Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCOC(C)=O.C(Cl)Cl.[NH3:52]>CO>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([C:26]([NH2:52])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: COC(=O)[C@@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reactant: N
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@@H](C(N)=O)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 96 %

Procedure:
In a sealed tube a solution of Methyl (2S,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 13, 24.1 mg, 0.04 mmol) in 7N Ammonia in MeOH (5 mL, 35.0 mmol) was stirred at 25° C. for 1 day. The solvent was evaporated to dryness and the crude was purified twice by silica cartridges (2 g) (1st time: with EtOAc and then 97.5:2.5 DCM/0.5 M NH3 in MeOH and 2nd time: from 98.75:1.25 to 95:5 DCM/0.5 M NH3 in MeOH) to give the title compound (22.5 mg, 0.038 mmol, 96% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-8.05 (m, 1H) 7.61-7.77 (m, 2H) 7.21-7.27 (m, 1H) 7.13-7.19 (m, 1H) 6.87-6.97 (m, 2H) 6.73-6.83 (m, 1H) 5.25-5.37 (m, 1H) 4.08-4.20 (m, 1H) 3.44-3.55 (m, 1H) 3.26-3.38 (m, 1H) 2.57-2.85 (m, 4H) 2.26-2.36 (m, 3H) 1.98-2.16 (m, 1H) 1.41-1.82 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28]C4CCCCO4)=[CH:21][CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][OH:28])=[CH:23][CH:24]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(C(=O)Nc2ccc(OCCOC3CCCCO3)cc2)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(OCCO)cc2)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of the crude 1-[(3,4-dichlorophenyl)methyl]-5-methyl-N-(4-{[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]oxy}phenyl)-1H-1,2,3-triazole-4-carboxamide (Intermediate 19) in methanol was added a saturated solution of HCl in ethyl acetate. The reaction was stirred to 60° C. for 18 hours. After evaporation, the title compound was obtained as a cream solid after recrystallisation from methanol (0.23 g, 54% from intermediate 6). HRMS calculated for C19H18Cl2N4O3 (M+H)+421.0834, found: 421.0837, Rt: 2.76 min. MP: 140° C.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][CH3:17])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>>[C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:2]([OH:1])([CH3:4])[CH3:3])[N:6]=[C:7]2[CH2:15][CH2:16][CH3:17])=[CH:25][CH:24]=1)#[N:33]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 95.3 %

Procedure:
Following a procedure similar to that as described in Example 68(a), but using 4.01 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9), 5.0 g of 4'-bromomethylbiphenyl-2-carbonitrile and 1.97 g of potassium t-butoxide, 6.86 g of the title compound were obtained as crystals, melting at 92°-93° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15](I)[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:4]1.[C-:23]#[N:24].[K+]>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:23]#[N:24])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:4]1
Reactant: O=C(N1CC(CCl)c2c1ccc1c(I)cccc21)C(F)(F)F
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
A mixture of 125 (148 mg, 0.34 mmol), KCN (120 mg, 1.9 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), and CuI (50 mg, 0.26 mmol) in dry THF (30 mL) was heated to reflux under N2 with vigorous stirring for 30 min. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), and then filtered through Celite. The filtrate was washed with water and brine, dried and concentrated under reduced pressure. Chromatography of the residue on silica gel eluting with EtOAc/petroleum ether (from 1:5 to 1:2) gave 1-(chloromethyl)-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-6-carbonitrile (126) (97 mg, 85%): mp (EtOAc/petroleum ether) 158-160° C.; 1H NMR (CDCl3) δ 8.63 (d, J=9.1 Hz, 1H), 8.26 (d, J=9.2 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.90 (dd, J=7.2, 1.0 Hz, 1H), 7.64 (dd, J=8.2, 7.2 Hz, 1H), 4.70-4.63 (m, 1H), 4.51-4.43 (m, 1H), 4.28-4.20 (m, 1H), 3.95-3.89 (m, 1H), 3.64-3.55 (m, 1H); 13C NMR S 154.7 (q, JC-F 38.3 Hz), 141.5, 132.0, 130.7, 129.0, 127.7, 127.5, 126.7, 119.7, 117.2, 115.9 (q, JC-F 288 Hz), 111.7, 52.7, 45.4, 42.6. Anal. (C16H10ClF3N2O.⅓H2O) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([F:13])[CH:5]=1)([O-:3])=[O:2].Cl.[CH3:15][NH:16][O:17][CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>N1C=CC=CC=1>[CH3:18][O:17][N:16]([CH3:15])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[F:13]
Reactant: CNOC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 60 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
4-Nitro-2-fluorobenzoic acid (5.03 g) was dissolved in pyridine (60.0 ml), and N,O-dimethylhydroxylamine hydrochloride (7.95 g), HOBt (5.50 g), and EDC (7.79 g) were added thereto. The obtained mixture was stirred at 60° C. for 15 hours. After the reaction mixture was allowed to cool, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue, and extraction and washing were carried out. The organic layer was sequentially washed with a 1N hydrochloric acid aqueous solution, saturated sodium-bicarbonate aqueous solution, and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized with a mixed solvent of tert-butylmethylether and n-heptane to obtain Compound 14a (5.28 g, 85%) as an opalescent solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:11][CH:10]1[CH:12]([F:14])[F:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:30]1([S:33]([NH:36][C:15]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][CH:10]2[CH:12]([F:13])[F:14])=[O:17])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1C(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
