Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(NCCc2cccc(OCc3ccccc3)c2)cc1Cl
Temperature: 80 °C
Yield: 96251.7 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-2-[3-(phenylmethoxy)phenyl]acetamide (4.5 g, 0.012 mmol) in THF (20 ml) on ice was added the borane-tetrahydrofuran complex (15 ml, 0.023 mol). The reaction was allowed to reflux at 80° C. for six hours. The reduction reaction was placed on ice, acidified using 4 N HCl, then stirred for twenty minutes. The reaction was then basified with an aqueous solution of potassium hydroxide. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (4.3 g, 99% yield): ES-MS (m/z) 372 [M+H]+.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)[CH2:2]2.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.[CH2:26](Cl)Cl>C(OCC)(=O)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:6]2[CH2:5][CH2:4][N:3]([C:8](=[O:10])[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:2][CH:1]2[OH:7])=[CH:21][CH:20]=1.[Br:18][CH2:19][C:24]1[CH:23]=[CH:11][C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:26]=1
Reactant: ClCCl
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(OCc1ccccc1)N1CCC2OC2C1
Solvent: CCOC(C)=O
Product: BrCc1ccc2ccccc2c1
Product: O=C(Cc1ccccc1)N1CCC(Oc2ccc(Br)cc2)C(O)C1

Procedure:
In an analogous manner to that described in Example 71(a)-(b), from benzyl rac-3-aza-7-oxa-bicyclo[4.1.0]heptane-3-carboxylate by reaction with 4-bromophenol there was obtained (3RS,4RS)-1-[4-(4-bromo-phenoxy)-3-hydroxy-piperidin-1-yl]-2-phenyl-ethanone as a colourless solid [Rf : 0.40 (SiO2, methylene chloride:ethyl acetate=2:1)], alkylation of which with 2-bromomethylnaphthalene gave benzyl (3RS,4RS)-4-(4-bromo-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 454, 456 (M-benzyl)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][CH2:19][O:20][C:13]=3[CH:12]=2)N)=[O:8])=[CH:5][CH:4]=1.[C:23]([OH:30])(=[O:29])[CH2:24][CH2:25][C:26]([CH3:28])=O>O>[CH3:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[C:11]3[C:16](=[CH:15][C:14]4[O:17][CH2:18][CH2:19][O:20][C:13]=4[CH:12]=3)[C:25]([CH2:24][C:23]([OH:30])=[O:29])=[C:26]2[CH3:28])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(=O)CCC(=O)O
Reactant: Cc1ccc(C(=O)N(N)c2ccc3c(c2)OCCO3)cc1
Agent: Cl
Solvent: O
Product: Cc1ccc(C(=O)n2c(C)c(CC(=O)O)c3cc4c(cc32)OCCO4)cc1
Temperature: 25 °C

Procedure:
A mixture of 5 g of N1 -(p-methylbenzoyl)-3,4-ethylenedioxyphenylhydrazine hydrochloride and 30 g of levulinic acid was heated for 3 hours at 85° - 90°C. The reaction mixture was cooled to a room temperature, and poured into 200 ml of water. The crude product was recrystallized twice from ethyl acetate to give 1-(p-methylbenzoyl)-2-methyl-5,6-ethylenedioxy-3-indolylacetic acid having a melting point of 170° - 171°C.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:9][C:8]=2[CH2:18][O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=1.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:39][O:38][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][N:15]2[CH2:16][CH2:17][CH:12]([C:10]3[O:11][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[C:8]([CH2:18][O:19][CH2:20][C:21]([F:22])([F:23])[F:24])[N:9]=3)[CH2:13][CH2:14]2)=[CH:33][C:32]=1[S:34]([NH2:37])(=[O:36])=[O:35]
Reactant: COc1ccc(CCCl)cc1S(N)(=O)=O
Reactant: FC(F)(F)COCc1nc(C2CCNCC2)oc1-c1ccccc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2CCC(c3nc(COCC(F)(F)F)c(-c4ccccc4)o3)CC2)cc1S(N)(=O)=O
Temperature: 100 °C

