Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]([OH:35])=[C:18]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22])(=[O:15])=[O:14])=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]([OH:35])=[C:18]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22])(=[O:14])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Solvent: O=C(O)C(F)(F)F
Product: NCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 68 %

Procedure:
A solution of N[3-[N″-[3-(tert-butoxycarbonylamino)propyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea (33 mg, 0.058 mmol) in 1 mL of trifluoroacetic acid was stirred at room temperature for 30 min. The solvent was concentrated. The residue was diluted with methanol, then concentrated. The process was repeated twice to give crude material. Recrystallization from methanol and water produced desired product (23 mg, 68%). EI-MS (m/z) 466.7, 468.8, 470.8 (M−).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])=[C:28]([O:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:27]=1)[C:10]([O:12][C@H:13]([CH3:24])[CH2:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])=[O:11])=O)(C)(C)C.[ClH:44]>O1CCOCC1>[ClH:44].[NH2:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])=[C:28]([O:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:27]=1)[C:10]([O:12][C@H:13]([CH3:24])[CH2:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17])=[O:11]
Reactant: CC(C)C(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H](C)COC(=O)c2ccccc2)cc1OC(=O)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C(=O)Oc1ccc(C[C@H](N)C(=O)O[C@H](C)COC(=O)c2ccccc2)cc1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
(1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(2-methylpropanoyloxy)phenyl]propanoate (1.25 g, 2.0 mmol) was dissolved in 20 mL of 2M HCl in dioxane. The reaction mixture was stirred at room temperature for 60 min. Dioxane was completely evaporated under reduced pressure. The resulting white solid was dissolved in water (15 mL) and washed with methyl tert-butyl ether. The aqueous phase was collected and mixed with acetonitrile (10 mL). Lyophilization gave the title compound (10) (0.66 g, 62% yield) as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.27 (6H, d, J=7.2 Hz), 1.28 (6H, d, J=7.2 Hz), 1.30 (3H, d, J=6.4 Hz), 2.8 (2H, m), 3.17 (1H, dd, J=14.4, 6.8 Hz), 3.20 (1H, dd, J=14.4, 6.4 Hz), 4.25 (1H, t, J=6.8 Hz), 4.31 (1H, dd, J=12.4, 6.4 Hz), 4.47 (1H, dd, J=12, 3.2 Hz), 5.31 (1H, m), 7.12 (1H, d, J=8 Hz), 7.14 (1H, d, J=2 Hz), 7.18 (1H, dd, J=8.2 Hz), 7.47 (2H, t, J=7.2 Hz), 7.58 (1H, t, J=7.2 Hz), 8.02 (2H, d, J=7.6 Hz). MS (ESI) m/z 500.16 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:28]=[O:29].CO>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:28]([NH:27][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN=C=O
Reactant: Nc1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CNC(=O)Nc1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
To a solution of Intermediate 58 (3.9 g, 10.7 mmol) in methylene chloride (35 mL) was added ethyl isocyanatoacetate (1.38 mL, 12.3 mmol). The mixture was stirred at room temperature for 5 hours. The crude reaction was cooled to 0° C. and then methanol (2.3 mL) was added. The mixture was stirred at room temperature for 0.5 hours and the solvent was removed under reduced pressure. Purification by column cromatography using methylene chloride/methanol (from pure methylene chloride to 98:2) as eluent gave the title compound (5.1 g, 95%) as oil.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:24])[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:11]([F:25])[CH:10]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:25][C:11]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]([OH:26])=[O:5])[CH:14]=[CH:13][C:12]=1[CH:15]=[CH:16][C:17](=[O:24])[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2cccnc2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C=Cc1ccc(C=CC(=O)c2cccnc2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 138 %

