Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:14](=[O:17])[CH2:15]C)=[CH:4][C:5]2[NH:9][C:8]([C:10]([OH:12])=[O:11])=[N:7][C:6]=2[CH:13]=1.CC1C(C(=O)CCCC)=CC2NC(C(O)=O)=NC=2C=1.C(C1C(OC)=CC2N=C(C(O)=O)NC=2C=1)(=O)CCC.C(C1C(Cl)=CC2N=C(C(O)=O)NC=2C=1)(=O)CCC.C1(C(C2C(C)=CC3N=C(C(O)=O)NC=3C=2)=O)CC1.C1(C(C2C(C)=CC3N=C(C(O)=O)NC=3C=2)=O)CCCCC1.COCCCC(C1C(C)=CC2N=C(C(O)=O)NC=2C=1)=O.CC1C(C(=S)CCCC)=CC2NC(C(O)=O)=NC=2C=1.CC1C(C(=O)CCCS(C)=O)=CC2NC(C(O)=O)=NC=2C=1.CC1C(C(=S)CCCC2C=CC=CC=2)=CC2NC(C(O)=O)=NC=2C=1.CC1C(C(=O)CCCS(C2C=CC=CC=2)=O)=CC2NC(C(O)=O)=NC=2C=1.C(C1C(C)=CC2N=C(C(OC)=O)NC=2C=1)(=O)CCC>>[C:14]([C:3]1[C:2]([CH3:1])=[CH:13][C:6]2[N:7]=[C:8]([C:10]([OH:12])=[O:11])[NH:9][C:5]=2[CH:4]=1)(=[O:17])[CH3:15]
Reactant: CCC(=O)c1cc2[nH]c(C(=O)O)nc2cc1C
Agent: CCCC(=O)c1cc2[nH]c(C(=O)O)nc2cc1Cl
Agent: CCCC(=O)c1cc2[nH]c(C(=O)O)nc2cc1OC
Agent: CCCC(=O)c1cc2[nH]c(C(=O)OC)nc2cc1C
Product: CC(=O)c1cc2[nH]c(C(=O)O)nc2cc1C

Procedure:
6-methyl-5-propionyl-benzimidazole-2-carboxylic acid; 6-methyl-5-valeryl-benzimidazole-2-carboxylic acid; 5(6)-butyrylbenzimidazole-2-carboxylic acid; 5-butyryl-6-methoxy-benzimidazole-2-carboxylic acid; 5-butyryl-6-chloro-benzimidazole-2-carboxylic acid; 5-cyclopropylcarbonyl-6-methyl-benzimidazole-2-carboxylic acid; 5-cyclohexylcarbonyl-6-methyl-benzimidazole-2-carboxylic acid; 5-(4-methoxy-butyryl)-6-methyl-benzimidazole-2-carboxylic acid; 6-methyl-5-(4-methylthiobutyryl)-benzimidazole-2-carboxylic acid; 6-methyl-5-(4-methylsulphinyl-butyryl)-benzimidazole-2-carboxylic acid; 6-methyl-5-(4-phenylthio-butyryl)-benzimidazole-2-carboxylic acid; 6-methyl-5-(4-phenylsulphinyl-butyryl)-benzimidazole-2-carboxylic acid; and methyl 5-butyryl-6-methyl-benzimidazole-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]([S:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20][CH2:21][CH3:22])[CH2:14]2)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[C:7]([S:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([N:20]([CH2:21][CH3:22])[C:34]([NH:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:28][CH:29]=1)=[O:35])[CH2:14]2)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCNC1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Solvent: ClCCl
Product: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
To a mixture of 2-(2-ethylaminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester and borane complex (11.0 g; 33 mmol), dissolved in CH2Cl2 (100 mL), is added 4-trifluoromethoxyphenyl isocyanate (10.2 g; 50.2 mmol) and the reaction was allowed to stir at RT for 18 h. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 11.2 g (62%) of 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionic acid tert butyl ester as a white foam.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH3:27][C:28]1[CH:32]=[C:31]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]2=[O:47])[S:30][C:29]=1[C:48]([O:50]CC)=[O:49]>>[CH3:27][C:28]1[CH:32]=[C:31]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]2=[O:47])[S:30][C:29]=1[C:48]([OH:50])=[O:49]
Reactant: CCOC(=O)c1sc(N2CCN(CC(=O)c3ccccc3)C2=O)cc1C
Agent: CCOC(=O)c1sc(N2CCN(CCOc3ccccc3)C2=O)cc1C
Product: Cc1cc(N2CCN(CC(=O)c3ccccc3)C2=O)sc1C(=O)O
Yield: 58 %

