Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)([O-])=O.I[CH3:25].[H-].[Na+]>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:25])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccncc2[N+](=O)[O-])CC1
Reactant: CI
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccncc2N)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-[1-(3-nitro-4-pyridyl)-4-piperidyl]carbamate (2100 mg, 6.514 mmol) (prepared according to methods similar to the one depicted in Step 1 of Preparation N-1) and iodomethane (4.623 g, 2.028 mL, 32.57 mmol) in DMF at 0° C. was added portionwise sodium hydride (312.7 mg, 7.817 mmol). The reaction was stirred at 0° C. for 1 h, and at room temperature for 1 h. The reaction was quenched by pouring the reaction mixture onto a saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate (2×50 mL). The combined organics was washed with brine (2×50 mL), dried and evaporated to leave an orange solid. To the crude solid dissolved in MeOH (50 mL) was added Pd/C (10%) (346 mg) and the mixture was stirred under a hydrogen atmosphere for 4 h. The reaction was filtered through celite and evaporated to leave tert-butyl (1-(3-aminopyridin-4-yl)piperidin-4-yl)(methyl)carbamate as a yellow oil. (600 mg, 20%) MS (ES+-tBu) 251.1.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][C:7]=1[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:76][C:77]1[CH:91]=[CH:90][C:89]([F:92])=[CH:88][C:78]=1[CH2:79][C:80]1[O:84][N:83]=[C:82]([C:85](O)=[O:86])[CH:81]=1>CO.CN(C=O)C>[C:15]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])=[C:6]2[CH2:5][CH2:4][NH:1][C:85]([C:82]1[CH:81]=[C:80]([CH2:79][C:78]2[CH:88]=[C:89]([F:92])[CH:90]=[CH:91][C:77]=2[F:76])[O:84][N:83]=1)=[O:86])#[N:16]
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCN=[N+]=[N-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 70 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A mixture of 3-(2-azidoethyl)-2-(triethylsilyl)-1H-indole-5-carbonitrile (0.400 g; 1.23 mmol) and triphenylphosphine (0.523 g; 2.00 mmol) in methanol (10 mL) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in a mixture of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid intermediate 74 (0.318 g, 1.33 mmol), HATU (0.506 g; 1.33 mmol) and N,N diisopropylethylamine (0.614 mL; 3.33 mmol) in DMF (10 mL), was stirred at room temperature for 72 hours. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate; the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane) to yield 0.338 g (48%) of N-(2-(5-cyano-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[K].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([SH:27])[CH:22]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1C
Reactant: Sc1cccnc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CSc2cccnc2)cc1-c1ccccc1C
Reaction time: 0.5 h

Procedure:
To a solution in DMF (2 mL) of 4-chloromethyl-2-(2-methylphenyl)benzoic acid methyl ester (275 mg, 1.0 mmol) was added 3-pyridinethiol potassium salt (224 mg, 1.5 mmol). The reaction mixture was stirred for 30 minutes and then was poured into water. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine, dried, filtered and concentrated in vacuo. Chromatography on silica gel (40% ethyl acetate-hexanes) gave 4-(3-pyridylthiomethyl)-2-(2-methylphenyl)benzoic acid methyl ester which was converted to the title compound by saponification of the methyl ester, coupling with methionine methyl ester hydrochloride, and saponification as described in Examples 319I-J. 1H NMR (300 MHz, DMSO-d6) δ 12.53 (bs, 1H), 8.49 (d, 1H), 8.38 (dd, 1H), 8.11 (d, 1H), 7.79 (dt, 1H), 7.43 (s, 2H), 7.31 (dd, 1H), 7.19 (m, 2H), 7.11 (m, 2H), 7.05 (m, 1H), 4.36 (s, 2H), 4.20 (m, 1H), 1.92-2.23 (m, 8H), 1.66-1.90 (m, 2H). MS (CI, NH3) m/e 467, 449. Anal calcd for C25H26N2O3S2: C, 64.35; H, 5.62; N, 6.00. Found: C, 64.00; H, 5.62; N, 5.89.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([CH3:17])([CH2:11][C:12](Cl)(C)[CH2:13][CH3:14])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:23]Cl>>[CH3:17][C:9]1([CH3:10])[CH2:11][CH2:12][C:13]([CH3:14])([CH3:23])[C:5]2[CH:6]=[C:1]([OH:7])[CH:2]=[CH:3][C:4]1=2
