Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH:22]=[CH:21][N:20]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26](Cl)=[O:27])[C:18]=3[N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:32][NH2:33]>ClCCl>[CH3:32][NH:33][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N:20]2[C:18]3[N:19]=[C:14]([NH:13][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[N:15]=[CH:16][C:17]=3[CH:22]=[CH:21]2)[CH:24]=1
Reactant: CN
Reactant: COc1cc(Nc2ncc3ccn(-c4cccc(C(=O)Cl)c4)c3n2)cc(OC)c1OC
Solvent: ClCCl
Product: CNC(=O)c1cccc(-n2ccc3cnc(Nc4cc(OC)c(OC)c(OC)c4)nc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[2-(3,4,5-trimethoxy-phenylamino)-pyrrolo[2,3-d]pyrimidin-7-yl]-benzoyl chloride in dichloromethane is added 5 equivalents of methylamine solution (2.0 M in tetrahydrofuran). After stirring at room temperature for 1 hour, the reaction is quenched with water. Removal of the solvent followed by purification with reverse phase HPLC gives N-methyl-3-[2-(3,4,5-trimethoxy-phenylamino)-pyrrolo[2,3-d]pyrimidin-7-yl]-benzamide as a white solid.
Reaction SMILES: [BH3-]C#N.[Na+].[NH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[C:10]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[O:32][CH:33]([F:35])[F:34])=[N:9]1.[OH:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O>CO>[CH:33]([OH:32])=[O:36].[Cl:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH:33]([F:34])[F:35])=[C:25]([C:10]2[C:11]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:12][N:8]([CH2:7][CH2:6][NH:5][CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[C:37]([OH:36])[CH:38]=3)[N:9]=2)[CH:30]=1
Reactant: O=Cc1cccc(O)c1
Reactant: NCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1cn(CCNCc2cccc(O)c2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Product: O=CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaBH3CN (28 mg, 0.45 mmol) was added to a solution of N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.22 mmol) in MeOH (10 mL) and 3-hydroxybenzaldehyde (55 mg, 0.45 mmol). The resulting solution was stirred for at room temperature overnight. The reaction was then quenched by the addition of 0.2 mL of water. The resulting mixture was concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 2.5% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (32.0% up to 36.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 32.0% in 2 min); Detector, UV 254/220 nm. This resulted in 25.7 mg (19%) of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(3-hydroxyphenyl)-methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide formate as a white solid. LCMS (Method 20) [M+H]+=554.2, RT=1.58 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.37 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.68-8.67 (m, 2H), 8.37 (s, 1H), 7.61 (dd, 1H, J=2.4, 8.8 Hz), 7.60 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.05 (t, 1H, J=73.2 Hz), 7.10-7.06 (m, 1H), 6.74-6.72 (m, 2H), 6.60 (d, 1H, J=7.2 Hz), 4.25 (t, 2H, J=6.0 Hz), 3.66 (s, 2H), 2.94 (t, 2H, J=6.0 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH2:14][CH2:15][O:16][CH3:17])[C:6]=2[N:18]=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[O:29][CH3:30].C(O)C>Cl.O>[CH3:30][O:29][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:20]=1[NH:19][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH2:14][CH2:15][O:16][CH3:17])[C:6]=2[N:18]=1)[C:24]([OH:26])=[O:25]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: COCCN1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: COCCN1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)O)cc3OC)nc21
Yield: 68.5 %

Procedure:
A mixture of 0.108 g (0.0004 mole) of 2-chloro-9-(2-methoxy-ethyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-40), 0.08 g (0.00048 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.11 g of 3-methoxy-4-[9-(2-methoxy-ethyl)-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-40a) as an off-white solid.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12](N(CC)CC)C.CI>C(Cl)Cl>[CH3:12][S:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1ccc2nc(S)oc2c1
Reactant: CCN(CC)CC
Solvent: CI
Solvent: ClCCl
Product: CSc1nc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the 2-mercaptobenzo[d]oxazol-6-ol (1.55 g, 9.28 mmol, 1.0 eq) in 20 mL of methylene chloride was added triethylamine (1.87 g, 18.56 mmol, 2.0 eq) and methyl iodide (1.77 g, 13.92 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at rt for 3 hours. The mixture was diluted with 100 mL of methylene chloride. The resulting mixture was washed with water (10 mL), brine (10 mL), then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was purified by silica gel column eluted with ethyl acetate and hexane to give the titled compound. MH+=182.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:13](OC)[C:14](=[O:17])NC)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Mg]Br.CCOCC>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14](=[O:17])[CH3:20])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)C(OC)N(CC(=O)O)C(=O)OC(C)(C)C
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)CN(CC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of N-[(tert-butoxy)carbonyl]-N-[(methoxy)-(methyl)carbamoylmethyl]glycine (1.0 g, 3.6 mmol; Helvetica Chimica Acta 2000, 83 1825), in anhydrous THF (30 mL) under an atmosphere of nitrogen, a solution of methyl magnesium bromide in ether (2.6 mL, 3M, 7.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, cooled back to 0° C., quenched with aqueous HCl, and diluted with ether. The organic extract was washed with brine (pH adjusted to ˜4-5 with addition of aqueous sodium hydroxide), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].N[C@@H:14]([C@H](C)CC)C(O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:7]([CH3:9])[CH2:8][CH3:14])[C:10]([OH:12])=[O:11])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC[C@@H](C)[C@H](N)C(=O)O
Product: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)O

