Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[CH:20]=[C:19]([Cl:28])[N:18]=1>C1COCC1.CCOC(C)=O>[Cl:28][C:19]1[N:18]=[C:17]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2
Reactant: Fc1ccc2cc(Cl)nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(Cl)cc3ccc(F)cc23)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 71.9 %

Procedure:
To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.56 g, 8.3 mmol) in THF (20 mL) was added NaH (0.33 g, 8.3 mmol) under nitrogen at 0° C. The mixture was warmed to RT over a 30 minute period and 1,3-dichloro-7-fluoroisoquinoline (0.9 g, 4.17 mmol) was added. The resulting mixture was stirred for 10 hours at RT. The mixture was subsequently diluted with EtOAc (100 mL), quenched with saturated aqueous NH4Cl (100 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=50:1-10:1 gradient) to give the title compound (1.1 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.00-7.98 (m, 1H), 7.82-7.80 (m, 2H), 7.62 (s, 1H), 5.67-5.63 (d, J=16 Hz, 1H), 3.69-3.66 (m, 1H), 3.53-3.487 (m, 3H), 2.30-2.22 (m, 2H), 1.41-1.39 (d, J=10.8 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[CH2:4][O:5][CH3:6].O.[S-2].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)C.O>[CH3:6][O:5][CH2:4][C:3]1[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=1[CH3:1])[NH2:11]
Reactant: COCc1cc([N+](=O)[O-])ccc1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: COCc1cc(N)ccc1C
Yield: 96.9 %

Procedure:
Methyl 2-methyl-5-nitrobenzyl ether (11.5 g) was dissolved in 125 ml of absolute ethanol. To this was added a solution of sodium sulfide monohydrate (48.3 g) and sodium bicarbonate (16.7 g) in 75 ml of water. The resulting mixture was refluxed until tlc indicated all the starting material was gone. The mixture was then concentrated in vacuo to an oily solid. Methylene chloride was added and the mixture filtered. The methylene chloride layer was separated and dried. After removal of the drying agent, the solvent was concentrated in vacuo to give 9.3 g of a mobile orange liquid,
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][CH3:12])[CH2:5][CH2:4]1)=O.[ClH:13].O1CCOCC1>CO>[ClH:13].[ClH:13].[CH3:12][O:11][CH2:10][CH2:9][N:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: COCCN1CCN(C=O)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COCCN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 57.2 g of 1-formyl-4-methoxyethylpiperazine in 100 mL of methanol was added dropwise 180 mL of 4N-hydrochloric acid/1,4-dioxane over 1.5 hours. The mixture was stirred at room temperature for 1 hour, and the resulting crystals were filtered, washed with isopropyl ether and dried in vacuo to give 68.8 g of the title compound.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[F:10][C:9]1[C:4]([CH2:3][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Fc1cccnc1CCl
Agent: BrCC1CCCCO1
Agent: Cl
Product: O=C1N(Cc2ncccc2F)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-3-fluoropyridine hydrochloride (Weidmann, K. et al., J. Med. Chem. (1992), (35):438) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (25%) as a colorless solid: mp 247-249° C. (dichloromethane/ether); 1H NMR (300 MHz, CDCl3) δ 8.35 (td, J=4.6, 1.34 Hz, 1H), 7.43-7.33 (m, 1H), 7.27-7.11 (m, 3H), 7.02-6.95 (m, 1H), 6.80-6.75 (m, 1H), 6.47 (s, 1H), 6.44 (s, 1H), 5.31 (dd, J=16.2, 1.5 Hz, 1H), 5.04 (dd, J=16.2, 1.4 Hz, 1H), 4.95 (d, J=8.9 Hz, 1H), 4.67 (d, J=8.9 Hz, 1H), 4.20-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.5, 159.6, 156.2, 155.2, 145.4, 145.3, 144.5, 142.9, 142.8, 142.2, 138.3, 132.6, 128.6, 124.3, 123.8, 123.3, 123.1, 121.3, 112.2, 109.0, 99.2, 80.2, 64.5, 63.9, 58.1, 40.7; MS (ES+) m/z 404.7 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.CN(C)C=O.[NH2:22][C:23]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)([CH3:27])[C:24]([OH:26])=[O:25]>CCOCC>[NH2:22][C:23]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][CH:14]=[C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[C:8](=[O:12])[NH:7][C:6]2=[O:13])=[CH:32][CH:33]=1)([CH3:27])[C:24]([OH:26])=[O:25]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CC(N)(C(=O)O)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(N)(C(=O)O)c1ccc(NC=C2C(=O)NC(=O)c3ccc(Br)cc32)cc1
Temperature: 110 °C
Yield: 33 %