A mixture of 1-(tert-butoxycarbonylamino)-2-(difluoromethyl)cyclopropanecarboxylic acid (975 mg, 3.88 mmol) and CDI (755 mg, 4.66 mmol) in tetrahydrofuran (10 mL) was heated at reflux for 1 h. It was then cooled to rt and then cyclopropanesulfonamide (564 mg, 4.66 mmol) was added, followed by DBU (0.702 mL, 4.66 mmol). This mixture was stirred at rt for 18 h. It was then concentrated in vacuo, diluted with water and adjusted to pH=4 using 1 N HCl. The acidic solution was extracted with EtOAc, washed with water (5×15 mL), dried (MgSO4), and concentrated in vacuo to yield 1.6 g of the crude product as a white solid. Recrystallization from hexane/EtOAc gave 1.15 g (84%) of tert-butyl 1-(cyclopropylsulfonylcarbamoyl)-2-(difluoromethyl)cyclopropylcarbamate as a white solid. LC-MS, MS m/z 377 (M+1+Na).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(#N)C.[CH2:25]([OH:28])[CH:26]=[CH2:27]>C(N(CC)CC)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([O:28][CH2:25][CH:26]=[CH2:27])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: C=CCO
Reactant: CC(C(=O)Cl)c1ccc2c(=O)c3ccccc3ccc2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCOC(=O)C(C)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
0.5 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionyl chloride is dissolved in 25 ml. of acetonitrile containing 0.5 ml. of allyl alcohol and 0.5 ml. of triethylamine. After 16 hours the mixture is evaporated to dryness and partitioned between ethyl acetate and water. The organic solution is washed, dried, passed through a short (10 g.) silica gel column, then evaporated to give allyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate as an oil [nmr spectrum in deuterochloroform relative to tetramethylsilane: 1.54 (doublet, CH3), 2.84 (quartet, CH), 4.55 (doublet, OCH2), 5.1-6.0 (multiplet, CH=CH2) and 7.00 ppm (singlet, 10, 11-H); mass spectrum: 318(M+) 233,205].
Reaction SMILES: [OH-:1].[Na+].BrBr.[Cl:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:7]=1[C:14](=[O:16])C.Br[O-].[Na+]>O.O1CCOCC1>[Cl:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:7]=1[C:14]([OH:16])=[O:1]
Reactant: [OH-]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (−5° C.) solution of sodium hydroxide (252 g, 6.3 mol) in water (800 mL) was added bromine (86 mL, 1.68 mol) dropwise. The temperature of the reaction mixture was kept below −5° C. during the addition. A solution of 1-(2,6-Dichloro-3-fluorophenyl)ethanone (100 g, 480 mmol) in dioxane (800 ml) was added to the solution of sodium hypobromide in 1 h while maintaining the temperature below 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. After the TLC showed absence of starting material, the excess sodium hypobromide was destroyed with sodium sulfite (100 g in 100 mL water). The resulting solution was heated to 90° C. for 2 h. The reaction mixture was acidified with conc. HCl with vigorous stirring. The acidic solution was concentrated to remove all the dioxane and then extracted with dichloromethane (2×500 mL). The organic layer was dried (Na2SO4) and concentrated to give an oily residue, which after trituration with hexanes gave the title compound as a white solid. 1H NMR (CDCl3, 300 MHz): δ=7.20 (dd, 1H, J=8.7, 8.4 Hz), 7.33 (dd, 1H, J=9.3, 4.5 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[CH2:17][N:16]3[C@@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]2=[C:26]([CH:46]=1)[O:27][CH2:28][C:29]1[CH:45]=[CH:44][CH:43]=[CH:42][C:30]=1/[C:31]/2=[CH:32]\B1OC(C)(C)C(C)(C)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[O-].[Na+]>O1CCCC1.CO.C(OCC)(=O)C.[Cl-].[Na+].O.ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]2=[C:26]([CH:46]=1)[O:27][CH2:28][C:29]1[CH:45]=[CH:44][CH:43]=[CH:42][C:30]=1/[C:31]/2=[CH:32]\[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[CH2:17][N:16]3[C@@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1N[C@@H]1C[C@@H]2COCCN2C1
Reactant: CC1(C)OB(/C=C2\c3ccccc3COc3cc(F)ccc32)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(/C=C2\c3ccccc3COc3cc(F)ccc32)ccc1N[C@@H]1C[C@@H]2COCCN2C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
