Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[N:16])[CH2:11][CH2:10]1.[C:17]1([S:23]([N:26]2[C:30]3=[N:31][CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[C:34](Cl)=[C:29]3[CH:28]=[CH:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:17]1([S:23]([N:26]2[C:30]3=[N:31][CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[C:34]([NH:8][C@H:9]4[CH2:14][CH2:13][C@H:12]([C:15]#[N:16])[CH2:11][CH2:10]4)=[C:29]3[CH:28]=[CH:27]2)(=[O:24])=[O:25])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: N#C[C@H]1CC[C@H](N)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1

Procedure:
A mixture of trans 4-amino-cyclohexanecarbonitrile trifluoroacetic acid salt (6.36 g, 26.7 mmol), 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (8.21 g, 24.3 mmol) and diisopropylethylamine (12.5 mL, 73.0 mmol) in propan-2-ol (200 mL) was heated at reflux for 3 hours. The cooled mixture was filtered and the precipitate washed with propan-2-ol to afford 9.04 g (87%) of trans 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanecarbonitrile as a bright yellow solid. LCMS (Method Q, ESI): RT=4.15 min, m+H=426.0; 1H NMR (400 MHz, CDCl3) δ: 9.11 (s, 1H), 9.07 (d, 1H), 8.20 (m, 2H), 7.63 (m, 2H), 7.53 (m, 2H), 6.67 (d, 1H), 4.06 (m, 1H), 2.66 (m, 1H), 2.24 (m, 4H), 1.83 (m, 2H), 1.58 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][NH:6][C:7]([N:9]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12][C:11]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:10]1=2)=[O:8])=[O:4].[CH2:25]([O:27][P:28]([O:32]CC)[O:29][CH2:30][CH3:31])[CH3:26].[Na+].[I-]>O1CCCC1.[Na+].[I-]>[CH2:25]([O:27][P:28]([CH2:2][C:3]([NH:5][NH:6][C:7]([N:9]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12][C:11]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:10]1=2)=[O:8])=[O:4])([O:29][CH2:30][CH3:31])=[O:32])[CH3:26]
Reactant: O=C(CBr)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CCOP(OCC)OCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)OCC
Yield: 83.5 %

Procedure:
To a stirring solution of 2.57 g (6.3 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(bromoacetyl) hydrazide (19), prepared as described in Example 19 above, in 75 mL of tetrahydrofuran (THF) was added 1.25 g (7.5 mmol) of triethylphosphite and 0.15 g (1 mmol) of NaI. After 22 hours of refluxing, an additional 0.62 g (3.75 mmol) of triethylphosphite and 0.05 g (0.33 mmol) of NaI were added to the reaction, which was refluxed an additional 24 hours. The solvent was then removed under aspirator vacuum, and the reaction mixture was chromatographed to yield 2.46 g (83%) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(diethoxyphosphinyl)acetyl]hydrazide (20), which was a beige foam. Analysis calculated for C20H23N3O6PCl (M.W. 467.85): C, 51.35; H, 4.96; N, 8.98; Cl, 7.58. Found: C, 51.02; H, 5.03; N, 8.83; Cl, 7.39.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=O)[CH3:17])[CH3:8]>C1C=CC=CC=1>[Cl:2][C:16](=[N:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:7][CH3:8])[CH3:17]
Reactant: CCc1ccccc1NC(C)=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCc1ccccc1N=C(C)Cl
Temperature: 25 °C
Yield: 83.7 %

