Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.[CH2:14]([O:17][CH2:18][C:19](Cl)=[O:20])[CH2:15][CH3:16]>>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:19](=[O:20])[CH2:18][O:17][CH2:14][CH2:15][CH3:16])=[C:7]([CH3:12])[CH:6]=1
Reactant: CCCOCC(=O)Cl
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Product: CCCOCC(=O)Nc1ccc(OC(=O)NC)cc1C

Procedure:
According to the procedure of Example 5, 3-methyl-4-aminophenyl N-methylcarbamate was reacted with n-propoxyacetyl chloride to yield a viscous oil as the product.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][N:5]=[C:4]([C:9]([OH:11])=[O:10])[CH:3]=1.[CH2:12](O)[CH3:13]>>[CH2:12]([O:10][C:9]([C:4]1[CH:3]=[C:2]([OH:1])[C:7]([OH:8])=[CH:6][N:5]=1)=[O:11])[CH3:13]
Reactant: O=C(O)c1cc(O)c(O)cn1
Reactant: CCO
Product: CCOC(=O)c1cc(O)c(O)cn1

Procedure:
4,5-Dihydroxy-pyridine-2-carboxylic acid (844 mg, 5.45 mmol) was dissolved in ethanol (20 mL). Gaseous hydrochloric acid was bubbled through the mixture for 5 minutes whilst it was cooled in an ice bath. The solution was then heated to reflux for 2 hours. This procedure was repeated a further two times and then the mixture heated for 24 hours. The volatiles were removed in vacuo and water added (5 mL). This was also removed under reduced pressure. The hydrochloride salt of the desired product was produced in this way and used without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(C(OCC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].CS(C)=O>O>[CH2:33]([O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)C(CCCCCCOCc1ccccc1)(CCCCCCOCc1ccccc1)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Temperature: 180 °C
Reaction time: 12 h
Yield: 73.3 %

Procedure:
First, 14.8 g of diethyl 2,2-bis(6-benzyloxyhexyl)malonate, 0.5 g of water, 2.3 g of lithium chloride, and 50 ml of dimethyl sulfoxide were placed in a 100 ml flask. Then, the mixture was stirred at 180° C. for 12 hours. The reaction mixture was poured into water, and an organic layer was extracted with methylene chloride. The methylene chloride layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 9.4 g of ethyl 2,2-bis(6-benzyloxyhexyl)acetate (Y: 72.9%). The compound thus obtained had a purity of 97.9% by GC.
Reaction SMILES: [S:1]1[CH:6]=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)[S:4][CH2:3][CH2:2]1.[NH2:14][CH:15]1[C:26](=[O:27])[N:17]2[C:18]([C:23]([OH:25])=[O:24])=[C:19]([CH3:22])[CH2:20][S:21][C@H:16]12>>[S:1]1[CH:6]=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:14][CH:15]2[C:26](=[O:27])[N:17]3[C:18]([C:23]([OH:25])=[O:24])=[C:19]([CH3:22])[CH2:20][S:21][C@H:16]23)=[O:10])[S:4][CH2:3][CH2:2]1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)C1=CSCCS1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12)C1=CSCCS1

Procedure:
2-(2,3-Dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetic acid (syn isomer, 1.15 g.) was allowed to react with 7-amino-3-methyl-3-cephem-4-carboxylic acid (1.07 g.) in a similar manner to that of Example 1 to give the captioned compound (0.8 g.), pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](=O)[CH2:25][OH:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:24]([CH2:25][OH:26])[CH2:23][Cl:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reactant: O=C(CO)CCl
Solvent: C1CCOC1
Product: OCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(o-fluorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-chloro-3-hydroxypropanone under nitrogen to give 7-chloro-2-[[2-chloro-1-(hydroxymethyl)ethylidene]hydrazino]-5-(o-fluorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(Cl)cc3)sc2Cc2ccccc2)cc1
Yield: 69.4 %

