Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1)(=[O:14])[CH3:13].Cl>CCOCC>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1)=[O:14]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)C1=CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)C1C=CCCC1)C(F)F
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 94.3 %

Procedure:
Ethyl difluoroacetate (4.71 g, 38 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (20 mL). To the stirred solution was added 25 weight % sodium methoxide (9.68 g, 45 mmol) followed by 1-acetyl-1-cyclohexene (4.27 g, 34 mmol). The reaction was stirred at room temperature overnight (17.5 hours), then treated with 3N HCl (20 mL). The organic layer was collected and washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a brown oil (6.48 g, 93%). 1H NMR (CDCl3) 300 MHz 15.00 (br s, 1H), 6.09 (s, 1H), 5.92 (t, J=54.4 Hz,1H) 2.31 (m, 4H), 1.64 (m, 4H); 19F NMR (CDCl3) 300 MHz: -126.94; M+202.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=2)[C:16]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[O:17])=[N:4][NH:3]1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[N:18]1([C:16]([C:15]2[CH:14]=[C:13]([CH:33]=[CH:32][CH:31]=2)[CH2:12][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:2](=[O:1])[NH:3][N:4]=2)=[O:17])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4c3CCCC4)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 55A (480 mg, 1.76 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 1 hour, and was concentrated. The residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 353 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.68-1.74 (m, 4H), 2.43-2.48 (m, 2H), 2.48-2.54 (m, 2H), 3.19-3.29 (m, 3H), 3.67-3.97 (m, 5H), 4.04 (s, 2H), 7.30-7.33 (m, 1H), 7.33-7.36 (m, 1H), 7.36-7.39 (m, 1H), 7.44 (t, J=7.48 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[C:10](Br)[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[C:10]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: CCOC(=O)Cc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Product: CCOC(=O)Cc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
Under argon, a mixture of [5-bromo-2-nitro-phenyl]acetic acid ethyl ester (2.02 g, 7.00 mmol) and 1-methyl-piperazine (1.40 g, 14.0 mmol) is heated at 65° C. for 24 h. The reaction mixture is partitioned between CH2Cl2 (25 mL) and H2O (25 mL), and the aqueous layer is extracted with CH2Cl2 (2×25 mL). The combined organic layers are washed with brine (25 mL), dried over Na2SO4, and concentrated at reduced pressure. The crude product is purified by FCC(CH2Cl2/MeOH 97.5:2.5) to afford the title compound as a yellow oil. ES+-MS: 308 [M+H]+.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[NH:47][C:48]([C:50]1[C:58]2[NH:57][C:56]([NH2:59])=[N:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49].C([O-])(O)=O.[Na+]>CN(C=O)C.CCN(C(C)C)C(C)C.O>[NH:44]1[CH:45]=[CH:46][N:42]=[C:43]1[NH:47][C:48]([C:50]1[C:58]2[N:57]=[C:56]([NH:59][C:14]([C:13]3[CH:12]=[N:11][CH:10]=[C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=3)=[O:16])[NH:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49]
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
0.1 g (0.46 mmol) of 5-Phenylethynyl-nicotinic acid, 0.19 g (0.5 mmol) of HBTU in a mixture of 2.0 ml of DMF and 0.30 mL of DIEA was reacted with 0.1 g (0.40 mmol) of 2-Amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (Intermediate B) as described in general procedure A. The reaction mixture was cooled to r.t. 5.0 mL of water and 5.0 mL of saturated NaHCO3 was added, and the resulting solid was filtered. The solid was washed with water, ether and dried to provide 0.08 g (43%) of 2-[(5-phenylethynyl-pyridine-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. LCMS: 448 (M+1)+.
Reaction SMILES: [C:1]([N:9]=[C:10]1[NH:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH:27]=[C:26]([CH2:28][CH2:29][CH2:30][NH2:31])[N:25]=[CH:24]1>C(#N)C.C(O)C>[C:1]([NH:9][C:10]([NH:14][CH2:13][CH:12]([OH:11])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:31][CH2:30][CH2:29][CH2:28][C:26]1[N:25]=[CH:24][NH:23][CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C1NCC(COc2ccccc2)O1)c1ccccc1
Reactant: NCCCc1c[nH]cn1
Solvent: CCO
Solvent: CC#N
Product: O=C(NC(=NCCCc1c[nH]cn1)NCC(O)COc1ccccc1)c1ccccc1
Yield: 38 %

