Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29]CC4C=CC=CC=4)[C:24]=3[O:37]CC3C=CC=CC=3)[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4].[H][H].OC1C(O)=CC=CC=1CCCCCCOC1C2C(=CC=CC=2)C=CC=1[C@H](C)C(O)=O>[Pd].C(OCC)(=O)C>[OH:37][C:24]1[C:25]([OH:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([C@H:2]([CH3:1])[C:3]([OH:5])=[O:4])[CH:15]=[CH:14]2
Reactant: C[C@H](C(=O)O)c1ccc2cc(OCCCCCCc3cccc(OCc4ccccc4)c3OCc3ccccc3)ccc2c1
Reactant: [H][H]
Agent: [Pd]
Agent: C[C@H](C(=O)O)c1ccc2ccccc2c1OCCCCCCc1cccc(O)c1O
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)O)c1ccc2cc(OCCCCCCc3cccc(O)c3O)ccc2c1
Yield: 85 %

Procedure:
A mixture of 4.9 g (8.3 mmol) of (S)-alpha-methyl-6-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-2-naphthaleneacetic acid and 0.5 g of 10% palladium on carbon in 100 mL of ethyl acetate was shaken in a hydrogen atmosphere for 22 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated at reduced pressure to an oil which was crystallized from ether-hexane to give 2.9 g (85% yield), mp 136°-139°, of (S)-[6-(2,3-dihydroxyphenyl)hexyloxy]-alpha-methyl-2-naphthaleneacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.Cl.[CH3:30][NH:31][CH2:32][CH2:33]N>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[N:31]([CH3:30])[CH2:32][CH2:33][N:28]=3)=[CH:25][CH:26]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: CNCCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc(C3=NCCN3C)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a lotion of the compound of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-methylphenyl}(4-cyanophenyl)carboxamide (830 mg, 2.1 mmol) in anhydrous methanol (5 ml) and ethyl acetate (10 ml) was saturated with hydrogen chloride gas at 0° C. The mixture was stirred at r.t. overnight. After the evaporated the solvent, the residue was dissolved in anhydrous methanol (5 ml) and N-methylethylenediamine (0.926 ml, 10.5 mmol) was added. The mixture was stirred under reflux condition for 2 hrs. After the evaporation of solvent, the crude residue was purified by RP-HPLC to give N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-methylphenyl}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamide as a white powder. MS found for C24H22ClN5O2 M+=448, (M+2)+=450.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH2:14][CH:15]([CH2:17][NH2:18])[O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH2:14][CH:15]([CH2:17][NH:18][C:29](=[O:30])[O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(-c2cccc3c2CC(CN)O3)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cccc3c2CC(CNC(=O)OCc2ccccc2)O3)cc1
Yield: 89.9 %

Procedure:
Treatment of (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.94 g, 7.03 mmol) with diisopropylethylamine (1.36 g, 10.55 mmol) followed by benzyl chloroformate (1.32 g, 7.74 mmol) generally according to the procedure described for Intermediate 12 provided 2.36 g (90%) of (±)-benzyl {[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. mp 134-136° C.; Anal. calcd. for C24H23NO3: C, 77.19; H, 6.21; N, 3.75. Found: C, 77.08; H, 6.3; N, 3.69.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([CH:10](C(OCC)=O)[C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[Na+].CCOC(C)=O.Cl>CO>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C#N)c(Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(CC(=O)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
To compound 1F (2.3 g, 7.4 mmol) in 20 mL of MeOH was added 1N NaOH solution (30 mL, 30 mmol), and stirred at RT for 5 hr. It was concentracted, EtOAc was added, then acidified with conc. HCl. The biphase solution was heated at 60° C. for 2 hr, and cooled to RT. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give the title compound (1.44 g). MS (ES) m/z 164 [M-CO2H]−.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:10]1[CH2:15][CH:14]([C:16](OCC)=[O:17])[CH:13]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=3)=[CH:23][C:22]=2[OH:36])[CH2:12][CH2:11]1)[CH2:8][CH3:9]>C1COCC1>[F:33][C:31]1[CH:32]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:13]3[CH2:12][CH2:11][CH:10]([CH2:7][CH2:8][CH3:9])[CH2:15][CH:14]3[CH2:16][OH:17])=[C:22]([OH:36])[CH:23]=2)[CH:28]=[C:29]([F:35])[C:30]=1[F:34]
Reactant: CCCC1CCC(c2ccc(-c3cc(F)c(F)c(F)c3)cc2O)C(C(=O)OCC)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC1CCC(c2ccc(-c3cc(F)c(F)c(F)c3)cc2O)C(CO)C1
Reaction time: 3 h