Reactant: ClCCl
Reactant: Oc1ccccc1
Reactant: CCC(C)(Cl)CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 0 °C
Yield: 83 %

Procedure:
A 200 mL round-bottomed flask equipped with stir bar was charged with a solution of phenol (10.2 g, 108 mmol) and 2,4-dichloro-2,4-dimethylhexane (21.8 g, 119 mmol) in dichloromethane (50 mL) at 0° C. Aluminum chloride (1.44 g, 10.8 mmol) was added slowly to the solution until the spontaneous reflux had subsided and the solution became pale orange in color. After stirring 10-15 min at 0° C., the reaction was poured into ice water (30 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated to give a pale yellow/white solid. Recrystallization from hexanes gave the product 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-ol 18.25 g (83%) as a white crystalline solid: 1H-NMR (400MHz, CDCl3) δ 7.17 (d, J=8.5 Hz, 1H, Ar-H), 6.76 (d, J=3.0 Hz, 1Hz, Ar-H), 6.62 (dd, J=8.5 Hz, 3.0 Hz, 1H, Ar-H), 4.52 (s, 1H, OH), 1.65 (s, 4H, 2CH2), 1.26 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3).
Reaction SMILES: [ClH:1].[CH:2]1([C:5]([CH:7]2[CH2:9][CH2:8]2)=[NH:6])[CH2:4][CH2:3]1>CS(C)=O>[Cl-:1].[N+:6]12[CH2:9][CH2:8][CH2:7][C:5]=1[CH2:2][CH2:3][CH2:4]2
Reactant: N=C(C1CC1)C1CC1
Reactant: Cl
Solvent: CS(C)=O
Product: C1CC2=[N+](C1)CCC2
Product: [Cl-]
Temperature: 100 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
A solution of dicyclopropylmethanimine hydrochloride (1.00 g, 6.87 mmol) in 6.0 ml of dimethyl sulfoxide was heated with stirring at 100° C. for 4 hours. The solvent was distilled out in vacuo and isobutyl alcohol (6 ml) was added to the residue. Precipitated crystals was obtained and dried in vacuo to afford 0.55 g (Yield: 55%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[C:5]2[N:10]([CH3:13])[CH:11]=[N:12][C:4]=2[CH:3]=1.[CH:14]1C=C(Cl)C=C(C(OO)=O)C=1.[O-:25][S:26]([O-:29])(=S)=O.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([S:26]([CH3:14])(=[O:29])=[O:25])[C:5]2[N:10]([CH3:13])[CH:11]=[N:12][C:4]=2[CH:3]=1
Reactant: CSc1nc(Cl)cc2ncn(C)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cnc2cc(Cl)nc(S(C)(=O)=O)c21
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
To a solution of 6-chloro-3-methyl-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.02 (450 mg, 2.11 mmol) in dichloromethane (16 mL) at 0° C., was added mCPBA (≦77%, 972 mg, 4.34 mmol) and mixture was warmed to room temperature. After 80 minutes, an additional 200 mg of mCPBA was added. After an additional twenty minutes, a solution of 50% saturated Na2S2O3 (aq) (20 mL) was added and reaction mixture stirred at room temperature for fifteen minutes. Layers were separated and aqueous was extracted with ethyl acetate (4×15 mL). All organic layers were combined, washed with saturated NaHCO3 (aq) (2×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 6-chloro-3-methyl-4-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine 2.04.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2.Cl>C(O)(C)C>[ClH:19].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc4[nH]ccc4c3)ncnc2cc1OCc1ccccc1
