Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:15]/[O:16][CH3:17])/[C:12]([OH:14])=[O:13])[N:10]=1)=[O:4].[I:18]N1C(=O)CCC1=O>CC(N(C)C)=O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([I:18])=[C:9](/[C:11](=[N:15]/[O:16][CH3:17])/[C:12]([OH:14])=[O:13])[N:10]=1)=[O:4]
Reactant: CO/N=C(\C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)N(C)C
Product: CO/N=C(\C(=O)O)c1nc(NC(=O)CCl)sc1I
Temperature: 60 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 13.9 g of 2-(2-chloroacetamidothiazol-4-yl)-2(Z)-methoxyiminoacetic acid in 30 ml of dimethylacetamide, 17.0 g of N-iodosuccinimide is added and the mixture is stirred at 60° C. for 1 hour. Then, the reaction mixture is processed as in Reference Example 37 to give 19.6 g (97% yield) of the above-identified compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4]N(C)C)[CH3:3].C(Cl)(=O)C.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:22]3[C:23]([CH3:26])=[N:24][N:25]=[C:21]3[CH2:20][N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[CH:33]=1.C(=O)(O)[O-].[Na+].[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:41][CH:40]=1>CN(C)C=O.C(O)C>[C:39]1([CH3:49])[CH:40]=[CH:41][C:42]([S:45]([OH:48])(=[O:46])=[O:47])=[CH:43][CH:44]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:22]3[C:23]([CH2:26][CH2:1][N:2]([CH3:4])[CH3:3])=[N:24][N:25]=[C:21]3[CH2:20][N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[CH:33]=1
Reactant: CN(C)CN(C)C
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Solvent: CCO
Product: CN(C)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 64.6 %

Procedure:
A stirred solution of N,N,N',N'-tetramethyldiaminomethane (2.244 g., 0.022 mole) in dry dimethylformamide (50 ml.) was cooled in an ice bath and treated dropwise with acetyl chloride (1.65 ml., 0.023 mole). The ice bath was removed and the mixture was kept at 25° for 45 min. and treated with 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (3.09 g., 0.01 mole). After 30 min. the mixture was poured into ice water, made alkaline with sodium bicarbonate, saturated with sodium chloride and extracted with chloroform. The extract was washed with a dilute salt solution, dried over anhydrous sodium sulfate and concentrated in vacuo using xylene and toluene to help remove residual dimethylformamide. A solution of the residue in ethanol was acidified with a solution of one equivalent of p-toluenesulfonic acid in ethanol and crystallized to give 8-chloro-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine p-toluenesulfonate in three crops; 2.69 g. of melting point 195°-196° C.; 0.751 g. of melting point 192°-195.5° C. and 0.033 g. of melting point 195°-197° C. The total yield was 64.6%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCN(CCCN)CC1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Product: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
Using 1-iodo-4-nitro-benzene (500 mg) instead of 1-bromo-3-nitro-benzene, and 3-(4-methyl-piperazin-1-yl)-propylamine (379 mg) instead of morpholine, in the same manner as Step A in Example 1-D-105, the desired compound was obtained (432 mg, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)[CH:23]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH2:35][CH3:36])[N:9]=2)=[CH:4][CH:3]=1.[CH2:37]([N:39]=[C:40]=[O:41])[CH3:38]>>[CH3:38][CH2:37][NH:39][C:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[C:14]=3[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH:23]=3)[NH:19]4)=[CH:11][N:10]([CH2:35][CH3:36])[N:9]=2)=[CH:6][CH:7]=1)=[O:41]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN5CCOCC5)c4)cc23)c(-c2ccc(N)cc2)n1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2ccnc3[nH]c(-c4cccc(CN5CCOCC5)c4)cc23)cc1

