Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.[Fe]>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 57.5 °C
Yield: 75.7 %

Procedure:
A mechanically-stirred solution of 4-(4-benzyloxyphenoxy)-1-nitrobenzene (5.6 g, 17 mmol) in absolute ethanol (50 ml) was treated with concentrated hydrochloric acid (6 ml). The solution was warmed to 55-60° C. under a nitrogen cover. Iron powder (6.5 g, 115 mmol) was added in several portions. A mild exotherm (while still being heated) brought the reaction temperature to 68° C. After completing the iron addition the reaction temperature was brought to 70° C. and maintained at that temperature for 1.5 hours. The mixture was then cooled to room temperature and filtered through a pad of Celite®. The filter cake was washed with ethanol (100 ml) and methylene chloride (50 ml), and the filtrate partitioned between methylene chloride and 1M potassium carbonate. The green aqueous layer was extracted a second time with methylene chloride and then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo afforded crude product (5.4 g), contaminated with unreacted starting material. Silica gel chromatography (Waters® LC2000 with 2 PrePak® columns, eluting with methylene chloride) provided the title compound (3.75 g, 76%), as well as unreacted starting material (1.2 g). 1H NMR(400 MHz): 3.53(2H,br s), 5.02(2H,s), 6.62-6.67(2H,m), 6.79-6.84(2H,m), 6.86-6.93(4H,m), 7.29-7.44(5H,m); MS(ESI)m/z 291.9([M+H]+,100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][CH:35]=O.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:34]([N:26]1[CH2:27][CH2:28][N:23]([C:19]2[CH:18]=[C:17]([S:14]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[C:30]([F:31])([F:33])[F:32])[CH2:9][C@H:10]3[CH3:29])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1)[CH3:35]
Reactant: CC=O
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CCN(c2cccc(S(=O)(=O)N3CCN(c4ccc(F)cc4C(F)(F)F)C[C@H]3C)c2)CC1
Yield: 91.3 %

Procedure:
To a solution of (2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperazin-1-ylphenyl)sulfonyl]piperazine (120 mg, 0.247 mmol) in MeOH (2 mL) was added CH3CHO (12 mg, 0.27 mmol), HOAc (17.7 μL, 0.3 mmol) and NaBH3CN (8 mg, 0.125 mmol) at room temperature. The resultant mixture was stirred till disappearance of starting material as monitored by LCMS. The solvent was removed. The crude product was purified by SiO2 column eluted with DCM/MeOH to give the desired product as a light yellow solid (116 mg, 100%). HRMS: calcd for C24H30F4N4O2S+H+, 515.20983. found (ESI-FTMS, [M+H]1+), 515.20891.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH2:23][CH:24]([O:30][CH:31]([CH3:33])[CH3:32])[C:25]([O:27]CC)=[O:26])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH:31]([O:30][CH:24]([CH2:23][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([CH2:14][NH:13][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:12][CH:11]=2)[CH:16]=1)[C:25]([OH:27])=[O:26])([CH3:33])[CH3:32]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Reactant: CC(C)c1ccc(C(=O)O)cc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(C(C)C)cc1

Procedure:
Using 4-isopropylbenzoic acid and ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-(3-[(4-isopropylbenzoyl)amino]methyl-4-methoxyphenyl)propanoic acid was obtained in the same method as in Example 19d) and then in Example 19e).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][O:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:8][C:7]=1C)=[O:5])C.[OH-].[Na+]>O1CCCC1CO>[C:16]([O:15][C:13]([O:12][NH:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1sc(NOC(=O)OC(C)(C)C)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: CC(C)(C)OC(=O)ONc1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred solution of ethyl-2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate (1.1 g, 4.2 mmol) in tetrahydrofuran-methanol (80 mL, 1:1) was treated with a 6N aq. NaOH solution (20 mL, 120 mmol). The mixture was stirred at rt for 24 h. Most of THF and methanol were removed by distillation under reduced pressure and the aq. Solution was acidified with 6 N aq. HCl solution (22 mL). The precipitated solid was filtered, washed with water and ether, air dried followed by drying in vacuo to obtain the title acid (940 mg, 96%) as an off-white solid.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([N:51]2[CH2:56][CH2:55][N:54](C(OC(C)(C)C)=O)[CH2:53][CH2:52]2)[CH:9]=[CH:10][C:11]=1[N:12](C(OC(C)(C)C)=O)[C:13]1[CH:18]=[C:17]([N:19]([CH3:43])[C:20]([N:22]([C:31]2[C:36]([Cl:37])=[C:35]([O:38][CH3:39])[CH:34]=[C:33]([O:40][CH3:41])[C:32]=2[Cl:42])COCC[Si](C)(C)C)=[O:21])[N:16]=[CH:15][N:14]=1)(=[O:4])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>C(Cl)Cl>[Cl:37][C:36]1[C:35]([O:38][CH3:39])=[CH:34][C:33]([O:40][CH3:41])=[C:32]([Cl:42])[C:31]=1[NH:22][C:20](=[O:21])[N:19]([C:17]1[N:16]=[CH:15][N:14]=[C:13]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([N:51]3[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]3)=[CH:7][C:6]=2[NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH:18]=1)[CH3:43]
Reactant: C=CC(=O)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N(C(=O)OC(C)(C)C)c1cc(N(C)C(=O)N(COCC[Si](C)(C)C)c2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(N2CCNCC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.2 %

