Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[N:36]=[C:35](/[CH:37]=[CH:38]/[CH2:39]O)[CH:34]=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:39]/[CH:38]=[CH:37]/[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:30][C:26]2[NH:25][CH:29]=[CH:28][N:27]=2)[N:36]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OC/C=C/c1cccc(Cc2ncc[nH]2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2cccc(Cc3ncc[nH]3)n2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 215 mg (1 mM) of (E)-3-{6-(1-imidazolylmethyl)pyridine-2-yl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 506 mg (95.7%).
Reaction SMILES: [CH:1]([P:3](=[O:17])([CH:15]=[CH2:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[CH2:2].Cl.[CH2:19]([NH2:21])[CH3:20].[OH-].[Na+].C(N)C1C=CC=CC=1>C1COCC1>[CH2:19]([N:21]1[CH2:16][CH2:15][P:3](=[O:17])([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=2)[CH2:1][CH2:2]1)[CH3:20]
Reactant: C=CP(=O)(C=C)c1ccc([N+](=O)[O-])c(OC)c1
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: NCc1ccccc1
Product: CCN1CCP(=O)(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.94 mmol), ethylamine hydrochloride (0.174 g, 2.12 mmol), and 1 N NaOH (2 mL) were dissolved in 50% aqueous THF (5 mL) and heated to 105° C. under nitrogen. After one hour, another portion of benzylamine was added to the reaction mixture. The reaction mixture was refluxed for an additional 2 h, and then cooled to rt. The reaction mixture was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The aqueous phase was washed once with CH2Cl2 and the organic layers were combined. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the compound (0.267 g, 46% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]([CH3:13])[CH3:12]>[I-].[Na+].C1(C)C(C)=CC=CC=1>[CH2:10]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCCCl
Reactant: CC(C)CNCC(C)C
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCN(CC(C)C)CC(C)C
Yield: 39.4 %

Procedure:
To 180 ml of xylene were added 176 grams of ethyl gamma-chlorobutyrate, 302.2 grams of diisobutylamine and 6.0 grams of sodium iodide and the mixture was heated to reflux on an oil bath of 120° to 140° C. for 62 hours. After cooling, salts separated out therefrom were removed by filtration, the filtrate was washed with ether, concentrated, and the residue was distilled in vacuo to give 112 grams of the colorless oily product, b.p. 102-6° C./2 mmHg.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][NH:2]1.C[O:7][C:8](=O)[CH:9]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:10]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=1)=O>N1C=CC=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[C:8](=[O:7])[N:2]3[CH2:3][CH2:4][CH2:5][N:1]3[C:10]=2[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=2)=[CH:21][CH:22]=1
Reactant: C1CNNC1
Reactant: COC(=O)C(C(=O)c1ccnc(SC)n1)c1ccc(F)cc1
Solvent: c1ccncc1
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CCC3)n1
Temperature: 90 °C
Yield: 37 %

Procedure:
To a solution of pyrazolidine (7.8 g, 54.16 mmol) in pyridine (100 mL) is added 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-oxo-propionic acid methyl ester, 3, (11.5 g, 36.1 mmol). The reaction mixture is heated to 90° C. for 16 hours. The solvent is removed in vacuo and the resulting residue purified over silica (100% EtOAc, followed by 10% MeOH/EtOAc) to afford 3.9 g (37% yield) of the desired product as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]1[CH2:11][C:12]([OH:14])=O.[Br:15][C:16]1[C:17]([C:22]2[NH:26][N:25]=[CH:24][N:23]=2)=[C:18]([NH2:21])[S:19][CH:20]=1>>[Br:15][C:16]1[C:17]([C:22]2[NH:26][N:25]=[CH:24][N:23]=2)=[C:18]([NH:21][C:12](=[O:14])[CH2:11][N:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][CH:10]=[C:4]23)[S:19][CH:20]=1
Reactant: O=C(O)Cn1c(=O)ccn2nccc12
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cn1c(=O)ccn2nccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetic acid (39 mg, 0.203 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (min)=2.451, method [7], MS(ESI) 420.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 7.77 (d, J=2.6 Hz, 1H), 6.97 (s, 1H), 6.25 (d, J=7.9 Hz, 1H), 5.94 (d, J=2.6 Hz, 1H), 4.98 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:13])[CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[C:5]([F:13])[CH:6]=1)[N:3]=[C:2]([CH2:1][Br:32])[CH:11]=[CH:10]2
Reactant: Cc1ccc2cc(F)cc(F)c2n1
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(F)c2nc(CBr)ccc2c1

