Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:20])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:26][C:22]([NH:21][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:20])[CH:14]=3)[NH:9]2)[CH:3]=1)([CH3:27])[C:23]([OH:25])=[O:24]
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NC(C)(C)C(=O)O)c1)N2
Temperature: 25 °C

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4,6-trimethyl-1,2,3,4-tetrahydro-quinoline (329.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) 2-methyl-2-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-propionic acid (104.8 mg, 29%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 353.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:12]([C@@H:14]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1)#[N:13].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Cl-].[Na+].O>[C:12]([C@@H:14]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:18][CH:17]=1)#[N:13]
Reactant: CC(C)(C)OC(=O)N[C@H](C#N)Cc1ccc(I)cc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](C#N)Cc1ccc(-c2cccc(C#N)c2)cc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
A solution of 3-cyanophenylboronic acid (4.74 g), (S)-tert-butyl 1-cyano-2-(4-iodophenyl)ethylcarbamate (10 g) and bis[bis(1,2-diphenylphosphino)-ethane]palladium (0) (0.243 g) in dioxane (100 mL) under nitrogen, was stirred for 10 min. A solution of potassium carbonate (7.43 g) in water (30 mL) was added and the resulting solution was stirred at 75° C. for 3 h. The cooled mixture was poured into water containing brine and extracted with ethyl acetate (3×150 mL). The combined organics were washed with saturated brine (3×50 mL), dried over sodium sulfate and adsorbed onto silica. The crude product was purified by flash silica chromatography, eluting with 20% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford (S)-tert-butyl 1-cyano-2-(3′-cyanobiphenyl-4-yl)ethylcarbamate (8.42 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH3:37])=[C:6]([C@@:8]2([F:35])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([C:21]([NH:23][C:24]([CH3:33])([CH3:32])[C:25]([O:27]C(C)(C)C)=[O:26])=[O:22])[C:9]2=[O:34])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH3:37])=[C:6]([C@@:8]2([F:35])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=3)[N:10]([C:21]([NH:23][C:24]([CH3:33])([CH3:32])[C:25]([OH:27])=[O:26])=[O:22])[C:9]2=[O:34])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)NC(C)(C)C(=O)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)NC(C)(C)C(=O)O)c2cc(C(F)(F)F)ccc21

Procedure:
(S)-tert-butyl 2-(3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indoline-1-carboxamido)-2-methylpropanoate (Ij4): Following general procedure (G), to a solution of XVIII4 (0.24 g, 0.44 mmol) in methylene chloride (5 mL), TFA (0.34 mL, 4.4 mmol) was added. After purification by Prep. HPLC, the title compound was obtained as a white foam solid (140 mg, 65% yield). mp: 107–110° C. MS: 487 (M−H−) (very weak). Anal. Calcd. for C21H17CIF4N2O5: C, 51.60; H, 3.51; N, 5.73. Found: C, 51.29; H, 3.68; N, 5.49. 1H NMR (CDCl3): δ 1.70 (s, 3H), 1.74 (s, 3H), 3.56 (s, 3H), 6.76 (dd, J=8.8 Hz, 1.3 Hz, 1H), 7.27 (m, 1H), 7.36 (dd, J=8.7 Hz, 2.6 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.79 (dd, J=2.5 Hz, 0.9 Hz, 1H), 8.59 (s, 1H), 8.78 (s, 1H). IR (KBr, cm−1): 3500, 3337, 1762, 1717, 1532, 1491, 1439, 1320, 1265, 1173, 1132, 1062.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][O:29]2)[CH2:25][CH2:24]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][O:29]2)[CH2:25][CH2:24]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Reactant: c1ccc2c(c1)COC21CCNCC1
Agent: Cl
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC2(CC1)OCc1ccccc12
Yield: 94 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.754 g, 2.18 mmol) obtained in Example 22, step 3 and 3H-spiro[isobenzofuran-1,4′-piperidine]hydrochloride (Journal of Organic Chemistry, 1976, vol. 15, item 2628, 0.491 g, 0.218 mmol), the title compound (0.484 g, 94%) was obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13])=O.[NH2:14][C:15]([NH2:17])=[S:16]>C(O)C>[C:6]1([CH3:13])[CH:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:14]=[C:15]([NH2:17])[S:16][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(C)c(C(=O)CBr)c(C)c1
Solvent: CCO
Product: Cc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 107 %

