Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]([NH:17][CH:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:28][NH:29][O:30][CH3:31]>ClCCl.N1C=CC=CC=1>[CH2:7]([O:14][C:15](=[O:16])[NH:17][CH:18]1[CH2:19][CH2:20][CH:21]([C:24](=[O:26])[N:29]([O:30][CH3:31])[CH3:28])[CH2:22][CH2:23]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CNOC
Reactant: O=C(NC1CCC(C(=O)O)CC1)OCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)C1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
Oxalyl chloride (0.796 mL, 9.1 mmol) was added slowly to a solution of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid (2.3 g, 8.3 mmil) in dichloromethane (20 mL). The mixture was stirred at room temperature under nitrogen for 1 hour. Solvent was removed under reduced pressure. N,O-Dimethylhydroxylamine hydrochloride (0.971 g, 9.96 mmol) in anhydrous pyridine (10 mL) was added to the reaction residue. The mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. Ethyl acetate solution was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1.0 g (38%) of (4-(methoxy-methyl-carbamoyl)-cyclohexyl)-carbamic acid benzyl ester as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.36 (m, 5H), 4.59 (s, 2H), 3.88 (m, 1H), 3.70 (s, 3H), 3.17 (s, 3H), 2.76 (m, 1H), 1.86 (m, 2H), 1.66 (m, 6H).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10](OC(C)(C)C)=O)[CH2:5][C:4]=2[CH:3]=[N:2]1.Br[CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20]>>[CH3:10][N:6]1[CH2:7][CH2:8][C:9]2=[N:1][N:2]([CH2:18][C:19]([OH:21])=[O:20])[CH:3]=[C:4]2[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]ncc2C1
Reactant: O=C(CBr)OCc1ccccc1
Product: CN1CCc2nn(CC(=O)O)cc2C1

Procedure:
tert-Butyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (500 mg) was submitted to alkylation with benzyl bromoacetate, followed by cleavage of the Boc protecting group and subsequent methylation of the free amine using a method analogous to that of Precursor for Example 209 step 209.2 to step 209.4. However, the mixture of regioisomers was separated at the end of the three steps (Biotage, DCM/MeOH/TEA) to afford the two isomers:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH3:16][C:17]([O:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=1)=[O:22])([CH3:19])[CH3:18]>>[C:17]([O:20][C:21](=[O:22])[NH:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([NH:15][C:13]2[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[N:11]3[N:12]=2)=[O:32])=[CH:29][CH:30]=1)([CH3:19])([CH3:16])[CH3:18]
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)cc1

Procedure:
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 75 mg; 0.37 mmol; 1.0 eq.) and boc-(4-aminomethyl)-benzoic acid (113 mg; 0.45 mmol; 1.2 eq.) as a white foam (35.4 mg, 22%). HPLC, Rt: 3.69 min. (purity 88.9%). LC/MS, M+(ESI): 434.1, M−(ESI): 432.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=[CH:14][C:15]1[CH:24]=[CH:23][C:18](/[CH:19]=[CH:20]/[CH:21]=O)=[CH:17][CH:16]=1.[O:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:13]=[CH:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:19]=[CH:20]/[CH:21]=[C:29]2\[C:28](=[O:30])[NH:27][C:26](=[O:31])[O:25]\2)=[CH:23][CH:24]=1
Reactant: Cc1oc(-c2ccccc2)nc1C=Cc1ccc(/C=C/C=O)cc1
Reactant: O=C1COC(=O)N1
Product: Cc1oc(-c2ccccc2)nc1C=Cc1ccc(/C=C/C=C2/OC(=O)NC2=O)cc1

Procedure:
(E)-4-[2-(5-Methyl-2-phenyl-4-oxazolyl)vinyl]cinnamaldehyde and 2,4oxazolidinedione were reacted in the same manner as in Reference Example 28 to yield (E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)vinyl]cinnamylidene]2,4-oxazolidinedione, which was then recrystallized from chloroform-methanol to yield yellow needles having a melting point of 274°-275° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH2:18][CH3:19])=[O:6]
Reactant: CCO
Reactant: Cc1cc(Cl)c(Cl)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Cl)c(Cl)cc1C
Yield: 97 %

