Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]([N+:18]([O-])=O)=[C:6]([CH:15]=2)[C:7]([NH:9][C:10]2[NH:14][N:13]=[N:12][N:11]=2)=[O:8])[O:2]1.[OH-].[Na+]>[Pd].O>[NH2:18][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:17][C:16]2=[CH:15][C:6]=1[C:7]([NH:9][C:10]1[NH:11][N:12]=[N:13][N:14]=1)=[O:8]
Reactant: O=C(Nc1nnn[nH]1)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc2c(cc1C(=O)Nc1nnn[nH]1)OCO2

Procedure:
Hydrogenation of 10 g of 4,5-methylenedioxy-2-nitro-N-(1H-tetrazol-5-yl)benzamide in 40 ml of aqueous 1N sodium hydroxide solution and 160 ml of water and using 1 g of 10% Pd/C gave 2-amino-4,5-methylenedioxy-N-(1H-tetrazol-5-yl)benzamide as brown needles melting at about 255° C. (dec) after recrystallization from a mixture of dimethylformamide and water.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](Cl)=[O:15])[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([C@H:25]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S@:43]([CH3:45])=[O:44])[CH2:33][CH2:32]2)[CH2:26][NH:27][CH3:28])[CH:21]=[CH:22][C:23]=1[Cl:24].C(N(CC)CC)C>CCOC(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([C@H:25]([CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S@:43]([CH3:45])=[O:44])[CH2:35][CH2:36]2)[CH2:26][N:27]([CH3:28])[C:14]([C:6]2[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:15])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CNC[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2c1CCCC2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc([N+](=O)[O-])cc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
3-Nitro-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride [from 3-nitro-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.150 g , 6.78 mmol) and PCl5 (0.190 g, 8.48 mmol) in EtOAc (1.5 mL) as described in T. Nakayama, T. Okutome, R. Matsui, M. Kurumi, Y. Sakurai, T. Aoyama, S. Fujii, Chem. Pharm. Bull. 32(10) 3968 (1984)] was dissolved in EtOAc (2 mL) and added to a stirred solution of N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine (0.3075 g, 0.678 mmol), triethylamine (0.124 mL, 0.892 mmol) and EtOAc (3.1 mL) and the mixture stirred overnight at ambient temperature. The reaction mixture was washed with 10% aqueous HCl, 5% aqueous NaOH and brine solutions, dried (MgSO4) and the solvent removed in vacuo to yield the title compound (0.168 g, 38%) which was converted to the citrate salt MS: m/z 656 (M+H). Analysis for C34H39Cl2N3O4S.C6H8O7.2.0H2O: calculated: C, 54.30; H, 5.81; N, 4.75; found: C, 54.10; H, 5.55; N, 4.55.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][NH:9][CH2:10][C:11]([OH:13])=O)[N:4]=[CH:3]1.[NH2:14][C@@H:15]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17]>>[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][NH:9][CH2:10][C:11]([NH:14][C@@H:15]([CH2:33][O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:23][CH:24]=2)=[O:17])=[O:13])[N:4]=[CH:3]1
Reactant: O=C(O)CNCCc1c[nH]cn1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CNCCc1c[nH]cn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 26.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-(1H-imidazol-4-yl)ethylamino)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 216, (S)-2-(2-(2-(1H-imidazol-4-yl)ethylamino)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (11.2 mg, 26.3%). 1H-NMR (400 MHz, DMSO-D6): σ 10.24 (s, 1H), 8.25 (d, 1H), 7.61 (d, 2H), 7.51 (s, 1H), 7.28 (m, 6H), 7.19 (t, 2H), 7.02 (m, 4H), 6.78 (s, 1H), 4.70 (m, 1H), 4.52 (s, 2H), 3.68 (m, 3H), 3.20 (s, 2H), 2.75 (m, 2H), 2.64 (m, 2H). MS (EI) for C29H30FN5O4: 532.6 (MH+).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:14])[CH:7]=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)C>O.CO>[C:8]1(=[CH:7][C:6]([OH:14])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C=C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C=C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