Procedure:
2-Bromo-1-mesitylethanone (2.43 g, 10.1 mmol) and thiourea (0.810 g, 10.6 mmol) were dissolved in 95% ethanol (20 mL). The reaction mixture was heated at reflux for 2.0 h. The solution was concentrated under reduced pressure, and the residue was recrystallized from 2-propanol to give the desired 4-mesitylthiazol-2-amine (2.36 g) as white solids: 1H NMR (500 MHz, CD3OD) δ 7.00 (2H, s), 6.67 (1H, s), 2.31 (3H, s), 2.19 (6H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[N:11]=3)[S:7][C:6]=2[CH:27]=1.[CH3:28][NH:29][C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)=[O:31].C([O-])(O)=O.[Na+]>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.CS(C)=O.O>[CH3:28][NH:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]3[CH:9]=[C:8]([C:10]4[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]5[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]5)[N:11]=4)[S:7][C:6]=3[CH:27]=2)[CH:33]=1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccc(Br)cc4s3)n2)CC1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CNC(=O)c1cccc(-c2ccc3cc(-c4ccnc(NCCCN5CCN(C)CC5)n4)sc3c2)c1
Temperature: 170 °C
Yield: 21.7 %

Procedure:
A microwave tube is charged with [4-(6-bromobenzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine (41 mg, 0.092 mmol), 1.6 equivalent of 3-(methylcarbamoyl)phenylboronic acid (27 mg, 0.15 mmol), 5 mol % of tetrakis(triphenylphosphine)palladium(0) (5.0 mg, 0.0046 mmol), 1.2 equivalent of NaHCO3 (10 mg, 0.11 mmol) and 2:1 DMSO/H2O solution (3 mL). The reaction is sealed and heated under microwave condition at 170° C. for 20 minutes, cooled down, filtered through SCX column and washed several time with dichloromethane/MeOH (1:1). The product is then released with 0.1 M NH3 solution in MeOH, collected and evaporated to give a brown oil. The oil is subjected to reverse phase purification, eluting with 5-95% CH3CN/0.01 N NH4HCO3 in water using a C18 Xterra column, to give the title compound as a pale yellow solid (10 mg, 40% yield). ES+(m/z) 501 [M+H].
Reaction SMILES: [C:1]1([OH:7])C=CC=CC=1.C(C1C=CC=CC=1O)(CC(C)(C)C)(C)C.C=O.[C:25]1([CH:32]=[CH:31][CH:30]=[C:28]([OH:29])[CH:27]=1)[OH:26]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:25]1([CH:32]=[CH:31][CH:30]=[C:28]([OH:29])[C:27]=1[CH:1]=[O:7])[OH:26]
Reactant: Oc1cccc(O)c1
Reactant: Oc1ccccc1
Agent: C=O
Agent: CC(=O)[O-]
Agent: CC(C)(C)CC(C)(C)c1ccccc1O
Product: O=Cc1c(O)cccc1O
Temperature: 40 °C

