Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]([NH:9][C@@H:10]([CH3:28])[CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][C:14]=1[F:27])(=[O:8])[CH3:7].B(OC)(OC)[O:30]C.[OH-].[Na+].OO.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>C1COCC1>[C:6]([NH:9][C@@H:10]([CH3:28])[CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[C:15]([OH:30])[C:14]=1[F:27])(=[O:8])[CH3:7]
Reactant: COB(OC)OC
Reactant: CC(=O)N[C@@H](C)COc1ncc(NC(=O)OC(C)(C)C)cc1F
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)COc1ncc(NC(=O)OC(C)(C)C)c(O)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6M hexane solution, 11.4 mL) was added dropwise to a mixture of tert-butyl (6-(((2S)-2-acetamidopropyl)oxy)-5-fluoropyridin-3-yl)carbamate (1.70 g) and THF (20 mL) at −78° C. under an argon atmosphere, and the obtained mixture was stirred at −78° C. for 1 hr. To the reaction mixture was added trimethyl borate (2.36 mL), the obtained mixture was allowed to warm to room temperature, and stirred at room temperature overnight. The reaction mixture was cooled to 0° C., and a mixture of 8M aqueous sodium hydroxide solution (2.60 mL) and aqueous hydrogen peroxide (30%, 5 mL) were added thereto. The obtained mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium thiosulfate solution at 0° C., and the mixture was acidified with 6M hydrochloric acid, and extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.541 g).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]([CH:13]=[CH:14][CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[C:11]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].O.[OH-].[Na+:37]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:37]
Reactant: CC(C)n1c(C=CC(O)CC(O)CC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Reaction time: 9.5 h
Yield: 77.5 %

Procedure:
A 1 liter reactor was loaded with Fluvastatin tert-butyl ester (70 g, 0.15 mole), water (576 ml), THF (280 ml) and NaOH (6 g). After 2 h THF (35 ml) was added and the mixture was stirred for another 9.5 h. The solution was extracted with ethyl acetate (2×200 ml). The aqueous phase was distilled and acetonitrile (1050 ml) was added and the mixture was stirred at room temperature over night. The product was isolated by filtration under nitrogen flow, washed with acetonitrile and dried at 40° C. in a vacuum oven for 24 h to obtain 50.4 g (77.6%) of fluvastatin sodium crystal Form LXXIII (water content: 5.9% wt. % by KF, LOD by TGA 6.0 wt. %).
Reaction SMILES: [CH:1]1([C@@H:4]2[O:12][CH2:11][C@:7]3([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[F:20])[NH:8][O:9][CH2:10][C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.N[C@@]1(C2C=CC(F)=CC=2F)CO[C@@H](COCC2C=CC=CC=2)C[C@H]1CO>>[NH2:8][C@@:7]1([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH2:11][O:12][C@@H:4]([CH:1]2[CH2:2][CH2:3]2)[CH2:5][C@H:6]1[CH2:10][OH:9]
Reactant: Fc1ccc([C@]23CO[C@@H](C4CC4)C[C@H]2CON3)c(F)c1
Agent: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Product: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](C2CC2)C[C@H]1CO
Yield: 101.8 %

Procedure:
rel-(3aR,5R,7aS)-5-Cyclopropyl-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C19) (1.19 g, 4.23 mmol) was converted to the product according to the method described for the synthesis of [(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C6) in Preparation P1. The product was obtained as a thick, pale amber gum (1.22 g), which was taken directly to the following step without additional purification. LCMS m/z 284.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.61-7.77 (br m, 1H), 6.90-7.05 (br m, 1H), 6.82 (ddd, J=12.7, 8.6, 2.6 Hz, 1H), 4.13 (dd, J=11.5, 2.5 Hz, 1H), 3.55 (br dd, J=11, 2 Hz, 1H), 3.32-3.49 (br m, 2H), 2.89 (ddd, J=11.3, 8.2, 2.5 Hz, 1H), 2.03-2.34 (br m, 2H), 1.81 (ddd, J=14.0, 4.0, 2.6 Hz, 1H), 1.01-1.13 (br m, 1H), 0.53-0.65 (m, 2H), 0.41-0.48 (m, 1H), 0.24-0.32 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[C:26]1([C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:32]([NH:34][C:35]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[S:36])(=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 89%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=1)(=O)=O.[CH3:15][CH2:16]O>>[CH2:15]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[N:9][CH:8]=1)[CH3:16]
Reactant: CCO
Reactant: CS(=O)(=O)OCc1ccc(C#N)nc1
Product: CCOCc1ccc(C#N)nc1

