Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+].[Cl:23][C:24]1[CH:44]=[CH:43][C:27]([CH2:28][CH2:29][NH:30][C:31](=[O:42])[C:32]2[CH:37]=[CH:36][C:35](Cl)=[C:34]([N+:39]([O-:41])=[O:40])[CH:33]=2)=[CH:26][CH:25]=1>CS(C)=O>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][CH2:29][NH:30][C:31]([C:32]2[CH:37]=[CH:36][C:35]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[C:34]([N+:39]([O-:41])=[O:40])[CH:33]=2)=[O:42])=[CH:43][CH:44]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)C1CCOc2cc(O)c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3[N+](=O)[O-])c(Cl)cc21
Temperature: 62 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
Methyl 6-chloro-7-hydroxychroman-4-carboxylate (100 mg, 0.412 mmol) (Preparation 4, substituting methanol for ethanol in Step C) was diluted with DMSO (1 mL) followed by the addition of K2CO3 (68.3 mg, 0.495 mmol) and N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (140 mg, 0.412 mmol). The reaction was heated to 62° C. and stirred for 3 hours. The reaction was cooled, loaded directly onto silica gel and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield methyl 7-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate (60 mg, 26.7% yield).
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>CO>[CH2:19]([NH:20][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NCCCCCCN
Reactant: CCCCCCCCCC1CO1
Solvent: CO
Product: CCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCC
Reaction time: 8 h

Procedure:
A solution of 1-undecene oxide (88.8 g.), hexamethylenediamine (1,6-hexanediamine, 30.3 g.) and methanol (400 ml.) was allowed to stand at 0° C. overnight, then at room temperature over the weekend. The solid was collected and recrystallized from ethanol, affording N,N'-(1,6-hexylene)-bis[2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = H, X = (CH2)6 ; Z = H) (m.p. 122.6°-129.0° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:19]=1[CH2:20][NH2:21].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:21][CH2:20][C:19]2[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=2[O:17][CH3:16])=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: COc1ccc(OC)c(CN)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1nc(C(=O)NCc2cc(OC)ccc2OC)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (0.1 mmol) in DMF (0.1 mL) was added 2,5-dimethoxybenzylamine (0.2 mmol), Et3N (0.2 mmol), and TBTU (0.1 mmol) sequentially. The reaction mixture was stirred at ambient temperature for 16 hours and water was added. The precipitates were collected and purified by column chromatography to provide the titled compound. 1H NMR (400 MHZ, DMSO-d6) δ 8.81 (t, J=6.4 Hz, 1H), 7.31 (broad s, 2H), 7.07 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.79 (dd, J=2.8, 8.8 Hz, 1H), 6.72 (d, J=3.2 Hz, 1H), 4.49 (q, J=7.2 Hz, 2H), 4.42 (d, J=6.4 Hz, 2H), 3.79 (s, 3H), 3.65 (s, 3H), and 1.33 (t, J=7.2, 3H). MS (m/e) positive mode: 357 (M+H)+, 379 (M+Na)+; negative mode: 355 (M−H)−.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[Cl:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:47]=[CH:48][C:43]([Cl:42])=[CH:44][CH:45]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc(Cl)cc1
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 4-chlorophenylboronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][C:17]=1[C:29]#[N:30].O[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.O>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][C:17]=1[C:29]#[N:30]
Reactant: CN1CCN(CCCO)CC1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of diisopropyl azodicarboxylate (12.1 ml) in methylene chloride (50 ml) was added dropwise during 30 minutes to a stirred mixture of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (12 g), 1-(3-hydroxypropyl)-4-methylpiperazine (9.7 g), triphenylphosphine (16.1 g) and methylene chloride (200 ml) that had been cooled to 5° C. The resultant mixture was allowed to warm to ambient temperature and was then stirred for 1 hour. Further portions of diisopropyl azodicarboxylate (1.2 ml) and triphenylphosphine (1.6 g) were added and the mixture was stirred at ambient temperature for a further 1 hour. The mixture was poured into water and the organic layer was separated, washed with a saturated brine solution, dried over magnesium sulphate and evaporated. The material so obtained was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the required starting material as a solid (14.5 g); NMR Spectrum: (DMSOd6) 1.95 (m, 2H), 2.13 (s, 3H), 2.24–2.5 (m, 10H), 4.0 (s, 3H), 4.25 (t, 2H), 7.43 (s, 1H), 7.51 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 375 and 377.
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[CH:6]\[CH:7]=[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])C.[OH-].[Na+]>CO>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])=[CH:7]/[CH:6]=[CH:5]\[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)/C=C\C=C(c1ccccc1F)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C\C=C(c1ccccc1F)c1ccccc1F
Yield: 96.1 %

