Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:21]([C:29]3[N:33](CCC#N)[N:32]=[N:31][N:30]=3)=[CH:22][N:23]([CH3:28])[C:24](=[O:27])[C:25]=2[CH3:26])=[C:15]([F:38])[CH:14]=1>C(Cl)Cl.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:21]([C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:22][N:23]([CH3:28])[C:24](=[O:27])[C:25]=2[CH3:26])=[C:15]([F:38])[CH:14]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(-c2nnnn2CCC#N)cn(C)c1=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1c(Nc2ccc(Br)cc2F)c(-c2nnn[nH]2)cn(C)c1=O
Reaction time: 2 h
Yield: 76.4 %

Procedure:
DBU (0.030 mL, 0.21 mmol) was added to a solution of 3-{5-[4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl]-tetrazol-1-yl}-propionitrile (30 mg, 0.069 mmol) in methylene chloride (1.5 mL). After 2 hours, the reaction mixture was diluted with ethyl acetate and washed with 1 N HCl. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Trituration with diethyl ether gave clean desired product (20 mg, 77%); MS APCI (−) m/z 377, 379 (M−, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 7.29 (dd, 1H), 7.13 (dd, 1H), 6.63 (t, 1H), 3.65 (s, 3H), 1.91 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]3[C:9]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:27](C)=O.[Na+]>C(Cl)Cl.[OH-].[Na+]>[CH3:27][N:12]1[CH2:11][CH2:10][C:9]2[C:15](=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:14][CH2:13]1
Reactant: c1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN1CCc2nn(-c3ccccc3)c(-c3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.5 %

Procedure:
To a solution of 33.5 mg of 2,3-diphenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 176, Step D) in 5 mL of CH2Cl2 were added 0.15 g of paraformaldehyde and 0.15 g of NaBH(OAc)3. The mixture was stirred at RT for 12 h and was diluted with 20 mL of 1 M NaOH. After stirring for 3 h, the mixture was extracted with CH2Cl2 (2×10 mL) and the combined organic layers were concentrated. Chromatography on SiO2 (0 to 5% 2 M NH3 in MeOH/CH2Cl2) gave 22.3 mg of the title compound as a white solid. MS (ESI): exact mass calculated for C20H21N3, 303.17. found, m/z 304.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.35-7.30 (m, 3H), 7.27-7.21 (m, 2H), 7.20-7.16 (m, 3H), 7.15-7.12 (m, 2H), 3.06-3.02 (m, 2H), 2.83-2.79 (m, 2H), 2.72-2.67 (m, 4H), 2.50 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[N:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14](=[O:20])[C@@H:13]([CH2:21][CH3:22])[N:12]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:11]=2[N:10]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(C(F)(F)F)=O>>[CH:23]1([N:12]2[C:11]3[N:10]=[C:9]([C:8]4[CH:7]=[CH:6][N:5]=[CH:4][C:3]=4[CH2:2][NH:1][S:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:36])=[O:35])[N:18]=[CH:17][C:16]=3[N:15]([CH3:19])[C:14](=[O:20])[C@H:13]2[CH2:21][CH3:22])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C1CCCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNS(=O)(=O)c3ccccc3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 114, with (R)-2-(3-(aminomethyl)pyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 105) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91) and with benzene sulfonylchloride instead of chloromethylcarbonate. LCMS (0.05% TFA): 507.2 m/z (M+H)+; 1H-NMR (MeOD, 500 MHz): δ: 8.82 (s, 1H), 8.76 (bs, 1H), 8.27 (d, 1H, J=5.0 Hz), 8.13 (s, 1H), 7.81 (d, 2H, J=8.0 Hz), 7.62 (t, 1H, J=8 Hz), 7.55 (t, 2H, J=8 Hz), 4.63 (s, 2H), 4.43 (m, 2H), 3.43 (s, 3H), 2.06˜1.65 (m, 10H), 0.88 (t, 3H, J=7.5 Hz).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][C:12]([C:16]#[N:17])=[N:13]2)=[CH:8][CH:7]=1)=[N+:2]=[N-:3].[CH2:24]([C:26]([OH:31])([CH2:29][CH3:30])[C:27]#[CH:28])[CH3:25].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu](I)I>[CH2:27]([C:26]([C:24]1[N:3]=[N:2][N:1]([CH2:4][CH2:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:11][C:12]([C:16]#[N:17])=[N:13]3)=[CH:8][CH:7]=2)[CH:25]=1)([OH:31])[CH2:29][CH3:30])[CH3:28]
Reactant: C#CC(O)(CC)CC
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(CCN=[N+]=[N-])cc2n1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)(CC)c1cn(CCc2ccc3c(-c4ccccc4)cc(C#N)nc3c2)nn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 7-(2-azidoethyl)-4-phenylquinoline-2-carbonitrile (128 mg, 0.43 mmol), 3-ethylpent-1-yn-3-ol (63 mg, 0.56 mmol), copper iodide (58 mg, 0.65 mmol) and diisopropylethylamine (375 μL, 2.2 mmol) in THF (5 mL) was stirred at rt for 6 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 394 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:13]([O:21][CH3:22])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[H-].[Na+].I[CH3:26]>C1COCC1>[CH:16]1([O:15][C:14]2[C:5]([N:4]([CH3:26])[C:1](=[O:3])[CH3:2])=[C:6]([CH:11]=[CH:12][C:13]=2[O:21][CH3:22])[C:7]([O:9][CH3:10])=[O:8])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1NC(C)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1N(C)C(C)=O
Temperature: 25 °C

