Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH2:17][C:18](=[CH:21]NC1C=CC=CC=1)[C:19]#[N:20])=[CH:8]2.[ClH:29].[NH2:30][C:31]([NH2:33])=[NH:32].C[O-].[Na+]>C(O)C>[ClH:29].[NH2:32][C:31]1[N:33]=[C:19]([NH2:20])[C:18]([CH2:17][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=3[O:2][CH3:1])[CH:8]=2)=[CH:21][N:30]=1
Reactant: COc1cc2cc(CC(C#N)=CNc3ccccc3)ccc2c(OC)c1OC
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc2cc(Cc3cnc(N)nc3N)ccc2c(OC)c1OC
Yield: 27 %

Procedure:
The aldehyde from above was converted to 2-(5,6,7-trimethoxy-2-naphthylmethyl)-3-anilinoacrylonitrile on a 8 mmol scale in the same manner as Example 5-A. The crude product from this reaction was cyclised with guanidine hydrochloride and sodium methylate in ethanol as in Example 5-B to give the title compound as the free base, 0.74 g (27% yield). This was recrystallised from ethanol plus an equivalent of hydrochloric acid, 0.26 g, mp 252°-254°. Anal. Calcd. for C18H20N4O3HCl: C 57.37; H, 5.62; N, 14.87; Cl, 9.41. Found: C, 57.11; H, 5.67; N, 14.79; Cl, 9.31.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:18][C:6]2[C:7]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:8][CH2:9][C:10]([F:12])([F:11])[C:5]=2[CH:4]=1.[CH3:19][C:20]1[C:21]([N:26]2[CH:30]=[C:29]([CH:31]=O)[C:28]([C:33]([O-])=[O:34])=[N:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1>>[Cl:2][C:3]1[S:18][C:6]2[C:7]3([O:8][CH2:9][C:10]([F:12])([F:11])[C:5]=2[CH:4]=1)[CH2:13][CH2:14][N:15]([CH2:31][C:29]1[C:28]([CH2:33][OH:34])=[N:27][N:26]([C:21]2[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:30]=1)[CH2:16][CH2:17]3
Reactant: Cc1cccnc1-n1cc(C=O)c(C(=O)[O-])n1
Reactant: FC1(F)COC2(CCNCC2)c2sc(Cl)cc21
Agent: Cl
Product: Cc1cccnc1-n1cc(CN2CCC3(CC2)OCC(F)(F)c2cc(Cl)sc23)c(CO)n1
Yield: 14 %

Procedure:
The title compound is prepared essentially as described in Example 60 by using 2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]hydrochloride and 1-(3-methylpyridin-2-yl)-4-formyl-pyrazole-3-carboxylate as starting materials in a 14% yield. MS (m/z): 481 (M+1).
Reaction SMILES: [C:1]1(CO)(CO)[CH2:6]CCC[CH2:2]1.C1(CO)CCC(CO)CC1.[CH:21]1([C:31]([O:33][CH3:34])=[O:32])[CH2:26][CH2:25][CH:24](C(OC)=O)[CH2:23][CH2:22]1>>[O:33]([CH3:34])[C:31]([CH2:21][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:2][CH2:1][CH3:6])=[O:32]
Reactant: OCC1(CO)CCCCC1
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: OCC1CCC(CO)CC1
Product: CCCCCCCCCC(=O)OC

Procedure:
A process according to claim 20, in which the cyclohexanedimethanol is 1,4-cyclohexanedimethanol, the dialkyl cyclohexanedicarboxylate is dimethyl 1,4-cyclohexanedicarboxylate, the hydrogenation zone is maintained at a temperature of from about 200° C. to about 260° C. and a pressure of from about 450 psia (about 31.03 bar) to about 1000 psia (about 68.95 bar).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[C:21]([OH:22])=[CH:20][C:10]2[CH2:11][C:12]3([O:19][C:9]=2[CH:8]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)([CH3:6])([CH3:5])[CH3:4].[CH2:23](Br)[CH:24]=[CH:25][CH3:26]>CN(C)C=O>[CH2:23]([O:22][C:21]1[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:8][C:9]2[O:19][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:11][C:10]=2[CH:20]=1)[CH:24]=[CH:25][CH3:26]
Reactant: CC=CCBr
Reactant: CC(C)(C)c1cc2c(cc1O)CC1(CCCCCC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CCOc1cc2c(cc1C(C)(C)C)OC1(CCCCCC1)C2
Yield: 93 %

