Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:19]([N:18]([C:26]1[N:27]=[CH:28][C:29]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:30][N:31]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:33])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Reactant: CN1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N2CCN(C)CC2)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and 1-methylpiperazine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile=65:35 to 15:85) to give the title compound.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[CH2:12]([O:15]CC=C(C)CCC=C(C)C)[CH:13]=C>>[C:12]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])(=[O:15])[CH3:13]
Reactant: C=CCOCC=C(C)CCC=C(C)C
Reactant: CC(C)=CCC/C(C)=C/CO
Product: CC(=O)OC/C=C(\C)CCC=C(C)C

Procedure:
A reaction was performed by the procedure of Example 1, except for using geraniol instead of 1-octanol. The reaction mixture was analyzed by gas chromatography to find that 1-allyloxy-3,7-dimethyl-octa-2,6-diene and geranyl acetate were formed in yields of 85% and 1%, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:11]3[CH2:16][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][C:12]=3[N:13]=2)=[C:4]([F:29])[CH:3]=1.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>>[CH2:20]([O:19][C:17]([N:15]1[CH2:16][C:11]2[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])=[N:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:33]([NH:32][CH2:30][CH3:31])=[O:34])=[CH:3][C:4]=3[F:29])=[N:13][C:12]=2[CH2:14]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(N)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)C3)c(F)c1
Yield: 34 %

Procedure:
Method as example 85 using (S)-ethyl 2-(4-amino-2-fluorophenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate and ethyl isocyanate as starting materials. The solvent was removed in vacuo and purified by prep HPLC (low pH) yielding the title compound (14.6 mg, 0.03 mmol, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][N:4]=1.[OH-].[Na+:14]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O-:9])=[O:8])=[CH:5][N:4]=1.[Na+:14]
Reactant: COC(=O)c1ccc(OC)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
methyl 6-methoxynicotinate (2.097 g, 12.56 mmol) was dissolved in dioxane (30 mL). An aqueous solution of NaOH (1.0N, 25 mL) was added to the solution and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to provide 2.2 g of sodium 6-methoxynicotinate.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]3[C:23]4[N:24]([CH:31]=[C:32]([N:34]5[CH2:38][CH2:37][C@H:36]([OH:39])[C:35]5=[O:40])[CH:33]=4)[N:25]=[CH:26][C:27]=3[C:28]([NH2:30])=[O:29])[C:17]([CH3:42])([CH3:41])[CH2:16]2)=[N:13][CH:14]=1)#[N:8].C(N(CC)CC)C.N1C=CC=CC=1>O1CCCC1.CN(C1C=CN=CC=1)C>[C:1]([O:39][C@H:36]1[CH2:37][CH2:38][N:34]([C:32]2[CH:33]=[C:23]3[C:22]([NH:21][C@@H:18]4[CH2:19][CH2:20][N:15]([C:12]5[N:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][N:11]=5)[CH2:16][C:17]4([CH3:42])[CH3:41])=[C:27]([C:28](=[O:29])[NH2:30])[CH:26]=[N:25][N:24]3[CH:31]=2)[C:35]1=[O:40])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: CC1(C)CN(c2ncc(C#N)cn2)CC[C@H]1Nc1c(C(N)=O)cnn2cc(N3CC[C@H](O)C3=O)cc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H]1CCN(c2cc3c(N[C@@H]4CCN(c5ncc(C#N)cn5)CC4(C)C)c(C(N)=O)cnn3c2)C1=O
Reaction time: 2 h
Yield: 22.5 %

