Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:15]=[C:14]2[CH:26]1[CH2:31][CH2:30][N:29](C)[CH2:28][CH2:27]1.O>CS(C)=O>[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:15]=[C:14]2[CH:26]1[CH2:31][CH2:30][N:29]([C:2]#[N:1])[CH2:28][CH2:27]1
Reactant: N#CBr
Reactant: CN1CCC(c2nn(-c3ccccc3)c3ccc(F)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CN1CCC(c2nn(-c3ccccc3)c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 93.6 %

Procedure:
To a stirred mixture of cyanogen bromide (4.05 g, 0.038 moles) and potassium carbonate (6.2 g, 0.045 moles) in dimethylsulfoxide (75 ml) was added dropwise a solution of 5-fluoro-1-phenyl-3-(1-methyl-4-piperidinyl)-1H-indazole (11.0 g, 0.036 moles) free base of Example 111(b) in hot dimethylsulfoxide (75 ml). The reaction was stirred at ambient temperature for 28 hours and then poured into water. The product was extracted (dichloromethane), dried (MgSO4) and concentrated to yield 10.8 g of an oil which crystallized upon standing. The product was recrystallized twice from isopropyl alcohol-ether and once from isopropyl alcohol which yielded 3.8 g (33%) of the 4-(5-fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carbonitrile, m.p. 137°-139°.
Reaction SMILES: CC1(C(Cl)=O)CCC(C(C)C)C1.C1(C(Cl)=O)CCCCC1.[C:22]([NH:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([C:39]2([CH3:47])[CH2:43][CH2:42][CH:41]([CH:44]([CH3:46])[CH3:45])[CH2:40]2)=[O:38])=[C:32]([O:48][C:49]([C:51]2([CH3:59])[CH2:55][CH2:54][CH:53]([CH:56]([CH3:58])[CH3:57])[CH2:52]2)=[O:50])[CH:31]=1)=[O:29])([CH3:25])([CH3:24])[CH3:23]>>[CH3:59][C:51]1([C:49]([O:48][C:32]2[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=2[O:36][C:37]([C:39]2([CH3:47])[CH2:43][CH2:42][CH:41]([CH:44]([CH3:46])[CH3:45])[CH2:40]2)=[O:38])[CH:28]([OH:29])[CH2:27][NH:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:50])[CH2:55][CH2:54][CH:53]([CH:56]([CH3:58])[CH3:57])[CH2:52]1
Reactant: CC(C)C1CCC(C)(C(=O)Oc2ccc(C(=O)CNC(C)(C)C)cc2OC(=O)C2(C)CCC(C(C)C)C2)C1
Agent: CC(C)C1CCC(C)(C(=O)Cl)C1
Agent: O=C(Cl)C1CCCCC1
Product: CC(C)C1CCC(C)(C(=O)Oc2ccc(C(O)CNC(C)(C)C)cc2OC(=O)C2(C)CCC(C(C)C)C2)C1

