Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[ClH:35].C(OCC)(=O)C>C(O)(=O)C>[ClH:35].[NH2:21][CH2:20][CH2:19][NH:18][C:16](=[O:17])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:6][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NCCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 2-(((4-([1,1′-biphenyl]-4-ylmethoxy)phenyl)acetyl)amino)ethylcarbamate (1.5 g) in acetic acid (100 ml) was added 4N hydrochloric acid/ethyl acetate (4 ml) at room temperature. After stirring at room temperature for 2 hr, the precipitate was collected by filtration, which was washed with ethyl ether and dried to obtain the titled compound (0.9 g).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22](=[O:23])[CH2:21][CH:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1>ClCCl>[O:23]=[C:22]1[N:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH:13]=2)[CH2:19][CH:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:21]1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)C1CC(=O)N(c2cccc(N)c2)C1
Solvent: ClCCl
Product: COC(=O)C1CC(=O)N(c2cccc(NC(=O)NCc3ccccc3)c2)C1
Temperature: 23 °C
Reaction time: 27 h

Procedure:
Benzyl isocyanate (2.3 mL, 18.6 mmol, 1.2 equiv) was added to a solution of methyl 1-(3-aminophenyl)-5-oxopyrrolidine-3-carboxylate (3.6169 g, 15.4 mmol, 1 equiv) in dichloromethane (77 mL). The resulting solution was stirred at 23° C. for 27 hr, during which time a white precipitate formed. The reaction was filtered, and the solid was collected to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 7.76 (t, 1H, J=1.8 Hz), 7.13-7.36 (m, 8H), 6.59 (t, 1H, J=5.9 Hz), 4.30 (d, 2H, J=5.9 Hz), 4.03 (dd, 1H, J=9.7 Hz, 8.7 Hz), 3.94 (dd, 1H, J=9.5 Hz, 6.1 Hz), 3.68 (s, 3H), 3.41-3.50 (m, 1H), 2.80 (dd, 1H, J=17.0 Hz, 9.5 Hz), 2.71 (dd, 1H, J=17.0 Hz, 7.0 Hz). MS: (+) 368.0 (M+H), 385.5, 390.0, 735.5; (−) 366.0 (M−H), 426.0, 733.5, 793.5.
Reaction SMILES: O[CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:13])[CH2:12][C:6]2=[N:5][N:4]=1.CS([O-])(=O)=O.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>CS(C)=O.C(Cl)Cl>[CH2:30]([N:32]([CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:13])[CH2:12][C:6]2=[N:5][N:4]=1)[CH2:33][CH3:34])[CH3:31]
Reactant: O=C1Cc2nnc(CO)n2-c2ccc(Cl)cc2N1c1ccccc1
Reactant: CCNCC
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCN(CC)Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2
Reaction time: 2 h