Procedure:
Hydrolysis of (Z)-5,5-bis(2-fluorophenyl)-2,4-pentadienoic acid ethyl ester (0.4 g) in methanol (5 mL) was carried out as before using 4N sodium hydroxide (0.6 mL). After acidification, the product was extracted into dichloromethane (2×30 mL). The combined dried extracts were evaporated and the residue crystallized from ether-hexane to yield 0.35 g of (Z)-5,5-bis(2-fluorophenyl)-2,4-pentadienoic acid mp 147°-148° C.
Reaction SMILES: [C:1](/[C:4](/[N:7]([CH:12]([CH3:14])[CH3:13])[C:8](=O)[CH2:9][CH3:10])=[CH:5]\[NH2:6])(=[O:3])[CH3:2].[OH-].[Na+].[Cl-].[NH4+]>CCO>[CH:12]([N:7]1[C:4]([C:1](=[O:3])[CH3:2])=[CH:5][N:6]=[C:8]1[CH2:9][CH3:10])([CH3:14])[CH3:13]
Reactant: CCC(=O)N(/C(=C/N)C(C)=O)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CCc1ncc(C(C)=O)n1C(C)C
Temperature: 85 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
N-[(E)-1-Acetyl-2-aminoethenyl]-N-isopropylpropanamide (Method 7; 373 g, 1.0 eq.) was stirred with sodium hydroxide (1.4 eq.) in EtOH (4 vol.eq.). The reaction was heated to reflux (85° C.) and stirred overnight. Ammonium chloride (2.0 eq.) was then added and this was stirred for 2 hours (the consistency of the reaction changed to a fine precipitate). The reaction was then allowed to cool, the solid was filtered off and discarded, and the solvent was then removed in vacuo. Acetone was then added to the residue, the solid was filtered off and discarded. The solvent was then removed in vacuo. Prep chromatography was then performed by eluting with 5% MeOH/DCM, to leave a brown oil (290 g, 86%). NMR 1.23 (3H, t), 1.43 (6H, d), 2.40 (3H, s), 2.77 (2H, q), 5.0 (1H, b s), 7.87 (1H, s).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:33][CH2:34][CH2:35][O:36][CH:37]([CH3:39])[CH3:38])[C:7]2[C:16]3[CH:15]=[CH:14][C:13](/[CH:17]=[CH:18]/[CH2:19][CH2:20][N:21]4[C:29](=[O:30])[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22]4=[O:31])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:32]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:33][CH2:34][CH2:35][O:36][CH:37]([CH3:38])[CH3:39])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]4[C:22](=[O:31])[C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:29]4=[O:30])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:32]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3cc(/C=C/CCN4C(=O)c5ccccc5C4=O)ccc3c2n1CCCOC(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOCc1nc2cnc3cc(CCCCN4C(=O)c5ccccc5C4=O)ccc3c2n1CCCOC(C)C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
2-{(3E)-4-[2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-7-yl]but-3-enyl}-1H-isoindole-1,3(2H)-dione (1.9 g, 3.6 mmol) was dissolved in ethanol (50 mL) and added to a Parr flask containing 10% palladium on carbon (0.3 g) wetted with ethanol. The flask was degassed three times, charged with hydrogen (50 psi) and shaken for 16 hours. The catalyst was removed by filtration through CELITE filter agent. Concentration of the filtrate under reduced pressure provided 1.9 g of 2-{4-[2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-7-yl]butyl}-1H-isoindole-1,3(2H)-dione as a pale yellow oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]#[C:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>>[C:22]1([C:21]#[C:20][C:17]2[CH:18]=[CH:19][C:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:3]=4)[CH2:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC(c2cccc(I)c2)=Nc2ccc(C#Cc3ccccc3)cc2N1
Product: C[Si](C)(C)C#Cc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1
Yield: 47.2 %

Procedure:
Prepared from 4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 11) (231 mg, 0.5 mmol) and trimethylsilylacetylene (0.4 mL, 1.0 mmol) according to the general procedure F. Obtained as a light brown solid (102 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[N:8]=[C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=1.CCCCCC.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C.[Fe]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([NH:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N:2]([CH3:22])[CH3:1])[N:8]=1)(=[O:11])=[O:12]
Reactant: CN(C)c1cccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(NS(=O)(=O)c2ccccc2N)n1
Yield: 77.1 %