Procedure:
A solution of methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate (1.6 g, 5.2 mmol, Example 1, Step 4) and anhydrous THF (30 mL) was added over 5 min to a mixture of sodium hydride (230 mg, 5.75 mmol) and anhydrous THF (10 mL) at 0° C. under N2. The reaction was allowed to warm to rt and after 20 min, cooled back to 0° C. A solution of iodomethane (1.06 g, 0.0075 mol) and anhydrous THF (10 mL) was added over 3 min. The reaction was allowed to warm to rt and after 30 min, concentrated. The residue was diluted with ethyl acetate (40 mL) and washed with brine (10 mL×2). The organic layer was dried, filtered, and concentrated to give methyl 3-(cyclopentyloxy)-4-methoxy-2-(N-methylacetamido)benzoate: MS (ESI): 322.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:5]([Cl:16])=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([O:23][CH3:24])[NH:20][N:19]=2)[N:3]=1.Cl.[F:26][C:27]1[CH:28]=[N:29][C:30]([C@@H:33]([NH2:35])[CH3:34])=[N:31][CH:32]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:5]1[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[N:7][C:2]([NH:35][C@H:33]([C:30]2[N:31]=[CH:32][C:27]([F:26])=[CH:28][N:29]=2)[CH3:34])=[N:3][C:4]=1[NH:17][C:18]1[CH:22]=[C:21]([O:23][CH3:24])[NH:20][N:19]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: COc1cc(Nc2nc(Cl)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Temperature: 160 °C
Yield: 86.6 %

Procedure:
A microwave reaction vessel was charged with N-{2,5-dichloro-6-[(5-methoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N′,N′-trimethylsulfamide (Method 29, 44.1 mg, 0.112 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 39.5 mg, 0.223 mmol), and DIPEA (0.062 ml, 0.352 mmol). Anhydrous n-BuOH (1 ml) was added, and the tube was sealed and heated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexane) to afford the title compound as a white solid (48.6 mg, 87%). LC-MS, 501 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 12.01 (s, 1H), 9.76 (s, 1H), 8.83 (s, 2H), 8.21 (s, 1H), 5.60 (s, 1H), 5.04-5.06 (m, 1H), 3.76 (s, 3H), 2.80 (s, 3H), 2.70 (s, 6H), 1.59 (d, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[Cl:8][C:9]([Cl:13])([Cl:12])[CH2:10]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:10][C:9]([Cl:13])([Cl:12])[Cl:8])=[O:6]
Reactant: O=C(O)CCCBr
Reactant: OCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CCCBr)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.9 %

