyl]oxy}pentanamide (7.20 g, 20.25 mmol in 50 mL benzene). Stir at room temperature for 2 hrs. Concentrate in vacuo to a chunky oil and purified via silica gel chromatography (eluent: 9:1 Hexane:Ethyl Acetate) to give the product as a yellow-green oil. Yield: 6.50 g (62%) 1H NMR (DMSO-d6) δ7.65–7.60 (m, 4H), 7.49–7.41 (m, 6H), 3.68–3.63 (t, 2H), 2.50–2.44 (t, 2H), 1.80–1.70 (m, 2H), 1.60–1.51 (m, 2H), 1.00 (s, 9H).
Reaction SMILES: [CH2:1]=[O:2].[C:3]1(=[O:9])[NH:7][C:6](=[O:8])[CH:5]=[CH:4]1>C(=O)([O-])[O-].[K+].[K+].O>[OH:2][CH2:1][N:7]1[C:6](=[O:8])[CH:5]=[CH:4][C:3]1=[O:9]
Reactant: C=O
Reactant: O=C1C=CC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1C=CC(=O)N1CO
Temperature: 25 °C

Procedure:
A mixture of 125 grams of water, 26 ml. of 37% aqueous formaldehyde solution, 25 grams of maleimide, and 0.1 gram of anhydrous potassium carbonate was heated at its reflux temperature for 90 minutes, cooled to ambient temperature, and filtered. After removal of the water by heating under vacuum, there was obtained 32 grams of N-hydroxymethylmaleimide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=1)[CH3:2].[CH3:16][C:17]([CH3:24])([CH3:23])[C:18](=O)[CH2:19][C:20]#[N:21]>CCO>[C:17]([C:18]1[CH:19]=[C:20]([NH2:21])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[CH:8][CH:9]=2)[N:14]=1)([CH3:24])([CH3:23])[CH3:16]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CCOC(=O)CCc1ccc(NN)cc1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Yield: 85.1 %

Procedure:
A mixture of 3-(4-hydrazinophenyl)propionic acid ethyl ester (13 g, 53.3 mmol) and 4,4-dimethyl-3-oxopentanenitrile (6.9 g, 55 mol) in EtOH (150 mL) was heated at reflux overnight. The reaction solution was evaporated under vacuum. The residue was purified by column chromatography to yield ethyl 3-(4-(3-t-butyl-5-amino-1H-pyrazol-1-yl)phenyl)propanoate (14.3 g, 85% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6); δ 7.44 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 5.34 (s, 1H), 5.11 (s, 2H), 4.04 (q, J=7.2 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H), 1.19 (s, 9H), 1.15 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 316 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13]CC)=O.O[C@@H](C1C=CC=C(O)C=1)[CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C>C(#N)C>[O:13]=[C:11]([C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([O:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[CH2:21][C:22]#[N:23]
Reactant: CCOC(=O)c1cccc(OCc2cccs2)c1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Solvent: CC#N
Product: N#CCC(=O)c1cccc(OCc2cccs2)c1

Procedure:
Condensation between ethyl 3-(thiophen-2-ylmethoxy)benzoate and acetonitrile following the method used in the preparation of phenol (Intermediate I) gave after flash column chromatography 3-oxo-3-(3-(thiophen-2-ylmethoxy)phenyl)propanenitrile as a colorless oil.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([CH2:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:17]([C:16]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(=O)Cc1cccnc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1cc2cccnc2[nH]1
Yield: 115.9 %

Procedure:
A solution of 1-[2-(t-butoxycarbonylamino)pyridin-3-yl]hexan-2-one (42) (4.2 g) (prepared, e.g, as described in Preparation 29), in dichloromethane (25 ml) and trifluoroacetic acid (10 ml) was stirred at room temperature overnight. The solution was concentrated under vacuum and the residue was partitioned between aqueous ammonium hydroxide and ether. The ether layer was washed with brine, dried, and the solvent was evaporated. The residue was further purified by silica gel chromatography, eluting with 30% ethyl acetate-hexane, to give 2-(n-butyl)-7-azaindole (2.9 g), a compound of Formula (43), as an oil, which crystallized on standing to a solid, m.p. 46°-47° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:29])[C:17]([C:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1C1=CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
Acryloyl chloride (0.217 mL, 1M in THF, 0.22 mmol) was added dropwise to a slurry of N′-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine (Intermediate 7, 100 mg, 0.22 mmol) and DIPEA (0.057 mL, 0.33 mmol) in THF (3 mL) at −5° C. over a period of 1 minute under N2. The resulting mixture was stirred at 0° C. for 15 minutes and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (5 mL) plus a few drops of CH3OH, and washed with sat. NaHCO3 (2 mL). The organic solution was then dried (MgSO4) and loaded onto silica in vacuo. Purification by FCC, eluting with 5-25% CH3OH in CH2Cl2 and concentration of appropriate fractions in vacuo provided a residue that was washed with CH3OH (0.3 mL) and dried in air to give the title compound (37 mg, 31%) as a beige crystalline solid. 1H NMR: 2.28 (3H, s), 2.38 (2H, m), 2.55 (2H, m), 2.98 (2H, d), 3.85 (3H, s), 5.6-5.72 (2H, m), 6.15 (1H, m), 6.41 (1H, m), 6.88 (1H, s), 7.10 (1H, t), 7.18 (1H, t), 7.47 (1H, d), 7.98 (1H, s), 8.33 (1H, s), 8.36 (1H, d), 8.42 (1H, s), 8.49 (1H, s), 9.29 (1H, s), 11.86 (1H, s); m/z: ES+ MH+ 515.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([O:11][CH3:12])(=[O:10])[CH2:6][C:7]([CH3:9])=O>>[CH3:12][O:11][C:5](=[O:10])[CH:6]=[C:7]([NH:4][CH2:3][CH2:1][OH:2])[CH3:9]
Reactant: COC(=O)CC(C)=O
Reactant: NCCO
Product: COC(=O)C=C(C)NCCO
Temperature: 0 °C
Yield: 91.2 %

Procedure:
To an ice-cooled sample of ethanolamine (6.1 g) was added methyl acetoacetate (11.6 g) dropwise. Compound (XXIII 14.5 g) was formed within 30 min (U.S. Pat. No. 1102800).