Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH:13]1[CH2:14][O:15]1
Reactant: Oc1ccccc1I
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Product: Ic1ccccc1OCC1CO1
Temperature: 70 °C
Yield: 79.6 %

Procedure:
To a round bottom flask under N2 was added 4.56 g (0.095 mole) of 50% NaH in oil. The NaH was washed twice with hexane, then 220 ml of DMF was added. Aliquots of 20.0 g (0.091 mole) of o-iodophenol were added over 15 minutes then 30.0 ml (0.450 mole) of epichlorohydrin was added and the solution heated to 70° C. After two hours the reaction was evaporated in vacuo, taken into CHCl3, washed with 10% NaOH, water, and brine and dried with MgSO4. The solvent was evaporated in vacuo to give 24.93 g of crude product. Distillation at 110°-114° C., 0.05 mm Hg gave 20.0 g (80.0%) of [(2-iodophenoxy)methyl]oxirane.
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]([CH2:25][O:26]P(OCC[N+](C)(C)C)(O)=O)[O:21][C:22](=[O:24])[CH3:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:1]([O:18][CH2:19][C@H:20]([CH2:25][OH:26])[O:21][C:22](=[O:24])[CH3:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)(O)OCC[N+](C)(C)C)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H](CO)OC(C)=O
Temperature: 100 °C

Procedure:
An ester analog of PAF, 1-hexadecanoyl-2-acetyl-sn-glycero-3-phosphocholine, was made by acetylation of 1-hexadecanoyl-2-lyso-sn-glycero-3-phosphocholine in a reaction with 0.5 ml of acetic anhydride and 20 mg of 4-dimethylaminopyridine in 1.25 ml of toluene; the sealed tube was heated at 100° C. for 2 hours and, after evaporation of the solvents with a stream of N2, the products were extracted by the method of Bligh and Dyer as described in Canadian Journal of Biochemical Physiology, Vol. 3, pp. 911-917, 1959. The product, 1-hexadecanoyl-2-acetyl-sn-glycerol-3-phosphocholine, was then treated with phospholipase C to produce 1-hexadecanoyl-2-acetyl-sn-glycerol, which was estimated on the basis of TLC to have a purity >95%.
Reaction SMILES: [CH:1]1([C:7]2[S:18][C:10]3[N:11]=[C:12]([CH3:17])[N:13]=[C:14]([C:15]#N)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[O:20]1CCO[CH2:22][CH2:21]1.CC[OH:28]>>[CH:1]1([C:7]2[S:18][C:10]3[N:11]=[C:12]([CH3:17])[N:13]=[C:14]([C:15]([O:20][CH2:21][CH3:22])=[O:28])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1COCCO1
Reactant: CCO
Reactant: Cc1nc(C#N)c2cc(C3CCCCC3)sc2n1
Agent: Cl
Product: CCOC(=O)c1nc(C)nc2sc(C3CCCCC3)cc12
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a mixture of 6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (23.5 g) and EtOH (100 mL) was added 4 M HCl/dioxane (100 mL), followed by stirring at 80° C. for 2 days. The reaction mixture was left to be cooled to room temperature and concentrated under reduced pressure. To the residue was added chloroform, followed by dissolving therein, and activated carbon (2 g) and basic silica gel (100 mL) were further added thereto, followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain ethyl 6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (30.8 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][C:19]=3[F:31])[C@H:12]([C:33](O)=[O:34])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.Cl.[CH3:37][NH2:38]>>[CH3:37][NH:38][C:33]([C@@H:12]1[CH2:11][C@@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:14][N:13]1[CH2:15][C:16](=[O:32])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=[O:30])=[CH:20][C:19]=1[F:31])=[O:34]
Reactant: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)O)Nc1ccc(-n2ccccc2=O)cc1F
Reactant: CN
Agent: Cl
Product: CNC(=O)[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1CC(=O)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
Using general procedure D (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid (example 12) was coupled with methylamine hydrochloride to give (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid methylamide. White solid. MS 532.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:16][C@H:17]([CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a 50 mL round-bottomed flask was added 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (147 mg, 0.61 mmol), 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (216 mg, 0.61 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (341.4 mg, 0.73 mmol) in chloroform (6 mL). DIEA (530 μL, 3.03 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (233 mg, 0.43 mmol, 71%): LC-MS (ES) m/z=541 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32]>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:32][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([F:27])[CH:29]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: NCc1cccc(F)c1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2cccc(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 62.1 %