Procedure:
0.13 g of oily sodium hydride and 0.74 g of 6-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane synthesized in Example 7 were treated with 0.33 ml of crotyl bromide in dimethylformamide in the same manner as in Example 8-1) to give 0.82 g of a mixture of geometrical isomers of 5-(2-butenyloxy)-6-t-butyl-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a colorless oil (yield 93%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:36])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6].Cl.O>O1CCCC1.C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:36])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2OCCCC)c1
Temperature: 68 °C
Reaction time: 5 h
Yield: 61.4 %

Procedure:
0.65 mL (0.65 mmol) of aqueous 1 M sodium hydroxide solution is added to a solution of 0.2 g (0.43 mmol) of methyl (Z)-3-[2-butoxy-3′-(1-methyl-3-butylureido)biphenyl-4-yl]-2-methoxyacrylate in 5 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 5 hours. After cooling, the reaction is stopped by addition of 1 mL aqueous 1 M hydrochloric acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The product is recrystallized from a pentane/acetone mixture to give 0.12 g (63%) of (Z)-3-[2-butoxy-3′-(1-methyl-3-butylureido)biphenyl-4-yl]-2-methoxyacrylic acid in the form of a white solid with a melting point of 106° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16](OC)[O:17]C)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C(O)=O>O>[CH2:1]([N:4]([CH2:15][CH:16]=[O:17])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(CC(OC)OC)C(=O)OCc1ccccc1
Solvent: O
Solvent: O=CO
Product: C=CCN(CC=O)C(=O)OCc1ccccc1
Yield: 100.2 %

Procedure:
A solution of benzyl N-allyl-N-(2,2-dimethoxyethyl)carbamate (30 g, 107 mmol) in formic acid (36.8 mL, 860 mmol) and water (4.84 mL) is stirred at room temperature overnight. The mixture is concentrated and diluted with hexanes/ethyl acetate (1:2) and water. The organic layer is separated, washed with brine solution until pH=6, and dried over sodium sulfate. The solvent is evaporated to give the title compound (25 g, 99%). ES/MS (m/e): 234 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3](=O)[CH2:4][CH:5]1O[N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1.[H+].[B-](F)(F)(F)F>C(O)C.[Ni]>[C:2]([C:3]1[N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=1)([CH3:17])([CH3:16])[CH3:1]
Reactant: CCOC(=O)C1=NOC(CC(=O)C(C)(C)C)C1
Agent: [Ni]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Product: CCOC(=O)c1cccc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
A solution of the product from Example 115C (4.95 g, 20.5 mmol) in ethanol (400 mL) was treated with Raney nickel (20.10 g) and 48% HBF4 solution (4.13 mL), and the reaction was shaken under a hydrogen atmosphere (50 psi) at 25° C. for 1 hour. The reaction mixture was filtered, diluted with water, basified with dilute NaOH solution, and partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 10% ethyl acetate in hexane to give the title compound (1.1 g, 26% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:12]=[CH:11][CH:10]=[CH:9][C:4]=2[N:5]=[C:6]([SH:8])[N:7]=1.[CH3:13][O-].[Na+].CO.CI>C(O)(=O)C>[OH:1][C:2]1[C:3]2[N:12]=[CH:11][CH:10]=[CH:9][C:4]=2[N:5]=[C:6]([S:8][CH3:13])[N:7]=1
Reactant: C[O-]
Reactant: Oc1nc(S)nc2cccnc12
Agent: [Na+]
Solvent: CI
Solvent: CO
Solvent: CC(=O)O
Product: CSc1nc(O)c2ncccc2n1