Procedure:
A procedure similar to that in Example 4 was used, 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and p-chlorobenzoyl chloride were used as starting materials, the resulting crude product was recrystallized with acetone to obtain a product as a white solid in a yield of 69.4%, mp: 182-183 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.78 (3H, s, OCH3), 4.21 (2H, s, CH2), 6.75 (2H, d, J=7.56 Hz, ArH), 7.22˜7.35 (9H, m, ArH), 7.60 (2H, d, J=7.56 Hz, ArH), 11.70 (1H, br, CONH); EI-MS m/e (%): 434.2 (M+, 100), 123.0 (83); HREI-MS Calcd. for C24H19ClN2O2S: 434.0856. found: 434.0859. Anal. Calcd. for C24H19ClN2O2S: C, 66.28; H, 4.40; N, 6.44. found: C, 65.91; H, 4.22; N, 6.50.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[C:35](=O)[CH2:34][CH:33]([C:37]3[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=3)[CH2:32][C:31]=2[O:49]CC)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:11][CH:10]=1)#[N:8].O>C(#N)C>[O:18]=[C:17]1[NH:16][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]#[N:8])=[CH:14][CH:13]=2)[C:30]2[C:31](=[O:49])[CH2:32][CH:33]([C:37]3[CH:38]=[C:39]([O:47][CH3:48])[C:40]([O:45][CH3:46])=[C:41]([O:43][CH3:44])[CH:42]=3)[CH2:34][C:35]=2[N:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=1
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(c2cc(OC)c(OC)c(OC)c2)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C2CC(=O)C3=C(C2)N(c2cccc(C(F)(F)F)c2)C(=O)NC3c2ccc(C#N)cc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium tert-butoxide (126 mg, 1.32 mmol) is added to a solution of 1-((4-cyanophenyl)-(2-ethoxy-6-oxo-4-(3,4,5-trimethoxyphenyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 19, 684 mg, 1.10 mmol) in acetonitrile (8 mL) and the mixture is stirred at room temperature for 2 h. Water is added and the mixture is extracted with ethyl acetate. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 190 mg; ESI mass spectrum [M+H]+=578, Retention time HPLC: 1.13 min, 1.14 min (1:1 mixture of diastereomers) (V011_S01).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)o1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
Methyl 5-methyl-2-furoate (3.68 g, 26.29 mmol) in methanol (30 ml) was treated with a solution of potassium hydroxide (2.80 g, 50.0 mmol) in water (15 ml) and the mixture stirred for 2 h at room temperature. The methanol was evaporated in vacuo, the residue dissolved in water and washed with ethyl acetate. The aqueous phase was acidified with SN hydrochloric acid, and the product extracted with ethyl acetate (x3). The combined organic solutions were dried and concentrated to yield the title compound as a yellow solid (3.12 g, 94%); m.p. 110-112° C.; (Found: M+, 126.0312. C6H6O3 requires M+ 126.0317); νmax (CH2C12) 3300-2700, 1688, 1524, 1424, 1305, 1210 and 1167 cm-1 ; δH (CDCl3, 90 MHz) 2.40 (3 H, s), 6.15 (1 H, d, J 4 Hz) and 7.22 (1 H, d, J 4 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:15](O)([CH3:17])[CH3:16]>>[C:15]([C:17]1[CH:11]=[C:6]([NH:5][C:2]2[C:11]3[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:7]=[CH:8][CH:9]=1)#[CH:16]
Reactant: CC(C)O
Reactant: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Product: C#Cc1cccc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 4-chloro-7-nitroquinazoline (2.0 g, 9.54 mmol), isopropanol (30 mL), and 3-thynylbenzenamine (1.2 g, 10.00 mmol) was refluxed for 5 h. The resulting mixture was cooled to room temperature and refrigerated. The precipitate was filtered out, washed with cold isopropanol several times, and dried in vacuo to give 2.6 g (94%) of N-(3-ethynylphenyl)-7-nitroquinazolin-4-amine as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:28])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(CC(c1ccc(Br)cc1)c1ccccc1Cl)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-(2-chloro-phenyl)-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI−): m/z=429.9 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([F:21])(C(OCC)=O)[C:9]([O:11][C:12](C)(C)[CH3:13])=[O:10])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([F:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(C(=O)OC(C)(C)C)c1ccc(Cl)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(F)c1ccc(Cl)nn1
Yield: 88.4 %

Procedure:
A solution of 1-tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)-2-fluoromalonate 45B (60.2 g, 189 mmol) in 300 mL TFA/DCM (1:1) was stirred at 25° C. for 2 hrs and then concentrated to dryness via rotary evaporation. The resulting residue was dissolved in EtOAc (300 mL), washed with saturated NaHCO3 solution, dried over MgSO4, and then concentrated to dryness to give the title compound, ethyl 2-(6-chloropyridazin-3-yl)-2-fluoroacetate 45C (36.6 g, 167 mmol, 89%). The material was used immediately without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (t, J=7.20 Hz, 3 H) 4.23 (qd, J=7.12, 4.42 Hz, 2 H) 6.43-6.62 (m, 1 H) 8.00-8.12 (m, 2 H). ESI-MS:m/z 219.0 (M+H)+.
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[NH:18]1[CH2:21][CH:20]([C:22]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=2)([OH:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:2]([N:18]2[CH2:21][CH:20]([C:22]([C:28]3[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=3)([OH:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:19]2)[C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[CH:12][CH:13]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1