Procedure:
To 4-[5-phenyl-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2-yl]-piperidine (0.750 g), prepared as in Intermediate 5, in dioxane is added 5-(2-chloro-ethyl)-2-methoxy-benzenesulfonamide (0.716 g), prepared as in Intermediate 1, Nal (0.429 g) and DIEA (1.15 ml). After heating at 100° C. for 18 hours, the reaction mixture is partitioned between EtOAc and dilute NaHCO3 solution. The organic phase is washed with saturated brine, dried (NaSO4) and concentrated. The residue is dissolved in CHCl3 (20 mL) and preadsorbed onto silica gel. Purification by flash chromatography on silica gel using a MeOH-EtOAc gradient (2-10%), followed by radial chromotography using a MeOH-CH2Cl2 gradient (1-5%) and crystallization from CH2Cl2 -EtOAc affords the title compound as a white solid.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.Cl.Cl.[CH3:15][NH:16][NH:17][CH:18]([CH3:20])[CH3:19]>C(O)(=O)C.N1C=CC=CC=1.O>[CH3:15][N:16]1[C:1](=[O:12])[CH2:2][C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5](=[O:7])[N:17]1[CH:18]([CH3:20])[CH3:19]
Reactant: CNNC(C)C
Reactant: O=C1Cc2ccccc2C(=O)O1
Agent: Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)N1C(=O)c2ccccc2CC(=O)N1C
Yield: 51.4 %

Procedure:
To the solution of homophthalic anhydride (6.80 g, 41.9 mmol) in 70 mL of glacial acetic acid was added 1-methyl-2-(1-methylethyl)hydrazine, dihydrochloride (6.75 g, 41.9 mmol) in 35 mL of pyridine (Rosen, et al., J. Heterocyclic Chem., 1969, 6, 9-12). The solution was refluxed for 12 h, cooled, diluted with water (300 mL), and extracted with chloroform (3×400 mL). The chloroform extract was washed with 10% hydrochloric acid (600 mL) and 5% sodium bicarbonate (600 mL) , dried over magnesium sulfate and concentrated to dryness. The mixture was purified by silica gel chromatography (hexane/ethyl acetate, 3/1) to afford 2,3,4,5-tetrahydro-3-methyl-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione (5 g, 51%).
Reaction SMILES: [O:1]=[S:2]1(=[O:12])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20](O)=[C:21]([C:24]#[N:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:11][CH2:10][CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:12])[CH2:3][CH2:4]3)=[C:21]([C:24]#[N:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Reactant: O=S1(=O)CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
3-(1,1-Dioxothiomorpholino)propan-1-ol (283 mg, 1.46 mmol) was added to a suspension of 4-chloro-6-cyano-7-hydroxyquinoline (200 mg, 0.97 mmol) in methylene chloride (30 ml), followed by the addition of triphenylphosphine (512 mg, 1.95 mmol) and a solution of diethyl azodicarboxylate (310 μl, 1.95 mmol) in methylene chloride (700 μl) in portions. After stirring for 5 minutes at ambient temperature, the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with a mixture of methanol/ethyl acetate/methylene chloride (5/50/45). After combining the fractions containing the expected product, the solvents were removed under vacuum and the residue was triturated with methanol, collected by filtration, washed with methanol and dried under vacuum to give 4-chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (321 mg, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C@@H:6]([C:22]1[CH:30]=[CH:29][C:25]2[CH2:26][CH2:27][O:28][C:24]=2[CH:23]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2([CH3:20])OCC[O:16]2)[C:8]1=[O:21])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C@@H:6]([C:22]1[CH:30]=[CH:29][C:25]2[CH2:26][CH2:27][O:28][C:24]=2[CH:23]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:16])[CH3:20])[C:8]1=[O:21])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCC2(C)OCCO2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCC(C)=O)C1=O

Procedure:
A solution of 4-1 (600 mg, 1.4 mmol), p-TSA (20 mg) and acetone (50 mL) was heated at reflux for 4 hr. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 4-2 as a colorless oil.
Reaction SMILES: [CH3:1][C@:2]12[C@H:12]([CH2:13]/[CH:14]=[C:15]3\[C@H:16]([OH:21])[CH2:17][O:18][C:19]\3=[O:20])[C:10](=[CH2:11])[CH2:9][CH2:8][C@@H:7]1[C@@:6]([CH2:23][OH:24])([CH3:22])[C@H:5]([OH:25])[CH2:4][CH2:3]2.[C:26]1(C)[CH:31]=CC(S([O-])(=O)=O)=C[CH:27]=1.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1.CS(C)=O>COC(OC)(C)C>[CH3:1][C@:2]12[C@H:12]([CH2:13]/[CH:14]=[C:15]3\[C@H:16]([OH:21])[CH2:17][O:18][C:19]\3=[O:20])[C:10](=[CH2:11])[CH2:9][CH2:8][C@@H:7]1[C@:6]1([CH3:22])[CH2:23][O:24][C:26]([CH3:31])([CH3:27])[O:25][C@@H:5]1[CH2:4][CH2:3]2
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: C=C1CC[C@@H]2[C@](C)(CO)[C@H](O)CC[C@@]2(C)[C@@H]1C/C=C1/C(=O)OC[C@H]1O
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: COC(C)(C)OC
Product: C=C1CC[C@@H]2[C@]3(C)COC(C)(C)O[C@@H]3CC[C@@]2(C)[C@@H]1C/C=C1/C(=O)OC[C@H]1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 2788.6 %