Procedure:
A mixture of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (191 mg, 0.50 mmole), N,N-dimethylformamide (2 mL) and 2-Amino-2-(4-amino-phenyl)-propionic acid (90 mg, 0.50 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator. The reaction mixture is diluted with ether, filtered, washed with acetonitrile and dried to give a dull yellow solid 71 mg (33%), mp 250-253° C.; MS (ESI): m/z 428.2, 430.2 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH:14](=O)[CH2:15][CH:16]([CH3:18])[CH3:17].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: CC(C)CC=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
(1S,2R,3S,4R)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 0.5 g, 2 7 mmol) was dissolved in methanol (25 mL). Isovaleraldehyde (0.233 g, 2 7 mmol) was added followed by acetic acid (1 mL). The solution continued to stir at 25° C. for 10 min. Sodium cyanoborohydride (0.424 g, 6.75 mmol) was added and the mixture was stirred at 25° C. for 5 h. The mixture was poured into aqueous half-saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-(3-methyl-butylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.43 g, 1.7 mmol, 63%), as a light yellow oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C15H27NO2 253.2, found 254.1 [M+H+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:46])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([O:43][CH2:44][CH3:45])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:46])=[CH:17][C:18]=4[O:43][CH2:44][CH3:45])=[N:42][C:27]2=3)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CCOc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 155 %

Procedure:
A solution of 0.0749 g (0.0712 mmole) 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-221) in 3 mL of dichloromethane was stirred with 3 mL of trifluoroacetic acid for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of dichloromethane, washed with 15 mL of sodium carbonate solution, twice with 15 mL of brine and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 90:10-0:100) to give 0.060 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-N-piperidin-4-yl-benzamide (I-222) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:3]=1[CH2:20][C:21](OC)=[O:22].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl>C1COCC1>[OH:22][CH2:21][CH2:20][C:3]1/[C:4](=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)CC1=C(C)c2ccccc2/C1=C\c1ccc(SC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CSc1ccc(/C=C2/C(CCO)=C(C)c3ccccc32)cc1
Reaction time: 1 h

Procedure:
To a solution of the ester from Step 3 (270 mg, 0.83 mmol) in dry THF (5 mL) at 0° C. was added a solution of diisobutyl aluminum hydride (1M) in toluene (2.1 mL, 2.1 mmol, 3.5 eq.). After 1 hour, the reaction mixture was added dropwise to a solution of 1N aqueous HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and evaporated to dryness. The crude product was chromatographed on silica gel eluting with a 1:3 mixture of ethyl acetate-hexane to afford pure title compound as a yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[S:21][C:22]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[CH:23][C:24]=3[CH3:25])=[CH:14][CH:13]=2)[CH2:7][C:8]([O:10]C)=[O:9])=[N:2]1.[Li+].[OH-]>C1COCC1.CO>[O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[S:21][C:22]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)=[CH:23][C:24]=3[CH3:25])=[CH:16][CH:17]=2)[CH2:7][C:8]([OH:10])=[O:9])=[N:2]1
Reactant: COC(=O)C[C@@H](c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1)c1ccon1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc([C@H](CC(=O)O)c2ccon2)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of 62.9 (64 mg, 0.13 mmol) in 3:1 THF/MeOH (2.8 mL) was added 1N LiOH (0.7 mL). The mixture was stirred for 1 Hour at room temperature, quenched with 1N HCl (0.8 mL), and extracted with EtOAc. The combined organics were washed with water and brine, dried (Na2SO4), and concentrated to afford 62 (45 mg, 70%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 7.65 (d, 2H), 7.60 (d, 2H), 7.20 (d, 2H), 7.15 (s, 1H), 6.95 (d, 2H), 6.07 (d, 1H), 5.10 (s, 2H), 4.55 (t, 1H) 3.35 (dd, 1H), 2.98 (dd, 1H), 2.28 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=O)[CH2:9][C:8](=[O:13])[CH2:7]1.C([O-])(=O)C.[NH4+:18]>C(O)C>[NH2:18][C:10]1[CH2:11][CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH2:7][C:8](=[O:13])[CH:9]=1
Reactant: [NH4+]
Reactant: O=C1CC(=O)CC(c2ccco2)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2ccco2)C1
Yield: 76.3 %

