Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:8]=[N:9][CH:10]=2)[C:4](=[S:7])[NH:5][N:6]=1.[CH3:11][O-].[Na+].CI>C(O)C>[CH3:11][S:7][C:4]1[N:3]2[CH:8]=[N:9][CH:10]=[C:2]2[CH:1]=[N:6][N:5]=1
Reactant: S=c1[nH]ncc2cncn12
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSc1nncc2cncn12
Temperature: 0 °C

Procedure:
To 1.52 gm. of imidazo[1,5-d]-as-triazine-4(3H)-thione in 25 ml. of ethanol is added 0.54 gm. of sodium methoxide. Then 0.63 ml. of methyl iodide is added and the mixture is stirred and heated under reflux for 80 minutes. The mixture is cooled to 0° C. giving a precipitate which is collected. This product is recrystallized from 25 ml. of methanol and treated with charcoal giving the desired product, m.p. 186°-190° C.
Reaction SMILES: [CH3:1][C:2](=[N:7]O)[C:3](=O)[CH2:4][CH3:5].[C:9]1(=[O:16])[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1>>[CH3:1][C:2]1[NH:7][C:11]2[CH2:12][CH2:13][CH2:14][C:9](=[O:16])[C:10]=2[C:3]=1[CH2:4][CH3:5]
Reactant: CCC(=O)C(C)=NO
Reactant: O=C1CCCC(=O)C1
Product: CCc1c(C)[nH]c2c1C(=O)CCC2

Procedure:
In a specific embodiment, the invention provides a method of manufacturing molindone through a 3-step process, wherein in the 1st step 2,3-pentadione is reacted with hydroxylamine hydrochloride to produce 2,3-pentanedione-2-oxime (SUMO-1); in the 2nd step 2,3-pentanedione-2-oxime and 1,3-cyclohexanedione are reacted to produce 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (SUMO-2); and in the 3rd step 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole reacts with bismorpholinomethane to produce molindone (SUMO-3).
Reaction SMILES: C(C1C=C(C2C=C(C3C=CC(C(OCC)=O)=CC=3)C=CC=2O)C=CC=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].BrCCCCO[Si](C(C)(C)C)(C)C.[C:53]([C:57]1[CH:58]=[C:59]([C:68]2[CH:69]=[C:70]([C:87]3[CH:92]=[CH:91][C:90]([C:93]([O:95][CH2:96][CH3:97])=[O:94])=[CH:89][CH:88]=3)[CH:71]=[CH:72][C:73]=2[O:74][CH2:75][CH2:76][CH2:77][CH2:78][O:79][Si:80]([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:82])[CH3:81])[CH:60]=[CH:61][C:62]=1N1CCCC1)([CH3:56])([CH3:55])[CH3:54]>>[C:53]([C:57]1[CH:58]=[C:59]([C:68]2[CH:69]=[C:70]([C:87]3[CH:88]=[CH:89][C:90]([C:93]([O:95][CH2:96][CH3:97])=[O:94])=[CH:91][CH:92]=3)[CH:71]=[CH:72][C:73]=2[O:74][CH2:75][CH2:76][CH2:77][CH2:78][O:79][Si:80]([C:83]([CH3:86])([CH3:84])[CH3:85])([CH3:81])[CH3:82])[CH:60]=[CH:61][C:62]=1[CH:14]1[CH2:15][NH:11][CH2:12][CH2:13]1)([CH3:54])([CH3:56])[CH3:55]
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)cc1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)cc1
Agent: CC(C)(C)[Si](C)(C)OCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc(C4CCNC4)c(C(C)(C)C)c3)c2)cc1
Yield: 97 %