Procedure:
3.35 g of 1-(Hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one, methanesulfonate in 15 ml dimethylsulfoxide at 0° is added dropwise with stirring to 3 ml of diethylamine in 10 ml dimethylsulfoxide. The reaction is stirred at 20° for 2 hours, diluted with methylene chloride, washed with water and then saturated aqueous sodium chloride. After drying, the solvent is evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([S:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22])([CH3:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:26][C:27]([F:41])([F:40])[C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[CH:36]=[CH:37]/[CH:38]=O)=[CH:30][CH:29]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([CH3:18])([S:19][C@@H:20]1[CH2:23][O:24][C@@H:38](/[CH:37]=[CH:36]/[CH:35]=[CH:34]/[C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:40])[F:41])=[CH:33][CH:32]=2)[O:22][CH2:21]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(SC(CO)CO)C(O)(Cn1cncn1)c1ccc(F)cc1F
Product: CC(C)(S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)OC1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Reaction was carried out in the same manner as in Example 4 using (RS)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol and (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal as described in Reference example 25 to obtain the title compound, a major product as a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20](I)[CH:19]=[CH:18][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[Si:23]([C:27]#[CH:28])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C=O)C.[Cu]I.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>[F:1][C:2]1[CH:21]=[C:20]([C:28]#[C:27][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=[CH:18][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(NCCO)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCO)c(F)c1
Yield: 72 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with TMS-acetylene in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-{2-fluoro-4-[(trimethylsilyl)ethynyl]anilino}-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as an off-white solid (72%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 11.45 (br s, 1H), 10.45 (s, 1H), 8.50 (t, J=5.4 Hz, 1H), 7.96 (s, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.42 (dd, J=11.5, 1.8 Hz, 1H), 7.30 (dd, J=8.3, 1.4 Hz, 1H), 5.65 (s, 1H), 4.71 (t, J=5.7 Hz, 1H), 3.49 (q, J=5.9 Hz, 2H), 3.29-3.24 (m, 2H), 0.24 (s, 9H). HRMS (FAB+) calcd C19H23FN3O3Si (MH+) 388.1493, found 388.1488.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:36].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:23]([CH:24]5[CH2:25][CH2:26][N:27]([C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])[CH2:28][CH2:29]5)=[O:36])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)CO)CC3)ccc1OCC2
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)C3CCN(C(C)(C)CO)CC3)ccc1OCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropan-1-ol from Example 1 (229 mg, 0.474 mmol) in DCM (10 mL) was added TFA (110 μL, 1.42 mmol) followed by a solution of m-CPBA (82 mg, 0.474 mmol) in DCM (2 mL). The resulting mixture was stirred for 1 h at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 10-35% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3 in MeOH affording 186 as a white solid (177 mg, 75%). LCMS: RT 2.45 min [M+H]+ 499.2. 1H NMR (DMSO, 400 MHz): δ 8.59 (1H, d, J=2.26 Hz), 7.97 (1H, s), 7.93 (1H, s), 7.53 (1H, dd, J=8.53, 2.28 Hz), 7.25 (1H, d, J=8.53 Hz), 5.80-5.67 (1H, m), 4.61-4.43 (4H, m), 4.22-4.16 (1H, m), 3.21 (2H, d, J=4.59 Hz), 3.06-2.96 (2H, m), 2.73-2.63 (1H, m), 2.17-2.05 (2H, m), 1.77 (1H, bd, J=12.25 Hz), 1.59 (1H, bd, J=12.59 Hz), 1.52-1.34 (8H, m), 0.88 (6H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:12][C:10]2[S:11][C:7]3[C:6]([O:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(Oc2ccccc2)c2sc(N)nc12
Product: COc1ccc(Oc2ccccc2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
Using 4-methoxy-7-phenoxy-benzothiazol-2-ylamine and 4-fluoro-benzoyl chloride the title compound was obtained crude, which was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2/EtOAc (1:1), to afford the pure title compound as a white solid (75% yield), MS: m/e=394.1 (M+).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]([CH3:24])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:5].Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1>>[CH3:5][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)[C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][C:8]=1[CH3:23])([CH3:24])[C:3]([OH:2])=[O:25]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCC2CNC(=O)N2C)cc1C
Product: Cc1cc(CCCC2CN(Cc3ccc4ccccc4c3)C(=O)N2C)ccc1OC(C)(C)C(=O)O

Procedure:
The titled compound was prepared using 2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid methyl Ester (0.100 g, 0.287 mmole) and 2-Bromomethyl-naphthalene (0.095 g, 0.431 mmole) to produce an oil (0.080 g, 59%). Mass [EI+] 476 (M+H)+, [EI−] 474 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:20]>CO>[NH2:20][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)(O)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: N
Solvent: CO
Product: CC(C)(O)Cn1cnc2c(N)nc3ccccc3c21

Procedure:
A mixture of 1.1 g (0.004 mole) of 4-chloro-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline and 30 ml of 15 to 20% ammonia in methanol was heated at 150° to 160° C. for five hours in a bomb reactor. The mixture was filtered and the solid washed sequentially with methanol, ethyl acetate, water, and methanol then dried. Recrystallization from a mixture of ethyl acetate and methanol gave white solid 4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline, m.p. 270°-272° C., Analysis: Calculated for C14H16N4O: % C, 65.6; % H, 6.3; % N, 21.9; Found: % C, 65.6; %H, 6.3; % N, 21.9.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([CH:17]=[CH:16][CH:15]=[C:13]([OH:14])[CH:12]=1)[OH:11]>O>[CH2:1]([C:15]1[CH:16]=[CH:17][C:10]([OH:11])=[CH:12][C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: Oc1cccc(O)c1
Solvent: O
Product: CCCCCCCCc1ccc(O)cc1O