Procedure:
A mixture of intermediate 59 (2.0 g, 5.42 mmol), 3-fluorobenzylamine (1.86 mL, 16.2 mmol) and MeOH (0.5 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and is purified twice by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 1.5 g of the product 87. 1H NMR (CDCl3) δ 7.50 (s, 1H), 7.40-7.30 (m, 1H), 7.30-7.15 (m, 2H), 7.10-6.90 (m, 9H), 7.85-7.75 (m, 2H), 5.50-5.30 (m, 2H), 4.80-4.55 (m, 2H), 1.15 (s, 9H); MS: m/z 446 (M++1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:13]([F:16])([F:15])[F:14])=[CH:4][C@H:5]1[C@H:7]([C:8](O)=[O:9])[C:6]1([CH3:12])[CH3:11].S(Cl)([Cl:21])=O>>[Cl:21][C:8]([C@H:7]1[C@H:5]([CH:4]=[C:3]([C:13]([F:16])([F:15])[F:14])[C:2]([F:18])([F:17])[F:1])[C:6]1([CH3:12])[CH3:11])=[O:9]
Reactant: CC1(C)[C@@H](C=C(C(F)(F)F)C(F)(F)F)[C@@H]1C(=O)O
Reactant: O=S(Cl)Cl
Product: CC1(C)[C@@H](C=C(C(F)(F)F)C(F)(F)F)[C@@H]1C(=O)Cl

Procedure:
A mixture of (+)-cis/trans-3-(3,3,3-trifluoro-2-trifluoromethyl-prop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid (0.4 g) and thionyl chloride (5.0 ml) was heated at the reflux temperature for a period of 2 hours, after which the excess thionyl chloride was removed by distillation under reduced pressure, leaving (+)-cis/trans-chlorocarbonyl-3-(3,3,3-trifluoro-2-trifluoromethyl-prop-1-en-1-yl)-2,2-dimethylcyclopropane.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[C:7]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])(=[O:9])[NH2:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]([Cl:33])=[O:32])[CH2:26][CH2:25]1)=[O:23].Cl.Cl.C(O)C>O.CC(C)=O.CC(C)=O>[OH2:2].[ClH:33].[C:7]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:31](=[O:32])[CH2:30][N:27]1[CH2:28][CH2:29][N:24]([C:22](=[O:23])[C:21]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:19]([O:18][CH3:17])[CH:20]=2)[CH2:25][CH2:26]1)(=[O:9])[NH2:8]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)N2CCN(CC(=O)Cl)CC2)cc1OC
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)N2CCN(CC(=O)Nc3ccccc3C(N)=O)CC2)cc1OC
Reaction time: 3 h

Procedure:
8.28 Grams of potassium carbonate was dissolved in 50 ml of water-acetone (1:2), then 13.6 g of o-carbamoylaniline was added thereto. Under ice-cooled condition, an acetone solution of 34.4 g of [4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetyl chloride was added dropwise to the said mixture, then the reaction was carried out at a room temperature for 3 hours. Acetone was removed by distillation, the residue obtained was extracted with chloroform and the extract was washed with water, dried then chloroform was removed by distillation. The residue obtained was purified by a silica gel column chromatography, the product obtained was converted into a hydrochloride by adding hydrochloric acid-ethanol, recrystallized from water-acetone to obtain 16 g of o-carbamoyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide monohydrochloride monohydrate in the form of colorless needle-like crystals. Melting point: 122.0°-125.0° C. (decomposed).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6](/[CH:8]=[N:9]/[C:10]([CH3:13])([CH3:12])C)[CH:7]=1.[CH2:15]([OH:19])CC#C.C(NC(C)C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:13]=[C:10]([CH2:12][CH2:15][OH:19])[N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: CC(C)(C)/N=C/c1cc(Br)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: OCCc1cc2ccc(Br)cc2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The product from Example 62D (1.3 g, 3.6 mmol), 3-butyn-1-ol (0.3 g, 4.3 mmol), CuI (0.04 g, 0.2 mmol), and PdCl2(PPh3)2 (0.08 g, 0.1 mmol) were combined in toluene (15 mL). The mixture was treated with diisopropylamine (0.54 g, 5.3 mmol) and stirred at room temperature for 4 hours. The mixture was then treated with additional CuI (0.07 g, 0.4 mmol) and heated at 100° C. for 4 hours. The mixture was allowed to cool to room temperature, diluted with 30 mL CH2Cl2, and filtered. The filtrate was washed with 2×10 mL 15% NaCl and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 9.08 (s, 1H), 8.09 (d, J=4 Hz, 1H), 7.73 (dd, J=8, 4 Hz, 1H), 7.63 (d, J=8 Hz, 1H), 7.48 (s, 1H), 4.08 (t, J=4 Hz, 2H), 3.92 (s, 1H), 3.15 (t, J=4 Hz, 2H). 13C NMR (CDCl3, 100 MHz) δ 153.8, 150.3, 134.5, 133.8, 129.4, 127.6, 120.0, 118.6, 62.3, 39.4. MS (DCI/NH3) 252, 254 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:35](=[O:36])[C:32]2[C:33]3[C:34]4[C:29](=[CH:30][CH:31]=2)[C:28]2[C:37]5[C:24]([C:25]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][OH:44])=[CH:26][CH:27]=2)=[CH:23][CH:22]=[CH:21][C:20]=5[C:19]=4[CH:18]=[CH:17][C:16]=3[C:14]1=[O:15])([CH3:3])[CH3:2].[C:45](Cl)(=[O:49])[C:46]([CH3:48])=[CH2:47]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:35](=[O:36])[C:32]2[C:33]3[C:34]4[C:29](=[CH:30][CH:31]=2)[C:28]2[C:37]5[C:24]([C:25]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45](=[O:49])[C:46]([CH3:48])=[CH2:47])=[CH:26][CH:27]=2)=[CH:23][CH:22]=[CH:21][C:20]=5[C:19]=4[CH:18]=[CH:17][C:16]=3[C:14]1=[O:15])([CH3:2])[CH3:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccc3c4cccc5c(CCCCCCO)ccc(c6ccc(c2c36)C1=O)c54
Product: C=C(C)C(=O)OCCCCCCc1ccc2c3ccc4c5c(ccc(c6cccc1c62)c53)C(=O)N(c1c(C(C)C)cccc1C(C)C)C4=O
Yield: 81 %