Procedure:
A mixture of 5-(2-furyl)cyclohexane-1,3-dione (1.78 g) and ammonium acetate (2.3 g) in ethanol (35 ml) was refluxed for 15 hours, and the reaction solution was concentrated under reduced pressure. To the residue was added water (30 ml), and the resulting crystals were filtered. The crystals were washed with water and ethyl acetate, and dried to give 1-amino-5-(2-furyl)cyclohexen-3-one (1.35 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([O:13][CH2:14][O:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=2[O:40][CH3:41])[C:4]=1[O:42][CH2:43][O:44][CH3:45].Cl[C:47]([O:49][CH2:50][CH3:51])=[O:48]>>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([O:13][CH2:14][O:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=2[O:40][CH3:41])[C:4]=1[O:42][CH2:43][O:44][CH3:45]
Reactant: CCOC(=O)Cl
Reactant: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c(OC)c1OCOC
Product: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OCOC)c(OC)c(C(=O)OCC)c(OCOC)c2OC)c(OC)c1OCOC

Procedure:
By using procedures similar to those described in Example 99, except that 1 g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-6-butyl-3-{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]pentyl}benzene was reacted with 0.3 ml of ethyl chloroformate in place of oxygen gas, there was obtained 1.3 g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-6-butyl-3-{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(ethoxycarbonyl)phenyl]pentyl}benzene. Colorless oily substance.
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:9][C@H:8]([N:10]([C:15]([C:17]2[C:18]([NH:27][CH2:28][C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[N:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:21][CH:22]=2)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][N:6]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:5]1)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:23]([C:20]1[N:19]=[C:18]([NH:27][CH2:28][C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[C:17]([C:15]([N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C@H:8]2[CH2:9][C@@H:4]([C:2]#[N:1])[CH2:5][N:6]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7]2)=[O:16])=[CH:22][N:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 11 h
Yield: 88.6 %

Procedure:
tert-Butyl (3R*,5S*)-3-(aminocarbonyl)-5-[({2-tert-butyl-4-[(2-furylmethyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-1-carboxylate (469 mg) was dissolved in pyridine (5 ml), trifluoroacetic anhydride (0.25 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 11 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The solution was washed successively with 1 M hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (5:95-80:20) was concentrated under reduced pressure to give the object compound (402 mg).
Reaction SMILES: Br[C:2]1[C:7]2[N:8]=[C:9]([C@:11]3([CH3:26])[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:28]#[N:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.[Cl-].[Na+].O>[C:28]([C:2]1[C:7]2[N:8]=[C:9]([C@:11]3([CH3:26])[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:29]
Reactant: N#C[Cu]
Reactant: C[C@@]1(c2nc3c(Br)cccc3s2)CCCN1C(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@]1(c2nc3c(C#N)cccc3s2)CCCN1C(=O)OCc1ccccc1

Procedure:
A mixture of EXAMPLE 5D (100 mg) and copper(I) cyanide (35.3 mg) in N,N-dimethylformamide (2.5 mL) was heated in a microwave reactor at 205° C. for 30 minutes. This reaction was repeated twice, and after cooling, the combined three reaction mixtures were treated with 5% aqueous citric acid and brine and extracted with ethyl acetate. The aqueous layer was treated with 5% aqueous potassium sodium tartrate and ethyl acetate. The combined organic layers were washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated, and the residue purified by flash chromatography using 98:2 dichloromethane/ethyl acetate to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])([OH:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25])([OH:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)(c1cccc(Cl)c1)c1ccccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccccc1C(O)(CC)c1cccc(Cl)c1

