Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:32]([CH3:41])([CH3:40])[C:33]([O:35]C(C)(C)C)=[O:34])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([C:32]([CH3:41])([CH3:40])[C:33]([OH:35])=[O:34])[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)C(=O)OC(C)(C)C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(C)(C)C(=O)O)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Tert-butyl 2-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2-methylpropanoate (25 mg, 0.035 mmol) was dissolved in TFA (344 μL), trifluoromethanesulfonic acid (15.48 mg, 0.103 mmol) was added, and the resulting mixture was stirred at 80° C. for 4 h. The reaction mixture was subsequently concentrated in vacuo and the residue was taken up in 100 mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/hexanes) gave impure product which was further purified by preparatory TLC (2 plates; silica gel). TLC plates were loaded with the impure material and eluted in 10% MeOH/DCM to give the title compound (70% yield) following extraction of the product-containing bands with methanol, filtration, and concentration in vacuo. 1H NMR (400 MHz, d4-MeOH) δ 9.00 (d, J=2.74 Hz, 1H) 8.58 (s, 1H) 8.39 (d, J=2.54 Hz, 1H) 8.16-8.24 (m, 2H) 4.01 (s, 3H) 2.52 (s, 3H) 1.59 (s, 6H). m/z (ESI, +ve) 414.0 (M+H)+. m/z (ESI, +ve ion) 414.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]=3[C:16]=2[CH:15]=1.O>N1C=CC=CC=1>[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][N:22]([S:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)(=[O:11])=[O:10])[CH2:21][C:20]=3[C:16]=2[CH:15]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: COc1cccc(S(=O)(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
3-Methoxybenzenesulfonyl chloride (0.04 mL, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 38 (50 mg, 55% yield) as a yellow solid. LC-MS (M+H=379, obsd.=379).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:49])[C@@H:14]([NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH2:15][NH:16][C:17]1[C:18]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)[C:19]=2[N:20]=[C:21]([CH3:23])[N:22]=1)(C)(C)C>C(Cl)Cl>[CH3:23][C:21]1[N:22]=[C:17]([NH:16][CH2:15][C@H:14]([NH:39][S:40]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)(=[O:41])=[O:42])[C:13]([OH:49])=[O:12])[C:18]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)[C:19]=2[N:20]=1
Reactant: Cc1nc(NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 ml of TFA were added to a solution of 70 mg of (2S)-3-(2-methyl-7-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(benzenesulfonylamino)-propionic acid tert-butyl ester (example 4b) in 5 ml DCM and stirred for 2 h at room temperature. Solvent and TFA were removed in vacuo, the residue was lyophilized from AcOH/H2O (1:1). Yield: 71 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25](OCC)=[O:26])[N:24]=2)[CH:21]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25]([NH:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][C:11]([F:13])([F:12])[F:14])[CH:4]=3)=[O:26])[N:24]=2)[CH:21]=1
Reactant: NCc1ccc(F)c(OC(F)(F)F)c1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1ccc(F)c(OC(F)(F)F)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (4-fluoro-3-(trifluoromethoxy)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: Br[C:2]1[C:3]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[C:11]([CH3:15])=[N:12][O:13][CH:14]=1)=[O:8].[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:5]1[CH:4]=[C:3]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:2]([C:38]2[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=2)=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[C:11]([CH3:15])=[N:12][O:13][CH:14]=1)=[O:8]
Reactant: Cc1nocc1NC(=O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nocc1NC(=O)c1cc(-c2cnn(C)c2)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Temperature: 120 °C

Procedure:
To a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-(3-methyl-4-isoxazolyl)-4-(4-morpholinylmethyl)benzamide (may be prepared as described in Example 21; 89 mg, 0.18 mmol) in 1,2-dimethoxyethane (3 ml) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40.4 mg, 0.19 mmol), sodium carbonate (0.35 ml, 0.35 mmol) and Pd(Ph3P)4 (12.23 mg, 10.59 μmol). The mixture was heated at 120° C. in a microwave for 35 minutes, the solvent removed in vacuo and the residue purified by MDAP to yield the title compound as a white solid. 12 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([S:11][CH3:12])=[N:8][CH:7]=[N:6]2.C1C(=O)N(Br)C(=O)C1.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:12][S:11][C:9]1[C:10]2=[C:2]([CH2:1][N:25]3[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]3)[CH:3]=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnn2ccc(C)c12