Procedure:
The reaction mixture of 135 mg (0.44 mmol) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile, 105 mg (0.367 mmol) of 1-azetidin-3-yl-1-(3,5-difluorophenyl)-2,2-dimethylpropan-1-ol (3) and 230 uL (1.32 mmol) of N,N-diisopropylethylamine in 6 mL of acetonitrile was refluxed for 3 h. Then it was concentrated and the residue was dissolved in 5 mL of hexane/ether. 1 mL of 1N HCl in ether was added to above solution to make salt. It was filtered and washed with hexane/ether. The residue was neutralized with base and was purified by silica gel chromatography with hexanes/ethyl acetate to afford one racemic diastereomer of the title compound; Mass Spectrum: m/e=481 (M+1 35Cl) and 483 (M+1 37Cl). Further elution of the column afforded the other racemic diastereomer of the title compound; Mass Spectrum: m/e=481 (M+1 35Cl) and 483 (M+1 37Cl).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CCCCCC.[CH:17]1([CH:22]=[CH:23][CH:24]([CH3:31])[CH2:25][C:26](OCC)=[O:27])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)C>Cl>[CH:17]1([CH:22]=[CH:23][CH:24]([CH3:31])[CH2:25][CH:26]=[O:27])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CC(C)C=CC1CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: CCO
Product: CC(C=CC1CCCC1)CC=O
Temperature: 0 °C
Yield: 69 %

Procedure:
Diisobutylaluminum hydride (95 ml of 1.0 M solution in hexane) was added into a hexane (200 ml) solution of ethyl 5-cyclopentyl-3-methylpent-4-enoate (used in example 1; 20.0 g; 95 mmol), at −65° C. After 3 hours stirring at the same temperature, ethanol (3 ml) was added, and the reaction mixture was poured into an ice-cold NH4Cl solution (200 ml) and diluted with 2 N HCl (100 ml). The organic layer was separated, washed with brine (3×200 ml), dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (hexane/MTBE 15:1) to give 10.9 g (69% yield) of 5-cyclopentyl-3-methylpent-4-enal.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[CH3:28][C:29]1[NH:30][C:31]([NH:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[N:32][N:33]=1>>[F:27][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:18])[N:34]([CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:31]2[N:32]([N:33]=[C:29]([CH3:28])[N:30]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: Cc1nnc(NC2CCOCC2)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOCC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1 g) and 5-methyl-N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.43 g, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH:18]([F:20])[F:19]>CN(C)C=O.O>[F:19][CH:18]([F:20])[O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: FC(F)Cl
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(O)c1
Yield: 25 %

Procedure:
To a well stirred suspension of 3,4-dihydroxy benzaldehyde (100 gm) and anhydrous potassium carbonate (120 gm) in dry N,N-dimethylformamide (1.0 lit) was passed chlorodifluoromethane gas for about 30 minutes at about 80-85° C. After an hour another lot of anhydrous potassium carbonate (25.0 gm) was added and stirred for about one and half hours. The third lot of anhydrous potassium carbonate (25.0 gm) was added and stirred for about one and half hours. The reaction mixture was then stirred for about 5-6 hours at an ambient temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified through silica gel column to give 4-difluoromethoxy-3-hydroxy benzaldehyde.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:9]1[CH:33]=[CH:32][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:36][Mg]Br.C(OCC)C>O1CCCC1>[F:35][C:2]([F:1])([F:34])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([C:20]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:26][CH:27]=3)([OH:21])[CH3:36])[CH2:18][CH2:19]2)=[CH:32][CH:33]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(=O)Nc1ccc(C(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)Nc1ccc(C(C)(O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-(4-(1-(4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)benzyl)piperidine-4-carbonyl)phenyl)acetamide (1.702 mmol, 855 mg) was dissolved in anhydrous tetrahydrofuran (20 mL) under nitrogen and cooled to −78° C. 3M Methylmagnesium bromide in diethyl ether (3.40 mmol, 1.134 mL) was added and the mixture stirred at −78° C. for 30 minutes before allowing to warm to room temperature and stirring for a further 4 hours. After this time, further 3M methylmagnesium bromide in diethyl ether (3.40 mmol, 1.134 mL) was added and the mixture stirred for 2 hours. The mixture was cooled to 0° C. and quenched with a saturated solution of ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (100 mL) and washed with water (30 mL) then brine (30 mL). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with dichloromethane to 15% methanol/dichloromethane) to afford the title compound (300 mg). MS (ESI) m/z 519.2 [M+H]+
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=1)[CH2:3][NH:4][C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]=1)=[CH:6][N+:7]([O-:9])=[O:8].[H][H]>C(O)C>[NH2:34][C:31]1[CH:30]=[CH:29][C:28]([CH:2]([OH:1])[CH2:3][NH:4][C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:16]=2)=[CH:6][N+:7]([O-:9])=[O:8])=[CH:33][CH:32]=1
Reactant: O=[N+]([O-])C=C(NCCCOc1cccc(CN2CCCCC2)c1)NCC(O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Solvent: CCO
Product: Nc1ccc(C(O)CNC(=C[N+](=O)[O-])NCCCOc2cccc(CN3CCCCC3)c2)cc1
Yield: 39.9 %

