Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][C:22]([CH3:33])([C:28]([O:30]CC)=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24].[OH-].[K+].O.Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])([CH3:33])[C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl)C(=O)O
Yield: 70.6 %

Procedure:
To a solution of the compound of Example 38 (16.8 g) in ethanol (167 mL) was added potassium hydroxide (2.40 g), and the resultant solution was stirred at 50° C. for 24 hours. To the reaction solution was added water, neutralized with 2 mol/L aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturatedbrine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane ethyl acetate=1:1) to obtain the target product (11.2 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1.[C:13]([O:17][C:18]([NH:20][C:21]([CH3:27])([CH3:26])[CH2:22][C:23](O)=[O:24])=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([NH:20][C:21]([CH3:27])([CH3:26])[CH2:22][C:23]([NH:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1)=[O:24])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: NC1Sc2ccccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)NC1Sc2ccccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 2-amino-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (Step A) and 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CD3OD): 1.26 (s,6H), 1.36 (s,9H), 2.47 (d,13 Hz,1H), 2.57 (d,13 Hz,1H), 5.52 (br s,1H), 6.31 (br s,1H), 7.00 (m,2H), 7.22 (m,2H). FAB-MS: calculated for C18H25N3O4S 379; found 380 (M+H,26%).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C(OCC)=O.S([N:27]=[N+:28]=[N-])(C1C=CC(C)=CC=1)(=O)=O>CCOCC.C(O)C>[N+:27](=[CH:4][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])=[N-:28]
Reactant: CC(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC=O
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
Sodium hydride (50% in oil, 0.53 g) is suspended in ether (20 ml), cooled to 0°, then treated dropwise with a mixture of acetophenone 1.2 ml) and ethyl formate (0.90 ml). The reaction is stirred 1 hr at 0° then overnight at 22°. The precipitate is filtered and washed well with ether to give a solid. The solid is suspended in ethanol (10 ml), cooled to 0°, then treated dropwise with tosyl azide (0.97 g). The reaction is stirred for 3 hrs, concentrated, dissolved in 1N sodium hydroxide and extracted with ether. The ether is washed with water, dried with sodium sulfate and concentrated to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:34])[NH:21][C:22]3[CH:23]=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][C:26]=4[O:32][CH3:33])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:35]([O:37]C)=[O:36])#[N:2].O[Li].O>C1COCC1.CO.C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:34])[NH:21][C:22]3[CH:23]=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][C:26]=4[O:32][CH3:33])=[CH:18][CH:19]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:35]([OH:37])=[O:36])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cnc5c(OC)cccc5c4)cc3)c(C#N)cc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc2cc(NC(=O)c3ccc(Oc4cc5c(cc4C#N)C(C(=O)O)CCO5)cc3)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
To a solution of methyl 6-cyano-7-(4-(8-methoxyquinolin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.061 g, 0.120 mmol) in THF (2 mL) was added LiOH—H2O (0.239 mL, 0.239 mmol) and added a few drops of methanol to ensure a homogeneous solution. The reaction was stirred at ambient temperature for 3 hours. A few drops of acetic acid were added to the reaction and the solution concentrated to a yellow/white solid. The crude material was purified by silica gel column chromatography using 5% methanol/dichloromethane+0.1% acetic acid to provide the desired product (0.023 g, 39%). MS (APCI)=496.3 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH2:12][N:13]1[C:20]2[N:16]([N:17]=[CH:18][CH:19]=2)[CH:15]=[CH:14]1)=O)C.[F-].[Na+].O>O1CCCC1>[OH:9][CH2:10][CH2:12][N:13]1[C:20]2[N:16]([N:17]=[CH:18][CH:19]=2)[CH:15]=[CH:14]1
Reactant: CCOC(=O)Cn1ccn2nccc12
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCCn1ccn2nccc12
Yield: 77 %

Procedure:
To a suspension of lithium aluminum hydride (1.57 g) in tetrahydrofuran (80 ml) was dropwise added a solution of 1-ethoxycarbonylmethyl-1H-imidazo[1,2-b]pyrazole (8 g) in tetrahydrofuran (40 ml) at 50° C. The mixture was refluxed for 1 hour. The reaction mixture was cooled under ice-bath. To a cooled mixture was added sodium fluoride (6.95 g) and then water (2.23 ml) was added thereto under ice-cooling. The insoluble material was filtered off and the filtrate was evaporated to give the crystals. The crystals were washed with isopropyl ether and dried to give 1-(2-hydroxyethyl)-1H-imidazo[1,2-b]-pyrazole (4.82 g).