Procedure:
Following the procedure as described in Example 54, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)-thiophene-2-carboxylate with ethyl 3-methyl-5-(2-oxo-3-(2-oxo-2-phenylethyl)-imidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a yellow solid in 58% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.36 (br s, 1H), 8.02 (d, J=7.3 Hz, 2H), 7.74-7.67 (m, 1H), 7.61-7.54 (m, 2H), 6.34 (s, 1H), 4.85 (s, 2H), 3.97-3.88 (m, 2H), 3.67-3.58 (m, 2H), 2.41 (s, 3H); MS (ES+) m/z 345.3 (M+1).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:12]=1[C:21]([F:24])([F:23])[F:22])[CH3:4]>CCO>[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[C:21]([F:22])([F:23])[F:24])[CH3:4]
Reactant: CCc1ccccc1-c1ccc(C(=O)OC)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 60 °C
Yield: 93.1 %

Procedure:
A 5N aqueous solution of NaOH (3 mL, 15 mmol) was added into a solution of methyl 2′-ethyl-2-(trifluoromethyl)biphenyl-4-carboxylate (3.05 g, 9.89 mmol) in EtOH (30 mL) and the resulting mixture was heated at 60° C. for 45 minutes. The reaction mixture was concentrated under vacuum. The residue was taken up with water (50 mL) and a 5N aqueous solution of HCl (5 mL), and then extracted with MTBE (2×100 mL). The organic layers were washed with brine (50 mL), combined, dried (MgSO4) and the solvent was removed under reduced pressure to give the title compound as a white powder (2.71 g, 93%). HPLC (Method A) Rt 4.8 min (Purity: 97.3%). LC/MS (Method B): 293.1 (M−H)−. 1H NMR (DMSO-d6, 300 MHz) δ 13.54 (s, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.22 (dd, J=7.9, 1.5 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.42-7.32 (m, 2H), 7.24 (m, 1H), 7.10 (d, J=7.5 Hz, 1H), 2.39-2.13 (m, 2H), 1.00 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:20][C:21]([CH3:23])=[O:22])[S:18][CH:19]=1)[CH3:14].N1CCCCC1.C(O)(=O)C>ClCCl>[CH2:13]([C:15]1[N:16]=[C:17]([C:20]([C:21](=[O:22])[CH3:23])=[CH:1][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=2[O:11][CH3:12])[S:18][CH:19]=1)[CH3:14]
Reactant: CCc1csc(CC(C)=O)n1
Reactant: COc1cc(C#N)ccc1C=O
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCc1csc(C(=Cc2ccc(C#N)cc2OC)C(C)=O)n1
Yield: 61.6 %

Procedure:
770 mg (4.78 mmol) of the compound from example 3A and 890 mg (5.26 mmol) of the compound from example 17A are dissolved in 15 ml of dichloromethane, and 0.473 ml (4.78 mmol) of piperidine and 0.247 ml (4.78 mmol) of acetic acid are added. The reaction mixture is heated under reflux with an inverse water trap overnight. The volatile components are removed in a rotary evaporator, and the crude product is purified by MPLC (Biotage 12M cartridge, eluent: isohexane/ethyl acetate 80:20→70:30). 920 mg (66% of theory) of 4-[2-(4-ethyl-1,3-thiazol-2-yl)-3-oxobut-1-en-1-yl]-3-methoxybenzonitrile are obtained as a mixture of the E/Z isomers {LC-MS (Method 1): Rt=2.39 min; (Elpos): m/z=313 [M+H]+} and without further working up.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:13]=1[C:14]([NH2:16])=[O:15].Cl>CN(C=O)C>[CH2:1]([O:8][C:17]1[CH:18]=[CH:19][CH:20]=[C:12]([F:11])[C:13]=1[C:14]([NH2:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: NC(=O)c1c(F)cccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl alcohol (24 ml, 0.229 mol) is added portionwise to a suspension of sodium hydride (9.16 g, 0.229 mol) in DMF (300 ml) and stirred at room temperature for 1 h. 2,6-Difluorobenzamide (30 g, 0.190 mol) is added in one portion and stirring is continued overnight at room temperature. The reaction mixture is poured into 1N HCl (1.5 l) and extracted with dichloromethane. The extract is washed with water and saline, dried (MgSO4), and evaporated to give product as a white solid suitable for use in the next step (39.6 g, 85%); MS for C14H12FNO2 m/z 246 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:41][CH2:42][C:43]([NH2:45])=[O:44])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[OH-].[Na+].C(=O)([O-])O.[Na+]>CO>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:41][CH2:42][C:43]([NH2:45])=[O:44]
Reactant: NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: NCC(N)=O
Reaction time: 3 h

