Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH3:32])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[NH:14][C:13]1=[O:23]>N1C=CC=CC=1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH2:31][CH3:32])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=3)[NH:14][C:13]2=[O:23])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOc1ccccc1C1(N)C(=O)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Product: CCOc1ccccc1C1(NC(=O)Oc2ccccc2)C(=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 111 %

Procedure:
1.2 ml (9.38 mmol) of phenyl chloroformate were added dropwise to 2.5 g (8.5 mmol) of product 10a dissolved in 50 ml of pyridine at 0° C. The reaction solution was then stirred at room temperature for 16 h. The solution was subsequently poured into ice-water, and the aqueous phase was extracted with ethyl acetate (AcOEt). The organic phase was washed several times with water, dried and concentrated in vacuo. 3.9 g of the product were obtained.
Reaction SMILES: C([Li])(CC)C.CN(C)CCN(C)CCN(C)C.[C:18]([Si:22]([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].CN([CH:38]=[O:39])C>O1CCCC1>[Si:22]([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH:29]=1)[CH:38]=[O:39])([C:18]([CH3:21])([CH3:19])[CH3:20])([CH3:23])[CH3:24]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(F)cc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(F)c(C=O)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
sec-Butyllithium (1.4M in cyclohexane, 2.78 ml) was added to dry tetrahydrofuran (10 mL) under nitrogen and the solution cooled to −78° C. N1-(2-(dimethylamino)ethyl)-N1,N2,N2-trimethylethane-1,2-diamine (0.674 g) was added slowly dropwise. A solution of tert-butyl(4-fluorophenethoxy)dimethylsilane (example 100, step a) (0.99 g) in dry tetrahydrofuran (3 mL) was then added dropwise over 5 minutes. Reaction mixture stirred for 2 hours at −78° C. DMF (2.1 ml) was added dropwise over 5 minutes and the mixture stirred at −78° C. for 1 hour followed by room temperature for 45 minutes. The reaction mixture was quenched by addition of water. Ethyl acetate (200 mL) was added and the organic washed three times with water, followed by twice with 2M HCl and then twice with water. The organic solution was washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.5 g.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:27]([N:29]1[C:41]2[CH:40]=[CH:39][C:38]([NH2:42])=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:28]>>[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([NH:42][C:38]1[CH:39]=[CH:40][C:41]2[N:29]([CH2:27][CH3:28])[C:30]3[C:35]([C:36]=2[CH:37]=1)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:17])(=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=CCl)CN3C(=O)c3ccccc3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 48% purity by LC/MS. MS(ESI+): m/z=458.4.
Reaction SMILES: C([O:7][CH2:8][C@H:9]([C:15]1[C:16]([Br:27])=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH3:26])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[Br:27][C:16]1[C:15]([C@H:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:8][OH:7])=[C:24]([CH3:25])[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]2
Reactant: Cc1ccc2c(Br)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc2c(Br)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl pivalate (50.0 g, 115 mmol) in THF (600 mL) and methanol (200 mL) was added 1M NaOH solution (300 mL, excess) at 0° C. The mixture was stirred at room temperature for 16 hours, diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product. LCMS-ESI+: calc'd for C17H22BrNO2: 352.1 (M+H+); Found: 352.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)=[O:5])[CH3:2].[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=[O:15])[NH:20][CH2:19][CH2:18][N:17]([CH3:21])[CH3:16])=[O:5])[CH3:2]
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 998.8 %

Procedure:
A stirred solution of 2-carboxymethyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (2.11 g, 10 mmol) in N,N-dimethylformamide (5 ml) and dichloromethane (50 ml) was added with N*1*,N*1*-dimethyl-ethane-1,2-diamine (968 mg, 11 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (5 g, 26 mmol) and 1-hydroxybenzotriazol (1.5 g, 11 mmol) in an ice-water bath. Upon completion of the addition, the mixture was stirred at room temperature overnight, added with cold water (50 ml) and extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated sodium bicarbonate solution (50 ml), water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[(2-dimethylamino-ethylcarbamoyl)-methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (28.1 g, 90.9%) as a colorless oil which was used as such.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH3:8])=[O:6].Cl[C:17]([F:22])([F:21])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:21][CH:17]([F:22])[O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:13])([F:14])[F:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(O)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(F)(F)F)c(OC(F)F)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 79.9 %