Procedure:
Following the procedure described in Example 48 using 4-[3-(4-aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(N-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine and ethyl isocyanate provided the title compound. ESMS (M+H)+: 550.6
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[C:28]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C1COCC1.C(=O)(O)[O-].[Na+]>[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:5][CH2:6][N:7]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:8][CH2:9]1)#[N:3]
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride (0.050 g, 0.12 mmol, 1.0 equiv), cyclohexanone (0.015 g, 0.15 mmol, 1.2 equiv), and Na(OAc)3BH (0.046 g, 0.22 mmol, 1.75 equiv) were mixed in 15 mL of 1% AcOH in THF. The reaction was stirred at room temperature for 16 h. The reaction was diluted with 25 mL of saturated sodium bicarbonate solution and the product was extracted 4×25 mL EtOAc. The organic extracts were combined and concentrated. The crude product was purified by semi-prep reverse-phase HPLC using 20 to 80% CH3CN in water over a gradient of 25 min to yield the desired product, pure, as a white solid (0.012 g, 21%); MS, m/z 448=M+1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22]C=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C=C[N:43]3[C:56](=[O:57])[N:55]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[N:54]=C3C=2OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][N:43]5[C:56](=[O:57])[N:55]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[N:54]=[C:22]5[C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1nc2c3oc(-c4ccccc4)c(I)c(=O)c3ccn2c1=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccn5c(=O)n(COCC[Si](C)(C)C)nc45)c3=O)cc2)CCC1
Yield: 78 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalene-3,6-dione was reacted to give the title compound as a pale yellow gum (24 mg, 78%). LCMS (Method A): RT=5.02 min, [M+H]+=655.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=[C:15]=[S:16])[N:3]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]2[CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][C:15](=[S:16])[N:5]2[N:6]=1
Reactant: Cc1nc(Cc2ccccc2N=C=S)n[nH]1
Solvent: Cc1ccccc1
Product: Cc1nc2n(n1)C(=S)Nc1ccccc1C2
Temperature: 25 °C

Procedure:
A suspension of 8 g of 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazole in 100 ml of toluene is refluxed overnight and cooled to room temperature to give 2-methyl-11H-1,2,4-triazolo[2,3-c][1,3]-benzodiazepine-5(6H)-thione. Treatment with methyl iodide as described above yields 2-methyl-5-methylthio-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 55 °C
Reaction time: 0.05 h
Yield: 54.8 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.72 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (418 mg, 2.58 mmol) in N,N-dimethylformamide (7 mL) was stirred 13 minutes. In one portion benzyl alcohol (534 μL, 5.16 mmol) was added. The solution was stirred for 17.5 hours at room temperature and 2.75 minutes at 55° C. The solution was allowed to cool to room temperature and water (10 mL) was added. The insoluble material was filtered and dried to give the title compound (360 mg, 55% yield, m.p. 254° C.).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:21].[C:22]([NH:29][C@H:30]([C:38](O)=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].N1(C2C=CN=CC=2)CCCC1.Cl>C(Cl)Cl>[O:9]=[C:8]1[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:3](=[O:21])[CH:2]1[NH:1][C:38](=[O:39])[C@@H:30]([NH:29][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN1C(=O)C(N)C(=O)N(c2ccccc2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CN1C(=O)C(NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N(c2ccccc2)c2ccccc21
Reaction time: 16 h
Yield: 111.3 %

Procedure:
A mixture of 2.4 g of the product of Step D, 40 ml of methylene chloride, 2.26 g (8.5 mmoles) of BOC-L-phenylalanine, 1.8 g (9.4 mmoles) of dicyclohexycarbodiimide and 1.26 g (8.5 mmoles) of 4-pyrrolidinopyridine was stirred for 16 hours. The mixture was poured into 100 ml of hydrochloric acid and the decanted organic phase was washed three times with water. After drying, the solvent was eliminated to obtain 5 g of a yellowish foam.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.I[CH2:14][CH3:15]>CN(C=O)C>[CH2:14]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[Br:3])[CH:9]=[CH:10]1)[CH3:15]
Reactant: CCI
Reactant: Brc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2cccc(Br)c21
Reaction time: 0.33 h

Procedure:
To a 60% dispersion of sodium hydride in mineral oil (0.80 g, 21 mmol), suspended in DMF (50 mL), was added 7-bromoindole (2.0 g, 10 mmol) in DMF (15 mL) followed by a solution of iodoethane (1.64 mL, 26.3 mmol). After 20 minutes, the mixture was quenched with saturated NaHCO3, and poured into EtOAc. The organic layer which was separated, washed with saturated NaHCO3, dried (MgSO4) and concentrated to afford 1-ethyl-7-bromoindole as a brown oil which was used without further purification.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Br:12][C:13]1[C:14]([Cl:23])=[N:15][CH:16]=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1.I[CH2:25][CH3:26]>O>[Br:12][C:13]1[C:14]([Cl:23])=[N:15][CH:16]=[C:17]([S:19]([CH2:25][CH3:26])(=[O:21])=[O:20])[CH:18]=1
Reactant: CCI
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCS(=O)(=O)c1cnc(Cl)c(Br)c1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Sodium sulfite (1.755 g, 13.92 mmol) and sodium bicarbonate (1.231 g, 14.65 mmol) were dissolved in water (37 mL) to give a colorless solution. The mixture was heated at 75° C. 3-Bromo-2-chloropyridine-5-sulfonyl chloride (2.132 g, 7.33 mmol) was added portionwise over 1 hour. The reaction mixture was stirred at 75° C. for 1 hour. The mixture was concentrated and N,N-dimethylformamide (13.88 mL) was added. Sodium bicarbonate (1.231 g, 14.65 mmol) and iodoethane (0.589 mL, 7.33 mmol) were added. The resulting mixture was heated to 75° C. for 2 hours and then cooled to ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate/heptane) to provide the title compound.
Reaction SMILES: [CH2:1]=[N:2][N:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH2:5][CH2:4]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C.O1CCCC1>[CH3:1][NH:2][N:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[CH2:5][CH2:4]1
Reactant: C=NN1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNN1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Yield: 55.8 %