Procedure:
A stirred solution of 4-bromobutyric acid (3.34 g, 20.0 mmol) in toluene (50 ml) was added 2,2,2-trichloroethanol (14.94 g, 0.10 mol) and p-toluenesulfonic acid monohydrate (7.60 g, 40.0 mmol) and refluxed with a Dean-Stark trap attached for 6 h. Water was removed continuously. The reaction mixture was cooled to room temperature and concentrated in vacuo. The mixture was added CH2Cl2 (75 ml) and washed with H2O (3×25 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to leave an oil. The residue was distilled to leave the title compound as a colourless oil (4.77 g, 79.9%) (bp 100° C. at 0.5 mmHg).
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C@@H:16]([CH2:47][C:48]([NH:50][NH2:51])=O)[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2].CO[CH:55](OC)[N:56](C)[CH3:57]>C(Cl)Cl>[CH2:1]([O:3][C@H:4]([CH3:52])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[CH2:15][C@H:16]([CH2:47][C:48]3[N:56]([CH3:57])[CH:55]=[N:51][N:50]=3)[NH:17][CH2:18][C@@H:19]2[O:20][CH2:21][C:22]2[CH:36]=[CH:26][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:24]=3[CH:23]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(=O)NN)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Solvent: ClCCl
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](Cc3nncn3C)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C

Procedure:
A solution of 1.0 mmol of [(2R,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl) -piperidin-2-yl]-acetic acid hydrazide in 5 ml of CH2Cl2 is treated at RT with1.1 mmol of N,N-dimethylformamide dimethylacetal and refluxed for 1 h. The mixture is cooled to RT, and concentrated under reduced pressure to afford the title compound, which is identified based on its Rf value.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][N:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[CH:11]=[CH:10]2)([CH3:3])[CH3:2].[O:16]1CCOCC1>>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][N:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH:15]=[O:16])[CH:11]=[CH:10]2)([CH3:3])[CH3:2]
Reactant: Cc1ccc2nccc(OC(C)C)c2n1
Reactant: C1COCCO1
Product: CC(C)Oc1ccnc2ccc(C=O)nc12
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 8-isopropoxy-2-methyl-[1,5]naphthyridine (1.13 g, 5.60 mmol) in 1,4-dioxane (40 mL) was added SeO2 (0.80 g, 7.20 mmol) and the reaction mixture was refluxed for 2 hrs, when the TLC showed no starting material left, then cooled to room temperature and filtered through celite. The solid was washed with hot AcOEt and the filtrate was then concentrated to give 8-isopropoxy-[1,5]naphthyridine-2-carbaldehyde as a light yellow solid (1.20 g, 100%). HR-MS-EI (+) m/e calcd for C12H12N2O2 (M+) 216.0899. found 216.0900
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[N:17]2)=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)C.[O-]CC.[K+].O.[Cl-].[NH4+]>CN(C=O)C>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[N:17]2)=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc(OC(C)=O)ccc1-n1nnnc1C
Agent: CC[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(O)ccc1-n1nnnc1C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
Ethyl 5-acetoxy-2-(5-methyltetrazol-1-yl)benzoate (164 g, 0.565 mol) was dissolved in 500 mL of DMF and immersed in a water bath. Potassium ethoxide (52.3 g, 0.621 mol) was added to this solution portionwise, keeping the reaction temperature below 40° C. After 30 minutes, the reaction was poured into 4 L of water and ammonium chloride was added to the solution until the product precipitated. After one hour of stirring, the precipitate was filtered and dried under a flow of air to give 98.5 g of ethyl 5-hydroxy-2-(5-methyltetrazol-1-yl)benzoate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Cl:27])[CH:25]=2)[N:20]=[C:19]([CH3:28])[C:18]=1[CH3:29]>>[Br:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([Cl:27])[CH:25]=4)[N:20]=[C:19]([CH3:28])[C:18]=3[CH3:29])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1nc2ccc(Cl)cc2c(Cl)c1C
Reactant: Brc1ccc2c(c1)NCC21CCOCC1
Product: Cc1nc2ccc(Cl)cc2c(N2CC3(CCOCC3)c3ccc(Br)cc32)c1C