Procedure:
A suspension of methyl 3-hydroxy-4-(trifluoromethyl)benzoate (see WO 2007/129745) (2.00 g), sodium chlorodifluoroacetate (2.08 g) and potassium carbonate (2.51 g) in N,N-dimethylformamide (30.0 mL) was stirred at 100° C. for 6 hours. After cooling the reaction mixture to room temperature, water was added to it and two extractions were conducted with ethyl acetate. The combined organic layers were washed with water three times and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-85:15) to give methyl 3-(difluoromethoxy)-4-(trifluoromethyl)benzoate as a colorless oil (1.96 g).
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]([CH:9]=O)[CH:8]=1)([O-:3])=[O:2].[CH2:11]1[C:16](=O)[CH2:15][C:13](=[O:14])[CH2:12]1.[NH2:18][C:19]1[N:23]([CH3:24])[NH:22][C:21](=[O:25])[CH:20]=1>>[CH3:24][N:23]1[C:19]2[NH:18][C:16]3[CH2:11][CH2:12][C:13](=[O:14])[C:15]=3[CH:9]([C:7]3[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[S:5][CH:6]=3)[C:20]=2[C:21](=[O:25])[NH:22]1
Reactant: O=C1CCC(=O)C1
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=Cc1csc([N+](=O)[O-])c1
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1csc([N+](=O)[O-])c1
Yield: 72.2 %

Procedure:
2-Nitrothiophene-4-carboxaldehyde (0.16 g, 1.0 mmol), 1,3-cyclopentadione (0.1 g, 1.0 mmol), and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.11 g, 1.0 mmol) were processed as described in Example 1 to provide 0.24 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.35 (m, 2H), 2.68 (m, 2H), 3.5 (s, 3H), 4.8 (s, 1H), 7.51 (d, 1H), 7.89 (d, 1H), 9.75 (bs, 1H), 10.47 (s, 1H); MS (ESI−) m/z 331 (M−H)−; Anal. calcd for C4H12N4O4S: C, 50.60;H, 3.64; N, 16.86. Found: C, 51.06;H, 3.68; N, 16.97.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[Cl-:13].[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N+:10]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:8]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: ClCCCCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: [Cl-]
Product: c1cnc(N2CC[N+]3(CCCCC3)CC2)nc1

Procedure:
Reaction of 1-(2-pyrimidinyl)piperazine (16.4 g., 0.1 mole), 1,5-dichloropentane (28.2 g., 0.2 mole) and sodium carbonate (21.2 g., 0.2 mole) in 300 ml. of isopropanol according to the procedure of Example 2 affords the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.C(N(C(C)C)CC)(C)C.[C:27]([CH2:31][CH2:32][C:33](Cl)=[O:34])([O:29][CH3:30])=[O:28]>C(Cl)Cl>[C:27]([CH2:31][CH2:32][C:33]([NH:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:34])([O:29][CH3:30])=[O:28]
Reactant: NCc1cc(-c2cccs2)[nH]c1-c1cccs1
Reactant: COC(=O)CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)NCc1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.1 %

