Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[F:1][C:2]1[C:10]2[N:9]([CH2:35][C:34]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH2:33])[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=CBr)c1ccc(F)cc1
Reactant: CN1CCc2[nH]c3c(F)cccc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C=C(Cn1c2c(c3cccc(F)c31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.98 mmol) was dissolved in DMF (4 mL). Copper (I) iodide (18 mg, 0.098 mmol), L-proline (22 mg, 0.19 mmol) and K3PO4 (416 mg, 1.96 mmol) were added and the reaction mixture was stirred for 10 min at RT. 1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (250 mg, 1.17 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. overnight (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water, and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.60 (m, 2H), 7.30-7.20 (m, 3H), 7.0 (m, 1H), 6.95 (m, 1H), 5.38 (s, 1H), 5.22 (s, 2H), 4.30 (m, 2H), 4.08 (s, 1H), 3.8-3.3 (m, 2H), 3.0 (m, 2H), 2.90 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13]>C1CCCCC1>[CH2:2]([C:3](=[N:13][NH:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:1]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCCCCCC(=O)CC
Solvent: C1CCCCC1
Product: CCCCCCC(CC)=NNC(=O)OC(C)(C)C

Procedure:
16.42 g (115 mmol) of 3-nonanone and 15.26 g (115.4 mmol) of tert-butyl carbazate are refluxed for 3 hours in 200 ml of cyclohexane. The solvent is removed in vacuo. This gives 30.54 g (product contains water) of a white solid, Rf=0.49 (cyclohexane/ethyl acetate=3:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19]4[CH:20]=[CH:21][C:22]([N+:24]([O-])=O)=[CH:23][C:18]=4[N:17]=[CH:16]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[ClH:27].N>C(O)C>[ClH:27].[NH2:24][C:22]1[CH:21]=[CH:20][C:19]2[N:15]([C:11]3[CH:10]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:14]=[CH:13][CH:12]=3)[CH:16]=[N:17][C:18]=2[CH:23]=1
Reactant: COc1cccc(-c2cccc(-n3cnc4cc([N+](=O)[O-])ccc43)c2)c1
Agent: Cl
Agent: N
Solvent: CCO
Product: COc1cccc(-c2cccc(-n3cnc4cc(N)ccc43)c2)c1

Procedure:
A mixture of 1-(3'-methoxy-3-biphenylyl)-5-nitrobenzimidazole (1.5 g, 4.9 mmol), tin(ll)chloride (2.7 g), conc. hydrochloric acid (20 ml), and ethanol (10 ml) was refluxed for 2 hours and then neutralized by the addition of concentrated ammonia and filtered through celite. The filter cake was washed with ethanol and then methylene chloride. The phases of the filtrate were separated and the aqueous phase was extracted twice with methylene chloride. The combined organic phases were washed with water, dried and the product was precipitated as the hydrochloride. Yield: 1.5 g, 4.3 mmol, 88%. mp 195°-200° C. (decomposition).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][CH:13]=[C:12]([CH:15]=O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.NO.C([N:22](CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CCCCCC>[Si:1]([O:8][CH2:9][C:10]1[O:14][CH:13]=[C:12]([C:15]#[N:22])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C=O)co1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NO
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(C#N)co1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-furaldehyde (3.2 g, 13 mmol) that was obtained in Example 1 (1b) in dichloromethane (40 ml) were added successively hydroxylamine hydrochloride (1.0 g, 15 mmol) and triethylamine (3.7 ml, 27 mmol) with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, the reaction mixture was evaporated in vacuo. Subsequently, to a solution of the residue obtained in toluene (40 ml) was added N,N′-dicyclohexylcarbodiimide (3.1 g, 15 mmol) with stirring, and the resulting mixture was stirred at 90° C. for 16 hours. After cooling to room temperature, hexane (40 ml) was added to the reaction mixture, and insoluble materials were removed by filtration with Celite. The filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:97) as the eluent to afford the title compound (1.8 g) in a yield of 57% as a colourless oily product.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]CC)=[O:8])[CH2:3]1.[OH-].[Li+:13]>C1COCC1.O>[CH2:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O-:9])=[O:8])[CH2:3]1.[Li+:13]
Reactant: C=C1CCC(C(=O)OCC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)[O-])C1
Temperature: 65 °C

