Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([Cl:15])[N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19]>C(N(CC)CC)C>[CH2:1]([C:5]1[N:6]=[C:7]([Cl:15])[C:8]([N+:12]([O-:14])=[O:13])=[C:9]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCC(N)CC
Solvent: CCN(CC)CC
Product: CCCCc1nc(Cl)c([N+](=O)[O-])c(NC(CC)CC)n1
Reaction time: 3 h

Procedure:
200 ml of alcohol and 4.5 g (44 m-moles) of triethylamine are added to 11 g (44 m-moles) of 2-n-butyl-4,6-dichloro-5-nitro-pyrimidine. At -50° C, 4.0 g (44 m-moles of 3-aminopentane are added dropwise. The reaction mixture is stirred for 3 hours and then evaporated. The residue is suspended in 100 ml of water and extraction is performed with ether. The ethereal extracts are dried over MgSO4 and evaporated to yield 10.5 g of 2-n-butyl-4-chloro-5-nitro-6-(3-pentylamino)-pyrimidine (nD20 : 1.5383) as a yellow oil
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:21])[C:16]=1[O:17][CH:18]([CH3:20])[CH3:19])[O:13][C:12]([CH3:23])([CH3:22])[CH2:11][C:10]2=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:21])[C:16]=1[O:17][CH:18]([CH3:20])[CH3:19])[O:13][C:12]([CH3:23])([CH3:22])[CH:11]=[C:10]2[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)Oc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O
Solvent: C1CCOC1
Product: CC(C)Oc1c(Br)cc2c(c1Cl)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 18.8 mL, 37.6 mmol), 6-bromo-8-chloro-7-isopropoxy-2,2-dimethyl-chroman-4-one, (Compound 11, 2.6 g, 7.5 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(]-pyrimidinone (DMPU, 4.5 mL, 37.6 mmol) in THF was reacted to afford the title compound as a yellow oil after purification by flash chromatography (silica gel, 5% to 10% ethyl acetate in hexanes).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:31]=1[CH2:32]Br>CC#N>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:32][C:31]3[C:30]([Cl:29])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:38])=[CH:19][CH:20]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OCc3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (5.00 g; 16.3 mmol) and K2CO3 (6.74 g; 48.8 mmol) in CH3CN (100 mL) was stirred for one hour at RT. Subsequently 2,6-dichlorobenzyl bromide (4.29 g; 17.9 mmol) was added and the resulting mixture was stirred overnight at RT. The reaction mixture was partitioned between EtOAc (250 mL) and 5% aqueous NaHCO3 solution (100 mL). The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1) to afford 3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester (7.40 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14](C)[C:15](=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH3:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
Tert-butyl N-[1-(4-chlorophenyl)piperidin-4-yl]-N-methylcarbamate (4.71 g, 14.5 mmol) prepared in Reference Example 165 was dissolved in methylene chloride (30 ml), to which trifluoroacetic acid (20 ml) was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in methylene chloride. The solution was neutralized with sodium hydroxide aqueous solution, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford N-[1-(4-chlorophenyl)piperidin-4-yl]-N-methylamine (3.1 g, yield 95%) as a pale brown oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:13][C:14]([F:27])([F:26])[S:15]([O:18]S(C(F)(F)F)(=O)=O)(=[O:17])=[O:16]>N1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:18][S:15]([C:14]([F:27])([F:13])[F:26])(=[O:16])=[O:17])=[C:10]([C:14]([F:27])([F:26])[F:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)c(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 173.8 %

