Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:26]=C)[CH:22]=2)[CH2:17]1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][N:6]=1)=[O:4].CC([OH:31])C.O.I([O-])(=O)(=O)=O.[Na+]>C(=O)([O-])[O-].[Na+].[Na+].[Os](=O)(=O)(=O)=O>[CH:26]([C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C@@H:16]([N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)=[CH:7][N:6]=1)=[O:4])[CH2:25][CH2:24]2)=[O:31]
Reactant: C=Cc1ccc2c(c1)CC[C@H](N(C)C(=O)c1ccc(OCC3CC3)cn1)C2
Reactant: CC(C)O
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(C(=O)c1ccc(OCC2CC2)cn1)[C@H]1CCc2cc(C=O)ccc2C1
Reaction time: 12 h

Procedure:
A mixture of N-methyl-N—((S)-6-vinyl-1,2,3,4-tetrahydronaphthalen-2-yl)-5-cyclopropylmethoxypyridine-2-carboxamide (1.40 g), 2-propanol (4 ml) and water (2 ml) was admixed with osmium(VIII) oxide (49 mg) and sodium metaperiodate (1.82 g), and the mixture was stirred for 12 hours. The reaction mixture was diluted with saturated sodium carbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The product was thus obtained with the molecular weight of 364.45 (C22H24N2O3); MS (ESI): 365 (M+H+).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([O:12]C)=[O:11])=[CH:6][C:5]=12.[OH-].[Na+].Cl>CO>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][C:5]=12
Reactant: COC(=O)c1ccn2ccnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccn2ccnc2c1
Reaction time: 8 h
Yield: 66.5 %

Procedure:
In 10 ml of methanol was dissolved 866 mg of methyl imidazo[1,2-a]pyridine-7-carboxylate, and then 5 ml of a 1M sodium hydroxide aqueous solution was added thereto, followed by stirring overnight. Then, 5 ml of 1M hydrochloric acid was added thereto and the solvent was removed by evaporation. A small amount of water, ethanol, and methanol were added thereto and crystals were collected by filtration to obtain 530 mg of the title compound.
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]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[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]([NH2:21])=[CH:17][C:16]=2[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-methylnitrobenzene (4.07 g) in methanol (40 ml) was added palladium on carbon (0.41 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/2 as an eluant to give the desired compound (2.73 g, two step yield, from Reference example 41, 53%) as a pale red oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15])#[N:2].C([O-])([O-])=O.[K+].[K+].[Cl:24][C:25]1[CH:42]=[CH:41][C:28]([CH2:29][CH2:30][NH:31][C:32](=[O:40])[C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1>CN1CCCC1=O>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][NH:31][C:32]([C:33]2[CH:38]=[CH:37][C:36]([O:39][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:35][CH:34]=2)=[O:40])=[CH:41][CH:42]=1
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Temperature: 110 °C
Reaction time: 6 h
Yield: 48.5 %

Procedure:
Methyl 6-cyano-7-fluorochroman-4-carboxylate (50 mg, 0.21 mmol) was diluted with 1-methyl-2-pyrrolidinone (2 mL) followed by the addition of K2CO3 (147 mg, 1.1 mmol) and N-(4-chlorophenethyl)-4-hydroxybenzamide (59 mg, 0.21 mmol). The reaction was bubbled with argon for 10 minutes and then heated to 110° C. and stirred for 6 hours. After the reaction was allowed to cool, it was loaded directly onto a Biotage 25 column and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield methyl 7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (50 mg, 48% yield). MS (ESI)=490.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=2)[CH:3]=1.O.[NH2:22][NH2:23]>CO>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([NH:22][NH2:23])=[O:16])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc(Oc2cc(N)nc(SC)n2)cc1
Solvent: O
Solvent: CO
Product: CSc1nc(N)cc(Oc2ccc(C(=O)NN)cc2)n1