Procedure:
A mixture of ethyl 3-methylenecyclopentanecarboxylate (900 mg, 5.84 mmol) and lithium hydroxide (280 mg, 11.67 mmol) in THF (15 mL) and water (6 mL) was heated at 65° C. for 18 hours. Analysis by TLC indicated that the starting ester had been completely consumed. The organic solvents were removed via rotary evaporator, and the remaining aqueous solution was freeze-dried to yield lithium 3-methylenecyclopentanecarboxylate. 1H NMR (400 MHz, CD3OD) δ ppm 4.84-4.73 (m, 2H), 2.71-2.59 (m, 1H), 2.57-2.35 (m, 3H), 2.29-2.16 (m, 1H), 2.01-1.91 (1H, m), 1.84-1.72 (m, 1H,).
Reaction SMILES: Br[C:2]1[C:3]([F:11])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[F:11][C:3]1[C:2]([C:12]#[N:13])=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2cc[nH]c2c1Br
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1c(F)ccc2cc[nH]c12

Procedure:
To a solution of 7-bromo-6-fluoro-1H-indole (D140) (1.0 g) in DMF (15 ml) were added Zn(CN)2 (2.2 g) and then Pd(PPh3)4 (1.1 g) in a microwave tube, then N2 atmosphere was bubbled in. The sealed vial was irradiated in the microwave at 150° C. for 2 hours. After cooling, DCM (80 mL) was added to the resulting mixture which was filtered and the filtrate was concentrated. The crude product was purified by column chromatography to afford 6-fluoro-1H-indole-7-carbonitrile (D141) (0.5 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=1)[N:7]=3.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([CH:31]2[CH2:35][CH2:34][CH2:33][NH:32]2)[CH2:27][CH2:26]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:19]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([N:32]5[CH2:33][CH2:34][CH2:35][CH:31]5[CH:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CN1CCC(C2CCCN2)CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCCC3C3CCN(C)CC3)cc1OCC2
Temperature: 110 °C
Yield: 16 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene, also named as 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 95 (300 mg, 0.80 mmol), 1-methyl-4-pyrrolidin-2-ylpiperidine (338 mg, 2.00 mmol), NaOtBu (232 mg, 2.40 mmol) and Pd(PtBu3)2 (20 mg, 0.04 mmol) in toluene (6 mL) was heated at 110° C. for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (C18, gradient 10-65% MeOH in H2O) then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was freeze-dried from MeCN/H2O to afford 141 (20 mg, 16%) as a white solid. LCMS: RT 2.91 min [M+H]+ 462.4. 1H NMR (DMSO, 400 MHz): δ 8.18 (1H, d, J=8.95 Hz), 7.87 (1H, s), 7.77 (1H, s), 6.49 (1H, dd, J=9.03, 2.41 Hz), 6.13 (1H, d, J=2.36 Hz), 5.94-5.93 (1H, m), 4.45-4.40 (4H, m), 3.74 (1H, s), 3.45-3.43 (1H, m), 3.14-3.11 (1H, m), 2.78 (2H, s), 2.12 (3H, s), 1.99-1.72 (5H, m), 1.71-1.51 (3H, m), 1.47 (6H, dd, J=6.60, 1.90 Hz), 1.33-1.31 (3H, m)
Reaction SMILES: Br[C:2](=[CH:6]OC)[C:3](=[O:5])[CH3:4].Cl.[C:10]([NH2:13])(=[NH:12])[CH3:11].C(N(CC)CC)C>O1CCCC1>[CH3:11][C:10]1[NH:12][CH:6]=[C:2]([C:3](=[O:5])[CH3:4])[N:13]=1
Reactant: COC=C(Br)C(C)=O
Reactant: CC(=N)N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1c[nH]c(C)n1
Yield: 230 %