Procedure:
1.48 g (5 mmol) of 2-benzoylimino-5-phenoxymethyloxazolidine and 0.69 g (5.5 mmol) of 3-(imidazole-4-yl)-propylamine are heated together under reflux in a mixture of 40 ml of acetonitrile and 10 ml of ethanol for 8 hours. The reaction mixture is concentrated by evaporation under vacuum and the product is isolated and purified by preparative layer chromatography (silica gel 60 PF254 containing gypsum: solvent; chloroform/methanol 98:2, ammoniacal atmosphere). Crystallisation from acetonitrile results in 0.8 g (38%) of colourless crystals, melting point 129° C.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:41])[C:35]#[C:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:30][CH:29]=1>C(#N)C>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([C:35]2[C:36]([CH2:37][CH2:38][CH2:39][CH3:40])=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=23)=[O:41])=[CH:32][CH:33]=1
Reactant: CCCCC#CC(=O)c1ccc(Br)cc1
Reactant: N[n+]1ccccc1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCc1nn2ccccc2c1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2.5 g of N-aminopyridinium mesitylene sulfonate (prepared by Synthesis, 1977 page 1, TAMURA, et al.), 25 ml of acetonitrile and 3.5 g of potassium carbonate was stirred for 15 minutes at ambient temperature and then the 2.27 g of the product of Step A in solution in 25 ml of acetonitrile were added.
Reaction SMILES: N(C(N(C)C)=O)=NC(N(C)C)=O.[OH:13][C:14]1[C:15]([C:32](=O)[CH3:33])=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:18]=[CH:17]2.O[CH2:36][CH2:37][NH:38]C(=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:33][C:32]1[C:15]2=[C:16]3[C:20](=[CH:21][CH:22]=[C:14]2[O:13][CH2:36][CH2:37][N:38]=1)[N:19]([S:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH:18]=[CH:17]3
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(=O)c1c(O)ccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=NCCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c21
Temperature: 43 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide) (73 mg, 0.43 mmol) was added to a solution of 1-[5-hydroxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethanone (Intermediate 23, 67 mg, 0.21 mmol), tert-butyl N-(2-hydroxy-ethyl)carbamate (0.14 g, 0.85 mmol) and triphenylphosphine (112 mg, 0.430 mmol) in DCM (5 mL). The mixture was heated at 43° C. for 1 hour and additional 1,1′-azobis(N,N-dimethylformamide) (0.030 g, 0.17 mmol) was added and the mixture was heated at 43° C. for an additional 2 hours. The mixture was cooled to room temperature and TFA (2.5 mL) was added and the mixture was stirred for 1 hour and evaporated. The residue was partitioned between DCM and 1 M NaOH. The organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using 5% MeOH in DCM as the eluent to give 75 mg of 1-methyl-8-(phenylsulfonyl)-3,8-dihydro-4H-[1,4]oxazepino[6,7-e]indole. Acetic acid (132 mg, 2.20 mmol) was added to a solution of the 1-methyl-8-(phenylsulfonyl)-3,8-dihydro-4H-[1,4]oxazepino[6,7-e]indole (75.0 mg, 0.22 mmol) in DCM (10 mL) and the mixture was allowed to stir for 10 minutes at room temperature before sodium triacetoxyborohydride (0.070 g, 0.33 mmol) was added all in one portion. The mixture was stirred for 30 minutes and transferred to a separation funnel and washed with 1 M NaOH and brine. The organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using MeOH:DCM:NEt3 (5:94:1) as the eluent to give the title compound (28 mg) as a white solid. MS m/z 343 [M+H]+.
Reaction SMILES: [Si:1]([NH:8][S:9]([C:12]1[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=1)(=[O:11])=[O:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1C=C(S(N)(=O)=O)N=C1.[Si](Cl)(C(C)(C)C)(C)C.C(N(CC)CC)C.CN([CH:46]=[O:47])C>>[Si:1]([NH:8][S:9]([C:12]1[N:13]=[C:14]([CH:46]=[O:47])[N:15]([CH3:17])[CH:16]=1)(=[O:10])=[O:11])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1cnc(S(=O)(=O)N[Si](C)(C)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: Cn1cnc(S(N)(=O)=O)c1
Solvent: CCN(CC)CC
Product: Cn1cc(S(=O)(=O)N[Si](C)(C)C(C)(C)C)nc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step A) Preparation of N-[tert-butyl(dimethyl)silyl]-1-methyl-1H-imidazole-4-sulfonamide: A mixture of 2.2 g (14 mmol) 1-methyl-1H-imidazole-4-sulfonamide, 2.1 g (14 mmol) t-butyldimethylsilyl chloride and 3.9 mL (28 mmol) triethylamine in 15 mL DMF was stirred at room temperature overnight Solvent was removed, and the residue was dissolved in EtOAc before being washed with water and brine. Drying (MgSO4) and removal of solvent gave 3 g of the subtitle product as a white solid, 1H NMR (DMSO) δ 7.7 (s, 1H), 7.6 (s, 1H), 7.35 (s, 1H), 3.7 (s, 3H), 0.9 (s, 9H)., 0.2 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:15]2[NH:16][C:17]([N:19]3[CH2:24][CH2:23][NH:22][C@H:21]([CH3:25])[CH2:20]3)=[N:18][C:14]=2[CH:13]=[C:12]([C:26]([F:29])([F:28])[F:27])[CH:11]=1.C(N(CC)C(C)C)(C)C>>[Cl:9][C:10]1[C:15]2[NH:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:2]4[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=4)[C@H:21]([CH3:25])[CH2:20]3)=[N:18][C:14]=2[CH:13]=[C:12]([C:26]([F:29])([F:28])[F:27])[CH:11]=1
Reactant: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CCN1
Reactant: Clc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CCN1c1ncccc1Cl

