Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:32])=[C:24]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:32][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CN(C)C=CC(=O)c1ccc(F)c(N(C)S(C)(=O)=O)c1
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1F)S(C)(=O)=O
Yield: 78.1 %

Procedure:
A mixture of 0.064 g (0.33 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.1 g (0.33 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 111 mg of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 77%).
Reaction SMILES: [CH:1]1([Ru:6][CH:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:16](O)([CH3:19])([CH3:18])[CH3:17]>O>[C:16]([Ru:6]([CH:1]1[CH:2]=[CH:3][CH:4]=[CH:5]1)[CH:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C1=CC([Ru]C2C=CC=C2)C=C1
Reactant: CC(C)(C)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)[Ru](C1C=CC=C1)C1C=CC=C1
Temperature: 120 °C
Yield: 20 %

Procedure:
8.0 g of bis(cyclopentadienyl)ruthenium, 3.0 g of aluminum chloride, and 80 g of polyphosphoric acid were mixed. The mixed solution was heated to 100° C. under a nitrogen atmosphere, to which 3.0 g of tert-butyl alcohol was added dropwise over 30 minutes, and then the mixture was heated to 120° C. to carry out the reaction for 4 hours. After the reaction, hot water was added to the solution to remove polyphosphoric acid, and then distillation treatment gave 2.0 g of tert-butylcyclopentadienyl(cyclopentadienyl)ruthenium. Five lots of tert-butylcyclopentadienyl(cyclopentadienyl)ruthenium were prepared by this preparing method, and subjected to film production as described later.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:20]([C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][NH:27][CH:28]3[CH3:31])=[CH:23][CH:22]=2)=[CH:19][CH:18]=[CH:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][C:21]([C:20]5[C:15]([F:14])=[N:16][CH:17]=[CH:18][CH:19]=5)=[CH:22][CH:23]=4)[CH:28]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(-c3cccnc3F)cc21
Product: CC1c2cc(-c3cccnc3F)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [P:1]([O-:10])([O:6][CH2:7][CH2:8][Cl:9])[O:2][CH2:3][CH2:4][Cl:5].C(Cl)(Cl)(Cl)[Cl:12]>C(N(CC)CC)C>[P:1]([Cl:12])(=[O:10])([O:6][CH2:7][CH2:8][Cl:9])[O:2][CH2:3][CH2:4][Cl:5]
Reactant: ClC(Cl)(Cl)Cl
Reactant: [O-]P(OCCCl)OCCCl
Solvent: CCN(CC)CC
Product: O=P(Cl)(OCCCl)OCCCl
Yield: 100 %

Procedure:
The amount of 1.9 moles of bis(2-chloroethyl) phosphite was reacted with excess carbon tetrachloride in the presence of a small amount of triethylamine. The bis(2-chloroethyl) phosphorochloridate formed was reacted with 0.86 mole of 2-butene-1,4-diol in the presence of pyridine. The product was isolated in the manner described in the above examples to obtain a yield of 100%. Identified by IR as tetrakis(2-bromoethyl) 2,3-butene diphosphate, the product had a refractive index (nD22) of 1.4852 and contained 29.65% chlorine and 12.24% phosphorus (compared to calculated percentages in C12H22Cl4O8P2 of 28.51% chlorine and 12.45% phosphorus).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:18][O:19][C:20]([C:22]1[C:30]2[O:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH:25]=[C:24]([OH:32])[CH:23]=1)=[O:21]>CN(C=O)C>[CH3:18][O:19][C:20]([C:22]1[C:30]2[O:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH:25]=[C:24]([O:32][C:14]2[CH:15]=[CH:16][C:11]([S:8]([CH3:7])(=[O:10])=[O:9])=[CH:12][CH:13]=2)[CH:23]=1)=[O:21]
Reactant: COC(=O)c1cc(O)cc2cc(C)oc12
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C)oc12
Temperature: 120 °C
Yield: 92 %