Procedure:
3-[3-Fluoro-4-(3-oxo-3-pyridin-3-yl-propenyl)-phenyl]-acrylic acid tert-butyl ester (550 mg, 1.55 mmol) was dissolved in DCM (15 ml) and TFA (5 ml). The resulting solution was stirred at RT for 4 h then the solvent was removed under vacuo giving 636 mg of 3-[3-fluoro-4-(3-oxo-3-pyridin-3-yl-propenyl)-phenyl]-acrylic acid as trifluoro acetate salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][C@H:16]2[CH2:18][O:17]2)[C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N+:36]([O-:38])=[O:37])=[CH:21][CH:20]=2)[C@@H:10]([O:39][CH2:40][C:41]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:53]1[CH:57]=[N:56][CH:55]=[N:54]1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([O:39][CH2:40][C:41]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[C@@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N+:36]([O-:38])=[O:37])=[CH:21][CH:20]=2)[C@H:12]([O:14][CH2:15][C@H:16]([OH:17])[CH2:18][N:53]2[CH:57]=[N:56][CH:55]=[N:54]2)[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3CO3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H](O)Cn3cncn3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (k) the (3R,4R,5S)-3-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was treated with [1,2,4]triazol and sodium hydride in N,N-dimethylformamide to yield the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-[1,2,4]triazol-1-yl-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 784 (M+H)+.
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1>C(O)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N+:5]=1[O-:1]
Reactant: Cc1cccc(Br)n1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cccc(Br)[n+]1[O-]
Temperature: 90 °C
Yield: 75.2 %

Procedure:
Hydrogen peroxide (30%, 1.76 mL, 17.4 mmol) was added to a solution of 2-bromo-6-methyl-pyridine (1.0 g, 5.80 mmol) in acetic acid (20 mL), and heated for 24 h at 90° C. The reaction mixture was cooled to ambient temperature, and partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed thoroughly with water and dried over anhydrous sodium sulfate. Concentration in vacuo afforded 2-bromo-6-methyl-pyridine 1-oxide (820 mg, 75%) as a brown liquid which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[CH3:32][C:33]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH:45]=O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])[CH3:34]>>[C:33]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=2[C:12]2[CH:13]=[C:14]([O:18][C:19]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=4[CH:22]=[CH:21][CH:20]=3)[N:15]=[CH:16][N:17]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:32])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCC4CCN(C(=O)OC(C)(C)C)CC4)ncn3)cccc2s1

Procedure:
The title compound was prepared from N-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide (Example 151) and N-Boc-4-piperidinylcarboxaldehyde according the procedure described in Example 159. MS(ESI, pos. ion) m/z: 643 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.O1CCCC1.[NH:15]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=S1(=O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-bromobenzaldehyde (150 mg, 0.811 mmol) was placed in a flask that was subsequently evacuated and backfilled with nitrogen (3×). Tetrahydrofuran (8107 μl) and thiomorpholine 1,1-dioxide (110 mg, 0.811 mmol) were then added and the reaction was allowed to stir at room temperature for 1 hour. Sodium triacetoxyborohydride (258 mg, 1.216 mmol) was weighed and quickly added to the solution (flask was uncapped during addition). The reaction was stirred at room temperature overnight. The reaction was diluted in ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was extracted and the aqueous layer was extracted 3× with ethyl acetate. All organics were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified via HPLC to yield the title compound. LRMS (APCI) calc'd for C11H15BrNO2S [M+H]+: 304. Found: 304.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.F[C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[CH:17]=[O:18]>>[CH:17]([C:16]1[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:15]=1[O:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: CC(C)(C(=O)O)c1cccc(O)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Product: CC(C)(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 4, using the following starting materials: 2-(3-hydroxy-phenyl)-2-methyl-propionic acid and 2-fluoro-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:22][NH:23][S:24](Cl)(=[O:26])=[O:25].[BH4-].[Na+]>N1C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH:12]2[C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[N:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[NH:1][S:24](=[O:26])(=[O:25])[N:23]2[CH3:22])=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cc(F)ccc1C(=O)c1ccc2cccnc2c1N
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(F)ccc1C1c2ccc3cccnc3c2NS(=O)(=O)N1C
Yield: 15.8 %