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([O:34][CH3:35])[CH:25]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(NC(C)C)(C)C.C(OCC)C>[CH3:35][O:34][C:26]1[CH:25]=[C:24]([CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])[CH2:23][C:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCC1
Reactant: COC(=O)c1ccc(CBr)cc1OC
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: COC(=O)c1ccc(CC2(C(=O)O)CCCC2)cc1OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1.61 mL of cyclopentanecarboxylic acid was dissolved in 5 mL of tetrahydrofuran, and this mixture was added dropwise to 50 mL of solution of lithium diisopropylamide in tetrahydrofuran prepared from 20.9 mL of n-butyllithium in n-hexane (1.56 M) and 4.58 mL of diisopropylamine at −30° C., and then this mixture was stirred for one hour at 50° C. and for another one hour at room temperature. After the reaction mixture was cooled to −30° C., a solution of 5.00 g of methyl 4-(bromomethyl)-2-methoxybenzoate in 5 mL of tetrahydrofuran was added dropwise to this mixture, which was then stirred for 1.5 hours at −10° C. and for another 1.5 hours at room temperature. A saturated aqueous solution of ammonium chloride and diethyl ether were successively added to the reaction mixture, and the organic phase was separated therefrom. A saturated aqueous solution of sodium hydrogen carbonate was added to the resultant organic phase, from which an aqueous phase was separated, followed by adjustment to pH 2 with 6M hydrochloric acid, and then the organic layer was separated therefrom by adding chloroform thereto. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:2] to yield 0.718 g of 1-[3-methoxy-4-(methoxycarbonyl)benzyl]-cyclopentanecarboxylic acid as colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:13])[S:11][CH:12]=2)=[CH:4][C:3]=1[C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=[O:15].[CH3:28][O-:29].[Na+]>CO>[CH3:28][O:29][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:13])[S:11][CH:12]=2)=[CH:4][C:3]=1[C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=[O:15]
Reactant: COc1cc(C(=O)c2cc(-c3csc(C)n3)ccc2F)cc(OC)c1OC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2csc(C)n2)cc1C(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
(2-Fluoro-5-(2-methylthiazol-4-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (50 mg, 0.13 mmol) as a synthetic intermediate of Compound 596 was dissolved in NaOMe (2 ml) and methanol (5 ml). The solution was heat refluxed for 3 hours. After completion of the reaction, the reaction solution was extracted with water and dichloromethane, and the organic layer was vacuum concentrated.