Procedure:
A mixture of 22.1 g (0.123 mot) of 4-hydroxypyrido[3,2-d]pyrimidine-2-thiol, 65 mL of 25 percent sodium methoxide in methanol (0.28 mol), 8.9 mL (20.1 g, 0.142 mol) of methyl iodide, and 500 mL of methanol was prepared and allowed to react at ambient temperature with stirring until the starting material thiol disappeared as determined by high pressure liquid chromatography (HPLC). The mixture was then acidified with acetic acid and the volatile components were removed by evaporation under reduced pressure. The residue was diluted with water and the solids were recovered by filtration, washed with ether, and dried overnight in a vacuum oven. The resultant white powder was the title compound melting at 229°-231° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([C:8]#[C:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC#Cc1cccc(Cl)c1F
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: OCCCc1cccc(Cl)c1F
Temperature: 60 °C
Reaction time: 11 h
Yield: 77 %

Procedure:
A suspension of Compound 63-1 (3.15 g) and chlorotris(triphenylphosphine)rhodium(I) (3.00 g) in toluene (90 ml) was stirred under a hydrogen atmosphere at 60° C. for 11 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (2.48 g) as a brown oil.
Reaction SMILES: C([O:8]C1C=C(CC#N)C=CC=1)C1C=CC=CC=1.[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([C:32]([CH3:36])([CH3:35])[C:33]#N)[CH:29]=[CH:30][CH:31]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CBr.CC(C[AlH]CC(C)C)C>[OH-].[Na+].CS(C)=O>[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([C:32]([CH3:36])([CH3:35])[CH:33]=[O:8])[CH:29]=[CH:30][CH:31]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CCc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C#N)c1cccc(OCc2ccccc2)c1
Agent: CBr
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C=O)c1cccc(OCc2ccccc2)c1

Procedure:
Commercially available (3-benzyloxy-phenyl)-acetonitrile (I) was converted to 2-(3-benzyloxy-phenyl)-2-methyl-propionitrile (II) using methyl bromide gas in NaOH/DMSO, followed by a reduction with DIBAL-H yielding 2-(3-benzyloxy-phenyl)-2-methylpropionaldehyde (III). Further reduction of III with NaBH4 afforded 2-(3-benzyloxy-phenyl)-2-methyl-propan-1-ol (IV). Wittig reactions of III with pentyltriphenylphosphonium bromide, trimethyl-4-phosphonocrotonate and trimethyl phosphonoacetate, produced 1-(1,1-dimethyl-hept-2-enyl)-3-phenethyl-benzene (V), 6-(3-benzyloxy-phenyl)-6-methyl-hepta-2,4-dienoic acid methyl ester (VIa), and 4-(3-benzyloxy-phenyl)-4-methyl-pent-2-enoic acid methyl ester (VIb) respectively (Scheme 1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=1[O:29][CH3:30].[CH2:31]([O:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:17][C:18](=[O:28])[C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=2[O:29][CH3:30])=[O:44])=[CH:46][CH:47]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: COc1cc(CC(NC(=O)c2ccc([N+](=O)[O-])cc2)C(=O)OC(C)(C)C)ccc1O
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)c3ccc([N+](=O)[O-])cc3)C(=O)OC(C)(C)C)cc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Prepared using General Procedure 3: To a stirred solution of tert-butyl 3-(4-hydroxy-3-methoxyphenyl)-2-(4-nitrobenzamido)propanoate INT-7 (1.34 g, 3.05 mmol) and TEA (1.28 mL, 9.15 mmol) in DCM (8 mL) at 0° C. was added 4-(heptyloxy)benzoyl chloride (0.81 mL, 3.36 mmol) dropwise. After warming to room temperature and stirring for 1 h, the mixture was quenched with saturated aqueous NaHCO3 (100 mL) and diluted with DCM (100 mL). The organic layer was dried over MgSO4 and concentrated. The product was purified by chromatography (EA/hexanes) to afford 1.70 g (86%) of 4-(3-(tert-butoxy)-2-(4-nitrobenzamido)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-8. LCMS-ESI (m/z) calculated for C35H42N2O9: 634; no mass ion observed, tR=3.26 min (Method 4).
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][C:20]([CH2:28][OH:29])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1.C1C(=O)N([I:47])C(=O)C1>CC#N>[CH3:39][Si:2]([CH3:38])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:47])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:18][CH2:19][C:20]([CH2:28][OH:29])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22]2)[CH:9]=1
Reactant: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate (733 mg, 1.27 mmol) in CH3CN (10 mL) was added NIS (313 mg, 1.39 mmol). The resulting solution was stirred at rt for 30 min before quenching with Na2S2O3 (sat.). CH3CN was removed under reduced pressure. The residue was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.6 in 50% EtOAc) to afford ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate as a colorless oil (811 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][S-:13].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:13][CH3:12])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: C[S-]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [Na+]
Product: CSc1cccc(F)c1[N+](=O)[O-]

