Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[C:20]([O:24][C:25]([CH2:27][C@@H:28]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:29](N1[C@H](C(C)C)COC1=O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[CH2:1]([O:8][C:29](=[O:30])[C@H:28]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a stirred solution of dry benzyl alcohol (0.55 ml, 5.33 mmol) in anhydrous tetrahydrofuran (18 ml) under a nitrogen atmosphere at 0° C. was added a hexane solution of n-butyllithium (2.58 ml, 4.00 mmol). To this solution was added the product from Example 97 in anhydrous tetrahydrofuran (10 ml). After stirring 1 h at 0° C. the reaction was quenched by adding excess saturated aqueous ammonium chloride. The volatiles were removed by rotary evaporation and the resulting aqueous residue extracted two times with ether. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo provided an oil which was purified by chromatography on SiO2 (15% ether acetate/hexanes) to provide the desired product (0.89 g, 94%) as a colorless oil. Mass spectrum: (M)+ =354.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C(N(CC)CC)C>[CH3:17][Si:18]([C:21]#[C:22][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:20])[CH3:19]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(C#C[Si](C)(C)C)c1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
To tert-butyl 3-bromobenzylcarbamate (220 mg, 1 mmol) in triethylamine (3 ml), trimethylsilyl acetylene (147 mg, 1.5 mmol) was added followed by cuprous iodide (8 mg, 0.04 mmol). After stirring for 5 min, dichloro bis (triphenylphosphine) palladium (II) (35 mg, 0.05 mmol) was added and the reaction mixture was heated at 90° C. for 18 h. Then the reaction mixture was filtered, diluted with ethyl acetate and washed with water. Organic layer was dried, evaporated and the crude residue was purified by column chromatography to obtain tert-butyl 3-((trimethylsilyl)ethynyl)benzylcarbamate in 67% yield.
Reaction SMILES: CC1(C)[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]([O:18][CH2:19]C)=[O:17])[CH:5]=[CH:4][C:3]1=2.CC1(C)C2C(=CC=C(C#C)C=2)[S:26]CC1.COC(Cl)=O.C([Li])CCC>>[CH3:12][C:9]1([CH3:13])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:14]#[C:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=2)[S:26][CH2:11][CH2:10]1
Reactant: CCOC(=O)C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Agent: COC(=O)Cl
Agent: [Li]CCCC
Product: COC(=O)C#Cc1ccc2c(c1)C(C)(C)CCS2

Procedure:
Employing the same general procedure as used for the preparation of ethyl 3-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)propiolate (Compound A), but instead using 2.0 g (10 mmols) of (4,4-dimethyl-thiochroman-6-yl)ethyne, 2 g (21.3 mmols) of methylchloroformate and 11 mmols of n-butyl lithium the title compound was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([O:17][CH2:18][CH3:19])=[CH:11][C:12]([CH:13]=[O:14])=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc(C=O)ccc1OCc1ccccc1
Solvent: ClCCl
Product: CCOc1cc(C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Benzyloxy-3-ethoxy-benzaldehyde (20 g) was dissolved in dichloromethane (100 ml) and a solution of nitric acid in dichloromethane (2M, 200 ml) was gradually added at a temperature under 30° C. The solution was stirred at room temperature for 10 min and then it was poured into ice-cold water. The organic phase was washed with 1M sodium hydroxide and water and then it was dried and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH3:22])=[C:16]([CH3:23])[CH:15]=2)[C:6]1=[O:24].C[Si]([N-][Si](C)(C)C)(C)C.[K+].F[C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH3:22])=[C:16]([CH3:23])[CH:15]=2)([C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)[C:6]1=[O:24]
Reactant: COc1c(C)cc(C2C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)cc(C2(c3ccc([N+](=O)[O-])cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Temperature: 20 °C
Yield: 240.8 %