Procedure:
Phosphorus pentachloride (8.97 g, 43 mmol) was dissolved in 100 mL of benzene. Under a gentle argon purge, N-(2-ethylphenyl)acetamide (Amide I) (6.52 g, 40 mmol) was added slowly with stirring at room temperature. The yellow solution was refluxed for 2 hours. Benzene was removed in vacuo, yielding a brown oil. The oil was distilled under reduced pressure (45-50° C., 0.10 Torr) affording 6.08 g (84%) of a clear oil. 1H NMR (400 MHz, C6D6): 7.07 (t, 2H), 6.99 (t, 1H), 6.80 (d, 1H), 2.50 (q, 2H), 2.08 (s, 3H), 1.11 (t, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]([CH3:14])=[O:13].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([CH:38]([CH3:40])[CH3:39])[N:25](/[CH:34]=[CH:35]/[CH:36]=[O:37])[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:18][CH:17]=1>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]([CH:38]([CH3:40])[CH3:39])[N:25](/[CH:34]=[CH:35]/[CH:36]([OH:37])[CH2:11][C:12](=[O:13])[CH3:14])[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:20][CH:21]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)CC(O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (4.1 ml, IM solution in THF) in dry THF (20 ml) at -78° under nitrogen was added dry acetone (275 μl). After 25 min, a solution of (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenal (881 mg) in dry THF (15 ml) was added dropwise over 10 min. Stirring was continued for 25 min at -78° then the reaction was quenched with saturated aqueous ammonium chloride solution (25 ml) and allowed to warm to room temperature. The layers were separated and the aqueous phase extracted with ethyl acetate (2×50 ml). The combined extracts were dried and evaporated to a white solid (1.09 g). FCC eluting with System A (1:1) gave the title compounds as a white solid (709.6 mg). (CDCl3) 7.35-7.45 and 7.20-7.29(2m,4H,C-2 and C-6 protons of 4-fluorophenyl), 7.10 and 6.90(2t,4H,C-3 and C-5 protons of 4-fluorophenyl,J=9 Hz), 6.70(d,1H,NCH=CHCH,J=13.7 Hz), 5.26(dd,1H,NCH=CHCH,J=13.7 Hz,6.3 Hz), 4.58(m,1H,NCH=CHCH), 3.15(m,2H,CH(CH3)2 and OH), 2.50(m,2H,CH(OH)CH2C(O)), 2.15(s,3H,CH2C(O)CH3), 1.40(d,6H,CH(CH3)2,J=7.5 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13])=O.O.[NH2:24][NH2:25]>C(O)C>[CH2:11]([C:10]1[CH:9]=[C:8]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[N:7]=[N:6][C:5]=1[C:3]([NH:24][NH2:25])=[O:2])[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)c1nnc(C(=O)N2CCCCC2)cc1CC(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)Cc1cc(C(=O)N2CCCCC2)nnc1C(=O)NN
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
The mono-methyl ester 5 (10 mg, 0.033 mmol) was dissolved in 3.5 mL anhydrous ethanol (dried over 4 Å molecular sieves). Hydrazine hydrate was added (55 μL, 1.65 mmol, 53 mg), and the reaction was stirred for 5.5 hours at room temperature under an atmosphere of nitrogen. The volatiles were evaporated under reduced pressure, and the product oil was triturated three times with ca. 3 mL diethyl ether. The bright yellow oil was dried under high vacuum to produce a 10 mg (quant.) of a pale yellow solid. MS: (ESI-TOF) MH+ expected: 306.1924, found: 306.1923.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1)[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:17]3[CH2:18][CH2:19][C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:16]3[CH2:14][CH3:15])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCC1NCCc2ccccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CCC1c2ccccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH3:8])[NH:5][C:6]=1[Br:7].C(=O)([O-])[O-].[Na+].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([N:3]1[C:2]([Br:1])=[C:6]([Br:7])[N:5]=[C:4]1[CH3:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nc(Br)c(Br)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Br)c(Br)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4,5-dibromo-2-methylimidazole (3.0 g, 12.5 mmol) in 25 mL DMF add sodium carbonate (2.0 g, 18.8 mmol) and benzyl bromide (1.64 mL, 13.8 mmol). Stir the solution at room temperature for 72 hours. Pour the reaction into water and extract with EtOAc. Wash the organic layer with water, saturated aqueous sodium chloride, and dry over sodium sulfate. Filter the mixture and concentrate to 3.8 g crude oil. Purify the oil by radial chromatography eluting with 40% EtOAc in hexanes. Concentrate the appropriate fractions to 3.1 g (75%) of the title compound as a colorless oil. MS(ES+): m/z=331.0 (M+H)+
Reaction SMILES: BrC1C=[CH:14][C:5]2S[C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=3[C:4]=2C=1.CC1(C)C(C)(C)OB(C2C=C(CCC[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])C=CC=2)O1>>[Br:13][C:10]1[CH:9]=[C:8]([CH2:4][CH2:5][CH2:14][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:7]=[CH:12][CH:11]=1
Reactant: Brc1ccc2sc3ccc(Br)cc3c2c1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: CC(C)(C)OC(=O)NCCCc1cccc(Br)c1