Procedure:
In a similar fashion using route 27 general procedure 71, (8-amino-quinolin-7-yl)-(4-fluoro-2-methyl-phenyl)-methanone (Intermediate 380) (200 mg, 0.71 mmol), N-methylsulfamyl chloride (Intermediate 213) (700 mg, 5.4 mmol), NaBH4 (81 mg, 2.14 mmol) and pyridine (6 ml) gave the title compound (40 mg, 16%) after purification by preparative HPLC (neutral conditions).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH3:1][N:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Under nitrogen, 96.7 g (1.1 mol) of N-methyl-N-tertbutylamine and 111 g (1.1 mol) of triethylamine was dissolved in 1050 mL of anhydrous tetrahydrofuran (THF). The solution was cooled to 0° C. and treated with 140.6 g (1.0 mol) of benzoyl chloride. The reaction was allowed to slowly warm to ambient temperature and stir overnight. Filtration and subsequent concentration in vacuo of the filtrate gave the crude product which was purified by sublimation (65°, 0.2 torr) to give 184 g (96%) of colorless N-methyl-N-tertbutybenzamide: mp 80.5°-82.0° C.; NMR (CDCl3) δ1.52 (s, 9H), 2.87 (s, 3H), 7.34-7.40 (m, 3H), 7.40-7.46 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].F[C:22]1[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:22]3[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[CH:24][N:23]=3)[CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCOC(=O)c1ccnc(F)c1
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)c1
Yield: 29.2 %

Procedure:
The same operation as in Example (158a) was performed using cis(±)-4-chloro-5-ethyl-N-(3-methoxypiperidin-4-yl)-1H-imidazole-2-carboxamide hydrochloride obtained in Example (159a) (38.22 mg, 0.12 mmol), ethyl 2-fluoropyridine-4-carboxylate (20 mg, 0.12 mmol) (reference: Journal of Medicinal Chemistry; English; 33; 6; 1990; 1667-1675) and diisopropylethylamine (45.85 mg, 0.35 mmol), to obtain 15.3 mg of the title compound as a yellow oily substance (30%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH:14]4[C:18]5[CH:19]=[C:20]([C:25]6[CH2:26][CH2:27][O:28][CH2:29][CH:30]=6)[CH:21]=[CH:22][C:23]=5[CH2:24][CH:13]34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1>[Pd].CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]4[C:18]5[CH:19]=[C:20]([CH:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)[CH:21]=[CH:22][C:23]=5[CH2:24][C@H:13]34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(c1ccc2[nH]cnc2c1)N1CCCC2c3cc(C4=CCOCC4)ccc3CC21
Agent: [Pd]
Solvent: CO
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cc(C4CCOCC4)ccc3C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (1H-benzoimidazol-5-yl)-[6-(3,6-dihydro-2H-pyran-4-yl)-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl]-methanone (48 mg), 10% palladium on carbon (10 mg), and methanol (3 mL) is shaken under hydrogen atmosphere (5 bar) at room temperature overnight. The catalyst is then separated by filtration and the filtrate is concentrated. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→9:1) to afford the title compound. Yield: 15 mg (31% of theory); LC (method 1): tR=2.63 min; Mass spectrum (ESI+): m/z=402 [M+H]+.
Reaction SMILES: Cl.Cl.[N:3]1([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:15]([C:17]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20])[CH3:16]>>[CH2:15]([C:17]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:18]=1[C:19]([NH:14][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:8]1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:20])[CH3:16]
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Reactant: CCc1cc(C(F)(F)F)ccc1C(=O)O
Agent: Cl
Product: CCc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=369.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) and 2-ethyl-4-(trifluoromethyl)-benzoic acid (CAS 854531-63-8).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:20]=[C:21](CCN)[CH:22]=[CH:23][CH:24]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:22]=[CH:21][CH:20]=1
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Reactant: NCCc1cccc(Cl)c1
Solvent: CN(C)C=O
Product: S=C(NCCc1cccc(Cl)c1)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A solution of 1-[(2-benzothiazolyl)-thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(3-chlorophenyl)ethylamine (0.63 g, 4 mmol) in dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.88 g (63%) of the title product:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CCOC(C)=O>O1CCCC1>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCOCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCCOCCO
Reaction time: 0.5 h