Procedure:
Dissolve 1-(2-chloro-benzyl)-3-(4-methoxy-3,5-dimethyl-phenyl)-1,3-dihydro-indol-2-one (222 mg, 0.57 mmol) in anhydrous DMF (5 mL) under nitrogen. Cool in an ice bath and add at 5-8° C. a 0.5M solution of potassium bis(trimethylsilyl)amide (1.2 mL, 0.6 mmol). After 10 min. remove the ice bath and allow to warm to 20° C. over 30 min. Add 1-fluoro-4-nitrobenzene (0.21 mL, 2 mmol) and heat at 80° C. for 3 h. Allow to cool to room temperature and partition between saturated NH4Cl solution (25 mL) and ethyl acetate (50 mL). Separate, dilute aqueous portion with water (25 mL) and extract with ethyl acetate (2×50 mL). Combine all organic portions and wash with 1N HCl (50 mL) and brine (50 mL). Dry (MgSO4), filter and concentrate in vacuo to give 704 mg of a yellow oil. Purify by flash chromatography (gradient of 50% hexanes/CH2Cl2 to 100% CH2Cl2) to give 259 mg (89%) of the title compound as a light yellow foam. MS (FAB, M+1): calcd for C30H25ClN2O4 513.1581. found 513.1577; 1H NMR(DMSO-d6): □8.23 (m, 2H), 7.55-4.63 (m, 4H), 7.35-7.27 (m, 3H), 7.16 (t, J=7.5, 6.8 Hz, 1H), 7.02 (m, 2H), 6.86 (s, 2H), 5.11 (s, 2H), 3.65 (s, 3H), 2.16 (s, 6H). Anal. Calcd for C30H25ClN2O4: C, 70.24; H, 4.91; N, 5.47. Found C, 70.05; H, 5.19; N, 5.42.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1.[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C([O-])=O.[Na+]>CO>[CH2:1]([O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([OH:16])=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[CH:11]=1)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 100 °C
Yield: 96.5 %

Procedure:
109 g (0.374 mol) of β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid methyl ester, 92.5 g (0.34 mol) of stearyl alcohol and 0.2 g of sodium formate (0.003 mol) are introduced into a vessel and melted and stirred at 100° C. under nitrogen. As soon as a melt is obtained, cautiously evacuation is carried out and at the same time the melt is heated to an internal temperature of from 150 to 160° C. The methanol formed is distilled off and condensed in a cold trap. As soon as an internal pressure of <10 mbar is reached, the internal temperature is increased to from 170 to 180° C. and further evacuation to <1 mbar is carried out. As soon as IT=180° and a pressure of <1 mbar is reached, those conditions are maintained for one hour and then, in the course of from 1 to 2 hours at IT=200-210° C., the excess β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid methyl ester is removed by distillation. The reaction melt then contains <0.2% starting materials and has a content of >98% β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid octadecyl ester. The reaction melt is cooled, and left to stand for crystallisation. Yield 96.5%; m.p. 51° C.
Reaction SMILES: [N:1]1([C:7](=[O:18])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([CH2:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:18])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CC(=O)N2CCOCC2)c1
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a stirred suspension of (3-nitro-phenyl)-acetic acid (2 g) in CH2Cl2 (40 ml, with a catalytic amount of DMF) at 0° C. under N2 was added oxalyl chloride (1.1 ml) drop wise. The reaction mixture was stirred for 40 min morpholine (2.5 g) was added. After stirring for 20 min, the reaction mixture was filtered. The filtrate was concentrated in vacuo to yield 1-morpholin-4-yl-2-(3-nitro-phenyl)-ethanone as a solid (2 g). A mixture of 1-morpholin-4-yl-2-(3-nitro-phenyl)-ethanone (2 g) and 10% Pd on activated carbon (0.2 g) in ethanol (30 ml) was hydrogenated at 30 psi for 3 h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g). A solution of 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g, 7.7 mmol) was dissolved in 6 N HCl (15 ml), cooled to 0° C., and vigorously stirred. Sodium nitrite (0.54 g) in water (8 ml) was added. After 30 min, tin (II) chloride dihydrate (10 g) in 6 N HCl (30 ml) was added. The reaction mixture was stirred at 0° C. for 3 h. The pH was adjusted to pH 14 with solid potassium hydroxide and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazin-phenyl)-1-morpholin-4-yl-ethanone (1.5 g). 2-(3-Hydrazinophenyl)-1-morpholin-4-yl-ethanone (3 g) and 4,4-dimethyl-3-oxopentanenitrile (1.9 g, 15 mmol) in ethanol (60 ml) and 6 N HCl (1 ml) were refluxed for 1 h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue that was extracted with ethyl acetate. The volatiles were removed in vacuo to provide 2-[3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)phenyl]-1-morpholinoethanone (4 g), which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[C:16]#[N:17].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[C:16]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)#[N:17]
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c(C#N)c1
Reactant: C1CNCCN1
Product: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c(C#N)c1