Procedure:
92.1 g (421 mmol) of the 3,4-dichloro-6-methylbenzoic acid obtained in the above step (2) was dissolved in 550 ml of ethanol as both an esterifying agent and a solvent, 20 ml of concentrated sulfuric acid as an acid catalyst was added, and the mixture was refluxed under heat for 7 hours. The ethanol was distilled off under reduced pressure, ice water was added, and the mixture was extracted with ethyl acetate twice. The resultant organic layer was consecutively washed with a sodium carbonate aqueous solution and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 103.4 g (yield 97%) of ethyl 3,4-dichloro-6-methylbenzoate as a crude product.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:19])=[CH:9][C:10]=2[Cl:18])[N:5]=1)([OH:3])=[O:2].[H][H]>CO.[Pt]=O>[C:1]([C@H:4]1[CH2:13][C@@H:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:19])=[CH:9][C:10]=2[Cl:18])[NH:5]1)([OH:3])=[O:2]
Reactant: COC(=O)c1cc(C(=O)O)nc2cc(Cl)cc(Cl)c12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Yield: 26.7 %

Procedure:
2-Carboxy-5,7-dichloro-4-methoxycarbonylquinoline (4.8 g) was dissolved in methanol (300 ml) and platinum oxide (0.48 g) was suspended in the solution. Rapid stirring under one atmosphere of hydrogen at room temperature for 75 minutes, followed by filtration and evaporation gave a crude product which was purified by chromatography on silica gel with 2.5% methanol, 0.5% acetic acid and 97% dichloromethane as eluent to give the title compound as a colourless solid (1.3 g, m.p. 154°-156° C.); δ (360 MHz, DMSO) 2.23 (1H, ddd, J=13.9, 7.1 and 5.3 Hz, CHACHBHCCHD), 2.66 (1H, dt, J=13.9 and 4.0 Hz, CHACHBHCCHD), 3.57 (3H, s, CH3), 3.86 (1H, dd, J=7.1 and 4.0 Hz, CHACHBHCCHD), 3.91 (1H, broad multiplet, CHACHBHCCHD), 5.74 (1H, broad s, NH), 6.56 (1H, d, J=1.9 Hz, 6-H or 8-H), 6.58 (1H, d, J=1.9 Hz, 6-H or 8-H); m/e 303 (M+) 198 (100%, M-H, CO2H and CO2Me); Found: C, 47.62; H, 3.60; N, 4.66. C12H11Cl2NO4 requires C, 47.39; H, 3.65; N, 4.61%.
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7]=1[C:15]([OH:17])=[O:16].[CH3:18]O>>[CH3:18][O:16][C:15]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][N:6]=1)[C:12]([OH:14])=[O:13])=[O:17]
Reactant: CO
Reactant: O=C(O)c1ccnc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(=O)O)ccn1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A 1.7 ml portion of concentrated sulfuric acid was added to 50 ml of methanol solution containing 5.0 g of pyridine-2,4-dicarboxylic acid, and the mixture was heated under reflux for 1 hour and 10 minutes. After cooling, this was poured into ice water and stirred at 5° C. for 3 hours, and the thus precipitated white solid was collected by filtration. A 5.7 g portion of this product was dissolved in 100 ml of methanol with heating, and the solution was cooled and then stirred at room temperature. By collecting the thus precipitated white solid by filtration, 2.5 g of the title compound was obtained.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[C:3]#[CH:4].C([Mg]Cl)#C.COC1C=C(C=CC=1)C=O.Br[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1/[C:30](=[CH:38]/[C:39]1[NH:40][CH:41]=[CH:42][C:43]=1[O:44][CH3:45])/[C:31](=[O:37])[NH:32]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[C:3]#[C:4][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1/[C:30](=[CH:38]/[C:39]1[NH:40][CH:41]=[CH:42][C:43]=1[O:44][CH3:45])/[C:31](=[O:37])[NH:32]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1cccc(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)c1

