Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH2:13][OH:14].CCOC(C)=O.CCCCCC>CCOC(C)=O.O=[Mn]=O>[OH:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: O=[N+]([O-])c1cc(CO)c(O)c(CO)c1
Agent: O=[Mn]=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=Cc1cc([N+](=O)[O-])cc(C=O)c1O
Yield: 40 %

Procedure:
A mixture of (2-hydroxy-5-nitro-1,3-phenylene)dimethanol (0.50 mmol) and MnO2 (3.5 mmol) was dissolved in 2 ml EtOAc and the reaction was refluxed for 24 hours while being monitored by TLC (using EtOAc/Hexane 30:70 as eluent). The reaction mixture, once completed, was concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica gel (using EtOAc/Hexane 30:70 as eluent) to give 2-hydroxy-5-nitroisophthalaldehyde (40% yield) as a yellow solid.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10](O)=[O:11])[CH:8]=[CH:9][C:2]=12.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>O1CCCC1>[N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][OH:11])[CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc2nsnc2c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1ccc2nsnc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzo[1,2,5]thiadiazole-5-carboxylic acid (2.00 g, 11.11 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. To this was added triethylamine (1.80 mL, 12.87 mmol) followed by isobutylchloroformate (1.62 mL, 12.40 mmol) in a dropwise manner. The resulting slurry was stirred for a further 30 minutes at 0° C. and then filtered into a mixture of sodium borohydride (0.83 g, 21.84 mol) in ice water (20 mL). The resulting mixture was stirred at 0° C. for 30 minutes, evaporated to one quarter of its volume and then extracted with dichloromethane (3×50 mL). The organic phases were combined and then dried over sodium sulfate. This was followed by concentration under reduced pressure to provide the desired product as a white solid which was used without further purification (1.50 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([OH:15])[CH:9]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:22]([O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:9]1)(=[O:24])[CH3:23]
Reactant: Cc1ccccc1C1=CC(O)CCCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1C=C(c2ccccc2C)CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound obtained in Step B (6.2 g/0.03 mol) in 100 ml of CH2Cl2 there are added, in succession, pyridine (4.9 ml/0.06 mol), DMAP (1.83 g/0.015 mol), and then, dropwise, acetic anhydride (5.7 ml/0.06 mol). The whole is then stirred at room temperature for 24 hours. The reaction mixture is then concentrated to dryness, taken up in AcOEt, washed with a dilute HCl solution (1N), a saturated NaHCO3 solution and then with a saturated NaCl solution; dried over MgSO4 and then concentrated to dryness. The residual yellowish oil is then purified by chromatography over silica gel to yield the title product in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccncc3)C2)cc(OC)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccncc3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-hydroxyethyl)pyrrolidine (0.32 g, 0.83 mmol) and N,N-diisopropylethylamine (0.46 mL, 2.64 mmol) in dichloromethane (50 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (0.096 mL, 1.24 mmol). After 1 hour, warm to ambient temperature. Again cool in an ice bath and add N,N-diisopropylethylamine (0.23 mL, 1.32 mmol) followed by methanesulfonyl chloride (0.096 ml, 1.24 mmol). After 1 hour, dilute the reaction mixture with dichloromethane and extract with a saturated aqueous solution of sodium bicarbonate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf=0.24 (silica gel, 5% methanol/dichloromethane/0.1% concentrated aqueous ammonia).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH:5]=[CH:4][C@H:3]1[NH2:7].C(N(CC)CC)C.C[O:16][C:17]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])=O>O1CCCC1>[OH:1][C@@H:2]1[CH2:6][CH:5]=[CH:4][C@H:3]1[N:7]1[C:17](=[O:16])[C:19]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:20]2[C:21]1=[O:22]
Reactant: COC(=O)c1ccccc1C(=O)Cl
Reactant: N[C@@H]1C=CC[C@H]1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C=CC[C@H]1O

Procedure:
A quantity of dl-trans-4-hydroxy-3-amino-cyclopentene is dissolved in 450 ml of tetrahydrofuran and 87 ml. (0.60 M) of triethylamine. The solution is cooled to 0° and treated dropwise with 59.6 g. (0.3 M) of o-methoxycarbonylbenzoylchloride over 50 min. The reaction is then allowed to warm to 25°. After 66 hours the reaction is partitioned between ethyl acetate and water. The ethyl acetate layer is dried over magnesium sulfate and distilled in vacuo to yield 62.4 g. of residual oil. This is chromatographed over 3 kg. of silica gel 60 eluted with 6 l. of (10-90), 2.5 l. of (15-85), and 11 l. of (20-80) acetonemethylene chloride. Two hundred fifty ml. fractions are collected. The product is found in fractions 38-61. These fractions crystallized on standing to yield 25.9 g. of dl-trans-4-hydroxy-3-phthalidocyclopentene.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC>C1(C)C=CC=CC=1.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>[CH:31]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1)=[CH2:32]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 5-bromo-2-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (1.50 g) in toluene (20 mL) were added tributyl(vinyl)tin (900 μL) and tetrakistriphenylphosphinepalladium(0) (315 mg), and the mixture was stirred under argon atmosphere at 110° C. overnight. After cooling to room temperature, the reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography. The title compound (950 mg, yield 71%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 437 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2Cl)=[O:5])[CH3:2].[CH:19]1(B(O)O)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[CH:19]1[CH2:21][CH2:20]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(Cl)c2c1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1ccc2ncc(C#N)c(C3CC3)c2c1

