Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:42]=[CH:41][N:8]([C@@H:9]2[O:40][C@H:14]([CH2:15][O:16][C:17]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:7](=[O:43])[N:6]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:53]([CH2:55][CH2:56][O:57][CH2:58]Cl)#[N:54].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([NH:4][C:5]1[CH:42]=[CH:41][N:8]([C@@H:9]2[O:40][C@H:14]([CH2:15][O:16][C:17]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C@@H:12]([OH:13])[C@H:10]2[O:11][CH2:58][O:57][CH2:56][CH2:55][C:53]#[N:54])[C:7](=[O:43])[N:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(C)=O)nc3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(C)=O)nc3=O)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 32.7 %

Procedure:
N4-Acetyl-5′-O-(4,4′-dimethoxytrityl)cytidine (588 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added thereto, and then 365 mg of dibutylstannyl dichloride (1.2 mmol) was further added. The reaction was performed at room temperature for 1 hour. Then, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethyl ether (1.3 mmol) was added dropwise, and the solution was stirred for 60 minutes. After the reaction completed, the reaction solution was added into an aqueous saturated sodium bicarbonate solution, and was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain N4-acetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl) cytidine (219 mg, yield 35%).
Reaction SMILES: CN1C(C)=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=N1.Br[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[C:30]([F:32])[C:29]([O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:28]([F:39])[CH:27]=2)[N:25]=1)=[O:19].[H-].[Na+]>CN(C=O)C>[F:39][C:28]1[CH:27]=[C:26]([C:24]2[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:25]3[C:9]4[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=4[CH:23]=[C:24]3[CH3:26])[S:22][CH:23]=2)[CH:31]=[C:30]([F:32])[C:29]=1[O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)COc1c(F)cc(-c2csc(NC(=O)CBr)n2)cc1F
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c(=O)n(C)c(=O)n2C)n1CC(=O)Nc1nc(-c2cc(F)c(OCC(C)(C)C)c(F)c2)cs1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 2 (50 mg, 0.258 mmol) with 2-bromo-N-{4-[4-(2,2-dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}acetamide (130 mg, 0.310 mmol) in the presence of NaH (15 mg, 0.625 mmol) in dry DMF (5.0 mL) to give 55 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 1.01 (s, 9H), 2.26 (s, 3H), 3.17 (s, 3H), 3.34 (s, 3H), 3.80 (s, 2H), 5.33 (s, 2H), 6.07 (s, 1H), 7.63 (s, 1H), 7.66 (s, 1H), 7.77 (s, 1H), 12.74 (br s, 1H); ESI-MS (m/z) 532.24 (M+H)+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:16]([NH:18][CH2:19][CH2:20][C:21]([O:23]CC1C=CC=CC=1)=[O:22])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6]>[Pd]>[NH2:1][C@H:2]([C:31]([OH:33])=[O:32])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6]
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Agent: [Pd]
Product: N[C@@H](CCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)O)C(=O)O
Yield: 96.7 %

Procedure:
In the same manner as Example 6 (iv), 2.50 g of Z-Glu(Phe-β-Ala-OBzl)-OBzl was hydrogenated in the presence of Pd-C and removed the protecting group to give 1.30 g of γ-Glu-Phe-β-Ala (Compound 33); yield 99%.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:6]([NH:8][CH:9]2[C:18]3[C:13](=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][C:17]=3[O:19][CH3:20])[CH2:12][CH2:11][CH2:10]2)[CH:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][O:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[C:18]2[C:13]=1[CH2:12][CH2:11][CH2:10][CH:9]2[NH:8][C:6]1[CH:7]=[C:2]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:3]=[CH:4][C:5]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C1CNCCN1
Reactant: COc1ccc(OC)c2c1CCCC2Nc1cc(F)ccc1S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(OC)c2c1CCCC2Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O
Yield: 71.6 %