Procedure:
Andrographolide (150 mg, 0.43 mmol) was dissolved in a mixture solution of 2,2-dimethoxypropane (0.2 mL), pyridinium p-toluene-sulfonate (3 mg) and toluene/DMSO (3 mL/0.4 mL), stirred at 80° C. for 1 hour, and cooled to room temperature at the end. The reaction was terminated by using triethylamine (0.1 mL), the reaction mixture was diluted with toluene (20 mL), washed with water (3×5 mL), the organic layer was dried using anhydrous Na2SO4 and concentrated, and the obtained white solid was washed with ethyl ether and filtrated to obtain the compound 1 (130 mg, 78%) (Srinivas et al., Bioorg. Med. Chem. Lett. 2004, 14, 4711-4717).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:15])=[N-]>CCOC(C)=O.CCOCC>[CH3:15][O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C=Cc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)/C=C/c1ccc(O)cc1

Procedure:
To a solution of 4-hydroxycinnamic acid (0.407 g, 2.48 mmol) in EtOAc, a solution of diazomethane in Et2O was added until the yellow color persisted. Excess diazomethane was quenched by the addition of AcOH and the reaction mixture was evaporated to dryness. The residue was dissolved in EtOAc and washed with 10% aqueous HCl, saturated NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography, using a gradient from 10%-20% EtOAc in hexane, to give E-3-(4-hydroxyphenyl)acrylic acid methyl ester as a white solid (0.362 g). To a solution of (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.215 g, 1.15 mmol) in THF at 0° C., triphenylphosphine (0.316 g, 1.21 mmol), diisopropyl azodicarboxylate (236 μL, 1.21 mmol) and E-3-(4-hydroxy-phenyl)-acrylic acid methyl ester (0.215 g, 1.21 mmol) were added. The reaction mixture was stirred for 2 h at 0° C., followed by 4 h at room temperature and then the solvent was evaporated in vacuo. The residue was purified by flash column chromatography, using 20%-30% EtOAc in hexane, to give crude (S)-3-[4-(E)-2-methoxycarbonylvinyl)phenoxy]pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])(=O)[CH3:2].Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][NH2:28])=[CH:23][CH:22]=1.CC([O-])=O.[Na+]>CCO>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:4]([C:1](=[N:28][O:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[CH3:2])[CH:9]=1
Reactant: NOc1ccc(F)cc1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NOc1ccc(F)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 96.1 %