Procedure:
Into a 1-liter reaction kettle equipped with a stirrer, thermometer, reflux condenser and an addition funnel, 128.3 grams of phenol (1.35 mole), 21.3 grams of t-octylphenol (0.10 mole) and 1.0 gram of zinc acetate catalyst were charged and heated to 35-45° C. Then, 59.9 grams of an aqueous formaldehyde (first) solution (37.6 wt. %; 0.75 mole) were added slowly for a period of about 10-15 minutes. After the formaldehyde addition, the reactor contents were stirred under reflux for about 90-180 minutes. Then, 24.0 grams of formaldehyde solution (second) (37.6 wt. %; 0.30 mole) were added into the reactor for a period of 15-30 minutes at 85-95° C. The reactor contents were again heated to reflux for an additional period of 90-180 minutes. A distillation set up was made and the water distillate was collected until the temperature of the reactor reached 125-130° C. under atmospheric conditions. After this, once again the reactor contents were stirred under reflux for 60-120 minutes. The water present in the reactor was then removed first by atmospheric distillation to 150-155° C. and later by applying vacuum and holding it for 15 minutes at 155-160° C. and under 26-28 inches of Hg vacuum. After this distillation, vacuum was released and the reflux condenser was attached again. Resorcinol (79.4 grams; 0.721 mole) was then added into the reactor at 130-150° C. slowly with constant stirring. After this addition, 35.3 grams of an aqueous formaldehyde solution (third) (37.6 wt. %; 0.442 mole) was added for about 45-60 minutes under reflux. Following the third formaldehyde addition, the reactor contents were held at reflux for an additional 30 minutes. Atmospheric and vacuum distillations were carried out once again to remove distillate to obtain a modified phenolic novolak resin with a resorcinolic novolak, produced in-situ from the resorcinol-formaldehyde reaction, having a softening point of 110.5° C.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([Cl:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH2:31]([N:33]([CH2:39]C)[CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])C>>[Cl:25][C:19]1[C:18]([F:26])=[C:17]([C:22]([F:23])=[CH:21][C:20]=1[CH3:24])[CH2:16][O:15][C:12]1[C:11]([C:27]([NH2:28])=[O:29])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][N:33]([CH3:39])[CH3:31])=[O:30])[S:14][N:13]=1
Reactant: CCN(CC)CCCCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1Cl
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN(C)C)c2C(N)=O)c(F)c1Cl

Procedure:
The title compound was prepared [4-carbamoyl-3-(3-chloro-2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-diethyl-butane-1,4-diamine by the procedure analogous to Example 1. MS (APCl, m/z): 476 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:21])=[O:20])=[O:9])[CH2:4]1)[CH3:2].NCC1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)(=O)=O.C(N1CC[C@@H](C(O)=O)C1)C>>[CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:20])=[O:21])=[O:9])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@H](C(=O)NCc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Agent: CCN1CC[C@@H](C(=O)O)C1
Agent: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CN)ccc2c1OCC1CC21
Product: CCN1CC[C@@H](C(=O)NCc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 188, starting from methyl (1aRS,7bSR)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (intermediate 102) and (R)-1-ethylpyrrolidine-3-carboxylic acid (Intermediate 196).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[CH:25][N:24]=[CH:23][N:22]=1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[C:27]([C:26]1[C:21]([NH:20][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:22][CH:23]=[N:24][CH:25]=1)#[N:28]
Reactant: N#Cc1cncnc1N
Reactant: O=C(O)CCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1cncnc1NC(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Under an atmosphere of nitrogen, oxalyl chloride (961 mg) was added dropwise to a solution of 5-phenylvaleric acid (Fluka, 1.00 g) in CH2Cl2 (8 ml) and DMF (0.4 ml). After stirring at ambient temperature overnight, the mixture was slowly added at 0° C. to a solution of 4-aminopyrimidine-5-carbonitrile (Aldrich, 505 mg) in pyridine (8 ml). The mixture was stirred overnight at r.t., taken up in CH2Cl2, washed with water, and dried (Na2SO4). After filtration, the solvent was evaporated, and the title compound (1.00 g, 64%) was obtained from the residue by column chromatography (silica gel, eluent gradient n-heptane/ethyl acetate=100:0-60:40). MS: m/e=281.3 [M+H+]. 1H NMR (d6-DMSO): δ 1.60-1.80 (m, 4H), 2.55-2.60 (m, 2H), 3.14 (t, 2H), 7.14-7.29 (m, 5H), 9.17 (d, 2H), 11.34 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([O:20]C)=[O:19])[N:9]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=[O:19])[N:9]=1
Reactant: COC(=O)c1cc2ccccc2c(-c2ccccc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2ccccc2c(-c2ccccc2F)n1
Temperature: 40 °C
Yield: 100 %

