Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: COCCN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CCOC)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 27.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.0 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](N)[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.Cl.N([O-])=O.[Na+].[I-:18].[K+]>O>[I:18][C:5]1[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: [I-]
Reactant: COc1cc(N)cc([N+](=O)[O-])c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(I)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
To a solution of 3-methoxy-5-nitro-phenylamine (7.5 g, 44.6 mmol) in water (20 mL) was added a concentrated hydrochloric acid (19.95 mL, 267.6 mmol, 36%) at 0° C. To this was added a chilled solution of sodium nitrite (5.62 g, 80.28 mmol) in water (28.4 mL) dropwise with a vigorous stirring. Then, the resulting colored mixture was stirred for 15 min at 0° C., and a cold solution of potassium iodide (14.81 g, 89.2 mmol) in water (28.4 mL) was added carefully. During this addition, a black brown solid was formed and after addition the ice-cold bath was removed, and the reaction mixture was heated to reflux. When the production of purple vapor ceased, the mixture was cooled to room temperature and the organic compound was extracted into dichloromethane (3×200 mL). The combined organic extracts were washed with brine solution (300 mL) and dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Then, the crude residue was purified by using a LC 120 column, eluting with 0-10% ethyl acetate in hexanes to obtain 1-iodo-3-methoxy-5-nitro-benzene (10 g, 80%) as a white solid: EI(+)-HRMS m/e calculated for C7H6INO3 (M+)+ 278.9392, found 278.9393.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:7]=1[CH:8]=[CH:9][S:10]([N:13]=[C:14]([O-])[CH2:15]Cl)(=[O:12])=[O:11]>>[CH:1]1([NH:4][C:14](=[N:13][S:10]([CH:9]=[CH:8][C:7]2[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:6]=2[Cl:5])(=[O:12])=[O:11])[CH3:15])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=S(=O)(C=Cc1c(Cl)cccc1Cl)N=C([O-])CCl
Product: CC(=NS(=O)(=O)C=Cc1c(Cl)cccc1Cl)NC1CC1

Procedure:
Reaction of Cyclopropylamine with N-(2,6-dichlorostyrylsulfonyl)chloroacetimidate according to the procedure of Example 32(b) affords N-cyclopropyl-N'-(2,6-dichlorostyrylsulfonyl) acetamidine, m.p. 121°-124° C. when crystallized from benzene.
Reaction SMILES: C(OC([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[C:15]([CH3:21])[C:14]([C:22](=[O:24])[CH3:23])=[C:13]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:21][C:15]1[C:14]([C:22](=[O:24])[CH3:23])=[C:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:20][C:19]=3[S:18][C:17]=2[N:16]=1
Reactant: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCN(C(=O)OC(C)(C)C)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCNC3
Temperature: 25 °C
Yield: 93 %

Procedure:
To a stirred solution of 70 mg (0.16 mmol) 3-acetyl-2-methyl-4-phenyl-5,8-dihydro-6H-9-thia-1,7-diaza-fluorene-7-carboxylic acid tert-butyl ester in 3 ml dicloromethane was added 0.2 ml trifluoroacetic acid. The mixture was stirred over night at RT, and then poured onto an aqueous solution of NaHCO3, and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford 48 mg (94%) 1-(2-methyl-4-phenyl-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl)-ethanone as a yellow solid. ES-MS m/e (%): 323 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]1([C@H:15]2[O:22][CH2:21][C@H:20]3[N:16]2[C:17](=[O:23])[CH:18]=[CH:19]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CS(C)=O.CC(OC)(C)C>[C:9]1([C@H:15]2[O:22][CH2:21][C@H:20]3[N:16]2[C:17](=[O:23])[C@@H:18]2[CH2:4][C@@H:19]23)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1C=C[C@H]2CO[C@H](c3ccccc3)N12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: O=C1[C@@H]2C[C@@H]2[C@H]2CO[C@H](c3ccccc3)N12
Reaction time: 0.5 h