Procedure:
Intermediate 2,8-di(tert-butyl 3-phenylpropylcarbamate)benzothiophene was synthesized by Suzuki reaction of 2,8-dibromodibenzothiophene and tert-butyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate, which was obtained from tert-butyl 3-(3-bromophenyl)propylcarbamate. Compound 116 was obtained following similar de-protection reaction condition in route 2.
Reaction SMILES: C([C:3]1([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([F:27])[CH:16]=2)[CH:10]2CC3[CH2:7][CH:8]([CH2:12][CH:4]1C3)[CH2:9]2)#N.C12CC1CCC(COC1C(C3CC3)=CC(C(O)=O)=C(F)C=1)C2.CS(N)(=O)=O.[N:55]1([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:58][CH2:57][CH2:56]1>>[N:55]1([S:59]([NH:62][C:19](=[O:20])[C:18]2[CH:22]=[C:23]([CH:24]3[CH2:25][CH2:26]3)[C:15]([O:14][CH2:13][CH:3]3[CH2:10][CH2:9][CH:8]4[CH:12]([CH2:7]4)[CH2:4]3)=[CH:16][C:17]=2[F:27])(=[O:61])=[O:60])[CH2:58][CH2:57][CH2:56]1
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2CCC3CC3C2)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCC3CC3C2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2- fluorobenzoic acid and making variations as required to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as solid (0.026 g, 5%): 1H NMR (300 MHz, CDCl3) δ 8.66 (d, J=16.5 Hz, 1H), 7.60 (d, J=9.1 Hz, 1H), 6.59 (d, J=14.5 Hz, 1H), 5.78-5.54 (m, 2H), 4.25 (t, J=7.7 Hz, 4H), 3.96-3.85 (m, 2H), 2.35-2.17 (m, 4H), 2.11-1.64 (m, 5H), 1.28-1.23 (m, 1H), 1.06-1.00 (m, 2H), 0.96-0.91 (m, 2H), 0.70-0.66 (m, 2H); MS (ES+) m/z 423.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH3:52][S:49]([NH:48][CH2:47][CH2:46][N:43]1[C:44]2[C:39](=[CH:38][CH:37]=[C:36]([CH2:35][O:34][C@@H:10]3[C@@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[O:32][CH3:33])=[CH:18][CH:19]=4)[CH2:12][CH2:13][NH:8][CH2:9]3)[CH:45]=2)[CH2:40][CH2:41][CH2:42]1)(=[O:50])=[O:51]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCNS(C)(=O)=O)CCC3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3c(c2)N(CCNS(C)(=O)=O)CCC3)cc1

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-3-[1-(2-methanesulfonylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R)-3-[1-(2-methanesulfonylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine as a light yellow oil; MS: 638 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)#[N:40]>>[NH2:30][C:29]1[S:28][C:27]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([C:39]#[N:40])[CH:46]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(C#N)c3)sc2N)c1N1CCC(CN)CC1
Yield: 42 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 3-cyanophenyl boronic acid gave 250 as a pale brown solid (36 mg, 42% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 9.09 (s, 1H), 8.42 (s, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H), 7.56 (s, 2H), 7.33 (s, 1H), 3.66 (s, 3H), 3.16-2.99 (m, 4H), 2.47 (d, J=5.7 Hz, 2H), 1.82-1.73 (m, 4H), 1.30-1.17 (m, 3H). LCMS (ES+) m/z 437 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([OH:19])([CH2:13]OS(C)(=O)=O)[CH2:10][C@H:9]1[C:20](=[O:31])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([OH:19])([CH2:13][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:10][C@H:9]1[C:20](=[O:31])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1C[C@](O)(COS(C)(=O)=O)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@](O)(CN2CCOCC2)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-methanesulfonyloxy methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.416 mmol) (prepared as described Scheme B13) in DMF (10 mL) was added morpholine (181 mL, 2.079 mmol) and the solution was stirred for 16 h at 80° C. The reaction mixture was diluted with EtOAc, washed with a saturated aqueous solution of NaHCO3 (3 times). The organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (CH2Cl2/MeOH 8:2) to give the desired material. MS (LC/MS): 472.1/474.1 [M+H]+, 470.0/472.1 [M−H]−; tR (HPLC conditions f): 1.58 min; 19F NMR (100 MHz, DMSO-d6) δ (ppm): −120.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41](O)=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:44]1([S:47]([NH2:50])(=[O:49])=[O:48])[CH2:46][CH2:45]1>CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([NH:50][S:47]([CH:44]3[CH2:46][CH2:45]3)(=[O:49])=[O:48])=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Yield: 52.7 %