Procedure:
(2S,3R)-2-(methoxycarbonylamino)-3-methylpentanoic acid was synthesized similar to N-methoxycarbonyl-L-Valine, using (2S,3R)-2-amino-3-methylpentanoic acid instead of L-Valine.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:1]([C@H:5]1[CH2:9][CH2:8][CH:7]([O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCC[C@H]1CCC(OS(=O)(=O)c2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a solution cooled with ice, of 94 mg of (1RS,3S)-3-butylcyclopentan-1-ol (prepared in Reference Example 11) in 2 ml of pyridine, 260 mg of p-toluenesulphonyl chloride was added, and the mixture was stirred for 30 min. at the same temperature and for 5 hrs at room temperature. The reaction solution was poured into ice-water. The mixture was extracted with a mixture of pentane and diethyl ether (1:1). The extract was washed with water, dried over magnesium sulphate, and concentrated under ambient pressure at 50° C. to give 190 mg of the title compound having the following physical characteristic.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:24].[CH:25]([C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=1)[O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:12]1([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:9]2[CH:8]=[CH:7][C:6](=[O:24])[N:5]([CH2:4][CH2:3][NH:2][CH2:25][C:27]3[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=3)[O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)COc1cccc(C=O)c1
Reactant: NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(CNCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
To a solution of 1-(2-aminoethyl)-5-(diphenylmethyl)pyridin-2(1H)-one hydrochloride (350 mg), ethyl (3-formylphenoxy)acetate (214 mg) and TEA (114 mg) in DCM (10 mL) was added sodium triacetoxyborohydride (326 mg) on ice bath temperature and the resulting mixture was stirred for 4 hours at ambient temperature. And then the reaction mixture was partitioned between DCM and saturated NaHCO3 aqueous solution The organic layer was washed with brine, dried over sodium sulfate and filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=99:1-90:10) to give ethyl {3-[({2-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]ethyl}amino)methyl]phenoxy}acetate (321 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[N:4]([CH3:8])[N:5]=[CH:6][CH:7]=1.[Cl:10][C:11]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl.FC(F)(F)C1C=CC=C[C:29]=1[O:30]C1CCNCC1>>[CH3:8][N:4]1[C:3](=[O:9])[C:2]([NH:1][C:29]([N:17]2[CH2:18][CH2:19][CH:14]([O:13][C:12]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:11]=3[Cl:10])[CH2:15][CH2:16]2)=[O:30])=[CH:7][CH:6]=[N:5]1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: Cc1ccc(Cl)c(OC2CCNCC2)c1
Reactant: Cn1nccc(N)c1=O
Agent: Cl
Product: Cc1ccc(Cl)c(OC2CCN(C(=O)Nc3ccnn(C)c3=O)CC2)c1
Yield: 28 %

Procedure:
Compound 56 is prepared from intermediate 4c and from 4-(2-chloro-5-methyl-phenoxy)-piperidine (obtained following the method described for intermediate 1a) applying synthesis method 7 (yield: 28%).
Reaction SMILES: [F:1][C:2]([F:22])([C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])C(O)=O.FF.[I:25]I>>[F:1][C:2]([I:25])([F:22])[C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: II
Agent: FF
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Yield: 13 %