Procedure:
A solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (350 mg, 1.16 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (190 mg, 1.16 mmol) and anhydrous NaOAc (104 mg, 1.27 mmol) in EtOH (16 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum, the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2) and the solvent removed under reduced pressure. The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:4) to afford N-{4-chloro-2-[1-(4-fluorophenoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 129 (458 mg, 96%), as a pale yellow solid. M.p. 71-73° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.23, br s, 1H, 7.69, d, J=9.0 Hz, 1H; 7.59, d, J=2.4 Hz, 1H, 7.40, dd, J=2.4 and 9.0 Hz, 1H, 7.18-7.03, m, 4H, 2.55, s, 3H.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[CH:12]=[CH2:13].C([O-])(=O)C.[NH4+]>COCCOC.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2](/[CH:13]=[CH:12]/[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C=CC(=O)OCCCC
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CCOCC
Product: CCCCOC(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Microencapsulated Pd(OAc)2 (prepared as described in Example 1, 0.25 g, 2 mol %, based on palladium content) was added to a solution of 4-bromo nitrobenzene (1 mmol), butyl acrylate (1.5 mmol) and ammonium acetate (3 mmol) in 1,2-dimethoxyethane (5 mL) and stirred at 90° C. for 8 h. The reaction mixture was cooled to room temperature, diluted with ether (50 mL) and filtered through a polyethylene frit (20-micron porosity). The filtrate was washed with water (2×20 mL), brine (20 mL) and dried (MgSO4). Evaporation under reduced pressure and purification by column chromatography gave butyl 4-nitro-trans-cinnamate 87%; IR: 1709, 1643, 1519 and 1343; 1H NMR (400 MHz; CDCl3): 8.24 (2H, d, J 8.8), 7.7 (1H, d, J 15.6), 7.67 (2H, d, J 8.5), 6.55 (1H, d, J 16.1), 4.23 (2H, t, J 7), 1.7 (2H, qn, J 7.6), 1.44 (2H, sext, J 7.6) and 0.97 (3H, t, J 7.4); 13C NMR (CDCl3): 166.0, 148.4, 141.5, 140.6, 128.5, 124.1, 122.6, 64.8, 30.6, 19.1 and 13.6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[N:13]([O-])=O.[Na+].[C:17]1([CH2:23][C:24]([OH:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>O>[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([N:1]=[N:13][C:20]2[CH:21]=[CH:22][C:17]([CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)([OH:11])=[O:10]
Reactant: O=N[O-]
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(N=Nc2ccc(CC(=O)O)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
4-Aminophenylacetic acid (3.75 g, 24.8 mmol) was suspended in water (75 mL) and concentrated hydrochloric acid (8 mL) was added. The solution was cooled to 0° C. in an ice bath with rapid stirring. Sodium nitrite (1.80 g, 26.1 mmol) in water (20 mL) was added dropwise to the 4-aminophenylacetic acid solution with rapid stirring. Care was taken to keep the temperature between 0–5° C. at all times, especially during the NaNO2 addition. The reaction was stirred for an additional 20 min. In the meantime, phenylacetic acid (10.1 g, 74.4 mmol) was dissolved in an aqueous NaOH solution (4.50 g, 113 mmol NaOH in 100 mL H2O). The solution was vigorously stirred at 17° C. and at pH 13.3. The diazonium salt solution was added dropwise to the phenylacetic acid solution. It is of utmost importance to keep the temperature of the phenylacetic acid solution between 17–18° C. and the pH between 13.2–13.3 at all times, especially during the diazonium salt addition. The temperature was regulated by the addition of ice and the pH regulated by the addition of 8 M NaOH. After addition was complete, the solution was allowed to warm to room temperature and stirred for an additional 30 min. The reaction mixture was suction filtered to remove any undissolved particulates or unwanted side products. The filtrate was acidified with aqueous HCl (10 mL conc. HCl in 20 mL H2O) which produced a dark red precipitate. The precipitate was collected by suction filtration and washed several times with cold H2O, until the filtrate was clear. The collected solid was air dried overnight to give the desired compound as a red solid in 37% yield: IR (KBr) 3030 (br), 1696, 1658, 1452, 1414, 1201, 850, 675 cm−1 FABMS m/z 299 (M+H)+, 320 (M+Na); 1H NMR (DMSO-d6) δ 3.47 (s, 4H), 7.33 (4H, d, J=8.1 Hz), 7.84 (4H, d, J=8.4 Hz).
Reaction SMILES: C(O[C:4](=[O:25])[NH:5][S:6]([C:9]1[CH:24]=[CH:23][C:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:22])[N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17][C:11]=2[CH:10]=1)(=[O:8])=[O:7])C.[CH:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:33][C:4]([NH:5][S:6]([C:9]2[CH:24]=[CH:23][C:12]3[CH2:13][CH2:14][N:15]([C:18](=[O:22])[N:19]([CH3:20])[CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)(=[O:8])=[O:7])=[O:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N(C)C)CC2
Reactant: NC1CCCCCC1
Product: CN(C)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCCC3)cc2CC1

Procedure:
By the reaction of [(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1-H-3-benzazepin-7-yl)sulfonyl]carbamic acid ethyl ester with cycloheptylamine in a manner analogous to that described in Example 12, there is obtained 1-cycloheptyl-3-[(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea.
Reaction SMILES: [Cl-].[Li+].Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[CH:7]2.C([Sn](CCCC)(CCCC)[C:19]1[S:23][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:21][CH:20]=1)CCC.CN(C=O)C>CCOC(C)=O.O.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:10]1[C:11]2[C:6](=[CH:5][C:4]([C:19]3[S:23][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:21][CH:20]=3)=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(C)=O)s1
Reactant: Brc1ccc2cnccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1ncc(-c2ccc3cnccc3c2)s1
Temperature: 100 °C
Yield: 93.1 %