Charge a flask with (7R,8aR)-(4-bromo-2-nitro-phenyl)-(hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine (50.9 g, 0.149 mol), (E)-2-((3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (57.5 g, 0.163 mol), triphenylphosphine (10.1 g, 39 mmol) and sodium methoxide (19.7 g, 0.346 mol) in tetrahydrofuran (1 L) and methanol (500 mL). Bubble nitrogen through the mixture for 30 min. Add palladium (II) acetate (3.00 g, 13 mmol) and bubble nitrogen through the mixture for an additional 30 min. Heat at reflux (60° C.) under nitrogen for 16 h. Cool to room temperature, filter through diatomaceous earth and concentrate in vacuo to obtain a solid. Dissolve in 1:1 ethyl acetate/brine (2 L) and pass through a pad of diatomaceous earth. Wash the pad with 1:1 ethyl acetate/brine (2×1 L) and then with 10% methanol in dichloromethane (4×1 L). Separate the layers and combine the organic phases. Dry the organic portion over sodium sulfate, filter, and concentrate to obtain an oil. Dissolve the oil in dichloromethane and pass through a silica gel pad. Rinse the pad with dichloromethane until higher Rf TLC component is removed. Elute with 1% methanol in dichloromethane and concentrate in vacuo to obtain a foam. Dissolve in ethyl acetate (2 L) and concentrate to approximately 200 mL. Add hexanes (1.5 L) and allow the suspension to stand at room temperature for one hour. Collect the orange solid by filtration and dry at 50° C./20 mm Hg to obtain the title compound (53 g, 73%). [α]D20−26 (c=1.0 in DMSO). 1H NMR (400 MHz, DMSO-d6) δ 1.08 (m, 1H), 2.02 (m, 1H), 2.17 (m, 1H), 2.41 (m, 2H), 2.88 (m, 1H), 3.17 (m, 1H), 3.40 (m, 1H), 3.73 (d, 1H), 3.82 (d, 1H), 4.12 (m, 1H), 5.02 (broad s, 1H), 5.59 (broad s, 1H), 6.60 (d, 1H), 6.81 (m, 2H), 6.96 (s, 1H), 7.05 (m, 2H), 7.28 (t, 1H), 7.38 (t, 1H), 7.60 (m, 2H), 7.84 (s, 1H), 8.05 (d, 1H). LC-MS m/z 458.3 [M+H]+.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][S:13][C:9]=3[C:8](=[O:14])[N:7]3[CH2:15][CH2:16][CH2:17][C@H:6]3[C:5]=12.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:18][C:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][S:13][C:9]=3[C:8](=[O:14])[N:7]3[CH2:15][CH2:16][CH2:17][C@H:6]3[C:5]=12
Reactant: O=C1c2sccc2-n2cncc2[C@@H]2CCCN12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2sccc2-n2cnc(Cl)c2[C@@H]2CCCN12

Procedure:
3.0 (12.2 mmol) of (S)-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one in 20 ml of dimethylformamide are stirred at 65° for 40 minutes with 1.63 g (12.2 mmol) of N-chlorosuccinimide. The solution is poured into water and extracted with chloroform. The organic phase is washed several times with water, dried over magnesium sulphate and evaporated. By column chromatography on silica gel there is obtained (S)-1-chloro-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8 one of melting point 180°-183°.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:6]1.CN1CCOCC1.Cl.[CH3:36][NH:37][OH:38]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([N:37]([OH:38])[CH3:36])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:6]1
Reactant: COCCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Reactant: CNO
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)N(C)O)cc12
Temperature: 4 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 1-(2,4-difluorobenzyl)-3-[(2-methoxyethoxy)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid 782 mg 2.078 mmol) in anhydrous DMF (10 ml) was added CDMT (438 mg 2.439 mmol 1.2 eq.) and NMM (N-methyl morpholine) (0.28 ml 2.493 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 2.0 hours, during which it slowly darkened to a deep orange. N-Methylhydroxylamine hydrochloride (868 mg 10.389 mmol 5.0 eq) was added and stirring continued for 10 hours. The reaction was judged to be complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. This oil was dissolved in EtOAc (30 mL) and washed with water (3×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the crude product which was purified by recrystallisation in hot IPA (20 ml) with cooling at 4° C. overnight to give 556 mg (66%) of 1-(2,4-difluorobenzyl)-N-hydroxy-3-[(2-methoxyethoxy)methyl]-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide as a pale tan powder. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—3 minutes, APCI, +mode): RT—1.08 min, m/e=344.2 (M+H+, base).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([CH3:17])([S:7]([CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=[O:9])=[O:8])[CH3:6])C.[OH-].[Na+].CC(OC)(C)C>C1COCC1>[CH3:17][C:5]([S:7]([CH2:10][CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)(=[O:9])=[O:8])([CH3:6])[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)CC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C(=O)O)S(=O)(=O)CC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 123 g (0.44 mol) of 2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid ethyl ester in THF (450 mL) are added 663 mL of 2M aqueous sodium hydroxide solution (1.33 mol). The reaction is stirred at room temperature for 1 h. To the reaction mixture is added TBME (1.25 L) and the layers are separated. The aqueous layer is cooled in an ice bath and then acidified with 37% aqueous HCl solution (123 mL). The resulting precipitate is isolated by filtration, washed with water (200 mL) and dried under reduced pressure at 50° C. to afford 101 g of 2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid as white crystalline solids. Yield: 91%; ES-MS: m/z 251 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.45 (2H, m), 1.49 (6H, s), 1.70-1.79 (2H, m), 2.13-2.28 (1H, m), 3.24 (2H, d, J=6.60 Hz), 3.28-3.38 (2H, m), 3.76-3.85 (2H, m), 13.65 (1H, br. s.)