Procedure:
To a solution of the acetylindoline (D11, 1.19 g, 4.9 mmol) in dry pyridine (10 ml) at 0° C. was added trifluoromethanesulphonic anhydride (1.52 g, 5.4 mmol). The mixture was then stirred overnight, while slowly warming to room temperature. The mixture was partially evaporated, the residual liquor was diluted well with water and the precipitate was filtered off. The crude product was dissolved in dichloromethane and the solution was washed with IN hydrochloric acid and brine, dried and evaporated to give the title compound (1.77 g, 96%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:18]([CH2:36][CH2:37][CH2:38][CH3:39])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=2)=[C:21]([O:34][CH3:35])[CH:20]=1)[CH2:15][CH2:16][CH3:17].O>O1CCCC1>[CH2:14]([N:18]([CH2:36][CH2:37][CH2:38][CH3:39])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[S:31][C:30]([CH:32]=[CH:5][C:3]#[N:4])=[CH:29][CH:28]=2)=[C:21]([O:34][CH3:35])[CH:20]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OC)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC#N)s2)c(OC)c1
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To 111 mg (4.63 mmol) of sodium hydride, 8 ml of tetrahydrofuran was added. To this mixture, 820 mg (4.63 mmol) of diethyl cyanomethylphosphonate was added dropwise under ice cooling, and the mixture was stirred for 30 minutes. Next, 860 mg (2.31 mmol) of 5-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]thiophene-2-carboaldehyde in tetrahydrofuran was added dropwise, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and subjected to extraction with ethyl acetate. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 828 mg of a deep red oily matter (yield: 90.7%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])/[C:3](/O)=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=O.[CH2:21]([O:23][C:24](=[O:29])/[CH:25]=[C:26](\[NH2:28])/[CH3:27])[CH3:22]>C(#N)C>[CH2:21]([O:23][C:24](=[O:29])[C:25]1[C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)=[N:28][C:26]=1[CH3:27])[CH3:22]
Reactant: O=C(/C=C(\O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC#N
Product: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1C
Yield: 48 %

Procedure:
To an acetonitrile (35 ml) solution of (Z)-4,4,4-trifluoro-3-hydroxy-1-(4-trifluoromethoxy-phenyl)-but-2-en-1-one (2.9 g, 10 mmol) was added ethyl-3-aminocrotonate (2.5 g, 19 mmol) under an argon atmosphere. The mixture was heated at reflux for 12 h. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, n-heptane/ethyl acetate) to yield 1.9 g (4.8 mmol, 50%) of the title compound as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1([N:22]=[C:23]=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:23]([NH:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:24]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1cccc2ccccc12
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1cccc2ccccc12

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(1-naphthyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 1-naphthyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product precipitated from methylene chloride and filtered. The resulting solid was titruated with 1:3 triethyl amino:methylene chloride. The filterate was concentrated in vacuo. The resulting residue was dissolved in methylene chloride and treated with 1 N HCl in water. The desired product precipitated from solution and was collected by filtration (0.11 g, 10%). EI-MS m/z 324 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5]2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCCn1ccc2cc(Br)ccc21
Product: CCCCn1ccc2cc(-c3ccc(OC)cc3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-butyl-1H-indole (Step 1 of Example 29) and 4-methoxyphenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 280. 1HNMR (400 MHz, DMSO-d6): δ 7.72 (s, 1H), 7.58 (dd, 2H, J=8.86 and 1.99 Hz), 7.54-7.49 (m, 2H), 7.37-7.35 (m, 2H), 6.98 (dd, 1H, J=7.33 and 7.34 Hz), 6.44 (d, 1H, J=3.05 Hz), 4.17 (t, 2H, J=7.01 Hz), 3.78 (s, 3H), 1.73 (p, 2H, J=7.16 Hz), 1.25 (h, 2H, J=7.46 Hz), and 0.88 ppm (t, 3H, J=7.3, 1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH:17]=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1COCC1>[N:19]1([CH2:17][C:15]2[S:14][C:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=3[CH:16]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C=O)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2sc(CN3CCCCC3)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carbalde-hyde (440 mg, 1.65 mmol) and piperidine (0.18 ml, 1.81 mmol) were dissolved in THF (10 ml), and NaBH(OAc)3 (523 mg, 2.47 mmol) and glacial acetic acid (94 μl, 1.65 mmol) were added. This mixture was stirred under a nitrogen atmosphere at room temperature for 24 hours. The solvent was then distilled off in vacuo and the residue was taken up in ethyl acetate (25 ml). The solution obtained was washed with NaHCO3 solution and NaCl solution and the combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. The crude product (580 mg) was employed directly in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([O:31][CH2:32][CH2:33][C:34]#[N:35])[CH2:28][C@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:52])([F:51])[F:50])[CH:39]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:44]([C:41]1[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][C:40]=1[O:48][C:49]([F:50])([F:51])[F:52])(=[O:46])=[O:45])[C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([O:31][CH2:32][CH2:33][C:34]#[N:35])[CH2:28][C@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccc(C)cc1C1(N2C[C@H](OCCC#N)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](OCCC#N)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 66.2 %