Procedure:
6.3 g (35 mmol) of 3-bromo-4-methoxy-3-buten-2-one, 16.7 g acetamidine hydrochloride (175 mmol) and 29.2 ml triethylamine (210 mmol) were combined in 300 ml tetrahydrofuran and heated at reflux for 6 hours. The solvent was removed in vacuo to a crude orange solid. The crude solid was dissolved in 200 ml ethyl acetate and concentrated to 25 ml by boiling off the solvent. Cooling in ice resulted in crystallization of a yellow solid. This was collected by filtration, washed first with ethyl acetate, then with ether and dried at 25° in vacuo to give 9.995 g (23%) of 1-(2-methyl-4-imidazolyl)ethanone, mp 124°-7°. nmr (DMSO-d6) (δ): 4.61 (s, 1H); 1.41 (s, 3H); 1.39 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([C:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2cnccn12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(Cl)c2cnccn12
Yield: 82.3 %

Procedure:
0.5 g of 6-acetylpyrrolo[1,2-a]pyrazine prepared in Preparation Example 15 was dissolved in 5 ml of chloroform; and 0.5 g of N-chlorosuccinimide was added threrto. The reaction mixture was refluxed for 2 hours and then concentrated. The residue was chromatographed over silica gel to yield 0.5 g of title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17]([NH:19][C@@:20]12[CH2:27][C:26](=[CH2:28])[CH2:25][C@@H:24]1[CH2:23][N:22]([C@@H](C1C=CC=CC=1)C)[CH2:21]2)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[CH2:5]([O:4][C:2]([N:22]1[CH2:23][C@@H:24]2[C@@:20]([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])([CH2:27][C:26](=[CH2:28])[CH2:25]2)[CH2:21]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C1C[C@@H]2CN([C@H](C)c3ccccc3)C[C@]2(NC(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: C=C1C[C@@H]2CN(C(=O)OCc3ccccc3)C[C@]2(NC(=O)OC(C)(C)C)C1
Temperature: 40 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
Benzyl chloroformate (0.250 ml, 1.75 mmol) was added to a solution of the residue containing (1S,5R)-1-tert-butoxycarbonylamino-7-methylene-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane (200 mg, equivalent to 0.437 mmol) in dichloromethane (1.94 ml) in a nitrogen atmosphere, and the mixture was stirred at room temperature for 15 hours and at 40° C. for four hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→87:13→86:14→83:17→80:20→75:25) to give 95.1 mg of the title compound as a transparent oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1>C(Cl)Cl.CO.O=[Mn]=O>[CH:12]([C:10]1[N:9]=[C:7]2[N:6]([CH:11]=1)[C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=1[S:8]2)=[O:13]
Reactant: OCc1cn2c(n1)sc1cc(Cl)ccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: O=Cc1cn2c(n1)sc1cc(Cl)ccc12