Procedure:
903 mg (23.8 mmol) of lithium aluminium hydride are initially introduced in 20 ml of THF, and a solution of 10 g (23.8 mmol) of ethyl 5-propyl-2-(3′,4′,5′-trifluoro-3-hydroxybiphenyl-4-yl)cyclohexanecarboxylate in 50 ml of THF is added dropwise with ice-cooling. The cooling is removed, and the batch is stirred at room temp. for 3 h, refluxed for 1 h and added to ice. After acidification using 2M sulfuric acid, the mixture is extracted three times with MTB ether, the combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is purified by chromatography on silica gel. The 3′,4′,5′-trifluoro-4-(2-hydroxymethyl-4-propylcyclohexyl)biphenyl-3-ol obtained is dissolved in 100 ml of THF, 6.24 g (23.8 mmol) of triphenylphosphine are added, and a solution of 5.3 g (26.2 mmol) of diisopropyl azodicarboxylate in 50 ml of THF is added dropwise with ice-cooling. The cooling is removed, and the batch is stirred at room temp. overnight. After addition of water, the organic phase is separated off, and the aqueous phase is extracted three times with MTB ether. The combined org. phases are washed with water and saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue is purified by chromatography on silica gel, giving 8-propyl-3-(3,4,5-trifluorophenyl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene as colourless crystals.
Reaction SMILES: [CH3:1][Si:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][CH:13]([CH2:16][C:17]1[N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:19]=[CH:20][N:21]=1)[CH2:14][OH:15].O[C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[CH3:31][Si:2]([CH3:1])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][CH:13]([CH2:16][C:17]1[N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:19]=[CH:20][N:21]=1)[CH2:14][O:15][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1CC(CO)Cc1nccn1COCC[Si](C)(C)C
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccnc1CC(COc1ccc(C=O)cc1)Cc1nccn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.7 %

Procedure:
To a tetrahydrofuran (2 mL) solution of the compound (120 mg) produced in Example 18 and a 4-hydroxybenzaldehyde (31 mg), triphenylphosphine (81 mg) and diethylazodicarboxylate (175 μL) were added in this order. The reaction solution was stirred at room temperature for 15 hours. To the reaction solution, water (20 mL) was added. The aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layer was washed with saturated sodium chloride solution (50 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=80:20→0:100→ethyl acetate:methanol: 28% aqueous ammonia=100:0:0→80:20:2) to obtain the title compound (85 mg) having the following physical properties.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]1[N:8]=[N:9][CH:10]=[CH:11][CH:12]=1>>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][NH:3][CH2:2][CH2:1][NH2:4])[N:8]=1
Reactant: ClCc1cccnn1
Reactant: NCCN
Product: NCCNCc1cccnn1

Procedure:
Reacting ethylenediamine with 3-chloromethylpyridazine by the procedure of Example 34 gives N-(3-pyridazinylmethyl)ethylenediamine. This intermediate is reacted with S-methylisothiouronium sulphate by the procedure of Example 1 to give the title compound.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+]>O>[CH:11](=[N:5][NH:6][C:7]([NH2:9])=[NH:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Agent: [K+]
Solvent: O
Product: N=C(N)NN=Cc1ccccc1
Temperature: 5 °C

Procedure:
160 g aminoguanidine bicarbonate are suspended in 1.1 1 water and brought into solution by means of 93-100 ml concentrated hydrochloric acid. 124.5 g benzaldehyde added at room temperature and 340 g of 50% strength potassium hydroxide solution are then allowed to run in. In the course thereof, the temperature rises to about 35°. Stirring is continued for a further hour, the mixture is cooled to 5° C. and the precipitate is filtered off and rinsed with 0.5 l water.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]([CH3:38])[C:15](=[O:37])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:33]3[N:32]=[C:31]([CH3:34])[NH:30][C:29]=3[CH:28]=[CH:27][CH:26]=2)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>ClCCl>[C:39]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]([CH3:38])[C:15](=[O:37])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:33]3[N:32]=[C:31]([CH3:34])[NH:30][C:29]=3[CH:28]=[CH:27][CH:26]=2)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=1)(=[O:41])[CH3:40]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCN)ccc1NC(=O)c1cccc2[nH]c(C)nc12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCNC(C)=O)ccc1NC(=O)c1cccc2[nH]c(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of N-[2-(4-aminobut-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-(2-methyl-1H-benzimidazol-4-yl)carbonylaminobenzamide (120 mg) in dichloromethane (10 ml) was added acetic anhydride (23.8 mg) and the mixture was stirred at ambient temperature for 1 hour. The solution was washed with water and brine and dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column (2% methanol in chloroform) and the product was solidified with diethyl ether to give N-[2-(4-acetylaminobut-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-(2-methyl-1H-benzimidazol-4-yl)carbonylaminobenzamide (87 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:30])[CH2:25][CH2:24]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]([O:20]C)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:38]>>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:30])[CH2:25][CH2:24]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18](=[O:20])[NH2:38])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N
Reactant: COC(=O)[C@@H]1CS[C@H]2C[C@@](CC3CCN(C(=O)OCC[Si](C)(C)C)CC3)(NC(=O)OC(C)(C)C)C(=O)N21
Product: CC(C)(C)OC(=O)N[C@]1(CC2CCN(C(=O)OCC[Si](C)(C)C)CC2)C[C@@H]2SC[C@@H](C(N)=O)N2C1=O