Procedure:
A solution of 5.3 g. of 1-(3-chlorophenyl)-1-(2-hydroxyphenyl)-propan-1-ol and 3.8 g. of monobromoacetic acid ethyl ester in 60 ml. of dry acetone is boiled in the presence of 0.8 g. of potassium iodide and 6 g. of anhydrous potassium carbonate for 5 hours, with stirring. After cooling the reaction mixture solvent is distilled off under reduced pressure, to the residue water is added and it is extracted with benzene. The benzene phase is extracted with water and a 5% aqueous sodium hydroxide solution, washed to neutral with water and dried over anhydrous magnesium sulfate. Benzene is then distilled off in vacuo and the residue is crystallized from n-hexane. 5.6 g. of the named compound are obtained, melting at 83°-84° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[S:6][CH:7]=1.[I-:18].[Na+].O>CC(C)=O>[I:18][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[S:6][CH:7]=1
Reactant: [I-]
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)cs2)c1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)c1cccc(-c2nc(CI)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
To a solution (10 mL) of the compound (1.0 g, 3.6 mmol) obtained in Example 21a in acetone was added sodium iodide (1.6 g, 11 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (370 mg, 28%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]#[N:29]>CN(C=O)C>[C:28]([CH2:27][CH2:26][CH2:25][N:8]1[C:9](=[O:11])[CH:10]=[C:5]([NH:4][C:3]2[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:2]=2[F:1])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]1)#[N:29]
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Reactant: N#CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCCC#N)c(=O)cc1Nc1ccc(I)cc1F

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with NaH and 4-bromobutyronitrile in DMF under the same conditions as for example 22, step A to give a crude solid which was purified by column chromatography on silica gel (50% EtOAc/hexanes as eluant). Ethyl 1-(3-cyanopropyl)-4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was isolated as a white solid (67%), m.p. (EtOAc) 157-159° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.30 (s, 1H), 8.51 (s, 1H), 7.77 (dd, J=10.1, 1.9 Hz, 1H), 7.61 (br d, J=8.4 Hz, 1H), 7.30 (t, J=8.5 Hz, 1H), 5.46 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.96 (t, J=7.2 Hz, 2H), 2.53 (t, J=7.2 Hz, 2H), 1.93 (pentet, J=7.2 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H). Anal. Calcd for C18H17FIN3O3: C, 46.1; H, 3.7; N, 9.0. Found: C, 46.4; H, 3.6; N, 8.9.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[OH:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][NH:25]1>CO.C(Cl)Cl>[OH:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC1CCCN1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1[nH]c2ccc(CN3CCCC3CO)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.169 mmol) with 2-hydroxymethylpyrrolidine (46 mg, 0.45 mmol) as described in General Procedure X to afford Iw (42.0 mg, 65.6%) as a tan solid, tlc Rf=0.15 (10% MeOH/CH2Cl2-0.25% Et3N), m/z obs=382 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]3[C:18]4[NH:17][C:16](=[O:19])[NH:15][C:14]=4[CH:13]=[C:12]([C:20]4[C:21]([CH3:26])=[N:22][O:23][C:24]=4[CH3:25])[CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:32]>CO.C(Cl)Cl>[CH:1]1([C:4]2[C:9]([C:10]3[C:18]4[NH:17][C:16](=[O:19])[NH:15][C:14]=4[CH:13]=[C:12]([C:20]4[C:21]([CH3:26])=[N:22][O:23][C:24]=4[CH3:25])[CH:11]=3)=[CH:8][CH:7]=[CH:6][N+:5]=2[O-:32])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1noc(C)c1-c1cc(-c2cccnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Solvent: CO
Solvent: ClCCl
Product: Cc1noc(C)c1-c1cc(-c2ccc[n+]([O-])c2C2CC2)c2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (35 mg, 0.1 mmol) was dissolved in MeOH/DCM (1/1 mL). To the solution was added 3-Chloroperoxybenzoic acid (69.75 mg, 0.4 mol) and the mixture stirred at RT overnight. The organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 2-cyclopropyl-3-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)pyridine 1-oxide.