Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[C:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O.C(OCC)(=O)C.O.[Cl-].[Na+].O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)CI
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(OCC(C)(C)C)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of methyl 3-hydroxybenzoate (7.68 g, 50.5 mmol) in N,N-dimethylformamide (100 ml) were added potassium carbonate (13.96 g, 101 mmol) and neopentyl iodide (10 g, 50.5 mmol), and the mixture was stirred at 100° C. overnight. The mixture was diluted with ethyl acetate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1, 10:1) to give methyl 3-(neopentyloxy)benzoate (4.69 g, 42%) as a colorless transparent oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=[O:18])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1oc(COc2ccc(/C=C/CO)cc2)nc1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1oc(COc2ccc(/C=C/C=O)cc2)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 34, (E)-3-[4-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2-propen-1-ol was subjected to oxidation with activated manganese dioxide to give (E)-3-[4-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2-propen-1-al. Recrystallization from chloroform ether gave colorless prisms, m.p.144°-146° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:7]2.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]1[NH:26][C:34](=[O:35])[NH:28][N:27]=1)=[CH:7]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3cccc(F)c23)C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(F)c23)C1
Yield: 47.3 %

Procedure:
To a mixture of (S)-tert-butyl 3-((8-fluoro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (500 mg, 1.12 mmol) in dioxane (10 mL) was added CDI (362 mg, 2.24 mmol) and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo to give crude product, which was purified by preparative HPLC to give the title compound (220 mg, 47.4%). ESI-MS m/z [M+H-Boc]+ 316.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[CH:12][CH:11]=2)[CH:3]=1.NC1N=C(Cl)C=C(Cl)N=1.FC(F)(F)C1C=C(OC2C=CC(N)=CC=2)C=CN=1.[CH3:54][C:55]1(B(O)O)[CH:60]=[CH:59][CH:58]=[C:57]([CH3:61])[CH2:56]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH3:61])[C:56]=1[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)n1
Reactant: CC1=CC=CC(C)(B(O)O)C1
Agent: Nc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Agent: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1-c1cc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a mixture of 6-chloro-N4-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine (1.0 g, 2.6 mmol; available by condensation of 2-amino-4,6-dichloropyrimidine and {4-[(2-trifluromethylpyridin-4-yl)oxy]phenyl}amine, described in WO 2003/099771, which is hereby incorporated by reference) and 1,3-dimethylphenylboronic acid (786 mg, 5.2 mmol) in DMF (13 m]L) was added aqueous Na2CO3 (2 M, 3.9 mL) and tetrakis(triphenylphosphin)palladium (0) (303 mg, 0.26 mmol). The resulting mixture was degassed for 10 min before it was placed in a microwave reactor (Emrys optimizer by Personal Chemistry) at 150° C. for 20 min. The resulting mixture was cooled to rt before it was filtered and insoluble material was rinsed with DMF. The filtrate was concentrated under vacuo and dissolved in EtOAc. The resulting mixture was washed with water and the organic layer was dried over Na2SO4. Removal of the solvent under vacuo gave the crude material, which was purified with 40 M biotage eluting with Hex/EtOAc (1/1) to provide the title compound as an off-white solid (657 mg, 56%): 1H NMR (DMSO-d6): δ 9.27 (s, 1H), 8.59 (d, 1H), 7.86-7.90 (m, 2H), 7.35 (d, 1H), 7.04-7.17 (m, 6H), 6.35 (s, 2H), 5.86 (s, 1H), 2.10 (s, 6H) ppm; MS ES 452 (M+H)+, RT=2.76 min.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4](N)=[C:3](N)[CH:2]=1.[OH2:10].NN.[OH2:13]>>[CH3:9][C:1]1[CH:2]=[C:3]([OH:13])[CH:4]=[CH:5][C:6]=1[OH:10]
Reactant: O
Reactant: Cc1ccc(N)c(N)c1
Agent: NN
Product: Cc1cc(O)ccc1O