Procedure:
A solution of 2-methyl-6,8-difluoroquinoline (0.147 g, 0.820 mmoles, Example 26a), benzoyl peroxide (9.93 mg, 0.0410 mmoles), and N-bromosuccinamide (0.168 g, 0.943 mmoles) in carbon tetrachloride (20 mL) is heated to reflux for 18 hours. The reaction is concentrated and the resulting residue purified by column chromatography (silica, 3:1 CH2Cl2:hexane, then CH2Cl2) to yield the title compound as a white solid. MS (ESI) 258, 260 (M+H)+, Br pattern.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].N1C(C)=CC=CC=1C.[H][H]>[Pd].C1COCC1>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:11]=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: O=Cc1cccc(C2CC=CO2)c1
Agent: [Pd]
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: OCc1cccc(C2CCCO2)c1
Yield: 70 %

Procedure:
EX-608C) A THF (15 mL) solution of the aldehyde from EX-608B (0.70 g, 4.0 mmol) and 2,6-lutidine (0.46 mL, 4.0 mmol) was stirred in a hydrogen atmosphere (50 psi) in the presence of 10% Pd/C (0.29 g) for 18 h at room temperature. The slurry was filtered through celite, and the solvent was removed. The residue was taken up in ethyl acetate and washed with 1 N HCl and brine. The organic layer was dried (MgSO4) and evaporated to give 0.50 g (70%) of the desired 3-(tetrahydro-2-furanyl)phenylmethanol product as a yellow oil. The formation of the desired product was monitored by the disappearance of the aldehyde (δ˜10) and olefin peaks in the 1H NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:34])=[CH:31][CH:30]=1>>[C:33]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][NH:27][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:42][CH:41]=1)(=[O:34])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(C(=O)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 96 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (272 mg, 0.64 mmol) with 4-(aminomethyl)benzophenone (prepared by following the procedure described in J. Biol. Chem. 1993, 268 (19), 14230) (270 mg, 1.3 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 17:3 and 4:1) to give 6-(4-benzoyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (300 mg, 96%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)=[N:6][CH:7]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[C:2]1[N:3]=[C:4]([C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:5]([C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: Cc1cc(C)cc(-c2ncc(Cl)nc2-c2cc(C)cc(C)c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)cc(-c2ncc(-c3c(C)cccc3C)nc2-c2cc(C)cc(C)c2)c1
Yield: 89 %

Procedure:
Next, a mixture of 1.21 g of 5-chloro-2,3-bis(3,5-dimethylphenyl)pyrazine, 1.10 g of 2,6-dimethylphenylboronic acid, 0.78 g of sodium carbonate, 15 mg of PdCl2(PPh3)2, 14 mL of water, and 14 mL of acetonitrile was degassed by bubbling argon for 15 minutes and irradiated with microwaves (2.45 GHz, 100 W) for 3 hours. To the mixture were further added 0.55 g of 2,6-dimethylphenylboronic acid, 0.39 g of sodium carbonate, and 7 mg of PdCl2(PPh3)2, and the mixture was degassed by bubbling argon for 15 minutes and heated again by irradiating with microwaves for 6 hours. The mixture was suction-filtered, and the resulting solid was washed with ethanol. The obtained solid was dissolved in dichloromethane, which was followed by filtration through Celite, alumina, and Celite in this order. The filtrate was concentrated to give 5-(2,6-dimethylphenyl)-2,3-bis(3,5-dimethylphenyl)pyrazine as white powder in 89% yield. Explanation of the following reactions is omitted because they are the same as those in Example 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=O.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[CH:14][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: CC(=O)c1ccccc1
Reactant: COc1cccc(OC)c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(OC)c1C=CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(39) To a solution of 2,6-dimethoxybenzaldehyde (250 mg, 1.50 mmol) and acetophenone (180 mg, 1.50 mmol) in 2.2 ml of methanol was added 1.0 ml of 40% sodium hydroxide in water at 10° C. After stirring overnight at room temperature, a solid precipitated. The precipitate was recrystallized from methanol to afford 350 mg (87.1%) of a white, flaky solid: mp 54.9-55.8° C. (lit. mp 54-55° C., Noyce and Jorgenson, J. Am. Chem. Soc., 1963, 85, 2420-2426). 1H NMR (250 MHz) δ 8.33-8.26 (d, 1H), 8.05-7.97 (m, 3H), 7.57-7.49 (m, 3H), 7.30 (m, 1H), 6.61-6.57 (d, 2H), 3.92 (s, 6H); 13C NMR 192.3, 160.6, 139.2, 136.0, 132.4, 131.7, 128.6, 125.1, 113.1, 105.8, 103.9, 56.0 ppm.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN>>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCN1CCCC1
Agent: NN
Product: NCCCCCN1CCCC1