Reaction SMILES: Br[C:2]1[N:3]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:4]2[C:9]([C:10]=1[S:11][C:12]1[C:13]([F:23])=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=[C:6]([Cl:24])[C:5]=2[F:25].BrC1C=N[CH:36]=[CH:37][CH:38]=1.N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[Cl:24][C:6]1[C:5]([F:25])=[C:4]2[C:9]([C:10]([S:11][C:12]3[C:13]([F:23])=[C:14]([CH:20]=[CH:21][CH:22]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([CH:37]3[CH2:38][CH2:36]3)[N:3]2[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][CH:7]=1
Reactant: Brc1cccnc1
Reactant: CCOC(=O)c1cccc(Sc2c(Br)n(-c3cccnc3)c3c(F)c(Cl)ccc23)c1F
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cccnc3)c3c(F)c(Cl)ccc23)c1F
Temperature: 140 °C
Reaction time: 40 h
Yield: 8.6 %

Procedure:
To a stirred solution of compound 2 (100 mg, 0.24 mmol) in toluene (5 mL) were added 3-bromopyridine (59.3 mg, 0.36 mmol), trans-1,2-diaminocyclohexane (11.2 mg, 0.098 mmol), K3PO4 (130 mg, 0.65 mmol), CuI (4.6 mg, 0.024 mmol) at RT under argon in a sealed tube. The solution was purged with argon; heated to 140° C. and stirred for 40 h. The mixture was cooled to RT, added n-hexane (6 mL), stirred for 5 minutes and then filtered. The filtrate was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water and brine solution, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. This was purified (silica gel; 5-10% EtOAc/hexanes) to afford compound 3 (10 mg, 8.4%) as a pale brown solid. 1H NMR (400 MHz, CDCl3): 8.77 (br s, 2H), 7.81 (d, J=8.0 Hz, 1H), 7.68-7.62 (m, 1H), 7.53-7.50 (m, 1H), 7.25-7.23 (m, 1H), 7.17-7.11 (m, 1H), 6.96 (t, J=7.6 Hz, 1H), 6.82 (dt, J=8.4, 1.6 Hz, 1H), 4.40 (q, 2H), 1.65-1.60 (m, 1H), 1.41 (t, J=7.2 Hz, 3H), 0.91-0.82 (m, 4H); LC-MS (ESI): m/z 485.5 (M+H+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[CH:14]1C=CC=C[CH:15]=1.C(O)C.S(=O)(=O)(O)O>O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:14][CH3:15])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(CCCBr)cc1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(CCCBr)cc1
Reaction time: 23 h

Procedure:
A mixture of p-(3-bromopropyl)benzoic acid (100.8 g.; 0.41 mole), benzene (290 ml.), ethanol (60 ml.) and concentrated sulfuric acid (1.4 ml.) is heated under reflux under a Dean and Stark constant water separator until the evolution of water ceases. The time required is 23 hours.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[C:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:9]1(=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)CCCCC=C1CCCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCCCCCC=C1CCCC1
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
To a stirred solution of 6-cyclopentylidene-hexanoic acid methyl ester (2.77 g, 14.1 mmol) in toluene (130 mL) was added DIBAL-H (35.3 mL, 1 M solution in hexane, 35.3 mmol) dropwise at 0° C. under N2. After sting at 0° C. for 30 min, the reaction was quenched by MeOH (10 mL). Saturated aqueous sodium potassium tartrate (80 mL) was added to the reaction mixture. After stirring for 1 h, the organic layer was separated and the aqueous phase was extracted with ether. The combined organic layers were washed with water and brine and dried. Evaporation of the solvent gave 6-cyclopentylidene-hexan-1-ol (2.47 g, 98%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.24 (1H, m), 3.63 (2H, t, J=6.6 Hz), 2.21 (4H, m), 1.97 (2H, m), 1.50–1.70 (6H, m), 1.34 (2H, m); 13C NMR (75 MHz, CDCl3) δ 143.28, 120.08, 63.22, 33.82, 33.00, 29.81, 29.75, 28.87, 26.72, 26.63, 25.73.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=O)=O.Br.Br.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[N:29]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:18]2[CH2:19][CH2:20][CH:21]([NH:24][C:25]3[S:26][C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[N:29]=3)[CH2:22][CH2:23]2)=[CH:13][CH:12]=1
Reactant: c1ccc2sc(NC3CCNCC3)nc2c1