Reactant: OC1CCNCC1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncnn2ccc(CN3CCC(O)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of 5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (200 mg, 1.12 mmol), NBS (218 mg, 1.23 mmol), and AKIN (spatula tip) in carbon tetrachloride (4 mL) was heated at 80° C. for 1 h. After cooling to rt, the solution was filtered to remove succinimide. To the filtrate was added 4-hydroxypiperidine (126 mg, 1.34 mmol, Aldrich) and DIPEA (214 μL, 1.23 mmol). The reaction was stirred at rt overnight and was then concentrated in vacuo. The residue was suspended in methanol and filtered. The filtrate was concentrated and the crude product was purified by flash chromatography on silica gel (20% MeOH/EtOAc) to give the title compound (229 mg, 74%) as a colorless solid. 1 H NMR (DMSO-d6) δ 8.25 (s, 1H), 7.88 (d, 1H, J=2 Hz), 6.81 (d, 1H, J=2 Hz), 4.54 (br s, 1H), 3.76 (s, 2H), 3.48-3.44 (m, 1H), 2.75-2.71 (m, 2H), 2.62 (s, 3H), 2.10-2.08 (m, 2H), 1.70-1.68 (m, 2H), 1.38-1.36 (m, 2H); MS(ESI+) m/z 279.3 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH2:12][CH2:13][CH3:14].C1C=CC=CC=1.S(=O)(=O)(O)O>O>[SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5]
Reactant: CCCCO
Reactant: O=C(O)c1ccccc1S
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCCCOC(=O)c1ccccc1S
Yield: 68.6 %

Procedure:
Using a procedure similar to that of Example IV, a mixture of 50 g (0.32 mole) of 2-mercaptobenzoic acid, 50 g (0.7 mole) of n-butanol, 200 ml of benzene and 1.1 g of sulfuric acid (93%) was heated at reflux for 24 hours during which time 5.9 ml of water was collected in the water separator. The mixture was cooled, washed, concentrated and the residual oil distilled to give n-butyl 2-mercaptobenzoate: 46.1 g (68.6% yield); bp 127°-128°C/ 1.0 mm; mol wt 210:
Reaction SMILES: [Cl:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[CH3:8].ClC1C=CC=CC=1C(C)CN([CH2:47][CH2:48][CH2:49][O:50][C:51]1[CH2:52][C:53](=[CH:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]=[CH:55][CH:56]=1)CC1C=CC=C(C(F)(F)F)C=1Cl>>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:7]([CH3:8])[CH2:6][N:5]([CH2:47][CH2:48][CH2:49][O:50][C:51]1[CH2:52][C:53](=[CH:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]=[CH:55][CH:56]=1)[CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([F:22])([F:23])[F:24])[C:2]=1[Cl:1]
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccccc2Cl)C1
Reactant: COc1ccccc1C(C)CNCc1cccc(C(F)(F)F)c1Cl
Product: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccccc2OC)C1
Yield: 90 %

Procedure:
The titled compound was prepared from N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-methoxyphenyl)propylamine in 90% yield in the same manner as the preparation of N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in Example 184f. MS (ESI) 564 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[CH:5]=1.[OH-].[Na+]>CO.O>[Cl:13][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=1)[C:3]([OH:14])=[O:2]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 3-chloro-5-nitro-benzoic acid methyl ester (325, 2.75 g, 12.76 mmol) in 60 mL of MeOH was added a solution of NaOH (EM, 5.10 g, 127.6 mmol) in 35 mL of H2O. The mixture was stirred for 2 h. MeOH was removed under reduced pressure, and the mixture was diluted with water, brought to pH 2 with con. HCl. Filtration followed by washing with water gave 2.35 g (92%) desired product. 1H NMR (400 MHz, DMSO-d6) δ 14.02 (s, 1H), 8.57-8.52 (m, 2H), 8.31 (dd, J=1.9, 1.2 Hz, 1H), 3.94 (s, 3H). MS (EI): m/z 200 (M−H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]([O:23]CC)=[O:22])[C:12]3=[O:26])[CH:9]=[CH:10][C:2]1=2.[OH-].[Na+].Cl>C(O)C>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]([OH:23])=[O:22])[C:12]3=[O:26])[CH:9]=[CH:10][C:2]1=2
Reactant: CCOC(=O)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