Procedure:
When 1-methyl-3-isopropylcyclopentanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(1-methyl-3-isopropylcyclopentanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(1-methyl-3-isopropylcyclopentanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH2:25][CH3:26])[C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O.C1COCC1>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH2:25][CH3:26])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CC)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(C(=O)O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-[4-(2-benzyloxy-5-bromobenzylamino)phenyl]butanoate (4.2 g) was diluted in a solution of methanol (20 ml) and THF (20 ml). A 2N aqueous solution of sodium hydroxide was added and the mixture stirred at ambient temperature for 18 hours. The volume of solvent was reduced to half the original volume and water (20 ml) added. The mixture was acidified with 2N HCl to pH 3 and extracted with ethyl acetate (3×50 ml). The combined extracts were dried (MgSO4) and evaporated and the residue was subjected to chromatography, eluting with 10% EtOAc/CH2Cl2, to give 2-[4-(2-benzyloxy-5-bromobenzylamino)phenyl]butanoic acid (yield 1.31 gum).
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:24])=[N:7]2.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>ClCCl>[Br:1][C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:24])=[N+:7]2[O-:33]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a stirred solution of (S)-ethyl 2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H) (248 mg, 0.63 mmol) in dichloromethane (8 mL) was added a solution of mCPBA (283 mg, 77%, 1.26 mmol) in DCM (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour before quenched with NaHCO3 solution. The mixture was extracted with DCM (30 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (212 mg, 82%). LCMS-ESI+ (m/z): 410.2, 412.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.Br[CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: BrCCc1ccccc1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(CCc1ccccc1)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 54.5 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), (2-bromoethyl)benzene (0.136 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.128 g (55%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[OH:4].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:34]=[CH:33][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>CN(C)C=O.C(O)(=O)C>[OH:4][C@H:3]([C:5]1[N:6]=[C:7]([C:10]([F:12])([F:13])[F:11])[S:8][CH:9]=1)[CH2:2][NH:1][CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:34]=[CH:33][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)c4csc(C(F)(F)F)n4)CC3)cc2)S1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.6 %

Procedure:
A mixture of (1S)-(2-amino-1-[2-trifluoromethyl]-1,3-thiazole-4-yl]ethanol (which was obtained in Example 105) (0.34 g, 1.59 mmol) and 5-[4-(4-oxopiperidine-1-yl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) (0.48 g, 1.59 mmol), sodium triacetoxyborohydride (0.67 g, 3.18 mmol), and acetic acid (0.33 mL) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hours, poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic extracts were washed with brine and dried over MgSO4. Evaporation and purification by flash chromatography (chloroform/methyl alcohol 9.5/5) gave a yellow solid (0.1 g, 13% yield); mp 108–113° C.; MS (ES) m/z: 501 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 1.44 (m, 2H), 1.93 (s, 2H), 3.23–2.66 (m, 7H), 3.62 (d, 2H) 4.68 (m, 1H), 4.94 (m, 1H), 6.86 (d, 2H), 7.5 (d, 2H), 8.3 (s, 1H); Anal. Calcd. for C21H23F3N4O3S2: C, 50.39; H, 4.63; N, 11.19. Found: C, 50.16; H, 5.16; N, 9.93.
Reaction SMILES: [NH:1]([C:3]1[S:7][CH:6]=[N:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH2:2].O=[C:14]([CH3:29])[CH:15]([C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=O)[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CO>[CH3:20][O:19][C:17](=[O:18])[CH2:16][C:15]1[C:14]([CH3:29])=[N:2][N:1]([C:3]2[S:7][CH:6]=[N:5][C:4]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:21]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CCOC(=O)c1ncsc1NN
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccccn1
Solvent: CO
Product: CCOC(=O)c1ncsc1-n1nc(C)c(CC(=O)OC)c1-c1ccccn1
Temperature: 90 °C
Yield: 68.8 %