Procedure:
Using Method D above, 3-hydroxy-3-(3-methoxyphenyl)-1-propyne (151 mg, 1.0 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 3-methoxybenzaldehyde (Aldrich) according to Method A above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1) (220 mg, 0.69 mmol) using (Ph3P)2PdCl2 (100 mg) (Aldrich) and CuI (55 mg) (Aldrich) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 70° C. for 18 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(3-methoxyphenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 66 mg, 24%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][C:15]=2[O:14]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH2:18][N:1]3[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]3)=[CH:16][C:15]=2[O:14]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CC1CCN(Cc2ccc3c(c2)OCO3)CC1
Yield: 85.1 %

Procedure:
A mixture of ethyl piperidine-4-acetate (0.34 g, 2.0 mmol), 3,4-methylenedioxybenzyl chloride (0.34 g, 2.0 mmol), sodium carbonate (1.0 g) and sodium iodide (0.10 g) in acetonitrile (30 ml) was heated under reflux for 16 hours and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on SiO2 using dichloromethane plus 0-20% ethyl acetate as eluant. Appropriate fractions were combined and evaporated to give the title compound (0.52 g) as a colourless oil which was characterised by its 1H-NMR spectrum.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1)[CH3:4].[Cl:11][C:12]1[C:17]([F:18])=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[C:17]([F:18])=[C:16]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[CH2:3][CH3:4])[N:15]=[CH:14][N:13]=1
Reactant: CCC1CCCCN1
Reactant: Fc1c(Cl)ncnc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC1CCCCN1c1ncnc(Cl)c1F
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
0.07 g of sodium hydride (60% oil suspension) was suspended in 3 ml of tetrahydrofuran. 1 ml of tetrahydrofuran solution of 0.14 g of 2-ethylpiperidine was added dropwise at room temperature therein slowly, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 1 ml of tetrahydrofuran solution of 0.2 g of 4,6-dichloro-5-fluoropyrimidine at room temperature, and stirred for 4 hours. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.22 g of 4-chloro-6-(2-ethylpiperidino)-5-fluoropyrimidine.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[H-].[Na+].[CH3:24]I>>[CH:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[S:5][C:6]([C:7]([OH:9])=[O:8])=[C:2]([O:1][CH3:24])[N:3]=2)=[CH:13][CH:14]=1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1sc(-c2ccc(OC(C)C)cc2)nc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COc1nc(-c2ccc(OC(C)C)cc2)sc1C(=O)O
Yield: 72 %

Procedure:
Ethyl 4-hydroxy-2-(4-isopropoxyphenyl)-5-thiazolecarboxylate prepared in Example 22 was methylated with sodium hydride and methyl iodide and hydrolyzed by a conventional process to give 2-(4-isopropoxyphenyl)-4-methoxy-5-thiazolecarboxylic acid (yield: 72%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCCCCOCc1ccccc1
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCCCOCc2ccccc2)CC1

Procedure:
1-(4-Benzyloxybutyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-4-benzyloxybutane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)=[N:9]O)=[CH:4][C:3]=1[O:25][CH:26]([CH3:28])[CH3:27].C([O-])(=O)C.[NH4+]>CCO.[NH4+].[OH-].[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[C:15]([O:17][C:18]([F:22])([F:23])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)[NH2:9])=[CH:4][C:3]=1[O:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)Oc1cc(C(=NO)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1cc(C(N)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a suspension of (4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone oxime (3.5 g, 8.6 mmol) in EtOH (30 mL) and conc. NH4OH (50 mL) was added ammonium acetate (754 mg, 19.8 mmol), followed by zinc powder (3.2 g, 49.1 mmol) and the reaction mixture was heated at reflux for 3 h. The reaction mixture was allowed to cool to rt then filtered through celite. The solid was washed with 1 N NaOH (10 mL) and MeOH (10 mL). The combined filtrate was extracted concentrated and the residue was partitioned between EtOAc and water. The organic layer was separated and washed with 1 N NaOH (15 mL), sat. NaCl (2×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield (4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanamine (2.8 g, 83% yield) as a light yellow oil. LCMS: RT=1.76 min [M−NH2] 377.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 6.97-7.09 (4H, m), 6.81-6.89 (2H, m), 5.76-6.03 (1H, m), 5.14 (1H, s), 4.52 (1H, ddd, J=11.97, 6.15, 6.04 Hz), 1.73 (2H, bs), 1.29-1.36 (6H, m).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([O:18][CH3:19])[CH:4]=1)=O.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27]>CN(C=O)C>[S:27]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:1]1[C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([O:18][CH3:19])[CH:4]=1
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1OC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2nc3ccccc3s2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.8 %