Procedure:
Cs2CO3 (2.36 g, 7.24 mmol) and 4-fluorophenyl methyl sulfone (631 mg, 3.62 mmol) were added to a solution of 5-hydroxy-2-methyl-benzofuran-7-carboxylic acid methyl ester (4d) (746 mg, 3.62 mmol) in DMF (5 mL). The mixture was heated to 120° C. overnight and then cooled to RT. The mixture was then quenched with H2O (80 mL) and extracted with EtOAc 92×100 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 4% CH3OH/CH2Cl2 to afford brown color oil (1.2 g, 92%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 2 H) 7.86-7.90 (m, 1 H) 7.58 (d, J=2.53 Hz, 1 H) 7.38 (d, J=2.53 Hz, 1 H) 7.05 (d, J=8.84 Hz, 1 H) 6.44 (s, 1H) 3.99 (s, 3 H) 3.05 (s, 3 H) 2.56 (s, 3 H); LCMS for C18H16O6S m/z 361.00 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH3:33])[CH3:26]>>[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29][C@H:28]1[CH3:33])[CH3:26]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCN1CCNC[C@H]1C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C[C@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (m, J=7.20, 7.20 Hz, 6H) 2.36 (s, 3H) 2.39 (br. s., 1H) 2.45-2.52 (m, 1H) 2.53-2.68 (m, 1H) 2.71-2.90 (m, 2H) 2.99 (br. s., 1H) 3.41-3.66 (m, 1H) 3.97 (br. s., 1H) 7.53 (d, J=7.83 Hz, 1H) 7.60 (s, 1H) 7.84 (d, J=8.08 Hz, 1H) 7.94 (d, J=7.79 Hz, 1H) 7.99 (s, 1H) 8.36 (d, J=8.59 Hz, 1H) 8.44 (d, J=1.77 Hz, 1H); ESI-MS m/z [M+H]+ 431.3.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])C.[OH-].[K+].C(O)(=O)C>C(O)C>[CH3:21][O:20][CH2:19][C:18]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[NH:10][C:9]=2[CH:8]=[N:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1ncc2[nH]c3c(c2c1COC)CCCC3
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COCc1c(C(=O)O)ncc2[nH]c3c(c12)CCCC3
Yield: 96.3 %

Procedure:
1.15 g of 5,6,7,8-tetrahydro-4-methoxymethyl-betacarboline-3-carboxylic acid ethyl ester is refluxed in 45 ml of ethanol with 5 ml of 2N aqueous potassium hydroxide solution for 2 hours. After cooling, it is acidified with glacial acetic acid. The precipitated product is suctioned off; the mother liquor is concentrated to approximately 30 ml. The precipitated product is again suctioned off. 1 g of 5,6,7,8-tetrahydro-4-methoxymethyl-beta-carboline-3carboxylic acid with a melting point greater than 260° C. is obtained.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:15]([O:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][Br:1])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(CO)CBr
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(CBr)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo-2,2-dimethyl-1-propanol (26.9 mL), 4-(dimethylamino)pyridine (2.67 g), and triethylamine (33.5 mL) were dissolved in toluene (250 mL) and cooled to 0° C. Pivaloyl chloride was added dropwise over 30 min (temperature rose to 15° C.) and upon completion the reaction was allowed to warm to 23° C. and stirred for 1 h. The reaction was filtered and the filtrate washed with 2N aqueous HCl (250 mL), aqueous sodium hydrogencarbonate solution (250 mL) and aqueous brine (250 mL). The organic layer was separated and the solvent evaporated to give the subtitle compound (53.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:17]([F:18])=[C:16]([NH2:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:17]([F:18])=[C:16]([NH:19][S:28]([CH3:27])(=[O:30])=[O:29])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(N)c(F)c(C(=O)OCC)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN(C)C(=O)c1cc(NS(C)(=O)=O)c(F)c(C(=O)OCC)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 75.1 %