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[CH2:11]([NH:15][C:16](=[O:49])[C@H:17]([CH3:48])[CH2:18][C@H:19]([OH:47])[C@@H:20]([NH:39]C(OC(C)(C)C)=O)[CH2:21][C@@H:22]([CH:36]([CH3:38])[CH3:37])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][C:34]#[N:35])[CH:25]=1)[CH2:12][CH2:13][CH3:14]>ClCCl>[CH2:11]([NH:15][C:16](=[O:49])[C@H:17]([CH3:48])[CH2:18][C@H:19]([OH:47])[C@@H:20]([NH2:39])[CH2:21][C@@H:22]([CH:36]([CH3:37])[CH3:38])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][C:34]#[N:35])[CH:25]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCC#N)c1)C(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)C[C@H](Cc1ccc(OC)c(OCC#N)c1)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.5 ml of a mixture of trifluoroacetic acid/dichloromethane=1:3 are added at 0° C., with stirring, to a solution of 35 mg of N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-cyanomethoxy-4-methoxy-phenyl)-octanoic acid (N-butyl)amide in 1 ml of dichloromethane, and the mixture is stirred for a further 3 hours at 0° C. and then concentrated by evaporation. The residue is purified by FC (5 g of silica gel, dichloromethane/methanol=9:1). This yields the title compound: Rf (dichloromethane/methanol=9:1)=0.19; Rt (I)=19.59 minutes; FAB-MS(M+H)+ =448.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([CH2:14][C:15]1[N:16]([CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[CH:17]=[CH:18][N:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[NH3:30]>CO>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([Cl:27])[CH:24]=1)[CH2:20][N:16]1[CH:17]=[CH:18][N:19]=[C:15]1[CH2:14][N:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[CH2:4][C:3]([NH2:30])=[O:2]
Reactant: COC(=O)CN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: N
Solvent: CO
Product: NC(=O)CN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
[[1-(3,5-Dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amino]-acetic acid methyl ester (7e) (81 mg, 0.19 mmol) was dissolved in a 7N solution of NH3 in MeOH (10 mL). The solution was heated at 100° C. with stirring in a sealed tube reaction vessel for 18 h. The volatiles were removed in vacuo and the residue purified by column chromatography (silica gel, 5% MeOH in CH2Cl2) to provide the desired product 7f (40 mg, 51%): ESI MS m/z 421 [C20H19Cl2FN4O+H]+.
Reaction SMILES: [S:1]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3][S:2]1.Cl.[CH3:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][NH2:15].P(C#N)(OCC)(OCC)=O>CN(C)C=O.O1CCCC1>[S:1]1[CH2:5][CH:4]([C:6]([NH:15][CH2:14][CH2:13][C:12]([O:11][CH3:10])=[O:16])=[O:8])[CH2:3][S:2]1
Reactant: COC(=O)CCN
Reactant: O=C(O)C1CSSC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)C1CSSC1
Yield: 9.4 %

Procedure:
The reaction was carried out as described in Example 97, but using 5 ml of a solution of 3.3 mmol of 1,2-dithiolane-4-carboxylic acid (prepared as described in Example 96) in anhydrous dimethylformamide, 5 ml of anhydrous tetrahydrofuran, 1.01 ml of torethylamine, 502 mg of β-alanine methyl ester hydrochloride and 0.55 ml of diethyl cyanophosphate. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate solution by evaporation under reduced pressure, and the residue was recrystallized from a 2:2 by volume mixture of ethyl acetate and hexane, to obtain 73 mg of the title compound as pale yellow crystals having an Rf value of 0.41 (silica gel thin layer chromatography; using a 2:1 by volume mixture of ethyl acetate and hexane as developing solvent).