Procedure:
A solution of N-(5-fluoro-2-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalen-1-amine (1.234 g, 3.26 mmol), piperazine (5.63 g, 65.1 mmol) and N,N-diisopropylethylamine (5.7 mL, 32.6 mmol) in acetonitrile (20 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 1.04 g of the crude aniline. The crude product was purified by PTLC (20% ethyl acetate in hexanes) to yield 610 mg (42%) of 1,2,3,4-tetrahydro-5,8-dimethoxy-N-(2-(methylsulfonyl)-5-(piperazin-1-yl)phenyl)naphthalen-1-amine: 1H NMR (400 MHz, CD3OD): δ 7.49 (d, 1H), 6.81 (d, 1H), 6.76 (d, 1H), 6.38-6.36 (m, 2H), 5.98 (d, 1H), 4.80 (br s, 1H), 3.79 (s, 3H), 3.67 (s, 3H), 3.37-3.32 (m, 4H), 2.98-2.92 (m, 1H), 2.88-2.82 (m, 7H), 2.44-2.36 (m, 1H), 2.20 (br d, 1H), 1.86-1.58 (m, 3H). MS (ESI) m/z: Calculated: 445.20; Observed: 446.2 (M++1).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]=O)=[CH:22][CH:21]=[CH:20][CH:19]=2>>[CH3:15][C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]=[C:8]1[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=3)[NH:10][C:9]1=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: Cc1[nH]c2ccccc2c1C=O
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: Cc1[nH]c2ccccc2c1C=C1C(=O)Nc2ccc(S(N)(=O)=O)cc21

Procedure:
5-Aminosulfonyl-2-oxindole was condensed with 2-methylindole-3-carboxaldehyde to give the title compound.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:31])=[C:6]([CH2:28][CH2:29][CH3:30])[C:7]2[O:12][C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=2[CH:27]=1)(=[O:3])[CH3:2].[C:32]1([O:42][CH2:43][CH2:44][CH2:45]Br)[C:41]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=2[CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:4]1[C:5]([O:31][CH2:45][CH2:44][CH2:43][O:42][C:32]2[C:41]3[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=3[CH:35]=[CH:34][CH:33]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:7]2[O:12][C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=2[CH:27]=1)(=[O:3])[CH3:2]
Reactant: BrCCCOc1cccc2c1CCCC2
Reactant: CCCc1c(O)c(C(C)=O)cc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c2c(cc(C(C)=O)c1OCCCOc1cccc3c1CCCC3)CCC(CCC(=O)OCC)(CCC(=O)OCC)O2
Reaction time: 6 h

Procedure:
A mixture of 204 mg (0.469 mmol) of the title product of Example 81, 378 mg (1.41 mmol) of the title product of Example 12, and 136 mg (0.985 mmol) of anhydrous potassium carbonate in 4 ml of dimethylformamide was stirred at 80° for six hours. A further 136 mg of potassium carbonate was added, and the mixture was heated for another six hours. The mixture was permitted to cool and was partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfite, filtered, and the solvent removed under reduced pressure. Chromotography of the residue over silica gel using 15% ethyl acetate/toluene as eluent gave the title compound, 114 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1>S(Cl)(Cl)=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:5]([CH3:9])([CH3:6])[CH3:4])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(N)cc1
Reaction time: 2 h