Procedure:
A mixture of 2,3-dichloro-pyridine (44 mg, 0.3 mmol, Aldrich), 7-chloro-2-[(3R)-3-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (80 mg, 0.25 mmol, Example 48a) and N,N-diisopropylethylamine (0.1 mL, 0.58 mmol, Aldrich) reacted under the conditions of Example 48b to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 430 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][CH:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[CH3:7].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][CH:6]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:17]1=[O:18])[CH3:7]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)CCC(C)Nc1ccccc1N
Solvent: C1CCOC1
Product: COC(=O)CCC(C)n1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To a solution of 4-(2-amino-phenylamino)-pentanoic acid methyl ester (1.05 g, 4.7 mmol) in THF (15 mL) was added 1,1′-carbonyldiimidazole (0.8 g, 4.9 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The resulting residue was purified by CombiFlash with 50% EtOAc in Hexane as the eluent to afford the desired 4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-pentanoic acid methyl ester (1.1 g, 94%).
Reaction SMILES: COC1C=C(C=CC=CC(N2CCN(CC[N:30]3[C:39]4[C:38](=[O:40])[N:36]([CH3:37])[C:35](=[O:41])[N:34]([CH3:42])[C:33]=4[N:32]=[CH:31]3)CC2)=O)C=CC=1OCOCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[N:36]1([C:38](=[O:40])[C:39]2[NH:30][CH:31]=[N:32][C:33]=2[N:34]([CH3:42])[C:35]1=[O:41])[CH3:37]
Reactant: COCCOCOc1ccc(C=CC=CC(=O)N2CCN(CCn3cnc4c3c(=O)n(C)c(=O)n4C)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Temperature: 25 °C