Yield: 96 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (5 g, 16.6 mmol), (prepared as described for the starting material in Example 1), 5-aminoindole (2.4 g, 18.2 mmol) in isopropanol (60 ml) containing 5N hydrogen chloride in isopropanol (260 μl, 1.6 mmol) was refluxed for 90 minutes. After cooling the volatiles were removed under vacuum. The solid was triturated with isopropanol, filtered, washed with isopropanol followed by ether and dried under vacuum to give 7-benzyloxy-4(indol-5-ylamino)-6-methoxyquinazoline hydrochloride (6.9 g, 96%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:20])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.CO.[Pt](=O)=O>[NH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:20])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19]
Reactant: Cn1nc2c(N)nc3ccccc3c2c1CCN
Agent: O=[Pt]=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cn1nc2c(N)nc3c(c2c1CCN)CCCC3
Reaction time: 24 h
Yield: 90.8 %

Procedure:
A solution of 1-(2-aminoethyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine dihydrochloride (7.20 g, 22.9 mmol) in trifluoroacetic acid (75 mL) was treated with platinum (IV) oxide (7.0 g) and shaken under hydrogen pressure (50 psi, 3.4×105 Pa) for 24 hours on a Parr apparatus. The reaction mixture was diluted with chloroform (50 mL) and methanol (25 mL) and filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure. The residue was suspended in concentrated hydrochloric acid (5 mL), stirred for 2 hours, treated with 50% aqueous sodium hydroxide to adjust the pH to 13, and stirred at ambient temperature overnight. The mixture was diluted with water (100 mL) and was extracted with chloroform (5×150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 5.10 g of 1-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as an off-white foam.
Reaction SMILES: [CH:1](=[N:3]O)[CH3:2].ClCl.[CH3:7][SH:8].[OH-:9].[Na+:10].[Cl-]>O.C(O)CO>[CH3:7][S-:8].[Na+:10].[CH3:7][S:8][C:1](=[NH:3])[CH2:2][OH:9]
Reactant: [OH-]
Reactant: CS
Reactant: CC=NO
Agent: ClCl
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: CSC(=N)CO
Product: C[S-]
Temperature: -10 °C
Reaction time: 0.42 h

Procedure:
Acetaldoxime (30 g., 0.5 mole) was dissolved in 200 g. of a solvent mixture containing 175 g. of water and 25 g. of ethylene glycol, and the solution was cooled to -5° to -10° C. Over a period of 20-30 minutes, 30 g. of chlorine was introduced to to the solution with good agitation. During chlorination, the reaction temperature was maintained at -5° to -10° C. An additional 6 g. of chlorine was added in 10 minutes. The mixture was stirred for 10-15 minutes at -10° C. A sodium methyl mercaptide solution was prepared by dissolving methyl mercaptan (25 g., 0.52 mole) in a caustic solution containing 40 g. of sodium hydroxide in 100 g. of water. The mercaptide solution was fed directly into the acethydroxamoyl chloride solution at -10° C. over a 15-20 minute period. The reaction mixture was stirred for an additional 15 minutes and then neutralized to pH 7.5 with a 50-percent caustic solution. The crystalline methyl hydroxythioacetimidate was recovered at -10° C. by filtration. The methyl hydroxythioacetimidate was reslurred in hexane, filtered and dried to obtain 47 gram of methylhydroxythioacetimidate mp 87°-89° C. This represented a 90% yield.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][NH2:11].O1CCOCC1>C(OCC)(=O)C>[NH:10]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[C:8]([NH2:9])=[N:11]1
Reactant: N#Cc1cccnc1Cl
Reactant: NN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1n[nH]c2ncccc12
Temperature: 150 °C

Procedure:
2-Chloro-3-cyanopyridine (2.77 g), hydrazine (5 mL), and dioxane (100 mL) were combined in a sealed tube and heated at 150° C. for 16 hr. The reaction mixture was cooled to room temperature and concentrated in vacuo to provide a crude residue. The resultant residue was dissolved in ethyl acetate (100 mL) and washed with saturated NaCl solution (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1H-pyrazolo[3,4-b]pyridin-3-ylamine as a yellow solid which was used without further purification.