Procedure:
1-Fluoro-3-methylsulfanyl-2-nitro-benzene was prepared from 1,3-difluoronitrobenzene and sodium methyl mercaptide in an analogous manner to Example 1251a. (1.513 g, 26%).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:27])=[CH:9][C:8]=1[CH3:28])C.[Li+].[OH-]>>[CH2:30]([O:29][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:27])=[CH:9][C:8]=1[CH3:28])[C:4]([OH:32])=[O:3])[CH3:31]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2sc(-c3ccccc3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCCc2sc(-c3ccccc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-{2-methyl-4-[2-(4-methyl-2-phenyl-thiazol-5-yl)-ethoxy]-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{2-methyl-4-[2-(4-methyl-2-phenyl-thiazol-5-yl)-ethoxy]-phenyl}-propionic acid as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19]CC(O)=O.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19]
Reactant: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 19.5 g. sample of (+) [(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-oxy]acetic acid is added to stirred molten (190° C.) pyridine hydrochloride, stirred for 1 hour then poured into ice water (800 ml). The (+)6,7-dichloro-2-cyclopentyl-2,3-dihydro--5-hydroxy-2-methyl-1H-inden-1-one, which separates is filtered, rinsed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[F:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O:55][C@@H:56]1[C@@H:61]([CH:62]2[CH2:64][CH2:63]2)[CH2:60][N:59]([C:65]2[C:70]([NH2:71])=[CH:69][N:68]=[C:67]3[CH:72]([O:75]C(=O)C)[CH2:73][CH2:74][C:66]=23)[CH2:58][C@H:57]1[NH:79]C(OC(C)(C)C)=O)(=O)C>ClCCCl.CCOC(C)=O.O>[NH2:79][C@H:57]1[C@H:56]([OH:55])[C@@H:61]([CH:62]2[CH2:64][CH2:63]2)[CH2:60][N:59]([C:65]2[C:70]([NH:71][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:17])=[CH:69][N:68]=[C:67]3[CH:72]([OH:75])[CH2:73][CH2:74][C:66]=23)[CH2:58]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C2CC2)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCCl
Product: N[C@@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C[C@H](C2CC2)[C@H]1O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (0.028 g, 0.11 mmol), HATU (0.056 g, 0.15 mmol) and DIPEA (0.051 mL, 0.29 mmol) in 1,2-dichloroethane (0.4 mL) was added a solution of (3R,4R,5S)-1-[7-(acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-cyclopropylpiperidin-4-yl acetate (0.050 g, 0.10 mmol) in 1,2-dichloroethane (0.5 mL). The reaction mixture was stirred at 45° C. for 1 h and then at ambient temperature overnight. The reaction mixture was diluted with EtOAc (40 mL) and H2O (3 mL). The layers were separated and the organic layer was washed with H2O (3×3 mL). The combined aqueous phases were extracted with EtOAc (3 mL). The combined organic extracts were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in THF (1.3 mL) and MeOH (0.4 mL) and to this was added 1 M aq. NaOH (1 mL) and the resulting mixture was stirred for 2.5 h at ambient temperature. The reaction mixture was diluted with EtOAc (40 mL) and neutralized by the addition of 1 M aq. HCl to adjust the pH to ˜7. The layers were separated, the organic layer was washed with H2O (3×3 mL) and the combined aqueous phases were extracted with EtOAc (3 mL). The combined organic extracts were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in 4 M HCl in 1,4-dioxane (2 mL) and stirred at ambient temperature for 30 min. The volatile organic solvents were removed under reduced pressure and the residue was re-dissolved in MeOH (5 mL) and neutralized by the addition of saturated NH4OH. The crude reaction mixture was purified by mass triggered preparative-HPLC (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the two 7-hydroxyl diastereoisomers of the title compound as two peaks.