Procedure:
With 720 mg of the compound obtained in Step 143-4 and 506 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 720 mg of the title compound (amorphous) was obtained by a similar procedure to Example 2.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:29]([O:31]CC)=[O:30])[CH:25]=4)[CH:20]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO>[CH3:1][C:2]1([CH3:34])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:29]([OH:31])=[O:30])[CH:25]=4)[CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc2cc(-c3ccc4c(c3)C(c3ccc(C)cc3)=CCC4(C)C)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(-c4ccc5cc(C(=O)O)ccc5c4)cc32)cc1
Temperature: 0 °C
Yield: 19.4 %

Procedure:
A solution of ethyl 5′,6′-dihydro-5′,5′-dimethyl-8′-(4-methylphenyl)-[2,2′-binaphthalene]-6-carboxylate (Compound 64) 0.19 g, 0.43 mmol), EtOH (8 ml) and 1N aqueous NaOH (2 ml) was heated to 60° C. for 3 hours. The solution was cooled to 0° C. and acidified with 1N aqueous HCl. The product was extracted into ethyl acetate, and the organic layers combined, washed with water, brine, dried (MgSO4), filtered and the solvent removed in-vacuo. The residue was recrystalized from THF/ethyl acetate at 0° C. to give 35 mg of pure material. The mother liquor was concentrated under reduced pressure and the residue purified by silica gel chromatography (100% ethyl acetate) to give an additional 125 mg of the title compound (overall yield=160 mg, 90%) as a colorless solid. 1H NMR (DMSO-d6) δ 8.57 (s, 1H), 8.11 (d, 1H, J=8.7 Hz), 7.96-7.82 (overlapping d's, 3H), 7.65 (d, 2H, J=7.6 Hz), 7.50 (d, 1H, J=7.9 Hz), 7.28 (s, 1H), 7.26 (d, 2H, J=8.3 Hz), 7.21 (d, 2H, J=8.3 Hz), 6.01 (t, 1H, J=4.5 Hz), 3.34 (br s, 1H), 2.31 (s, 3H), 2.31 (d, 2H, J=4.5 Hz), 1.31 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].Br.[CH2:11]([NH:13][CH2:14][CH2:15][CH2:16]Br)[CH3:12]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][CH2:16][CH2:15][CH2:14][NH:13][CH2:11][CH3:12])[CH:8]=1
Reactant: CCNCCCBr
Reactant: Cc1ccc(Cl)cc1N
Agent: Br
Solvent: ClCCl
Product: CCNCCCNc1cc(Cl)ccc1C
Yield: 92.5 %

Procedure:
A mixture of 5-chloro-2-methylaniline (12.3 g) and the N-ethyl-1-amino-3-bromopropane hydrobromide salt of Example 3, Step C (8.6 g) was heated at 100° C. under nitrogen for 20 minutes. After cooling, a solid mass formed which was partitioned between dichloromethane and 1 N sodium hydroxide. The organic phase was washed with brine, dried over anhydrous potassium carbonate, filtered and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 100% dichloromethane to 9:1 dichloromethane-methanol containing 0.2% ammonium hydroxide) provided the title compound (7.3 g, 92.8%) as a brown oil, which was used as such in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)=O)C.F[C:27]1C=CC(OC2C=CC(C3C=CN=C(C(O)=O)N=3)=CC=2)=CC=1.ICC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:15]2[CH:16]=[CH:17][C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([C:4](=[O:3])[CH3:27])[N:11]=3)=[CH:13][CH:14]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1nccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: O=C(O)c1nccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CC(=O)c1nccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Yield: 62 %