Procedure:
(6-Cyanopyridin-3-yl)methyl methanesulfonate (199 mg, 0.94 mmol) in 2 mL anhydrous EtOH was heated at 85° C. in a sealed tube for 3.5 h. The mixture was concentrated and purified by silica gel chromatography (elution with 0-25% EtOAc/Hex) to afford 5-(ethoxymethyl)picolinonitrile (104 mg).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:21]=[C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:11]([C:7]2[CH:6]=[C:5]([CH2:4][CH2:3][C:1]#[N:2])[CH:10]=[CH:9][N:8]=2)=[N:12]1
Reactant: COC(=O)c1ccccc1S
Reactant: N#CCCc1ccnc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 50 %

Procedure:
4-(2-Cyanoethyl)-2-pyridinecarbonitrile (0.70 g, 4.5 mmol) and methyl thiosalicylate (1.1 g, 6.2 mmol) were dissolved in toluene (3.5 ml), and triethylamine (1.2 ml, 8.9 mmol) was added thereto. The reaction mixture was refluxed for 8 hrs and kept at room temperature. The precipitated crystals were collected by filtration and washed with toluene. The obtained crystals were recrystallized from tetrahydrofuran-ethanol to give the titled compound (0.66 g, 51%) as white crystals
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](O)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[C:16]1([S-:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+]>>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: [S-]c1ccccc1
Reactant: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Na+]
Product: CCOC(=O)c1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Yield: 64.4 %

Procedure:
The product from Example 53a (22.6 g, 67.6 mmol) was reacted with sodium thiophenolate (7.54 g, 67.6 mmol) for 24 h following the procedure from Example 1e giving the title compound as a solid (13.2 g, 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[CH:16](O)=[O:17]>>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][CH:16]=[O:17])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: O=CO
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Product: CCCCC1OC(=O)c2cc(NC=O)ccc21
Temperature: 0 °C

Procedure:
A solution of 3.07 g (0.015 mol) of the compound obtained in Example 4 in 15 ml of 85% formic acid is heated to 60° C. An hour later the reaction mixture is poured into ice-water. The separated solid is collected and crystallised from dilute ethanol to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][C:4]=1[O:12][CH3:13])#[N:2].[NH2:14][C:15]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([CH3:20])[C:16](OC)=[O:17]>>[OH:27][C:24]1[CH:23]=[CH:22][C:21]([C:15]2([CH3:20])[C:16](=[O:17])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([O:12][CH3:13])[CH:5]=3)[C:10](=[O:11])[NH:14]2)=[CH:26][CH:25]=1
Reactant: COC(=O)C(C)(N)c1ccc(O)cc1
Reactant: COc1cc(N=C=O)ccc1C#N
Product: COc1cc(N2C(=O)NC(C)(c3ccc(O)cc3)C2=O)ccc1C#N

Procedure:
The procedure of Example C is used, with 4-cyano-3-methoxyphenyl isocyanate starting from 2.2 g of methyl 2-amino-2-(4-hydroxyphenyl)propionate. After chromatography over silica and evaporation of the solvents 3.6 g of product, a yellowish solid, is obtained (Yd=92%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:8][C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[OH:10].C(Cl)CCCCCCC>>[C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH2:4][CH2:7][CH2:8][CH2:9][CH3:11].[C:17]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16][C:9]([CH2:8][C:7]([O:23][CH2:24][CH3:25])=[O:22])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[OH:10]
Reactant: CCCC(=O)O
Agent: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Solvent: CCCCCCCCCl
Product: CCCCCCCC(=O)O