Procedure:
4-Aminobenzoic acid (5.0 g) was suspended in thionyl chloride (50 ml) and heated to a gentle reflux. After two hours the solution went completely clear, and so the reaction was allowed to cool and the thionyl chloride was removed under reduced pressure, the last traces by azeotrope with dichloromethane (3×50 ml). The resulting acid chloride was dissolved in more dichloromethane (50 ml) and a solution of t-butanol (15 ml) in dichloromethane (15 ml) was added to the stirred solution which was cooled in an ice bath. A solid white precipitate was formed--the hydrochloride salt of the title compound. This was isolated by evaporation of the dichloromethane, followed by suspension of the solid in ethyl acetate (100 ml) and filtration. The material was suspended in 10% aqueous sodium hydrogencarbonate solution (100 ml) and extracted into dichloromethane (3×100 ml). The organic layer was dried, filtered and evaporated to leave a pale cream solid (4.67 g, 66%), m.p. 106°-109° C. (lit. m.p. 109.5° C.). (R. Adams et al (1926) J. Amer. Chem. Soc., 48, 1758), the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:30](=[O:31])[CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)[C:3]1=[O:20]
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Product: COc1cccc(CC(=O)N[C@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3-(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylacetylchloride. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.: m.p. 198°-199° C.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([N:7]=[C:8]=[S:9])[CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:3]3[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=3)=[S:9])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: S=C=Nc1cccnc1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=S)Nc1cccnc1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A solution of pyridine-3-isothiocyanate (0.136 g, 1.0 mmol) in chloroform (5 mL) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g, 1.0 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). The reaction mixture was maintained at ambient temperature over the weekend. The reaction was quenched with ethanol and then concentrated under vacuum to provide an off-white solid. This material was purified by flash chromatography (silica gel, eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated under vacuum to provide 0.2 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-(3-pyridyl)thiourea as a white solid, m.p. 118–120° C. Mass spec M+1=468.3. Analysis: Calculated for C26H25N7S: % C, 66.79; % H, 5.39; % N, 20.97; Found: % C, 64.29; % H, 5.46; % N, 20.06.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[CH:18]=1.C([Li])CCC.[C:24](=[O:26])=[O:25].Cl>C1COCC1.CCCCCC>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH2:9][O:10][C:5]3[CH:4]=[CH:3][C:2]([C:24]([OH:26])=[O:25])=[CH:18][C:6]=3[CH:7]=2)=[CH:12][CH:13]=1
Reactant: O=C=O
Reactant: Cc1ccc(C2=Cc3cc(Br)ccc3OC2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C2=Cc3cc(C(=O)O)ccc3OC2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Into a solution of 6-bromo-3-(4-methylphenyl)-2H-1-benzopyran (0.5 g) in THF (15 ml) was added at −78° C. 1.6 M butyl lithium (a hexane solution) (1.14 ml) under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for one hour, was then mixed with dry ice and was stirred for additional one hour. After addition of 1 N hydrochloric acid (10 ml), the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration, and the crystals were washed with diethyl ether and hexane to obtain 3-(4-methylphenyl)-2H-1-benzopyran-6-carboxylic acid (218 mg) as colorless crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=4)[N:17]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[CH3:32][N:33]([CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl>[CH3:34][N:33]([CH3:32])[CH2:35][CH2:36][CH2:37][N:38]1[CH2:39][CH2:40][N:41]([C:27]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:18]3[N:17]=[C:16]([C:13]4[CH:12]=[CH:11][C:10]([S:7]([CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)(=[O:8])=[O:9])=[CH:15][CH:14]=4)[CH:21]=[CH:20][N:19]=3)=[CH:31][CH:30]=2)=[O:29])[CH2:42][CH2:43]1
Reactant: CN(C)CCCN1CCNCC1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3ccc(S(=O)(=O)C4CCOCC4)cc3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCCN1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(S(=O)(=O)C5CCOCC5)cc4)n3)cc2)CC1
Reaction time: 12 h
Yield: 22.2 %

Procedure:
4-{4-[4-(Tetrahydropyran-4-sulfonyl)-phenyl]pyrimidin-2-ylamino}benzoic acid 4 (0.26 g, 0.6 mmol) was dissolved in THF (5 mL). To this solution was added 1-(N,N-dimethylaminopropyl)piperazine (0.130 g), EDCI (0.136 g), and HOBt (0.096 g). The mixture was stirred 12 h. The mixture was then diluted with CH2Cl2 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude solid was subjected to preparative HPLC (20-70 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na2SO4), filtered, and concentrated to afford [4-(3-dimethylamino-propyl)piperazin-1-yl]-(4-{4-[4-(tetrahydropyran-4-sulfonyl)phenyl]pyrimidin-2-ylamino}phenyl)methanone 5 (0.079 g, 22%): HPLC Retention Time; 7.93 min. (Method B) M+1=593.3
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1.O>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[O:24][CH:28]=[CH:27][CH:26]=3)=[CH:3][CH:4]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: OB(O)c1ccco1
Reactant: Oc1ccc(C(=C2CCCCCCC2)c2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(C(=C2CCCCCCC2)c2ccc(-c3ccco3)cc2)cc1
Yield: 76 %