4.5 g (13 mmol) of ethyl 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in ethanol (100 ml), and 4.1 g (26 mmol) of a 25% aqueous solution of sodium hydroxide was added thereto. The solution was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and water was added to the residue thus obtained. The mixture was acidified using 10% hydrochloric acid. A solid precipitated therefrom was separated by filtration, washed with water, and then dried to obtain 3.9 g (yield: 94%) of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[C:9]([C:11]([NH:13][CH3:14])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[C:24]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:29]=1)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:35]([NH:34][C:30]4[CH:29]=[C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:33]=[CH:32][N:31]=4)=[O:36])=[CH:17][CH:16]=3)[C:9]([C:11]([NH:13][CH3:14])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1ccnc(NC(=O)Oc2ccccc2)c1
Reactant: CNC(=O)c1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(C)(C)C)ccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of DMF (1 mL) was added Intermediate X (50 mg, 0.18 mmol) followed by phenyl (4-tert-butylpyridin-2-yl)carbamate (48 mg, 0.18 mmol) and triethylamine (25 μL, 0.18 mmol). The reaction was stirred at rt overnight, concentrated to dryness, and purified by HPLC to afford 22 mg of the above compound (0.04 mmol, yield 26%). 1H-NMR (DMSO-d6) δ 10.9 (s, 1H), 9.48 (s, 1H), 8.17 (d, J=5.4 Hz, 1H), 8.06 (s, 1H), 7.88 (s, 1H), 7.02 (d, J=5.0 Hz, 1H), 7.61 to 7.54 (m, 3H), 7.29 (d, J=8.3 Hz, 2H), 7.04 (dd, J=5.5, 1.6 Hz, 1H), 2.61 (d, J=4.7 Hz, 3H), 1.25 (s, 9H); MS [M+H]+=459.2; LCMS RT=2.49.
Reaction SMILES: C[O-].[Na+].[CH:4]([NH2:6])=[NH:5].O=[C:8]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10][CH:9]1[C:22](OC)=[O:23].C(O)(=O)C>CO>[OH:23][C:22]1[C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[N:6]=[CH:4][N:5]=1
Reactant: N=CN
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2ncnc(O)c2CC1
Reaction time: 0.25 h

Procedure:
A solution of NaOMe in MeOH (13.6 mL, 25% in MeOH, 59.5 mmol) is added to a stirred solution of formamidine (2.2 g, 21 mmol) in MeOH (50 ml) at rt. The mixture is stirred for 15 min. 1-tert-Butyl 4-methyl 5-oxoazepane-1,4-dicarboxylate (5 g, 7.5 mmol) is added and the mixture is stirred at rt overnight. Acetic acid (2.33 g, 38.5 mmol) is added and the solvent is removed in vacuo. Water (30 ml) is added to the residue and the solution is extracted with DCM (3×30 ml). The combined extracts are washed with brine (40 ml), dried (Na2SO4) and evaporated, to provide a yellow solid that is used in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1)([O-:12])=[O:11]>O.[OH-].[Na+].C1C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:21])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)C[C@H](NC(=O)Nc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 2 h
Yield: 79.4 %

Procedure:
4.56 g (0.0568 mol) of L-aspartic acid are dissolved in water by addition of sodium hydroxide until a pH close to 10 is obtained. A solution of 10 g (0.0568 mol) of 4-nitrophenyl isocyanate in 50 cm3 of benzene is then added at room temperature. The solution is stirred vigorously for two hours whilst maintaining the pH at around 10 by successive addition of a concentrated sodium hydroxide solution. The weak precipitate formed is eliminated by filtration and the filtrate is washed with 3×50 cm3 of ethyl ether. The aqueous phase is then acidified and extracted with ethyl acetate, which makes it possible to obtain, after drying over anhydrous sodium sulfate and after concentration, 13.4 g (yield 76%) of a yellow solid of which the melting point is 118°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].Cl.CN(C)[CH:22]=[O:23]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:22]=[O:23]
Reactant: Fc1cc2cc[nH]c2cc1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(F)c(F)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5,6-difluoro-1H-indole (1.0 g) in N,N-dimethylformamide (10 mL) was added phosphoryl chloride (1.2 g) at 0° C., and this mixture was stirred at room temperature for 4 hours. To this mixture was added 2 mol/L aqueous sodium hydroxide solution (5 mL), and this resulting mixture was stirred at 70° C. for 0.5 hours. After cooling to ambient temperature, this mixture was poured into 1 mol/L hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.1 g).