Procedure:
A solution of 53 g of 2-hydroxyethyl ether (0.5 mol) in 200 mL of tetrahydrofuran was prepared, and the solution cooled in an ice-water bath. The solution was placed under a slow stream of argon. Sodium bis(trimethylsilyl)amide (125 mL, 0.125 mol, 1 M in tetrahydrofuran) was added dropwise over a 30 minute period. The mixture was stirred an additional 30 minutes, then 24.4 g of tert-butyl 2-bromoacetate (0.125 mol) was added. The mixture was then stirred for 1 hour. The ice-water bath was removed, and the mixture transferred to a separatory funnel using 250 mL of 1 M NaH2PO4. The mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were dried over sodium sulfate, filtered, and the solvent removed by rotary evaporator to give a clear yellow liquid. The liquid was purified by chromatography using 500 mL of silica gel and eluting with ethyl acetate/hexanes 1:1. The product was isolated as a clear, gold liquid. Obtained 5.49 g TLC Rf 0.50 (EtOAc). NMR (DMSO-d6)δ 1.42 (s, 9H), 3.42 and 3.54 (m, 8H), 3.98 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[O:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([CH:21]=[O:22])[C:14]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[O:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([C:21]([OH:25])=[O:22])[C:14]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2oc3c(OC)ccc(C=O)c3c2C1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)N1CCc2oc3c(OC)ccc(C(=O)O)c3c2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
2-ethoxycarbonyl-6-methoxy-1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine-9-carbaldehyde (from step 8) (170 mg, 0.559 mmol) was dissolved in acetone (10 ml): water (2.5 ml). To this solution sulfamic acid (81.0 mg, 0.838 mmol) was added and then reaction was cooled to 0° C. Then sodium chlorite (85 mg, 0.950 mmol) in water (2.5 ml) was added drop wise to maintain temperature below 10° C. and reaction was further stirred for 2 h. Reaction was quenched with water (20 ml) and precipitate was filtered on and dried to give 120 mg of white solid as the product.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:29]=[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[C:6]2[CH:43]=[CH:44][C:45]([C:47]#[N:48])=[CH:46][C:5]1=2)(=[O:3])[CH3:2].[ClH:49]>O1CCOCC1.CCOCC>[ClH:49].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:29]=[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[C:6]2[CH:43]=[CH:44][C:45]([C:47]#[N:48])=[CH:46][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccccc2F)cc1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2cc(-c3ccccc3F)ccc2OC)c2ccc(C#N)cc2N(C(C)=O)[C@H]1C
Yield: 68 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((2′-fluoro-4-methoxybiphenyl-3-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (39 mg, 59.3 μmol) in 4 M HCl in dioxane (296 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-5-acetyl-7-cyano-1-((2′-fluoro-4-methoxybiphenyl-3-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (23.9 mg, 68%) as a white solid. MS m/z 558 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[CH:2].I[C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([S:27][CH3:28])[N:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:28][S:27][C:19]1[N:18]=[C:17]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=2)[C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[C:22]([C:23]([F:26])([F:24])[F:25])=[CH:21][N:20]=1
Reactant: CSc1ncc(C(F)(F)F)c(I)n1
Reactant: C#Cc1cccc(C(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1ncc(C(F)(F)F)c(C#Cc2cccc(C(=O)OC(C)(C)C)c2)n1
Temperature: 120 °C

Procedure:
t-Butyl 3-ethynylbenzoate (I17) (1.603 g, 7.93 mmol), 4-iodo-2-(methylthio)-5-(trifluoromethyl)pyrimidine (I14) (1.647 g, 5.15 mmol), PdCl2(PPh3)2 (0.316 g, 0.45 mmol), PPh3 (0.355 g, 1.35 mmol), Cu(I)I (0.232 g, 1.22 mmol) and trethylamine (4.00 mL, 28.7 mmol) were combined in DMF (20 mL) and the resulting mixture heated at 120° C. under microwave irradiation for 25 minutes. The mixture was then concentrated under reduced pressure and purified twice using silica gel column chromatography (10-20% EtOAc/petroleum benzine 40-60° C. then 50-100% DCM/petroleum benzine 40-60° C.) to give the title compound (I18) (0.624 g, 31%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J=0.8 Hz, 1H), 8.25 (m, 1H), 8.08 (m, 1H), 7.78 (m, 1H), 7.48 (m, 1H), 2.63 (s, 3H), 1.61 (s, 9H).