Reaction SMILES: BrC1C=CC(NC2C(C(O)=O)=CN=C(Cl)C=2Cl)=C(Cl)C=1.O.[NH2:22][NH2:23].[CH2:24]([O:26][C:27](=[O:45])[C:28]1[C:33]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:36]=2[Cl:42])=[C:32]([Cl:43])[C:31]([Cl:44])=[N:30][CH:29]=1)[CH3:25]>CN(C)C(=O)C.CCOC(C)=O>[CH2:24]([O:26][C:27](=[O:45])[C:28]1[C:33]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:36]=2[Cl:42])=[C:32]([Cl:43])[C:31]([Cl:44])=[N:30][CH:29]=1)[CH3:25].[CH2:24]([O:26][C:27](=[O:45])[C:28]1[C:33]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:36]=2[Cl:42])=[C:32]([Cl:43])[C:31]([NH:22][NH2:23])=[N:30][CH:29]=1)[CH3:25]
Reactant: NN
Agent: CCOC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(NN)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
4-(4-Bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid ethyl ester (48) was prepared by standard methods from 4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid. Hydrazine monohydrate (0.59 mL, 12.16 mmol) was added to a solution of 4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid ethyl ester (48) (1.72 g, 4.05 mmol) in N,N-dimethylacetamide (20 mL). After stirring at 90° C. for 1 hour, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated. Purification by flash column chromatography using the Biotage system (20:1 CH2Cl2:EtOAc) provided the desired product (49) (307 mg, 18%).
Reaction SMILES: [C:1]1([S:7][CH2:8][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([Li])[CH2:14][CH2:15]C.CC(C)C=O>C1COCC1.CCCCCC.[Cl-].[Na+].O>[C:1]1([S:7][CH:8]=[C:14]([CH3:15])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)CSc1ccccc1
Agent: CC(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)=CSc1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 3.92 g (20 mmol) of phenylthiomethyltrimethylsilane in 10 ml THF at 0° is added 20 ml n-butyllithium in hexane. The resulting yellow solution is stirred for 15 min at 0°, and a solution of 1.44 g (20 mmol) of 2-methyl-1-propanal in 5 ml THF is added. The reaction mixture is stirred for 15 min at 0°, then for 2 hr at 25°. Brine (15 ml) is added and the product extracted with ether. The organic layer is dried over calcium sulfate, filtered and the solvent is removed under vacuum to give 2-methyl-1-propenyl phenyl sulfide, which is purified by distillation under vacuum.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].O.[NH2:10][NH2:11]>CCO.CCOC(C)=O>[CH:2]([C:3]1[NH:11][N:10]=[C:5]([NH2:6])[CH:4]=1)([CH3:8])[CH3:1]
Reactant: NN
Reactant: CC(C)C(=O)CC#N
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)c1cc(N)n[nH]1
Yield: 59.2 %

Procedure:
To a solution of 4-methyl-3-oxopentanenitrile (15 g, 135 mmol) in EtOH (150 mL) was added hydrazine hydrate (7.30 g, 146 mmol) slowly at 0° C. The reaction mixture was heated to reflux for 4 h. Removal of EtOH under reduced pressure gave an oily residue that was dissolved in EtOAc (200 mL) and washed with freshly prepared brine (2×50 mL). The organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc gave 5-isopropyl-1H-pyrazol-3-amine, Compound (ii) (10 g, 59% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 1.22 (d, 6H), 2.80-2.92 (m, 1H), 4.80 (brs, 3H), 5.41 (s, 1H).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH:10]=[O:11].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH2:14]([O:13][C:9](=[O:12])[CH:10]([O:11][C:18](=[O:20])[CH3:19])[NH:2][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:8])[CH2:15][CH2:16][CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCOC(=O)C=O
Reactant: CC(C)(C)OC(N)=O
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O

Procedure:
A solution of 23.4 g. (0.2 mol.) of t-butyl carbamate [Org. Syn., 48, 32 (1968); U.S. Pat. No. 3,072,710] and 32.2 g. (0.25 mol.) of n-butyl glyoxylate (Org. Syn., Col. Vol. 4, 124) in 150 ml. of acetic anhydride was refluxed for 1.25 hours. The reaction mixture was then cooled, the solvent was removed in vacuo and the residue was molecularly distilled at 130°/.05 mm. to give the title compound.