Procedure:
Perfluoroheptanoic acid 9.5 g (0.026 mole), iodine 4.0 g (0.016 mole) and Freon 113 (500 ml) were mixed and treated with approximately 33% fluorine diluted with nitrogen until the color due to iodine disappeared. The mixture was washed with water containing a small amount of sodium thiosulfite and dried over magnesium sulfate. 1.5 g (13% yield) of perfluorohexyl iodide was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[CH:7]([OH:9])[CH3:8].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(O)c1sc(-c2cccnc2)nc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCCl
Product: CC(=O)c1sc(-c2cccnc2)nc1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanol (120 mg, 0.5 mmol) was dissolved in 1,2-dichloroethane (10 ml). Pyridinium chlorochromate (216 mg, 1 mmol) was added to the reaction mixture. The reaction mixture was stirred at 70° C. for 3 hours, cooled to ambient temperature, poured onto a silica gel plug and eluted with dichloromethane. The eluent was evaporated under reduced pressure, and the residue dried to dryness to get 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanone in form of a white solid. 1H NMR (300 Mz, DMSO-d6): δ: 9.17 (s, 1H), 8.75 (d, 1H, J=4.8 Hz), 8.37 (d, 1H, J=8.1 Hz), 7.58 (m, 1H), 2.66 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH2:16])=[O:10])=[CH:4][CH:3]=1.ClC1C=CC(N)=CC=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][N:32]=2)[C:27]([CH:34]=O)=[CH:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][CH2:34][C:27]2[C:28]3[C:33](=[N:32][CH:31]=[CH:30][CH:29]=3)[NH:25][CH:26]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccsc1C(=O)Nc1ccc(Cl)cc1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)c1sccc1NCc1c[nH]c2ncccc12

Procedure:
Prepared according to the procedure described in EXAMPLE 5 using N-(4-chlorophenyl) 3-aminothiophene-2-carboxamide (prepared as described in EXAMPLE 1, part 1, using 4-chloroaniline instead of 4-trifluoromethoxyaniline) and 7-azaindole-3-carboxaldehyde (EXAMPLE 8, part 1) instead of 2-(N-methylcarbamoyl)pyridine-4-carboxaldehyde. MS (ES+): 383, 385 [MH+]
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.CCCCCCC=CCCC.[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:11]1
Reactant: CC1=CC(=O)C(C)(c2ccccc2)O1
Reactant: O=Cc1ccccn1
Agent: CCCC=CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CC1(c2ccccc2)OC(C=Cc2ccccn2)=CC1=O
Temperature: 80 °C
Yield: 40 %

Procedure:
To a solution of 2-pyridinecarboxaldehyde (1.2 mL, 1.2 mM) and 2,5-dimethyl-2-phenyl-3(2H)-furanone (1.5 g, 8 mM) in ethanol (15 mL), was added 1,8-diazebicyclo[4.5.0]undec-7ene (DBU, 0.2 mL, 1.3 mM). The reaction solution was heated at 80° C. for 5 hours. After the reaction solution cooled to room temperature, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with dichloromethane (3×100 mL). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. Purification by trituration with 10% diethyl ether in hexane gave a pale pink solid (887 mg, 40% yield), m.p. 74.5°-76° C.
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:39]([F:40])=[CH:38][C:10]3[N:11](CC4C=CC(C5C=CC=CC=5)=CC=4)[C:12]([O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:41])=[CH:3][CH:2]=1.C1CC=CCC=1>[OH-].[OH-].[Pd+2].CCOC(C)=O.CCO>[C:1]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:39]([F:40])=[CH:38][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:41])=[CH:5][CH:6]=1
Reactant: COC(=O)C1CCCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCC=CC1
Solvent: CCOC(C)=O
Product: COC(=O)C1CCCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)C1

Procedure:
A suspension of methyl 3-{[5-(biphenyl-4-yl)-1-(biphenyl-4-ylmethyl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (0.080 g, 0.127 mmol) and Pearlman's Catalyst (0.016 g, 0.023 mmol) in EtOAc (1.5 ml) and EtOH (0.75 ml) was treated with 1,4-cyclohexadiene (0.24 ml, 2.56 mmol). The resulting reaction mixture was microwaved at 120° C. for 90 minutes and then cooled. The cooled reaction mixture was filtered through a Celite™ pad and the filtrate was removed in vacuo. Purification of the resulting residue by reverse phase HPLC eluting with 50-100% MeCN/H2O afforded the title compound as a white solid. LC-MS: calculated for C27H24F2N2O3 462.18, observed m/e: 463.01.01 (M+H)+ (Rt 2.31/4 min).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][CH:16]=[N:17][N:8]2[C:7]1=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:19]N1C(=O)CCC1=O>C1COCC1>[Br:19][C:12]1[NH:11][C:10]2[C:9]3=[N:15][CH:16]=[N:17][N:8]3[C:7](=[O:18])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c(=O)n2ncnc2c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2ncnc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-pentyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (20 mg, 0.081 mmol) in THF (5 mL) was added N-bromosuccinimide (19 mg, 0.11 mol). The reaction mixture was stirred at room temperature for 1 hour and then quenched by phenol. After removing solvent, the residue was purified by preparative LCMS (method B) to yield the desired product. 1HNMR (400 MHz, CD3OD): δ 8.30 (s, 1H), 4.30 (t, J=7.4 Hz, 2H), 1.86 (m, 2H), 1.41 (m, 4H), 0.93 (t, J=7.0 Hz, 3H). LCMS calculated for C11H14BrN6O (M+H): 325.0. found: 325.0, 327.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12].[BH4-].[Na+].O>C1COCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([NH:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)S(=O)N=C(c1ccccc1)c1cc(Br)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)NC(c1ccccc1)c1cc(Br)ccc1N
Temperature: -50 °C
Reaction time: 8 h