Reactant: COc1ccc(CCOS(C)(=O)=O)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(CCN2CCC(Nc3nc4ccccc4s3)CC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A mixture of 2.3 parts of [2-(4-methoxyphenyl)ethyl] methanesulfonate, 4 parts of N-(4-piperidinyl)-2-benzothiazolamine dihydrobromide, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide was stirred overnight at 70° C. The reaction mixture was poured onto water and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.5 parts (41%) of N-[1-[2-(4-methoxyphenyl)-ethyl]-4-piperidinyl]-2-benzothiazolamine; mp. 142.5° C. (178).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:4]=1.Cl.[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[CH3:32]>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:37])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:4]=1
Reactant: CCOC(=O)CN
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1
Agent: Cl
Product: CCOC(=O)CNc1nc(SC)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1[N+](=O)[O-]

Procedure:
In a similar manner, 2-methylthio-4-chloro-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (K), is treated with glycine ethyl ester hydrochloride, a compound of formula (D), to yield 2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (L).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([OH:12])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=C1Nc2c(Br)cccc2C1=O
Solvent: O
Product: O=C1Nc2c(Br)cccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
7-bromoisatin (0.113 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[C:22]([N+:33]#[C-:34])[S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:4]=1.Cl[CH2:36][O:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:22]([N+:33]#[C-:34])([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:36][O:37][CH3:38])[CH:4]=1
Reactant: [C-]#[N+]C(=C1CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C)S(=O)(=O)c1ccc(C)cc1
Reactant: COCCl
Product: [C-]#[N+]C(COC)(C1=CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared according to the process described in Example 8a, starting with 3-methoxy-17-(isocyano-p-methylphenylsulfonylmethylene)-androsta-3,5-diene (477 mg, 1 mmol) and chloromethylmethylether (0.2 ml). Yield: 385 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:35]1[N:40]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:39][CH2:38][O:37][CH2:36]1.C(=O)([O-])O.[Na+]>O1CCCC1.N1C=CC=CC=1.CN(C)C=O.ClCCl>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:27])[CH3:28])=[CH:14][C:10]=1[C:11]([NH:47][C:44]1[CH:43]=[CH:42][C:41]([N:40]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[CH:46][CH:45]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)c1cc(C(=O)Nc2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A dichloromethane (30 mL) solution of 2,4-bis-benzyloxy-5-isopropylbenzoic acid (F370-IM1, 2 g, 5.31 mmol) was mixed with dimethylformamide (0.053 mL, 0.05 mmol) and oxalylchloride (0.61 mL, 6.38 mmol) under ice cold conditions and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue thus obtained was dissolved in tetrahydrofuran (30 mL) and pyridine (10 mL). To the solution was added 4-(4-morpholino)aniline (1.04 g, 5.84 mmol) under ice cold conditions. The reaction was carried out at room temperature for 1 hour. Dichloromethane (50 mL) and 5% aqueous sodium hydrogencarbonate (20 mL) were added to the reaction mixture. The aqueous layer was separated and extracted with dichloromethane, the combined organic layers thus obtained were washed with saturated aqueous sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure. To the residue were added ethyl acetate (5 mL), toluene (5 mL) and hexane (20 mL), and the resulting suspension was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to obtain the title compound (F370-IM2: white crystals, 2.47 g, 87%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[O:11][C:12]=2[CH3:13])=[CH:6][CH:5]=[N:4]1)[CH3:2].C1C(=O)N([Cl:25])C(=O)C1>C1COCC1>[Cl:25][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[C:8]1[CH:9]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[O:11][C:12]=1[CH3:13]
Reactant: CCn1nccc1-c1cc(C(=O)OC)oc1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCn1ncc(Cl)c1-c1cc(C(=O)OC)oc1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A mixture of methyl 4-(1-ethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (950 mg, 4.06 mmol) and NCS (650 mg, 4.87 mmol) in THF (10 mL) was heated at 70° C. in a sealed tube. After 2 h, the reaction mixture was concentrated and purified via column chromatography (silica, 10-20% EtOAc/Hexane) affording the title compound (970 mg, 89%) as a white solid: LC-MS (ES) m/z 269 (M+H)+.