Procedure:
In an Erlenmeyer flask of approximately 500 ml capacity 0.263 g 3,4-toluene diamine (2.15 millimoles) is combined with 56 milliliters of distilled water and 66 milliliters of hydrazine hydrate. Subsequent additions of 2.2 millimoles CoCl2 · 6H2O in 2.62 milliliters of aqueous solution and 0.288 g of methylhydroquinone give, after shaking, a yellow-orange composition containing approximately 35% hydrazine and 0.6% of 3,4-toluene diamine/cobalt/methylhydroquinone catalyst. The molar ratio 3,4-toluene diamine/cobalt (II) is approximately 1.0 in this composition.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]([CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C@H:24]1[N:37]2[C:28]([CH2:29][O:30][C:31]3[C:36]2=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=3)=[N:27][NH:26][C:25]1=[O:47].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:34]2[CH:35]=[C:36]3[C:31](=[CH:32][CH:33]=2)[O:30][CH2:29][C:28]2[N:37]3[C@H:24]([CH3:23])[C:25](=[O:47])[NH:26][N:27]=2)[CH:10]([CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CN(C(=O)OC(C)(C)C)CC=C1OS(=O)(=O)C(F)(F)F
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(B4OC(C)(C)C(C)(C)O4)cc3N21
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: O
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CC=C1c1ccc2c(c1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
To a mixture of 3-methyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Preparation #13, 5.07 g, 14.69 mmol), (R)-4-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #11, Step E, 2.8 g, 8.16 mmol) and K3PO4 (3.46 g, 16.32 mmol) in DMF (60 mL) and water (10 mL) was added Pd(Ph3P)4 (3.77 g, 3.26 mmol). The reaction mixture was stirred at 80° C. overnight then cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 3-50% EtOAc in petroleum ether) to give 3-methyl-4-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.5 g) as a yellow liquid. Further purification by prep-HPLC (Table 3, Method 33) ave 3-methyl-4-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.5 g, 44%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 8.03 (brs, 1H), 7.02-6.93 (m, 2H), 6.87 (s, 1H), 5.81 (brs, 1H), 4.77 (q, J=6.8 Hz, 1H), 4.66-4.53 (d, J=13.2 Hz, 2H), 4.47-4.18 (m, 1H), 3.95-3.77 (m, 2H), 3.32 (d, J=13.2 Hz, 1H), 2.79 (brs, 1H), 1.53 (m, 3H), 1.51 (s, 9H), 1.02 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 44) Rt=3.339 min.; MS m/z: 414 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:12][C:13]([CH3:15])=[O:14]>>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:13]([CH3:15])([OH:14])[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(C)c1ccc(CCl)cc1
Product: CC(C)c1ccc(CC(C)(C)O)cc1

Procedure:
The reaction of a Grignard compound, prepared from 20 g (119 mmol) 4-isopropylbenzyl chloride, with 11.4 mL (155 mmol) acetone yields the target compound as a colorless oil. Yield: 13.0 g (57%); mass spectrometry: [M+H]+=193.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:11]=1>>[CH3:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([N:4]3[CH2:3][C@@H:2]([CH3:1])[CH2:6][S:5]3(=[O:8])=[O:7])=[CH:11][C:12]=2[S:32]([CH3:35])(=[O:34])=[O:33])=[O:17])[CH2:23][CH2:22]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: C[C@@H]1CNS(=O)(=O)C1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@@H](C)CS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 4.6 %

Procedure:
Using (R)-4-methylisothiazolidine 1,1-dioxide (203 mg) described in Preparation Example 7 and (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110 and by the reaction and treatment in the same manner as in Example 1, the title compound (23 mg) was obtained.
Reaction SMILES: [F:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[C:5](=[O:15])[NH:4][CH:3]1OC.Cl.O1CCOCC1>C(#N)C>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[C:5](=[O:15])[NH:4][CH:3]=1
Reactant: COC1NC(=O)c2ccc([N+](=O)[O-])cc2C1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: O=c1[nH]cc(F)c2cc([N+](=O)[O-])ccc12
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
To a solution of Intermediate 3D (8.1 g, 33.7 mmol) in acetonitrile (100 mL) was added 4.0N HCl in dioxane (25.3 mL, 101 mmol). The mixture was stirred at 65° C. for 1.5 h. HPLC and LCMS indicated complete conversion of starting material. Solvent was removed to give Intermediate 3E (8.1 g, 33.1 mmol, 98% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38-8.46 (m, 2H) 8.31 (dd, J=8.79, 2.20 Hz, 1H) 7.61 (d, 1H); 19F NMR (376 MHz, DMSO-d6) δ ppm −160.17 (s., 1F); MS (ESI) m/z: 209.2 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][CH:11]=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH2:23][CH3:24])=C(Cl)[N:15]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[N:15]=[C:14]([Cl:13])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4[CH2:23][CH3:24])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=CNc1ccc2c(c1)OCO2
Reactant: CCn1cnc2c(Cl)nc(Cl)nc21
Product: CCn1cnc2c(Nc3ccc4c(c3)OCO4)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-benzo[1,3]dioxol-5-yl-formamide and 2,6-dichloro-9-ethyl-9H-purine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[CH2:18][CH2:19][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH:22]=3)[CH:14]=[C:13]([NH:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([CH:17]3[CH2:18][CH2:19][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH2:22]3)[CH:14]=[C:13]([NH:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[N:12]=2)[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@H](Nc1cc(C2=CCN(S(C)(=O)=O)CC2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@H](Nc1cc(C2CCN(S(C)(=O)=O)CC2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Yield: 38.5 %