Procedure:
Methyl 1-(2-fluorophenyl)isoquinoline-3-carboxylate (0.096 g, 0.34 mmoles) was dissolved in methanol (5 mls) followed by sodium hydroxide (1M, 0.51 mls, 0.51 mmoles) and the reaction heated (40° C.) overnight. The solution was then evaporated and the residue diluted with water (10 mls), and ethyl acetate (10 mls). This mixture was then acidified hydrochloric acid (1M HCl) to ˜pH 5.0 and the layers separated. The aqueous layer was further extracted with ethyl acetate (2×10 mls) and the organic layers combined and washed with water (10 mls) and brine (10 mls). The organic solution was evaporated to leave a white residue (0.091 mgs, 100% yield, 90% pure).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(O)c[n+]1[O-]
Reaction time: 1 h
Yield: 96.6 %

Procedure:
5-Hydroxy-2-methylpyridine (25 g) was suspended in chloroform (500 ml) and treated with m-chloroperbenzoic acid (57 g of material described as 57-86% pure). After stirring for 1 hour the solution was dried with MgSO4 and poured onto a silica column. Elution with EtOAc to remove byproducts and then with 20-50% EtOH in EtOAc gave the product (27.7 g).
Reaction SMILES: C([O:8][C:9]1[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)(=[O:20])=[O:19])=[CH:14][C:13]=1[F:30])C1C=CC=CC=1.O1CCCC1>C(O)C>[CH2:35]([C:33]1[CH:32]=[CH:31][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH2:24][N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)(=[O:20])=[O:19])=[CH:14][C:13]=2[F:30])=[C:9]([OH:8])[CH:34]=1)[CH3:36]
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)NCCCn3ccnc3)cc2F)c(OCc2ccccc2)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(S(=O)(=O)NCCCn3ccnc3)cc2F)c(O)c1
Yield: 42.3 %

Procedure:
According to the procedure of example 20 (b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for 4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(3-imidazol-1-yl-propyl)-benzenesulfonamide (160 mg; 0.31 mmol) and tetrahydrofurane for ethanol (3 mL), the title compound (55 mg; 42%) was obtained as a clear oil, after purification via preparative TLC (dichloromethane/methanol/triethylamine)
Reaction SMILES: [NH2:1][C:2]1[C:13]2[C@@:12]3([CH3:16])[C@H:14]([CH3:15])[C@H:8]([N:9]([C:17]([C:19]4[CH:27]=[CH:26][C:22]5[N:23]=[CH:24][NH:25][C:21]=5[CH:20]=4)=[O:18])[CH2:10][CH2:11]3)[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:28][CH3:29].CO[CH:32]1[CH2:36][CH2:35][CH:34](OC)O1>C(O)(=O)C.O>[N:23]1[C:22]2[CH:26]=[CH:27][C:19]([C:17]([N:9]3[CH2:10][CH2:11][C@:12]4([CH3:16])[C@H:14]([CH3:15])[C@H:8]3[CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:28][CH3:29])=[C:2]([N:1]5[CH:32]=[CH:36][CH:35]=[CH:34]5)[C:13]=34)=[O:18])=[CH:20][C:21]=2[NH:25][CH:24]=1
Reactant: COc1ccc2c(c1N)[C@]1(C)CCN(C(=O)c3ccc4nc[nH]c4c3)[C@H](C2)[C@H]1C
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1-n1cccc1)[C@]1(C)CCN(C(=O)c3ccc4nc[nH]c4c3)[C@H](C2)[C@H]1C
Temperature: 25 °C

Procedure:
A solution of [(2R,6R,11S)-7-amino-8-methoxy-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-(3H-benzoimidazol-5-yl)-methanone (150 mg) and 2,5-dimethoxy-tetrahydrofuran (50 μL) in acetic acid (2 mL) is stirred at 110° C. for 3 h. After cooling to ambient temperature, the solution is diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with brine and dried (MgSO4). Then, the solvent is removed to afford the title compound as a foam-like solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:13])=[C:5]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:4]=1[CH3:20].Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=1>>[F:30][C:24]1[CH:23]=[C:22]([N:17]2[CH2:18][CH2:19][N:14]([C:5]3[C:4]([CH3:20])=[C:3]([O:2][CH3:1])[C:11]4[O:10][CH:9]([CH3:12])[CH2:8][C:7]=4[C:6]=3[CH3:13])[CH2:15][CH2:16]2)[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COc1ccc(Br)cc1F
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Product: COc1ccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)C4)CC2)cc1F
Yield: 38.6 %