Procedure:
In a sealed tube, a mixture of N-[6-(dimethylamino)pyridin-2-yl]-2-nitrobenzenesulfonamide (1.0 g, 3.10 mmol) and Fe powder (0.85 g, 11.5 mmol) in acetic acid (10 mL) was heated at 60° C. for approximately 15 min with TLC monitoring (hexane:EtOAc, 1:1). The reaction mixture was poured into saturated aqueous NaHCO3 solution (100 mL) and extracted with EtOAc (3×50 mL), the combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by gradient flash chromatography, eluting with 0-45% EtOAc in hexane yielded the title compound (0.7 g, 2.39 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][OH:11])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[CH3:22][C:23]1[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:9]([NH:8][C:6]2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=[C:2]([NH:28][C:25]3[CH:24]=[C:23]([CH3:22])[NH:27][N:26]=3)[N:7]=2)[CH2:10][OH:11])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1N[C@@H](CO)c1ccc(F)cc1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccc([N+](=O)[O-])c(N[C@@H](CO)c3ccc(F)cc3)n2)n[nH]1
Temperature: 90 °C
Yield: 69.4 %

Procedure:
A mixture of (R)-2-(6-chloro-3-nitropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Method 29, 0.36 g, 1.2 mmol), 5-methyl-1H-pyrazol-3-amine (0.14 g, 1.4 mmol), and DIEA (0.25 ml, 1.4 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 90° C. for 6 days. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc) to give the title compound as a yellow solid (0.31 g, 73%). 1H NMR (400 MHz) δ 12.06 (s, 1H), 10.40 (br, 1H), 9.58 (br, 1H), 8.11 (d, J=9.2 Hz, 1H), 7.40 (m, 2H), 7.16 (m, 2H), 6.20 (br, 1H), 6.02 (s, 1H), 5.29 (br, 1H), 5.24 (t, J=4.4 Hz, 1H), 3.85 (m, 1H), 3.74 (m, 1H), 2.20 (s, 3H). MS: Calcd.: 372. Found: [M+H]+ 373.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21]C)[CH:19]=4)[CH2:14][CH2:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br.CO.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([OH:21])[CH:19]=4)[CH2:14][CH2:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-[1-(4-chlorophenyl)cyclopropyl]-7-methoxy-3,4-dihydroisoquinoline (700 mg, 2.2 mmol) in methylenehloride (10 ml) under nitrogen was cooled to −78° C. Borontribromide (BBr3, 4.2 ml 1M in methyleneloride, 4.2 mmol) was added dropwise. The reaction was allowed to warm up to room temperature and stirred overnight. Methanol was added (5 ml) and the resulting mixture poured into water neutralized with 1M sodiumbicarbonate and extracted consecutively with methylenehloride and water. The organic layer was dried (Na2SO4), the solvents removed and the black residue purified by chromatography. Yield: 320 mg, (1.1 mmol, 48%).
Reaction SMILES: [OH2:1].Cl.[CH2:3]([O:19][C:20]([C:22]1[CH:23]=[C:24]([S:47](Cl)(=[O:49])=[O:48])[CH:25]=[C:26]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:29])[CH:27]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[Zn].C(Cl)(Cl)Cl>[CH2:3]([O:19][C:20]([C:22]1[CH:23]=[C:24]([S:47]([OH:49])(=[O:1])=[O:48])[CH:25]=[C:26]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:29])[CH:27]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCCCC)cc(S(=O)(=O)Cl)c1
Reactant: O
Agent: Cl
Agent: [Zn]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCCCC)cc(S(=O)(=O)O)c1
Reaction time: 0.5 h