Procedure:
Butyryl chloride (4 μl, 0.034 mmol) was added to a stirred suspension of 4-(((R)-1-(5-cyanopyrimidin-2-yl)-3,3-dimethylpiperidin-4-yl)amino)-6-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (15 mg, 0.031 mmol, from Example 115) and triethylamine (0.013 mL, 0.092 mmol) in tetrahydrofuran (0.5 mL). After 2 h at room temperature, no reaction was observed. Pyridine (5.0 μl, 0.061 mmol), DMAP (0.5 mg, 4.09 μmol) and additional butyryl chloride (3.5 μl, 0.034 mmol) were added. After 24 h at room temperature, the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-55% B over 25 minutes, then a 10-minute hold at 55% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (3.9 mg, 22% yield). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.51 (s, 2H), 8.12 (s, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.32 (d, J=1.5 Hz, 1H), 5.54 (t, J=8.4 Hz, 1H), 4.45 (d, J=13.4 Hz, 1H), 4.17 (dd, J=10.2, 3.7 Hz, 1H), 3.95 (td, J=9.7, 2.5 Hz, 1H), 3.87-3.79 (m, 1H), 3.52-3.44 (m, 1H), 3.22 (d, J=13.4 Hz, 1H), 2.80-2.70 (m, 1H), 2.47-2.35 (m, 2H), 2.25-2.15 (m, 2H), 1.87-1.77 (m, 1H), 1.69 (sxt, J=7.3 Hz, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 0.97 (t, J=7.4 Hz, 3H); MS (ES+) m/z: 560.4 (M+H); LC retention time: 1.98 min (analytical LCMS Method I).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[C:14]2[N:15]=[N:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][NH:10]1.[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:28][C:29](O)=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1C2N=CC=C(OC(N(C)C)=[N+](C)C)C=2N=N1.ON1C2N=CC=CC=2N=N1>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:28][C:29]([N:10]1[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[N:15][C:14]=2[CH:9]1[CH3:8])=[O:30])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC1NCCc2ccnnc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: CN(C)C(Oc1ccnc2[nH]nnc12)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC1c2nnccc2CCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 73.9 mg (0.281 mmol) of 8-methyl-5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, trifluoroacetate salt (Intermediate 34), 93.6 mg (0.281 mmol) of (3R)-3-[(tert-butoxycarbonyl)amino]4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3) and 0.150 mL (0.843 mmol) of N,N-diisopropylethylamine in 2.5 ml of DMF were added O-(7-azabenzotriazol-yl)-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (HATU; 128 mg, 0.337 mmol), 1-hydroxy-7-azabenzotriazole (HOAt; 45.9 mg, 0.337 mmol). The reaction was stirred at room temperature for 18 h. Then the reaction mixture was partitioned between ethyl acetate and 0.5M aqueous sodium bicarbonate solution. The aqueous phase was extracted with three portions of ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The mixture was purified by preparative TLC (100% ethyl acetate), then by chiral HPLC (ChiralCell OJ column, 14% ethanol/hexanes) to afford the title compound as a solid. The slower eluting isomer was used in Step B below. LC/MS: 409 (M+1-56).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:28][CH3:29])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=O)[O:20]C3C=CC=CC=3)=[CH:12][CH:11]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[C:1]([C:5]1[N:6]=[C:7]([CH2:28][CH3:29])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:40][S:37]([C:34]3[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][CH:35]=3)(=[O:39])=[O:38])=[O:20])=[CH:12][CH:11]=2)[CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCc1nc(C(C)(C)C)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: CCc1nc(C(C)(C)C)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(4-tert-butyl-2-ethyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 489 [M+H]+, 487 [M−H]−, 1H-NMR (CDCl3)δ1.12 (3H, t, J=7.5 Hz), 1.31 (9H, s), 2.62 (2H, q, J=7.5 Hz), 2.84 (2H, t, J=7.0 Hz), 3.45-3.54 (2H, m), 6.48 (1H, br),6.65 (1H, s), 7.17 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 7.43 (2H, d, J=8.4 Hz), 7.82 (2H, d, J=8.8 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH2:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[OH-].[K+]>CO>[NH:15]1[CH2:16][CH:17]=[C:18]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([C:10]([NH2:12])=[O:11])[CH:5]=3)[NH:1][CH:2]=2)[CH2:19][CH2:20]1
Reactant: NC(=O)c1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 40.6 %