Procedure:
In a manner similar to that of Example 2a, by reacting 123 mg of ethyl 3″-tert-butyl-4′-hydroxy-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate (0.27 mmol) with 110 mg (0.34 mmol) of caesium carbonate and 80 μL of 1-bromo-4-(tert-butyldimethylsilanyloxy)butane (0.30 mmol), 170 mg of ethyl 3″-tert-butyl-4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=97%) in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]([N:9]([CH3:21])[CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]2)=[O:8])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:30][NH:31][CH2:32][CH2:33][CH2:34][OH:35].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C.C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7](=[O:8])[N:9]([CH2:10][CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18](=[O:20])[N:31]([CH2:32][CH2:33][CH2:34][OH:35])[CH3:30])[CH2:16][CH2:17]2)[CH3:21])=[CH:22][CH:23]=1
Reactant: CNCCCO
Reactant: CN(CC[C@H]1CC[C@H](C(=O)O)CC1)C(=O)Oc1ccc(Cl)cc1
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CC[C@H]1CC[C@H](C(=O)N(C)CCCO)CC1)C(=O)Oc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
A solution of 1.02 g (3.00 mmol) of trans-4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexanecarboxylic acid in 30 mL of CH42Cl2 was treated at RT with 2 drops of DMF, followed by 0.28 mL (3.30 mmol, 1.1 eq) of oxalyl chloride within 5 min, and stirring was continued for 90 min. The solution was evaporated, redissolved in 15 mL of CH2Cl2 and added to a solution of 0.80 g (9.00 mmol, 3 eq) of 3-(methylamino)-1-propanol [Powell et al., Synthesis (4) 338-340 (1986)]and 2.09 mL (15.00 mmol, 5 eq) of Et3N in 12 mL of CH2Cl2 at 0° C. The reaction was kept at RT for 1 h then partitioned between Et2O (×3)/ aqueous saturated NaHCO3. The organic phases were washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 90 g silica gel (EtOAc:CH2Cl2 1:1 to 4:1) gave 0.95 g (77%) of pure trans-(2-{4-[(3-hydroxy-propyl)-methyl-carbamoyl]-cyclohexyl}-ethyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 411 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]([CH2:11][S:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:30][C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33].O>ClCCl>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:11][S:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:9][O:10][C:32](=[O:33])[C:31]([CH3:36])([CH3:35])[CH3:30])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CSC[C@@H](CO)NC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)OC(C)(C)C)cc1
Reaction time: 6 h
Yield: 86.4 %

Procedure:
[(R)-2-hydroxy-1-(4-methoxy-benzylsulfanylmethyl)-ethyl]-carbamic acid t-butyl ester (71.3 g, 227.9 mmol) prepared in Step C was dissolved in dichloromethane (300 mL). Triethylamine (58 mL, 414.4 mmol) and trimethylacetic acid chloride (28 mL, 227.9 mmol) were added thereto, and the mixture was stirred for 6 h at 0°. Water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (81.0 g, Yield 95%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1.[OH:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:21]=[CH:22][C:23]3[C:24]4[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][C:25]=4[N:26]([CH3:29])[C:27]=3[CH:28]=2)[C:16](=[O:41])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CN(C=O)C.C(Cl)Cl>[CH3:29][N:26]1[C:27]2[CH:28]=[C:20]([N:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:2][C:3]4[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=4)=[CH:15][C:16]3=[O:41])[CH:21]=[CH:22][C:23]=2[C:24]2[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][C:25]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(O)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: FC(F)(F)c1ccc(CBr)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 29.8 %

Procedure:
2-(Bromomethyl)-5-(trifluoromethyl)pyridine (140 mg, 0.58 mmol), tert-butyl 7-(4-hydroxy-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (230 mg, 0.58 mmol) and K2CO3 (160 mg, 1.16 mmol) were stirred in acetonitrile/DMF (3 mL/0.5 mL) for 72 h. The mixture was diluted with methylene chloride, washed with water and concentrated to provide the title compound (96 mg, 29%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 1H), 8.00 (dd, J=8.2, 2.0 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.28-7.26 (m, 1H), 7.00 (d, J=7.7 Hz, 1H), 6.12 (dd, J=7.6, 2.7 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 5.26 (s, 2H), 4.63-4.58 (br m, 2H), 3.87-3.76 (br m, 2H), 3.63 (s, 3H), 2.86-2.76 (br m, 2H), 1.50 (s, 9H).
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]1[C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:69])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[O:10]=[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]1[C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:48][CH2:49][C:50](=[O:51])[N:52]2[CH2:53][CH2:54][N:55]([C:58](=[O:69])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[C:65]([F:66])([F:68])[F:67])[CH2:56][CH2:57]2)=[O:23])=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccc(-n2ccccc2=O)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-n2ccccc2=O)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 14.9 %