Procedure:
4-n-octyl resorcinol is prepared by heating 1-octanol with resorcinol in the presence of 20 wt % alumina. The 1-octanol is added at such a rate that the temperature is maintained at 275° C, with continuous removal of the water formed.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:19]2[NH:20][CH:21]=[N:22][C:18]=2[CH:17]=[C:16]([Cl:23])[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[Cl:13][C:14]1[C:19]2[N:20]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=3)[CH:21]=[N:22][C:18]=2[CH:17]=[C:16]([Cl:23])[N:15]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Clc1cc2nc[nH]c2c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc(Cn2cnc3cc(Cl)nc(Cl)c32)cc1
Reaction time: 2 h

Procedure:
1-(Bromomethyl)-4-(trifluoromethyl)benzene (6.36 g, 26.6 mmol) was added to a stirred solution of 4,6-dichloro-3H-imidazo[4,5-c]pyridine (5.0 g, 26.6 mmol) and cesium carbonate (10.40 g, 31.9 mmol) in DMA (30.0 ml) at room temperature and was stirred for 2 h. Water was added, and the solids were filtered and dried overnight. Crude 1H NMR showed ˜4:1 ratio of undesired 4,6-dichloro-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-c]pyridine:desired 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine. The crude residue was purified by silica gel chromatography (EtOAc/DCM, 0% to 20%) to afford the desired 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine (fraction 1) and the undesired 4,6-dichloro-1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-c]pyridine (fraction 2). 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine: MS ESI calc'd for C14H8Cl2F3N3 [M+H]+ 346. found 346.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[N:27]([CH2:28][C:29](=[O:37])[NH:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:26]4[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:25]=4[N:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22][C:23]3[N:27]([CH2:28][C:29](=[O:37])[NH:30][CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)[C:26]4[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:25]=4[N:24]=3)[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3nc4cc(C#N)ccc4n3CC(=O)NC3CCCCC3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1nc2cc(C#N)ccc2n1CC(=O)NC1CCCCC1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[4-(1-tert-butoxycarbonylpiperidin-4-yloxy)-phenylaminomethyl]-1-(cyclohexylcarbamoylmethyl)-5-cyanobenzimidazole (247 mg) in dimethylformamide (2.5 ml) were added potassium carbonate (175 mg) and ethyl bromoacetate (0.07 ml), and the mire was stirred at room temperature for 24 hours. Thereto were added potassium carbonate (175 mg) and ethyl bromoacetate (0.07 ml), and the mixture was stirred at room temperature for 24 hours. Further, ethyl bromoacetate (0.07 ml) was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (124 mg).
Reaction SMILES: COP([CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)(=O)OC.[H-].[Na+].[N:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1>C1COCC1>[N+:21]([C:17]1[CH:16]=[C:15]([C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:32][C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: COP(=O)(OC)C(OC1CCCCO1)c1cccc([N+](=O)[O-])c1
Reactant: O=Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(C(=Cc2ccncc2)OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110 %

Procedure:
[(3-Nitro-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-phosphonic acid dimethyl ester (40.7 g, 0.105 mol) was dissolved in dry THF (1 L) under nitrogen. Sodium hydride (60% suspension in mineral oil)(6.3 g, 0.158 mol, 1.5 eq) was added and the mixture was stirred for 10 minutes at room temperature. Neat 4-picolinaldehyde (10 mL, 0.105 mol, 1 eq) was then added dropwise and the mixture was heated to 60° C. and stirred at this temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure to ⅓ of the original volume and then diluted with water (500 mL). pH was adjusted to 7-8 by adding a saturated solution of NaHCO3 and the mixture was extracted with ethyl acetate (4×300 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. An oil (37.7 g) was obtained, which was used without further purification in the following step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[CH:13]([O-])=[O:14].[Na+]>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>[CH:13]([C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1)=[O:14]
Reactant: CC(C#N)Cc1cccc(Br)c1
Reactant: O=C[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: CC(C#N)Cc1cccc(C=O)c1
Reaction time: 0.5 h