Procedure:
Reduction of 2 g (3.2 mmol) of N-(2,6-diisopropylphenyl)-9-(6-acetoxy-1-hexynyl)perylene-3,4-dicarboximide (cf. Example 10, 1.) in accordance with the hydrogenation instructions indicated for alkynylperylenes in Liebigs Ann./Recueil 1997, 395-407 gave a quantitative yield of the corresponding acetoxyhexyl derivative, which could be hydrolyzed as per Example 10, 2. in 98% yield to N-(2,6-diisopropylphenyl)-9-(6-hydroxyhexyl)perylene-3,4-dicarboximide. This, when reacted with methacryloyl chloride in accordance with Example 10, 3., gave the desired product in 81% yield as a red, amorphous solid.
Reaction SMILES: Br[CH2:2][CH:3]1[O:5][CH2:4]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)=[CH:9][C:8]=1[NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][C:8]=1[NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:2][CH:3]2[O:5][CH2:4]2)[CH:31]=1
Reactant: BrCC1CO1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OCC2CO2)c1

Procedure:
1-Bromo-2,3-epoxypropane (1.5 ml) was added to a stirred mixture of N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-hydroxybenzamide (1.5 g), caesium carbonate (2.84 g) and DMA (100 ml) and the resultant solution was stirred at ambient temperature for 18 hours. The mixture was poured into water (750 ml). The precipitate was isolated, washed with water and dried under vacuum at 60° C. There was thus obtained the title compound (1.3 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.73 (m, 1H), 2.85 (m, 1H), 3.2 (t, 4H), 3.75 (t, 4H), 3.91 (m, 1H), 4.43 (m, 1H), 7.2 (m, 3H), 7.37 (m, 4H), 7.66 (m, 3H), 7.56 (m, 3H), 7.8 (s, 1H), 9.9 (s, 1H), 10.14 (s, 1H); Mass Spectrum: M−H− 486.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:10]([NH:12][C:13](=[N:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])SC)#[N:11]>>[C:10]([NH:12][C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])=[N:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])#[N:11]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: NCCCCCCCN
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCCCCCCN
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.8 %