Procedure:
DIPEA (213 mg, 0.27 mL, 1.65 mmol) was added to a stirred solution of 4-(2-oxo-2H-pyridin-1-yl)-benzoic acid (120 mg, 0.55 mmol) in DMF (2 mL). HOBT (74.5 mg, 0.55 mmol) and EDCI (126.5 mg, 0.66 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (196 mg, 0.55 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 42 mg (14.7% yield) of 4-(2-Oxo-2H-pyridin-1-yl)-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 94.83%. 1H NMR (DMSO-d6): δ 8.0 (m, 2H), 7.9 (m, 2H), 7.7 (m, 2H), 7.5 (m, 4H), 6.5 (m, 1H), 6.4 (t, 1H), 4.2 (m, 2H), δ 3.9-3.6 (m, 4H), 3.5-3.4 (m, 2H), 3.2-3 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1)[CH3:2].CN(C)C=O.[I:18]N1C(=O)CCC1=O.O>ClCCl>[CH2:1]([O:3][C:4]1[C:5]2[C:12]([I:18])=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1)[CH3:2]
Reactant: CCOc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidine (11, 1.60 g, 9.8 mmol) in 50.0 mL of dichloromethane, N,N-dimethylformamide (2.0 mL, 26 mmol) and N-iodosuccinimide (2.40 g, 10.7 mmol) are added and the reaction stirred at room temperature for 2 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried with sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (12, 2.70 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[C:21]([C:27]1[O:28][C:29]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([OH:39])[C:30]=2[C:31](=[O:33])[CH:32]=1)([O:23][CH2:24][CH2:25][CH3:26])=[O:22].[I-].[K+]>CC(C)=O.CN(C)C=O>[C:21]([C:27]1[O:28][C:29]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([O:39][CH2:2][C:3]3[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]4[CH:18]=[CH:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)=[CH:5][CH:4]=3)[C:30]=2[C:31](=[O:33])[CH:32]=1)([O:23][CH2:24][CH2:25][CH3:26])=[O:22]
Reactant: CCCOC(=O)c1cc(=O)c2c(O)c(Cl)ccc2o1
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cc(=O)c2c(OCc3ccc(OCc4ccc5ccccc5n4)cc3)c(Cl)ccc2o1

Procedure:
0.78 g of 2-(4-chloromethylphenoxy)methylquinoline, 0.76 g of 2-carbopropoxy-6-chloro-5-hydroxy-4-oxo-4H-1-benzopyran and a catalytic amount of potassium iodide are combined in 50 ml of acetone and 2 ml of dimethylformamide, and refluxed for 19 hours. The crude solid obtained on cooling is purified by flash chromatography to give 2-carbopropoxy-6-chloro-5-(4-(quinolin-2-ylmethoxy)benzyloxy) 4-oxo-4H-1-benzopyran having an m.p. of 173°-74° C.
Reaction SMILES: [Na].C[CH:3]([C:9]([O:11]CC)=O)[C:4]([O:6]CC)=O.[C:14]([C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1)(=O)[CH3:15].[OH-].[K+]>C(O)C.O>[CH3:15][CH:14]1[CH:17]2[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[C:4](=[O:6])[CH2:3][C:9]1=[O:11]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CC(=O)C1=CCCCC1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1C(=O)CC(=O)C2CCCCC12
Reaction time: 0.5 h

Procedure:
Sodium metal (2.31 g, 101.0 mmol) is dissolved in 50 ml of ethanol, and diethyl methylmalonate (17.6 g, 101.0 mmol) is added, after which the mixture is stirred for approx. 30 min. under reflux. 1-Acetyl-1-cyclohexene (12.50 g, 101.0 mmol) is added and the mixture is stirred under reflux overnight. Potassium hydroxide (12.47 g, 222.2 mmol) dissolved in 40 ml of water is added and the mixture is heated under reflux for 4 hr. The ethanol is removed by rotary evaporation, and the residue is dissolved in water and washed with ether. The aqueous layer is acidified with conc. HCl and extracted with ether. The combined extracts are dried and the solvent is removed to give 4a,5,6,7,8,8a -hexahydro-4-methylnaphthalene-1,3(2H,4H)-dione.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](O)=O)=[CH:5][C:4]([CH3:17])=[N:3]1.O=P(Cl)(Cl)[Cl:20].[NH4+].[OH-]>>[CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:9]([C:10]([Cl:20])=[C:5]2[C:4]([CH3:17])=[N:3]1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Nc2ccccc2C(=O)O)n(C)n1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nn(C)c2nc3ccccc3c(Cl)c12
Temperature: 0 °C