Procedure:
The same procedure was used as for preparation of triethyl citrate butyrate but using octyl chloride.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH2:47]1[C:52]2([CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[CH2:51][CH2:50][CH:49]([OH:58])[CH2:48]1>>[Cl:17][C:18]1[C:19]([O:58][CH:49]2[CH2:48][CH2:47][C:52]3([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]3)[CH2:51][CH2:50]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OC1CCC2(CCCCC2)CC1
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OC2CCC3(CCCCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with spiro[5.5]undecan-3-ol, the title compound was obtained as a colorless solid (0.03 g, 7%). 1H NMR (300 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.29 (d, J=12.6 Hz, 1H), 4.68-4.60 (m, 1H), 2.86 (s, 6H), 1.84-1.74 (m, 2H), 1.66-1.51 (m, 4H), 1.39-1.21 (m, 12H); MS (ES−) m/z 445.2, 447.2 (M−1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([N:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:16][C:15]1=[O:31])(=[O:13])[CH3:12].[CH2:32]([O:39][CH2:40][C:41]1[C:42]([O:51][CH3:52])=[N:43][CH:44]=[CH:45][C:46]=1[C:47](=[O:50])[CH2:48][CH3:49])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([O:39][CH2:40][C:41]1[C:42]([O:51][CH3:52])=[N:43][CH:44]=[CH:45][C:46]=1[C@@:47]([OH:50])([CH2:48][CH3:49])[CH2:12][C:11]([N:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:16][C:15]1=[O:31])=[O:13])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Reactant: CCC(=O)c1ccnc(OC)c1COCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@](O)(CC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1)c1ccnc(OC)c1COCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A 10 ml round bottomed flask was charged with 389.4 μL lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 0.385 mmol, 1.1 eq) and the solution was cooled to −78° C. 108.4 mg (4R,5S)-3-acetyl-4,5-diphenyl-oxazolidin-2-one (0.385 mmol, 1.1 eq), as obtainable from Example 8, in 650 μL THF were slowly added (addition time: 5 min). During the addition, the color changed from colorless to bright yellow. After 2 h at −78° C., the solution was cooled to −95° C. and 100.0 mg 1-(3-benzyloxymethyl-2-methoxy-pyridin-4-yl)-propan-1-one (0.350 mmol), as obtainable from Example 7, dissolved in 400 μL THF were slowly added (addition time: 5 min). The solution was kept for additional 30 min at −95° C. and then for 45 min at −78° C. Subsequently, the reaction was quenched by addition of 5 mL aqueous 0.5 M HCl. The mixture was extracted three times with 10 mL, in total 30 mL dichloromethane and the combined extracts were dried over 1 g sodium sulfate (30 min) and filtered. The filter cake was washed with 2 mL dichloromethane. After removal of solvent in a rotary evaporator (40° C., 5 mbar), the title compound was obtained as a colorless oil (206.7 mg, 104% by weight, dr=92:8 (1H-NMR).
Reaction SMILES: C([O:8][C:9]1[CH:38]=[C:37]([Cl:39])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH2:21][CH2:20]3)[C:15]2=[O:36])=[C:11]([Cl:40])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[Cl:39][C:37]1[CH:38]=[C:9]([OH:8])[CH:10]=[C:11]([Cl:40])[C:12]=1[CH2:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C@H:19]2[CH2:20][CH2:21][C@H:22]([O:25][Si:26]([CH:27]([CH3:28])[CH3:29])([CH:33]([CH3:34])[CH3:35])[CH:30]([CH3:31])[CH3:32])[CH2:23][CH2:24]2)[C:15]1=[O:36]
Reactant: [H][H]
Reactant: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(O)cc3Cl)C2=O)CC1)(C(C)C)C(C)C

Procedure:
Stir (R)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-trans-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-2-one (Preparation 17) (1.83 g, 3.03 mmol) and palladium hydroxide (20% on carbon) (0.200 g, 10% by weight) in 100 ml of Ethyl Acetate. Bubble hydrogen gas through the solution while stirring at room temperature for 5 minutes. Stir the mixture under the hydrogen gas atmosphere for 5 hours. Filter through celite and strip the solvent to receive 1.42 g of the title compound (91%). Mass spectrum (apci) m/z=514 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([S:12][CH3:13])[CH:11]=1)[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2.[OH-].[Na+]>C1COCC1.CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([S:12][CH3:13])[CH:11]=1)[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(SC)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Reaction time: 48 h
Yield: 70.7 %