Procedure:
At RT NaH (oil free, 12.5 mmol) is added to DMSO (15 mL). The mixture is treated portionwise with trimethylsulfoxonium iodide (12.7 mmol) and stirred for 30 min. A solution of (2R,5S)-2-Phenyl-3-oxa-1-azabicyclo[3.3.0]oct-6-en-8-on (4.97 mmol, J. Org. Chem. 1999, 64, 547-555) in DMSO (3.0 mL) is added and the mixture is stirred for 16 h. After cooling to 4° C. water and TBME (100 mL) are added, the layers are separated and the aq. layer is extracted with TBME (100 mL). The combined organic layers are concentrated in vacuo and the residue is purified by FC (heptane/EtOAc 1/1) to give the desired product as a pale yellow oil. LC-MS (basic): tR=0.77 min; [M+H]+=216.3.
Reaction SMILES: [Cl:1][C:2]1[C:8]([C:9]2([CH3:12])[CH2:11][CH2:10]2)=[CH:7][C:5]([NH2:6])=[C:4]([O:13][CH3:14])[CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=O.C([BH3-])#N.[Na+]>CO.CC(O)=O>[Cl:1][C:2]1[C:8]([C:9]2([CH3:12])[CH2:10][CH2:11]2)=[CH:7][C:5]([NH:6][CH2:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(Cl)c(C2(C)CC2)cc1N
Reactant: CCOC(=O)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CNc1cc(C2(C)CC2)c(Cl)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of 4-chloro-2-methoxy-5-(1-methylcyclopropyl)aniline (450 mg, 2.13 mmol) in MeOH (20 mL) at RT, AcOH (3 drops) and ethyl glyoxalate (326 mg, 3.19 mmol, 50% in toluene) were added. The mixture was stirred at RT for 2 h and then sodium cyanoborohydride (403 mg, 6.39 mmol) was added to the mixture. The resulting mixture was stirred at 50° C. for 16 h. The mixture was allowed to cool to RT, and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product (636 mg). ESI-MS m/z: 298.2[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH3:12])=[C:4]([N+:26]([O-])=O)[CH:3]=1.[C:29](O)(=O)[CH3:30]>[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH2:10][CH:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH3:12])[C:29]([CH3:30])=[N:26][C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: CC(CCNc1ccc(F)cc1[N+](=O)[O-])N1CCN(c2ccc(F)cc2)CC1
Agent: [Zn]
Product: Cc1nc2cc(F)ccc2n1CCC(C)N1CCN(c2ccc(F)cc2)CC1

Procedure:
To a refluxing, stirred mixture of (4-fluoro-2-nitro-phenyl)-{3-[4-(4-fluorophenyl) piperazin-1-yl]-butyl}-amine (0.38 gm), 10 ml acetic acid are added small portions of Zn dust (excess) until a nearly colorless reaction mixture is obtained approx. 4 hours). Insolubles are removed by filtration, washed with acetic acid and the combined acetic acid layer concentrated to a black oil. This oily residue is dissolved in ethyl acetate (50 ml) and washed with 2×10 ml water and brine. The organic layer is collected, the sovent removed and the residue purified by flash chromatography (solid phase: SiO2 ; eluent: gradient starting with ethyl acetate followed by ethyl acetate/methanol 8:2). Obtained are 0.1 gm of 5-fluoro-1-{3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-butyl}-2-1H-benzoimidazole. (M+/Z 384.47).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([O:21][CH3:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH:7]=1.C(OC(=O)[C@@H](OC)CC1C=CC(OCC(O)=O)=CC=1)C>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([O:21][CH3:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]([OH:16])=[O:15])[CH:7]=1
Reactant: COC(=O)C(Cc1cccc(OCC(=O)OC(C)(C)C)c1)OC
Agent: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Product: COC(=O)C(Cc1cccc(OCC(=O)O)c1)OC

Procedure:
The title compound was prepared from 3-(3-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acid methyl ester (PREPARATION 4, step 1) via the same procedure used to prepare (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) to produce a yellow oil. MS (ES) for C13H16O6 [M+H]+: 269.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:14](COCC[Si](C)(C)C)[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[CH3:2]>CCOC(C)=O.C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Yield: 91 %