Procedure:
With 15 ml of ethanol was mixed 0.8 g of N-[2-hydroxy-2-(4-nitrophenyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine, and hydrogen gas was introduced thereinto in the presence of 0.1 g of 5% (by weight) palladium carbon at ordinary temperature and under atmospheric pressure for 7 hours until the absorption of hydrogen gas ceased. Subsequently, the catalyst was removed by filtration and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by a column chromotography (Wako Silica Gel C-200, eluent; chloroform:methanol=5:1 by volume) to obtain 0.3 g (yield 40%) of amorphous N-[2-(4-aminophenyl)-2-hydroxyethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl] -1,1-ethenediamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:16]3[C:17]([O:25][CH3:26])=[N:18][C:19]([NH:22][CH2:23][CH3:24])=[N:20][CH:21]=3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:23]([NH:22][C:19]1[N:18]=[C:17]([O:25][CH3:26])[C:16]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:30]=[N:29][C:28]([CH3:27])=[CH:33][CH:32]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)=[CH:21][N:20]=1)[CH3:24]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(OC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-c4ccc(C)nc4)c3)c(C)n2)c(OC)n1
Temperature: 90 °C
Yield: 61.8 %

Procedure:
A solution of Example C1 (0.15 g, 0.4 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.57 mmol) in dioxane (4 mL) was sparged with Ar, treated with a solution of K2CO3 (0.11 g, 0.8 mmol) in water (1 mL) and heated at 90° C. for 2 h. The mixture was cooled to RT, diluted with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to afford N-ethyl-4-methoxy-5-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine as an orange foam (0.106 g, 61%). 1H NMR (400 MHz, DMSO-d6): δ 9.11 (d, J=2.4 Hz, 1H), 8.74 (s, 1H), 8.54 (d, J=5.7 Hz, 1H), 8.29 (dd, J=8.1, 2.4 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.02 (d, J=1.9 Hz, 1H), 6.79 (dd, J=5.7, 2.4 Hz, 1H), 3.96 (s, 3H), 3.36-3.34 (m, 2H), 2.51 (s, 3H), 2.38 (s, 3H), 1.15 (s, 3H); MS (ESI) m/z: 429.2 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:26])[N:9]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:10](=[O:13])[C:11]=1[CH3:12].[I-:27].[Na+]>C(C(C)=O)C.C(OCC)(=O)C>[I:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:26])[N:9]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:10](=[O:13])[C:11]=1[CH3:12]
Reactant: CC1=C(CCCCCCl)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CC1=C(CCCCCI)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 80 °C
Reaction time: 19 h
Yield: 77.9 %

Procedure:
A mixture of 11.68 g of 4-[3-(5-chloropentyl)-2,5-dihydro-4-methyl-2,5-dioxo-1H-pyrrol-1-yl]-2-(trifluoromethyl)benzonitrile and 18.2 g of sodium iodide in 180 ml of ethylmethylketone was stirred under a nitrogen atmosphere for 19 hours at 80° C. After cooling, it was diluted with ethyl acetate and washed with water as well as saturated sodium chloride solution. After drying on sodium sulfate and concentration by evaporation, 11.26 g of the title compound was obtained as a white solid.