Procedure:
(Z)-1-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-ethene-Fmoc-glycineamide (1.08 g, 1.82 mmols) was dissolved in 20 ml of methanol, and 1.0 ml (2.0 mmols) of a 2-N sodium hydroxide aqueous solution was added thereto. The mixture was stirred for 3 hours. A saturated solution of sodium hydrogencarbonate was added thereto, and the mixture was extracted three times with dichloromethane. The extract was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The product was purified using a silica-gel plate (mixture of 5-% methanol and dichloromethane) to produce 479 mg of the final product in a yield of 70.7%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]3[C:15]=2[CH2:16][N:17]([CH3:27])[C:18]3=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[Na+]>C(O)C.[Fe]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]3[C:15]=2[CH2:16][N:17]([CH3:27])[C:18]3=[O:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN1Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ccc(N)c2C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
To a solution of 4-(2-methyl-7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (5.37 g, 14 mmol) in ethanol (200 mL), iron powder (3.98 g, 70 mmol) and 1N hydrogen chloride (28 mL) are added and the mixture is stirred at 60° C. for 2 hours. The mixture is cooled to room temperature, and then 1N sodium hydroxide (28 mL) is added. After removing insoluble material by filtration, the mixture is concentrated. The residue is extracted twice with dichloromethane. The organic layer is successively washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo to afford 4-(7-Amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (4.9 g) as pale green amorphous solids in 99% yield. Rf=0.18 (Hexane/AcOEt=111). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.49 (s, 9H), 2.85 (t, 4H), 3.13 (s, 3H), 3.54 (t, 4H), 4.28 (s, 2H), 5.03 (s, 2H), 6.56 (d, 1H), 6.96 (d, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1I>[Cu](I)I.O1CCOCC1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:9]1[CH:10]=[CH:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1
Reactant: Fc1ccccc1I
Reactant: c1ccc(-c2cc[nH]n2)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Fc1ccccc1-n1ccc(-c2ccccc2)n1
Temperature: 110 °C
Yield: 36 %

Procedure:
Add dioxane (7 mL) to a mixture of 3-phenyl-1H-pyrazole (2 g, 13.9 mmol), copper iodide (132 mg, 0.05 mmol) and potassium carbonate (555 mg, 4.2 mmol). Add 2-fluoroiodobenzene (1.94 mL, 16.6 mmol), trans-cyclohexyldiamine (0.35 mL, 2.78 mmol). Heat at 110° C. for about 18 hours. Cool to RT and filter through a silica gel pad eluting with ethyl acetate. Concentrate and purify (silica gel chromatography, eluting with hexane:ethyl acetate 84:16) to give the desired compound (36%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(N(CC)CC)C.[CH3:14][SiH:15]([CH3:17])Cl>O1CCCC1>[CH3:14][SiH:15]([CH3:17])[N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6]
Reactant: O=C1NCCO1
Reactant: C[SiH](C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[SiH](C)N1CCOC1=O