Procedure:
340 mg of methyl (3R,6R,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2-trimethylsilanylethoxycarbonyl)piperidin-4-ylmethyl]hexahydropyrrolo[2,1-b]thiazole-3-carboxylate were dissolved at 0° C. in 35 ml of an ammonia-saturated methanol solution. The mixture was allowed to reach room temperature in the course of 4 h, and then the solvents were removed in vacuo. The residue was employed without further purification in the next reaction.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22]>>[N+:5]([CH:4]=[C:3]([NH:8][C:9]#[C:10][CH3:11])[NH:22][CH2:21][CH2:20][S:19][CH2:18][C:17]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:12])([O-:7])=[O:6]
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Reactant: Cc1nc[nH]c1CSCCN
Product: CC#CNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C

Procedure:
A solution of the product of Step A is treated with about an equimolar amount of 2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamine [prepared by the procedure described in U.S. Pat. No. 3,950,353] to produce, after workup and chromatography, the title product.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:10]=[CH:9]2)C=CC=CC=1>O1CCCC1.Cl>[F:25][C:22]([F:23])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccc(OCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(OCCc2c[nH]cn2)cc1

Procedure:
A solution of 640 mg (1.28 mmol) of 1-triphenylmethyl-4-[2-(4-trifluoromethylphenoxy)ethyl]-1H-imidazole in 2 ml of tetrahydrofuran and 5 ml of 2N hydrochloric acid is heated at 70° C. for 2 hours. The tetrahydrofuran is then evaporated under reduced pressure and the residue extracted with diethyl ether. The aqueous solution is basified with potassium carbonate and the white solid is filtered and washed 3 times with water to give the title compound, M.p.: 105°-109° C.
Reaction SMILES: [OH-].[K+].[C:3]1([C:12]([O:14]CC)=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1.Cl>C(O)C>[CH2:10]([O:9][C:7]([C:3]1([C:12]([OH:14])=[O:13])[CH2:4][CH2:5][CH2:6]1)=[O:8])[CH3:11]
Reactant: CCOC(=O)C1(C(=O)OCC)CCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)O)CCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Potassium hydroxide (aq 10% b/w) (152.3 mL, 272 mmol) was added dropwise over 50 minutes to a 0° C. solution of diethyl cyclobutane-1,1-dicarboxylate (49.52 g, 247 mmol) in 95% ethanol (220 mL). Stirring was continued overnight while allowing the ice bath to warm to r. t. LC/MS after 1 hr indicated a 79.4% complete reaction, ca. 86% after overnight. Additional 10% aq KOH was added (0.11 eq, 15.26 mL, total now 1.21 eq) in small portions over 2 minutes, and stirring was continued for 1 hr. LC/MS after 37 min indicated 96% complete reaction. More 10% aq KOH solution was added in small portions over 2 minutes (0.11 eq, 15.26 mL, total now 1.32 eq), and stirring was continued for 37 minutes. LC/MS after 27 min indicated a complete reaction, with minimal formation of the dicarboxylic acid side product (5.5%). The reaction flask was immersed in an ice bath and acidified by the slow addition of 20% HCl, (ca. 220 mL). Most of the ethanol was removed under high vacuum with minimal heat (Bath less than 50° C.). Brine was added (100 mL), followed by 3 extractions with EtOAc (250 mL each). The combined EtOAc layers were washed with 100 mL of brine, dried over Na2SO4, and concentrated under vacuum to yield the title compound as an oil which after standing under vacuum became a white solid. LC/MS: m/e 173.14 (M+H), 195.12 (M+H+ Na), 155.11 (M+H-18, water). This material was used in the next step without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH:20]([C:22]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=O)[CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH:20]([CH2:22][N:24]5[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]5)[CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1)N1CCCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Brc1cccc(Nc2ncnc3sc4c(c23)CCC(CN2CCCCC2)C4)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Anhydrous THF (3 mL) was added to a 50 mL round bottom flask followed by N-(3-bromophenyl)-7-(1-piperidinylcarbonyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine (27, 0.21 mmol, 1equiv). This was cooled to 0° C. in an ice-water bath for 5 min. Diisobutylaluminum hydride, 0.6 mL (DIBAL-H, 0.64 mmol, 1.0M in THF) was added and the reaction was stirred at 0° C. for 30 min before warming to rt for 2 h until reaction was complete by TLC. The reaction mixture was quenched with a satd solution of Rochelle's salt (3 mL) followed by water (3 mL). The reaction was extracted with EtOAc (3×10 mL). The organic layer was dried over anhyd Na2SO4 and concentrated to give a crude oil which was purified via flash column chromatography MeOH/CH2Cl2 1:9 w/0.5% NH4OH to provide the required product, 30, as an oil (70 mg, 72%). 1H-NMR (CD2Cl2-d4) δ 8.36 (s, 1H), 7.94 (t, 1H), 7.50–7.47 (m, 1H), 7.15–7.13 (m, 2H), 7.10 (s, 1H), 2.95–2.91 (m, 3H), 2.29–2.05 (m, 7H), 1.52–1.47 (m, 5H), 1.36 (t, 1H); LCMS RT=2.36 min; [M+H]+=459.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].O>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: FC(F)(F)Oc1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
To a sealed tube was added 2,4-dichloropyrimidine (100 mg, 0.671 mmol), 4-(trifluoromethoxy)phenylboronic acid (138 mg, 0.671 mmol), tetrakis(triphenylphosphine)palladium0) (78 mg, 0.067 mmol), acetonitrile (2 mL) and 2M Na2CO3 in H2O (1.007 mL, 2.014 mmol). Argon was bubbled through the reaction mixture for 1 min. The reaction mixture was then sealed and stirred at 90° C. for 16 hrs. The reaction was cooled to rt and diluted with EtOAc (30 ml). The resulting organic solution was washed with water (30 ml) and saturated aqueous NaCl (30 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-40% EtOAc/Hex to give the product, 2-chloro-4-(4-(trifluoromethoxy)phenyl)pyrimidine, (62 mg, 0.226 mmol, 33.6% yield) as a white solid. Anal. Calcd. for C11H6ClF3N2O m/z 273.9, found: 275.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7](=[N:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH3:8])[CH2:3]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:23][S:24]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7](=[N:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH3:8])[CH2:3]1)(=[O:26])=[O:25]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCC(OS(C)(=O)=O)C1
Reaction time: 0.5 h