Reaction SMILES: [C:1](O)(=O)[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.C=C1OC(=O)C1.ClCl.[Cl:20]CC(=O)CC(Cl)=O.NC(N)=O>>[Cl:20][CH2:1][C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1
Reactant: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Reactant: O=C(Cl)CC(=O)CCl
Agent: C=C1CC(=O)O1
Agent: ClCl
Agent: NC(N)=O
Product: O=c1cc(CCl)[nH]c(=O)[nH]1

Procedure:
German OS No. 2,025,247 teaches that orotic acid can be prepared by converting, in a first stage, diketene and chlorine to γ-chloroacetoacetic acid chloride, in a second stage, reacting the γ-chloroacetoacetic acid chloride with urea to form 6-chloromethyluracil, separating the 6-chloromethyluracil and oxidizing the 6-chloromethyluracil with hydrogen peroxide to orotic acid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH3:15])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C=O)C>[Cl:19][C:9]([C:8]1[CH:12]=[C:13]([CH3:14])[C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([CH3:15])[CH:7]=1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound 3,5-dimethyl-4-hydroxybenzoic acid (5.04 g, 30.33 mmol) was mixed with pyridine (20 mL). Acetic anhydride (3.72 g, 36.4 mmol) was added and the mixture was stirred at room temperature for 4 h. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid in quantitative yield (6.33 g). The compound 4-acetoxy-3,5-dimethyl-benzoic acid (0.36 g, 1.73 mmol)) was dissolved in dichloromethane (5 mL) and oxalyl chloride (0.3 mL, 3.46 mmol) was added dropwise, followed by 1 drop of DMF. The reaction mixture was stirred at room temperature under nitrogen for 2 h. The solvent was evaporated in vacuo to obtain acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester in quantitative yield (0.392 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Br>C1COCC1>[CH2:1]([O:8][C:9](=[O:23])[C:10]1([CH2:34][C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[CH3:37])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1CC1(C(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-t-butoxycarbonyl isonipecotic acid benzyl ester (13.34 g, 41.8 mmol) in THF (100 ml) at −78° C. was added sodium bis-trimethysilylamide (59 ml of a 1.0 M THF solution, 59 mmol) over 15 min. The resulting orange solution was stirred at −78° C. for 1 hr and then treated dropwise with 2-methyl benzyl bromide (6.80 ml, 50.7 mmol) and then allowed to warm slowly to room temperature over 16 hrs. The reaction was quenched with saturated aqueous NH4Cl, diluted with H2O, and extracted with EtOAc. The combined organic extracts were washed with brine, and concentrated in vacuo to an orange gum. Chromatography (SiO2, gradient elution, 20 to 30% EtOAc in hexanes) afforded the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:65]1([NH2:68])[CH2:67][CH2:66]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:68][C:65]3([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=4[C:58]([F:57])([F:69])[F:70])[CH2:67][CH2:66]3)=[O:21])=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)O
Reactant: NC1(c2ccccc2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)NC1(c2ccccc2C(F)(F)F)CC1
Yield: 13.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoic acid (Intermediate-15, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropyl ethyl amine (2.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-12, 0.082 g, 0.410 mmol) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.27-1.31 (m, 4H), 3.90 (s, 3H), 7.47 (t, J=8.1 Hz, 2H), 7.54-7.69 (m, 6H), 7.87 (t, J=8.4 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.61 (s, 1H); MS (m/z): 547.15 (M+).