Procedure:
10.0 g (40.4 mmol) of 6-(4-chloro-3-cyano-phenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are reacted with 10 g of piperazine in a manner analogous to Example 1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11])(=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1c2ccccc2CC1C(=O)O
Reaction time: 0.25 h

Procedure:
To a solution of indoline-2-carboxilic acid (8.16 g, 50 mmol) and triethyl amine (10 mL, 71.74 mmol) in anhydrous CH2Cl2 (60 mL) containing catalytic amount of DMAP was added dropwise a solution of propionyl chloride (5.55 g, 60 mmol) in CH2Cl2 (20 mL) at 0° C. The reaction mixture was stirred at this temperature for 15 min and then at room temperature for 2.5 hours. The reaction mixture was washed successively with 5% aqueous KHSO4 solution (2×20 mL), brine (25 mL), dried over Na2SO4, and evaporated under reduced pressure to dryness. The residue was crystallized from methanol to yield 1-propionyl-2,3-dihydro-1H-indole-2-carboxylic acid as a white solid, 9.19 g (83%): mp 173-175° C.; 1H NMR (DMSO-d6) δ1.05 (3H, t, J=7.6 Hz, Me), 2.51 (2H, d, J=7.6 Hz, CH2), 3.17 (1H, d, J=16.0 Hz, CH), 3.57 (1H, dd, J=11.0 Hz, J=16.0 Hz, N—CH), 5.15 (1H, d, J=16.0 Hz, CH), 6.98-7.01 (1H, m, ArH), 7.15-7.23 (2H, m, 2×ArH), 8.07-8.09 (1H, m, ArH), 13.26 (1H, brs, exchangeable, OH). Anal. Calcd. for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.73; H, 6.07; N, 6.34.
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)[NH2:27]>>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:26]([C:28]5[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=5)[N:27]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Reactant: Cc1cc(NN)ccn1
Product: Cc1cc(-n2nccc2-c2nn(-c3ccc4c(c3)OC(F)(F)O4)ccc2=O)ccn1

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=410.2 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[NH:16][C:15](=O)[CH2:14][CH2:13][CH2:12][C:11]=3[CH:18]=2)[CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[NH:16][C:15](=[S:28])[CH2:14][CH2:13][CH2:12][C:11]=3[CH:18]=2)[CH:2]=1
Reactant: O=C1CCCc2cc(-c3cccnc3)ccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1CCCc2cc(-c3cccnc3)ccc2N1
Temperature: 25 °C

Procedure:
The title compound from Example 2 Step D (0.200 g, 0.839 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane2,4-disulfide (0.255 g, 0.629 mmol) were suspended in toluene (1.7 mL) and then heated to reflux for several hours. The reaction solution was then cooled to room temperature and concentrated. Purification by flash chromatography on silica gel (0-10% methanol in ethyl acetate) provided the title compound: LCMS m/z 255.03 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.81 (s, 1H), 8.48-8.47 (m, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.58-7.56 (m, 2H), 7.42 (dd, J=4.8, 7.9 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 2.74-2.71 (m, 2H), 2.68-2.65 (m, 2H), 2.26-2.20 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[CH3:9][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:9][C:4]1([CH2:7][NH2:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#CC1CCOCC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(CN)CCOCC1
Reaction time: 1.5 h