Procedure:
In a microwave reactor, 0.358 g (1.91 mmol) of ethyl 5-hydrazinyl-1,3-thiazole-4-carboxylate were added to 0.450 g (1.91 mmol) of methyl 4-oxo-3-(pyridin-2-ylcarbonyl)pentanoate in 4 ml methanol. In a microwave oven the closed vessel was heated at 90° C. for 2 hours. After removal of the solvent, the residue was extracted repeatedly with dichloromethane/water. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. Chromatography of the residue gave 0.508 g of product (61.8% of theory), NMR (CDCl3, 300 MHz): 1.12 (t, 3H); 2.35 (s, 3H); 3.66 (s, 2H); 3.69 (s, 3H); 4.08 (s, 3H); 7.19 (m, 1H); 7.32 (m, 1H); 7.66 (m, 1H); 8.51 (m, 1H); 8.72 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@H:7]([F:9])[CH2:6][N:5]1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Li+]>O1CCCC1.O.O>[C:10]([N:5]1[CH2:6][C@@H:7]([F:9])[CH2:8][C@H:4]1[C:3]([OH:18])=[O:2])(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1C[C@H](F)CN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Part A (cis)-1-benzoyl-4-fluoro-L-proline methyl ester (3.7 g, 14.74 mmole) in tetrahydrofuran-water (37 ml-7 ml) was added 31 ml of a 1N solution of lithium hydroxide in water. The reaction was stirred at room temperature for 2 hours. The tetrahydrofuran was evaporated, the pH of the residual aqueous solution was adjusted to 8 and extracted with ethyl acetate. The organic extracts were discarded. The aqueous phase was acidified to pH 2 with concentrated HCl and extracted with dichloromethane. The organic extracts were washed with brine and dried (sodium sulfate). The organic solution was filtered and concentrated to 2.9 g of solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:24]I.O>CN(C)C=O>[CH3:24][O:14][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15][C:10]=2[N:11]=1
Reactant: O=c1nc(-c2ccccc2F)c2c3c(sc2[nH]1)CCCC3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2F)c2c3c(sc2n1)CCCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 16.1 g of 4-(o-fluorophenyl)-1,2,5,6,7,8-hexahydrobenzothieno[2,3-d]pyrimidin-2-one in 322 of dimethylformamide is added 2.88 g of 67% sodium hydride. The mixture is stirred for 1 hour at room temperature, and 22.83 g of methyl iodide in 68 ml of dimethylformamide is added thereto at 10°C. The resulting reaction mixture is stirred for 2 hours at room temperature, then poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction 2-methoxy-4-(o-fluorophenyl)-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 98° - 100°C. From the second fraction, 1-methyl-4-(o-fluorophenyl)-1,2,5,6,7,8-hexahydrobenzothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 221° - 222.5°C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:13][CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:8][C:7]1[C:2]([O:9][CH:10]2[CH2:11][CH:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:13]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CC(C)(C)OC(=O)NC1CC(O)C1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC(Oc2nccnc2Cl)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of 2,3-dichloro-pyrazine (3.0 g, 20 mmol) and tert-butyl (3-hydroxycyclobutyl)carbamate (see PREPARATION 4B; 3.65 g, 20 mmol) in DMSO (50 mL) was added Cs2CO3 (13.2 g, 40 mmol), and then the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with water and filtered. The filtrate cake was washed with water, and dried to give tert-butyl (3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)carbamate (4.5 g, 15.2 mmol, 76%). ESI-MS (M+1): 300 calc. for C13H18ClN3O3 299.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=O)=[N:9]2)=[CH:4][CH:3]=1>CC(O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:14]([CH:16]2[CH2:18][CH2:17]2)=[N:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: O=C(NNc1cnc2ccc(Br)cc2n1)C1CC1
Solvent: CC(=O)O
Product: Brc1ccc2ncc3nnc(C4CC4)n3c2c1
Temperature: 100 °C

