Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].I[CH3:4].[F:5][CH:6]([F:30])[CH2:7][N:8]1[C:12]([N:13]2[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:15][CH2:14]2)=[C:11]([N+:27]([O-:29])=[O:28])[CH:10]=[N:9]1.O>C1COCC1>[F:30][CH:6]([F:5])[CH2:7][N:8]1[C:12]([N:13]2[CH2:19][CH2:18][CH2:17][C@@H:16]([N:20]([CH3:4])[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:15][CH2:14]2)=[C:11]([N+:27]([O-:29])=[O:28])[CH:10]=[N:9]1
Reactant: CI
Reactant: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)C(F)(F)F)[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (438 mg, 2.07 mmol), (R)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide (438 mg, 2.07 mmol) and DIPEA (1 mL) in EtOH (4 mL) was heated at 155° C. in the microwave for 5 hr. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale orange gum (518 mg). A portion of this gum (39 mg, 0.10 mmol) in dry THF (2 mL) was treated with sodium hydride (60% in mineral oil, 5 mg, 0.12 mmol). After stirring at room temperature for 10 min, iodomethane (0.01 mL, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 2 hr. The reaction was repeated on the remaining (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide. Water (50 mL) was added carefully and the mixture was extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and the solvent was removed under reduced pressure to give (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide as a pale yellow gum (518 mg). This gum (514 mg, 1.29 mmol) was dissolved in MeOH (20 mL) and treated with ammonium formate (325 mg, 6.15 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 85° C. for 2 hr. After cooling to room temperature the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between DCM (50 mL) and water (30 mL) and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure to afford (R)—N-(1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide as a pale yellow gum (348 mg, 46% over three steps). 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 6.19 (tq, J=55.4, 4.4 Hz, 1H), 4.65-4.15 (m, 3H), 3.40-3.10 (m, 4H), 3.10 and 2.97 (2s, 3H), 2.80 (br s, 2H), 2.10-1.70 (m, 6H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([C:15]2[CH:35]=[CH:34][C:18]([CH2:19][N:20]3[C:24]4[N:25]=[C:26]([S:32][CH3:33])[N:27]([CH2:30][CH3:31])[C:28](=[O:29])[C:23]=4[CH:22]=[CH:21]3)=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[CH2:30]([N:27]1[C:28](=[O:29])[C:23]2[CH:22]=[CH:21][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([C:13](=[O:14])[C:12]4[CH:36]=[CH:37][C:9]([OH:8])=[CH:10][CH:11]=4)=[CH:35][CH:34]=3)[C:24]=2[N:25]=[C:26]1[S:32][CH3:33])[CH3:31]
Reactant: CCn1c(SC)nc2c(ccn2Cc2ccc(C(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(SC)nc2c(ccn2Cc2ccc(C(=O)c3ccc(O)cc3)cc2)c1=O
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
In THF (76.8 ml) was dissolved 7-[4-(4-t-butyldimethylsilyloxybenzoyl)benzyl]-3-ethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one (4.10 g) followed by addition of 1M-tetrabutylammonium fluoride-THF (7.68 ml), and the mixture was stirred for 30 minutes. To this reaction mixture was added water and the THF was distilled off. Then, ethyl acetate was added to the residue and the organic layer was separated. The organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was then distilled off under reduced pressure. The residue was triturated with ether and the resulting powder was collected by filtration, rinsed with ether, methanol and hexane, and dried to provide the title compound as crystalline powder (3.0 g)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C>C1COCC1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([B:23]([OH:24])[OH:22])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Biphenylboronic acid was prepared differently than described in the literature (see Yabroff, D. L.; Branch, G. E.; Bettman, B. J. Am. Chem. Soc. 1934, 56, 1850-1857). To a solution of 4-bromobiphenyl (2.00 g, 8.58 mmol) in THF (20 mL) at -78° C. was added n-butyllithium (4.0 mL of 2.5 M in hexanes) in a slow stream via syringe. After 15 minutes, triisopropylborate (3.0 mL, 13 mmol) was added in a slow stream via syringe. After 10 minutes, the resultant homogeneous solution was allowed to warm to ambient temperature over 45 minutes and partitioned between EtOAc (50 mL) and 10% aqueous HCI (50 mL). The aqueous layer was separated and extracted with more EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a crude product which was triturated with hexanes to yield 1.53 g (90%) of 4-biphenylboronic acid as a white solid. 1H NMR (DMSO-d6): δ 8.05 (s, 2H), 7.83 (d, 2H, J=8.5 Hz), 7.65 (d, 2H, J=7.0 Hz), 7.60 (d, 2H, J=8.1 Hz), 7.43 (t, 2H, J=7.4 Hz), 7.33 (t, 1H, J=7.2 Hz). Anal. C12H11BO2 : C, 72.78; H, 560. Found: C, 72.51; H, 5.62.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:32])([F:33])[F:31])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[O:13])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21
