Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][C:25]=1[F:36])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:6]1[CH2:19][C:20]([O:22]C)=[O:21].[OH-].[Na+].O1CCOCC1>O>[NH2:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][C:25]=1[F:36])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:6]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: COC(=O)CC1CN(CCSc2cccs2)CCC1CCC(N)c1c(F)cnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(C(N)CCC3CCN(CCSc4cccs4)CC3CC(=O)O)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A mixture of 0.355 g of methyl (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate in 1.66-cm3 of a 1 N aqueous sodium hydroxide solution and 5-cm3 of dioxane was heated at a temperature in the region of 60° C., with stirring, for 2 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. The evaporation residue obtained was taken up in 30-cm3 of water and 30-cm3 of diethyl ether, the aqueous phase was separated after settling out and neutralized with 1.66-cm3 of a 1 N aqueous hydrochloric acid solution and was then extracted twice with 100-cm3 of ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and then concentrated to dryness according to the same conditions above. 0.238 g of (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid were obtained in the form of a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([O:15][CH3:16])=[CH:9][CH:10]=[C:11]([CH2:13][OH:14])[CH:12]=1.O1CCCC1.[H-].[Na+].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>O>[F:24][C:25]([F:34])([F:35])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:14][CH2:13][C:11]1[CH:12]=[C:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]([O:15][CH3:16])=[CH:9][CH:10]=1
Reactant: COc1ccc(CO)cc1-c1ncccn1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COCc2cccc(C(F)(F)F)c2)cc1-c1ncccn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet was added 3.24 gm of the 5-pyrimidyl-4-methoxyphenylcarbinol and 70 ml of anhydrous tetrahydrofuran. The system was cooled to 0° C. and after cooling 0.45 gm of sodium hydride was added. The system was stirred for an additional 20 minutes and 2.8 ml of 3-trifluoromethylbenzylchloride added. The system was allowed to come to room temperature and was then heated to reflux for 20 hours at this time, water was added to the system and the product extracted with methylene chloride. The methylene chloride was washed with water and then dried over sodium sulfate. The methylene chloride was removed by stripping to give 4.13 gm of the 5-pyrimidyl-4-methoxyphenylcarbinol 3-trifluoromethylbenzylether as an orange oil and listed as Compound No. 7 in Table I.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[Mg].Br[C:14]1[CH:23]=[CH:22][C:17]2[O:18]CCO[C:16]=2[CH:15]=1>C1COCC1>[O:11]1[C:4]2[CH:9]=[CH:8][C:7]([C:17]3([OH:18])[CH2:22][CH2:23][CH2:14][CH2:15][CH2:16]3)=[CH:6][C:5]=2[O:3][CH2:2][CH2:1]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc2c(c1)OCCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)OCCO3)CCCCC1
Reaction time: 16 h

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (7.8 g, 50 mmole) in 50 ml dry THF was added to a of the Grignard reagent prepared from magnesium metal (1.34 g, 55 mmole) and 6-bromo-1,4-benzodioxane (10.75 g, 50 mmole). The mixture was stirred for 16 hr, quenched with saturated NH4Cl and extracted with ether. The ether extracts were dried with Na2SO4 and the solvent removed in vacuo. Acetone (75 ml) and 1 N HCl (75 ml) were added and the solution was stirred 18 hr to give a tan precipitate which was filtered and air dried (6.38 g, 59.1%). This material was used without further purtification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1F.[CH:10]1([CH:13]([OH:25])[CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1.[H-].[Na+].O>CS(C)=O>[CH:10]1([CH:13]([O:25][C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])[CH2:12][CH2:11]1
Reactant: CN(CCC(O)C1CC1)C(=O)OC(C)(C)C
Reactant: Fc1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(CCC(Oc1cc(Cl)ccc1Cl)C1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.8 %

Procedure:
1,4-Dichloro-2-fluorobenzene (165 mg, 1.00 mmol) and (3-cyclopropyl-3-hydroxypropyl)methylcarbamic acid, 1,1-dimethylethyl ester (230 mg, 1.00 mmol) were dissolved in dimethylsulfoxide (10 ml) under nitrogen at room temperature. To the resulting solution was added sodium hydride (60% in oil) (80 mg, 2.00 mmol). The solution was then allowed to stir at room temperature under nitrogen for 24 h. The mixture was then poured into water and extracted with diethyl ether three times. The combined organic fractions were washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue eluted down a flash chromatography column using 10% ethyl acetate/isohexane as eluent to give 175 mg (47%) of the title compound as an oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:28][OH:29]>C(O)C>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=[N:28][OH:29])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=Cc1ccc(-c2ccc(CN3CCCC3)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1ccc(-c2ccc(CN3CCCC3)cc2)cc1
Yield: 33.7 %

