Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:7]([CH3:8])[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[O:3]1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:11]1[CH:12]=[CH:13][C:4]2[O:3][C:2]([CH3:1])([CH3:14])[CH:7]([CH3:8])[C:6](=[O:9])[C:5]=2[CH:10]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CC1C(=O)c2ccccc2OC1(C)C
Agent: O=S(=O)(O)O
Product: CC1C(=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To a solution of 2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (81 g, 0.426 mol) in concentrated sulfuric acid (695 ml) at 0° C. was added a solution containing concentrated sulfuric acid (30 ml) and nitric acid (65%, 175 ml) while maintaining the temperature below 5° C. After stirring for three hours at 5° C., the mixture was added to ice/water and the crude product recovered by filtration. This product was dried and washed with diisopropyl ether to give 44 g of 6-nitro-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one, m.p. 78° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C@@H:5]([NH:7]C(=O)OCC1C=CC=CC=1)[CH3:6])[CH3:2]>CO>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C@@H:5]([NH2:7])[CH3:6])[CH3:2]
Reactant: CCOC(OCC)[C@H](C)NC(=O)OCc1ccccc1
Solvent: CO
Product: CCOC(OCC)[C@H](C)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To the solution of (S)-benzyl 1,1-diethoxypropan-2-ylcarbamate 844 mg (3.00 mmol) in methanol 50 ml, 5% palladium on carbon 30 mg was added and stirred at room temperature for 2 hours under hydrogen atmosphere. The reaction mixture was filtered on celite and washed with methanol 200 ml and the mother solution was concentrated in vacuo to obtain the title compound 442 mg (100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4([NH:37]C(=O)OC(C)(C)C)[CH2:36][CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH2:23][CH2:24][OH:25])[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:45].O1CCOCC1>C(Cl)Cl>[ClH:45].[ClH:45].[ClH:45].[NH2:37][C:33]1([C:30]2[CH:31]=[CH:32][C:27]([N:26]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([NH:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NCCO)c5)nc43)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(NCCO)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.6 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[(2-hydroxyethyl)amino]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (73.0 mg, 0.123 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the minute and stirred at room temperature for 3.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (61.2 mg, 82.6%) as yellow solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1O)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=N[C:27]2[C:32](C=1O)=[CH:31][CH:30]=[CH:29][C:28]=2C(F)(F)F.[O-]C1C=CC=CC=1.[K+].Cl>CN(C=O)C.[Cu]>[O:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1c(Br)cnc2c(C(F)(F)F)cccc12
Reactant: Oc1c(Oc2ccccc2)cnc2c(C(F)(F)F)cccc12
Agent: [Cu]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(Oc3ccccc3)cnc12
Yield: 35 %

Procedure:
3-phenoxy-8-(trifluoromethyl)quinolin-4-ol: A solution of 3-bromo-8-(trifluoromethyl)quinolin-4-ol (1.28 g, 4.38 mmol), potassium phenoxide (4.24 g, 45.1 mmol), and copper powder (0.100 g, 1.61 mmol) in DMF (30 mL) is treated with CuBr (0.943 g, 6.57 mmol) and heated at reflux for 6 days. The cooled reaction is poured into 2N aq HCl and extracted with ethyl acetate. The combined extracts are washed with sat aq NaHCO3, water, brine, and dried with magnesium sulfate. The extracts are concentrated and the residue is chromatographed with 1:9 ethyl acetate:hexanes to afford the title compound as a orange solid (0.471, 35%). mp 153-155° C.; Calcd mass for C16H10NF3O2 is 305.25, found by ESI MS, 306 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19])([O-])=O.C(OP(OCC)OCC)C>>[CH2:12]1[C:11]2[C:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:18]=3[CH:17]=[CH:16][C:15]=2[C:14](=[O:19])[CH2:13]1
Reactant: O=C1CCc2c1cccc2-c1ccccc1[N+](=O)[O-]
Agent: CCOP(OCC)OCC
Product: O=C1CCc2c1ccc1[nH]c3ccccc3c21
Temperature: 120 °C
Yield: 51.7 %

Procedure:
Biphenyl 89 (9 g, 35 mmol) and triethylphosphite were added to a sealed bomb and heated at 120° C. overnight. After cooling to room temperature, the mixture was filtered to give 4 g of 1,2-dihydro-6H-cyclopenta[c]carbazole-3-one. Precipitation with diethyl ether yielded an additional 2 g of desired product. Common yield 90 as yellow powder was 77.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br)=[CH:4][CH:3]=1.[I-:15].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][I:15])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CCCCCCBr)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ccc(CCCCCCI)cc1