Procedure:
Dissolve 5-amino-6-fluoro-N-methyl-N-propyl-isophthalamic acid ethyl ester (0.162 g, 0.58 mmol) in dichloromethane (1.5 mL). Cool to 0° C. Add pyridine (51.2 μL, 0.63 mmol) and methanesulfonyl chloride (44.5 μL, 0.58 mmol) to the solution. Allow the reaction to warm to room temperature and stir for 2 days. Quench with water (10 mL) and extract with dichloromethane (2×30 mL). Combine the organic layers and wash with saturated aqueous sodium chloride (20 mL), dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 40:60 ethyl acetate:dichloromethane) to give the title compound as a solid (157 mg, 76%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH:4]=[CH:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].[OH-].[Na+].CCCCCC.CC(C)=[O:24]>C(O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([NH2:10])=[O:24])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: N#CC=CNC=CC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Product: NC(=O)c1cnccc1C(F)(F)F
Yield: 26.5 %

Procedure:
3-[(4,4,4-Trifluoro-3-oxo-1-butenyl)amino]-2-propenenitrile (a mixture of IIa and IIb; 1.90 g, 10 mmol) was dissolved in ethanol (15 ml), and sodium hydroxide (600 mg, 17 mmol) was added. The mixture was heated under reflux for 8 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/acetone=1/1) to obtain 0.53 g (yield 26.5%) of the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:9]2)C=C.CN(C)[C:21]1[CH:26]=CC=C[CH:22]=1>CCCCCC>[CH2:26]([C:13]1[C:5]([OH:4])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2)[CH:21]=[CH2:22]
Reactant: C=CCOc1cccc2[nH]c(C(=O)OCC)cc12
Reactant: CN(C)c1ccccc1
Solvent: CCCCCC
Product: C=CCc1ccc2[nH]c(C(=O)OCC)cc2c1O
Temperature: 200 °C
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
2.79 g (11.4 mmol) of ethyl 4-allyloxyindole-2-carboxylate was added to 8.8 g of N,N-dimethylaniline, and the mixture was stirred for 15 minutes at 200° C. under a nitrogen atmosphere. 2.7 g of a crude product was obtained by adding n-hexane to the reaction mixture and collecting deposited crystals by filtration. This crude product was purified by column chromatography (silica gel, chloroform) to obtain 1.4 g (yield: 50.2%) of the target compound. This compound was recrystallized from a mixture of ethyl acetate and n-hexane to obtain colorless needles of the title compound.
Reaction SMILES: [CH3:1][Al](C)C.Cl[C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[CH:14]=[N:13][NH:12][C:11]=12.[NH4+].[Cl-]>C1COCC1.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>[CH3:1][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[CH:14]=[N:13][NH:12][C:11]=12
Reactant: C[Al](C)C
Reactant: Clc1nccc2cn[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nccc2cn[nH]c12
Temperature: 65 °C
Reaction time: 16 h

Procedure:
Trimethylaluminum (23.9 mL, 47.8 mmol, 2M sol. in toluene) was added to a vigorously stirred solution of 7-chloro-1H-pyrazolo[3,4-c]pyridine (3.67 g, 23.9 mmol) and Pd(PPh3)4 (1.38 g, 1.19 mmol) in THF (109 mL) under argon. The reaction mixture was stirred at 65° C. for 16 h. The mixture was cooled to RT and poured into sat. aq. NH4Cl. The resulting suspension was filtered, the solid washed with water and discarded. The filtrate and the combined washings were extracted with EtOAc (3×). The combined organic extracts were washed with brine then dried (Phase separator) and concentrated under reduced pressure to give 7-methyl-1H-pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 134 [M+H]+, tR (HPLC conditions k): 0.25 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:23]=[C:22](OC(C)C)[NH:21][N:20]=2)=[N:4][C:5]([NH:8][CH:9]([C:11]2[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=[N:6][CH:7]=1.[CH:28]1(C2NN=C(NC3C(F)=CN=C(N[C@H](C4N=CC(F)=CN=4)C)N=3)C=2)CC1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:23]=[C:22]([CH3:28])[NH:21][N:20]=2)=[N:4][C:5]([NH:8][CH:9]([C:11]2[N:12]=[CH:13][C:14]([F:17])=[CH:15][N:16]=2)[CH3:10])=[N:6][CH:7]=1
Reactant: C[C@H](Nc1ncc(F)c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(NC(C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(NC(C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Temperature: 180 °C
Yield: 61.9 %