Procedure:
1,7-Diaminoheptane (5.2 g) was warmed gently until molten and to it was added N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (2.69 g). After stirring for 15 hours at room temperature the reaction mixture was extracted with ether to remove excess of the diamine starting material and then purified on a silica gel chromatographic colum, eluting with isopropanol to give the title compound (1.08 g), m.p. 84°-87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[C:30]([Si:34]([CH3:45])([CH3:44])[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH2:43])=[N:39]1)([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([Si:34]([CH3:45])([CH3:44])[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH:43][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[NH:10]2)=[O:29])=[N:39]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (72.42 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide (77.3 mg, 59%) as an off-white powder. HRMS (ES+) m/z Calcd for C34H45Cl2N5O2S+H [(M+H)+]: 654.2793. found: 654.2790.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:28][CH2:27][N:26]3[N:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=[C:25]3[CH2:24]2)[C:11](=O)[N:10]1[CH3:37].CO>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:28][CH2:27][N:26]3[N:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[N:31]=[C:25]3[CH2:24]2)[CH2:11][N:10]1[CH3:37]
Reactant: CN1C(=O)[C@H](N2CCn3nc(C(F)(F)F)nc3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Solvent: C1CCOC1
Solvent: CO
Product: CN1C[C@H](N2CCn3nc(C(F)(F)F)nc3C2)C[C@H](N)[C@H]1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step A (320 mg, 0.603 mmol) was partially dissolved in THF (20 mL) at room temperature. Borane-methyl sulfide complex (3.62 mL, 3.62 mmol) was added. The mixture was stirred at room temperature for 1 h, and then refluxed overnight. Borane-methyl sulfide complex (1.206 mL, 1.206 mmol) was added to the solution and the mixture was stirred at room temperature for 0.5 h, and then heated to (65-67° C.) for 6 h. Methanol (4 mL) was added with caution and the mixture was concentrated under reduced pressure. The residue was dissolved in n-PrOH (45 mL) and the solution was refluxed for overnight. The residue was purified by column chromatography on silica gel Biotage 25M™, eluting with EtOAc/CH2Cl2 (gradient from 0% to 60%) to give the desired product which was treated with 1:1 TFA/CH2Cl2 for 1 h. The residue was purified by preparative TLC on silica gel, eluting with CH2Cl2/MeOH/aqueous NH3 (90/9/1) to give the title compound. LC-MS: 416.91 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:34])=[CH:24][C:25]([O:32][CH3:33])=[C:26]([CH:31]=1)[C:27]([O:29]C)=[O:28].CO.[OH-].[Na+].Cl>O.C1COCC1>[F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:34])=[CH:24][C:25]([O:32][CH3:33])=[C:26]([CH:31]=1)[C:27]([OH:29])=[O:28]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)c(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the above prepared methyl 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate (assumed 0.211 mmol) in a mixture MeOH (2 mL)/THF (2 mL) at r.t. under N2 was added sodium hydroxide (0.84 mL, 0.84 mmol). The mixture was stirred at r.t. for 24 hours. The mixture was added with 2 ml 1N HCl, and concentrated until off white solids formed. The mixture was added with 5 ml H2O, the solids filtered and washed with 3×2 ml H2O and dried (75.1 mg). 1H NMR (500 MHz, CD3OD) δ 7.95 (m, 2H), 7.73 (s, 1H), 7.51 (d, J=8.24, 1H), 7.30-7.25 (t ovelapping with m, 3H), 7.13 (s, 1H), 3.99 (s, 3H), 2.96 (s, 3H), 2.28 (s, 3H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=452.23, HPLC Rt=1.582.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH2:10][N:9]=1.[H-].[Na+].[H-].[H][H].[O:28]1[CH2:33][CH2:32][N:31]([P:34](Cl)([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:35])[CH2:30][CH2:29]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([O:22][P:34]([N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)([N:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[O:35])[CH2:10][N:9]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
Reactant: O=P(Cl)(N1CCOCC1)N1CCOCC1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCC(OP(=O)(N1CCOCC1)N1CCOCC1)=N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4.74 g (15 mmoles) of 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one in 80 ml of dry tetrahydrofuran at room temperature was added 875 mg of a 50% dispersion of sodium hydride in oil (18 mmoles of hydride). The mixtute was stirred at room temperature for 1 hr until hydrogen evolution stopped. Dimorpholinophosphinic chloride (7.5 g, 30 mmoles) was added and the resulting mixture was stirred at room temperature for 3 hrs. Solids (mixture of product and salt) were collected and partitioned between water and methylene chloride. The methylene chloride layer was dried and evaporated. Crystallization of the residue from methylene chloride ether gave colorless needles, mp 214°-216°.
Reaction SMILES: N1([C:6]2[CH2:10][CH2:9][CH2:8][CH:7]=2)CCCC1.[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:19])[CH2:17]Br)=[CH:14][CH:13]=1.C([OH:24])C>>[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:19])[CH2:17][CH:6]2[CH2:7][CH2:8][CH2:9][C:10]2=[O:24])=[CH:14][CH:13]=1
Reactant: C1=C(N2CCCC2)CCC1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CCO
Product: O=C(CC1CCCC1=O)c1ccc(Br)cc1

Procedure:
(0.18 mole) of 1-pyrrolidino-1-cyclopentene and 50 g. (0.18 mole) of p-bromophenacyl bromide by the method described in Example 39a gave 20.8 g. (41%) of crystals, m.p. 59°-61° (from ethanol).