Procedure:
The title compound was prepared by the procedure of Example 15, step (c) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-acetyl-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 40.0 mg, 0.0862 mmol). Silica gel chromatography (10% EtOAc/DCM) afforded the title compound (26.2 mg, 91%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 11.59 (s, 1H), 9.79 (s, 1H), 8.50 (d, 1H, J=8.6 Hz), 7.92 (dd, 1H, J=8.6, 2.0 Hz), 7.82 (d, 1H, J=2.0 Hz), 7.78 (s, 1H), 5.92 (m, 1H), 2.62 (s, 3H), 2.23-2.39 (m, 4H), 1.77-1.94 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C19H18N4O2, 335.1 (M+H), found 335.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH2:19][CH2:18][CH:17]([O:20][Si](C(C)(C)C)(C)C)[CH2:16][CH:15]=3)=[CH:11][CH:12]=2)[N:7]([CH3:28])[CH:6]=1)=[O:4].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH:15]=3)=[CH:11][CH:12]=2)[N:7]([CH3:28])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cn(C)c2cc(C3=CCC(O[Si](C)(C)C(C)(C)C)CC3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cn(C)c2cc(C3=CCC(O)CC3)ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
A solution of 6-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohex-1-enyl]-1-methyl-1H-indole-3-carboxylic acid methyl ester (0.710 g, 1.78 mmol) in THF (10 mL) is treated with Bu4NF (2.22 mL, 1.0 M in THF). The mixture is stirred at room temperature for 5 h and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with a gradient of 25-80% EtOAc/Hexanes to provide the 6-(4-hydroxy-cyclohex-1-enyl)-1-methyl-1H-indole-3-carboxylic acid methyl ester (0.320 g, 63%). MS m/z 286.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]>>[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:17][CH2:16]/[CH:15]=[C:14](/[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)\[CH3:18])=[CH:33][CH:34]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2ccc(F)cc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(F)cc3)cc2)cc1)OCC
Yield: 89.1 %

Procedure:
The title compound (849 mg, 89%) was prepared as a colourless gum from (E)-3-(4′-fluoro-biphenyl-4-yl)-but-2-en-1-ol (500 mg, 2.06 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (516 mg, 2.17 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([O:9]C)[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1.CCl>>[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1
Reactant: COc1cc(OC)nc(N)n1
Agent: CCl
Agent: Cl
Product: COc1cc(O)nc(N)n1

Procedure:
19.2 g of 2-amino-4,6-dimethoxy-pyrimidine hydrochloride are heated at 150° C. for 2 hours, in the course of which methyl chloride is removed and 2-amino-4-hydroxy-6-methoxy-pyrimidine is formed. After the addition of 80 ml of 40% sodium hydroxide solution and 100 ml of dioxane, there are introduced at 70° to 75° C., during 45 minutes, 22 g of difluorochloromethane. The organic phase is then separated, concentrated to about 1/5 of its volume and poured into water, and the solid precipitate is removed. The yield is 2.4 g of 2-amino-4-difluoromethoxy-6-methoxy-pyrimidine, m.p. 106° to 107° C. (compound No. 1.7).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].CNCCNC.[NH:16]1[CH:20]=[CH:19][CH:18]=[N:17]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:8]=[C:7]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: c1cn[nH]c1
Reactant: Nc1ccc(I)cc1Cl
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ccc(-n2cccn2)cc1Cl
Reaction time: 3 h
Yield: 93 %