Procedure:
Compound 6 was prepared from commercially available 4,6-dichloro-2-(methylthio)pyrimidine followed scheme 4. To prepare compound 6.1,4,6-Dichloro-2-(methylthio)pyrimidine was reacted with ammonia in THF in a sealed tube to provide 4-Amino-6-chloro-2-(methylthio)pyrimidine in good yield. Amino group of the resulting compound was protected with suitable protecting group such as BOC to afford compound 6.1. Compound 6.1 was then reacted with methyl 4-hydroxybenzoate in the presence of base to provide the amine protected intermediate, 2 which upon deprotection under acidic condition to afford methyl 4-(6-amino-2-(methylthio)pyrimidin-4-yloxy)benzoate (3). Reaction of compound 3 with hydrazine hydrate in methanol provided 4-(6-amino-2-(methylthio)pyrimidin-4-yloxy)benzohydrazide (6.4) in good yield. The hydrazide was then reacted with S-methyl N-[3-(trifluoromethyl-phenyl)thiourea in the presence of base to yield compound 6.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:35][CH:36]3[CH2:38][CH2:37]3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[C:25]([O:27]CC5C=CC=CC=5)[N:24]=[CH:23][N:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:49][C:50]([O:52][CH3:53])=[O:51].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([NH:35][C:11]2[C:12]3[N:13]([C:15]([C:18](=[O:19])[NH:20][C:21]4[CH:26]=[C:25]([OH:27])[N:24]=[CH:23][N:22]=4)=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][CH2:49][C:50]([O:52][CH3:53])=[O:51])[CH2:7][CH2:6]3)[CH:10]=2)[CH2:38][CH2:37]1
Reactant: COC(=O)CBr
Reactant: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4cc(OCc5ccccc5)ncn4)n3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4cc(O)ncn4)n3n2)CC1
Temperature: 45 °C
Reaction time: 14 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-N-(6-(benzyloxy)pyrimidin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (30.0 mg, 0.058 mmol) in DCM (2 mL) was added DIEA (0.041 mL, 0.234 mmol) and methyl 2-bromoacetate (13.40 mg, 0.088 mmol). The reaction solution was stirred at 45° C. for 14 hrs. The reaction mixture was concentrated and treated with TFA (0.270 mL, 3.50 mmol) at 65° C. for 1 hr. The reaction mixture was concentrated and diluted with MeOH, and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to obtain methyl 2-((trans)-4-(8-(cyclopropylamino)-3-(6-hydroxypyrimidin-4-ylcarbamoyl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylamino)acetate (11 mg, 0.022 mmol, 38.0% yield). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.295 minutes. [M+H]=496.19. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43-12.79 (1H, m), 11.67 (1H, s), 9.11 (2H, d, J=4.77 Hz), 8.31 (1H, s), 7.96 (1H, s), 7.63 (1H, s), 6.90-7.18 (2H, m), 5.95 (1H, s), 4.14 (2H, t, J=5.65 Hz), 3.80 (3H, s), 3.53-3.79 (1H, m), 2.91-3.21 (1H, m), 2.21 (2H, d, J=10.79 Hz), 2.10 (2H, d, J=11.54 Hz), 1.61 (2H, br. s.), 1.24 (2H, d, J=12.30 Hz), 0.76 (2H, d, J=5.02 Hz), 0.62 (2H, d, J=2.51 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc(CO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-formylbenzonitrile (5.0 g, 15.4 mmol) in methanol (50 mL) was added sodium borohydride (0.61 g, 16.1 mmol) at 0° C. The reaction mixture was stirred at rt for 30 min and concentrated. Purification via ISCO system (CH2Cl2/MeOH-20/1) afforded the title product (4.76 g) as an off-white solid. LC-MS (ESI): m/z 328 [M+H]+; 3.96 min (ret time).
Reaction SMILES: CO[CH:3]([O:6][CH3:7])[O:4][CH3:5].[CH2:8]([O:15][C:16]([NH:18][CH:19]1[CH2:23][O:22][CH2:21]C1=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:7][O:6][C:3]1([O:4][CH3:5])[CH:19]([NH:18][C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[CH2:23][O:22][CH2:21]1
Reactant: O=C(NC1COCC1=O)OCc1ccccc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1(OC)COCC1NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
Trimethylorthoformate (29 ml) was added dropwise to a refluxing solution of 4-benzyloxycarbonylamino-tetrahydrofuran-3-one (18 g, 78 mmol) and PTSA (500 mg) in MeOH (100 ml). After 3 hours, the reaction mixture was filtered and concentrated to afford, after column chromatography, the title compound as a yellow oil, 16.2 g, 76%.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:19]([CH3:21])[CH3:20].CCOC(C)=O>CN(C)C=O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CC(C)I
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1nc(I)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 72 h
Yield: 68.9 %