Procedure:
To a methanol (50 ml)-tetrahydrofuran (30 ml) mixed solvent was added the compound (4.93 g, 16.53 mmol) obtained in step D, sodium cyanoborohydride (1.35 g, 21.49 mmol) was added under ice-cooling with stirring, and acetic acid (1 ml) and methanol (10 ml) solution were added dropwise by a small amount. After the completion of the dropwise addition, the mixture was further stirred at the same temperature for 30 min. The reaction mixture was poured into diluted aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (chloroform-methanol) to give the title compound (2.77 g, yield 56%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[N:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.[OH-].[Na+]>>[NH2:8][C:6]1[N:5]([OH:18])[C:4](=[NH:9])[N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: [Na+]
Agent: [OH-]
Product: N=c1nc(Cl)cc(N)n1O
Reaction time: 4 h
Yield: 44.7 %

Procedure:
A 30 g. (0.15 mole) quantity of 4-chloro-2,6-diaminopyrimidine is dissolved in 600 ml. of hot 3A alcohol, the solution cooled to 0°-10° C. and 41.8 g. (0.24 mole) of m-chloroperbenzoic acid is added. The mixture is held at 0°-10° C. for 4 hours and filtered. The solid is shaken for 2 hours in 0.24 mole of 10% sodium hydroxide and filtered. The solid is washed with water and dried to yield 19.3 g. of crude product. This product is extracted for 1 hour with 900 ml. of boiling acetonitrile to yield 14.8 g. (44.7% yield) of 6-amino-4-chloro-1,2-dihydro-1-hydroxy-2-imino pyrimidine, m.p. 193° C.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[C:87]([O:91][C:92]([NH:94][C@H:95]1[CH2:99][CH2:98][N:97]([CH2:100][C:101]([OH:103])=O)[C:96]1=[O:104])=[O:93])([CH3:90])([CH3:89])[CH3:88]>>[C:87]([O:91][C:92]([NH:94][C@H:95]1[CH2:99][CH2:98][N:97]([CH2:100][C:101]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:103])[C:96]1=[O:104])=[O:93])([CH3:88])([CH3:89])[CH3:90]
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CC(=O)O)C1=O
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CC[C@H](NC(=O)OC(C)(C)C)C3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 34 %

Procedure:
The title compound was prepared in 34% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except (S)-2-(3-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 770.6 (M+H)+, 2.07 min (method 6). 1H NMR (400 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 6.83-6.60 (m, 1H), 5.29 (d, J=4.8 Hz, 1H), 4.76 (s, 1H), 4.63 (br. s., 1H), 4.32-4.16 (m, 1H), 4.07-3.84 (m, 2H), 3.44 (d, J=7.0 Hz, 2H), 2.70-2.56 (m, 2H), 2.55-2.44 (m, 1H), 2.43-2.31 (m, 1H), 2.13 (dd, J=6.3, 17.1 Hz, 1H), 2.08-1.95 (m, 1H), 1.94-1.82 (m, 2H), 1.81-1.73 (m, 2H), 1.71 (s, 3H), 1.68-1.62 (m, 1H), 1.61-1.48 (m, 6H), 1.46 (s, 9H), 1.43-1.22 (m, 6H), 1.13 (br. s., 1H), 1.10 (d, J=3.8 Hz, 3H), 1.02 (s, 6H), 0.95 (br. s., 3H), 0.94 (br. s., 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>C(#N)C>[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:16])=[O:13]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Solvent: CC#N
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Cl)cn1