Procedure:
tert-butyl 4-(3-acrylamido-4-((tert-butoxycarbonyl)(6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)ureido)pyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (59 g, 0.06 mmol) was stirred in DCM (2.0 ml). TFA (97 μl, 1.3 mmol) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated. The remaining residue was dissolved in DCM and washed with saturated NaHCO3, dried over MgSO4 and evaporated. The resulting material was dissolved in THF (2.0 ml) and NH4OH (74 μl, 1.9 mmol) was added. The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was evaporated to obtain the title compound (34 mg, yield: 90%) which was taken to the next step without further purification. 1H-NMR (400 MHz, DMSO-d) δ 2.62 (br. s., 4H) 3.08-3.27 (m, 7H) 3.77-4.03 (m, 6H) 5.72 (d, 1H) 6.11-6.34 (m, 2H) 6.40-6.62 (m, 1H) 6.70-6.98 (m, 2H) 7.22-7.37 (m, 2H) 8.32 (s, 1H) 8.70 (s, 1H) 9.58 (br. s., 1H) 12.06 (s, 1H); ESI-MS: 601 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH:9](Br)Br)[N:3]=1.C(=O)([O-])[O-:13].[Ca+2].O>CS(C)=O>[Br:1][C:2]1[N:3]=[C:4]([CH:9]=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C(Br)Br)nc1Br
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(F)c(Br)n1
Temperature: 150 °C
Reaction time: 15.5 h
Yield: 66.5 %

Procedure:
After a solution of 2-bromo-6-(dibromomethyl)-3-fluoropyridine (615 mg) and calcium carbonate (391 mg) in dimethylsulfoxide (6.5 mL) was stirred while heating at 150° C. for 4.5 hr, the reaction mixture was reverted to room temperature and stirred for 15.5 hr. After water was added thereto, the mixtue was stirred and then extracted with ethyl acetate. The organic phase was washed with water and brine, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=98:2-82:18) to afford the title compound (240 mg).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[C:16]1[CH2:27][CH2:28][CH2:29][CH3:30].C(OCC)C>ClCCl>[NH2:26][C:19]1[C:18]2[N:17]=[C:16]([CH2:27][CH2:28][CH2:29][CH3:30])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCN
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Phenylisocyanate (0.056 mL, 0.5 mmol) was added to a chilled solution of of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane (150 mL). The ice bath was removed. A white precipitate formed after 5 minutes. The reaction mixture was allowed to stir for 30 minutes and then it was concentrated under reduced pressure to provide an off-white crystalline solid. This material was isolated by filtration using a small amount of diethyl ether to transfer the material to the filter and then dried in an Abderhalden drying apparatus to provide 185 mg of N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N′-phenylurea, m.p. 195.8-196.8° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:32](=[O:33])[NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Product: O=C(Nc1ccccc1)N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1

Procedure:
200 mg (0.551 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted with 85 mg (0.716 mmol) of phenyl isocyanate in analogy to Example 16a. The title compound ##STR97## is obtained as white foam (160 mg, 60%). TLC: toluene/ethyl acetate (1:1) Rf =0.40, FD-MS: M+ =481, 483; IR: 1600-1690 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:24]1([CH:30]=[CH:31][C:32](Cl)=[O:33])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.O>C(#N)C>[CH:24]1([CH:30]=[CH:31][C:32]([NH:17][CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:33])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)C=CC1CCCCC1
Reactant: NCCc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(C=CC1CCCCC1)NCCc1cccc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
To a solution of 2-[3-benzyloxyphenyl]ethylamine (2.3 g) (prepared in a manner analogous to that described in Example 1E) in acetonitrile (25 cm3) was added powdered potassium carbonate (2.1 g) followed by 3-cyclohexylpropenoyl chloride (1.72 g) in acetonitrile (10 cm3) which was added over ten minutes. The resulting mixture was stirred for one hour and was then treated with water (40 cm3) and SVM (3 cm3) thereby causing the precipitation of an oil which solidified to give a pale tan solid after several minutes. This solid was filtered off, washed with 5% SVM in water and sucked dry. Yield=3.08 g m.p. 98°-100° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22])=[CH2:18].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:2]1([CH2:1][N:8]2[CH2:12][CH2:18][CH:17]([C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[C:21]#[N:22])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1C#N
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.21 h
Yield: 57.6 %