Procedure:
Prepared according to procedure M using 6-bromo-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (0.3 g, 1.12 mmol) and 4,6-dichloro-2,3-dimethylquinoline (0.2783 g, 1.23 mmol) to give 6-bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.03 (1H, d, J=9.0 Hz), 7.71 (1H, dd, J=8.9, 2.3 Hz), 7.65 (1H, d, J=2.2 Hz), 7.22 (1H, d, J=7.8 Hz), 6.83 (1H, dd, J=7.8, 1.5 Hz), 5.94 (1H, d, J=1.5 Hz), 4.04 (1H, d, J=9.8 Hz), 3.80-3.93 (3H, m), 3.39-3.54 (2H, m), 2.68 (3H, s), 2.22 (3H, s), 1.94-2.06 (2H, m), 1.85 (1H, d, J=13.4 Hz), 1.73 (1H, dd, J=13.4, 1.5 Hz); Mass Spectrum (ESI) m/e=457.1 [M+1 (79Br)] and 459.1 [M+1 (81Br)].
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N:12]3[C:16](=[O:17])[CH:15]=[CH:14][C:13]3=[O:18])[CH:10]=[CH:11][C:5]=2[N:4]=1.NC1C=CC2N=C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)N(C(OC(C)(C)C)=O)C=2C=1.[CH2:51]([CH:63]1CC(=O)O[C:64]1=O)[CH:52]=[CH:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]CC>>[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N:12]3[C:13](=[O:18])[CH2:14][CH:15]([CH2:64]/[CH:63]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:16]3=[O:17])[CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: Nc1nc2ccc(N3C(=O)C=CC3=O)cc2[nH]1
Reactant: CCCCCCCCCC=CCC1CC(=O)OC1=O
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Product: CCCCCCCCC/C=C\CC1CC(=O)N(c2ccc3nc(N)[nH]c3c2)C1=O
Yield: 91 %

Procedure:
Following the same procedure to synthesize 1-(2-amino-1H-benzo[d]imidazol-6-yl)-1H-pyrrole-2,5-dione hydrochloride, tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.161 g, 0.359 mmol) was reacted with (2-dodecen-1-yl)succinic anhydride (0.096 g, 0.359 mmol) to give the title product (0.142 g, 91% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.46 (d, 1H), 7.28 (s, 1H), 7.19 (d, 1H), δ 5.62 (m, 1H), δ 5.47 (m, 1H), δ 3.19 (t, 1H), δ 2.99 (t, 1H), δ 2.65 (m, 2H), δ 2.06 (m, 2H), δ 1.63 (d, 2H), δ 1.28 (m, 14H), δ 0.89 (t, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 179.8, 176.9, 151.5, 134.9, 133.7, 129.4, 128.3, 124.9, 122.8, 111.4, 110.6, 40.2, 36.1, 34.9, 33.7, 32.5, 31.9, 29.6, 29.4, 29.1, 27.2, 22.6, 13.4 ppm; HRMS (ESI) Calcd for C23H32N4O2 (M+) 396.2525. Found 396.2522.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7]1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:8]2[N:9]([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]([F:42])([F:41])[F:30])[CH:28]=[C:27]([F:29])[CH:26]=3)[N:7]=2)=[CH:20][CH:21]=1
Reactant: O=c1n(Cc2cc(F)cc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: O=c1n(Cc2cc(F)cc(-c3ccccc3C(F)(F)F)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 122, 59 mg (0.12 mmol) of the compound from Example 103A were reacted with 36 mg (0.18 mmol) of 2-(trifluoromethyl)phenylboronic acid. This gave 43 mg (64% of theory) of the target compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([S:32][CH2:33][CH:34]([CH3:40])[C:35]([O:37]CC)=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][C:25]([Cl:31])=[CH:26][CH:27]=3)[N:22]=2)[CH:14]=1)(=[O:3])[CH3:2].[OH-].[Na+].CC(O)=O>CO.C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([S:32][CH2:33][CH:34]([CH3:40])[C:35]([OH:37])=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][C:25]([Cl:31])=[CH:26][CH:27]=3)[N:22]=2)[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)CSC(CCc1ccccc1C(C)=O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1CCC(SCC(C)C(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the ester of Step 7 (3.844 g, 6.67 mmol) and 1.0N NaOH (13 mL) in 55 mL of MeOH:THF 3:2 was stirred at r.t. for 24 h. 25% Aq NH4OAc was then added and the mixture was acidified with AcOH. The title acid was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica with acetone:toluene:AcOH 5:95:1. Yield 3.491 g, 95%.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[C:6]([CH:16]([S:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:7][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][CH:10]=1.ClC1C=CC=C(C(OO)=[O:41])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOCC.CCCCCC>[Cl:4][C:5]1[C:6]([CH:16]([S:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[O:41])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:7][C:8]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])=[N:9][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)Nc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 82.2 %

