Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:24]O.B(F)(F)F>O>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([O:16][CH3:24])=[O:15])=[CH:10][CH:9]=2)=[CH:20][CH:21]=1
Reactant: CO
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Agent: FB(F)F
Solvent: O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 71.9 %

Procedure:
10 g of α-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid was reacted with 80 g of methanol in the presence of 5 g of boron trifluoride at 55° to 60° C. for 3 hours. The reaction product was poured into water, and extracted with chloroform. The extract was washed with dilute alkali (i.e., 2-3% NaOH aqueous solution) and water, and dried. Then, the chloroform was evaporated off. The residue was distilled at reduced pressure to afford 7.5 g of the final product having a boiling point of 165° to 167° C./3mmHg. The yield was 74%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[C:9]1([C:2]2[CH:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: c1ccc(-c2cc(-c3ccccc3)ncn2)cc1
Yield: 38 %

Procedure:
First, into a recovery flask equipped with a reflux pipe, 5.02 g of 4,6-dichloropyrimidine, 8.29 g of phenylboronic acid, 7.19 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile were put, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for one hour to be heated. Here, into the flask, 2.08 g of phenylboronic acid, 1.79 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile were further put, and the reaction container was heated again by irradiation with microwaves (2.45 GHz, 100 W) for one hour. Then, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained extract was washed with water, dried with magnesium sulfate, and then filtered. The solvent of the filtrate was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane as a developing solvent. As a result, a pyrimidine derivative Hdppm (yellow white powder, yield of 38%) was obtained. Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, produced by CEM Corporation). A synthesis scheme (a-1) of Step 1 is shown below.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)[N:13]=[CH:12][N:11]=1.Cl.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]=2[C:41]([F:44])([F:43])[F:42])[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:26][CH2:27][N:28]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[CH:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[N:20][CH:21]=5)[N:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:37])=[CH:34][C:33]=2[C:41]([F:44])([F:42])[F:43])[CH2:29][CH2:30]1
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(N)cc1Nc1cc(-c2cncnc2)ncn1
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1cc(-c2cncnc2)ncn1
Reaction time: 17 h

Procedure:
This compound was prepared in the same manner as in Example 1, except that 4-methyl-3-[6-(5-pyrimidinyl)pyrimidin-4-ylamino]aniline (Reference Example 21) and 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 2) were used, and that the reaction was conducted at room temperature for 17 hours and the resulting crude crystals were washed with ethyl acetate.
Reaction SMILES: [N+](C1C=CC=CC=1N=NC1C=C(C(C)(C)C)C=CC=1O)([O-])=O.[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[N:33][C:34]1[CH:39]=[C:38]([C:40]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:41])[CH:37]=[CH:36][C:35]=1[OH:48])([O-])=[O:24]>>[OH:48][C:35]1[CH:36]=[CH:37][C:38]([C:40]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:41])=[CH:39][C:34]=1[N:33]1[N+:23]([O-:24])=[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[N:32]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Yield: 89.9 %