Procedure:
A mixture of tetrahydropyran-4-carbonitrile (5.00 g) and THF (50 ml) was admixed at 0° C. with lithium hexamethyldisilazide (1 M, 63 ml), and, after 90 minutes, methyl iodide (4.26 ml) was added dropwise with good cooling. After 12 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was dissolved in THF (200 ml), and lithium aluminum hydride (3.79 g) was added. The mixture was boiled at reflux for 6 hours, Water (3.8 ml) and then sodium hydroxide solution (40%; 3.8 ml) were cautiously added dropwise to the cooled suspension. The precipitate was filtered off and the filtrate was concentrated. This afforded the product with the molecular weight of 129.20 (C7H15NO); MS (ESI): 130 (M+H+).
Reaction SMILES: [C:1]1([NH:7][N:8]=[CH:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:11][C:12]#[N:13].[Na+].C1(N2CC(=O)NN2)C=CC=CC=1.[Cl-].[Na+]>O.C(O)(=O)C.C(O)(C)(C)C>[CH3:10][CH:9]1[NH:13][C:12](=[O:11])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:8]1
Reactant: N#C[O-]
Reactant: CC=NNc1ccccc1
Agent: O=C1CN(c2ccccc2)NN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC(=O)O
Product: CC1NC(=O)N(c2ccccc2)N1
Temperature: 5 °C

Procedure:
A 500 gallon reactor is charged with 61.1 pounds of tert-butanol (88/12 azeotrope with water) which is stirred and cooled to 5° C. To this is added 22.0 pounds (0.203 lb-mole) of acetaldehyde phenylhydrazone. While maintaining the temperature of the reaction mixture at 0° to 5° C., 15.6 pounds (0.240 lb-mole) of 85% pure sodium cyanate in 44.5 pounds of water is added during a five-minute period. The reaction mixture is maintained at 5° C. as it is stirred during a 30 minute period. While maintaining the reaction mixture at about 10° C., 14.8 pounds (0.247 lb-mole of acetic acid is added during about a 30-45 minute period. Upon completion of the addition, the reaction mixture is stirred for three hours at about 10° C. until the reaction is complete. The reaction endpoint and the concentration of the phenyltriazolidinone intermediate are determined by gas chromatograph. At the end of this time, a solution of 12.6 pounds of sodium chloride in 35.8 pounds of water is stirred into the reaction mixture. The aqueous phase is separated when the reaction mixture temperature is about 15° C. After this time, 67.8 pounds of water is added to the reaction mixture and 73.4 pounds of tert-butanol/water (88/12) is removed by distillation at an overhead temperature of 80° C. The residue is cooled to 0° C., and a solid is collected by filtration. The solid is dried at 80° C./5 mm Hg for 24 hours to yield 3-methyl-1-phenyl-1,2,4-triazolidin-5-one.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([O:16]CC)=O)[NH:12][CH:13]=1.ClC1C=CC=CC=1C1C=C(C(OC)=O)[NH:29][N:30]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([NH:29][NH2:30])=[O:16])[NH:12][CH:13]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C)c2C)c[nH]1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)n[nH]1
Product: Cc1cccc(-c2c[nH]c(C(=O)NN)c2)c1C
Yield: 59 %

Procedure:
According to the same procedure as in the Step 22-1-3 except that ethyl 4-(2,3-dimethylphenyl)-1H-pyrrole-2-carboxylate obtained in the Step 24-1-3 was used instead of methyl 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate, the title compound (25 mg, 59%) was obtained.
Reaction SMILES: C([O-])(=O)C.[NH4+].C([NH:10][C:11]([C:13]1[C:18]([CH2:19][C:20](=O)[CH3:21])=[C:17]([CH3:23])[CH:16]=[CH:15][N:14]=1)=[O:12])(C)(C)C.[OH-].[Na+]>C(O)(=O)C>[CH3:23][C:17]1[C:18]2[C:13](=[C:11]([OH:12])[N:10]=[C:20]([CH3:21])[CH:19]=2)[N:14]=[CH:15][CH:16]=1
Reactant: CC(=O)Cc1c(C)ccnc1C(=O)NC(C)(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2c(C)ccnc2c(O)n1
Temperature: 110 °C
Yield: 99.2 %