Procedure:
Similar procedure as described in example 46d was used, starting from 4-chloro-3-cyano-quinoline-6-carboxylic acid ethyl ester (example 46c), cyclopropylboronic acid, sodium carbonate and POPd to give 3-cyano-4-cyclopropyl-quinoline-6-carboxylic acid ethyl ester as colorless oil. LC-MS m/e 267 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([N+:21]([O-:23])=[O:22])=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:8].[NH:24]1[CH2:26][CH2:25]1>C1COCC1>[N:24]1([C:2]2[C:3]([N+:21]([O-:23])=[O:22])=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=2)[C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[O:8])[CH2:26][CH2:25]1
Reactant: C1CN1
Reactant: O=C(NCCn1ccnc1)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: O=C(NCCn1ccnc1)c1cc(N2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 36.8 %

Procedure:
A stirred suspension of the above benzamide (150 mg, 0.44 mmol) in THF (40 mL) was treated with aziridine (91 μL, 1.76 mmol) at room temperature for 4 h, then additional aziridine (91 μL) was added. After a further 4 h, the mixture was concentrated under reduced pressure below 25° C., and the residue was partitioned between EtOAc and saturated NaCl. Evaporation of the organic layer gave a product that was triturated with EtOAc then recrystallized from MeCN/EtOAc/petroleum ether to give 7 (56 mg, 37%): mp >250° C.; 1H NMR [(CD3)2SO] δ8.91 (t, J=5.6 Hz, 1H, NH), 8.66 (s, 1H, H-3), 7.67 (s, 1H, imidazole-H), 7.29 (s, 1H, H-6), 7.24 & 6.93 (2xs, 2H, imidazole-H), 4 16 (t, J=5.9 Hz, 2H, NHCH2CH2), 3 62-3.51 (m, 2H, NHCH2), 2.49 (s, 4H, aziridine-H). Anal. Calcd. for C14H14N6O5: C, 48.55;H, 4.07; N, 24.27. Found: C, 48.69;H, 4.00; N, 24.10%.
Reaction SMILES: C([N:4]1[CH2:11][CH:10]2[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([NH:7][O:8][CH2:9]2)[CH2:5]1)C=C.Cl>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:12]1([C:6]23[CH2:5][NH:4][CH2:11][CH:10]2[CH2:9][O:8][NH:7]3)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CCN1CC2CONC2(c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: c1ccc(C23CNCC2CON3)cc1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
5-Allyl-6a-phenyl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (3.89 g, 16.89 mmol) is dissolved in chloroform (168 mL) and the solution is degassed with dry nitrogen for 10 minutes. N,N-Dimethylbarbituric acid (13.19 g, 84.45 mmol) is added to the solution and the solution is degassed with nitrogen for another 5 min Tetrakis(triphenylphosphine) palladium (1.95 g, 1.69 mmol) is added and the reaction is stirred for 18 hours. 1 N Hydrochloric acid (50 mL) is added and the mixture is stirred for 20 minutes. The solution is extracted with aqueous hydrochloric acid (3×75 mL) and the combined HCl solution is washed with dichloromethane. The pH is adjusted to approximately 13 with 5 N sodium hydroxide solution. The mixture is extracted with dichloromethane (3×75 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (3.21 g, 92%). EI/MS (m/e): 191.3 (M+H).
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[C:5]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]([OH:20])=[O:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)([OH:7])=[O:6]>>[C:2]([O:19][C:18]([C:10]12[CH2:16][CH:14]3[CH2:13][CH:12]([CH2:17][C:8]([C:5]([O:7][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([CH2:15]3)[CH2:9]1)[CH2:11]2)=[O:20])([CH3:4])([CH3:3])[CH3:1]
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Reactant: C=C(C)C
Product: CC(C)(C)OC(=O)C12CC3CC(C1)CC(C(=O)OC(C)(C)C)(C3)C2