Procedure:
The crude product N′-(7-bromoquinoxalin-2-yl)cyclopropanecarbohydrazide was dissolved in HOAc (5 mL) and then heated to 100° C. overnight. The solvent was removed under vacuum and the residue was washed with water and dried in vacuo to afford the title product 8-bromo-1-cyclopropyl-[1,2,4]triazolo[4,3-a]quinoxaline as yellow solid in 42% overall yield (100 mg). m/z 291 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][C:10](=[O:12])[N:9]([C@H:13]([C:16]([NH2:18])=[O:17])[CH2:14][CH3:15])[CH2:8]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+].FCC1CN([C@@H](CC)C(N)=O)C(=O)C1.O=C1CC(CN2C=NN=N2)CN1[C@@H](CC)C(N)=O.O=C1CC(CN2C=NC=N2)CN1[C@@H](CC)C(N)=O.O=C1CC(CN2C=CN=N2)CN1C(CC)C(N)=O.C(SCC1CN([C@@H](CC)C(N)=O)C(=O)C1)(C)C.C(N)(=O)CCC.O=C1CC(CN2CCSCC2)CN1[C@@H](CC)C(N)=O>C(#N)C>[N:19]([CH2:6][CH:7]1[CH2:8][N:9]([C@@H:13]([CH2:14][CH3:15])[C:16]([NH2:18])=[O:17])[C:10](=[O:12])[CH2:11]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@@H](C(N)=O)N1CC(COS(C)(=O)=O)CC1=O
Agent: CCC(C(N)=O)N1CC(Cn2ccnn2)CC1=O
Agent: CCCC(N)=O
Agent: CC[C@@H](C(N)=O)N1CC(CF)CC1=O
Solvent: CC#N
Product: CC[C@@H](C(N)=O)N1CC(CN=[N+]=[N-])CC1=O
Temperature: 10 °C
Reaction time: 8 h

Procedure:
In a 3 l three necked flask fitted with mechanical stirrer and reflux condenser, under inert atmosphere, 89.7 g (322 mmoles, 1 eq) of {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl methanesulfonate 37 are dissolved in 300 ml of acetonitrile. 27.3 g (419 mmoles, 1.3 eq) of sodium azide are added in one portion, with 150 ml of acetonitrile. The mixture is brought to reflux in 20 min, and stirred overnight. 3.1 g (48 mmoles, 0.2 eq) of sodium azide are added and reflux continued for a total of 44 hours. After cooling down to 10° C., the mixture is filtered, the precipitate washed with 3×50 ml of acetonitrile and the combined organic fractions concentrated to dryness to give 77.3 g of crude 32. It is crystallised from 150 ml of ethyl acetate at 10° C. to give 60 g of pure 32, 82%. Alternatively, (2S)-2-[4-(fluoromethyl)-2-oxo-1-pyrrolidinyl]butanamide 44, (2S)-2-[2-oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 39, (2S)-2-[2-oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 40, (2S)-2-[2-oxo-4-(1H-1,2,4-triazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 55, 2-[2-oxo-4-(1H-1,2,3-triazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 56, (2S)-2-{4-[(isopropylsulfanyl)methyl]-2-oxo-1-pyrrolidinyl}butanamide 24, (2S)-2-[2-oxo-4-pyrrolidinylmethyl)-1-pyrrolidinyl]butanamide 15, (2S)-2-[2-oxo-4-(4-thiomorpholinylmethyl)-1-pyrrolidinyl]butanamide 17, are prepared in similar ways, from activated alcohol derivatives, such as mesylates, tosylates or halides.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:16]1([CH2:22][S:23][CH:24]([C:28]([OH:30])=O)[C:25]([OH:27])=[O:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:31]1[CH2:35]O[CH2:33][CH2:32]1>>[OH:30][C:28]1[CH:33]=[C:32]([CH2:31][CH2:35][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:27][C:25](=[O:26])[C:24]=1[S:23][CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: C1CCOC1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=c1oc(CCc2ccccc2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4-phenethylacetophenone (0.786 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 164°-166° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.75 (t, 3 H), 2.85 (t, 2 H), 3.92 (s, 2 H), 5.92 (s, 1 H), 7.23 (m, 9H), 11.69 (bs, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:30]2[CH:29]=[CH:28][C:16]3[C:17](=[O:27])[N:18]([CH2:24][CH2:25]O)[C:19](=[O:23])[C:20]4=[CH:21][CH:22]=[C:13]([C:14]=2[C:15]=34)[C:12]1=[O:31])([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:33]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:30]2[CH:29]=[CH:28][C:16]3[C:17](=[O:27])[N:18]([CH2:24][CH2:25][Br:33])[C:19](=[O:23])[C:20]4=[CH:21][CH:22]=[C:13]([C:14]=2[C:15]=34)[C:12]1=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)c1ccccc1N1C(=O)c2ccc3c4c(ccc1c24)C(=O)N(CCO)C3=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccccc1N1C(=O)c2ccc3c4c(ccc1c24)C(=O)N(CCBr)C3=O