Procedure:
To a solution of 400 mg (1.54 mmol) of 3-aminomethyl-2,5-dithienylpyrrole (XVIII) and 378 ul (3.07 mmol) of diisopropylethylamine in 15 ml of anhydrous methylene chloride was added 3-carbomethoxypropionyl chloride (1.6 ml, 9.23 mmol). After stirring for 5 minutes at room temperature, the reaction mixture was quenched by the addition of 1 ml of water. The aqueous layer was extracted three times with 5 ml portions of chloroform and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude reaction product was chromatographed on 100 g of silica gel. Elution with chloroform:methanol, 95:5, gave 456 mg (39%) of the amide (XXVI) as a greenish solid having a mp of 48°-49° C., and Rf :0.55 (chloroform:methanol, 98:2).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=O)OCC)C.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:23].[CH2:27]([O:29][C:30]([CH:32]1[CH:34]([CH:35]=O)[C:33]1([CH3:38])[CH3:37])=[O:31])[CH3:28]>O1CCCC1.O>[CH2:27]([O:29][C:30]([CH:32]1[CH:34]([CH:35]=[C:9]([Cl:23])[C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C:33]1([CH3:38])[CH3:37])=[O:31])[CH3:28]
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Reactant: CCOP(=O)(Cc1ccc(Cl)cc1)OCC
Reactant: ClC(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1C(C=C(Cl)c2ccc(Cl)cc2)C1(C)C
Temperature: -70 °C
Yield: 54.3 %

Procedure:
26.3 g (0.1 mol) of 4-chlorobenzyl-phosphonic acid diethyl ester were dissolved in 400 ml of absolute tetrahydrofuran and the solution was cooled to -70° C. 0.11 mol of n-butyl-lithium (15% strength solution in hexane) were added dropwise, in counter-current with nitrogen and while stirring thoroughly, and the reaction mixture was then subsequently stirred at -70° C. for a further 15 minutes. 15.4 g (0.1 mol) of carbon tetrachloride were then added dropwise at -70° C., also under nitrogen, and the reaction mixture thereby became red-brown in color. After stirring for a further 15 minutes, 18.6 g (0.1 mol) of 2,2-dimethyl-3-formyl-cyclopropanecarboxylic acid ethyl ester were added at -65° C. The reaction mixture was then allowed to come to room temperature and was subsequently stirred at 25° C. for a further 3 hours. The reaction mixture was then poured into 2 liters of water and extracted with 600 ml of ether. The ether phase was dried over sodium sulphate, the solvent was stripped off in vacuo and the oily residue was distilled at 150°-155° C./2 mm Hg. 2,2-Dimethyl-3-(2-chloro-2-p-chlorophenyl-vinyl)-cyclopropanecarboxylic acid ethyl ester was obtained in 54.3% yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:9][CH:10]=1)=[O:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][CH2:12][CH2:13][NH:14][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:9][CH:10]=1)=[O:5]
Reactant: COC(=O)c1ccc(CCCN)o1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCNS(C)(=O)=O)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a solution of 5-(3-amino-propyl)-furan-2-carboxylic acid methyl ester hydrochloride salt (see Preparation 2a) (150 mg, 0.683 mmol), and triethylamine (0.313 mL, 2.25 mmol) in CH2Cl2 (15 mL) at 0° C. was added methanesulfonyl chloride (86 mg, 0.75 mmol). The reaction was stirred at room temperature for 18 h. The organic solution was washed consecutively with dilute HCl, water, saturated NaHCO3, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to provide the title sulfonamide (156 mg). MS 262 (M+1).
Reaction SMILES: [OH-].[K+].[N+](=[CH2:5])=[N-].C(O)C.[C:9]([C:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:12][OH:13])#[N:10]>O.C(OCC)C>[CH3:5][O:13][CH:12]=[C:11]([C:9]#[N:10])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#CC(=CO)CCCCc1ccccc1
Reactant: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: COC=C(C#N)CCCCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3.0 grams of potassium hydroxide in 6 mL of water was placed in a commercially available diazomethane generator. Ethanol, 8 mL, was added to the generator, and the contents of the generator were slowly warmed to 60° C. to 70° C. To this was added dropwise a solution of 4.6 grams (0.021 mole) of Diazaid® in a minimum amount of diethyl ether. The diazomethane generated was condensed on a cold finger and, in turn, was allowed to drip into a stirred, cooled solution of 2.5 grams (0.012 mole) of 2-cyano-6-phenyl-1-hexen-1-ol in a minimum of diethyl ether. The complete generation of diazomethane required about 30 to 45 minutes. Upon completion of the diazomethane generation, the reaction mixture was allowed to warm to ambient temperature. After this time the reaction mixture was concentrated under reduced pressure, yielding 2.4 grams of 1-methoxy-2-cyano-6-phenyl-1-hexene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]=O.[OH-].[Na+].[NH2:5][CH2:6][C:7]([OH:9])=[O:8].[P:10]([O-:15])([O:13][CH3:14])[O:11][CH3:12].Cl>O>[C:7]([CH2:6][NH:5][CH2:1][P:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12])([OH:9])=[O:8]
Reactant: NCC(=O)O
Reactant: C=O
Reactant: COP([O-])OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COP(=O)(CNCC(=O)O)OC
Reaction time: 0.17 h

