Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[CH:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:12]=2[N:11]=1.CN(C(O[N:31]1[N:39]=[N:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:38]1([O:21][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:11][C:12]=3[CH:19]=2)=[O:22])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[N:39]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)O)ccc21
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)On3nnc4ccccc43)ccc21
Reaction time: 72 h

Procedure:
A mixture of 2-(2,6-dichloro-phenylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (1.0 g, 3.0 mmol), TBTU (955 mg, 3.0 mmol) and TEA (835 μL, 5.9 mmol) in 15 mL DMF was stirred for 72 h. The mixture was poured onto water, the solid filtered off, washed with water and dried.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt]=O>[OH:3][CH:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1)[CH3:2]
Reactant: CC(=O)c1ccc2ccccc2n1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(O)C1CCc2ccccc2N1
Yield: 77.3 %

Procedure:
2-Acetylquinoline (21.0 g, 0.123 mol) in acetic acid (210 mL) was hydrogenated over platinum oxide (1.0 g) under atmospheric pressure of hydrogen at room temperature until the theoretical amount of hydrogen was consumed. The mixture was passed through celite and concentrated. The residue was purified by column chromatography with 5:1 to 1:1 hexane/ethyl acetate to give 16.85 g of 2-(1-hydroxyethyl)tetrahydroquinoline (78%): 1H NMR (270 MHz, CDCl3) δ6.95 (m, 2H), 6.62 (td, 1H, J=7.3, 1 Hz), 6.51 (dd, 1H, J=7.3, 1 Hz), 3.81 (dq, 1H, J=10.2, 6.6 Hz), 1.87 (m, 1H), 1.76 (m, 1H), 1.20 (d, 3H, J=6.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH2:15])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:16](OCC)(=O)[CH:17]=[O:18]>C1(C)C=CC=CC=1>[O:18]=[C:17]1[CH:16]=[N:1][C:2]2[C:14](=[CH:13][CH:12]=[C:4]([O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=2)[NH:15]1
Reactant: CCOC(=O)C=O
Reactant: CCOC(=O)COc1ccc(N)c(N)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc2[nH]c(=O)cnc2c1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
To a solution of ethyl 2-(3,4-diaminophenoxy)acetate (1.3 g, 6.18 mmol) in toluene (10 mL) was added ethyl glyoxalate solution (2.52 mL, 12.37 mmol) and the reaction mixture was heated at 90° C. for 4 h. The reaction was cooled to room temperature. The solid was filtered, washed with diethyl ether (10 mL) and dried to yield ethyl 2-((2-oxo-1,2-dihydroquinoxalin-6-yl)oxy)acetate (1.1 g, 68%). LCMS: RT 1.18 min. LCMS (ES-API), m/z 247(−ve mode).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([N:22]2[C@@H:30]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C@@H:29]3[C:24]([C:25]4[CH:39]=[CH:38][C:37]([C:40]([O:42]C)=[O:41])=[CH:36][C:26]=4[CH2:27][CH2:28]3)=[N:23]2)[CH:17]=[CH:18][C:19]=1[C:20]#[N:21].IC.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:13][C:14]1[CH:15]=[C:16]([N:22]2[C@@H:30]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[C@:29]3([CH3:1])[C:24]([C:25]4[CH:39]=[CH:38][C:37]([C:40]([OH:42])=[O:41])=[CH:36][C:26]=4[CH2:27][CH2:28]3)=[N:23]2)[CH:17]=[CH:18][C:19]=1[C:20]#[N:21]
Reactant: COC(=O)c1ccc2c(c1)CC[C@H]1C2=NN(c2ccc(C#N)c(Cl)c2)[C@H]1C1CCCC1
Reactant: CC(C)NC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CO
Product: C[C@]12CCc3cc(C(=O)O)ccc3C1=NN(c1ccc(C#N)c(Cl)c1)[C@H]2C1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
To a solution of diisopropylamine (0.0772 mL, 0.551 mmol) in tetrahydrofuran (1.5 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 0.206 mL, 0.514 mmol). After 10 minutes, a solution of (3S,3aR)-methyl 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate, Example 93 (159 mg, 0.367 mmol) in tetrahydrofuran (3.0 mL) was added dropwise. After 1 hour at −78° C., iodomethane (0.0343 mL, 0.551 mmol) was added. The reaction was kept at −78° C. and monitored by LCMS. After 2 hours, another 0.015 mL of iodomethane was added. Lithium hexamethyldisilazide (1.0 M in tetrahydrofuran, 0.100 mL, 0.100 mmol) was added, followed by another 0.015 mL iodomethane. Allowed to slowly warm to room temperature overnight. The reaction was treated with 0.5 mL methanol and 0.5 mL 2.5 N NaOH. After 4 hours, the reaction mixture was neutralized with 0.5 mL of 3 N hydrogen chloride and concentrated under a stream of nitrogen. The residue was dissolved in dimethylformamide/methanol, filtered through a syringe filter and purified by reverse-phase HPLC (60 to 95% acetonitrile/water/0.05% trifluoroacetic acid) to give the title compound (yellow solid, 48.6 mg, 0.112 mmol, 30.