A mixture of KOH (1.0 g, 18 mmol) dissolved in water (25 mL) and Intermediate 3 (1.6 g, 9.5 mmol) dissolved in MeOH (5 mL) was stirred for 18 hours at room temperature. The reaction was refluxed for one hour, cooled, then extracted with EtOAc. The aqueous layer was acidified with 1N NCl and extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated in vacuo to provide 1.3 g (100%) of Intermediate 4. 1H NMR (DMSO-d6) δ: 1.55 (br s, 6H) 2.1 (m, 2H), 2.8 (m, 2H), 5.5 (s, 1H), 11.9 (s, 1H); MS ES−m/e 139.1 (p−1).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.Cl.[CH2:12]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O.ClCCl>[CH2:12]([O:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:39]=[CH:38][C:34]([C:35]([O:1][N:2]4[C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[N:4]=[N:3]4)=[O:36])=[CH:33][CH:32]=3)[CH2:29][CH2:30]2)=[CH:23][CH:24]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCOc1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCOc1ccc(N2CCN(c3ccc(C(=O)On4nnc5ccccc54)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
To a solution of 1-hydroxybenzotriazole (5.35 g) and 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (15 g) in the mixture of triethylamine (9.64 ml) and dichloromethane (450 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) (12.6 g) and stirred for 4 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoyloxy]benzotriazole (16.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OC(=O)C)(=O)C>C(N(CC)CC)C>[C:10]1([C:16](=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:17]([OH:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1ccc(Cl)cc1)c1ccccc1

Procedure:
A mixture of 56.2 g 4-chlorobenzaldehyde, 54.4 g phenylacetic acid, 80 ml acetic anhydride and 40 ml triethylamine was refluxed for 5 hours. Unreacted 4-chlorobenzaldehyde was removed by steam distillation and the residue dissolved in aqueous alcohol and treated with decolourising carbon. Crystals of α-phenyl-4-chlorocinnamic acid were obtained on acidification of the solution. The product was recrystallised from alcohol and found to have a melting point of 202°-4° C. The chlorosulphonyl derivative was prepared according to the method described in Example 1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]>C1COCC1.CO>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Oc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Under H2, 25 (2.7 mmol) was dissolved in a mixture of THF/MeOH (5/20 ml) and was then hydrogenated at room temperature for 1 h under 30 PSI. Pd (c) was filtered and the solvent removed via a rotary evaporator. The residue was purified by chromatography on silica gel using 7:3 hexane/ethyl acetate as the eluent to yield 560 mg (71%) of 26 as a white solid.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([O:42][CH3:43])=[O:41])[C:34]([CH3:44])=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[Br:45]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:45][CH2:44][C:34]1[C:35]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][C:37]2[C:32]([CH:33]=1)=[CH:31][C:30]([C:2]([OH:1])([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=1)[CH:3]([CH3:5])[CH3:4])=[CH:39][CH:38]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2cc1CBr
Yield: 99.5 %

Procedure:
Methyl 6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-3-methyl-2-naphthoate (5.93 g) was suspended in carbon tetrachloride (150 ml) and N-bromosuccinimide (2.01 g) and 2,2′-azobisisobutyronitrile (0.17 g) were added. The reaction mixture was heated under reflux for 4 hrs. and the solvent was concentrated. The residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give a crude title compound (6.70 g) as a brown amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](N2N=CC=N2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:16][C:17]1[CH:18]=[N:19][NH:20][CH:21]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:19]2[CH:18]=[C:17]([CH3:16])[CH:21]=[N:20]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: Cc1cn[nH]c1