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[N:6]1([CH2:11][CH:12]([N:14]2[C:27]3[CH:26]=[C:25]([C:28]([OH:30])=O)[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH:31]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(#N)C>[CH:31]1([NH:36][C:28]([C:25]2[CH:24]=[CH:23][C:22]3[S:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH:12]([CH3:13])[CH2:11][N:6]4[CH2:7][CH2:8][CH2:9][CH2:10]4)[C:27]=3[CH:26]=2)=[O:30])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Reactant: NC1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NC3CCCC3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (5.2 cc) is added to a suspension, cooled to 5° C., of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (3.9 g) in methylene chloride (120 cc). The suspension is stirred for 3 hours at 25° C. and then concentrated to dryness at 30° C. under reduced pressure (30 mm Hg; 4 kPa) to give a yellow residue which is taken up in methylene chloride (50 cc) at 5° C. Cyclopentylamine (5 cc) is added and the mixture is stirred for 12 hours at 25° C., and saturated sodium bicarbonate solution (150 cc) is then added. The mixture is extracted with ethyl acetate (2×100 cc). The organic phase is washed successively with distilled water (100 cc) and with brine (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give a yellow oil which is dissolved in boiling acetonitrile (70 cc). Crystallization is primed by scratching. After cooling, the solid is separated by filtration, washed with acetonitrile (2×3 cc) and dried at 40° C. under reduced pressure (1 mm Hg; 0.13 kPa). N-Cyclopentyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (2.1 g) is obtained in the form of cream-coloured crystals, m.p. 132° C.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[OH:5][C:6]1[CH2:11][CH:10]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[CH2:9][C:8](=[O:21])[C:7]=1[C:22](=[O:25])[CH2:23][CH3:24].[C:26](Cl)(=[O:30])/[CH:27]=[CH:28]/[CH3:29].Cl>ClCCl>[OH:21][C:8]1[CH2:9][CH:10]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[C:14]([C:26](=[O:30])/[CH:27]=[CH:28]/[CH3:29])[C:13]=2[CH3:20])[CH2:11][C:6](=[O:5])[C:7]=1[C:22](=[O:25])[CH2:23][CH3:24]
Reactant: C/C=C/C(=O)Cl
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C/C(=O)c1c(C)cc(C)c(C2CC(=O)C(C(=O)CC)=C(O)C2)c1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 115.7 %

Procedure:
To a suspension of aluminum trichloride (4.0 g, 0.03 mole) in dichloromethane (20 ml) at 0° C. was added 3-hydroxy-5-mesityl-2-propionylcyclohex-2-en-1-one (2.9, 0.01 mole) in dichloromethane (10 ml). The mixture was stirred at 0° C. for five minutes and then crotonyl chloride (1.1 g, 0.01 mole) was added. Stirring was continued at 0° C. for 30 minutes and then at 20° C. for 3 hours. The brown solution was poured into cold dilute hydrochloric acid (2M, 200 ml) and shaken occasionally as it was allowed to warm to room temperature. The organic phase was separated and the aqueous phase was shaken with chloroform (2×100 ml). The combined organic extracts were dried over magnesium sulphate and evaporated to give 3-hydroxy-5-(3-crotonyl-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one (4.1 g, 83%) as a pale brown oil. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.16 (3H, t); 1.93 (3H, d, J=7 Hz); 2.07 (3H, s); 2.17 (3H, s); 2.38 (3H, s); 2.2-4.0 (7H, m); 6.1-6.8 (2H, m); 6.86 (1H, s); 18.20 (1H, s).