Procedure:
To a stirred solution of ethyl 6-chloro-8-(methylthio)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Step 3, 0.203 g, 0.575 mmol) in THF:EtOH:H2O (7:2:1, 5 mL), was added aqueous sodium hydroxide (0.63 mmol, 0.25 mL of 2.5 N soln.) and allowed to stir for two days. The resulting clear, yellow solution was concentrated in vacuo, was diluted with water (35 mL), and was acidified with concentrated HCl resulting in formation of a yellow suspension. Vacuum filtration of the suspension yielded the title compound as a yellow powder (0.132 g, 71%). 1HNMR (acetone-d6/300 MHz) 7.87 (s, 1H), 7.34 (d, J=2.2 Hz, 1H), 7.25 (d, J=2.2 Hz, 1H), 5.93 (q, 1H, J=7.05 Hz), 2.53 (s, 3H). LRMS m/z 323 (M−H); ESHRMS m/z 322.9782 (M−H, C12H7F3O3ClS, Calc'd 322.9757). Anal. Calc'd for C12H8F3O3ClS: C, 44.39; H, 2.48. Found: C, 44.63; H, 2.52.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][CH:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+].C(O)C.O>C(OCC)C.CS(C)=O.CCCCCC.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)CC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)C(c1ccccc1)=CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,3-Dihydro-5,6-dimethoxy-3-phenyl-1H-inden-1-one (8.010 g, 29.85 mmol) and NaBH4 (1.355 g, 35.82 mmol) were stirred in diethylether (100 mL) at 0° C. as ethanol (100 mL) was added slowly. The mixture was allowed to stir at room temperature for 24 hours. The mixture was then poured onto crushed ice and then washed with diethylether (3×100 mL). The organic fractions were then dried over MgSO4, filtered, and the volatile components were removed under vacuum resulting in the isolation of a yellow solid. This solid was refluxed in anhydrous DMSO (150 mL) for 5 hours and then cooled to room temperature. The mixture was poured onto crushed ice and the total volume was diluted to 500 mL using H2O. This mixture was then washed using diethylether (5×100 mL). The organic fractions were then combined, washed with H2O (1×100 mL) and then dried over MgSO4. The mixture was filtered and the volatile components were removed resulting in the isolation of a dark red oil. Chromatography of the oil on silica gel using hexane/CH2Cl2 (1/1 vol) as the diluent resulted in the isolation of the 5,6-dimethoxy-3-phenyl-1H-indene as a yellow microcrystalline solid (4.91 g, 65.2 percent yield).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[S:38])[NH:16][NH:17][C:18](=O)[C:19]3[CH:24]=[C:23]([CH2:25][C:26]#[C:27][CH3:28])[C:22]([O:29][CH2:30][O:31][CH3:32])=[CH:21][C:20]=3[O:33][CH2:34][O:35][CH3:36])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>>[CH2:25]([C:23]1[C:22]([O:29][CH2:30][O:31][CH3:32])=[CH:21][C:20]([O:33][CH2:34][O:35][CH3:36])=[C:19]([C:18]2[N:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)[C:15](=[S:38])[NH:16][N:17]=2)[CH:24]=1)[C:26]#[C:27][CH3:28]
Reactant: CC#CCc1cc(C(=O)NNC(=S)Nc2ccc(CN3CCOCC3)cc2)c(OCOC)cc1OCOC
Agent: [Na+]
Agent: [OH-]
Product: CC#CCc1cc(-c2n[nH]c(=S)n2-c2ccc(CN3CCOCC3)cc2)c(OCOC)cc1OCOC

