Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](OCC)=[O:19])[CH:8]=1)=[O:5].[CH2:34]([CH2:36][NH2:37])[OH:35].C(N(CC)C(C)C)(C)C>CO>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([NH:37][CH2:36][CH2:34][OH:35])=[O:19])[CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Reactant: NCCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCO)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Yield: 41.7 %

Procedure:
Ethyl 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Example 113, 40 mg, 0.09 mmol), ethanolamine (15.7 mg, 0.26 mmol) and N,N-diisopropylethylamine (33.3 mg, 0.26 mmol) in methanol (1 mL) was heated at 50° C. in a sealed vial for 17 hours. The reaction was cooled and purified using reverse phase column chromatography eluting with 3-50% MeCN in water with 0.1% ammonia to afford the title compound as a white solid (18 mg, 44%).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+].O.Cl>CO>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:5]([CH3:6])[C:4]([OH:23])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Cc2ccc(Cl)cc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(Oc1ccc(Cc2ccc(Cl)cc2Cl)cc1)C(=O)O

Procedure:
17.5 g of 2-[p-(2,4-dichlorobenzyl)-phenoxi]-propionic acid ethyl ester were refluxed for 2 hours with a solution of 2.5 g of caustic soda in 100 ml of methanol. After cooling, 100 ml of water were added and the mixture was acidified with 2n hydrochloric acid. The propionic acid liberated precipitated in the form of a colorless oil which, on cooling in icewater, solidified to become a colorless wax-like mass. The yield is 15.3 g. ##STR11##
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH3:27][CH:28]([NH2:32])[CH2:29][O:30][CH3:31]>>[CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](=[O:24])[NH:32][CH:28]([CH3:27])[CH2:29][O:30][CH3:31])=[CH:20][N:19]=3)=[O:17])[CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: COCC(C)N
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(C)COC)cn2)CC1
Yield: 82 %

Procedure:
By the same procedure as described in the example 24, the synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2-methoxyisopropylamine. And then, the product was recrystallized with isopropanol and hexane to give a desired compound.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C:10](=[O:11])[C@H:9]([NH:7][CH3:6])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N1CCc2ccccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 46.3 %

Procedure:
N-((1R)-2-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamic acid tert-butyl ester (6.12 g, 13.8 mmol) was dissolved in dichloromethane (40 ml). The solution was cooled to 0° C. Trifluoroacetic acid (40 ml) was added. The reaction mixture was stirred for 90 min at 0° C. Dichloromethane (110 ml) and a saturated aqueous solution of sodium hydrogen carbonate (150 ml) were added successively. Solid sodium hydrogen carbonate was added until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×60 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (130 g), using dichloromethane/methanol/25% aqueous ammonia 100:10:1 as eluent, to give 2.20 g of (2R)-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(methylamino)-3-(2-naphthyl)-1-propanone.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)[OH:5].[Cl:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][NH:22][C:23]([C:25]2[C:26](=[O:37])[C:27]3[CH:34]=[C:33]([CH2:35]Cl)[O:32][C:28]=3[N:29]([CH3:31])[CH:30]=2)=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][NH:22][C:23]([C:25]2[C:26](=[O:37])[C:27]3[CH:34]=[C:33]([CH2:35][N:2]([CH2:3][CH:4]([OH:5])[C:6]4[CH:15]=[CH:14][C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:7]=4)[CH3:1])[O:32][C:28]=3[N:29]([CH3:31])[CH:30]=2)=[O:24])=[CH:19][CH:18]=1
Reactant: CNCC(O)c1ccc2ccccc2n1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccc2ccccc2n1
Temperature: 90 °C
Yield: 48.6 %