Procedure:
To 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.766 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added cesium carbonate (300 mg, 0.919 mmol) followed by 2-iodopropane (0.080 mL, 0.805 mmol), and the reaction mixture was stirred over the weekend (3 days) at 80° C. in a sealed vessel. The reaction was allowed to cool down to room temperature. The mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to afford 3-iodo-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (160 mg) as a white solid. LC/MS (ES) m/z=3.4.0 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([N:33](C(OC4C=CC=CC=4)=O)[C:34](=O)[O:35]C4C=CC=CC=4)[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]>CN(C)C=O>[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]([N:2]4[CH2:5][CH2:4][CH2:3]4)=[O:35])[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]
Reactant: C1CNC1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC4)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
Azetidine hydrochloride (104 mg, 1.11 mmol) and triethylamine (0.155 ml, 1.11 mmol) were added to a dimethylformamide (1 ml) solution of phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (116 mg, 0.222 mmol) synthesized in Production example 5-2; and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with a solvent mixture of ether-hexane=1:1; and the resultant solid was filtered off to yield the title compound (50 mg) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)CC2C=CC(OC)=CC=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1.Cl[CH2:42][C:43]([NH:45][CH3:46])=[O:44].[I-].[Na+].CCN(CC)CC.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>CN(C=O)C.CCOC(C)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:16][C:17]2[N:22]=[C:21]([NH:23][CH:33]3[CH2:34][CH2:35]3)[C:20]3=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]3[N:18]=2)=[CH:4][C:5]([C:14]#[N:15])=[CH:6][C:7]=1[CH:8]1[CH2:9][CH2:10][N:11]([CH2:42][C:43]([NH:45][CH3:46])=[O:44])[CH2:12][CH2:13]1
Reactant: CNC(=O)CCl
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C4CCNCC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)CN1CCC(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC1
Temperature: 100 °C

Procedure:
A mixture of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, Example 208D (in 12163-US-psp), (25 mg, 0.045 mmol), 2-chloro-n-methylacetamide (97 mg, 0.090 mmol), sodium iodide (13.53 mg, 0.090 mmol) and Et3N (0.024 mL, 0.135 mmol) in DMF (1.2 mL) in a microwave vial was heated at 100° C. in a microwave reactor for 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine, and dried over Na2SO4. Removal of the solvent followed by silica gel chromatography eluting with DCM containing 0 to 2% MeOH to afford the PMB-protected product which was dissolved in DCM (0.7 ml), and TFA (0.7 ml) and anisole (0.025 mL, 0.226 mmol) were added. The resulting mixture was heated at 50° C. for 3 h. After removal of solvent the residue was taken in MeOH/DCM and applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with large amount (5 CV) of mixture of 2 N solution of ammonia in methanol and DCM (1:1). Removal of the solvents to afford 2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-1-yl)-N-methylacetamide (15.6 mg).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[N:11]=[C:10]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[CH:5][CH:4]=1.BrBr.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][CH2:15][C:14]([C:12]1[N:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH:13]=1)=[O:16]
Reactant: CC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Br
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CBr)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 23 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
Aqueous HBr (0.98 ml of a 48% solution) was added to a solution of 1-[1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazol-4-yl]-ethanone I-7f (1.60 g, 4.38 mmol) in acetic acid (20 ml). Bromine (0.226 ml, 4.38 mmol) was added next to the reaction mixture in a dropwise manner. The resultant orange solution was stirred at 23° C. for 1 h before warming to 40° C. for 40 min and then cooling to 23° C. for 60 h. The reaction mixture was poured into a mixture of ice and saturated aqueous sodium bicarbonate, and the resultant mixture was extracted with ethyl acetate (2 200-ml portions). The combined organics were washed with saturated aqueous sodium bicarbonate (100 ml) and were dried over anhydrous magnesium sulfate and concentrated to afford 2-bromo-1-[1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazol-4-yl]-ethanone I-7g (1.03 g, 53%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([NH:20][C:21]1[CH:40]=[CH:39][C:24]([O:25][CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[C:23]([Cl:41])[CH:22]=1)=[O:19])=[O:12].[ClH:42]>O1CCOCC1>[ClH:41].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([NH:20][C:21]1[CH:40]=[CH:39][C:24]([O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][C:22]=1[Cl:42])=[O:19])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)c3[nH]cnc3C(=O)Nc3nc4ccccc4[nH]3)cc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1nc2ccccc2[nH]1)c1nc[nH]c1C(=O)Nc1ccc(OC2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
A flask was charged with tert-butyl 4-(4-(4-(1H-benzo[d]imidazol-2-ylcarbamoyl)-1H-imidazole-5-carboxamido)-2-chlorophenoxy)piperidine-1-carboxylate (260 mg, 0.45 mmol), 4 N hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) and 1,4-dioxane (50 mL), and the reaction mixture was stirred for 15 hours at room temperature. The resulting solid was filtered off and air dried to give 0.228 g of N4-(1H-benzo[d]imidazol-2-yl)-N5-(2-chloro-4-(piperidin-4-yloxy)phenyl)-1H-imidazole-4,5-dicarboxamide hydrochloride (99% yield). 1H-NMR (400 MHz, DMSO-d6): δ 13.9 (s, br, 1H), 13.7 (s, 1H), 12.2 (s, 1H), 10.4 (s, 1H), 8.41-8.39 (m, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.45 (s, 2H), 7.07 (s, 2H). MS (EI): 450 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:12])([CH3:1])[C:3]1=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
3,3-Dimethyl-1,3-dihydro-indol-2-one (5.5 g, 34 mmol) was dissolved in dimethylformamide (50 mL) and sodium hydride (1.4 g, 38 mmol) was added portionwise and the mixture was stirred 30 minutes then benzyl bromide (4.8 mL, 41 mmol) was added. The mixture was stirred 2 hours then quenched with saturated aqueous ammonium chloride, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-20% ethyl acetate in hexane) to afford 7.1 g (83%) of 1-benzyl-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16](/[N:19]=[CH:20]/[C:21]4[O:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=4)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[O:4][C:3]1=[O:29].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[CH3:1][N:2]1[N:6]=[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][CH2:20][C:21]4[O:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=4)=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)[O:4][C:3]1=[O:29]
Reactant: Cn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1nc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Yield: 85.9 %