Procedure:
Ammonium acetate (10.0 g, 130 mmol) followed by 4-methyl-3-(2-oxo-propyl)-pyridine-2-carboxylic acid tert-butylamide (1.61 g, 6.48 mmol) are added to acetic acid (20 mL) and the reaction mixture is heated at 110° C. for 3 h. The reaction mixture is cooled to RT and 20% NaOH is added until pH 6-7. The aqueous layer is extracted with DCM (3 times) and the combined organic layers are washed with brine, dried and evaporated under reduce pressure to furnish 4,6-dimethyl-[1,7]naphthyridin-8-ol (1.12 g, 99%) that is used as such.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][NH:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27](Br)=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([N:11]2[CH2:12][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][C:10]2=[O:13])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CC(Cc2ccccc2)CN1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc(N2CC(Cc3ccccc3)CC2=O)sc1C(=O)NCc1ccccc1
Yield: 13.1 %

Procedure:
A mixture of 4-benzylpyrrolidin-2-one (0.068 g, 0.39 mmol), N-benzyl-2-bromo-4-methylthiazole-5-carboxamide (0.10 g, 0.32 mmol), cesium carbonate (0.16 g, 0.48 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.006 g, 0.060 mmol) and xantphos (0.008 g, 0.013 mmol) in anhydrous toluene (3 mL) was subjected to microwave irradiation at 120° C. for 15 min. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate/hexanes (1/1)) to afford the title compound as a white solid (0.017 g, 13%): mp 143-144° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.38-7.11 (m, 10H), 5.91 (br s, 1H), 4.56 (d, J=5.5 Hz, 2H), 4.25-4.13 (m, 1H), 3.85-3.72 (m, 1H), 2.95-2.68 (m, 4H), 2.61 (s, 3H), 2.52-2.39 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 173.0, 162.3, 155.3, 152.6, 138.2, 137.9, 128.8, 128.7, 127.9, 127.6, 126.8, 118.6, 52.6, 44.0, 40.1, 37.7, 33.4, 17.2; MS (ES+) m/z 406.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Li+].[Cl-]>C1(C)C=CC=CC=1>[CH2:14]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11])[CH:13]=[CH2:12]
Reactant: COc1cc(C#N)ccc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C#N)cc1OC

Procedure:
A mixture of 4-bromo-3-methoxybenzonitrile (1.4 g, 6.7 mmol), allyl-tributyl-stannane (2.7 g, 8.1 mmol), LiCl (0.86 mg, 20 mmol) and Pd(PPh)4 (0.2 g) in 25 mL of anhydrous toluene was refluxed under N2 overnight. Checked the reaction with TLC and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product 4-allyl-3-methoxybenzonitrile. MS m/z: 174 (M+1)+.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.Cl.[CH3:15][O:16][NH2:17].C1(C)C(C)=CC=CC=1>O>[CH3:15][O:16][N:17]1[C:1](=[O:13])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7]
Reactant: CON
Reactant: O=C(O)Cc1ccccc1C(=O)O
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1C
Product: CON1C(=O)Cc2ccccc2C1=O

Procedure:
A mixture of homophthalic acid (9.0 g., 0.05 mole) and methyoxyamine hydrochloride (4.25 g., 0.05 mole) in 125 ml. of xylene was refluxed for 90 minutes, with water collected in Dean Stark trap as it formed. The reaction mixture was cooled and concentrated by vacuum to one half its original volume, then diluted with ethylacetate, washed with water and dried over sodium sulfate. Recrystallization from isopropanol and ethanol, followed by drying at 100° C. for 4 hours yielded pale pink crystals of 2-methoxyisoquinoline-1,3 (2H, 4H)-dione, m.p. 113°-114° C.