Procedure:
The same procedure as in Example 14 was repeated, except that 2-nitro-2'-hydroxy-5'-t-butylazobenzene 15.0 g was replaced by 2-nitro-2'-hydroxy-5'-t-octylazobenzene 17.7 g, thus producing 15.2 g of 2-(2'-hydroxy-5'-t-octylphenyl)benzotriazole-N-oxide having a melting point of 106.0° to 111.0° C. at the yield of 90.2%.
Reaction SMILES: I[C:2]1[C-:3]([N:7]([CH3:9])[CH3:8])[CH:4]=[CH:5][CH:6]=1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[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.COCCOC>[CH3:16][C:17]1[CH:10]=[C:14]([C:2]2[C-:3]([N:7]([CH3:9])[CH3:8])[CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=1.[CH-:18]1[CH:19]=[CH:20][CH:21]=[CH:16]1.[Fe+2:15]
Reactant: OB(O)c1ccccc1
Reactant: CN(C)[c-]1cccc1I
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(-c2ccc[c-]2N(C)C)c1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Racemic iodide 12i (102 mg, 0.29 mmol), PhB(OH)2 (78 mg, 0.57 mmol) and Pd(PPh3)4 (33 mg, 2.86×10−2 mmol) were added to a dry Schlenk flask, followed by DME (3 mL) and an aqueous solution of 3 M aqueous NaOH (0.25 mL, 0.70 mmol). Argon was bubbled through the resulting mixture for 10 minutes, and the system was heated at reflux for 17 h. The reaction was allowed to cool to room temperature, diluted with Et2O, washed with water (1×5 mL), brine (1×5 mL), dried over Na2SO4, filtered, and all volatiles were removed in vacuo. Flash column chromatography (silica gel, 98:2 hexane/EtOAc) afforded 56 (85 mg, 93%) as an orange oil: Rf 0.41 (90:10 hexane/EtOAc); IR (KBr, CHCl3) vmax 3093, 2940, 2848, 2778, 1605, 1487, 1452, 1416 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.61 (d, 1H, J=7.8 Hz), 7.49 (s, 1H), 7.23 (t, 1H, J=7.5 Hz), 7.04 (d, 1H, J=7.5 Hz), 4.23 (s, 1H), 4.18 (s, 5H), 4.11 (s, 1H), 4.02 (t, 1H, J=2.7 Hz), 2.52 (s, 6H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 139.0, 137.1, 129.0, 127.7, 126.7, 125.7, 112.4, 77.9, 69.1, 66.7, 62.2, 58.1, 44.6, 21.5; EIMS [m/z (%)] 319 (M+, 100); HRMS (EI) calcd for C19H21N56Fe: 319.1023. Found 319.1025.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.C(N(CC)CC)C>O1CCCC1.O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:15]2[CH2:16][CH:13]([O:12][C:11]3[CH:17]=[CH:18][CH:19]=[C:9]([C:8]([F:7])([F:20])[F:21])[CH:10]=3)[CH2:14]2)=[O:31])=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
A mixture of 5.4 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate [1:1] and 3.38 g (0.022 mole) of 4-chlorophenyl isocyanate was stirred in 20 ml of tetrahydrofuran for 15 min then treated with 5 ml of triethylamine. The reaction mixture was exothermic and was stirred for 18 hr as it cooled to ambient temperature. The reaction mixture was diluted with 100 ml of water and the residue which separated solidified. Filtration yielded 8.9 g of crude wet solid. Recrystallization from methyl isobutyl ketone and 30/60 petroleum ether yielded 3.65 g (49.7%) of fine white crystals, m.p. 138°-140° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[CH:5]([OH:7])[CH3:6].Cl[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([C:18]#[N:19])[CH:12]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:17][C:15]1[N:14]=[C:13]([C:18]#[N:19])[CH:12]=[C:11]([O:7][CH:5]([CH3:6])[C:4]([F:9])([F:8])[F:3])[CH:16]=1
Reactant: CC(O)C(F)(F)F
Reactant: Cc1cc(Cl)cc(C#N)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc(OC(C)C(F)(F)F)cc(C#N)n1
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
Into 6 ml of N,N-dimethylformamide was suspended 0.18 g of sodium hydride (60% oily), and 0.44 g of 1,1,1-trifluoro-2-propanol was added at 10° C. After stirring for 10 minutes, 0.49 g of 4-chloro-6-methylpyridine-2-carbonitrile was added, the mixture was stirred for 1 hour, and the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert-butyl=methyl=ether. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.72 g of 6-methyl-4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carbonitrile.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[Cl:22])C>CCO.[OH-].[Na+]>[Cl:22][C:6]1[CH:7]=[CH:8][C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH2:15][CH2:16]2)=[CH:10][C:5]=1[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)c1cc(N2CCN(CCN(C)C)CC2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCN1CCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
A solution of 2-chloro-5-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-benzoic acid ethyl ester (0.46 g, 1.36 mmol) in EtOH (6 mL) and NaOH 10% (2 mL) was heated at reflux overnight, then the reaction mixture was cooled to room temperature and the organic solvent concentrated by evaporation under reduced pressure. The resulting solution was neutralized by dropwise addition of 1N HCl and the water was then evaporated under reduced pressure. The resulting residue was dissolved in EtOH (10 mL), the insoluble material was filtered off and the filtrate concentrated under reduced pressure at room temperature, to obtain 0.24 g of the title compound (58%) without additional purification.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][NH:36]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[NH:26][N:25]=[N:24][CH:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][NH2:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[NH:26][N:25]=[N:24][CH:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Product: NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12)c1csc(N)n1
Yield: 41.5 %