Procedure:
A solution of Example 27 (33.7 mg), sodium carbonate (27.6 mg), and hydroxylamine hydrochloride (18 mg) in ethanol (5 mL) was set to reflux for 16 hours. Inorganic solid was filtered out and washed with DCM and acetone. Organic layer was concentrated under reduced pressure to give the titled compound (12 mg) without purification. 1H NMR (400 MHz, CDCI3)δ8.19 (s, 1 H), 7.82-7.69 (m, 8 H), 4.37 (d, J=6.3, 2 H), 3.35 (m, 2 H), 3.10-3.03 (m, 2 H), 2.06-1.94 (m, 2 H), 1.93-1.88 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([O:13]CC)=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].CO.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cn(C)c(=O)c(C)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cl)c(C(=O)O)cn(C)c1=O
Reaction time: 0.67 h
Yield: 100 %

Procedure:
To a solution of ethyl 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (172 mg, 0.75 mmol) dissolved in a 4:1 mixture of THF:MeOH (5 mL) (v:v), was added a aqueous solution of LiOH (1.52 mmol, 1M). After stirring for 40 min, the reaction mixture was acidified to pH˜1 with HCl(1N, aq) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered and concentrated under the reduced pressure to give an off-white solid as the title compound. (163 mg, 100% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[CH2:25]([NH:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:40])[CH3:39])[CH:7]=[N:6][CH:5]=2)=[N:9][N:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reaction time: 5 h
Yield: 67.8 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-N-benzyl-8-phenylphthalazin-1-amine (60.0 mg, 0.149 mmol) in DCM (20 mL) was added pyridine (0.0241 mL, 0.297 mmol) at room temperature followed by acetyl chloride (0.0106 mL, 0.149 mmol) and stirred at the same temperature for 5 h. The volatile components were removed under reduced pressure and the resulting residue was purified by preparative HPLC (Condition 19 as described in general methods) to yield N-(5-(4-(benzylamino)-5-phenylphthalazin-1-yl)pyridin-3-yl)acetamide (45.0 mg, 67.9%) as a white solid. LCMS (Condition 4): retention time 2.44 min, [M+1]=446.2. HPLC (Condition 28): retention time=6.44 min, purity 97.94%. 1H NMR (400 MHz, DMSO-d6) δ 2.13 (s, 3 H), 4.51 (d, J=4.8 Hz, 2 H), 5.06 (dd, J=4.8 Hz, J=5.2 Hz, 1 H), 7.02-7.04 (m, 2 H), 7.23-7.29 (m, 3 H), 7.42-7.52 (m, 5 H), 7.68 (dd, J=1.6 Hz, J=7.2 Hz, 1 H), 7.85-7.93 (m, 2 H), 8.36 (dd, J=2.0 Hz, J=2.4 Hz, 1 H), 8.52 (d, J=2.0 Hz, 1 H), 8.84 (d, J=2.0 Hz, 1 H), 10.37 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][O:1][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:10][CH:9]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: ClCc1ccccn1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCOCc3ccccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 24 (t)] with 2-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[3-(pyridin-2-ylmethoxy)-propyl]-phenyl]-piperidine-1-carboxylate as a colourless, amorphous solid, which was used in the following step without further purification and characterization.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C)C(C([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)=O)=CC=CC=1.O.Cl.C([O:27][CH2:28][CH3:29])C>>[OH:13][C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[C:19]=1[C:28]([C:29]1[CH:18]=[CH:19][CH:14]=[CH:15][C:16]=1[CH3:17])=[O:27]
Reactant: Cc1cc(C)cc(OC(=O)c2ccccc2C)c1
Reactant: CCOCC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1cc(C)c(C(=O)c2ccccc2C)c(O)c1