Procedure:
A mixture of rac-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 1, 100 mg), 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 9, 200 mg) and DIPEA (0.150 ml) in n-BuOH (2.5 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 180° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 min) to give 5-chloro-N2-[1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as solid (55 mg). The tile compound was obtained after chiral purification using SFC conditions (Chiralpak AD-H, 20% i-PrOH/80% CO2/0.1% Dimethylethylamine). 1H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H) 8.83 (s, 2H) 7.88 (s, 1H) 7.44 (s, 1H) 5.93 (s, 1H) 4.92-5.29 (m, 1H) 2.20 (s, 3H) 1.49 (d, 3H); m/z 350.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7](=[O:29])[CH:8]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[Cl:28])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([CH3:19])[CH:12]=3)[C:4]=2[CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7](=[O:29])[CH:8]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[Cl:28])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:19])[CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(C2=NC(Cc3ccc(F)cc3Cl)C(=O)Nc3ccc(Cl)cc32)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C2=NC(Cc3ccc(F)cc3Cl)C(=O)Nc3ccc(Cl)cc32)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7-Chloro-3-(2-chloro-4-fluorobenzyl)-5-(4-methoxy-3-methylphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.158 g, 0.345 mmol) was dissolved in dichloromethane (DCM, 2 mL) and BBr3 in DCM (1 M, 1.73 mL, 1.73 mmol) was added dropwise. The mixture was stirred at room temperature for 4 h. then quenched with methanol and diluted with ethyl acetate. The organic solution was washed with saturated sodium bicarbonate (aq) then brine. It was concentrated onto silica gel then chromatographed on silica gel eluting with 35-40-45% ethyl acetate in hexanes to give 7-chloro-3-(2-chloro-4-fluorobenzyl)-5-(4-hydroxy-3-methylphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one as a yellow oil which precipitated as a pale yellow solid from chloroform (158 mg, 0.345 mmol).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Br[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1.C(OCC)(=O)C>CN(C=O)C>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[N:17][CH:18]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(Oc2ccc(Br)cn2)cc1
Temperature: 60 °C

Procedure:
To a mixture of 4-trifluoromethoxyphenol (4.4 ml) and sodium hydride (60% dispersion in mineral oil, 1.35 g) in dry DMF (3 ml) was added a solution of 2,5-dibromopyridine in dry DMF (3 mL). The mixture was heated at 60° C. for 8 h. Upon cooling, ethyl acetate was added and the mixture was washed with NH4Cl 1N. The organic layer was dried (Na2SO4) and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent:AcOEt/Hexane 1:10) to afford 1.08 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[Cl:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][C:30]2[C:31](=[O:38])[N:32]=[C:33](SC)[NH:34][CH:35]=2)=[CH:25][CH:24]=1>C(O)C>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][C:30]2[C:31](=[O:38])[N:32]=[C:33]([NH:15][CH2:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]4[CH:16]=[CH:17][C:2]([Cl:1])=[C:3]([C:18]([F:19])([F:20])[F:21])[CH:4]=4)=[CH:8][CH:9]=3)[NH:34][CH:35]=2)=[CH:25][CH:24]=1
Reactant: CSc1nc(=O)c(Cc2ccc(Cl)nc2)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: CCO
Product: O=c1nc(NCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1ccc(Cl)nc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (0.317 mmol, 1.0 eq) and 5-(6-chloro-pyridin-3-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.190 mmol, 0.6 eq) were dissolved in dry ethanol (300 μL) and stirred at 130° C. overnight. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of MeOH in DCM: 0-7% in 15 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 5-(6-chloro-pyridin-3-ylmethyl)-2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-1H-pyrimidin-4-one (0.084 mmol, yield: 26%, HPLC-MS/UV:[M+H]+=536.33; rt: 1.24 mins; purity: 95%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.89 (t, J=7.17, 2H), 3.57 (s, 2H), 3.59-3.66 (m, 2H), 5.23 (br.s., 1H), 6.95 (dd, J=8.51, J=9.86, 2H), 7.03 (dd, J=9.41 J=2.24, 1H), 7.17-7.23 (m, 3H), 7.27-7.30 (m, 2H), 7.39 (dd, J=9.07, J=8.31, 1H), 7.47 (dd, J=8.06, J=2.51, 1H), 7.65 (s, 1H), 8.28 (d, J=2.26, 1H), 12.01 (br.s., 1H)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([C:18](=[O:22])[C:19](O)=[O:20])=[C:9]1[CH2:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[C:26]1([CH3:35])[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH3:35])[CH:27]=3)=[CH:14][CH:15]=2)[C:10]2[C:18](=[O:22])[C:19](=[O:20])[O:24][CH2:23][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C(O)C(=O)c1c(CO)n(Cc2ccccc2)c2ccc(Br)cc12
Agent: [K]
Product: Cc1cccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)COC(=O)C2=O)c1