Procedure:
8.6 g. of 37% formaline (= 0.1 moles of formaldehyde) are added to a stirred solution of 4.0 g. (0.1 moles) of sodium hydroxide and 7.5 g. (0.1 moles) of glycine in 40 ml. of water at 0° to 5° C. After 10 minutes of stirring 11 g. (0.1 moles) of dimethyl phosphite are added, and stirring is continued for 2 hours at 90° to 100° C. The reaction mixture is cooled, acidified with hydrochloric acid, and extracted to obtain dimethyl N-carboxymethyl-aminomethyl-phosphonate. The hygroscopic product melts at 73°-75° with decomposition.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[CH2:12][OH:13].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>CCOCC>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[CH:12]=[O:13]
Reactant: OCc1cc(I)ccc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1cc(I)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
A methylene chloride solution (99 mL) of (2-chloro-5-iodophenyl)methanol (9.01 g, 33.5 mmol) and PCC (8.67 g, 40.2 mmol) were combined and stirred at rt. After 16 h, Et2O was added and the solution stirred for 30 minutes. The solution was then filtered and the organic layer was washed with H2O (2×), NaHCO3 (3×), and brine. The organic layer was dried (Na2SO4), concentrated, and purified by Biotage chromatography (0%-20% EtOAc/hexanes) to afford 5.94 g of product (67%). 1H NMR (400 MHz, chloroform-d) δ ppm 10.38 (s, 1 H) 8.22 (d, J=2.02 Hz, 1 H) 7.83 (dd, J=8.46, 2.15 Hz, 1 H) 7.21 (d, J=8.59 Hz, 1 H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[CH3:17].[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O.CS(C)=O>[CH3:17][C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Reactant: O=Cc1cccc(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
2-Bromo-1,3-dimethyl-5-[3-(methylsulfonyl)propoxy]benzene (1.0 g), 3-formylphenylboronic acid (0.49 g, 1.05 eq), tripotassium phosphate (1.32 g, 2.0 eq), 10% Pd—C(PE) (0.1 g, 1.38 mol %), rac-BINAP (26.8 mg, 1.38 mol %), dimethyl sulfoxide (10 mL) and water (5 mL) were added. After nitrogen substitution, the mixture was stirred at 80° C. for 3 hr. The obtained reaction mixture was analyzed by high performance liquid chromatography to find the title compound (91.2% peak area).
Reaction SMILES: FC(F)(F)C([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].OO.[F:23][C:24]([I:30])([F:29])[C:25]([F:28])([F:27])[F:26]>>[F:14][C:15]([F:20])([F:19])[C:16]([O:18][I:30]([O:5][C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])[C:24]([F:29])([F:23])[C:25]([F:28])([F:27])[F:26])=[O:17]
Reactant: O=C(O)C(F)(F)F
Reactant: FC(F)(F)C(F)(F)I
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Product: O=C(OI(OC(=O)C(F)(F)F)C(F)(F)C(F)(F)F)C(F)(F)F
Reaction time: 3 h
Yield: 85 %