Procedure:
By using 1-(7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (552 mg, 2.0 mmol) synthesized in Reference example 88 and 4-bromo-2-fluoro-1-methoxybenzene (720 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 309 mg (yield 39%). Melting point was 120 to 122° C. (ethanol-water).
Reaction SMILES: Cl[C:2]1[N:31]=[CH:30][C:5]2[N:6]=[C:7]3[CH2:12][C@H:11]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=4[F:21])[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9][N:8]3[C:4]=2[CH:3]=1.[CH2:32]([Sn](CCCC)(CCCC)C=C)[CH2:33]CC>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.O1CCOCC1>[F:21][C:14]1[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=1[C@@H:11]1[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:9][N:8]2[C:4]3[CH:3]=[C:2]([CH:32]=[CH2:33])[N:31]=[CH:30][C:5]=3[N:6]=[C:7]2[CH2:12]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cnc(Cl)cc32)C[C@@H]1c1cc(F)c(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cc2c(cn1)nc1n2C[C@H](NC(=O)OC(C)(C)C)[C@@H](c2cc(F)c(F)cc2F)C1
Temperature: 25 °C

Procedure:
An oven dried flask charged with 30 mg (0.066 mmol) of tert-butyl [(7R,8R)-3-chloro-8-(2,4,5-trifluorophenyl)-6,7,8,9-tetrahydropyrido[3′,4′:4,5]imidazo[1,2-a]pyridine-7-yl]carbamate, 0.024 mL (0.079 mmol) of tributyl(vinyl)tin, 23 mg (0.020 mmol) of tetrakis(triphenylphosphine)palladium(0) and 1.5 mL of dry dioxane was put under nitrogen and heated to reflux for 72 h. The reaction mixture was cooled to ambient temperature, filtered through a pad of Celite and the filter cake rinsed with 50 mL of ethyl acetate. The filtrate was evaporated in vacuo and the crude residue was purified directly by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 5% to 90% acetonitrile/water with 0.1% TFA) to afford the title compound as a white foam. LC/MS 445.2 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]1[CH2:28][C@@H:8]1[CH2:9][O:10][C:11]1[C:12]([O:25]C=O)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]2.O>O1CCCC1>[OH:7][CH2:28][C@@H:8]1[O:25][C:12]2=[C:13]3[C:17](=[CH:18][CH:19]=[C:11]2[O:10][CH2:9]1)[NH:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]3
Reactant: CCOC(=O)c1cc2c(OC=O)c(OC[C@H]3CO3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c3c(ccc2[nH]1)OC[C@H](CO)O3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Saturated aqueous potassium carbonate solution (200 ml) was added to a stirred solution of ethyl (R)-5-(2,3-epoxypropoxy)-4-formyloxyindole-2-carboxylate (22.0 g; prepared in a similar manner to that described above) in tetrahydrofuran (250 ml) and the mixture was stirred at room temperature for 72 hours. The mixture was poured into water (1000 ml) and extracted with ethyl acetate (4×400 ml). The combined extracts were dried over sodium sulphate and the solvent evaporated under reduced pressure to give ethyl (S)-2,3-dihydro-2-(hydroxymethyl)-7H-1,4-dioxino[2,3-e]indole-8-carboxylate (17.65 g) as a pale purple solid; m.p. 152-153° C.
Reaction SMILES: [Br:1]Br.[N:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.O>C(O)C>[Br:1][C:12]1[CH:13]=[CH:14][C:9]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[CH:10][CH:11]=1
Reactant: c1ccc(N2CCOCC2)cc1
Reactant: BrBr
Solvent: O
Solvent: CCO
Product: Brc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
Bromine (10.8 g, 67.4 mmol) was added to a solution of 4-(4-morpholinyl)benzene (10.0 g, 61.3 mmol) in ethanol (100 mL) at 0° C., and the mixture was stirred for 1 hour at room temperature. Water (100 mL) was poured into the reaction mixture, which was then extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate and water, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (10.7 g, yield 72%).