Procedure:
4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid ethyl ester: A mixture of 4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid (3.15 g, 10.2 mmol), iodoethane (2.0 mL, 25 mmol), and cesium carbonate (7.00 g, 21.5 mmol) in DMF (100 mL) was maintained at 70°-80° C. for 16 hours. The mixture was then partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed 3 times with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give an oil. Purification by column chromatography (1:1 hexane/ethyl acetate) afforded the desired product (2.14 g, 62%) as an oil which solidified upon standing at room temperature overnight, mp 61°-63° C. 1H NMR (CDCl3): δ 8.88 (d, J=5.4 Hz, 1H), 8.16 (d, J=8.7 Hz, 2H), 7.77 (d, J=5.4 Hz, 1H), 7.12-7.05 (m, 6H), 4.55 (q, J=7.5 Hz, 2H), 1.49 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[C:28]=1[CH3:36].CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:35])[C:28]=1[CH3:36]
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: COC(=O)c1cccc(N=C=O)c1C
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c1C

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 9.1) was reacted with 3-isocyanato-2-methyl-benzoic acid methyl ester ([480-439-28-9]) in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 3 days under reflux conditions to give the title compound as yellow oil. MS: m/e=517.2 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]2([CH3:39])[CH2:38][O:37][CH2:36]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.COB([C:45]#[C:46][Si:47]([CH3:50])([CH3:49])[CH3:48])OC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:9]3([CH:8]([C:6]4[CH:7]=[C:2]([C:45]#[C:46][Si:47]([CH3:48])([CH3:49])[CH3:50])[CH:3]=[CH:4][C:5]=4[O:33][CH2:34][C:35]4([CH3:39])[CH2:38][O:37][CH2:36]4)[CH2:13][C:12](=[O:14])[NH:11][CH:10]3[C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COB(C#C[Si](C)(C)C)OC
Reactant: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Br)ccc2OCC2(C)COC2)C12C(=O)Nc1cc(Cl)ccc12
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: C1CCOC1
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(C#C[Si](C)(C)C)ccc2OCC2(C)COC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C

Procedure:
To a mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.08 mmol), trimethylsilylacetylene boronic acid dimethyl ester (0.7 M, 0.7 mL, 0.49 mmol) and K3PO4 (100 mg, 0.48 mmol) in THF was added Pd(PPh3)4 (15 mg) under argon. The reaction mixture was heated at 80° C. for 20 h, purified by prep-HPLC to give the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][N:5]([CH3:7])[CH:6]=1.C(N(CC)CC)C.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[C:3]([NH:8][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][Cl:16])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(N)n1
Reactant: O=C(Cl)CCCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc(Br)c(NC(=O)CCCCl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-1-methyl-1H-pyrazol-3-amine (310 mg) and triethylamine (0.37 mL) in THF (8.8 mL) was added 4-chlorobutanoyl chloride (0.22 mL) under ice-cooling, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (456 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[OH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1.O>CN(C=O)C>[OH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH2:30]1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: OCC1CCCNC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCC(CO)C4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.7 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the solution were added 3-(hydroxymethyl)piperidine (191 mg). The mixture was stirred at room temperature for 72 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[3-(hydroxymethyl)piperidinomethyl]phenyl]-3-(4-methylphenyl)cinnamamide (Compound 66) (160 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([F:27])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)cc1OC
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 15.8 %

Procedure:
The title compound was prepared by following the procedure as described for step-6 of Intermediate-26 by using methyl 4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-1 of Intermediate-34, 0.100 g, 0.20 mmol), 4-fluoro-3-(trifluoromethyl)aniline (0.044 g, 0.34 mmol), trimethyl aluminium (2M solution in toluene) (1.0 mL) and dry toluene (8.0 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.94 (s, 3H), 3.78 (t, 1H), 7.52 (t, 2H), 7.71-7.82 (m, 3H), 8.03 (d, J=6.6 Hz, 2H), 10.38 (s, 1H), 12.69 (br s, 1H).