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br. s., 1H), 8.10 (d, J=8.2 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J=9.0 Hz, 1H), 4.57 (d, J=5.9 Hz, 1H), 3.01-3.10 (m, 2H), 1.91-2.11 (m, 3H), 1.71-1.82 (m, 1H), 1.09-1.56 (m, 7H), 1.06 (s, 3H). ES-MS m/z 434 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:15]([O-])([OH:17])=[O:16]>C(OCC)(=O)C.CCCCCC>[N+:15]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2][CH:3]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CCCCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)CCCCCc1ccc([N+](=O)[O-])cc1
Temperature: -10 °C

Procedure:
6-Phenylhexanoic acid (30 g) was added dropwise over 6.5 hours to 125 ml of 90% nitric acid with cooling to -30° to -20° C. When the addition was complete, the mixture was allowed to warm to -10° C. for 30 minutes and it was then poured into ice water. The resulting mixture was extracted with diethyl ether and the ether extract was washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then evaporated to leave a crude yellow solid which was subjected to high pressure liquid chromatography using ethyl acetate/hexane/glacial acetic acid as the eluent. This chromatography removed dinitrated material and gave a yellow slush which was recrystallized from a mixture of toluene and hexane to give 6-(4-nitrophenyl)hexanoic acid.
Reaction SMILES: [OH:1][CH:2]([CH:13]([OH:24])[C:14]([O:16]N1C(=O)CCC1=O)=O)[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[C:56]3[C:51](=[C:52]([Cl:58])[CH:53]=[C:54]([Cl:57])[CH:55]=3)[CH2:50][N:49]([CH3:59])[CH2:48]2)=[CH:43][CH:42]=1)(=[O:40])=[O:39]>>[Cl:57][C:54]1[CH:55]=[C:56]2[C:51](=[C:52]([Cl:58])[CH:53]=1)[CH2:50][N:49]([CH3:59])[CH2:48][CH:47]2[C:44]1[CH:43]=[CH:42][C:41]([S:38]([NH:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][NH:25][C:3](=[O:5])[CH:2]([OH:1])[CH:13]([OH:24])[C:14]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37][S:38]([C:41]2[CH:42]=[CH:43][C:44]([CH:47]3[C:56]4[C:51](=[C:52]([Cl:58])[CH:53]=[C:54]([Cl:57])[CH:55]=4)[CH2:50][N:49]([CH3:59])[CH2:48]3)=[CH:45][CH:46]=2)(=[O:40])=[O:39])=[O:16])(=[O:40])=[O:39])=[CH:46][CH:45]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)C1
Reactant: O=C(ON1C(=O)CCC1=O)C(O)C(O)C(=O)ON1C(=O)CCC1=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)C(O)C(O)C(=O)NCCOCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1
Yield: 19.8 %

Procedure:
Compound 227 was prepared following the procedure outlined in Example 168 using bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (49.6 mg, 0.144 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 82, 157 mg, 0.288 mmol). Purification by preparative HPLC gave the title compound (34.5 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.89 (d, 4H), 7.53 (s, 2H), 7.45 (d, 4H), 6.83 (s, 2H), 4.77-4.74 (m, 6H), 4.46 (d, 2H), 4.43 (t, 2H), 3.89-3.84 (m, 2H), 3.62-3.53 (m, 19H), 3.49-3.41 (m, 13H), 3.14 (s, 6H), 3.08 (t, 4H). MS (m/z): 1206.94 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH2:42][CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH2:42][CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (233 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K20) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (288 mg, 67%).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)#[N:2].C[O-].[Na+].[C:11](O)(=[O:13])C>CO>[S:5]1[CH:6]=[CH:7][C:3]([C:1](=[NH:2])[O:13][CH3:11])=[CH:4]1
Reactant: N#Cc1ccsc1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccsc1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