Procedure:
The title compound was prepared from [1-benzyl-5-bromo-2-(hydroxymethyl)-1H-indol-3-yl](oxo)acetic acid, potassium salt and m-tolylboronic acid in substantially the same manner, as described in step 4 of Example 9. The product was obtained as a grey solid, mp: 225–226° C.; Mass spectrum (ESI, [M+H]+) m/z 382. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.22 (d, 1H, J=8.40 Hz), 7.65 (dd, 1H, J=8.45 and 1.83 Hz), 7.49 (s, 1H), 7.47–7.34 (m, 3H), 7.31 (d, 1H, J=7.33 Hz), 7.27 (d, 2H, J=8.40 Hz), 7.18 (d, 1H, J=7.48 Hz), 5.92 (s, 2H), 5.55 (s, 2H), and 2.39 ppm (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1.[ClH:18].CC(O)=O>>[ClH:18].[F:1][C:2]1([F:17])[CH2:7][CH2:6][CH:5]([CH2:8][NH2:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(F)(F)CC1
Agent: Cl
Solvent: CC(=O)O
Product: NCC1CCC(F)(F)CC1

Procedure:
tert-Butyl [(4,4-difluorocyclohexyl)methyl]carbamate (505 mg, 2.03 mmol) was stirred in 5 mL of 1M HCl/AcOH at rt for 2 h. The solvent was evaporated. The residue was washed with ether, filtered and dried. Yield: 330 mg (88%). 1H NMR (400 MHz, METHANOL-D4): δ 1.28-1.40 (m, 2H), 1.71-1.82 (m, 2H), 1.84 (d, J=3.12 Hz, 2H), 1.86-1.89 (m, 1H), 2.03-2.15 (m, 2H), 2.85 (d, J=7.03 Hz, 2H).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=[O:38])(=[O:33])=[O:32]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:31]([C:34]3[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=3)[C:37]([OH:39])=[O:38])(=[O:33])=[O:32])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Product: O=C(O)c1cccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)c1

Procedure:
The title compound was prepared from of 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol and 3-chlorosulfonyl-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a white solid, mp 169-171° C.; MS m/e 559 (M-H)+;
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[Cl:12][C:13]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:14]=1[O:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH:21]([CH3:31])[C:22]([O:29][CH3:30])=[CH:23][C:24](OCC)=[O:25])=[CH:18][CH:17]=1>O>[Cl:12][C:13]1[CH:37]=[C:36]([C:38]([F:39])([F:41])[F:40])[CH:35]=[CH:34][C:14]=1[O:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH:21]([CH3:31])[C:22]([O:29][CH3:30])=[CH:23][CH2:24][OH:25])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COC(=CCO)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
To a mixture of lithium aluminum hydride (200 mg) and anhydrous ether (5 ml.) is added dropwise at 0°, a mixture of ethyl 4[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate (400 mg) and ether (5 ml.). After addition is complete, the mixture is stirred for about minutes. Wet ether and water is added to destroy excess hydride. Filtration and evaporation of filtrate gives 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-penten-1-ol.