Procedure:
The procedure described for 202 was employed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol (49) (0.150 g, 0.404 mmol), PdCl2(PPh3)2, (0.028 g, 0.40 mmol), 2-furanylboronic acid (0.090 g, 0.80 mmol), Na2CO3 (0.086 g, 0.808 mmol), and THF/H2O (4:1, 5 mL). The reaction mixture was refluxed for 10 h. Standard workup and purification by flash silica gel chromatography provided 110 mg (76%) of the title compound 203 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 7.70 (d, J=0.9 Hz, 1H), 7.59 (d, J'6.0 Hz, 2H), 7.15 (d, J=6.3 Hz, 2H), 6.94 (d, J=6.6 Hz, 2H), 6.86 (d, J=2.4 Hz, 1H), 6.67 (d, J=6.3 Hz, 1H), 6.55 and 6.54 (dd, J1=2.4 Hz, J2=1.2 Hz, 1H), 2.48-2.47 (m, 4H), 1.60 (br s, 2H), 1.50-1.45 (m, 8H). 2.37 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 357 (M−H)−.
Reaction SMILES: CON(C)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:4]([C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)=[O:12])[CH2:16][CH2:15]1
Reactant: CON(C)C(=O)c1cccc(C)c1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a solution of N-methoxy-N,3-dimethylbenzamide (2.86 g, 16 mmol) in THF (50 mL) was added cyclopropylmagnesium bromide (2 N in THF, 40 mmol, 20 mL) dropwise at 0° C. After addition, the reaction mixture was stirred for 4 hours at room temperature and quenched with 30 mL of aqueous NH4Cl. The aqueous phase was separated and extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated to give crude product as a yellow oil (2.56 g, 100%). LC-MS (M+H): m/z 161. 1H NMR (400 MHz, CDCl3): δ ppm 7.817 (s, 2H), 7.367-7.332 (m, 2H), 2.697-2.635 (m, 1H), 2.417 (s, 3H), 1.247-1.209 (m, 2H), 1.046-1.000 (m, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:15]([N:16]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)(=O)=[O:21])COC)=[CH:14][C:13]([Cl:34])=[CH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O.O1CCOCC1>[C:1]1([NH:7][C:8]([C:10]2[C:15]([NH:16][S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)=[O:21])=[CH:14][C:13]([Cl:34])=[CH:12][N:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)Nc1ccccc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccccc1)c1ncc(Cl)cc1NS(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid phenylamide (120 mg, 0.224 mmol) was magnetically stirred in water (1.0 mL) and 4N HCl in dioxane (2.5 mL) at 85° C. (oil bath) for 4 h. Upon consumption of the reactant, the reaction mixture was concentrated, the residue neutralized (pH 7) with aqueous sodium bicarbonate, and the aqueous layer was extracted with EtOAc (3×80 mL). The combined organic extracts were dried (MgSO4), filtered, and chromatographed on silica gel using ethyl acetate-hexane gradient (0:100 to 50:50) to provide pure final product. MS m/z 490.0 (M+H).
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.S(=O)(=O)(O)O.O.C(=O)(O)[O-].[Na+].[CH2:25](O)[CH3:26]>C(OCC)(=O)C>[C:1]([O:13][CH2:25][CH3:26])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(O)c(O)c1

Procedure:
Ethyl caffeate was prepared as follows. Caffeic acid (1 g) was boiled under reflux in absolute ethanol (30 ml) in the presence of concentrated sulphuric acid (0.5 ml) for two hours. The reaction mixture was then poured into water (100 ml), and then ethyl acetate (100 ml) and 0.1M sodium bicarbonate solution (100 ml) were added. The organic phase was washed successively with 0.1M sodium bicarbonate solution (3×100 ml) and water (2×100 ml) before being dried (sodium sulphate, anhydrous), filtered and evaporated under vacuum to yield a tan coloured crystalline solid. The product was recrystallised from water giving ethyl caffeate as a tan coloured powder in 43% yield. mp 142-143° C.
Reaction SMILES: [Na+].O[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1)S([O-])(=O)=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH:22]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:3][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:9][CH:10]=2)=[O:15])[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: C1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc(C(O)S(=O)(=O)[O-])cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of hydroxyl-[4-(4-isopropyl-piperazine-1-carbonyl)-phenyl]-methanesulfonic acid sodium salt (54.6 g, 0.150 mol), piperidine (28.0 g, 0.330 mol), and Montmorillonite-K10 (10.9 g, 20% by wt. relative to starting material) in dichloroethane (820 mL) was stirred at room temperature for 16 h. NaBH(OAc)3 (44.5 g, 210.0 mmol) was added in portions over 1 h, and the resulting suspension was stirred at room temperature for 5 h. Diatomaceous earth (5.4 g) was added and the suspension was stirred for an additional 30 min. The reaction mixture was filtered through a pad of diatomaceous earth, rinsing with dichloroethane (2×100 mL). The filtrate was washed with 1 N NaOH (2×200 mL). The aqueous layers were combined and back-extracted with dichloroethane (2×100 mL). The organic layers were combined, dried (Na2SO4), and concentrated to yield the title compound as its corresponding free base, as a pale yellow oil.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[CH:17][CH:16]=1>>[ClH:1].[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:30]([C:29]3[CH:28]=[CH:27][C:26]([C:23]4[S:24][CH:25]=[C:21]([C:18]5[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=5)[N:22]=4)=[CH:34][CH:33]=3)=[O:31])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)cs2)cc1
Reactant: C1CC(N2CCCNCC2)C1
Agent: Cl
Product: O=C(c1ccc(-c2nc(-c3ccc(F)cc3)cs2)cc1)N1CCCN(C2CCC2)CC1

Procedure:
The title compound (E8) was prepared from 1-(cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) and 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]benzoic acid using the procedure described in Example 7. MS APCI-436 (MH+).