Procedure:
In accordance with a conventional method in which isobutene is used under acidic conditions, 10 mmol of 1,3-dicarboxyadamantane was t-butoxylated to give 1,3-di(t-butoxycarbonyl)adamantane.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.Cl.[C-:10]#[N:11].[K+]>O>[OH:8][C:5]1([C:10]#[N:11])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: [C-]#N
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CN1CCC(O)(C#N)CC1
Temperature: 10 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To freshly distilled 1-methylpiperidin-4-one (81.72 g, 0.72 mole) in water (200 cc), were added about 100 cc HCl 37% to pH 3. The reaction mixture was cooled in an ice bath and potassium cyanide (49 g, 0.75 mole) in water (200 cc) was added at an adequate rate in order to maintain an internal temperature of about 10° C. The reaction was stirred two hours more after the addition and then filtered. After washing with water and drying, the product, 4-hydroxy-4-cyano-1-methylpiperidine, was obtained in 67% yield as a white powder (67 g, 0.48 mole, mp. 135° C.).
Reaction SMILES: [C:1]([C:4]1[C:5]2[N:6]([CH:41]=[N:42][N:43]=2)[C:7]([CH2:32][C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:40])=[N:8][C:9]=1[NH:10][C:11]1[C:16]([F:17])=[CH:15][C:14]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[C:13]([F:31])[CH:12]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[CH2:32][C:7]1[N:6]2[CH:41]=[N:42][N:43]=[C:5]2[C:4]([C:1]([NH2:2])=[O:3])=[C:9]([NH:10][C:11]2[CH:12]=[C:13]([F:31])[C:14]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][C:16]=2[F:17])[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(Nc3nc(Cc4c(Cl)cccc4Cl)n4cnnc4c3C(N)=O)cc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c(Nc2cc(F)c(N3CCNCC3)cc2F)nc(Cc2c(Cl)cccc2Cl)n2cnnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 15G (230 mg, 0.36 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL) dropwise. The mixture was stirred at ambient temperature for 4 hours and concentrated. The solid was washed with ethanol and dried under vacuum to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 12.38 (d, J=1.5 Hz, 1H), 9.71 (s, 1H), 8.95 (d, J=2.1 Hz, 1H), 8.76 (br. s, 2H), 8.14 (d, J=2.1 Hz, 1H), 7.56-7.54 (m, 2H), 7.45-7.40 (m, 1H), 7.25-7.17 (m, 1H), 7.05-6.99 (m, 1H), 4.96 (s, 2H), 3.24-3.23 (m, 4H), 3.15-3.11 (m, 4H). MS: 533 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[C:14]([OH:16])=O)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:28])[NH:26][NH2:27])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:28])[NH:26][N:27]=[C:14]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[CH:5][C:4]=2[C:1](=[O:3])[CH3:2])[OH:16])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)c1cnc2ccccc2c1C(=O)O
Reactant: NNC(=O)Nc1cccc(Cl)c1
Product: CC(=O)c1cnc2ccccc2c1C(O)=NNC(=O)Nc1cccc(Cl)c1

Procedure:
In the same manner, 3-acetyl-4-quinolinecarboxylic acid is reacted with 4-(3-chlorophenyl)semicarbazide to give 3-acetyl-4-quinolinecarboxylic acid 4-(3-chlorophenyl)semicarbazone, m.p. 229° (compound 104).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH2:31][CH:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:29]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:28]3[CH2:31][CH:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:29]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(NC(=O)OC(C)(C)C)C2)n1
Yield: 90 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole and tert-butyl 3-azetidinylcarbamate gave tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinylcarbamate in 90% yield: mp (CH2Cl2/hexanes) 217-220° C.; 1H NMR (DMSO-d6) δ 7.98 (d, J=8.0 Hz, 1H), 7.73 (t, JHF=53.0 Hz, 1H), 8.24 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.42 and 4.36-4.32 (2m, 3H), 4.01-3.98 (m, 2H), 3.79-3.77 (m, 4H), 3.68 (m, 4H), 1.40 (s, 9H). Anal. Calcd. for C24H30F2N8O4: C, 54.1; H, 5.7; N, 21.0. Found: C, 54.4; H, 5.8; N, 21.2%.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[CH:14]=[C:13]([Br:17])[S:12]2)(C)(C)C>O1CCOCC1>[ClH:1].[Br:17][C:13]1[S:12][C:11]2=[N:10][C:9]([NH2:8])=[CH:16][N:15]2[CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cn2cc(Br)sc2n1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cn2cc(Br)sc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4M HCl in dioxane (2 mL) was added compound 10 (0.13 mmol). The reaction mixture was stirred at room temperature for 4 hrs. The mixture was concentrated under vacuum and the solid was dried in vacuo to give compound 11 as a white solid in quantitative yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 5.26 (s, 2H), 8.20 (s, 1H), 9.92 (brs, 1H), 10.05 (brs, 1H); and MS (ESI, EI+) m/z=218.02-220.03 (MH+).
Reaction SMILES: C([C:3]12[CH:8]([C:9]([OH:11])=[O:10])[CH:7]1[CH2:6][CH2:5][C:4]2=[O:12])C.[OH-].[Na+]>>[O:12]=[C:4]1[CH2:5][CH2:6][CH:7]2[CH:3]1[CH:8]2[C:9]([OH:11])=[O:10]
Reactant: CCC12C(=O)CCC1C2C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1C2CCC(=O)C21