Procedure:
88 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-N6-(pyrazin-2-yl)pyridine-2,6-diamine was dissolved in 5 ml of methanol, and 599 mg of ammonium formate and 18 mg of palladium hydroxide 20% on carbon were added thereto, and the mixture was heated at reflux for 3 hours. 599 mg of ammonium formate and 18 mg of palladium hydroxide 20% on carbon were added to the reaction solution, and the reaction solution was further heated at reflux for 2 hours. The reaction solution was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate. The solution was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 34 mg of the objective compound as pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[O:14]1C=CC=[CH:16][CH:15]1OCCBr.O>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][CH2:16][CH2:15][OH:14]
Reactant: COc1ccc(O)cc1OC
Reactant: BrCCOC1C=CC=CO1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(OCCO)cc1OC
Reaction time: 0.33 h

Procedure:
A mixture of 3,4-dimethoxyphenol (155 mg, 1.0 mmol) and 60% sodium hydride (50 mg, 1.25 mmol) in DMA (6 ml) was stirred for 20 min under an atmosphere of nitrogen. 2-(2-Pyranyloxy)ethylbromide (220 mg, 1.0 mmol) was added dropwise. The reaction mixture was stirred for 6 hours at room temperature and then the mixture was poured into water (100 ml). The mixture was extracted with ethyl acetate (2×30 ml) and the combined organic extracts were dried (MgSO4). The organic phase was concentrated and the residue was dissolved in 2-propanol (30 ml) and 4 N HCl (20 ml) was added. The mixture was heated at reflux temperature for 30 min and then stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (50 ml). The organic solution was dried (MgSO4) and the solvent was evaporated. The oily residue was purified on silica gel (50 g) eluting with a mixture of heptane and ethyl acetate (3:2). This afforded 100 mg (50%) of 2-(3,4-dimethoxyphenoxy)ethanol.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([OH:19])=[C:14]([Cl:20])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1(C)C=CC=CC=1.O.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+]>[Br:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([O:19][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[C:14]([Cl:20])[CH:13]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Agent: [Cu+]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cccnc1Oc1cc(Cl)c(Br)cc1Cl
Temperature: 140 °C

Procedure:
To a solution of 2-chloro-nicotinic acid (100 mg, 0.64 mmol, 1.0 equiv; [CAS RN 2942-59-8]) and 4-bromo-2,5-dichloro-phenol (184 mg, 0.76 mmol, 1.2 equiv; [CAS RN 1940-42-7]) in toluene (1 mL) was added caesium carbonate (517 mg, 1.59 mmol, 2.5 equiv; [CAS RN 534-17-8]) and tetrakis(acetonitrile)copper(I) hexafluorophosphate (47 mg, 0.13 mmol, 0.2 equiv; [CAS RN 64443-05-6]). The reaction mixture was heated by microwave irradiation to 140° C. for 1 h. The solvent was evaporated under reduced pressure and the crude reaction product taken up in water (100 mL) acidified to pH 1 by addition of a solution of 1 M HCl and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane/methanol affording 170 mg (73%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO): δ7.21 (dd, J=−7.6 Hz, J=4.8 Hz, 1H), 7.42 (s, 1H), 7.76 (s, 1H), 8.29 (dd, J=4.8 Hz, J=1.9 Hz, 1H), 8.50 (dd, J=7.7 Hz, J=2.0 Hz, 1H). MS (ISN): 362.0 [M−H]−.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.Br[CH2:14][CH2:15][CH2:16][Cl:17].O>CN(C)C=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2
Reactant: ClCCCBr
Reactant: Oc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCOc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (0.8 g, 17 mmol of a 50% oil dispersion) in dimethylformamide (20 ml), under nitrogen, was added dropwise 7-hydroxyindole (2.1 g, 15.7 mmol) in dimethylformamide (20 ml). After complete addition, the reaction was stirred at ambient temperature for 0.5 hour and then cooled to 15° C. To this cooled solution was added, dropwise, 1-bromo-3-chloropropane (2.5 g, 15.7 mmol) in dimethylformamide (5 ml). The reaction was then stirred at ambient temperature for 16 hours. The reaction was poured into water, and the aqueous suspension extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4), and the solvent was concentrated to afford a dark brown oil. Following flash chromatography on silica gel, 7-(3-chloropropoxy)indole was obtained as a colorless oil, 1.0 g.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([OH:8])[CH3:7])=[CH:4][CH:3]=1.[CH2:11]1[CH2:16][O:15][CH:14]=[CH:13][CH2:12]1>Cl.CCOCC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([CH3:7])[O:8][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:16][O:15]2)=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1
Reactant: C1=COCCC1
Agent: Cl
Solvent: CCOCC
Product: CC(OC1CCCCO1)c1ccc(Br)cc1
Temperature: 0 °C