Procedure:
An 0.4 g. portion of 5-chloro-2-aminopyridine was dissolved in 20 ml. of acetonitrile and reacted with 0.7 g. of 2-chloro-6-fluorobenzoyl isocyanate as described in Example 1. The yield was 0.65 g. of the product named above, m.p. 210°-215° C. Elemental analysis gave the following results:
Reaction SMILES: [CH3:1][C:2]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14](O)=[O:15])=[CH:8][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.[H-].[Na+].[NH2:42][C:43]1[S:44][S:45][C:46](=[S:48])[N:47]=1>O1CCCC1.O>[CH3:1][C:2]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([NH:42][C:43]2[S:44][S:45][C:46](=[S:48])[N:47]=2)=[O:15])=[CH:8][CH:7]=1
Reactant: Nc1nc(=S)ss1
Reactant: CC(C)=CCCC(C)=CCOc1ccc(CCC(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCCC(C)=CCOc1ccc(CCC(=O)Nc2nc(=S)ss2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
3-{4-[(3,7-Dimethyl-2,6-octadienyl)oxy]phenyl}propionic acid (1.00 g, 3.31 mmol) was dissolved in tetrahydrofuran (11 ml), and 1,1′-carbonyldiimidazole (0.643 g, 3.97 mmol) was added thereto. The imidazole mixture was stirred for 1 hour at 0° C. Sodium hydride (60% oil suspension 0.132 g, 3.31 mmol) was suspended in tetrahydrofuran (11 ml), and 3-amino-1,2,4-dithiazole-5-thione (0.497 g, 3.31 mmol) was added thereto. After being stirred for 30 minutes at 0° C., the reaction mixture, with the imidazole mixture added thereto, was stirred for 2 hours at 0° C. The mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel column chromatography (chloroform), to give 3-{4-[(3,7-dimethyl-2,6-octadienyl)oxy]phenyl}-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)propanamide (Compound 3) (0.847 g, 59%).
Reaction SMILES: C1(S([CH:10]2[CH:16]=[C:15]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13][C@@H:12]([O:24][Si](C)(C)C)[C@H:11]2[CH3:29])(=O)=O)C=CC=CC=1.CCN(CC)CC.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.CO>C(Cl)Cl.CCOC(C)=O>[CH3:29][C@H:11]1[CH:10]=[CH:16][C:15]([S:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH2:13][C@H:12]1[OH:24]
Reactant: C[C@H]1C(S(=O)(=O)c2ccccc2)C=C(Sc2ccccc2)CC[C@H]1O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H]1C=CC(Sc2ccccc2)=CC[C@H]1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
22 or 23 (2.15 g, 4.81 mmol) was dissolved in dry methylene chloride (20 mL), and 4.0 mL of Et3N (28.7 mmol) was added at room temperature, followed by addition of 3.0 mL (16.6 mmol) of TMSOTf. This mixture was brought to reflux under N2, and stirred for 8 h until the starting material was consumed (monitored by TLC using 30% ethyl acetate in hexanes). The reaction mixture was cooled to 0° C., and the excess TMSOTf was quenched by adding MeOH (1.0 mL, 24.7 mmol), diluted with EtOAc (20 mL), separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were concentrated via rotary evaporation, dissolved in a mixture of THF (30 mL) and H2O (10 mL). 10 mL of AcOH were added to the mixture and left stirring at room temperature for 3 h. It was then transferred to a 1 L beaker and saturated aqueous NaHCO3 was carefully added until the solution became slightly basic, copious CO2 evolved during this process. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed by saturated NaHCO3, followed by brine, and dried over Na2SO4. Flash column chromatography (EtOAc-hexane; 1:4) afforded 0.97 g (86%) of 29 as an oil. Care must be taken during purification that the mixture not be exposed to silica for extended time since this will cause some decomposition. The product slowly decomposes at 25° C., but stores well at −10° C. [α]20D=+200.5 (c=0.55, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.20-7.33 (m, 5H), 6.27 (t, J=5.4 Hz, 1H), 5.92 (d, J=11.4 Hz, 1H), 5.69 (dd, J=4.8, 11.4 Hz, 1H), 4.17 (br s, 1H), 2.59-2.68 (m, 2H), 2.42-2.52 (m, 1H), 1.97 (br s, 1H), 1.22 (d, J=7.2 Hz, 3H); 3C NMR (CDCl3, 75 MHz) δ 137.2, 136.1, 133.9, 131.5, 129.9, 129.5, 129.2, 126.7, 76.4, 40.8, 38.3, 16.7; LRMS (CI): m/z 233 [M+H]+; HRMS (CI) calculated for C14H17OS, 233.1000; found, 233.0991.