Product: CN(C)CCNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) N1,N1-dimethyl-ethane-1,2-diamine gave the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:23]([O:36][C:37]([NH:39][C:40]1[NH:41][C:42](=[O:53])[C:43]2[N:44]=[CH:45][N:46]([CH2:49][C:50](O)=[O:51])[C:47]=2[N:48]=1)=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:46]1[CH:45]=[N:44][C:43]2[C:42](=[O:53])[NH:41][C:40]([NH:39][C:37]([O:36][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:38])=[N:48][C:47]1=2)[CH3:2]
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Yield: 70.1 %

Procedure:
The title compound (2.61 g, 70%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [2-N-(benzhydryloxycarbonyl)-guanin-9-yl]-acetic acid (2.10 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 11.63 (bs, 1H), 11.23 (bs, 1H), 8.27 (d, 1H), 8.17 (t, 1H), 7.80 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (m, 2H), 7.50˜7.25 (m, 10H), 6.86 (s, 1H), 5.12 (s, 1.2H), 4.93 (s, 0.8H), 4.44 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (s, 1.2H), 4.04 (q, 1.2H), 3.65 (t, 1.2H), 3.45 (t, 1.2H), 3.41 (t, 0.8H), 3.21 (t, 0.8H), 1.23 (t, 1.2H), 1.17 (t, 1.8H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9](=[O:21])[C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=2)([CH3:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:22](Cl)(=[O:24])[CH3:23]>>[C:22]([NH:1][C:2]1[C:3]([NH:8][C:9](=[O:21])[C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=2)([CH3:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CC(C)(Oc1cccc(Cl)n1)C(=O)Nc1ncccc1N
Product: CC(=O)Nc1cccnc1NC(=O)C(C)(C)Oc1cccc(Cl)n1

Procedure:
Acetylation of N-(3-Amino-pyridin-2-yl)-2-(6-chloro-pyridin-2-yloxy)-2-methyl-propionamide using acetyl chloride gives N-(3-Acetylamino-pyridin-2-yl)-2-(6-chloro-pyridin-2-yloxy)-2-methyl propionamide 1H NMR (400 MHz, CDCl3):): δ 1.79 (s, 6H), 2.12 (s, 3H), 6.83 (d, 1H, J=8 Hz), 6.90 (d, 1H, J=8 Hz), 7.25 (t, 1H, J=8 Hz), 7.54 (t, 1H, J=8 Hz), 7.85 (brs, 1H), 8.14 (d, 1H, J=8 Hz), 8.26 (d, 1H, J=8 Hz), 9.61 (brs, 1H), MS (EI) m/z: 349 (M+1), mp: 185° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]1=[CH:11]2)#[N:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:12]1=[CH:11]2)#[N:2]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(OC(C)C)c(C#N)c3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCCC2CC(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of ethyl 2-(2-(3-cyano-4-isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (70 mg, 0.157 mmol) in dioxane (1 mL) was added 1 M LiOH aqueous solution (0.627 mL, 0.627 mmol). The reaction was stirred at room temperature for 8 h, diluted with water, and acidified to pH 4 with 0.5 M aqueous citric acid solution. The light pink solid was collected to give the title compound (63 mg). LCMS m/z=419.4 [M+H]+; 1H NMR (400 MHz, CDCl3) 1.40 (d, J=6.1 Hz, 6H), 1.55-1.65 (m, 1H), 1.98-2.12 (m, 1H), 2.15-2.25 (m, 2H), 2.65 (dd, J=16.1, 8.6 Hz, 1H), 3.01 (dd, J=−16.1, 5.3 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.92 (m, 1H), 4.12-4.18 (m, 1H), 4.61-4.68 (m, 1H), 5.01 (s, 2H), 6.22 (s, 1H), 6.86 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]3[CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16](=O)[CH2:17][CH2:18][C:19](=O)[CH3:20].O.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[CH3:20][C:19]1[N:1]([C:2]2[C:10]3[O:9][C:8]4[CH2:11][CH2:12][CH2:13][CH2:14][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: Nc1cccc2c3c(oc12)CCCC3
Reactant: CC(=O)CCC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C)n1-c1cccc2c3c(oc12)CCCC3
Yield: 72.1 %

Procedure:
A mixture of 6-amino-1,2,3,4-tetrahydrodibenzofuran (230 mg), 2,5-hexanedione (145 mg) and conc. hydrochloric acid (1 drop) in ethanol (3 ml) was refluxed for 1 hour and poured into water. The mixture was neutralized with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from a mixture of ethanol and water to give 6-(2,5-dimethylpyrol-1-yl)-1,2,3,4-tetrahydrodibenzofuran (235 mg).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[C:4]2[C:21]([CH3:24])=[N:22][O:23][C:3]1=2.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[C:13]([C:12]1[CH:11]=[CH:10][C:9]([C:7]2[C:6]3[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=3[C:4]3[C:21]([CH3:24])=[N:22][O:23][C:3]=3[CH:2]([NH:1][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[N:8]=2)=[CH:16][CH:15]=1)#[N:14]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(C#N)cc1)=NC2N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1noc2c1-c1ccccc1C(c1ccc(C#N)cc1)=NC2NC(=O)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a round bottomed flask was added 4-(4-amino-1-methyl-4H-benzo[c] isoxazolo[4,5-e]azepin-6-yl)benzonitrile (69 mg, 0.22 mmol) and DMAP (2.7 mg, 0.022 mmol). The flask was purged with nitrogen, acetonitrile (5 mL) was added (5 mL), and the solution was cooled to 0° C. Isobutyryl chloride (55 μL, 0.53 mmol) and triethylamine (79 μL, 0.57 mmol) were added and the reaction was allowed to warm to ambient temperature and stirred for 2 h. The reaction was quenched with a 1:1 mixture of sat. aq. NaHCO3:brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated, and purified on a Biotage (isocratic elution 30% EtOAc: 70% Hexanes) to provide the title compound as white solid (66 mg). LC/MS m/z 385 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=C)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[O:14]=[O+][O-].CSC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc(Cl)cc1C(=O)OC
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)c1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Into a solution of methyl 5-chloro-2-vinylbenzoate (16.3 g, 82.89 mmol) in dry DCM (250 mL) was bubbled O3 at −78° C. over a 30 minute period. Next, nitrogen gas was bubbled into the solution until it turned colorless. Dimethylsulfane (10.3 g, 165.79 mmol) was added dropwise. The resulting mixture was warmed to RT, stirred for 2 hours, and concentrated. The crude product was purified by silica gel column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=40:1) to give the title compound as a white solid (10 g, 60%). 1H NMR (400 MHz, CDCl3) δ ppm 10.52 (s, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.55 (dd, J=8.0 Hz and 2.0 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15](=[O:32])[NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][CH2:50][C@@H:51]([C:52]#[N:53])[N:43]2[C:42]1=[O:54]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])=[O:32])[C:9]([NH:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][CH2:50][C@@H:51]([C:52]#[N:53])[N:43]2[C:42]1=[O:54])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Reactant: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Product: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C#N)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((4S,7S,10aS)-7-cyano-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-N6-((S)-2-oxo-1-o-tolylazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 71 (10 mg, 0.019 mmol) and Intermediate 36 (5.2 mg, 0.020 mmol) to give a white solid (8.0 mg, 57% yield). Anal. Calcd. for C43H51N5O4S m/z 733.7. found: 734.3 (M+H)+; 1H NMR (400 MHz, CDCl3) (Rotamers) δ ppm 7.39-6.79 (16H, m), 5.35 (1H, d, J=3.8 Hz), 5.24 (1H, d, J=4.9 Hz), 5.02-4.90 (1H, m), 4.87-4.77 (1H, m), 4.07-3.88 (1H, m), 3.58-3.29 (1H, m), 3.02-2.86 (1H, m), 2.85-2.70 (4H, m), 2.66-2.36 (3H, m), 2.21-2.09 (5H, m), 2.05-1.47 (14H, m), 1.46-1.15 (2H, m).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:9][CH:8]=1.Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39])=[O:27].C(=O)(O)[O-].[Na+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:9][CH:8]=1)[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][C:30]=1[C:38]([F:39])([F:40])[F:41])=[O:27]
Reactant: COCCNCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Reactant: CC(C)c1ccc(NC(=O)CBr)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN(CC(=O)Nc1ccc(C(C)C)cc1C(F)(F)F)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
0.533 g (1.65 mmol) of tert-butyl 2-(4-{[(2-methoxyethyl)amino]methyl}phenoxy)-2-methylpropanoate (Example III-33) is initially charged in 6 ml of dimethylformamide. At room temperature, 0.588 g (1.81 mmol) of 2-bromo-N-[4-isopropyl-2-(trifluoromethyl)phenyl]acetamide (Example III-17) and 0.152 g (1.81 mmol) of sodium bicarbonate are added. The mixture is set at 90° C. for 2 hours. The reaction mixture is then allowed to cool, and water is added. The mixture is extracted once with ethyl acetate and the organic phase is washed three times with water and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and freed from the solvent under reduced pressure. The residue is purified chromatographically on silica gel (cyclohexane/ethyl acetate 4:1) and the product is then dried under reduced pressure. This gives 0.885 g (95% of theory) of the title compound.