Procedure:
A solution of N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (16.62 g, 70.0 mmol) in dichloromethane (15 mL) are added dropwise, over a 45-minute period, to a solution of 2-ethenylbenzonitrile (6.00 g, 46.0 mmol) and trifluoroacetic acid (0.57 g, 5.0 mmol) in dichloromethane (55 mL). The resulting solution was stirred at room temperature for an additional 10 to 15 minutes, and then heated with saturated aqueous sodium bicarbonate solution (ca 10-15 mL). The organic layer was decanted, washed with water, and dried over anhydrous magnesium sulfate. Filtration and concentration of the solution provided an orange oil which was chromatographed (silica-gel, hexanes-ethyl acetate 5:1) to afford the title compound (6.95 g, 58%) as a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[Cl:36][C:37]([Cl:47])([O:39][C:40](=O)[O:41]C(Cl)(Cl)Cl)[Cl:38]>ClCCl>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][NH:2][C:40](=[O:41])[O:39][C:37]([Cl:47])([Cl:38])[Cl:36])=[C:7]([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH:8]=1)=[O:22]
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OC(Cl)(Cl)Cl)c(-c3ccnn3C)c2)c1

Procedure:
N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (80.0 mg, 198 μmol), triethylamine (277 μl, 10 eq) and triphosgene (64.8 mg, 1.1 eq) were dissolved in 5 mL of dichloromethane and stirred under reflux for 5 mins. The solvent was removed under vacuum and 4 mL of ethyl acetate was added. It was divided in two and used immediately in the preparation of compound 5 and 7 without purification. LCMS m/z (%)=528 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[C:8]([OH:10])=[O:9].[CH2:11](OS(OCC)(=O)=O)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:7][C:4]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([Cl:1])[S:6][N:5]=1
Reactant: O=C(O)c1c(Cl)nsc1Cl
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(Cl)nsc1Cl
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
Into a 500-mL round-bottom flask, was placed dichloro-1,2-thiazole-4-carboxylic acid (10 g, 50.50 mmol, 1.00 equiv), acetone (100 mL). This was followed by the addition of EtOSO3Et (19.54 g) dropwise with stirring at 0° C. in 3 min. To this was added potassium carbonate (28.02 g, 202.73 mmol, 4.01 equiv). The resulting solution was stirred for 30 min at 58° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of H2O. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (12:88). This resulted in 1.353 g (12%) of ethyl 3,5-dichloro-1,2-thiazole-4-carboxylate as yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:10])[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C(O)(=O)C[C:28](CC(O)=O)([C:30](O)=[O:31])[OH:29]>C(O)CO.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:3]2[C:4]([NH:8][S:9]([CH2:12][CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)(=[O:11])=[O:10])=[N:5][CH:6]=[N:7][C:2]=2[O:29][CH2:28][CH2:30][OH:31])=[CH:20][CH:21]=1
Reactant: O=S(=O)(CCc1cccs1)Nc1ncnc(Cl)c1-c1ccc(Cl)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: OCCO
Solvent: O
Product: O=S(=O)(CCc1cccs1)Nc1ncnc(OCCO)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
2-Thiophen-2-yl-ethanesulfonic acid [6-chloro-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide (930 mg) was added to a solution of K-tert. butylate (1.16 g) in ethylene glycol (10 ml). The mixture was stirred at 110° C. for 12 h before it was diluted with water (150 ml), acidified with 10% aq. citric acid (13 ml). The resulting precipitate was collected, washed with water and diethyl ether and dried to give (820 mg) 2-thiophen-2-yl-ethanesulfonic acid [5-(4-chloro-phenyl)-6-(2-hydroxy-ethoxy) -pyrimidin-4-yl]-amide as a beige powder. LC-MS: tR=4.43 min, [M+1]+=440.01, [M−1]−=437.99.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:9][CH2:10]2)=[CH:6][C:5]=1[CH:19]=[O:20].O>C(O)C>[OH:20][CH2:19][C:5]1[CH:6]=[C:7]2[C:11]([CH2:10][CH2:9][CH:8]2[CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[CH:12][C:4]=1[OH:3]
Reactant: O=Cc1cc2c(cc1O)CCC2Cc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1cc2c(cc1O)CCC2Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (10 mg) is added into a solution of 6-hydroxy-3-(1H-imidazol-4-ylmethyl)-indan-5-carbaldehyde (58 mg) in ethanol (10 ml). The mixture is stirred at room temperature for one hour and then poured into water. Work-up of the mixture gives the crude product which is purified by flash chromatography and recrystallized from ethyl acetate.