Procedure:
A 3-dimethylsilyl-2-oxazolidinone was prepared in accordance with the following procedure. To a stirred mixture of 34.8 grams of 2-oxazolidinone and 40.4 grams of triethylamine in 600 ml of a tetrahydrofuran solvent, 45 ml of dimethylchlorosilane was added dropwise over a 30-minute period. The mixture was then heated in a distillation apparatus with continuous reflux for a period of 30 minutes. The resultant mixture was cooled and then filtered.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9]C)=O)[N:6]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CO>[NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:9])[N:6]=1
Reactant: COC(=O)c1nc(N)sc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1nc(N)sc1-c1ccccc1
Yield: 45.1 %

Procedure:
5.0 g (21.3 mmol) of methyl 2-amino-5-phenyl-4-thiazolecarboxylate (which was prepared as described in J. Chem. Soc. Perk. Trans. I (1982) 159-164) and 6.84 g (42.7 mmol) of t-butyl (2-aminoethyl)carbamate were heated under reduced pressure for 2 hours at a bath temperature of 140°, whereby the methanol formed was distilled off continuously. After cooling the residue was dissolved in 50 ml of methylene chloride and chromatographed on 200 g of silica gel with a 9:1 mixture of methylene chloride and methanol as the eluting agent. The fractions which were pure according to the thin-layer chromatogram were combined and evaporated under reduced pressure, whereby there were obtained 4.5 g of a red, crystallizing oil. Crystallization from methanol and an ether/hexane mixture yielded 3.48 g (45%) of t-butyl [2-(2-amino-5-phenyl-4thiazolecarboxamido)ethyl]carbamate as beige crystals which were used without further purification.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.F.[OH-].[K+]>>[CH3:12][C:5]1[CH:10]=[C:9]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:8]=[C:7]([CH3:11])[CH:6]=1
Reactant: Cc1cccc(C)c1
Reactant: C=C(C)C
Agent: F
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(C)cc(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
1,3-Dimethyl-5-tertiary-butylbenzene is prepared as described in U.S. Pat. No. 2,860,169. According to this procedure, 448 g. (8.0 moles) of isobutene were dissolved in 961 g. (9.0 moles) of meta-xylene at 0° C. and added over a period of 4.2 hours to 150 g. (7.5 moles) of liquid hydrogen fluoride contained in a copper flask equipped with a stainless-steel stirrer, addition-tube and gas-outlet. The flask was cooled in an ice-bath. Stirring was continued for 2 hours after the end of the addition period. The contents of the flask were poured on crushed ice, neutralized with excess potassium hydroxide and the organic phase separated, washed with sodium bicarbonate solution, dried and distilled. The final product contained 17% by weight of unconverted meta-xylene, 76% of 1,3-dimethyl-5-tertiary-butylbenzene and 7% of higher boiling products.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[C:22](Cl)(=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[O:20]=[C:14]1[CH:13]([N:5]2[C:4](=[O:21])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:7]=[C:6]2[CH3:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: CCCCCCC(=O)Cl
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Solvent: C1CCOC1
Product: CCCCCCC(=O)Nc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 80 °C
Yield: 18.8 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.49 g, 1.6 mmol) in tetrahydrofuran (10 mL), was added heptanoyl chloride (0.88 mL, 5.7 mmol) and heated at 80° C. for two hours. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give heptanoic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-amide as a white solid (120 mg, 18% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 7.12 min (95.5%); mp, 230-232° C.; 1HNMR (DMSO-d6) δ 0.86 (t, J=7 Hz, 3H, CH3), 1.24-1.36 (m, 6H, 3CH2), 1.56-1.65 (m, 2H, CH2), 2.18-2.23 (m, 1H, CHH), 2.40 (t, J=7 Hz, 2H, CH2), 2.59-2.88 (m, 6H, CHCH2, CH3), 5.32 (dd, J=6, 11 Hz, 1H, CH), 7.26-8.55 (m, 3H, Ar), 11.09 (s, 1H, NH), 11.74 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.87, 20.65, 21.89, 23.35, 24.66, 28.05, 30.60, 30.95, 37.64, 56.73, 107.43, 115.12, 120.32, 135.63, 139.85, 147.86, 154.71, 163.07, 169.28, 171.51, 172.57. LCMS MH=399; Anal Calcd For C21H26N4O4+0.3H2O: C, 62.45; H, 6.64; N, 13.87. Found: C, 62.28; H, 6.66; N, 13.61.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.P(Br)(Br)[Br:11]>C(OCC)C>[Br:11][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[I:1]
Reactant: OCc1ccccc1I
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCc1ccccc1I
Yield: 91 %