Procedure:
A mixture of 1H-indole-5-carboxamide (1.8 g), 4-piperidone hydrochloride monohydrate (3.4 g), and potassium hydroxide (11 g) in methanol (100 ml) was heated at reflux for 16 h. The mixture was cooled, and partitioned between ethyl acetate (200 ml) and saturated potassium carbonate (200 ml). The aqueous phase was separated, and extracted with ethyl acetate (100 ml. The organic extracts were combined, dried and the solvent evaporated in vacuo to give a semi-solid which was triturated with absolute ethanol (10 ml), and washed with ether (3×20 ml). The resultant solid was dried in vacuo to give the title compound, (1.1 g) m.p. 225°-230°.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].[N:37]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:46]3[CH2:47][CH2:48][CH:43]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:44][CH2:45]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Product: Cc1ccccc1-c1cc(N2CCC(N3CCOCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 40.6 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (47.6 mg) was reacted with 4-(morpholine-4-yl)piperidine (38.3 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-[4-(morpholine-4-yl)piperidine-1-yl]-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (24.2 mg, 41%).
Reaction SMILES: C([O-])(O)=O.[Na+].[C:6]1([S:12]([CH2:15][CH2:16][S:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:25]1([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCCCCC>O1CCOCC1>[C:6]1([S:12]([CH2:15][CH2:16][S:17][C:18]2[C:23]([NH:24][C:32](=[O:33])[CH2:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: Nc1cccnc1SCCS(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=C(CC1CCCCC1)Nc1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
336 mg (4.0 mmol) NaHCO3 were added to a solution of 294 mg (1.0 mmol) [2-[2-(benzenesulfonyl)-ethylsulfanyl]-pyridin-3-yl]amine (VPF-002) in dioxane (10 ml) and the mixture was stirred for 10 min at RT. Then 321 mg (2.0 mmol) 2-cyclohexylacetylchloride were added at 5° C. and the mixture was stirred for a further 16 h at RT. Then it was diluted with EE and filtered through kieselguhr. The filtrate was washed with a saturated aqueous NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 6:1) of the residue yielded 368 mg (0.9 mmol, 88%) N-[2-[2-(benzenesulfonyl)-ethyl-sulfanyl]-pyridin-3-yl]-2-cyclohexyl acetamide. MS: m/z 419.1 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>CO.O1CCOCC1>[CH3:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:17]2[N:18]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:15][CH:16]=2)=[CH:26][CH:25]=1)(=[O:28])=[O:29].[ClH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)c1ccc(OCc2csc(C3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (615 mg, 1.36 mmol) in methanol (10 mL) was treated with 10 mL of 4N HCl in dioxane. The resulting solution was stirred at room temperature for 30 minutes. Then all the solvents were removed in vacuo to afford the desired product as a HCl salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24]C(C)(C)C)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([OH:24])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
tert-Butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.643 g) was dissolved in DCM (19 ml), and trifluoroacetic acid (19 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated under reduced pressure. Anhydrous DCM (4 ml) was added and the solution concentrated under reduced pressure. Repetitive addition of DCM and concentration under reduced pressure provided the title compound (0.56 g) as a white foam.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].[C:17]1(=[O:31])[N:21]([CH2:22][C:23](Cl)=[O:24])[C:20](=[O:26])[C:19]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:18]12>ClCCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:23](=[O:24])[CH2:22][N:21]3[C:20](=[O:26])[C:19]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:18]4[C:17]3=[O:31])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:12]
Reactant: CN1C(=O)CCc2ccccc21
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CN1C(=O)CCc2cc(C(=O)CN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 85 °C
Reaction time: 6 h
Yield: 48.4 %