Procedure:
2-Methyl-propane-2-sulfinic acid (2-amino-5-bromo-phenyl)-phenyl-methyleneamide (70 g, 184 mol) is dissolved in 98:2 THF/H2O (800 mL) and was cooled to −50° C. Then NaBH4 (17.5 g, 462 mol) is added and the mixture is stirred at room temperature overnight. Then H2O is added and concentrated and extracted with EtOAc. The organic layer is concentrated to give product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([Br:22])C(=O)C1>CN(C=O)C.ClCCl>[Br:22][C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[O:10][C:9](=[O:14])[C:8]=2[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(Br)ccc2[nH]c(=O)oc(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 135.1 %

Procedure:
A solution of Example 385A (10.5 g, 54.4 mmol) in DMF (100 mL) and dichloromethane (200 mL) was cooled to 0° C., treated portionwise with NBS (14.4 g, 80.9 mmol) over 40 minutes, stirred overnight at room temperature and filtered. The filtrate was concentrated to provide the desired product (˜20 g) which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=O)=[CH:12][CH:13]=1)=[O:6].[Cl-].[OH:30][NH3+:31].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[N:31][OH:30])=[CH:12][CH:13]=1)=[O:6]
Reactant: [NH3+]O
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3=O)nc1)c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(Nc1ccc(Oc2cccc3c2CCC3=NO)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
800 mg of 3,4-dichloro-N1-{6-[(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl}benzamide obtained in Example 1 and 670 mg of hydroxyammonium chloride (hydroxylamine hydrochloride) were suspended in 40 ml of ethanol and, after adding 5.4 ml of pyridine to the resulting suspension, the mixture was stirred at 60° C. After 30 minutes, the reaction solution was distilled off under reduced pressure. To the resulting residue, 60 ml of ethyl acetate was added and the solution was washed in turn with water and a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After ethyl acetate was distilled off, ether was added to the residue and the deposited crystal was isolated by filtration and then washed with ether to obtain the titled compound (430 mg, white powder).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].C(O[C:12](=O)[CH2:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[CH3:15])C>C1(C)C=CC=CC=1>[Cl:22][C:18]1[CH:17]=[C:16]([N:14]([CH2:13][C:12]2[NH:7][CH2:6][CH2:5][N:8]=2)[CH3:15])[CH:21]=[CH:20][CH:19]=1
Reactant: NCCN
Reactant: CCOC(=O)CN(C)c1cccc(Cl)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CN(CC1=NCCN1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 29.4 %

Procedure:
To dry toluene (4 ml) under an inert atmosphere at 0° C. was added a toluene solution of trimethylaluminium (2.13 ml, 4.26 mmol, 2 M solution). A solution of ethylenediamine (0.29 ml, 4.26 mmol) in toluene (1.5 ml) was then added dropwise and the reaction mixture was then allowed to warm to room temperature and stirred for 100 min at this temperature before being re-cooled to 0° C. To this mixture was added dropwise a solution of [(3-chloro-phenyl)-methyl-amino]-acetic acid ethyl ester (0.49 g, 2.13 mmol) in toluene (3 ml). The reaction mixture was then heated at reflux for 2.5 h and then cooled first to room temperature and finally to 0° C. The mixture was quenched by dropwise addition of methanol (1 ml) and when all gas evolution had ceased the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was triturated in ether to yield a white solid (0.14 g, 29%) which was collected by filtration; MS (ISP): 226.2, 224.1 ([M+H]+.).
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)(C)(=O)=O.[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][N:26]([CH2:5][CH2:6][C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: Cc1cccc(C#CCCS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(C#CCCN2CCC(O)(Cc3ccccc3)CC2)c1
Yield: 20.7 %

Procedure:
A mixture of 1-mesyl-4-(3-methylphenyl)but-3-yne (344 mg, 1.45 mmol), 4-benzyl-4-hydroxy-piperidine (332 mg, 1.73 mmol) and K2CO3 (598 mg, 4.34 mmol) in 15 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×20 ml). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a brown oil (100 mg, 20%): 1H NMR (CDCl3) 1.37 (s, 1 H), 1.55 (m, 2 H), 1.75 (m, 2 H), 2.30 (s, 3 H), 2.41 (m, 2 H), 2.60 (m, 3 H), 2.75 (m, 5 H), 7.11-7.31 (m, 9 H).