Procedure:
(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid may be prepared by reacting carbethoxymethyl dimethylsulfonium bromide with 2-cyclopenten-1-one in the presence of a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene to afford ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate. This ester may then be reacted with an aqueous solution of potassium cyanide or sodium cyanide and ammonium carbonate to produce an intermediate hydantoin, (the Bucherer-Bergs reaction), which is then hydrolysed using sodium hydroxide, to afford a diastereomeric mixture of diethyl 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. The desired diastereomer may be obtained by crystallization with oxalic acid. This diastereomer may then be resolved by forming a crystalline salt with (+)-di-p-toluoyl-D-tartaric acid and recovering (-)-diethyl 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate. Hydrolysis of this diester using aqueous sodium hydroxide gives (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. Alternatively, the ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid may be hydrolysed using sodium hydroxide to give 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid. This acid may then be resolved by forming a crystalline salt with (S)-1-phenylethylamine and recovering (+)-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid. This acid may then be converted into (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid by reaction with an aqueous solution of potassium cyanide or sodium cyanide and ammonium carbonate to produce an intermediate hydantoin (the Bucherer-Bergs reaction) followed by hydrolysis of the hydantoin using sodium hydroxide. This procedure may also be modified by performing the resolution step on the hydantoin rather than on the 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid. In this case, (R)-1-phenylethylamine has been found to be a suitable resolving agent.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:5][C:4]=1[C:15]([O:17]CC)=[O:16])[CH3:2].[OH-].[Na+].C(O)C>O1CCCC1>[CH2:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:5][C:4]=1[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)[nH]c1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1[nH]c(-c2ccc(F)cc2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A mixture of ethyl 5-ethyl-2-(4-fluorophenyl)imidazol-4-carboxylate (2.81 g), 4N aqueous sodium hydroxide solution (14 ml), ethanol (35 ml) and tetrahydrofuran (15 ml) was stirred at room temperature overnight, followed by refluxing for 3 hours. 4N aqueous sodium hydroxide solution (28 ml) was added to the mixture and the mixture was refluxed overnight. After cooling, the reaction mixture was concentrated under reduced pressure and neutralized by 10% hydrochloric acid, and precipitated solid was collected by filtration. The solid was dissolved in tetrahydrofuran, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether to obtain first crop of 5-ethyl-2-(4-fluorophenyl)imidazol-4-carboxylic acid (1.06 g) as colorless powder. Moreover, the filtrate was purified by HP-20 resin (trade name, available from Nippon Rensui K.K.) (solvent: water→methanol) to give second crop of 5-ethyl-2-(4-fluorophenyl)imidazol-4-carboxylic acid (1.60 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][NH:8][C:7]2=O)[CH3:2].O=P(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[Cl:19][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: CCOc1cc2c(=O)[nH]cnc2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1cc2c(Cl)ncnc2cc1OC
Temperature: 125 °C
Yield: 34 %

Procedure:
According to the procedure described in Example 6A Step 5, a mixture of 6-ethoxy-7-methoxyquinazolin-4(3H)-one (0.52 g, 2.36 mmol) and POCl3 (1 mL) in toluene (10 mL) was heated at 125° C. for 3.5 hours. The residue was purified by silica gel chromatography with 0-25% EtOAc/hexane as eluants to afford 4-chloro-6-ethoxy-7-methoxyquinazoline as a solid (0.19 g, 34%). 1H NMR (300 MHz, CDCl3) δ 8.9 (s, 1H), 7.4 (s, 1H), 7.3 (s, 1H), 4.3 (t, 2H), 4.1 (s, 3H), 1.6 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:28]([C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[N:27]=1)([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[N:28]([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)[N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccnc2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)nn4-c4cccnc4)c3)c2cc1OC
Yield: 57.7 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (91 mg, 0.3 mmol), prepared as described in Example 113A, in THF (2 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (110 mg, 0.34 mmol), described in the previous step. The crude was purified by silica gel chromatography (DCM/MeOH 2-10%) to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)urea (91 mg, 58%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, J=7 Hz, 6H), 2.89 (m, 1H), 3.99 (s, 6H), 6.35 (s, 1H), 6.92 (d, J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.34-7.39 (m, 2H), 7.52-7.55 (m, 3H), 7.97 (d, J=7.2 Hz, 1H), 8.55 (s, 1H), 8.58-8.60 (m, 2H), 8.77 (d, J=2.4 Hz, 1H), 9.19 (s, 1H); LC-MS (ESI) m/z 526 (M+H)+.