Procedure:
Prepared from 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid etherate (100 mg, 0.15 mmol) and cyclopropylsulfonamide (24 mg, 0.20 mmol) as described in the general procedure above. Flash chromatography (2% methanol/methylene chloride) gave 55 mg (53%) of [4-cyclopropanesulfonylaminocarbonyl-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo-[14.3.0.04,6]-nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: 1H NMR (500 MHz, CD3Cl3) δ 0.89–0.95 (m, 1H), 1.03–1.16 (m, 3H), 1.22 (s, 9H), 1.18–1.48 (m, 8H), 1.78 (m, 1H), 1.87 (m, 1H), 1.94 (m, 1H), 2.29 (q, J=9.0 Hz, 1H), 2.56 (m, 1H), 2.67 (dd, J=7.9 Hz, 2.7 Hz, 2H), 2.90 (m, 1H), 4.04 (dd, J=11.3 Hz, 4.0 Hz, 1H), 4.29 (m, 1H), 4.61 (m, 2H), 4.97–5.03 (m, 2H), 5.70 (m, 1H), 5.94 (s, 1H), 6.67 (s, 1H), 7.25 (m, 1H), 7.47 (t, J=7.3 Hz, 1H), 7.64 (t, J=7.3 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.97 (d, J=5.8 Hz, 1H), 8.17 (d, J=8.5 Hz, 1H), 10.20 (s, 1H). LC-MS (Method A, retention time: 3.67 min), MS m/z 696 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[F:11].[Li+].CC([N-]C(C)C)C.CN([CH:23]=[O:24])C>C1COCC1>[Cl:1][C:2]1[C:3]([F:11])=[CH:4][CH:5]=[C:6]([O:8][CH2:9][CH3:10])[C:7]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: CCOc1ccc(F)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(Cl)c1C=O
Reaction time: 0.12 h

Procedure:
To a cold (−78° C.) solution of 2-Chloro-4-ethoxy-1-fluorobenzene (5.0 g, 28.6 mmol) in THF (100 mL) was added LDA (1.8 M in THF/heptane/ethylbenzene; 40 mL, 72 mmol). After 7 minutes, DMF (7 mL, 85.8 mmol) was added dropwise while keeping the temperature below −60° C. After 40 minutes, the reaction mixture was quenched with sat. aq. ammonium chloride. The organic layer was separated and the aq. layer was washed with ethyl acetate (2×50 mL). The combined organic layer was washed with water (30 mL) followed by brine. The organic layer was dried (Na2SO4) and concentrated to give a 1:1 mixture of the target compound and a regioisomeric aldehyde. The mixture was purified by column chromatography (5/95, ethyl acetate/hexanes) to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=1.46 (t, 3H, J=7.2 Hz), 4.11 (q, 2H, J=7.2 Hz), 6.84-6.86 (m, 1H), 7.25-7.28 (m, 1H), 10.48 (s, 1H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[NH4+].[Cl-]>C(O)C.[Fe]>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([NH2:16])=[C:9]([S:8][C:1]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1SCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc(Cl)cc1Sc1ccccc1
Temperature: 70 °C
Yield: 82.4 %