Reaction SMILES: [C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][C:38]=3[CH3:47])[C:8](=[O:35])[C@@H:9]([NH:20][C:21](=[O:34])[C@@H:22]([N:25](C)[C:26](=O)OC(C)(C)C)[CH2:23][CH3:24])[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=2[CH:4]=1)#[N:2].[ClH:50]>O1CCOCC1.CCOCC>[ClH:50].[C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][C:38]=3[CH3:47])[C:8](=[O:35])[C@@H:9]([NH:20][C:21](=[O:34])[C@@H:22]([NH:25][CH3:26])[CH2:23][CH3:24])[C@H:10]([CH3:19])[N:11]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC[C@H](NC)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Yield: 85 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxobutan-2-yl(methyl)carbamate (117 mg, 170 μmol) in 4 M HCl in dioxane (848 μl) was stirred for 1 h. The reaction was diluted with Et2O and the resulting solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)butanamide hydrochloride (90.5 mg, 85%) as a white solid. MS m/z 590 (MH)+.
Reaction SMILES: [Br-].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5].[CH2:33]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH2:44][CH2:45][CH:46]=O)[CH2:40][CH2:39]1)[CH2:34][CH2:35][CH2:36][CH3:37].O>COC(C)(C)C>[CH2:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[CH:46][CH2:45][CH2:44][C@H:41]2[CH2:40][CH2:39][C@H:38]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:43][CH2:42]2)=[CH:11][CH:12]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](CCC=O)CC1
Reactant: CCCCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC[C@H]1CC[C@H](CCC=Cc2ccc(OCCCC)cc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
A mixture of 54 g of (4-butyloxyphenyl)methyl-triphenylphosphonium bromide and 450 ml of absolute t-butyl methyl ether was treated with 12 g of solid potassium t-butylate at 0° C. and while gassing with nitrogen. After completion of the addition the reaction mixture was stirred at 0° C. for a further 15 minutes (whereby a deep orange coloration resulted) and then treated within 30 minutes at 0° C. with a solution of 15 g of 3-(trans-4-pentylcyclohexyl)propionaldehyde in 150 ml of absolute t-butyl methyl ether. Subsequently, the reaction mixture was stirred at room temperature overnight and then poured into 1000 ml of water and extracted three times with 200 ml of diethyl ether each time. The organic phases were washed twice with 500 ml of concentrated sodium chloride solution each time, dried over magnesium sulfate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with hexane/toluene (vol. 4:1) gave 21 g of 1-butyloxy-4-[4-(trans-4 -pentylcyclohexyl)-1-butenyl]benzene (cis/trans mixture). Recrystallization from ethanol gave pure trans isomer with m.p. (C-SB) 46° C., SB --SA 74° C., SA --N 76° C. and cl.p. (N--I) 91° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:21]=[CH2:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[C:15]([CH3:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[O:25]1>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:21]2[CH2:22][O:25]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[C:15]([CH3:20])=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(OCc2ccccc2)c2[nH]c(=O)c(C)cc12
Reactant: CC1(C)OO1
Solvent: CC(C)=O
Product: Cc1cc2c(C3CO3)ccc(OCc3ccccc3)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 8-benzyloxy-3-methyl-5-vinyl-1H-quinolin-2-one (300 mg) is added to a 0.1M solution of dimethyldioxirane in acetone (12.4 mL). After stirring at room temperature for 2 hours, the solvent is removed in vacuo to yield the product.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][C@@H:8]([CH2:19][CH2:20][CH3:21])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:12]([O:11][C:9](=[O:10])[C@H:8]([CH2:19][CH2:20][CH3:21])[CH2:7][C:6]([OH:22])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC[C@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC[C@H](CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A stirred solution of (2R)-2-propyl-succinic acid 1-benzyl ester 4-tert-butyl ester (4.56 g, 14.88 mmol) in anhydrous DCM (20 mL), at 0° C., was treated with a solution of trifluoroacetic acid (10 mL) in anhydrous DCM (10 mL). The reaction mixture was allowed to warm to ambient temperature over 3 h before being concentrated under reduced pressure. The residue was dissolved in dry DCM, before concentrating again. This process was repeated several times in order to remove excess trifluoroacetic acid to leave the sub-title compound (3.70 g, 99%) as a gum: 1H NMR (400 MHz, CDCl3) δ 0.82-0.99 (3H, m), 1.21-1.76 (4H, m), 2.45-2.60 (1H, m), 2.76-3.00 (2H, m), 5.10-5.21 (2H, m), 7.28-7.43 (5H, m), 7.83-8.18 (1H, m).