Procedure:
6-(4-Chlorophenyl)hexyl iodide [VIa; Ar is 4-ClC6H4, R is H] was prepared from 17 g. of 6-(4-chlorophenyl)hexyl bromide (Preparation C13) and 10.2 g. of sodium iodide in 325 ml. of acetone, to give 21 g. of product as an oil.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1([C:8]([F:11])([F:10])[F:9])[O:7]CC[O:4]1.FF.C([O-])([O-])=O.[K+].[K+].[F:21][C:22](Cl)(Cl)[C:23](Cl)([F:25])[F:24]>>[F:1][CH:2]([F:12])[C:3]1([C:8]([F:11])([F:10])[F:9])[O:7][C:23]([F:25])([F:24])[CH:22]([F:21])[O:4]1
Reactant: FC(F)(Cl)C(F)(Cl)Cl
Reactant: FC(F)C1(C(F)(F)F)OCCO1
Agent: FF
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC1OC(C(F)F)(C(F)(F)F)OC1(F)F

Procedure:
2-Difluoromethyl-2-trifluoromethyl-1,3-dioxolane (50 g.) was placed in a 500 ml. flask along with 1,2,2-trifluoroperchloroethane (Freon 113) (425 ml.) and the solution cooled to -20° C. The mixture was fluorinated with 20% fluorine in argon at a fluorine rate of 0.1 mole per hour until about 1.5 moles of fluorine were added. An 8° (Centigrade) exotherm was observed during the reaction. The acidic mixture was stirred over K2CO3 until the vapors above the mixture no longer tested strongly acidic. The mixture was filtered and Freon 113 was stripped out of the filtrate, leaving 59 g. of crude product. By preparative chromatography pure 2-difluoromethyl-2-trifluoromethyl-4,4,5-trifluoro-1,3-dioxolane (12 g.) was isolated from the crude material.
Reaction SMILES: [Si]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37]([OH:39])=O)=[CH:33][CH:32]=1)(C(C)(C)C)(C)C.Cl.[NH2:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([O:58]C)=[O:57])=[O:53].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Si](O[Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>C(Cl)Cl>[F:48][C:45]1[CH:44]=[CH:43][C:42]([C@@H:9]([OH:8])[CH2:10][S:11][C@H:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:21][CH:22]=3)[C@@H:13]2[C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([NH:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([OH:58])=[O:57])=[O:53])=[O:39])=[CH:40][CH:41]=2)=[CH:47][CH:46]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)O)cc1)c1ccc(F)cc1
Reactant: COC(=O)CNC(=O)CN
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)NCC#Cc1ccc(N2C(=O)[C@H](SC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(OCC(=O)NCC(=O)NCC(=O)O)cc2)cc1
Reaction time: 2 h

Procedure:
{4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 8) (19.4 mg, 0.027 mmol) (9.7 mg, 0.014 mmol) was dissolved in DCM (1 ml, dry). Methyl glycylglycinate hydrochloride (3.1 mg, 0.017 mmol) followed by N-methylmorpholine (4 μl, 0.041 mmol) were added. TBTU (5.8 mg, 0.018 mmol) was added and the reaction mixture was stirred for 2 hours. LC-MS confirmed the formation of the methylester and TBDMS-ether of the title compound, M/z: 839.58 (M−1). The solvent was removed under reduced pressure. The residue was dissolved in MeCN (1 ml). Triethyamine (40 μl, 0.287 mmol), water (10 μl) and LiCl (23.6 mg, 0.55 mmol) were added and the reaction mixture was stirred over the weekend. LC-MS showed complete hydrolysis giving the TBDMS-ether of the title compound, M/z: 827.32 (M+1) and 825.56 (M−1). The solvent was removed under reduced pressure. The crude was dissolved in acetic acid (1 ml) and water (100 μl) and LiCl (27 mg, 0.64 mmol) were added. The reaction mixture was stirred for 6 hours and 30 minutes. Additional LiCl (30 mg, 0.71 mmol) and water (40 μl) were added and the reaction mixture was stirred overnight. The acetic acid was co-evaporated with toluene and the residue was purified with preparative HPLC on a C8 column. A gradient from 20 to 60% MeCN in a 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and most of the MeCN was removed under reduced pressure. The residue was lyophilised to give a the title compound. 2.91-2.96 (m, 2H), 2.98 (s, 3H), 3.38 (d 2H), 3.74 (d, 2H), 4.01 (s, 2H), 4.33 (d, 1H), 4.55 (s, 2H), 4.72 (t, 1H), 5.10 (d, 1H), 7.01 (d, 2H), 7.11 (t, 2H), 7.21 (d, 2H), 7.32-7.42 (m, 6H), 7.47 (b, 1H), 8.37 (t, 1H). M/z: 713.33 (M+1) and 711.45 (M−1).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccccc3OC)c(N(C)C(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (290 mg, 0.99 mmol, 1.00 equiv), 2-methoxyphenylboronic acid (453.5 mg, 2.96 mmol, 3.00 equiv), Pd(PPh3)4 (228 mg, 0.20 mmol, 0.20 equiv), K3PO4 (837 mg, 3.97 mmol, 4.00 equiv), 1,4-dioxane (4 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum and applied onto a silica gel column with ethyl acetate/petroleum ether (1:40). This resulted in 100 mg (28%) of methyl 3-(isopropyl(methyl)amino)-2-(2-methoxyphenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH3:7])(=[O:6])=[O:5].[C:8]([C:12]1[C:21]([N:22]([CH3:24])[CH3:23])=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][C:13]=1[N:25]([CH3:27])[CH3:26])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O>[C:8]([C:12]1[C:13]([N:25]([CH3:27])[CH3:26])=[CH:14][C:15]([C:16](=[O:17])[CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])=[CH:20][C:21]=1[N:22]([CH3:24])[CH3:23])([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)c1cc(N(C)C)c(C(C)(C)C)c(N(C)C)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(C(=O)CS(C)(=O)=O)cc(N(C)C)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 2.4 g. of sodium hydride (50% suspension in oil) and 7.05 g. of dimethylsulfone in 17.5 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 2 hours at 50° C. 6.9 G. of methyl 4-tert. butyl-3,5-bis(dimethylamino)benzoate were then added, and the mixture was stirred at room temperature for 1.5 hours. The solution was diluted with 150 ml. of ice water, the precipitated solid material filtered off, washed with water and recrystallized from methanol, there being obtained 4'-tert. butyl-3',5'-bis(dimethylamino)-2-methylsulfonylacetophenone having a melting point of 177°-179° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH:14]=O)([CH3:13])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])([CH2:14][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(C)(C=O)COC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(C)(CNc2ccccc2)COC1(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 45.8 %