Procedure:
In a DMF (3 mL) solvent in the presence of Na2S2O5 (136.1 mg, 0.71 mmol), a solution including Compound 122a (188.7 mg, 0.71 mmol) and 2-aminothiophenol (0.08 mL, 0.71 mmol) was stirred at room temperature for 2 days. After DMF was evaporated, the residual was distributed between ethyl acetate and water. An organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (EtOAc) (7:1) to obtain Compound 122b (244.8 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[CH3:16]C1C=CC(C=O)=CC=1.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([CH3:16])=[CH:8][CH:7]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccc(C)cc1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 4-methylbenzaldehyde instead 4-fluorobenzaldehyde. 1H-NMR (CDCl3): δ=2.35 (s, 3H); 3.83 (s, 3H); 6.13 (s, 1H); 7.21 (d, 2H); 7.28 (d, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:57])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:54])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:53])[CH2:21][CH2:22][C@@:23]3(/[CH:39]=[CH:40]/[C:41]([NH:43][C@H:44]([C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=4)[CH3:45])=[O:42])[CH2:35][CH2:34][C:33]([CH:36]([CH3:38])[CH3:37])=[C:24]32)[C:15]1([CH3:56])[CH3:55])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:52][C:48]1[CH:47]=[C:46]([C@@H:44]([NH:43][C:41](=[O:42])/[CH:40]=[CH:39]/[C@:23]23[CH2:35][CH2:34][C:33]([CH:36]([CH3:38])[CH3:37])=[C:24]2[C@@H:25]2[C@@:20]([CH3:53])([CH2:21][CH2:22]3)[C@@:19]3([CH3:54])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:55])([CH3:56])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:57])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH3:45])[CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2cccc(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of 1-tert-butyl 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((S)-1-(3-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (1556 mg, 1.934 mmol) in DCM (12 mL) stirred at room temp was added TFA (4 mL, 51.9 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was evaporated to dryness, then diluted with 200 ml DCM. The organic phase was washed with saturated NaHCO3 solution (200 mL*3), water and brine. The organics were dried and concentrated under reduced pressure to afford the crude product which was purified by preparative-HPLC to give the title compound (550 mg, 38%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.40-7.17 (m, 4H), 6.85 (d, J=15.3 Hz, 1H), 5.72-5.49 (m, 2H), 5.18 (t, J=7.2 Hz, 1H), 4.50 (dd, J=5.6, 10.7 Hz, 1H), 3.28-3.10 (m, 1H), 2.74-2.62 (m, 1H), 2.62-2.50 (m, 1H), 2.24 (br. s., 3H), 2.08-1.92 (m, 2H), 1.89-0.70 (m, 49H); LC/MS: m/z calculated 747.5. Found 748.2 (M+1)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:11]=[C:10]2[CH2:26][C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH3:32].[CH2:33]([Sn:37](Cl)([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36].O>O1CCCC1>[CH3:32][N:28]1[CH2:29][CH2:30][CH2:31][C@@H:27]1[CH2:26][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([Sn:37]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:33][CH2:34][CH2:35][CH3:36])[CH:8]=2)[N:12]([Si:16]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[CH:23]([CH3:25])[CH3:24])[CH:11]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C[C@H]2CCCN2C)c2cc(Br)ccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)c(C[C@H]1CCCN1C)cn2[Si](C(C)C)(C(C)C)C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