Procedure:
As shown in the above Reaction Scheme 1, 1,5-dibromopentane is reacted with potassium phthalimide in a suitable solvent to give N-(5-bromopentyl)phthalimide (2). The compound (2) is reacted with pyrrolidine in the presence of potassium carbonate and sodium iodide to give N-(5-pyrrolidin-1-ylpentyl)phthalimide (3). The compound (3) is reacted with hydrazine to provide 5-(pyrrolidin-1-yl)pentylamine (4). The compound (4) is reacted with di-t-butyl dicarbonate to give t-butyl (5-pyrrolidin-1-ylpentyl) carbamate (5). Then, the compound (5) is reacted with lithium aluminum hydride in a suitable solvent to give N-methyl-N-[5-(pyrrolidin-1-yl)pentyl]amine (6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[N:14]([CH2:20][CH3:21])[C:15](=[O:19])[C:16](=O)[NH:17][C:12]=2[CH:11]=[N:10]1.O=P(Cl)(Cl)[Cl:24].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:24][C:16]1[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13]2[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=[CH:11][C:12]=2[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1c(=O)c(=O)[nH]c2cnn(-c3ccc(F)cc3F)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(Cl)nc2cnn(-c3ccc(F)cc3F)c21
Temperature: 110 °C

Procedure:
A mixture of 1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[3,4-b]pyrazine-5,6(4H,7H)-dione (330 mg, 1.13 mmol) in 5 mL of toluene was treated with POCl3 (0.16 mL, 1.70 mmol) followed by N,N-diisopropylethylamine (0.16 mL, 0.9 mmol). The reaction mixture was heated in an oil bath at 110° C. for 2.5 h. The volatiles were removed on the rotovap and the residue was dissolved in ice cold DCM (20 mL) and washed with NaHCO3 saturated solution, dried over MgSO4, filtered and concentrated affording 5-chloro-1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one as a brown amorphous solid. The material was used without further purification. MS (ES+): 311.0 (M+H)+.
Reaction SMILES: C1(C2OC(C)=C(COC3C=CC(CO[C:20]4[C:24]([CH:25]=O)=[CH:23][N:22]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:21]=4)=CC=3)N=2)C=CC=CC=1.Cl.NO.[N:39]1C=CC=CC=1.C(O)C>O>[C:27]1([N:22]2[CH:23]=[C:24]([C:25]#[N:39])[CH:20]=[N:21]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: N#Cc1cnn(-c2ccccc2)c1
Yield: 137.6 %

Procedure:
A mixture of 3-[{4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.70 g), hydroxylamine hydrochloride (0.16 g), pyridine (0.30 g) and ethanol (30 mL) was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Acetic anhydride (20 mL) was added to residue, and the mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)}-1-phenyl-1H-pyrazole-4-carbonitrile as colorless crystals (0.35 g, 51%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 162-163° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([S:26][CH3:27])=[C:21](B(O)O)[CH:22]=1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:18]=[C:17]([CH3:16])[CH:22]=[CH:21][C:20]=2[S:26][CH3:27])[C:11]=1[CH3:12]
Reactant: CSc1ccc(C)cc1B(O)O
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Product: CSc1ccc(C)cc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
Prepared according to procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (130 mg, 0.51 mmol) and 5-methyl-2-(methylthio)phenylboronic acid to give 4-chloro-5,7-difluoro-3-methyl-2-(5-methyl-2-(methylthio)phenyl)quinoline. Mass Spectrum (ESI) m/e=350.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH2:14])[CH3:13]>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]([NH:14][CH2:12][CH3:13])=[S:11]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: CCN
Product: CCNC(=S)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dimethylphenyl isothiocyanate (16.3 g; 0.1 mol) was added dropwise to 110 mL of 70% aqueous ethylamine solution. The mixture was stirred for 1 hour at ambient temperature. Excess ethylamine was evaporated under a stream of nitrogen. The mixture was diluted with water (100 mL). The solid was collected by filtration and washed with water and dried to give 20.0 g of N-(2,6-dimethylphenyl)-N′-ethylthiourea.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNCCCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Product: CN(CCCC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1