Product: Cc1ccc(-n2cc(C)cn2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 4-methyl-1H-pyrazole. MS (ESI) 217 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH2:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:16]([N:26]([CH3:34])[C@H:27]([C:31](O)=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16]([N:26]([CH:27]([CH:28]([CH3:30])[CH3:29])[C:31]([NH:15][CH:13]([CH3:14])[CH2:12][C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:32])[CH3:34])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(N)Cc1ccc(O)c(C(C)(C)C)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)C(C(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.31 g (1.50 mmol) of 2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethylamine, 0.40 g (1.50 mmol) of Z-N-Me-Val-OH and 0.30 g (2.25 mmol) of HOBT in DMF (5 ml), 0.35 ml (2.25 mmol) of DIC was added under cooling with ice. After being stirred at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3, water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol=125:1) to give 2-[N-(benzyloxycarbonyl)-N-methylamino]-N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-3-methylbutanamide in the amount of 0.55 g (81%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2].[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropoxyphenyl)indole-3-carboxylic acid ethyl ester (250 mg, 0.59 mmol and 4-trifluoromethylphenylboronic acid (167 mg, 0.88 mmol) and was used in the subsequent step without purification.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(O/[CH:7]=[CH:8]/[C:9](=O)[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])C>CO>[CH3:1][N:2]1[CH:7]=[CH:8][C:9]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[N:3]1
Reactant: CNN
Reactant: CCO/C=C/C(=O)C(F)(F)C(F)(F)F
Solvent: CO
Product: Cn1ccc(C(F)(F)C(F)(F)F)n1

Procedure:
7.18 g (156 mmol) of methylhydrazine are added dropwise to a solution of 30.9 g (142 mmol) of (1E)-1-ethoxy-4,4,5,5,5-pentafluoropent-1-en-3-one (preparation: Synthesis 2000, 5, 738-742) in 56 ml of methanol, and the reaction mixture is heated under reflux for 18 hours. The majority of the methanol is distilled off at atmospheric pressure and the residue is poured on to ice. The aqueous phase is extracted three times with dichloromethane and the organic phase is then washed three times with saturated sodium chloride solution. After drying over sodium sulphate, the solvent is distilled off at reduced pressure on a rotary evaporator. This gives 15.8 g of 1-methyl-3-pentafluoroethyl-1H-pyrazole (52%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:35](O)[CH2:36][CH2:37][OH:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:35][CH2:36][CH2:37][OH:38]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 5-methyl-3-(2-nitrophenylsulfonyloxy)phenol (1.1 g, 4.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (1.22 g, 6.0 mmol) and 1,3-propanediol (1.52 g, 20 mmol) in anhydrous tetrahydrofuran (40 mL) was added 1,1'-(azodicarbonyl)dipiperidine (1.51 g, 6.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (60 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (1.05 g, 71%). 1H-NMR (300 MHz, CDCl3) δ 7.99 (d, J=7.7 Hz, 1H), 7.84 (m, 2H), 7.70 (m, 1H), 6.65 (s, 1H), 6.61 (s, 1H), 6.58 (s, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.82 (t, J=5.9 Hz, 2H), 2.27 (s, 3H), 2.00 (t, J=6.0 Hz, 2H), 1.67 (br s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]1=[O:17]>C(O)(C)C>[CH:8]([O:7][C:6]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][CH2:2][CH2:3][CH2:4]1)=[O:17])([CH3:13])[CH3:9]
Reactant: O=c1oc2cc([N+](=O)[O-])ccc2n1CCCCl
Solvent: CC(C)O
Product: CC(C)OC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21

Procedure:
3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid isopropyl ester was prepared from 3-(3-chloro-propyl)-6-nitro-3H-benzoxazol-2-one and isopropyl alcohol in an analogous manner to Example 1426a. Product isolated as a yellow oil (413 mg, 63%). LCMS (m/e) 281 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.89-7.81 (m, 2H), 7.55-7.35 (m, 1H), 5.10-4.96 (m, 1H), 4.24 (t, 2H, J=5.5 Hz), 3.85 (t, 2H, J=5.6 Hz), 2.20-2.09 (m, 2H), 1.27 (d, 6H, J=5.7 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:19]([C:21]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:20]#[C:19][C:21]2([OH:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:3]=1)=[O:17]
Reactant: C#CC1(O)CCCCCCC1
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: O=C(NCCC(O)c1cccc(C#CC2(O)CCCCCCC2)c1)C(F)(F)F

Procedure:
Sonogashira reaction of 25 with 1-ethynyl-cyclooctanol yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(2-(1-hydroxycyclooctyl)ethynyl)phenyl)propyl)acetamide as yellow oil. Yield (0.54 g, 44%). This compound was used without further purification in the next step.