Procedure:
2-chloro-4-iodoaniline (760 mg, 3 mmol), N,N′-dimethylethylenediamine (96 μL, 0.9 mmol), 1H-pyrazole (430 mg, 6.3 mmol) were dissolved in DMF (3.8 mL). Cs2CO3 (1.86 g, 5.7 mmol) and CuI (57 mg, 0.3 mmol) were added and the reaction was placed in a 140° C. oil bath. After 3 h, the volatiles were removed in vacuo. The residue was diluted with dichloromethane and purified via flash column chromatography (1% MeOH/dichloromethane) to furnish 2-chloro-4-(1H-pyrazol-1-yl)aniline (540 mg, 93%) as a golden brown oil which crystallized overnight at −20° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[N+](C1C=C(S(O[CH2:32][CH:33]2[CH2:35][O:34]2)(=O)=O)C=CC=1)([O-])=O>CC#N>[N+:10]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[O:9][CH2:32][CH:33]1[CH2:35][O:34]1)[C:1]#[N:2])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCC2CO2)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
4-Cyano-2-nitrophenol (0.80 g; 4.9 mmol) and K2CO3 (0.68 g; 4.9 mmol) were refluxed in MeCN (40 mL) for 1 h. The solvent was removed on a rotary evaporator and the residue dissolved in DMF (10 mL). 2-{[(3-Nitrophenyl)sulfonyloxy]methyl}oxirane (1.2 g, 4.9 mmol; see Example B above) was added to the resultant solution. The solution was stirred at 40° C. for 12 h and filtered. The precipitate was washed with H2O to give the sub-title compound in a 65% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([O:30][Si](C(C)(C)C)(C)C)[CH2:26][CH2:25]4)[C:20]3=[O:38])=[C:13]([Cl:39])[CH:12]=2)=[CH:6][CH:5]=1.Cl>CCO>[CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]([Cl:39])[C:14]([CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:25][CH2:26][CH:27]([OH:30])[CH2:28][CH2:29]4)[C:20]3=[O:38])=[C:15]([Cl:17])[CH:16]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Oc2cc(Cl)c(CC3CCN([C@H]4CC[C@@H](O[Si](C)(C)C(C)(C)C)CC4)C3=O)c(Cl)c2)cc1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(Oc2cc(Cl)c(CC3CCN(C4CCC(O)CC4)C3=O)c(Cl)c2)cc1
Temperature: 60 °C

Procedure:
Dissolve 90 mg of 4-(4-{1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-2-oxo-pyrrolidin-3-ylmethyl}-3,5-dichloro-phenoxy)-benzoic acid methy ester (Preparation 73) in 10 mL EtOH and treat with 1 mL 1 N aqueous HCl. Heat at 60° C. for 2 hours. Concentrate to dryness under vacuum and purify by radial chromatography using 5% MeOH in CHCl3 to recover 73 mg of product. Mass spectrum (api-es) m/z 492 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8][Br:9])=[CH:5][CH:4]=1)#[N:2].[BrH:13].[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([NH2:30])=[S:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)C>CO>[BrH:9].[BrH:13].[CH2:14]([N:21]1[CH2:22][CH2:23][CH:24]([NH:27][C:28]2[S:29][CH:8]=[C:7]([C:6]3[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:30]=2)[CH2:25][CH2:26]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC(=S)NC1CCN(Cc2ccccc2)CC1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: Br
Solvent: CCOCC
Solvent: CO
Product: N#Cc1ccc(-c2csc(NC3CCN(Cc4ccccc4)CC3)n2)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
12.46 g of 4-cyanophenacyl bromide are added to 18.38 g of N-(1-benzylpiperid-4-yl)thiourea hydrobromide in 200 ml of methanol, and then the reaction mixture is heated under reflux for 4 hours. The mixture is cooled to room temperature and then, successively, 200 ml of diethyl ether are added and the precipitate is filtered and washed with diethyl ether in order to obtain white crystals which melt at 280° C.; yield: 86%.
Reaction SMILES: [CH3:1]O.[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].S(=O)(=O)(O)O>ClCCCl>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:1])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: COC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
Methanol (59 mL, 3.0 equivalent amounts) was added to a 1,2-dichloroethane (400 mL) solution of 2-(3,4-dichlorophenyl) acetic acid (100 g, 0.488 mol). The solution was heated to 50° C., and then concentrated sulfuric acid (10 mL) was dropwise added over a period of 15 minutes, followed by stirring at 50° C. for 1.5 hours. The reaction solution was cooled to room temperature, followed by liquid separation to remove a sulfuric acid layer, and the obtained organic layer was sequentially washed with water, a saturated sodium hydrogencarbonate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a colorless oil (105 g, yield: 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:16][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[O:15]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: Cc1cc(C(C)(C)C)c(O)cc1CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cc1cc(O)c(C(C)(C)C)cc1C
Yield: 95 %