Procedure:
Anhydrous aluminum chloride (20 g.) was added in portions during 5 minutes to 3,5-dimethylphenyl o-toluate (36.3 g.) and the mixture was heated at 140°-150° C. for 3 hours. After cooling, water (300 ml.) and concentrated hydrochloric acid (25 ml.) were added and the mixture was stirred and heated on the steam-bath until hydrolysis was complete. After cooling, the mixture was stirred with diethyl ether (110 ml.) and filtered through charcoal and kieselguhr. The layers were separated and the aqueous phase was extracted with more diethyl ether (2×50 ml.). The combined ethereal solutions were washed with water, dried over sodium sulphate and evaporated in vacuo. The residue crystallised slowly. Light petroleum (b.p. 40°-60° C.; 50 ml.) was added and the solid was filtered off, washed with light petroleum (b.p. 40°-60° C.) at 0° C. and dried in a vacuum desiccator. The solid was recrystallised from methanol to give 2-hydroxy-2',4,6-trimethylbenzophenone (15.9 g.), m.p. 65° -67° C.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:10]([OH:12])=[O:11].CI>O1CCCC1>[Cl:6][C:7]1[C:8]([CH3:1])=[C:9]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:10]([OH:12])=[O:11]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(C(=O)O)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
n-Butyl lithium (2.5M in hexanes, 180 ml) was added during 1 hour to a stirred solution of 3,4-dichlorobenzoic acid (40.0 g) at -78° C. and stirring maintained at that temperature overnight. A solution of methyl iodide (72 ml) in tetrahydrofuran was then added during 1.5 hours and the mixture kept at -78° C. for 3 hours and allowed to warm to room temperature overnight. The solvent was evaporated and the mixture added to water, acidified (concentrated hydrochloric acid) and extracted (ethyl acetate). The extract was dried (magnesium sulphate), evaporated and triturated (ether) to give 3,4-dichloro-2-methylbenzoic acid (33.3 g) as a white solid, m.p. 177°-178° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].Cl.[CH2:13]([NH2:15])[CH3:14]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][NH:15][CH2:13][CH3:14])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CCN
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CCNCc1cccc([N+](=O)[O-])c1
Yield: 47 %

Procedure:
Using m-nitrobenzaldehyde as a starting material and also using ethylamine hydrochloride as a reagent, the same procedure of Example 42 gave 2.8 g of the titled compound (yield, 47%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:27]([NH:29][CH2:30][CH2:31][OH:32])[CH3:28]>>[CH2:27]([N:29]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:30][CH2:31][OH:32])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2)c(OCCCCl)c1
Reactant: CCNCCO
Product: CCN(CCO)CCCOc1cc(CNC(=O)OC(C)(C)C)ccc1-c1ccccc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 139 using tert-butyl N-[2-(3-chloropropoxy)biphenyl-4-ylmethyl]carbamate instead of 3-(3-chloropropoxy)-4-phenylbenzonitrile and 2-ethylaminoethanol instead of pyrrolidine.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=O)[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][C:7]=1[O:16][CH3:17].CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([CH2:10][OH:11])=[CH:8][C:7]=1[O:16][CH3:17]
Reactant: COC(=O)c1ccc(OCC(=O)N(C)C)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(CO)ccc1OCCN(C)C
Temperature: 5 °C
Yield: 100 %

Procedure:
Methyl 4-{[2-(dimethylamino)-2-oxoethyl]oxy}-3-(methyloxy)benzoate (for a preparation see Intermediate 22) (1.4 g, 5.2 mmol) was dissolved in THF (50 ml) and cooled in an ice-bath under nitrogen. The mixture was then treated cautiously with 1M ether solution of lithium aluminium hydride (5.5 mL) and the mixture was stirred at 5° C. allowing to warm to RT overnight. The reaction mixture was quenched by cautious addition of aq. saturated NaHCO3 solution (1 mL), followed by MgSO4 (2 g) and stirring for 30 min. The solids were removed by filtration, washed with ethyl acetate, and the filtrate was evaporated to give the title compound (1.18 g, 100%) as a yellow oil: LCMS (System A) RT=0.34 min, ES+ve m/z 226 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH2:9][O:10][CH:11]2[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.O>C(O)(=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([CH2:9][O:10][CH:11]2[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(COC2CCC3(CC2)OCCO3)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(OCc2cccc(C(F)(F)F)c2)CC1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 2, using 7.9 grams (0.025 mole) of 8-(3-trifluoromethylphenylmethoxy)- 1,4-dioxaspiro[4.5]decane, and 25 mL of water in 50 mL of acetic acid, yielding 4-(3-trifluoromethylphenylmethoxy)cyclohexanone.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:32][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23]3)[C:7]=2[C:6]=1[CH3:33])=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:33])=[C:5]([C:3]([OH:4])=[O:2])[S:32][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([O:21][C@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23]2)[CH:16]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(S(C)(=O)=O)C3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(S(C)(=O)=O)C3)c12
Reaction time: 4 h