Procedure:
2-Formyl-7-chloroimidazo[2,1-b]-benzthiazole was prepared according to the procedure outlined in Example 1, (Step 3). Starting from 7-chloroimidazo[2,1-b]-benzthiazole-2-methanol (4.0 g 16.8 mmol) in methylene chloride/MeOH (300 mL: 50 mL) and active MnO2 (20 g, excess), 2.2 g (55% yield) of the aldehyde derivative was isolated as brown solid. (M+H) 236.
Reaction SMILES: C1([C@@H]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)CC#N)CCCC1.C(#N)C.CC(C)([O-])C.[K+].C1COCC1>C(OCC)(=O)C.[Cl-].[NH4+]>[NH:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@@H](CC#N)C4CCCC4)c3)ncnc21
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 5 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
Into a 22 L four-neck flask equipped with overhead stirring, thermocouple, 2 L addition funnel and nitrogen inlet was charged (3S)-3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile ((S)-10, 491 g, 1.11 mol) and acetonitrile (4.5 L) at room temperature. The mixture was cooled to 0-10° C. before being treated dropwise with a 1M solution of potassium tert-butoxide in THF (KOtBu, 2.0 L, 2.0 mol, 1.8 equiv) via the addition funnel over 1.5 hours. Following the addition of base the reaction mixture was allowed to return to room temperature and was stirred at room temperature for 12-24 h. When LC/MS showed the reaction was deemed complete, the reaction mixture was diluted with ethyl acetate (EtOAc, 6 L) and 50% (w/w) aqueous ammonium chloride solution (NH4Cl, 4 L). The two layers were separated, and the aqueous fraction was back extracted with ethyl acetate (2 L). The combined organic fractions were washed with water (2 L) and brine (3 L), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure to afford the crude 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 354 g, 350.1 g theoretical, 101.1% yield) as an amber oil, which solidified upon standing at room temperature in vacuo. This crude material was subsequently recrystallized in acetonitrile to afford pure compound 5 (308 g, 350.1 g theoretical, 88% yield) as white crystals (99.5 area % by HPLC), which was found to be identical in every comparable aspect to the material made from Method A, B, C, and D.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14]S(CCCNCCC2C3SC(=O)NC=3C(O)=CC=2)(=O)=O)=[CH:5][CH:4]=1.CO>C1COCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:8]=1
Reactant: O=c1[nH]c2c(O)ccc(CCNCCCS(=O)(=O)NCCOCCc3ccc(Cl)cc3)c2s1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCCOCCc1ccc(Cl)cc1
Yield: 252.7 %

Procedure:
The product from step b (6 g) was added portion wise to a stirred solution of boranetetrahydrofuran (1.0 M in THF, 85 ml). The reaction was then heated at reflux under an inert atmosphere for 3 hours. The reaction was cooled and methanol (10 mls) was cautiously added. The solvents were removed in vacuo and the residue redissolved in methanol (100 ml) to which was added concentrated hydrochloric acid (sg. 1.18, 4 ml). This solution was heated at reflux for 30 minutes and then the solvent removed in vacuo. The residue was taken up into water and washed with ether. Sodium bicarbonate was added and the aqueous extracted with ethyl acetate. The ethyl acetate was washed with water, brine and dried (MgSO4). The volatiles were removed in vacuo to provide the subtitle compound as a oil (5.5 g) which was used without further purification.
Reaction SMILES: [F:1][CH:2]([CH:6]1[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1)[CH:3]([F:5])[F:4].O.C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[F:1][CH:2]([CH:6]1[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1)[CH:3]([F:4])[F:5]
Reactant: FC(F)C(F)C1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=CO
Product: O=C1CCC(C(F)C(F)F)CC1