Procedure:
To a solution of 502 mg (0.86 mmol) of the theophylline derivative in 8 ml of methanol was added, under argon atmosphere, 360 mg (1.90 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, adjusted to a pH value of 10 by the addition of a saturated aqueous solution of sodium hydrogencarbonate, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue (540 mg) was subjected to silica gel column chromatography, eluted with chloroform-methanol (50:1), to give 225 mg (0.45 mmol) of 7-[2-[4-[5-(3-methoxy-4-hydroxyphenyl)-2,4]-pentadienoyl]piperazin-1-yl]ethyl]theophylline.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]1[CH2:21][N:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]([O:16]C(C)(C)C)=[O:15])[N:8]2[C:7]1=[O:22])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([S:4][CH2:5][CH:6]1[CH2:21][N:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]([OH:16])=[O:15])[N:8]2[C:7]1=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC1CN2CCCC(C(=O)OC(C)(C)C)N2C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC1CN2CCCC(C(=O)O)N2C1=O

Procedure:
1.69 of tert.butyl 2-acetylthiomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (diastereomer A) were treated with 10 ml of trifluoroacetic acid at room temperature for 2 hours. The solution was evaporated and the residue was re-evaporated with toluene several times. The residue was then crystallized from acetone to give 1.1 g of 2-acetylthiomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]-pyridazine-5-carboxylic acid having a melting point of 166°-168° C. (decomposition).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9](Cl)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CS(C)=O>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([N:17]3[C:16](=[O:18])[C:15]4=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]4[C:13]3=[O:23])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC1CCN(C2CCCCC2)C1
Agent: [K]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1C1CCN(C2CCCCC2)C1

Procedure:
A rapidly stirred suspension of 160 g. of N-cyclohexyl-3-chloropyrrolidine, 148 g. of potassium phthalimide and 700 ml. of dimethyl sulfoxide is heated at 110°-113° C. for 16 hours and filtered while hot. Water is added and the precipitate is filtered off, washed with water, air-dried and recrystallized from iso-octane-benzene to give 1-cyclohexyl-3-phthalimidopyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]([O:23]C)=[O:22])=[CH:10][CH:9]=2)=[O:4].CO.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]([OH:23])=[O:22])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccccc3)c(C(=O)OC)c(-c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)O)ccc2c(=O)n1Cc1ccccc1
Reaction time: 12 h
Yield: 98.7 %

Procedure:
To a solution of 2-benzyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3,6-dicarboxylic acid dimethyl ester (1.75 g) in THF (10 ml) were added methanol (10 ml) and 8N-aqueous sodium hydroxide solution (1 ml) at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and water was added, after which conc. hydrochloric acid (1 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (1.67 g).
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6]([C@@H:8]([NH:17][C@@H:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[S:20][CH2:19]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])C>C(O)C>[Na+:2].[C:6]([C@@H:8]([NH:17][C@@H:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([O-:29])=[O:28])[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[S:20][CH2:19]1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CN1C(=O)[C@@H](N[C@@H](CCc2ccccc2)C(=O)O)CSc2ccccc21
Reaction time: 0.5 h