Procedure:
To a solution of 32.2 g of 3-hydroxy-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine in 500 ml of methylene chloride, were added, with ice-cooling, 9.3 ml of methanesulphonyl chloride, followed by 16.7 ml of triethylamine. The mixture was stirred for 30 minutes, with ice-cooling, and then water was added, after which the mixture was extracted with methylene chloride and the extract was washed with water and dried, to give 36 g of the title compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][C:33]=3[F:34])[N:30]=[C:29]([C:35]([O:37]CC)=[O:36])[CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][C:33]=3[F:34])[N:30]=[C:29]([C:35]([OH:37])=[O:36])[CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)c(F)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2cc3ccc(C(=O)O)nc3cc2F)cc1
Temperature: 90 °C
Yield: 95.3 %

Procedure:
A 1 N solution of sodium hydroxide (154.6 μL, 154.6 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-7-fluoro-2-quinolinecarboxylate (44.8 mg, 77.3 μmol) in tetrahydrofuran and methanol (1:1, 1.6 mL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (154.6 μL), water added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 40.6 mg (95%) of 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-7-fluoro-2-quinolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.52 (br s, 1H), 8.56 (d, J=9 Hz, 1H), 8.21 (d, J=9 Hz, 1H), 8.09 (d, J=9 Hz, 1H), 7.98 (d, J=12 Hz, 1H), 7.65-7.61 (m, 2H), 7.56 (d, J=9 Hz, 2H), 7.56-7.52 (m, 1H), 6.96 (d, J=9 Hz, 2H), 4.90 (s, 2H), 3.48 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). HRMS C29H21Cl2FN2O4 m/z 551.0941 (M+H)+Cal; 551.0952 (M+H)+Obs.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:34][CH:33]=[CH:32][N:31]=2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.[Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C(C)(C)C)(C)C.CO>ClCCl>[OH:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[C:35]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:34][CH:33]=[CH:32][N:31]=2)[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ncccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)N(CCO)C(=O)c1nc(Cc2ncccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Yield: 85.1 %

Procedure:
5-Benzyloxy-6-hydroxy-2-(3-phenyl-pyridin-2-ylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (166) (140 mg, 85.93%) as a light yellow sticky solid was synthesized from 5-benzyloxy-6-hydroxy-2-(3-phenyl-pyridin-2-ylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (165) (200 mg, 0.33 mmol) following the procedure as described for 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (132). Silica thin layer chromatography was performed (5% methanol in dichloromethane, Rf=0.4).