3-cyanothiophene (0.66 g, 6.0 mmol) was dissolved in methanol (6 ml), and sodium methoxide (0.03 g, 0.6 mmol) was added. The mixture was stirred at room temperature for 28 hours. After the reaction was completed, acetic acid (0.03 g, 0.6 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether (50 ml) was added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 3-thiophenecarboximidate.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=[O:13].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:13][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]2[C:2]([Cl:1])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[CH:21]=1
Reactant: c1ccncc1
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)Oc1cccnc1

Procedure:
This salt is stirred under nitrogen and anhydrous conditions for 1 hour with 6.5 ml of pyridine and 1.5 g of [o-(2,6-dichloro-anilino)-phenyl]-acetic acid at 20°-30°C and the mixture is then evaporated in vacuo at a maximum temperature of 40°C. The residue is dissolved in 50 ml of ether and while cooling with ice, washed with saturated potassium hydrogen carbonate solution, 1 N-hydrochloric acid, and with ice water. The bulk of the [o-(2,6-dichloro-anilino)-phenyl]-acetic acid-3-pyridyl ester remains in the ether layer and, after this latter has been dried with magnesium sulphate and evaporated in vacuo, is obtained therefrom as a pale brown oil which crystallises on trituration. The new ester contains as impurity 1-(2,6-dichloro-phenyl)-2-hydroxy-indole from which it can be separated by being dissolved in ether/petroleum ether 1:1 and filtered through a silica gel column. The [o-(2,6-dichloro-anilino)-phenyl]-acetic acid-3-pyridyl ester is obtained from the filtered ether/petroleum ether solution (evaporation in vacuo) in the form of colourless crystals which, after precipitation with petroleum ether from an ethereal solution, melt at 84°-86°C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>C(O)C>[ClH:34].[ClH:34].[N:11]1([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Agent: Cl
Solvent: CCO
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(4-(4-t-Butoxycarbonyl-piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one (10.24 g, 22 mmol) was suspended in ethanol (150 ml), and a solution of hydrogen chloride in ethanol (5M, 75 ml) added at 0°. A complete solution occurred, and the solution was left to stir 18 hours at ambient temperature, as product precipitated. After dilution with anhydrous diethyl ether (200 ml), the product (8.91 g) was filtered off.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:23][CH3:24])[C:19](OC)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:23][CH3:24])[CH2:19][OH:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CO)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(4-(tert-butoxycarbonylamino)-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (5 g, 11.3 mmol), as described in Example 3 Step A, in tetrahydrofuran (50 mL) was added lithium aluminium hydride (644 mg, 16.95 mmol) at 0° C. The mixture was gradually warmed to room temperature and stirred for 4 h. Water (10 mL) was carefully added to the reaction mixture, then extracted with ethyl acetate. The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with PE/EA (30/1 to 10/1, v/v) to give the title compound as a colorless amorphous solid. LC/MS m/z=359.9 [M-tBu+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([N:11]([CH2:19][CH3:20])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH3:10].[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]([CH2:9][CH3:10])[CH2:19][CH3:20])=[CH:13][CH:14]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CCN(CC)c1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(C)=O)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