Procedure:
7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.1 g.) was treated with conc. hydrochloric acid (1.3 g.) in a similar manner to that of Example 21-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(aminoethoxyimino)acetamido]-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.7 g.).
Reaction SMILES: [Cl:1][C:2]1[S:18][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.O.[NH2:20][NH2:21]>CO>[Cl:1][C:2]1[S:18][C:5]2[N:6]=[C:7]([NH:20][NH2:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: NN
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)sc2N1
Solvent: O
Solvent: CO
Product: NNC1=Nc2sc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
1.1 g (0.00376 mol) of 7-chloro-1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepine-2-thione are dissolved in 400 ml of absolute methanol with warming and 1 ml of 100% hydrazine hydrate is added. The solution is concentrated to 50 ml and left to crystallize in a refrigerator. After filtration under vacuum and drying, there is obtained 7-chloro-2-hydrazino-5-phenyl-3H-thieno[2,3-e]-1,4-diazepine as colorless crystals, melting at 204°-207° C. (decomposition from 185° C.).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCC1>CO>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]2([CH2:1][C:2](=[O:3])[C:4]3[C:5](=[CH:6][CH:7]=[C:8]([Br:10])[CH:9]=3)[O:11]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCN(Cc3ccccc3)CC2)Oc2ccc(Br)cc21
Reaction time: 11 h
Yield: 66.6 %

Procedure:
A mixture of 2-hydroxy-5-bromoacetophenone (5.85 g, 27.2 mmol), N-benzyl-4-piperidone (5.14 g, 27.21 mmol) and pyrrolidine (1.11 ml, 13.60 mmol) in MeOH (100 ml) was heated to reflux. After 11 h, the solvent was removed under vacuum and the crude mixture was purified by column chromatography (eluent: hexane/AcOEt 90:10 to 70:30) to give 1′-benzyl-6-bromo-spiro[chromane-2,4′-piperidine]-4-one (7.0 g) as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:21]=[CH:22][C:23]=1[C:24](O)=[O:25]>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:24]([C:23]4[CH:22]=[CH:21][C:20]([C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=5)=[CH:19][C:18]=4[F:17])=[O:25])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3F)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 3-fluoro-4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
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: [I-]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 36.9 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 3-fluorophenylboronic acid (0.025 g; 0.181 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.345 mmol), sodium iodide (0.052 g; 0.345 mmol), in dimethoxyethane (3 mL) and water (1 mL), heated in a sealed tube at 130° C. for 18 hours. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.026 g (36%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[C:5](/[CH3:16])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)Cc1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.7 %

Procedure:
After (E)-3-(3-fluoro-4-methoxy-phenyl)-2-methyl-acrylic acid ethyl ester (0.728 g, 3.0 mmol) obtained in Step A was dissolved in EtOH (10 mL), 10% Pd/C (0.073 g) was added thereto, and the mixture was stirred at room temperature under hydrogen atmosphere for 12 hours. After the termination of the reaction, the reactant was filtered by using celite, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (0.726 g, 98%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([Sn](CCCC)(CCCC)CCCC)[CH:6]=[CH:5][N:4]=1.[C:22]([O:26][C:27](=[O:40])[N:28]([C:30]1[C:31]2[N:32]([C:36](Br)=[CH:37][N:38]=2)[CH:33]=[CH:34][N:35]=1)[CH3:29])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:22]([O:26][C:27](=[O:40])[N:28]([CH3:29])[C:30]1[C:31]2[N:32]([C:36]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=3)=[CH:37][N:38]=2)[CH:33]=[CH:34][N:35]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(C(=O)OC(C)(C)C)c1nccn2c(Br)cnc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2cnc3c(N(C)C(=O)OC(C)(C)C)nccn23)n1
Temperature: 25 °C