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:19][C@H:18]([CH3:20])[O:17][CH2:16][C@:14]2([C:21]2[S:22][CH:23]=[C:24]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[CH:31][N:30]=3)=[O:28])[N:25]=2)[N:15]=1)(=O)C1C=CC=CC=1.[ClH:39]>C1(C)C=CC=CC=1.ClCCl>[ClH:39].[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:19][C@H:18]([CH3:20])[O:17][CH2:16][C@:14]2([C:21]2[S:22][CH:23]=[C:24]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:37])[F:38])=[CH:31][N:30]=3)=[O:28])[N:25]=2)[N:15]=1
Reactant: C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2nc(NC(=O)c3ccc(OC(F)F)cn3)cs2)CO1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2nc(NC(=O)c3ccc(OC(F)F)cn3)cs2)CO1
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
SiliCycle, SiliaMetS® Diamine (4.72 g, 5.36 mmol) was added to a solution of C9 (1.00 g, 1.79 mmol) in toluene (10 mL), and the reaction mixture was heated at reflux overnight. After being cooled to 35° C., the reaction mixture was diluted with dichloromethane (10 mL), stirred for 10 minutes at 35° C., and filtered through diatomaceous earth to remove the SiliCycle reagent. The filter pad was rinsed with dichloromethane and the combined filtrates were heated to reflux and displaced with isopropyl acetate (4×10 mL) to a final volume of 15 mL. This mixture was heated to 50° C., treated with concentrated hydrochloric acid (0.17 mL, 2.0 mmol), and subsequently cooled to 0° C. to 5° C. and allowed to granulate for 1 hour. The solid was collected via filtration and washed with cold propan-2-yl acetate to afford the product as a solid. This material was crystalline by powder X-ray diffraction analysis. Yield: 0.67 g, 1.4 mmol, 78%. 1H NMR (400 MHz, DMSO-d6) δ 11.30 (br s, 1H), 10.73 (s, 1H), 9.6-9.9 (v br s, 1H), 8.6-8.9 (v br s, 1H), 8.63 (d, J=2.7 Hz, 1H), 8.24 (d, J=8.6 Hz, 1H), 7.93 (dd, J=8.7, 2.8 Hz, 1H), 7.84 (s, 1H), 7.51 (t, JHF=72.8 Hz, 1H), 3.96 (AB quartet, JAB=12.2 Hz, ΔνAB=62.6 Hz, 2H), 3.75-3.85 (m, 1H), 3.02-3.11 (m, 3H), 1.73-1.82 (m, 1H), 1.39-1.52 (m, 1H), 1.21 (d, J=6.2 Hz, 3H).
Reaction SMILES: [CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18][NH2:19])=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[CH2:28]([O:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][C:37]([CH:41]=O)=[N:38]2)=[CH:33][C:32]=1[F:43])[CH3:29]>C(O)C>[CH2:28]([O:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][C:37](/[CH:41]=[N:19]/[NH:18][C:15]3[N:14]=[CH:13][C:12]([C@H:7]([N:4]4[CH2:5][CH2:6][C@@:2]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:1])[CH2:3]4)[C:8]([F:9])([F:10])[F:11])=[CH:17][CH:16]=3)=[N:38]2)=[CH:33][C:32]=1[F:43])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN([C@@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: CCOc1cc2nc(C=O)ccc2cc1F
Solvent: CCO
Product: CCOc1cc2nc(/C=N/Nc3ccc([C@H](N4CC[C@](C)(NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (Example 122, Steps A and B; 5.113 g, 13.13 mmol) in ethanol (25 mL) was added 7-ethoxy-6-fluoroquinoline-2-carbaldehyde (2.878 g, 13.13 mmol) and stirred overnight at ambient temperature. The precipitate was filtered to give desired product as a pale yellow solid (5.276 g). The filtrate was subjected to chromatography (C18, 300 g, 75 mL/min, 10% MeCN/H2O to 95% MeCN over 25 column volumes) and combined with the filtered product to give tert-butyl (S)-1-((S)-1-(6-((E)-2-((7-ethoxy-6-fluoro quinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-ylcarbamate (6.322 g, 10.70 mmol, 81.53% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.C(OC(=O)[NH:27][CH2:28][CH2:29][NH2:30])(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:43].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:43].[ClH:43].[NH2:27][CH2:28][CH2:29][NH:30][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CO
Product: NCCNC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 60 °C
Yield: 77.6 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg, 1.00 mmol) obtained in Step 6 of Example 1, N-(2-aminoethyl)carbamic acid tert-butyl ester (240 mg, 1.50 mmol), 1-hydroxybenzotriazole monohydrate (176 mg, 1.30 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg, 1.40 mmol) and N-methylmorpholine (0.22 mL, 2.00 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 moL/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 111 (206 mg, 54%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:27][CH2:28][O:29][CH3:30])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].CO>C1COCC1>[CH3:30][O:29][CH2:28][CH2:27][N:9]1[C:8]2[CH:31]=[CH:32][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:25])([F:24])[F:26])[CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 89.9 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (723.0 mg) was prepared by following General Procedure E starting from 1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (829.0 mg) and sodium hydroxide (2.0 N solution, 3.0 mL) MeOH (1.0 mL) and THF (3.0 mL). LCMS: m/z 454; and 1H NMR (DMSO-d6, 400 MHz): δ 8.14 (1H, s), 7.95 (1H, m), 7.84-7.82 (1H, m), 7.63 (1H, br. m), 7.51 (1H, m), 7.55-7.52 (1H, m), 7.39-7.36 (1H, m), 4.39-4.36 (2H, t), 3.74-3.71 (2H, t), 3.24 (3H, s), —COOH proton signal was not observed.