Procedure:
N,N-biisopropylethylamine (0.11 mL) and rac-2-(methylamino)-1-quinolin-2-ylethanol (Preparation 47, 0.125 g) were added to a suspension of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The reaction mixture was allowed to cool to room temperature, poured into water (25 mL), and was extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2, 97/3, 9515). The product was then recrystallized from ethyl acetate and then methanol to yield 0.106 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 154-159° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.64, 8.48, 8.29-8.27, 7.94-7.87, 7.70-7.66, 7.62-7.60, 7.57-7.52, 7.41-7.33, 6.85, 5.53, 4.95-4.91, 4.55, 3.74, 3.74-3.72, 2.89-2.85, 2.79-2.74, 2.36; MS (ESI+) m/z 531 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1([C:21]([NH2:23])=[O:22])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=2)[CH2:10]1.CO[C:26](OC)(OC)[CH2:27][CH2:28][CH3:29]>C1(C)C=CC=CC=1>[N+:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]1([C:21](=[O:22])[NH:23][C:26]([CH2:27][CH2:28][CH3:29])=[N:8]1)[CH2:17]2)([O-:20])=[O:19]
Reactant: CCCC(OC)(OC)OC
Reactant: NC(=O)C1(N)Cc2ccc([N+](=O)[O-])cc2C1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1=NC2(Cc3ccc([N+](=O)[O-])cc3C2)C(=O)N1

Procedure:
A solution of (±)-2-amino-5-nitroindane-2-carboxamide, trifluoroacetate salt (described in Intermediate 3, 25.0 mg, 0.075 mmol) and 1,1,1-trimethoxybutane (0.060 mL, 0.373 mmol) in toluene (5 mL) was heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound. MS: m/z=274 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[CH:9]=1.C1C(=O)N([I:46])C(=O)C1>CC#N>[CH3:36][Si:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][O:30][CH2:29][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:37])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:46])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)C1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-1-carboxylate 3.95 g, 7.0 mmol) in CH3CN (30 mL) was added NIS (1.65 mg, 7.0 mmol). The mixture was stirred at rt for 2 h and diluted with EtOAC (50 mL) and washed with saturated sodium thiosulfate, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Biotage (CH2Cl2/EtOAc, 100:1 to 10:1) to the title compound as a light brown oil. LC/MS RT=2.49 min. Mass calculated for, M+H 689.23, observed 389.17.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20][CH2:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]([N:20]([CH2:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:19])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1cc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1cc2ccccc2[nH]1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (17.10 g, 68.6 mmole) was added to a solution of 2-(methylaminomethyl)-1H-indole (10.00 g, 62.4 mmole), from Preparation 33, and triethylamine (9.60 mL, 68.6 mmole) in DMF (100 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the mixture was extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated. Flash chromatography on silica gel (20% ethyl acetate/hexanes) gave the title compound (14.80 g, 80%) as an off-white solid: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: Cl[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:3]1[C:8]([Cl:9])=[CH:7][C:6]([N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]=[N:11]2)=[CH:5][C:4]=1[Cl:18].[N:26]1[CH:31]=[CH:30][CH:29]=[N:28][C:27]=1[NH2:32]>C(Cl)Cl>[Cl:18][C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]=[N:11]2)[CH:7]=[C:8]([Cl:9])[C:3]=1[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[NH:32][C:27]1[N:28]=[CH:29][CH:30]=[CH:31][N:26]=1
Reactant: Nc1ncccn1
Reactant: O=c1cnn(-c2cc(Cl)c(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Solvent: ClCCl
Product: O=c1cnn(-c2cc(Cl)c(C(Nc3ncccn3)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Temperature: 150 °C
Yield: 6.1 %