Procedure:
To a stirred solution of 1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin (17.7 g) and aluminum chloride (44.5 g) in 1,2-dichloroethane (26 ml) was added dropwise a solution of 2-phthalimidoacetyl chloride (25 g) in 1,2-dichloroethane (45 ml). The reaction mixture was stirred for 6 hours at 85° C. and then 22 hours at 60° C. After cooling, the mixture was poured into ice water and extracted with chloroform. The extract was washed successively with water, an aqueous solution of sodium bicarbonate and water, dried and evaporated. The residue was triturated with ethyl acetate and the resultant precipitates were collected by filtration, washed with ethyl acetate and dried to give 18.51 g of 1-methyl-2-oxo-6-phthalimidoacetyl-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: CC(C)([O-])C.[K+].[O:7]([CH2:15][C@@:16]12[C@@H:33]3[C@H:24]([C@H:25]4[C@@:29]([CH2:31][CH2:32]3)([CH3:30])[C:28](=[O:34])[CH2:27][CH2:26]4)[CH2:23][CH2:22][C:21]1=[CH:20][C:19](=[O:35])[CH2:18][CH2:17]2)[Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[Cl-].[NH4+]>CS(C)=O>[O:7]([CH2:15][C@@:16]12[C@@H:33]3[C@H:24]([C@H:25]4[C@@:29]([CH2:31][CH2:32]3)([CH3:30])[C:28](=[O:34])[CH2:27][CH2:26]4)[CH2:23][CH:22]=[C:21]1[CH2:20][C:19](=[O:35])[CH2:18][CH2:17]2)[Si:8]([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@]12CCC(=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
To a solution of potassium t-butoxide in dimethylsulfoxide at 25° C. under nitrogen is added a solution of 19-t-butyldimethylsiloxy-4-androstene-3,17-dione in dimethylsulfoxide with stirring. After 15 minutes the mixture is poured onto a cold aqueous ammonium chloride solution. The solid which forms is rapidly filtered, washed well with water and dissolved in ether. The ether solution is washed well with water and dried over sodium sulfate. Evaporation of the ether at room temperature yields 19-t-butyldimethylsiloxy-5-androstene-3,17-dione.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:21][CH2:20][CH2:19][N:18]([C:22](OCC4C=CC=CC=4)=O)[CH2:17][CH2:16]3)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[C:32]1(=O)[CH2:35]C[CH2:33]1>CCO.[Pd]>[CH:22]1([N:18]2[CH2:19][CH2:20][CH2:21][CH:15]([C:13]([N:11]3[CH2:10][CH:9]([O:8][C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)[CH2:12]3)=[O:14])[CH2:16][CH2:17]2)[CH2:35][CH2:32][CH2:33]1
Reactant: Cc1ccc(OC2CN(C(=O)C3CCCN(C(=O)OCc4ccccc4)CC3)C2)cn1
Reactant: O=C1CCC1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(OC2CN(C(=O)C3CCCN(C4CCC4)CC3)C2)cn1
Reaction time: 12 h
Yield: 40.2 %

Procedure:
A mixture of benzyl 4-({3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}carbonyl)azepane-1-carboxylate (37 mg, 87 μmol), cyclobutanone (13 μl, 0.18 mmol) and 5% Pd/C (5 mg) in EtOH (4 ml) were stirred under a hydrogen atmosphere for 12 hours. The reaction was then filtered over celite and concentrated. The residue was dissolved in EtOAc (30 ml) and washed with water (3×15 ml), dried (MgSO4), filtered and concentrated. The residue was purified by silica FCC (using a gradient of eluents; 98:2:1 to 90:10:1 DCM/MeOH/2M NH3 in MeOH) to give the title product as colourless oil (12 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:42]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[S:42])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=S)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 93.2 %

Procedure:
In a manner similar to the method described in example 30, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.21 mmol) prepared in example 36b was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.2 g, 0.49 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one as a white solid (Yield 0.095 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][CH2:10][C@H:9]2[C:13]([N:15]2[CH2:24][C@@H:23]([N:25]([CH:32]3[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33]3)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][C@H:16]2[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:14])=[CH:4][CH:3]=1.[O:40]([C:42]#[N:43])[K].C(O)(=O)C>CN(C=O)C>[NH2:43][C:42]([N:11]1[CH2:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:9]([C:13]([N:15]2[CH2:24][C@@H:23]([N:25]([CH:32]3[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33]3)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][C@H:16]2[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:14])[CH2:10]1)=[O:40]
Reactant: N#CO[K]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)[C@@H]1CN(C(N)=O)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4S)-1-{[(3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl}-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolineamide (84 mg, 0.15 mmol) prepared in Example E1-1 in DMF was added dropwise KOCN (24 mg, 0.3 mmol) and a catalytic amount of acetic acid. The reaction mixture was stirred at rt for 1 h, extracted with EtOAc, washed with excessive amount of water and brine, and the organic solution was dried over MgSO4. The residue was purified by HPLC to give the title compound.