Procedure:
To a mixture of lithium chloride (0.295 g, 6.94 mmol) (flame-dried), 6-bromoisoquinoline (0.1805 g, 0.868 mmol), and Pd(PPh3)4 (0.0501 g, 0.0434 mmol) in a microwave reaction vessel, was added a solution of N-(5-(tributylstannyl)thiazol-2-yl)acetamide (0.561 g, 1.30 mmol) in DMF (2.00 mL, 0.868 mmol). The mixture was sealed and heated at 100° C. (oil bath) overnight. After cooling, the mixture (solidified) was diluted with EtOAc and water (2 mL each) and sonicated for 10 minutes. The resulting mixture was filtered, and the solid was washed with water and more EtOAc to provide N-(5-(isoquinolin-6-yl)thiazol-2-yl)acetamide (0.2177 g, 0.808 mmol) as a yellow solid. LCMS (M+H+) 270.3 calc. for C14H12N3OS 270.3; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.32 (br s, 1H), 9.27 (s, 1H), 8.48 (d, J=5.67 Hz, 1H), 8.13-8.15 (m, 3H), 8.06 (d, J=7.20 Hz, 1H), 7.85 (d, J=5.67 Hz, 1H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][N:3]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([NH:7][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Solvent: c1ccncc1
Product: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a rt solution of 550 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine (prepared in accordance with the procedure set forth in UK 2 185 255, Example 2A) in 8.5 mL pyridine was added 370 μL of benzoyl chloride. The reaction was stirred for 1 h and then concentrated under reduced pressure. The residue was dissolved in chloroform and washed with 0.5 N hydrochloric acid and then saturated aqueous sodium carbonate. The organic portion was dried with sodium sulfate and concentrated under reduced pressure and purified by means of MPLC (12 g SiO2, 40% ethyl acetate:heptane) to give the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:23]([Mg]Br)[CH2:24][CH2:25][CH2:26][CH3:27].Cl>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)C(=Cc1ccc(OC)cc1OC)C(=O)OCC
Reactant: CCCCC[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CCCCCC(c1ccc(OC)cc1OC)C(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
A solution of 9.15 g (29.7 mmol) of ethyl 3-(2,4-dimethoxyphenyl)-2-ethoxycarbonyl-2-propenoate (prepared as described in Preparation 1) in 9 ml of diethyl ether was added to 72 ml (36 mmol) of a 0.5M ice-cooled solution of pentylmagnesium bromide in diethyl ether, and the resulting mixture was stirred at the same temperature for 1.5 hours. At the end of this title, the reaction mixture was poured into a 10% aqueous solution of hydrochloric acid in ice, and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 200 g of silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 8.65 g (yield 77%) of the title compound as an oily substance.
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][Mg]Br)[CH2:19][CH2:18]1)[CH3:16].Cl[SiH]1CCC(C2C=CC(F)=C(F)C=2)CC1.C([C@H]1CC[C@H](CC[Mg]Br)CC1)CCC>>[CH2:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][Si@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[CH2:4][CH2:3]2)[CH2:19][CH2:18]1)[CH3:16]
Reactant: CC[C@H]1CC[C@H](CC[Mg]Br)CC1
Reactant: Fc1ccc(C2CC[SiH](Cl)CC2)cc1
Agent: CCCC[C@H]1CC[C@H](CC[Mg]Br)CC1
Agent: Fc1ccc(C2CC[SiH](Cl)CC2)cc1F
Product: CC[C@H]1CC[C@H](CC[Si@H]2CC[C@H](c3ccc(F)cc3)CC2)CC1

Procedure:
The preparation was conducted in the same manner as in Example 18, except that 22.8 g (100 mmol) of 1-chloro-4-(p-fluorophenyl)-1-silacyclohexane and 2-(trans-4-ethylcyclohexyl) ethylmagnesium bromide were used instead of 24.6 g (100 mmol) of 1-chloro-4-(3,4-difluorophenyl)-1-silacyclohexane and 2-(trans-4-n-butylcyclohexyl)ethylmagnesium bromide.