Procedure:
To a methylene chloride (10 ml) solution of N-[5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanesulfonamide (331 mg, 0.696 mmol) was added 3-chloroperbenzoic acid (120 mg, 0.696 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 50 minutes. At the same temperature, 3-chloroperbenzoic acid (60 mg, 0.348 mmol) was added to the reaction mixture. After stirring at 0° C. for 10 minutes, a saturated aqueous solution of sodium thiosulfate was added to the reaction mixture. The resulting mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure. To the residue thus obtained was added ether and the solid thus precipitated was collected by filtration to give the title compound (281 mg, 0.572 mmol, 82%) as a white powder.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]1[O:13][CH:10]1[CH:11]=[CH2:12].Cl>CCOCC.C1COCC1>[C:1]1([CH2:12][CH:11]=[CH:10][CH2:9][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C=CC1CO1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC=CCc1ccccc1
Temperature: -10 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a -10° C. solution of phenylmagnesium bromide, 3M in ether (68 mL) was added a solution of cupric acetate (5.6 g) and butadiene monoxide (6.43 mL) in THF (200 mL) over 40 min while maintaining the reaction temperature below -5° C. The reaction was stirred at -10° C. for 1 h, room temperature for 16 h, refluxed for 15 min then cooled to room temperature. Aqueous HCl (10%, 100 mL) was added and the mixture extracted with ethyl acetate. The organic solution was washed with aqueous HCl (10%), NaHCO3 (saturated) and brine (saturated), dried (MgSO4) and concentrated to yield a blue liquid. The residue was chromatographed to yield the title compound (6.3 g, 30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[F:42])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:22]1([CH2:36][CH2:37][OH:38])[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]1=[O:35])[C:11]([NH:13][O:14]CC1C=CC=CC=1)=[O:12])=[O:6]>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[F:42])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:22]1([CH2:36][CH2:37][OH:38])[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]1=[O:35])[C:11]([NH:13][OH:14])=[O:12])=[O:6]
Reactant: O=C(NCCC(C(=O)NOCc1ccccc1)C1(CCO)CCN(CCc2ccccc2)C1=O)c1ccc(F)c(F)c1
Solvent: CCO
Product: O=C(NCCC(C(=O)NO)C1(CCO)CCN(CCc2ccccc2)C1=O)c1ccc(F)c(F)c1
Reaction time: 6 h

Procedure:
A solution of α-[2-[(3,4-difluorobenzoyl)amino]ethyl]-N-benzyloxy-3-(2-hydroxyethyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (117 mg, 0.202 mmol) is dissolved in EtOH (3 mL) and purged with N2. Pearlman's catalyst (10 mg) is added and the atmosphere is replaced with H2. After 6 hours, the mixture is filtered through celite, washing the residual solids with MeOH, EtOH, and CH2Cl2. The filtrate is concentrated and resubjected to the same procedure. The recovered material (99 mg) is purified by silica gel chromatography (8 g SG; 5, 10% MeOH/CHCl3) to give 45 mg of a white, amorphous solid. The solid is triturated with Et2O/hexane, filtered, and dried. This provides 39 mg (40%) of the title compound as a white, powdery solid (mp 135°-137° C.):
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[I:15]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1.CCOCC.O>[F:6][C:7]1[C:8]([I:15])=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(F)c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(F)c1I
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 75.9 %

Procedure:
n-Butyllithium (1.6 M in hexanes, 26 mL, 42 mmol) was added dropwise to a stirred, cooled (-78° C.) solution of 3-fluoroanisole (5.0 g, 40 mmol) in THF (150 mL) and the mixture was stirred at -78° C. for 2.5 h. Iodine (11.1 g, 43 mmol) in THF (50 mL) was added dropwise and the mixture was allowed to warm to room temperature. Water (200 mL), saturated aqueous sodium thiosulfate (100 mL) and ether (300 mL) were added and the layers were separated. The aqueous layer was extracted with ether (200 mL), the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (99:1) to give the title compound as a pale yellow oil (7.65 g, 77%). 1H NMR (360 MHz, CDCl3) δ 7.27 (1H, dt, Jd 6.6 Hz, Jt 8.2 Hz), 6.71 (1H, t, J 8.2 Hz), 6.62 (1H, d, J 8.2 Hz), and 3.90 (3H, s).