Reaction SMILES: NC1C(OC)=CC2C(=O)N(C)CCCC=2C=1.[NH2:17][C:18]1[C:23]2[C:24](=[O:30])[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][C:22]=2[CH:21]=[CH:20][C:19]=1[O:31][CH3:32].Cl.COCCO.Cl[C:40]1[N:45]=[C:44]([NH:46][C:47]2[CH:56]=[CH:55][CH:54]=[CH:53][C:48]=2[C:49]([NH:51][CH3:52])=[O:50])[C:43]([Cl:57])=[CH:42][N:41]=1>O1CCOCC1>[Cl:57][C:43]1[C:44]([NH:46][C:47]2[CH:56]=[CH:55][CH:54]=[CH:53][C:48]=2[C:49]([NH:51][CH3:52])=[O:50])=[N:45][C:40]([NH:17][C:18]2[C:23]3[C:24](=[O:30])[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][C:22]=3[CH:21]=[CH:20][C:19]=2[O:31][CH3:32])=[N:41][CH:42]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1ccc2c(c1N)C(=O)N(C)CCC2
Agent: COc1cc2c(cc1N)CCCN(C)C2=O
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2c(OC)ccc3c2C(=O)N(C)CCC3)ncc1Cl
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
7-Amino-8-methoxy-2-methyl-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (110 mg, 0.50 mmol) and 9-Amino-8-methoxy-2-methyl-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (prepared following the procedure of 7c) were added as an unseparated mixture with 4 M of Hydrogen chloride in 1,4-Dioxane (300 uL), 2-Methoxyethanol (10 mL, 100 mmol), and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (2 eq) charged into Radley tube. Heat 110° C. for about 3 hours, cooled to room temperature. Solid precipitated out and was filtered. This material was dissolved in dichloromethane/MeOH and treated with 3 eq. of MP-carbonate, stirred 30 min, filtered and concentrated to give 2-[5-Chloro-2-(8-methoxy-2-methyl-1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-9-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as an orange solid (51 mgs, 21%). Melting point: 185-187° C. 1H-NMR (DMSO, 400 MHz): 8.67 (broad m, 1H), 8.67 (s, 1H), 8.47 (broad s, 1H), 8.00 (d, J=7.0 Hz, 1H), 7.47-7.43 (m, 1H), 708-7.03 (m, 2H), 6.82 (d, J=7.8 Hz, 1H), 3.81 (s, 3H), 3.17-3.07 (m, 2H), 2.85 (s, 3H), 2.69-2.65 (m, 2H) 2.50 (s, 3H), 1.78-1.71 (m, 2H); LC/MS: 481.37 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]([O:20][CH3:21])[C:11]=1[CH2:22][CH:23]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:26]([NH:25][CH2:23][CH2:22][C:11]1[C:12]([O:20][CH3:21])=[N:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=1[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CCNC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
A mixture of [4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxy-6-(trifluoromethyl)pyridin-3-yl]acetaldehyde (1.55 g, 4.26 mmol), aminodiphenylmethane (1.11 mL, 6.40 mmol), and powdered molecular sieves (4 Å, 2.80 g) in DCM (20 mL) was stirred for 30 min. Then sodium triacetoxyborohydride (132 mg, 0.625 mmol) was added. The resulting mixture was stirred overnight, diluted with DCM, filtered, and washed with sat. aq. Na2CO3. The layers were separated, and the aq. solution was extracted with DCM. The combined DCM layers were dried over Na2SO4, and evaporated. The residue was purified by column chromatography (silica gel, 100% DCM) to yield N-benzhydryl-2-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methoxy-6-(trifluoromethyl)pyridin-3-yl]ethanamine (1.42 g, 62.8%). 1H NMR (CDCl3, 400 MHz): δ 7.48 (s, 1H), 7.18-7.38 (m, 10H), 4.84 (s, 1H), 4.78 (s, 2H), 3.81 (s, 3H), 2.77 (m, 4H), 1.62 (br s, 1H), 0.97 (s, 9H), 0.12 (s, 6H). LC-MS calc. for C29H37F3N2O2Si: 530.26; Found: 531 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18](O)(=[O:22])[C:19]([CH3:21])=[CH2:20]>>[C:18]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: C=C(C)C(=O)O
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Product: C=C(C)C(=O)CCCCCCOc1ccc(C(=O)O)cc1

Procedure:
A solution of 4-(6-hydroxyhexyloxy)benzoic acid (24.0 g, 0.10 mol, prepared as described in Example 3) was treated with methacrylic acid as described above to give 4-(6-methacryloylhexyloxy)benzoic acid after recrystallization from tetrahydrofuran-hexane (1:2) (19.9 g, 67%): mp 81°-94° C., nematic mesophase; NMR (CDCl3) 9.82(bs, 1H), 8.0(d, 2H), 6.87(d, 2H), 6.05(s, 1H), 4.15(t, 2H), 4.0(t, 2H), 1.9(s, 3H), 1.85(m, 8H).