Procedure:
A 3-neck flask equipped with a condenser and 2 septa was flushed with N2, then the flask was charged with 0.6 g (2.7 mmol) 3-(3-bromophenyl)-2-methylpropionitrile (9-2), 0.275 g (4 mmol) sodium formate, 0.155 g (0.13 mmol) tetrakis(triphenylphosphine)Palladium and flushed with CO from a balloon for 5 min. The solids were suspended in 10 mL DMF and CO continued to bubble into the liquid. The flask was heated in an oil bath at 100′ for 20 min then 110′ while stirring. The color changed from yellow to a deep orange color after 1.5 h, and HPLC/MS analysis showed no starting material and one major product. The reaction was cooled and quenched with brine. The product was extracted into EtOAc, dried over Na2SO4, filtered and concentrated. The product was dissolved in 1 mL CH2Cl2 and purified on an Isco automated system affixed with a Biotage Flash 25(M) cartridge eluted with 0-50% EtOAc in hexane at 25 mL/min over 15 min and hold for 30 min. The product eluted last. MS 174.1 NB#212867-104
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=O)[CH2:16]2)=[O:10])=[C:4]([F:28])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:35]1(C(Cl)=O)[CH2:37][CH2:36]1>O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:35]4[CH2:37][CH2:36]4)=[O:22])[CH2:16]3)=[N:12][NH:11][C:9]2=[O:10])=[C:4]([F:28])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)NNC(=O)Nc2ccc(Br)cc2F)C1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,1-dimethylethyl (3S)-3-[2-(2-{[(4-bromo-2-fluorophenyl)amino]carbonyl}hydrazino)-2-oxoethyl]-1-pyrrolidinecarboxylate (3.59 mmol) in water (150 mL) was treated with potassium carbonate (17.96 mmol). The reaction was heated to reflux and was stirred overnight. A white solid had formed on the top of the aqueous solution. The reaction was allowed to cool to room temperature. Analysis by LCMS indicated complete consumption of the starting material and the mixture was concentrated to dryness in vacuo. The crude material was dissolved in dichloromethane (100 mL) and was treated with a solution of cyclopropanecarbonyl chloride (3.59 mmol) in dichloromethane (5 mL). After 30 min of stirring, LCMS analysis indicated that the intermediate amine had converted to a mixture of the desired product and a product that corresponded to bis-acylated product. The reaction solution was concentrated to dryness in vacuo and was dissolved in methanol (50 mL). The suspension was stirred at room temperature for 30 min. Analysis by LCMS indicated that the majority of the material now existed as a mixture of the desired product and the intermediate amine. Additional portions of cyclopropanecarbonyl chloride (3.59 mmol) were added to the reaction mixture twice (30 min apart). Analysis by LCMS indicated the complete conversion of the intermediate amine. The reaction mixture was diluted with water (100 mL) and acidified to pH˜4 using 1N aq HCl. The methanol was removed in vacuo, and the resulting aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aq sodium bicarbonate, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to dryness. The resulting solid was purified by flash chromatography (0-10% methanol/dichloromethane) to give the title compound as a white amorphous solid (850 mg, 58% yield). MS(ES)+ m/e 409/411 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=[C:6]2[C:5]1=[O:17])([CH3:3])[CH3:2]>C1COCC1.CN(C=O)C.[Pd]>[CH:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=[C:6]2[C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)c2ccc(N)cc2C1=O
Yield: 99.1 %

Procedure:
N-Isopropyl-4-nitrophthalimide (10.0 g, 43.0 mmol) was dissolved in a mixture of THF (200 mL) and DMF (100 mL). 10% Palladium catalyst on carbon (1,0 g, 50% wet weight) was added and the mixture was hydrogenated in a low-pressure apparatus (1 atm.) overnight. The catalyst was then removed by filtering the mixture through a short pad of celite. The filtrate was evaporated to dryness to afford a quantitative yield (8.70 g) of pure N-isopropyl-4-aminophthalimide.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]=2[OH:25])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]OS(OC)(=O)=O.O>CN(C)C=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:11]1[N:12]([CH3:13])[C:8]([C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([O:25][CH3:30])[C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:19]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(O)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1c(C(=O)OCC)c(OC)c(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
Ethyl 5-(p-chlorobenzoyl)-3-ethoxycarbonyl-4-hydroxy-1-methylpyrrole-2-acetate (537 mg, 1.37 mmole) is added to a suspension of 70 mg of 50% sodium hydride (1.46 mmole prewashed with hexanes) in 5 ml of dry dimethylformamide (DMF) under nitrogen. After gas ceased to evolve, 150 μl of dimethylsulfate (1.57 mmole) is added all at once. The resulting yellow-orange solution is stirred for an additional 10 minutes before it is poured into 100 ml of water to precipitate the crude product. The mixture is stirred well followed by filtration. The collected residue is washed with water and dried in vacuo to afford 505 mg of crude ethyl-5-(p-chlorobenzoyl)-3-ethoxycarbonyl-4-methoxy-1-methylpyrrole-2-acetate.