Triethylamine (22.3 g, 30.6 mL, 0.22 mol) was added to a suspension of N,N-diethyl-p-phenylenediamine hydrochloride (20 g, 0.1 mol) in dichloromethane (150 mL) at room temperature. The mixture was cooled to 0° C. and acetyl chloride (7.85 g, 0.1 mol) was added dropwise, with stirring. The mixture was allowed to warm to room temperature, and the precipitate which had formed was removed by filtration. The solid residue was washed with dichloromethane, and the combined dichloromethane solutions were concentrated. The dark oil produced was triturated with hexanes (100 mL) to afford a light brown crystalline solid, which was purified by recrystallization from 50% aqueous ethanol to afford the N-acetyl-4-diethylaminoaniline (16.5 g, 80% yield) as a gray solid. The structure of this compound was confirmed by mass spectroscopy and by 1H NMR spectroscopy.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:33]1[C:35]2([CH2:40][NH:39][CH2:38][CH2:37][N:36]2C(OC(C)(C)C)=O)[CH2:34]1>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:39]3[CH2:40][C:35]4([CH2:33][CH2:34]4)[NH:36][CH2:37][CH2:38]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC12CC2
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCNC3(CC3)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate to afford an off-white powder. HPLC (Condition 4) tR=4.44 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=475 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.27-0.54 (m, 4H) 2.82 (br. s, 2H) 2.96-3.20 (m, 5H) 6.64 (br. s, 1H) 7.32 (d, J=8.21 Hz, 2H) 7.86 (d, J=8.99 Hz, 3H) 8.29 (br. s, 1H) 8.71 (br. s, 1H) 10.37 (br. s, 1H) 13.00 (br. s, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:14][CH3:15])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[NH2:8].[C:16](=[O:19])([O-])[O-].[K+].[K+]>>[CH3:15][O:14][CH2:5][CH2:6][C:16]([NH:8][C:7]1[C:6](=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([O:14][CH3:15])=[O:13])=[O:19]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: COCCC(=O)Nc1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
To a suspension of 12.6 g (100 mmol) of the sodium salt obtained in the above (i) in 100 ml of benzene was dropwise added 8.0 ml (110 mmol) of thionyl chloride under stirring at room temperature for a period of 5 min. The mixture was then heated under reflux for 30 min. After chilling with ice, insolubles were removed by filtration. To the filtrate were added 15.1 g (100 mmol) of methyl anthranilate and 13.8 g (100 mmol) of potassium carbonate. The resulting mixture was then heated under reflux for 4 hrs. After the addition of ice water, the reaction mixture was washed sequentially with 6 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then was dried over anhydrous sodium sulfate. The solvent was distilled off to leave 8.8 g of an oily product. The oily product was crystallized from hexane to give 8.3 g of the desired compound as a pale yellow crystal.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11](=[O:27])[CH:12]([C:17](=[O:26])[NH:18][O:19]C(=O)C(C)(C)C)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:7][N:6]1[C:28](=[O:53])[N:29]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[NH:47][N:46]=[N:45][N:44]=2)=[CH:33][CH:32]=1)=[O:4].[OH-].[Na+].Cl>CO>[OH:19][NH:18][C:17]([CH:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:11]([NH:10][C@@H:8]1[CH2:7][N:6]([C:28](=[O:53])[N:29]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[NH:47][N:46]=[N:45][N:44]=3)=[CH:35][CH:36]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)=[O:27])=[O:26]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)N1C[C@@H](NC(=O)C(CC(C)C)C(=O)NOC(=O)C(C)(C)C)C[C@H]1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)N1C[C@@H](NC(=O)C(CC(C)C)C(=O)NO)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
(2S,4S)-4-[2-(2,2-Dimethylpropionyloxycarbamoyl)-4-methylpentanoylamino]-1-{pentyl[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]carbamoyl}pyrrolidine-2-carboxylic acid methyl ester (2.2 g, 3 mmol) was dissolved in MeOH (20 mL). An aqueous solution of NaOH (1M, 10 ml; 10M, 1 mL) was added, and the mixture was stirred at room temperature for 15 minutes. The solution was acidified with HCl and extracted (EtOAc, 2×50 mL). The combined organics were washed with saturated aqueous NaCl (50 mL), dried over Na2SO4, and the solvent evaporated. The residue was purified by reverse phase preparative HPLC (twice) to afford the title compound (657 mg, 1.03 mmol). MS m/z: [M+H]+ calcd for C32H42N8O6, 634.7. found 635.3.