Procedure:
87 ml of water and 18.2 ml (0.218 mol) of 12N-HCl were added to the solution of 87 ml of chloroform and 8.65 g (0.0121 mol) of the white solid containing 3,5-dihexadecyloxycarbonylbenzenesulfonyl chloride, and then 7.93 g of zinc was added thereto at 5° C. followed by stirring for 4 hours and 30 minutes. After the insoluble component was removed therefrom, the solution was extracted with 100 ml of chloroform, washed with saturated brine, and dried with Glauber's salt. After removing Glauber's salt, the solution was concentrated under reduced pressure, and the residue was recrystallized from hot hexane to obtain a colorless crystal of 3,5-dihexadecyloxycarbonylbenzenesulfonic acid. (Yield: 4.43 g, 48% (based on sodium 3,5-dimethyloxycarbonylbenzenesulfonate), m.p.: 63°-65° C.).
Reaction SMILES: [CH:1]([O:14][C:15](=[O:60])[C@@H:16]([O:41]/[N:42]=[C:43](/[C:47]1[N:48]=[C:49]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[S:50][CH:51]=1)\[C:44]([OH:46])=O)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:40])[NH:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:21][CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:61]1([CH2:66][C@H:67]2[NH:70][C:69](=[O:71])[C@H:68]2[NH2:72])[CH:65]=[N:64][CH:63]=[N:62]1.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>CN(C=O)C.CCOC(C)=O>[N:61]1([CH2:66][C@@H:67]2[C@H:68]([NH:72][C:44](=[O:46])/[C:43](=[N:42]\[O:41][C@H:16]([C:15]([O:14][CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:60])[CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[NH:40])[NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:31][CH2:32]4)=[CH:23][CH:24]=3)/[C:47]3[N:48]=[C:49]([NH:52][C:53]([O:55][C:56]([CH3:58])([CH3:59])[CH3:57])=[O:54])[S:50][CH:51]=3)[C:69](=[O:71])[NH:70]2)[CH:65]=[N:64][CH:63]=[N:62]1
Reactant: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/O[C@@H](COc2ccc(C(=N)NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(c2ccccc2)c2ccccc2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/O[C@@H](COc2ccc(C(=N)NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2cncn2)cs1
Reaction time: 3 h
Yield: 97.2 %

Procedure:
To a solution of (S,Z)-2-(((1-(benzhydryloxy)-3-(4-(N-(1-(tert-butoxycarbonyl)piperidin-4-yl)carbamimidoyl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (Prepared according to WO2013110643, 72 mg, 0.085 mmol), (3S,4R)-4-((1H-1,2,4-triazol-1-yl)methyl)-3-aminoazetidin-2-one (15.7 mg, 0.094 mmol) and HATU (42.2 mg, 0.111 mmol) in DMF (854 μL) was added DIPEA (44.8 μL, 0.256 mmol). After stirring at for 3 h it was diluted with EtOAc, washed with water, NaHCO3 (aq satd), brine, dried over Na2SO4 and concentrated in vacuo, affording the title compound (82 mg, 87%) as an olive film. LCMS: Rt=0.97 min, m/z=992.5 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C>CS(C)=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2nc(CO)cs2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2nc(C=O)cs2)CC1

Procedure:
The reaction described in Preparation 44 was repeated, but using 2.4 g of 2-(4-methyl-1-piperazinyl)thiazol-4-yl-methanol, 5.4 g of sulfur trioxide pyridine complex, 3.4 g of triethylamine, and 30 ml of dimethyl sulfoxide, giving the title compound as a pale brown oil.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:38][CH2:39][CH3:40])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:17]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:15]2[CH:14]=[CH:13][C:12]3[N:8]([CH2:7][C:6]([OH:41])=[O:5])[C:9]([CH2:38][CH2:39][CH3:40])=[N:10][C:11]=3[CH:16]=2)=[CH:36][CH:35]=1
Reactant: CCCc1nc2cc(N(CCOc3ccc(Cl)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(CCOc3ccc(Cl)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[[2-(4-Chloro-phenoxy)-ethyl]-(4-fluoro-benzenesulfonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.71 (m, 2H), 7.41 (m, 2H), 7.28 (m, 3H), 7.11 (d, 1H), 6.95 (d, 1H), 6.82 (m, 2H), 4.66 (s, 2H), 3.98 (m, 4H), 2.71 (t, 2H), 1.72 (m, 2H), 0.99 (t, 3H). MS calculated for C26H25FClN3O5S—H: 544, observed: 544.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCn1nc2c(Cl)cccc2c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCCCn1nc2c(Cl)cccc2c1-c1ccc(O)cc1
Yield: 49.4 %

Procedure:
Prepared according to Method D step C from 7-chloro-3-(4-methoxyphenyl)-2-pentyl-2H-indazole (0.015 g, 0.045 mmol), boron tribromide (0.05 mL, 0.5 mmol) and 0.2 mL of cyclohexene to give the product (0.007 g).
Reaction SMILES: [Si]([O:8][CH2:9][C@@:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO.O1CCOCC1>[CH3:35][C@:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@](C)(CO)C5)CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
The compound (280 mg, 0.55 mmol) obtained in Example 33-1) was dissolved in methanol (3 mL). A 4 N solution (1.37 mL) of hydrochloric acid in dioxane was added to the solution, and the mixture was stirred at room temperature for 1 h. The solvent was distilled off, the residue was dissolved in a mixed solvent of methylene chloride (50 mL) and methanol (2 mL), and the mixture was separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (10 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 50%) to obtain the title compound (175 mg, 81%) in a colorless solid form.