Procedure:
To a mixture of 18.6 ml (132 mmols) of trifluoroacetic anhydride and 32 ml of trifluoroacetic acid was added dropwise 1.66 ml of a 30% aqueous hydrogen peroxide solution (H2O2, 16.3 mmols and H2O, 71.7 mmols) in an ice bath. After completion of the addition, the mixture was stirred for 3 hours and 0.90 ml (8.13 mmols) of pentafluoroethyl iodide was added thereto, followed by allowing the mixture to react at 0° to 5° C. for 24 hours. The solvent was then distilled off to obtain 3.3 g (85% yield) of di(trifluoroacetoxy)iodopentafluoroethane as a white fluffy crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]1)[NH:20][C:19]2=[O:29]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)[nH]c(=O)c2c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 2-methoxyphenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O4, 362.1; m/z found, 363.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.00 (br s, 1H), 12.84 (br s, 1H), 8.98 (s, 1H), 8.28 (s, 1H), 8.21 (d, J=1.7 Hz, 1H), 7.97 (dd, J=8.4, 2.1 Hz, 1H), 7.74 (d, J=7.0 Hz, 1H), 7.43-7.39 (m, 2H), 7.19-7.16 (m, 1H), 7.09 (td, J=7.5, 1.0 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[N:3]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[N:3]=1
Reactant: CCCOc1nc(Cl)ccc1C(N)=O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCCOc1nc(Cl)ccc1C#N
Temperature: 55 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 6-chloro-2-propoxy-nicotinamide (3.80 g, 17.71 mmol) and pyridine (8.50 mL, 106.21 mmol) in acetonitrile (25 mL) was added phosphorus oxychloride (4.81 mL, 53.13 mmol) over a period of 5 min. The reaction was stirred at 55° C. for 1 h. Acetonitrile was evaporated in vacuo and the resulting residue was neutralized with 1N NaOH at 0° C. until pH reached to ˜7. The reaction mixture was extracted with EtOAc (100 mL). The organic layer was collected and the aqueous layer was further extracted with EtOAc (3×50 mL). All organics were combined washed with brine (2×25 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (3.4 g, 98%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29 (d, J=7.9 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 4.31 (t, J=6.5 Hz, 2H), 1.79-1.66 (m, 2H), 0.96 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:12]=3[NH:11][C:10]=2[CH:20]=1)=[O:5])[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[CH:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:12]=3[NH:11][C:10]=2[CH:20]=1)=[O:5])[CH3:2]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)c1ccc2c3c([nH]c2c1)C(C)(C)CCC3
Product: CCCCCCCCC1CCC(C)(C)c2[nH]c3cc(C(=O)OCC)ccc3c21
Yield: 103.2 %

Procedure:
Using the procedure of Example 9, 4.8 g of the ethyl ester from Example 6 was alkylated with 4.38 g of 1-bromooctane to provide 5,6,7,8-tetrahydro-6,6-dimethyl-9-octyl-9H-dibenzo[b,d]pyrrole-3-carboxylic acid ethyl ester (7.0 g;100%) as a yellow oil after purification on a small pad of silica gel.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:14]Br>CC(O)=O>[Br:14][CH2:2][C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a solution of methyl 4-acetylbenzoate (8.91 g, 50.0 mmol) in AcOH (80 mL) was added Br2 (2.71 mL, 52.5 mmol) dropwise. The mixture was stirred at room temperature for 2 h. The mixture was cooled to 0° C. and the solid was filtered. The precipitate was washed with 1:1 MeOH in water and was desiccated to give methyl 4-(2-bromoacetyl)benzoate (10.6 g, 82%) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 8.19-8.12 (m, 2H), 8.04 (d, J=8.5 Hz, 2H), 4.47 (s, 2H), 3.96 (s, 3H).