Procedure:
To a solution of 2-iodobenzyl alcohol (50 g) in diethyl ether (500 mL), cooled in an ice-bath, was added dropwise phosphorus tribromide (28 mL). The reaction mixture was chilled in a refrigerator for 3.5 h, then quenched by slow addition of methanol (50 mL). The mixture was washed with water, then saturated sodium bicarbonate, then water (100 mL each). The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to a white solid, which was triturated in hexane and collected by filtration to yield 58 g (91%) of the title material of Step A as a solid, mp 55-57° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH2:19]Br)=[O:4].[CH3:21][O:22][C:23](=[O:36])[CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH2:19][N:25]([CH2:24][C:23]([O:22][CH3:21])=[O:36])[S:26]([C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)(=[O:28])=[O:27])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(CC2CCCC2)c1CBr
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1CC1CCCC1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A mixture of 5-bromo-2-bromomethyl-1-cyclopentylmethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.5 g, 6.14 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (1.42 g, 5.84 mmol), sodium iodide (1.84 g, 12.3 mmol) and potassium carbonate (1.70 g, 12.3 mmol) in DMF (40 mL) was stirred at r.t. for 16 h. Water was added, and the resulting suspension was extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes) to give 2.76 g of the title compound. MS: (+) m/z 591.19, 593.14 (M+Na, 79/81Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@H:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Product: COc1c(Nc2ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc2c1CC[C@@H](N1CCOCC1)CC2

Procedure:
The title compound was prepared from 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 881 heating at 140° C. Product was isolated as an off-white solid (43 mg, 39%). LCMS (m/e) 539 (M+H); 1H NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H, J=8.1 Hz), 7.86 (s, 1H), 7.41 (broad s, 1H), 6.88 (d, 1H, J=8.3 Hz), 6.31 (s, 2H), 5.81 (s, 1H), 5.62 (s, 1H), 4.27 (t, 1H, J=8.1 Hz), 3.97 (s, 4H), 3.72 (s, 3H), 3.39-3.54 (m, 2H), 3.08 (m, 4H), 2.88 (m, 2H), 2.75 (dd, 1H, J=11.9, 14.2 Hz), 2.49 (d, 1H, J=8.1 Hz), 2.42 (m, 3H), 2.20 (d, 1H, J=9.4 Hz), 1.61 (d, 1H, J=8.3 Hz), 1.50 (m, 2H). Alternatively the title compound can be prepared from (S)-1-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine using the procedures outlined above. (S)-1-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine is prepared from racemic 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine by resolution using SFC chromatography on a Chiralcel OJ-H (2×25 cm) column using 12% isopropanol/CO2 (0.1% DEA) or by the following methods:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.Cl>Cl[Ni](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>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:1][O:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:13]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: Brc1cccnc1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: c1ccc(OCc2cccnc2)cc1

Procedure:
This substance was prepared by a dichlorobis-(triphenylphosphine)nickel (II) catalyzed reaction between 3-methoxyphenylmagnesium bromide (from 50 g of 3-bromo-anisole and 5.9 g of Mg in THF) and 31.8 g of 3-bromopyridine. Yield 23.1 g (62%), bp. 102°/0.15 mmHg, mp. (HCl) 187.5-9° C.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[O:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1B(O)O>C1(C)C=CC=CC=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[O:4][CH:3]=1
Reactant: COc1ccc2c(=O)c(Br)coc2c1
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2coc3cc(OC)ccc3c2=O)c(OC)c1
Reaction time: 5 h

Procedure:
A solution of 13 (4.0 g, 15.8 mmol) and 2,4-dimethoxy benzeneboronic acid (3.4 g, 19.0 mmol) and Pd(Ph3)4 (0.79 g) in toluene/EtOH (50 mL/5 mL) and 2M Na2CO3 aq. (30 mL) was heated to reflux. After 5 h, the reaction was cooled and the organic layer dried over MgSO4, concentrated and chromatographed on silica gel (EtOAc/hexanes 3:7 to EtOAc/hexanes 1:1) to yield 14 as a solid which was triturated with MeOH to give a tan solid.