Procedure:
At 20 to 25° C., 6.2 g of 8-(1,2,2-trifluoroethyl)-1,4-dioxaspiro[4.5]decane were stirred in 40 ml of formic acid for 16 h. The reaction solution was subsequently poured into water, adjusted to pH 8 using potassium carbonate, extracted with methylene chloride and the organic phase was dried and concentrated to give the title product as a colourless oil which was reacted further without any purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[N:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]1=[O:19]>>[CH2:9]([O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:16]2[CH2:17][CH2:18][NH:13][C:14](=[O:19])[CH2:15]2)[CH:7]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)COc1cc(Cl)ncn1
Reactant: O=C1CNCCN1
Product: CC(C)COc1cc(N2CCNC(=O)C2)ncn1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of intermediate C using 4-chloro-6-isobutoxypyrimidine and piperazin-2-one.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N(CC)CC)C.Cl[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH2:7]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])[S:27]([CH:26]=[CH2:25])(=[O:29])=[O:28])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(CNCc1ccccc1)OCC
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)N(Cc1ccccc1)CC(OCC)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzylamino-acetaldehyde diethyl acetal (14.6 ml, 61.3 mmol) and triethylamine (19.0 ml, 122.0 mmol) in dichloromethane (200 ml) at 0° C. under argon was added 2-chloro-1-ethanesulfonyl chloride (10.0 g, 61.3 mmol). After stirring at rt for 3 h, the reaction mixture was quenched with water (300 ml), extracted with dichloromethane (200 ml×2), washed with brine (150 ml), dried over MgSO4, filtered, and concentrated in vacuo to give the title compound which was used in next step without further purification; 1H NMR (CDCl3): 1.23 (t, 6H), 3.22(d, 2H), 353 (m, 2H), 3.72 (m, 2H), 4.52 (s, 12H), 4.63 (t, 1H), 5.88 (d, 1H), 6.23 (d, 1H), 6.50–6.43 (m, 1H), 7.35 (m, 5H); LCMS: 268 (MH+−46).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(Cl)Cl.Cl.[OH:12][C:13]1[CH:36]=[CH:35][C:34]([O:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:33][C:14]=1[C:15]([NH:17][C:18]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])=[O:16]>N1C=CC=CC=1>[C:1]([N:41]1[CH2:40][CH2:39][CH:38]([O:37][C:34]2[CH:35]=[CH:36][C:13]([OH:12])=[C:14]([CH:33]=2)[C:15]([NH:17][C:18]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=[O:16])[CH2:43][CH2:42]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(OC2CCNCC2)ccc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, pyridine (0.30 mL) and acetic anhydride (6.7 μL) were sequentially added to a methylene chloride (1 mL) suspension of 2-(2-hydroxy-5-(piperidin-4-yloxy)benzamido)-4-phenylbenzoic acid hydrochloride (0.030 g), followed by stirring at room temperature for 1 hour. Pyridine (0.20 mL) and acetic anhydride (5.4 μL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, and methanol (0.5 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.19 mL) were added to the residue, followed by stirring at room temperature for 1 hour. To the reaction mixture, 1 mol/L hydrochloric acid (5 mL) and ethyl acetate were added. The organic layer was separated, washed with 1 mol/L hydrochloric acid, water, and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Dioxane (0.5 mL), methanol (0.5 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.32 mL) were added to the obtained residue, followed by stirring at 70° C. for 30 minutes. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and water was added to the obtained residue. After adjusting the pH to 3 with 6 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 0.022 g of 2-(5-(1-acetylpiperidin-4-yloxy)-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][CH:11]2[C:16]([N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[OH-].[Na+]>C(COC)OC.CO>[CH2:26]([N:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([CH:11]1[C:12]2[C:7](=[C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])[CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:17])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)COc1cccc2c1CCCC2C(=O)N(Cc1ccccc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: O=C(O)COc1cccc2c1CCCC2C(=O)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of the compound prepared in example 1 (204 mg) in dimethoxyethane (3 ml) and methanol (2 ml) was added 1N aqueous solution of sodium hydroxide. After stirred for 2 h, the mixture was quenched by addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium salfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→ethyl acetate) to give the title compound (171 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:28])[CH:9]([NH:20]C(=O)OC(C)(C)C)[CH2:10][C:11]2[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:20][CH:9]([CH2:10][C:11]1[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=1)[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:28]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 101.8 %

Procedure:
To 1,1-dimethylethyl (1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((5-(trifluoromethyl)-2-furanyl)methyl)ethylcarbamate (1.70 g, 4.21 mmol) was added trifluoroacetic acid (15 ml) at 0° C. and the mixture was stirred for 10 min. The reaction solution was concentrated, diluted with water (20 ml) and extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-(trifluoromethyl)-2-furanyl)-1-propanol (1.30 g, 100%).