Procedure:
3-Methyl-5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9b, 0.40 g, 1 mmol) on reduction with sodiumcyanoborohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 3-methyl-5-[1-(4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (10b, 343 mg, 86%).
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](/[CH2:14][P:15]([O:21]CC)([CH2:17][CH:18]([CH3:20])[CH3:19])=[O:16])\[C:9]([O:11]CC)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(/C=C(\CP(O)(CC(C)C)=O)/C(OCC)=O)CCCCC1.C1(/C=C(/CP(O)(CC(C)C)=O)\C(OCC)=O)CCCCC1.OP(C/C(=C\C(C)CCC(O)=O)/C(O)=O)(CC(C)C)=O>Cl.C(OCCCC)(=O)C.C(O)C.[OH-].[Na+]>[CH:1]1(/[CH:7]=[C:8](\[CH2:14][P:15]([OH:21])([CH2:17][CH:18]([CH3:19])[CH3:20])=[O:16])/[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)/C(=C\C1CCCCC1)CP(=O)(CC(C)C)OCC
Agent: CC(C)CP(=O)(O)C/C(=C\C(C)CCC(=O)O)C(=O)O
Agent: CCOC(=O)/C(=C/C1CCCCC1)CP(=O)(O)CC(C)C
Agent: CCOC(=O)/C(=C\C1CCCCC1)CP(=O)(O)CC(C)C
Solvent: CCO
Solvent: CCCCOC(C)=O
Product: CC(C)CP(=O)(O)C/C(=C\C1CCCCC1)C(=O)O
Yield: 49.5 %

Procedure:
A solution of 11.1 g (32.2 millimoles) of ethyl (E)-3-cyclohexyl-2-(ethoxyisobutylphosphinoyl)methylpropenoate in 100 ml of 4.3 N hydrogen chloride-butyl acetate was heated in a sealed tube for 48 hours. After cooling, the solvent was evaporated under reduced pressure to give a mixture of ethyl (Z)-3-cyclohexyl-2-(hydroxyisobutylphosphinoyl)methylpropenoate and ethyl (E)-3-cyclohexyl-2-(hydroxyisobutylphosphinoyl)methylpropenoate as a pale yellow oil. The (Z):(E) ratio determined by 1H-NMR was 90:10. The mixture was dissolved in a mixture of 32 ml of ethanol and 16 ml of 6 N sodium hydroxide, and heated under reflux for 3 hours. After cooling, the solvent was evaporated under reduced pressure. The residue was dissolved in 100 ml of water and made strongly acidic with hydrochloric acid, whereupon crystals precipitated. The crystals were collected by filtration and recrystallized from methanol-water (2:1) to give 4.6 g (yield 49%) of (Z)-3-cyclohexyl-2-(hydroxyisobutylphosphinoyl)methylpropenoic acid. Its melting point and IR and 1H-NMR were identical with those of the product obtained in Example 5 (b).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:18][CH3:19].[BH4-].[K+].Cl>O>[OH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:18][CH3:19]
Reactant: CCC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Product: CCC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A stirred suspension of (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)acetic acid (12.12 g., 0.04 mole) in water (400 ml.) is cooled to 5° C. and treated during a one hour period with solution of potassium borohydride (4.0 g., 0.075 mole) in water (200 ml.). The reaction is stirred for 1 hour then acidified with hydrochloric acid affording 10.6 g. (87%) of (1-hydroxy-2-ethyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 121°-122° C. after recrystallization from benzene.
Reaction SMILES: [CH2:1]([N:8]([CH3:21])[C:9]([NH:11][C@@H:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCOCC1>[CH2:1]([N:8]([CH3:21])[C:9]([NH:11][C@@H:12]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](NC(=O)N(C)Cc1ccccc1)C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(Cc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 63B (0.046 g, 0.057 mmol) in dioxane (1.6 mL) was treated with an aqueous solution of lithium hydroxide (0.63 mL, 0.5 N), and the mixture was stirred at 25° C. for 16 hours. An aqueous HCl solution (0.60 mL, 1N) was added, the reaction mixture was partitioned between ethyl acetate and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the crude product, which was used without further purification.