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:19]>O>[Br:19][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(N2CCC(O)CC2)cc1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: OC1CCN(c2ccc(Br)cc2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-aminophenyl)piperidin-4-ol (3.7 g, 319 mmol) in 60 mL of HBr 48%, a solution of NaNO2 (1.38 g, 20 mmol) in 15 mL of water was slowly added at 0° C. The mixture was stirred for 30 minutes and added to a solution of CuBr (1.57 g, 11 mmol) in 50 mL of HBr 48%. The resulting mixture was stirred and refluxed for 2 hours. The suspension thus obtained was partitioned between 2N NaOH and ethyl acetate. The organic layer was washed with aqueous NaCl, dried over Na2SO4 and concentrated to afford crude compound as grey solid 4.6 g. MS (m/z): 256 (M)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[C:2]([N:1]=[C:15]=[S:16])[CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(Cl)ccc1N1CCOCC1
Solvent: O
Solvent: C1COCCO1
Product: S=C=Nc1cc(Cl)ccc1N1CCOCC1

Procedure:
Reaction of 4-(2-amino-4-chlorophenyl)morpholine (8.5 g) with thiophosgene (4.6 ml) in dioxan (25 ml) and water (100 ml) for 30 minutes at 0° C. and for 3 hours at room temperature gave 5-chloro-2-morpholinophenyl isothiocyanate as a pale yellow solid (m.p. 86°-87° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[C:5]([O:14][CH3:15])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[CH3:13].I[CH2:19][CH2:20][CH2:21][CH:22]([N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])[CH3:23].C(N(CC)CC)C>C(OCCO)C.C(=O)(O)[O-].[Na+]>[CH3:15][O:14][C:5]1[C:4]([O:16][CH3:17])=[CH:3][C:2]([NH:1][CH2:19][CH2:20][CH2:21][CH:22]([N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[CH3:23])=[C:11]2[C:6]=1[C:7]([CH3:13])=[CH:8][C:9]([CH3:12])=[N:10]2
Reactant: COc1cc(N)c2nc(C)cc(C)c2c1OC
Reactant: CC(CCCI)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: CCN(CC)CC
Product: COc1cc(NCCCC(C)N2C(=O)c3ccccc3C2=O)c2nc(C)cc(C)c2c1OC
Temperature: 135 °C
Yield: 33 %

Procedure:
A solution of 8-amino-5,6-dimethoxy-2,4-dimethylquinoline (20.0 g, 86 mmole), 1-iodo-4-phthalimidopentane (38.4 g, 112 mmole) and triethylamine (11.3 g, 112 mmole) in 2-ethoxyethanol (230 ml) was heated at reflux (135° C.) for 5 hr. After cooling, the solution was diluted with 5% aqueous sodium bicarbonate (0.5 l) and then extracted with methylene chloride (2× 250 ml). The combined extracts were washed with water (2× 250 ml) and brine (100 ml) and then dried (potassium carbonate). Filtration, then evaporation of the solvents, afforded a black tar. The tar was chromatographed over silica gel (0.7 kg) with benzene. The orange-brown material eluting first from the column was crystallized from ethanol (10% solution), affording 12.7 g (33%) of the title compound as orange plates, mp 141°-144°. Further recrystallization of a small amount gave an analytical sample with mp 144.5°-146.5°; the analysis was satisfactory after drying at 110° (the analysis corresponded to a hemihydrate after drying at 78°).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([F:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:21])=[O:14])=[C:11]([F:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1F
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1F

Procedure:
4-Benzyloxy-2-fluoro-benzoic acid (2 g, 8.12 mmol) was suspended in thionyl chloride (5.9 mL) and heated to reflux for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was dissolved in toluene and re-concentrated twice to remove residual thionyl chloride. This procedure provided the title compound in crude form, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:19][C:20]#[CH:21])([CH2:16][C:17]#[CH:18])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:23][OH:24]>>[OH:24][NH:23][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:19][C:20]#[CH:21])[CH2:16][C:17]#[CH:18]
Reactant: NO
Reactant: C#CCC(CC#C)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Product: C#CCC(CC#C)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 85 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from (4-methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid (0.25 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g of the product was isolated. Yield 85%; white solid; mp 156° C.; MS: 321.9 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ2.00-2.13 (m, 2H), 3.00-3.30 (m, 4H), 3.90(s, 3H), 7.01 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 8.76 (brs, 1H), 10.65 (brs, 1H); IR (KBr, cm−1): 3392s, 3293s, 3271m, 2955m, 1650s, 1594s;