Procedure:
To a stirred solution of (RS)-4-formyl-2,2,4-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (300 mg) at r.t. in methanol (3 ml) was added aniline (132 mg) and the mixture was heated at 80° C. for 3 h. NaBH4 (93 mg) was then added and the mixture was stirred at 60° C. for 16 h, then cooled to r.t. and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient:heptane/ethyl acetate) to give (RS)-2,2,4-trimethyl-4-phenylaminomethyl-oxazolidine-3-carboxylic acid tert-butyl ester (181 mg, 46%) as a yellow oil. MS (ISP): 321.1 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:42]([O:43][CH3:44])=[CH:41][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:42]([O:43][CH3:44])=[CH:41][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCOCC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CC(=O)N1CCOCC1)CC2
Yield: 55 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-morpholin-4-yl-ethanone. Product was isolated as an off-white foam (60 mg, 55%). MS (ESI+): 630.6 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.36 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.58 (t, 1H), 7.52 (s, 1H), 7.25 (t, 1H), 6.67 (s, 1H), 3.89 (s, 3H), 3.74 (s, 7H), 3.67 (m, 2H), 3.30 (s, 2H), 2.87 (m, 2H), 2.76 (s, 8H), 2.68 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[N:5][C:4]=1[NH2:19].[CH2:22](OC(OCC)CBr)[CH3:23]>>[F:21][C:2]([F:1])([F:20])[C:3]1[C:4]2[N:5]([CH:22]=[CH:23][N:19]=2)[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: Nc1nnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Reactant: CCOC(CBr)OCC
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3nccn3n2)cc1
Yield: 94.6 %

Procedure:
Prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridazin-3-ylamine (example C.26 step 9) (4.44 g, 14.4 mmol) and bromoacetaldehyde diethyl acetal (90%, 4.98 mL, 29 mmol) as described in example C.20 step 1. Obtained the title compound as a yellow solid (4.51 g, 94%). MS (ISP) 332.0 [(M+H)+].
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([C:16]1[C:17]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:18]([C:22]2[CH2:26][CH2:25][CH2:24][C:23]=2[C:27]2[CH:28]=[N:29][CH:30]=[C:31]([CH:35]=2)[C:32]([OH:34])=[O:33])[CH:19]=[CH:20][CH:21]=1)([F:15])[F:14]>O1CCOCC1>[F:12][C:13]([C:16]1[C:17]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:18]([C:22]2[CH2:26][CH2:25][CH2:24][C:23]=2[C:27]2[CH:28]=[N+:29]([O-:9])[CH:30]=[C:31]([CH:35]=2)[C:32]([OH:34])=[O:33])[CH:19]=[CH:20][CH:21]=1)([F:15])[F:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1cncc(C2=C(c3cccc(C(F)(F)F)c3OCc3ccccc3)CCC2)c1
Solvent: C1COCCO1
Product: O=C(O)c1cc(C2=C(c3cccc(C(F)(F)F)c3OCc3ccccc3)CCC2)c[n+]([O-])c1
Reaction time: 8 h
Yield: 17.6 %