n-ButylLithium (7.80 ml of a 2.5M solution in hexanes, 19.49 ml) was added dropwise to a solution of 5-bromo-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1-triisopropylsilylindole (6.28 g, 13.97 mmol) (Preparation 58) in tetrahydrofuran (430 ml) at -78° C. The reaction was then stirred at -70° C. for 1/2 hour whereupon tri-n-butylstannylchloride (3.97 ml, 4.64 mmol) was added and the reaction stirred at -70° C. for 20 minutes. The reaction was then warmed to room temperature and 14.4 ml of water was added and the resulting solution partitioned (971/2:21/2) to afford, after combination and evaporation of the appropriate fractions, the title compound as an oil. Found: C,70.29; H,8.72; N,8.17. C30H43N3O2Si.1/8CH2Cl2 requires: C,70.07; H,8.44; N,8.14%.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:27]([CH3:28])=[CH:26][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]4[N:24]([CH3:25])[N:23]=[CH:22][C:19]4=[N:20][CH:21]=3)[S:15][C:11]=2[C:10]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].C(#N)C.[OH2:39]>>[C:1]([O:5][C@@H:6]([C:9]1[C:27]([CH3:28])=[CH:26][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]4[N:24]([CH3:25])[N:23]=[CH:22][C:19]4=[N:20][CH:21]=3)[S:15][C:11]=2[C:10]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([OH:39])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(-c3cnc4cnn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: O
Solvent: CC#N
Product: Cc1cc2nc(-c3cnc4cnn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)benzo[d]thiazol-6-yl)ethanol (50 mg, 0.099 mmol)in acetonitrile/water (2 mL/0.5 mL) was added CrO3/H5IO6 (0.439M, 1.1 mL, 0.483 mmol) and CrO3 (20 mg, 0.198 mmol). The reaction solution was stirred at room temperature for 1 h and quenched with 5% Na2S2O3 solution. The mixture was extracted with ethyl acetate, washed with water and brine. The organic solution was dried and concentrated to give crude which was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C27H25ClN4O3S: 521.14 (M+H+); Found: 521.2 (M+H+), 1H NMR (400 MHz, CD3OD) δ 9.20 (d, J=8 Hz, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.71-7.59 (m, 4H), 5.27 (s, 1H), 4.16 (s, 3H), 2.62 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([Si](C(C)C)(C(C)C)C(C)C)[CH:18]=[CH:17]3)=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:33][O:34][C:35](=[O:38])[C:36]#[CH:37].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:33][O:34][C:35](=[O:38])[CH:36]=[CH:37][N:19]1[C:20]2[C:16](=[CH:15][C:14]([CH2:13][CH2:12][C:11]3[C:2]([CH3:1])=[N:3][C:4]4[C:9]([CH:10]=3)=[CH:8][CH:7]=[CH:6][N:5]=4)=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: C#CC(=O)OC
Reactant: Cc1nc2ncccc2cc1CCc1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(=O)C=Cn1ccc2cc(CCc3cc4cccnc4nc3C)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A mixture of 2-methyl-3-[2-(1-triisopropylsilanyl-1H-indol-5-yl)-ethyl]-[1,8]naphthyridine (0.25 g, 0.74 mmol), propynoic acid methyl ester (0.07 g, 0.84 mmol), and tetrabutylammonium fluoride [1.0 M] (2.23 mL, 2.23 mmol) was stirred at room temperature overnight. The solvent was removed under reduced pressure to give a crude mixture which was purified via column chromatography with silica gel, eluting with methylene chloride/methanol (95/5) to give the title compound (66% yield) as an E/Z isomeric mixture. 1H NMR (CDCl3) δ 9.00 (m, 1H), 8.23 (s, 1H), 8.08 (m, 1H), 7.80 (m, 1H), 7.50 (d, 1H). Mass Spectrum (LCMS, ESI) calculated for C22H22N3O2 372.2 (M+H); found 372.2.