Procedure:
A mixture of 2 ml of ethanol, 6 ml of 1N aqueous sodium hydroxide and 0.2 g of 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid obtained in Example 7 is allowed to stand at room temperature for 30 minutes and concentrated under reduced pressure at room temperature to about 1 ml. The concentrated solution is acidified slightly with acetic acid, and the deposited colorless prisms are collected by filtration to yield 0.134 g of 3(R)-[1(S)-carboxy-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid monosodium salt, m.p. 166°-169° C.
Reaction SMILES: S(Cl)(Cl)=O.CN(C)C=O.[CH3:10][O:11][C:12]([CH:14]([CH2:21][CH:22]=[CH2:23])[CH2:15][CH2:16][CH2:17][C:18]([NH2:20])=O)=[O:13].N>C(OCC)C.O>[CH3:10][O:11][C:12]([CH:14]([CH2:21][CH:22]=[CH2:23])[CH2:15][CH2:16][CH2:17][C:18]#[N:20])=[O:13]
Reactant: C=CCC(CCCC(N)=O)C(=O)OC
Agent: N
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCC(CCCC#N)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (1.125 l, 1.835 kg, 15.42 mol) is cooled to 0°, and dimethylformamide (1.199 l, 1.132 kg, 15.50 mol) is added dropwise over a period of 2 h keeping the temperature below 10°. After the addition is complete the reaction is allowed to come to room temperature over 2 h. To this is then added 5-methoxycarbonyl-oct-7-enoic acid amide (see example 22c), 2.671 kg, 13.42 mol) neat over a period of 3 h. The reaction is allowed to stir at room temperature for 18 h and is combined with material from a similar run and then diluted with diethyl ether (35 l). The solution is cooled to 0° and is admixed with 8 kg of ice and 12 l of water. The mixture is stirred for 30 min and is then basified with aqueous ammonia (12 l, 2.5M). The layers are separated and the organic phase is washed with water (12 l) and brine (12 l) and dried over anhydrous sodium sulfate (7.5 kg). This is then filtered and evaporated to yield a crude oil which is redissolved in diethyl ether (24 l) and this solution is stirred over 7 kg of silica gel for several h. After filtration and evaporation there is obtained partially purified material which is then distilled to obtain 5-methoxycarbonyl-oct-7-enenitrile, b.p. 118°-120°/0.15 mm Hg (=0.20 mbar).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:61][N:62]1[CH:66]=[C:65]([CH2:67][C:68](O)=[O:69])[CH:64]=[N:63]1>CN(C)C(=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][C:68](=[O:69])[CH2:67][C:65]6[CH:64]=[N:63][N:62]([CH3:61])[CH:66]=6)=[C:7]5[CH:8]=[CH:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: Cn1cc(CC(=O)O)cn1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1C=CC(NC(=O)Cc2cnn(C)c2)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 68 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.165 M and 0.47 M in N,N-dimethylacetamide, respectively, 275 μL, 0.042 mmol Example 23e and 0.13 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.25 M in N,N-dimethylacetamide, 253 μL, 0.063 mmol), and 2-(1-methyl-1H-pyrazol-4-yl)acetic acid (0.40 M in N,N-dimethylacetamide, 125 μL, 0.05 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified using reverse phase HPLC(C8, acetonitrile/water (0.1% TFA), 5-100%) to give 0.0168 g (68%) of the title compound as the TFA salt. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.03 (d, J=2.14 Hz, 1H), 7.57 (s, 2H), 7.42 (dd, J=8.54, 2.44 Hz, 1H), 7.38 (s, 1H), 7.16 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.78 (m, 2H), 6.50 (m, 2H), 4.59 (m, 2H), 4.06 (s, 3H), 3.81 (s, 3H), 3.52 (s, 2H). MS (APCI+) m/z 483.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:3][CH2:4][CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[Si:7]([O:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:20]([CH3:21])([CH3:22])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCCCC(O)CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCC(=O)CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 71.2 %

Procedure:
A solution of 49 (233 mg, 0.374 mmol) in CH2Cl2 (1 mL) was treated with PCC (121 mg, 0.561 mmol) at room temperature. Stirring was continued for 2 h. The mixture was diluted with Et2O, and the mixture was applied onto a plug of silica. The solid was washed with Et2O. The sample was concentrated, and the oily residue was chromatographed [silica, hexanes/ethyl acetate (10:1) to yield a colorless oil (166 mg, 71%): 1H NMR δ 1.82-1.88 (m, 4H), 2.55-2.58 (m, 4H), 3.65-3.72 (m, 4H), 7.43-7.45 (m, 12), 7.69-7.71 (m, 8H).