Procedure:
3-Chloroperbenzoic acid (25 mg, 0.11 mmol) was added to a solution of 5-{2-[trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}nicotinic acid (44 mg, 0.1 mmol) in dioxan (2 ml) and left overnight at room temperature. The resulting mixture was evaporated to dryness and purified by preparative mass directed chromatography to give the title compound as an off-white solid (8 mg, 18%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: OB(O)c1ccnc(Cl)c1
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-6-(4-fluoro-phenyl)-4-trifluoromethyl-pyrimidine (example A.45) (1.5 g, 5.42 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (1.02 g, 6.48 mmol) according to the general procedure IVb. Obtained as a light brown solid (0.49 g, 26%). MS (ISP) 354.2 [(M+H)+]; mp 138.5° C.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][Si:10]([CH3:19])([CH3:18])[C:11]1[O:15][CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=1.S(=O)(=O)(O)O>O1CCCC1>[OH:17][CH:16]([C:13]1[CH:12]=[C:11]([Si:10]([CH3:19])([CH3:18])[CH3:9])[O:15][CH:14]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(O)c2ccccc2)co1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of phenylmagnesium bromide (0.41 ml, 1.27 mmol, 3.1M solution in ethyl ether) under argon at 0°, was added dropwise 5-trimethylsilyl-3-furaldehyde (0.194 g., 1.15 mmol) in 2 ml tetrahydrofuran. This solution was allowed to warm to room temperature, stirred for 30 minutes, and poured over crushed ice containing several drops of concentrated sulfuric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a colorless oil. This material was purified by flash chromatography (silica, 10% ethyl acetate/hexane) to give the desired alcohol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C([O-])([O-])=O.[K+].[K+].[C:28]1([CH:34]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:35][NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[C:39]=2[Cl:48])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[C:49]1([CH:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:35][N:36]([CH2:2][CH2:3][CH2:4][OH:5])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[C:39]=2[Cl:48])[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: OCCCBr
Reactant: FC(F)(F)c1cccc(CNCC(c2ccccc2)c2ccccc2)c1Cl
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a stirring solution of 3-bromo-propanol (77 ul, 0.84 mmol) in acetonitrile (10 ml) was added Nal (0.25 g, 1.7 mmol) and K2CO3 (0.23 g, 1.7 mmol). The mixture was stirred at 85° C. for 1 h, and then N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine (0.43 g, 1.12 mmol) was added. The reaction mixture was heated at 85° C. overnight. The reaction mixture was concentrated, the residue was dissolved in EtOAc, and washed with H2O. The EtOAc extracts were dried over Na2SO4, filtered, and concentrated. The crude mixture was purified by preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H2O, UV detection at 254 nm) to give 225 mg (60%) of the title compound as a white solid. MS (ESI) 448.0 (M+H+).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12].[CH2:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[F:11][C:7]1[C:6]([CH3:12])=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:21]2[N:22]([CH:2]=1)[CH:23]=[CH:24][CH:25]=[CH:26]2
Reactant: c1ccc(Cc2ccccn2)cc1
Reactant: Cc1c(F)cccc1CC(=O)CBr
Solvent: CC(C)=O
Product: Cc1c(F)cccc1Cc1cn2ccccc2c1-c1ccccc1
Yield: 33.8 %

Procedure:
The compound of step 2 (1.50 g, 6.12 mmol) and 2-benzyl-pyridine (2.071 g, 12.24 mmol) were dissolved in acetone (30 ml) and the mixture was stirred under reflux overnight. The mixture was concentrated to dryness and the residue was purified by chromatography on silica gel (cyclohexane) to give 0.653 g of the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][N:21]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[C:22](=[O:34])[N:23]2[C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[C:18]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:50])[CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[C:18]1[CH:17]=[C:16]([NH:15][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:25]=[C:24]2[C:19]=1[CH2:20][N:21]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)[C:22](=[O:34])[N:23]2[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(N)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NC4CCN(C(=O)OC(C)(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl 4-oxopiperidine-1-carboxylate (37.9 mg, 0.19 mmol) was added to a mixture of 7-amino-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (78 mg, 0.15 mmol) in 1 mL of 1,2-dichloroethane. NaBH(OAc)3 (58 mg, 0.27 mmol) was added after 45 min. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with ca 5 mL of 2.5M aqueous NaOH, extracted with (3×20 mL) of ethyl acetate, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography, eluting with 90:10 hexanes-ethyl acetate to yield tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]amino}piperidine-1-carboxylate. Mass spectrum (ESI) 721.2 (M+1).