Procedure:
A mixture of 269 parts of p-bromo-α-methylbenzyl alcohol and 225 parts of 2H-3,4-dihydropyran is stirred and cooled to 0° C. Then there are added dropwise 10 drops of concentrated hydrochloric acid solution and the whole is stirred in an ice-bath (room temperature is reached). After stirring for 24 hours, the reaction mixture is poured onto 1200 parts of ether. The organic phase is washed twice with a sodium hydrogen carbonate solution and twice with water, dried, filtered and evaporated. The residue is distilled, yielding 2-(p-bromo-α-methylbenzyloxy)tetrahydropyran; b.p. 165°-177° C. at 20 mm. pressure.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[N:40]1[CH:45]=[CH:44][N:43]=[CH:42][C:41]=1[CH2:46][NH2:47]>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:47][CH2:46][C:41]4[CH:42]=[N:43][CH:44]=[CH:45][N:40]=4)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cnccn1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCc1cnccn1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.4 %

Procedure:
Add 10 ml dry DMF to a flask under N2 containing 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (500 mg, 1.33 mmol, 1.0 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (279 mg, 1.46 mmol, 1.1 eq), Dimethyl-pyridin-4-yl-amine (16 mg, 0.132 mmol, 0.1 eq), and C-Pyrazin-2-yl-methylamine (217 mg, 1.99 mmol, 1.5 eq). Stir for 18 hours at room temperature. Remove solvent on rotovap and purify by silica gel chromatography to give 4-(3-Phenyl-indole-1-sulfonyl)-N-pyrazin-2-ylmethyl-benzamide (127 mg, 20% yield). Mass Spectrum (m/e): 468.95 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[N:25]=2)=[N:10]1.C1C(=O)N([Br:38])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:38])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[N:25]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)OC)cs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nc(CC(=O)OC)cs2)=NC1c1ccc(F)cc1Br
Yield: 70.4 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(4-(2-methoxy-2-oxoethyl)thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with NBS (0.39 g, 2.2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.81 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[CH2:12]([N:19]1[C:28](=O)[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:30]([O-:32])=[O:31])[CH:25]=2)[C:20]1=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C1COCC1>[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:30]([O-:32])=[O:31])[CH:25]=2)[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2C(=O)N1Cc1ccccc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
To a suspension of sodium borohydride (2.13 g, 56.2 mmole) in THF (56 mL) at 0° C. was added boron trifluoride etherate (9 mL, 73 mmole) dropwise. After stirring the contents for 1 hr., dione (16) (5.0 g, 16.9 mmole) in THF (150 mL) was added at 0° C. over a period of 1.5 hr. The contents were warmed to 25° C. for 30 min. and then refluxed for 16 hr. The completed reaction was cooled to 0° C. and cautiously quenched with aqueous 1N sodium hydroxide (75 mL, 75 mmole) while maintaining the temperature at approximately 9° C. The quenched reaction was stirred for 30 min. at 0° C., 1 hr. at 25° C., 50° C. for 18 hrs. and then cooled to 20° C. The solvents were removed under vacuum, ethyl acetate (100 mL) was added and the layers separated. The organic layer was washed with brine, treated with sodium sulfate and the solvents removed under vacuum to afford 4.73 g of a light brown oil which was of sufficient purity to employ in the next step.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:17][CH:16]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: FC(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A 250 mL flask was charged with 4-(trifluoromethyl)phenylboronic acid (4.85 g, 25.5 mmol), 4-bromoiodobenzene (7.22 g, 25.5 mmol), Pd(OAc)2 (57.2 mg, 0.255 mmol) and sodium carbonate (5.41 g, 51.0 mmol). The flask was flushed with nitrogen, then n-propanol (40 mL) and water (8 mL) were added. The mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to provide 4-bromo-4′-(trifluoromethyl)biphenyl (5.4 g, 70%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.62-7.73 (m, 4H), 7.57-7.61 (m, 2H), 7.43-7.47 (m, 2H).