Procedure:
4-[4-Fluoro-2-((S)-1-methanesulfonyl-piperidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (130 mg) was dissolved in THF (3 ml) and a solution of lithium hydroxide* H2O (60 mg) in water (3 ml) was added. The mixture was stirred for 4 h. HCl (2M) was added to adjusted to pH 5 and the volatile solvent partially removed until crystallization occurred. The solid was collected by filtration. The filter cake was washed with water and was dried to give the desired product.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:12][C:13]([NH2:15])=[S:14]>CCO>[CH3:11][C:2]1[S:14][C:13]([NH2:15])=[N:12][C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1sc(N)nc1-c1ccccc1
Yield: 109.7 %

Procedure:
A mixture of 2-bromo-1-phenylpropan-1-one (3.00 g, 19.5 mmol) and thiourea (1.56 g, 20.5 mmol) in 95% EtOH (30 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 5-methyl-4-phenylthiazol-2-amine (4.07 g) as yellow solids in 77% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 2H), 7.54-7.49 (m, 5H), 2.28 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:8][CH2:7][CH2:6]2)#[N:2].[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:25][CH2:26][C:27]([N:14]([CH2:13][CH:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCNCC1CCCc2cc(C#N)ccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CC1CCCc2cc(C#N)ccc21)C(=O)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-Butyl (2-{[(6-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}ethyl)carbamate (110 mg, 0.334 mmol), chloroacetyl chloride (42 mg, 0.37 mmol) and TEA (135 mg, 1.34 mmol) in 20 mL DCM was stirred at RT for 12 hours. The mixture was diluted with 50 mL DCM and then washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified via prep-TLC (EtOAc/Petroleum Ether=1:1) to give the title compound. MS m/z: 406 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:13]=O)[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(O)C>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:13]=[N:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([F:15])[CH:17]=2)[CH:3]=1
Reactant: Nc1cccc(F)c1
Reactant: COC(=O)c1cc(C)c(C)cc1C=O
Solvent: CCO
Product: COC(=O)c1cc(C)c(C)cc1C=Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
To a solution of the product of above-mentioned (25-a) (0.64 g, 3.3 mmol) in absolute ethanol (16 ml) was added 3-fluoroaniline (0.37 g, 3.3 mmol), and stirred at 25° C. for 2 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform) to give 0.45 g of methyl 4,5-dimethyl-2-{[(3-fluorophenyl)imino]methyl}benzoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2].[CH:42]1([C:45]2[CH:46]=[N:47][NH:48][CH:49]=2)[CH2:44][CH2:43]1>>[C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:47]3[CH:46]=[C:45]([CH:42]4[CH2:44][CH2:43]4)[CH:49]=[N:48]3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:22])[F:23])=[N:14]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1n[nH]cc1C1CC1
Reactant: Cc1c(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Product: Cc1c(Cc2ccc(-n3cc(C4CC4)cn3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compounds was prepared by the method of Preparation 18a using {8-chloro-2-difluoromethoxy-4-methyl-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid tert-butyl ester and 4-cyclopropyl-1H-pyrazole.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]([O:12][C:13](=[O:45])[CH:14]([CH2:40][CH2:41][CH2:42][CH2:43][OH:44])[CH2:15][C:16]1([C:21](=[O:39])[NH:22][C@H:23]2[CH2:28][CH2:27][C@@H:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:11])([CH3:10])[CH3:9].Cl>N1C=CC=CC=1>[C:8]([O:12][C:13](=[O:45])[CH:14]([CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:15][C:16]1([C:21](=[O:39])[NH:22][C@H:23]2[CH2:28][CH2:27][C@@H:26]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:10])([CH3:9])[CH3:11]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)C(CCCCO)CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(=O)OCCCCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Valeryl chloride (0.2 ml, 1.98 mmole) was added dropwise to a stirred, ice cold solution of 3-{1-[(cis-4-benzyloxycarbonylcyclohexyl)carbamoyl]cyclopentyl}-2-(4-hydroxybutyl)propanoic acid t-butyl ester (0.7 g, 1.32 mmole) in dry pyridine (5 ml). The mixture was allowed to stand overnight at room temperature and ice was added, the pH was adjusted to 3 by the addition of 2N hydrochloric acid and the mixture was extracted with diethyl ether. The organic extract was dried (Na2SO4) and evaporated to give a gum which was chromatographed on silica eluting with hexane containing increasing proportions of diethyl ether to give the title product as a gum. Found: C,70.06; H,8.91; N,2.58. C36H55NO7 requires C,70.44; H,9.03; N,2.28%.