Procedure:
Into a 300-ml four-necked flask, were charged 22.2 g of 2-methyl-4-t-butyl-5-hydroxyphenylacetic acid, 150 ml of toluene, 27.0 g of octadecyl alcohol and 1 g of p-toluenesulfonic acid. The mixture was heated under reflux for about one hour while removing the liberated water from the reaction system. After completion of the reaction, the reaction mixture was freed from the catalyst by washing with water and from the solvent by distillation under reduced pressure to obtain 45.0 g (95% yield) of pale yellow octadecyl 2-methyl-4-t-butyl-5-hydroxyphenylacetate which was recrystallized from methanol to yield white crystals melting at 53.0°-54.5° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:48]=[CH:47][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:40]=[CH:39][C:22]([C:23]([NH:25][CH2:26][C:27]([CH3:38])([CH3:37])[CH2:28][NH:29]C(=O)OC(C)(C)C)=[O:24])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])[N:13]=2)=[CH:8][CH:7]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50].C(Cl)Cl>>[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50].[NH2:29][CH2:28][C:27]([CH3:38])([CH3:37])[CH2:26][NH:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16]2[CH:15]=[C:14]([O:41][CH2:42][C:43]([F:44])([F:46])[F:45])[N:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:48][CH:47]=3)[N:17]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(OCC(F)(F)F)nc(NCc3ccc(OCCCBr)cc3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN)CNC(=O)c1ccc(Nc2cc(OCC(F)(F)F)nc(NCc3ccc(OCCCBr)cc3)n2)cc1

Procedure:
tert-butyl (3-(4-((2-((4-(3-bromopropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate (35 mg, 0.047 mmol) was stirred in TFA/DCM (1:1) solution (2 mL) for 1 h. The solution was concentrated and free TFA to give N-(3-amino-2,2-dimethylpropyl)-4-((2-((4-(3-bromopropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzamide which was carried to the next step without purification.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][N:27](CCO)[CH2:26][C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:33])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[Cl:39][CH2:40][C:41](Cl)=[O:42]>C(Cl)Cl>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][N:27]([C:41](=[O:42])[CH2:40][Cl:39])[CH2:26][C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:33])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(CCO)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)CCl)C2
Reaction time: 1.5 h
Yield: 112.9 %

Procedure:
4-(Benzyloxy)-1-(2-(2-hydroxyethyl)-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (100 mg, 0.23 mmol) was stirred in a mixture of CH2Cl2 (2 mL) and saturated NaHCO3 solution (2 mL) and chloroacetyl chloride (32 mg, 0.28 mmol) was added. After 1.5 h, the organic layer was removed and concentrated to provide the title compound (120 mg, 100%) as a yellow oil: ESI MS m/z 462 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[N:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[CH2:3]1.[Cl:17][C:18]1[C:26]([Cl:27])=[C:25]([F:28])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21]>>[Cl:17][C:18]1[C:26]([Cl:27])=[C:25]([F:28])[CH:24]=[CH:23][C:19]=1[C:20]([N:7]1[CH:2]([CH3:1])[CH2:3][C:4]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:9]=[N:8][C:5]=2[CH2:6]1)=[O:21]
Reactant: CC1Cc2c(nnn2-c2ccccn2)CN1
Reactant: O=C(O)c1ccc(F)c(Cl)c1Cl
Product: CC1Cc2c(nnn2-c2ccccn2)CN1C(=O)c1ccc(F)c(Cl)c1Cl

Procedure:
Example 121 was prepared from 6-methyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine and 2,3-dichloro-4-fluorobenzoic acid using the conditions described in Example 65. MS (ESI) mass calcd. C18H14Cl2FN5O, 405.06. m/z found, 406.1 [M+H]+.