Procedure:
The title compound was prepared following general procedure 10, starting from 4-cyanobenzyl bromide and tert-butyl 4-(methylamino)butanoate hydrochloride (Watanabe). It was obtained as a yellow oil (586 mg, quantitative). LC/MS (Method B): 289.2 (M+H)+. HPLC (Method A) Rt 3.02 (Purity: 91.8%).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([NH2:6])=[O:5])[CH2:2]1.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](Cl)=[N:16][N:15]=[CH:14]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([NH2:6])=[O:5])[CH2:2]1)=[N:16][N:15]=[CH:14]2
Reactant: NC(=O)C1CCCNC1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C1CCCN(c2nncc3cc(Br)ccc23)C1
Temperature: 190 °C
Yield: 99.4 %

Procedure:
A glass microwave reaction vessel was charged with nipecotamide (0.17 g, 1.4 mmol), 6-bromo-1-chlorophthalazine (0.110 g, 0.45 mmol), potassium carbonate (0.062g, 0.45 mmol) and 3 mL acetonitrile. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 190° C. for 20 min (watts, Powermax feature on, ramp time 1 min). The mixture was purified directly via flash chromatography (silica gel) eluting with 4/1 hexanes/EtOAc to 4/1 hexanes/EtOAc to give (0.15 g) 1-(6-bromophthalazin-1-yl)piperidine-3-carboxamide as a white solid. Found MS (ES+): 335, 337(M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:15]([O:17]CC)=[O:16])[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH2:13][CH3:14])[CH3:2].[Li+].[OH-].C(O)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:15]([OH:17])=[O:16])[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH2:13][CH3:14])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC)c2[nH]nc(CC)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)O)cc2c(CC)n[nH]c12
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of ethyl 7-ethoxy-3-ethyl-1H-indazole-5-carboxylate (389 mg, 1.48 mmol) in THF (13 mL) was added 1 M LiOH (3.0 mL, 3.0 mmol). The mixture was heated at reflux overnight. To the reaction was added trace amounts of ethanol to aid in solubilizing materials. Continue heating at reflux for an additional 2 hours. The reaction was cooled to room temperature, concentrated, triturated with 1 N HCl, the filtered solids were then washed with water and air dried to provide the title compound (347 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][C:6]=1[Br:7].S(=O)(=O)(O)O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:16])=[O:9])[O:5][C:6]=1[Br:7]
Reactant: O=C(O)c1cc(Br)c(Br)o1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(Br)o1
Temperature: 50 °C
Reaction time: 96 h
Yield: 92 %

Procedure:
To a solution of 4,5-dibromo-2-furancarboxylic acid (5.7 g, 21.1 mmol) in methanol (106 ml) was added sulfuric acid (11.3 ml, 211 mmol). The resulting solution stirred at 50° C. over 4 days. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification providing methyl 4,5-dibromo-2-furancarboxylate (5.5 g, 19.4 mmol, 92% yield): LCMS (ES) m/e 283 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:8][C:4]1[CH:3]=[C:2]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:7]=[CH:6][N:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cc(Br)ccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A mixture of 2.5 g of 4-bromo-2-chloropyridine (12.6 mmol), 2.2 ml of (trimethylsilyl)acetylene (15.1 mmol), 153 mg of copper(I)iodide (0.79 mmol) and 287 mg of bis(triphenylphosphine)palladium(II)chloride (0.41 mmol) in triethylamine (15 ml) was stirred at RT for 1 h. The triethylamine was then removed in vacuo, water was added and the mixture was extracted with diethylether. The combined organic extracts were then washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to give a residue which was purified by column chromatography (heptane/EtOAc 100:0 to 98:2) to give 2-chloro-4-trimethylsilanylethynyl-pyridine (2.394 g, 91%) as a light yellow liquid. MS (ISP) 210.1 (M+H)+.