Procedure:
A mixture of N-(1,3-dimethyl-pyrazol-5-yl) anthranilic acid (7 g, 0.03 mol) and POCl3 (40 ml) was heated on a steam bath for 3 hours. The reaction mixture was then poured into ice-water (600 ml) and then basified with NH4OH. The mixture was extracted with ether (3×200 ml) and the combined ether layers were dried over MgSO4 and evaporated to afford 7.0 g of 1,3-dimethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline, m.p. 127°-129° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH:17]=[CH:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH:17]=[CH:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[S:29])[NH:10][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2cc(Br)ccc2-n2ccc3cccc1c32
Solvent: Cc1ccccc1
Product: S=C1Nc2cc(Br)ccc2-n2ccc3cccc1c32
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of 9-bromobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6(7H)-one (12.8 g), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (8.3 g), and toluene (500 ml) was refluxed for 2 hrs. The reaction mixture was allowed to stand overnight at room temperature. The precipitate was collected, washed with hexane, and dried overnight under vacuum at 40° C. to provide 9.6 g, (71.5%) of product. Recrystallization from chloroform gave the analytical sample, mp 214°-215° C.
Reaction SMILES: 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(OC)=O)=CC=2)=CC3)CC1.CN(C)CC[C:45]([NH:47][C@:48]12[CH2:82][CH2:81][C@@H:80]([C:83]([CH3:85])=[CH2:84])[C@@H:49]1[C@@H:50]1[C@@:63]([CH3:66])([CH2:64][CH2:65]2)[C@@:62]2([CH3:67])[C@@H:53]([C@:54]3([CH3:79])[C@@H:59]([CH2:60][CH2:61]2)[C:58]([CH3:69])([CH3:68])[C:57]([C:70]2[CH:78]=[CH:77][C:73]([C:74]([OH:76])=[O:75])=[CH:72][CH:71]=2)=[CH:56][CH2:55]3)[CH2:52][CH2:51]1)=[O:46].[O:87]=[C:88]1[N:92]([CH2:93]C(O)=O)[CH2:91][CH2:90][O:89]1>>[CH3:66][C@:63]12[C@@:62]3([CH3:67])[C@@H:53]([C@:54]4([CH3:79])[C@@H:59]([CH2:60][CH2:61]3)[C:58]([CH3:69])([CH3:68])[C:57]([C:70]3[CH:78]=[CH:77][C:73]([C:74]([OH:76])=[O:75])=[CH:72][CH:71]=3)=[CH:56][CH2:55]4)[CH2:52][CH2:51][C@@H:50]1[C@H:49]1[C@H:80]([C:83]([CH3:85])=[CH2:84])[CH2:81][CH2:82][C@:48]1([NH:47][C:45](=[O:46])[CH2:93][N:92]1[CH2:91][CH2:90][O:89][C:88]1=[O:87])[CH2:65][CH2:64]2
Reactant: 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
Reactant: O=C(O)CN1CCOC1=O
Agent: 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
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCOC3=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: 29 %

Procedure:
The title compound was prepared in 29% 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 2-(2-oxooxazolidin-3-yl)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 657.5 (M+H)+, 1.97 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.82 (s, 1H), 5.29 (dd, J=1.7, 6.3 Hz, 1H), 4.76 (d, J=1.5 Hz, 1H), 4.64 (s, 2H), 4.43 (dt, J=1.7, 8.2 Hz, 2H), 3.98-3.84 (m, 2H), 3.74 (t, J=8.1 Hz, 2H), 2.69-2.56 (m, 2H), 2.40 (dd, J=8.1, 12.4 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.98-1.81 (m, 2H), 1.81-1.75 (m, 1H), 1.73 (br. s., 1H), 1.71 (s, 3H), 1.70-1.65 (m, 1H), 1.61-1.43 (m, 7H), 1.42-1.29 (m, 4H), 1.29-1.21 (m, 2H), 1.16-1.12 (m, 1H), 1.10 (s, 3H), 1.02 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[NH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH2:32][C:33]1[CH:38]=[C:37]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:22])=[O:23])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(N)c3)c2c1
Yield: 26.6 %