Procedure:
To a suspension of 1.8 g of 2-benzylthio-4-chloro-nitrobenzene in 100 ml ethanol was added 2 g powdered iron and 20 mL of 0.33N NH4Cl. The mixture was heated at 70° C. for 6 hr. The mixture was cooled and filtered through a pad of Celite. The filtrate was condensed and purified by flash chromatography (hexane/ethyl acetate 4:1 as eluent) to yield 1.25 g of an oil. LC-MS showed a single peak with the expected (M+H+) of 236.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH3:23][C:24]1[N:29]=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:26][CH:25]=1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:33][S:30]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=2)(=[O:32])=[O:31])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: Cc1cccc(S(N)(=O)=O)n1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1cccc(C)n1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 6-methyl-pyridine-2-sulfonic acid amide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 2.45 (s, 3), 3.61 (s, 3), 4.73 (s, 2), 6.38 (s, 1), 6.97 (m, 2), 7.23 (m, 2), 7.77 (m, 1), 8.17 (m, 1), 8.54 (s, 1). 13C NMR (125 MHz, CDCl3) δ: 18.71, 48.22, 63.10, 92.48, 115.65, 115.82, 124.67, 130.24, 130.34, 131.09, 138.70, 139.36, 150.54, 152.19, 159.14, 161.66, 163.62, 170.80.
Reaction SMILES: [CH:1]1([C@H:6]([C:24](=[O:33])[NH:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C@@H:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:8]([NH:10][N:11]([CH2:16][CH:17]([CH3:19])[CH3:18])[S:12]([CH3:15])(=[O:14])=[O:13])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ONC([C@H]([C@@H](CC(C)C)C(NN(CC(C)C)S(C)(=O)=O)=O)CSC1C=CC=CC=1)=O.CS(C(C=C(C)C)C(NN)=O)(=O)=O.C(N(S(C)(=O)=O)NC(=O)CC=C(C)C)C(C)C>>[CH:1]1([C@H:6]([C:24](=[O:33])[NH:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C@@H:7]([CH:20]=[C:21]([CH3:23])[CH3:22])[C:8]([NH:10][N:11]([CH2:16][CH:17]([CH3:18])[CH3:19])[S:12]([CH3:15])(=[O:14])=[O:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@@H](C(=O)NOC1CCCCO1)C1CCCC1
Agent: CC(C)=CC(C(=O)NN)S(C)(=O)=O
Agent: CC(C)=CCC(=O)NN(CC(C)C)S(C)(=O)=O
Agent: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@H](CSc1ccccc1)C(=O)NO
Product: CC(C)=C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@@H](C(=O)NOC1CCCCO1)C1CCCC1

Procedure:
In an analogous manner to that described in the first paragraph of Example 45, starting from 0.357 g of a mixture of 2(R)-[(S)-(cyclopentyl)[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]methyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide and 2(R)-[(S)-(cyclopentyl)[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]methyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methyl-3-pentenohydrazide there was obtained 0.219 g of a mixture of 2(R)-[(S)-(cyclopenyl)(hydroxycarbamoyl)methyl]-2′-isobutyl-2′-(methanesulphonyl-4-methyl-3-pentenohydrazide (compound A) and 2(R)-[(S)-(cyclopentyl)hydroxycarbamoyl)methyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methyl-3-pentenohydrazide (compound B) in the form of a white solid. The compounds were then separated by preparative high-performance liquid chromatography on a DYNAMAX 5 mm C18 300A column with dimensions of 21.4×50 mm using the gradient elution method specified below:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([S:20](Cl)(=[O:22])=[O:21])=[N:18][CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:22])=[O:21])=[N:18][CH:19]=1
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2-AMINOTHIAZOLE (0.29 g, 0.0029 mol) in Pyridine (2 mL, 0.02 mol) was added portionwise 5-Bromo-pyridine-2-sulfonyl chloride (0.50 g, 0.0019 mol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure, diluted with Ethyl acetate, washed with 1.0 N HCl, H2O and brine, dried with anhydrous sodium sulfate, filtered and concentrated to give the product was obtained as a yellow solid.