Procedure:
A mixture of 2-[4-[chloro(4-chlorophenyl)methyl]-3,5-dichlorophenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.00719 mol) and 2-pyrimidinamine (0.00863 mol) was heated for 2 hours at 150° C. in an autoclave. The mixture was cooled to RT. This fraction was taken up into CH2Cl2, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by HPLC (eluent: (0.5% NH4OAc in H2O)/CH3OH/CH3CN gradient elution from 70/15/15 over 0/50/50 to 0/0/100). The desired fractions were collected and the solvent was evaporated. The residue was coevaporated with EtOAc. The residue was stirred in DIPE, filtered off, washed and dried, yielding 0.21 g of (±)-2-[3,5-dichloro-4-[(4-chlorophenyl)[(2-pyrimidinyl)amino]-methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (comp. 413).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](O)[CH2:3][CH2:2]1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH2:2]1
Reactant: OC1CCOc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C1=Cc2ccccc2OC1
Yield: 764.2 %

Procedure:
A mixture of 4-chromanol (30 g; 0.02 mole), benzene (200 ml) and 4-toluenesulfonic acid (200 mg) was refluxed, with a Dean-Stark trap, until separation of water ceased (ca. 3 hrs.). It was then washed successively with saturated NaHCO3 aqueous solution and water, dried over anhydrous MgSO4 and evaporated under reduced pressure to yield an almost colorless liquid which was distilled under vacuum to give benzopyran (20.2 g, 76.4%) b.p. 73°-78°/3 torr.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:32])=[CH:14][CH:15]=2)[N:10]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:24][C@@H:21]1[CH2:22][CH2:23][N:19]([C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH3:32])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[OH:8])[N:18]=2)[CH2:20]1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3c(O)cccc3F)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (500 mg, 1.14 mmol) in CH2Cl2 (15 mL) was added TFA (5 mL). The mixture was stirred for 1 h and then neutralized with a 1 M NaOH solution, and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 3-20% EtOAc/CH2Cl2 gave 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol. LC/MS: m/z 339.5 (M+H)+ at 0.56 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:31])[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]COC)=[C:19]([O:27]COC)[CH:18]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([NH:11][C:12](=[O:31])[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:27])[CH:18]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: COCOc1ccc(C=CC=CC(=O)NC/C=C(\C)CCC=C(C)C)cc1OCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)=CCC/C(C)=C/CNC(=O)C=CC=Cc1ccc(O)c(O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a solution of 1.96 g of 5-(3',4'-dimethoxymethoxyphenyl)pentadienoic acid geranylamide in 40 ml of methanol is added 0.09 g of p-toluenesulfonic acid monohydrate. The mixture is stirred at 50° C. for 3 hours. The reaction mixture is poured onto water and extracted with chloroform. The organic layer is washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (99:1) is obtained 1.40 g of 5-(3',4'-dihydroxyphenyl)pentadienoic acid geranylamide (15). Spectroscopic data of the product support the structure of the formula (15) below.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18]Cl>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: COCCOCCl
Product: CCOc1cc(C=O)ccc1OCOCCOC
Yield: 91.5 %

Procedure:
The hydroxyl group of 3-ethoxy-4-hydroxybenzaldehyde (2.0 g) was protected by use of 2-methoxyethoxymethyl chloride (1.5 g) in accordance with (production process 1), to thereby produce 3-ethoxy-4-methoxyethoxymethoxybenzaldehyde (2.8 g, yield: 91%). The thus-produced 3-ethoxy-4-methoxyethoxymethoxybenzaldehyde (2.8 g) and 3,4-dimethoxybenzyl cyanide (2.0 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.35 g, yield: 37%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]([CH2:27]C)[CH2:25][CH3:26]>>[CH3:23][CH:24]([CH3:27])[CH2:25][CH2:26][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CCC(CC)CBr
Product: CC(C)CCN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 132 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-(bromomethyl)pentane and conditions outlined in procedure V. M.p.=143-146° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.9 (d, 1H), 7.75 (d, 2H), 7.55 (m, 1H), 3.05 (s, 2H), 2.7 (d, 2H), 2.35-2.2 (m, 4H), 1.95 (d, 2H), 1.8-1.7 (d, 2H), 1.6-1.5 (m, 1H), 1.35-1.25 (m, 2H), 0.9-0.8 (m, 6H); LCMS: 372 [M+H].
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][CH2:8][C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][NH:14][C:13](=O)[CH2:12][CH2:11][CH2:10]1.B.C1COCC1.CO.Cl>C1COCC1>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][CH2:8][C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: O=C1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CCN1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCCNCC2)cc(C(F)(F)F)c1
Temperature: 65 °C