Procedure:
N-[3-(3-Aminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 276 mg of 3-aminophenylboronic acid, 20 ml of dimethylformamide, 1.6 ml of a saturated aqueous sodium hydrogencarbonate solution and 25 mg of tetrakis(triphenylphosphine)palladium[0]. 102 mg of N-[3-(3-aminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 220° C. (analysis C20H18N4O4S2 % calculated C, 54.29; H, 4.10; N, 12.66; O, 14.46; S, 14.49. % found C, 53.48; H, 4.11 N, 12.50; S, 13.95).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:43])[C:15]2([CH:18]3[CH2:22][CH2:21][N:20]([C:23]4[C:32]([O:33][CH3:34])=[C:31]5[C:26]([C:27](=[O:41])[C:28]([C:38]([OH:40])=[O:39])=[CH:29][N:30]5[CH:35]5[CH2:37][CH2:36]5)=[CH:25][C:24]=4[F:42])[CH2:19]3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClC(Cl)C>[CH:35]1([N:30]2[C:31]3[C:26](=[CH:25][C:24]([F:42])=[C:23]([N:20]4[CH2:21][CH2:22][CH:18]([C:15]5([N:14]([CH3:43])[CH:11]6[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]6)[CH2:17][CH2:16]5)[CH2:19]4)[C:32]=3[O:33][CH3:34])[C:27](=[O:41])[C:28]([C:38]([OH:40])=[O:39])=[CH:29]2)[CH2:37][CH2:36]1
Reactant: COc1c(N2CCC(C3(N(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(N2CCC(C3(N(C)C4CCNCC4)CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 7-(3-{1-[(1-tert-butoxycarbonyl-piperidin-4-yl)-methyl-amino]-cyclopropyl}-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid in dichloroethane (2.0 mL) was added trifluoroacetic acid (1.0 mL, ˜13 mmol) at 0° C. during a period of 5-6 minutes. The resulting solution was stirred at room temperature for one hour. The solvent was removed to yield yellow oil, which was partitioned between CH2Cl2 and sat. aq NaHCO3. The separated aqueous phase was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The product was isolated as a yellow solid (85 mg, 100%). ESI MS m/z 499.4 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:28][C:29]#[N:30]>CN(C=O)C>[C:29]([CH2:28][N:11]1[CH:12]=[C:13]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:10]1)#[N:30]
Reactant: N#CCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cn(CC#N)nc2-c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.1 g) was taken in dry DMF (2 ml) and a solution of tert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 g in 2 ml of DMF) was added slowly at 0° C. The reaction mixture was stirred for 30 min at 0° C. and a solution of chloroacetonitrile (0.138 g) in DMF (1 ml) was added very slowly. The reaction mixture was allowed to stir over night at room temperature. The reaction mixture was quenched with cold water (5 ml) and extracted with ethyl acetate (3×40 ml). Evaporation of solvent under reduced pressure gave crude product, which, was purified by column chromatography using ethyl acetate\hexane (2:8) as eluent to afford tert-butyl 4-(1-(cyanomethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate as pure solid product.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=[CH:22][CH:21]=4)[C:12]3=[O:30])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.C(N(C(C)C)C(C)C)C.Cl[CH2:42][C:43](Cl)=[O:44].[F:46][C:47]([F:51])([F:50])[CH2:48][NH2:49]>ClCCCl>[CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:17])([CH3:18])[N:13]([CH2:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=[CH:22][CH:21]=4)[C:12]3=[O:30])=[CH:8][CH:9]=2)[N:4]([C:43](=[O:44])[CH2:42][NH:49][CH2:48][C:47]([F:51])([F:50])[F:46])[CH2:3]1
Reactant: NCC(F)(F)F
Reactant: O=C(Cl)CCl
Reactant: CC1(C)CNc2cc(N3C(=O)N(Cc4ccnc5ccccc45)C(C)(C)C3=O)ccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(C(=O)CNCC(F)(F)F)c2cc(N3C(=O)N(Cc4ccnc5ccccc45)C(C)(C)C3=O)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 100 mg 3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione in 2 ml 1,2-dichloroethane in a process vial 0.08 ml ethyl-diisopropyl-amine and 27.2 mg chloroacetylchloride were added at 0° C. After stirring for 1 hour at 0° C. 119.4 mg 2,2,2-trifluoro-ethylamine were added. The resulting mixture was stirred for 1 hour at room temperature and then further 119.4 mg 2,2,2-trifluoro-ethylamine were added. The vial was sealed with a teflon septum and placed in the microwave cavity. The reaction mixture was stirred for 15 minutes at 100° C. by microwave-assisted heating (Emrys Optimizer, Personal Chemistry). After further 15 minutes stirring at 150° C. the solution was heated for 1 hour at 150° C. The solvent was removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoracetic acid). Lyophilization of the solution yielded a white solid.