Procedure:
4-[4-(morpholin-4-ylmethyl)-phenyl]-1-[5-(but-2-ynyl)-2,4-bismethoxymethoxy-benzoyl]thiosemicarbazide (F461-IM01: 71.3 mg, 0.133 mmol) and 5% aqueous sodium hydroxide (5 mL) were placed in a 30 mL eggplant shaped flask and heated under reflux for 2.5 hours. After completing the reaction, the reaction mixture was extracted with methylene chloride and concentrated under reduced pressure. The crude product (F461-IM02) thus obtained was subjected to the next reaction without purification in particular.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].Cl[Sn]Cl.O>C(O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:7])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(C)cccc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(C)cccc1Cl
Temperature: 97 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
N-[(2-Chloro-6-methylphenyl)carbonyl]-4-nitro-L-phenylalanine methyl ester (1.51 g, 4.0 mmol) and SnCl2.H2O (4.5 g, 20 mmol) were suspended in 30 mL of ethanol. The suspension was stirred at a bath temperature of 97° C. for 1 hr. After it was cooled to room temperature, the solvent was evaporated and the residue was dissolved in 15 mL of water. The aqueous solution was then made alkaline by addition of solid K2CO3 to pH>10 and was extracted with ethyl acetate (3×100 mL). The combined extracts were dried over K2CO3 and were concentrated to give 4-amino-N-(2-chloro-6-methylbenzoyl)-L-phenylalanine methyl ester as a light yellow foam (1.37 g).
Reaction SMILES: FC1C=CC=C(F)C=1C(NC1SC(C2C=CC=C(C(F)(F)F)C=2)=C(C=O)N=1)=O.C[Mg+].[Br-].[F:32][C:33]1[CH:60]=[CH:59][CH:58]=[C:57]([F:61])[C:34]=1[C:35]([NH:37][C:38]1[S:39][C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=2)=[C:41]([C:43]([OH:46])(C)[CH3:44])[N:42]=1)=[O:36]>>[F:32][C:33]1[CH:60]=[CH:59][CH:58]=[C:57]([F:61])[C:34]=1[C:35]([NH:37][C:38]1[S:39][C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:54])[F:55])[CH:48]=2)=[C:41]([CH:43]([OH:46])[CH3:44])[N:42]=1)=[O:36]
Reactant: CC(C)(O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: C[Mg+]
Agent: O=Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: [Br-]
Product: CC(O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1

Procedure:
Compound 74 was prepared from Compound 67 and MeMgBr similarly as described for the preparation of Compound 68.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[NH:5][CH:6]=[N:7]2.O=P(Cl)(Cl)[Cl:15]>C1(C)C=CC=CC=1>[Cl:15][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:1])[N:7]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc2nc[nH]c(=O)c12
Solvent: Cc1ccccc1
Product: Cc1cccc2ncnc(Cl)c12
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 1A (1.44 g, 9.0 mmol) in toluene (24 ml) was added POCl3 (13.5 ml) and DEA (3.6 ml). The mixture was refluxed under N2 for 30 min. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was dissolved in EtOAc, washed with 10% citric acid solution, followed by saturated NaHCO3. The residue was dried with MgSO4, filtered, and concentrated to give 1B (1.37 g, 85%) as a solid. 1H-NMR (400 MHz, CDCl3): 8.96 (s, 1H), 7.94 (d, J=8.52 Hz, 1H), 7.80 (dd, J=7.17 Hz, J=8.52 Hz, 1H), 7.51 (d, J=7.17 Hz, 1H), 3.05 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[OH:15][CH:16]([CH2:24][OH:25])[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH:16]([OH:15])[CH2:24][OH:25])[CH2:23][CH2:22]2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: OCC(O)CN1CCNCC1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(SC)nc1N1CCN(CC(O)CO)CC1

Procedure:
Grams 4.6 of 2-methylthio-4-chloropyrimidine-5-carboxylic acid ethyl ester and 6.4 g of 1-(2,3-dihydroxypropyl)piperazine in 50 ml dioxane were refluxed for 30 minutes. The mixture was cooled and settled, then the solvent was evaporated and the dried residue purified on column eluting with chloroform:methanol (9:1). Grams 4.8 of 2-methylthio-4-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyrimidine-5-carboxylic acid ethyl ester as an oil, were obtained.