Procedure:
To a solution of 6-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-6-phenylazocan-2-one (18 mg, step H) in THF (0.10 mL) at room temperature was added borane-THF complex (1.50 M solution in THF, 0.10 mL) and the resulting solution was heated at 65° C. in a sealed vial for 3 h. The solution was cooled to room temperature, and methanol (0.10 mL) was added slowly followed by 1N hydrochloric acid (0.10 mL), and the reaction mixture was heated at 65° C. for 2 h. The solvents were removed in vacuo, dichloromethane and 1N sodium hydroxide were added, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound as an oil. 1H NMR (400 MHz, CDCl3) δ 1.58 (5H, m), 2.09 (3H, m), 2.30 (1H, m), 2.94 (4H, m), 3.44 (1H, d, J=8.8 Hz), 3.47 (1H, d, J=8.8 Hz), 4.42 (2H, s), 7.21 (1H, m), 7.37 (4H, m), 7.55 (2H, s), and 7.73 (1H, s). HPLC retention time (1.88 min, column: 4.6×50 mm XTERRA C18 S5, flow rate: 5 mL/min, gradient: 0-100% MeOH/H2O 0.1% TFA over 2 min). MS: 446 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][C:12]1[C:20]2[N:19]=[C:18]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:17]([CH2:30][CH2:31][CH2:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[C:45]1([CH2:51][CH2:52][CH2:53]Br)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C)C=O>[CH:8]([O:11][C:12]1[C:20]2[N:19]=[C:18]([CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:17]([CH2:30][CH2:31][CH2:32][CH:33]3[CH2:34][CH2:35][N:36]([CH2:53][CH2:52][CH2:51][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:37][CH2:38]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: CC(C)Oc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(CCCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-isopropoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate (0.29 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by column chromatography to yield the title product as a white crystalline solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]1[CH:27]=[CH:28][C:29](B(O)O)=[N:30][CH:31]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][N:30]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: OB(O)c1ccc(F)cn1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(F)cn1
Yield: 3.6 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 5-fluoropyridine-2-boronic acid (available from Combi-Blocks Inc.; 71 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(5-fluoro-pyridin-2-yl)-benzoic acid (4 mg, 4%). LCMS analysis indicated that the material was ˜100% pure, as measured by UV at 214 nm. LRMS m/z 444.8 (M+H+).
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]([NH2:21])([CH3:20])[CH3:19])=[N:14][CH:15]=2)[CH:7]=[CH:6][N:5]=1)=O.[NH2:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1>>[NH2:21][C:18]([CH3:20])([CH3:19])[C:17]#[C:16][C:13]1[N:14]=[CH:15][C:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([NH:22][CH:23]3[CH2:24][C:25]([CH3:32])([CH3:31])[NH:26][C:27]([CH3:30])([CH3:29])[CH2:28]3)[N:9]=2)=[CH:11][CH:12]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CS(=O)c1nccc(-c2ccc(C#CC(C)(C)N)nc2)n1
Product: CC(C)(N)C#Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cn1

Procedure:
3-[5-(2-Methanesulfinyl-pyrimidin-4-yl)-pyridin-2-yl]-1,1-dimethyl-prop-2-ynylamine (500 mg, 1.76 mmol) and 4-amino-2,2,6,6-tetramethylpiperidine (0.61 ml, 3.54 mmol) were heated to 120° C. for 1 hour and the reaction mixture purified directly by chromatography on silicagel (TBME/MeOH/ammonia:95/4.5/0.5) to give the title compound as yellow crystals.