Reaction SMILES: CN1CCOCC1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([C:22]([O:24]CC)=O)[S:20][CH:21]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9].ClC(OCC(C)C)=O.Cl.[CH3:36][O:37][C:38](=[O:44])[C@H:39]([CH:41]([CH3:43])[CH3:42])[NH2:40]>C1COCC1.C(N(CC)CC)C>[CH3:42][CH:41]([CH3:43])[CH:39]([NH:40][C:22]([C:19]1[S:20][CH:21]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=2)[N:18]=1)=[O:24])[C:38]([O:37][CH3:36])=[O:44]
Reactant: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
N-methyl morpholine (1.8 gm) was added to a solution of 4-(4-nitrophenyl)thiazole-2-carboxylic acid (Intermediate 3, step B, 4.5 gm) in THF (300 ml). The reaction mixture was stirred for 5 minutes and then cooled to −20° C. Isobutyl chloroformate (2.45 gm) was added to it and the reaction mixture was stirred for 20 minutes. To it was added L-valine methyl ester hydrochloride (7.2 gm) previously neutralized with triethylamine (4.63 gm) and the reaction mass was stirred for 3 hours as the temperature rose to RT. Organic solvent was concentrated and compound was purified by column chromatography (silica gel, EtOAc-petroleum ether) to obtain yellow solid as title compound. Yield: 4.4 gm (67%). 1H NMR (DMSO-d6, 300 MHz): δ 8.36 (d, 2H), 8.14 (d, 2H), 7.94 (s, 1H), 7.80 (d, 1H), 4.77 (t, 1H), 3.83 (s, 3H), 2.37 (m, 1H), 1.071 (s, 6H).
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16]Br)[C:14](=[O:18])[O:13][CH2:12][C@H:11]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:10](=[O:27])[O:9][C@H:8]1[CH3:28])(=[O:5])[CH:2]([CH3:4])[CH3:3].CCCC[SnH](CCCC)CCCC>C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH3:16])[C:14](=[O:18])[O:13][CH2:12][C@H:11]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:10](=[O:27])[O:9][C@H:8]1[CH3:28])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a solution of (3S,6S,7R,8R)-8-(bromomethyl)-3-(tert-butoxycarbonylamino)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (238 mg, 0.51 mmol) in benzene (3 mL) was added Bu3SnH (178 mg, 0.61 mmol) and AIBN (2 mg) at room temperature (about 22° C.). The reaction solution was heated to reflux, stirred for 1 hr, and the solution was cooled to room temperature. The solvent was removed under vacuum and the residue was purified via column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (185 mg, 94%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 5.40-5.12 (m, 2H), 5.00 (t, J=9.8 Hz, 1H), 4.93-4.71 (m, 2H), 3.69-3.47 (m, 1H), 2.69-2.50 (m, 2H), 1.45 (s, J=4.7 Hz, 9H), 1.28 (d, J=6.3 Hz, 3H), 1.21 (dd, J=7.0, 1.2 Hz, 6H), 1.13 (d, J=6.7 Hz, 3H); ESIMS m/z 410 ([M+Na]+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.C(O)(=O)[CH2:9][C:10]([OH:12])=[O:11].C([O-])(=O)C.[NH4+]>CN(C=O)C.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccs1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1cccs1
Temperature: 100 °C

Procedure:
A mixture of thiophene-2-carbaldehyde (Compound 66a) (1.20 g, 0.0107 mol), malonic acid (1.11 g, 0.0107 mol) and ammonium acetate (0.825 g, 0.0107 mol) in DMF (8.5 mL) was heated to 100° C. for 3 h. The system was diluted with ethyl acetate and washed with water and dried over MgSO4. The solvent was removed in vacuo and the title compound was purified by silica gel column chromatography using 3:1 Hexanes:ethyl acetate as the eluent.