Procedure:
0.92 g (2.22 mmol) of 1-(2-tert. butylphenyl)-6-(2-hydroxyethyl)-1H-indolo[5,4,3-def]isoquinoline-2,5,7(6H)-trione was dissolved in 60 mL of chloroform and heated to a boil. Then, 15 mL (15.54 mmol) of phosphorus tribromide was added dropwise within 20 minutes and the solution was heated at reflux for 2 hours. The reaction mixture was then poured onto ice, and the aqueous phase was extracted with chloroform. The combined organic phases were dried over magnesium sulfate. The purification was carried out by column chromatography on silica gel with toluene as the developing solvent.
Reaction SMILES: C1(C(Cl)=O)CCC1.C1(C(Cl)=O)CCCCC1.[C:17]([NH:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH:34]2[CH2:37][CH2:36][CH2:35]2)=[O:33])=[C:27]([O:38][C:39]([CH:41]2[CH2:44][CH2:43][CH2:42]2)=[O:40])[CH:26]=1)=[O:24])([CH3:20])([CH3:19])[CH3:18]>>[CH:41]1([C:39]([O:38][C:27]2[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=2[O:31][C:32]([CH:34]2[CH2:35][CH2:36][CH2:37]2)=[O:33])[CH:23]([OH:24])[CH2:22][NH:21][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:40])[CH2:44][CH2:43][CH2:42]1
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C2CCC2)c(OC(=O)C2CCC2)c1
Agent: O=C(Cl)C1CCC1
Agent: O=C(Cl)C1CCCCC1
Product: CC(C)(C)NCC(O)c1ccc(OC(=O)C2CCC2)c(OC(=O)C2CCC2)c1

Procedure:
When cyclobutanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(cyclobutanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(cyclobutanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:36]([CH3:38])[CH3:37]>CN(C)C=O>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:36]([CH3:38])[CH3:37])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc21
Yield: 45 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 44), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a colorless foam (45%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:21]>CC(O)=O>[O:21]=[C:10]1[C:9]2[C:18](=[CH:19][CH:20]=[C:7](/[CH:6]=[CH:5]/[C:4]([OH:22])=[O:3])[CH:8]=2)[O:17][C:12]2([CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Temperature: 85 °C
Reaction time: 3 h

Procedure:
HCl 20% aq. (5 ml, 30 mmol) was added to a suspension of (±)-(E)-3-[1-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (Intermediate 1, Step B) (464 mg, 1.2 mmol) in glacial AcOH (5 ml). The mixture was stirred at 85° C. for 3 h and then evaporated under vacuum to give (±)-(E)-3-[4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid (370 mg) as a white solid (hydrochloride salt).
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:7][CH2:6][CH:5]([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.Cl.[CH3:15][NH:16][O:17][CH3:18].C([Mg]Br)CC.[Cl-].[NH4+]>O1CCCC1>[F:13][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]([N:16]([O:17][CH3:18])[CH3:15])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Reactant: CNOC
Agent: CCC[Mg]Br
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCC(F)(F)CC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A mixture of ethyl 4,4-difluorocyclohexane-1-carboxylate (1.9 g, 9.88 mmol) and tetrahydrofuran (60 ml) was cooled to −70° C., and N,O-dimethylhydroxyamine hydrochloride (1.44 g, 14.8 mmol) was added. Further, 1.05 M n-propylmagnesium bromide (24.2 ml, 25.2 mmol) was added dropwise to the reaction mixture at −55° C. over five minutes so that the internal temperature did not exceed −35° C., and the reaction mixture was stirred at 0° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane) to give the title compound (1.7 g, yield 83%).