Procedure:
2-Methylsulfanyl-4-tributylstannanyl-pyrimidine (19.1 g, 46.0 mmol) was stirred in degassed toluene (achieved by bubbling nitrogen though solvent for 2 hours) (200 mL) under nitrogen, then (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-carbamic acid tert-butyl ester (13.1 g, 40.0 mmol) (from Example 7 supra) was added followed by bis(triphenylphosphine)palladium (II) chloride (1.12 g, 1.60 mmol) and the reaction was heated at reflux. The reaction was cooled to room temperature and concentrated to dryness. The residue was purified by column chromatography on silica gel (petroleum ether to EtOAc, TLC Rf=0.17, 20% EtOAc in petroleum ether) and then triturated with DIPE to give methyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester. (Yield 8.00 g, 54%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].C([Al+]CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[N:3]=[C:4]2[C:5]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: CC(C)(C)C(=O)Cl
Agent: CC[Al+]CC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a slurry of 5-bromo-4,7-diazaindole (1.97 g, 9.95 mmol) in 40 mL of dichloromethane at 0-5° C. was added diethylaluminum chloride (1.0 M in hexane, 30 mL, 30 mmol). The reaction mixture was stirred at 0-5° C. for 30 min., then pivaloyl chloride (12 mL, 97 mmol) was added. The mixture was heated to reflux and stirred for 15 h, then cooled to 0-5° C. Sat. aq. NaHCO3 (40 mL) was carefully added, and the mixture was then partitioned between 300 mL of a sat. aq. NaCl solution and 300 mL of ethyl acetate. The mixture was filtered through a plug of celite and the layers were separated. The aqueous layer was extracted with 300 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated to a residue. Silica gel chromatography (20->60% EtOAc/hexanes) afforded 2.50 g (89%) of 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-nitro-5-(trifluoromethyl)benzoic acid (52.2 g, 0.222 mol) in THF (370 mL) at 0° C. was added BH3 (1M in THF, 444 mL) slowly. The reaction mixture was allowed to stir and warm to rt. After 30 min, the reaction was quenched by the addition of sat. aq. NaHCO3 at 0° C. and extracted with Et2O. The organic solutions were combined, washed with brine, dried over MGSO4, filtered and concentrated. The crude material (45.8 g, 93%) was used in the next step without purification.
Reaction SMILES: [N+:1]1([O-])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C1C=CC=CC=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>C(Cl)Cl>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:22]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: [O-][n+]1cccc2ccccc21
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Product: c1ccc2nc(-c3c[nH]c4ccccc34)ccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 6 %

Procedure:
To a solution of quinoline-N-oxide (0.5 mmol) in 2 mL DCM at 0° C. in a 3 mL plastic tube fitted with a frit was added 58 uL of benzoyl chloride (0.5 mmol). The reaction mixture was stirred for 15 min at 0° C. and then indole (0.5 mmol) was added. The reaction was warmed to 20 ° C. and stirred for 4 h. The solid precipitate was filtered and washed with DCM (3×2 mL) to give solid 2-(3-indolyl)quinoline (6-100% yield).
Reaction SMILES: [CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3(O)[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][CH:13]34)=[CH:21][C:20]([CH:25]=[CH2:26])=[CH:19][CH:18]=5)[C:8]=2[C:28]([F:31])([F:30])[F:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.N1C=CC=CC=1.Cl>[CH:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[CH2:26])=[CH:19][CH:18]=5)[C:8]=2[C:28]([F:29])([F:30])[F:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=Cc1ccc2c(c1)CCC1C2=NOC1(O)c1noc(C2CCCCC2)c1C(F)(F)F
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(C2CCCCC2)c1C(F)(F)F
Temperature: 110 °C
Yield: 16 %

Procedure:
A stirred mixture of 3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol and thionyl chloride (0.030 g, 0.252 mmol) in toluene (5.0 mL) and pyridine (1.5 mL) was heated at 110° C. for 10 minutes. The reaction mixture was cooled, diluted with 1 N aqueous hydrochloric acid (5.0 mL), and extracted with ethyl acetate (3×20 mL). The ethyl acetate extracts were combined and concentrated to give 3-(5-cyclohexyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole [0.016 g, 0.039 mmol, 16%] as an orange solid. The product had an HPLC ret. time=4.916 min. (condition B). LC/MS M+1=415.08.