Reaction SMILES: [BH4-].[Na+].[N:3]1([C:9]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH:20]=[O:21])=[CH:16][NH:17]3)=[CH:13][CH:12]=2)=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[OH:21][CH2:20][C:15]1[C:14]2[C:18](=[CH:19][C:11]([C:9]([N:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)=[O:10])=[CH:12][CH:13]=2)[NH:17][CH:16]=1
Reactant: O=Cc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccc2c(CO)c[nH]c2c1)N1CCOCC1
Reaction time: 2 h

Procedure:
Sodium borohydride (220 mg, 5.81 mmol, 3.0 eq) was added to a stirred solution of product 27a) (500 mg, 1.94 mmol, 1.0 eq) in methanol (10 mL) at room temperature and stirring was continued for 2 h. The methanol was removed under vacuum, water (50 mL) was added, and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and evaporated. White solid. Yield: 400 mg (80% of theory).
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)[N:33]=[CH:32][CH: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].[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[C:27](=[O:28])[N:26]2[C@@H:22]([CH2:23][C@@H:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C@@:19]2([C:41]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:42])[C@@H:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3ccnc4ccccc34)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(C)(=O)=O)NC(=O)[C@@H]2C[C@@H](Oc3ccnc4ccccc34)CN2C1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)NS(C)(=O)=O)NC(=O)[C@@H]2C[C@@H](Oc3ccnc4ccccc34)CN2C1=O

Procedure:
(1S,4R,6S,14S,18R)-7-cis-[14-tert-butoxycarbonylamino-2,15-dioxo-18-(quinolin-4-yloxy)-3,16-diaza tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid, the product of Step F in Example 30 (50 mg, 0.075 mmol) was reacted in analogous fashion with methanesulfonamide (12 mg, 0.12 mmol) as described in the preceding procedure above to give 10 mg (20%) of (1S,4R,6S,14S,18R)-7-cis-[4-methanesulfonylaminocarbonyl-2,15-dioxo-18-(quinolin-4-yloxy)-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white solid: 1H NMR (300 MHz, CDCl3) δ 1.26 (s, 9H), 1.22-1.94 (m, 11H), 2.27 (m, 1H), 2.55 (m, 1H), 2.67 (m, 2H), 3.17 (s, 3H), 4.05 (m, 1H), 4.27 (m, 1H), 4.61 (t, J=8.1 Hz, 1H), 4.73 (d, J=11.0 Hz, 1H), 4.96-5.02 (m, 2H), 5.35 (s, 1H), 5.71 (q, J=8.8 Hz, 1H), 6.73 (d, J=5.1 Hz, 1H), 6.93 (bs, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 8.15 (d, J=7.7 Hz, 1H), 8.77 (d, J=5.5 Hz, 1H). LC-MS (Method A, retention time: 2.43 min), MS m/z 670 (M++1). Preparation of Example 32, 2(S)-tert-butoxycarbonylamino-3-pentenylsulfanylpropionic acid methyl ester (Example 32) for use in Example 33.