Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:8]=1)[CH3:2]
Reactant: CCOC(=O)CNc1cc(Cl)nc(Cl)n1
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(Cl)nc(NCc2ccc(Cl)cc2)n1

Procedure:
A stirred mixture of 10.0 g. (0.04 mole) of N-(2,6-dichloro-4-pyrimidinyl)glycine ethyl ester, prepared in Example 8, 5.6 g. (0.04 mole) of p-chlorobenzylamine and 4.24 g. (0.04 mole) of sodium carbonate in 100 ml. of ethanol was heated under reflux for 6 hours. The reaction mixture was filtered and the filtrate was cooled in ice. The precipitate thus formed was collected and recrystallized from benzene with petroleum ether being added to initiate precipitation to give 4.1 g. of product, m.p. 168°-170°C.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:35][N:34]2[C:31]2[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(-n2nc(-c3ccc(O)cc3O)c3ccc(O)cc32)cc1
Yield: 17.4 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.400 g, 1.60 mmol), sodium acetate (0.267 g, 3.3 mmol) and 4-nitrophenylhydrazine hydrochloride (0.463 g, 2.5 mmol) to give 0.101 g of product as a pink solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([Cl:17])[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C([O-])(=O)C.[K+].O>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:14]1[N:13]=[CH:12][C:11]2[CH:10]=[N:9][N:8]([C:6]3[N:7]=[C:2]([C:28]4[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:26][CH:27]=4)[CH:3]=[CH:4][CH:5]=3)[C:16]=2[CH:15]=1
Reactant: Clc1cc2c(cn1)cnn2-c1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a solution of 1-(6-bromo-2-pyridyl)-6-chloro-pyrazolo[4,3-c]pyridine (150 mg, 0.485 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-3,6-dihydro-2 h-pyridine-1-carboxylic acid tert-butyl ester (180 mg, 0.581 mmol), and 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) chloride (32 mg, 0.039 mmol) in Acetonitrile 5.0 mL was added 1.00 M of Potassium acetate in Water (0.73 mL, 0.73 mmol) and 1.00 M of Sodium carbonate in Water (0.73 mL, 0.73 mmol). The reaction mixture was stirred at 95° C. for 2 h. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 35% EtOAc) to give tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (185 mg) in 92% yield. MS (ESI) m/z: 412.2
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]3[N:17]=[C:18]4[C:24]([CH:25]=[O:26])=[CH:23][N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:19]4=[N:20][CH:21]=3)=[N:7][N:8]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[C:4]([F:35])[CH:3]=1.S(=O)(=O)([OH:38])N.Cl([O-])=O.[Na+].OP([O-])(O)=O.[K+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]3[N:17]=[C:18]4[C:24]([C:25]([OH:38])=[O:26])=[CH:23][N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:19]4=[N:20][CH:21]=3)=[N:7][N:8]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[C:4]([F:35])[CH:3]=1
Reactant: NS(=O)(=O)O
Reactant: CN(C)CCn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2c(F)cc(Cl)cc21
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CCn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2c(F)cc(Cl)cc21
Yield: 110.5 %

Procedure:
2-[6-Chloro-1-(2-dimethylamino-ethyl)-4-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (46 mg, 0.09 mmol) was dissolved in THF (1.3 ml) and water (0.4 ml) and sulfamic acid (83 mg, 0.85 mmol) was added. A solution of sodium chlorite (17 mg, 0.185 mmol) and potassium phosphate monobasic (232 mg, 1.7 mmol) in water (1.4 ml) was slowly added. After 1 h the reaction mixture was poured into ethyl acetate and water. The pH was adjusted to 6, the layers were separated and the aqueous layer was extracted five times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give 53 mg of 2-[6-chloro-1-(2-dimethylamino-ethyl)-4-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid.
Reaction SMILES: C(O[C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[O:18])[CH3:17].C[O-].[Na+]>CO>[F:8][C:5]([F:6])([F:7])[C:4](=[O:9])[CH2:17][C:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1)=[O:18]
Reactant: CC(=O)c1ccccn1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CC(=O)C(F)(F)F)c1ccccn1
Yield: 81.2 %

Procedure:
Trifluoro-acetic acid ethyl ester (9.82 mL, 82.5 mmol) was added to a solution of 1-pyridin-2-yl-ethanone (5.00 g, 41.2 mmol) in methanol (40 mL) containing sodium methoxide (61.8 mmol). The reaction mixture was heated at reflux overnight, concentrated under reduced pressure and acidified with aqueous hydrochloric acid (10%). The aqueous solution was extracted with ethyl acetate (10×50 mL). The organic layers were collected, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to give 4,4,4-trifluoro-1-pyridin-2-yl-butane-1,3-dione (7.26 g, 81%).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].C(OC([N:67]([CH2:76][CH2:77][S:78][S:79][C:80]([CH3:83])([CH3:82])[CH3:81])[CH2:68][CH2:69][C:70](OCC#N)=[O:71])=O)(C)(C)C.C(N(CC)CC)C>CN(C=O)C>[C:80]([S:79][S:78][CH2:77][CH2:76][NH:67][CH2:68][CH2:69][C:70]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:71])([CH3:83])([CH3:82])[CH3:81]
Reactant: CC(C)(C)OC(=O)N(CCSSC(C)(C)C)CCC(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)SSCCNCCC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
((2R,3S,5R)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate tetrabutylammonium salt (Compound 1h, 44.6 mg, 0.314 mmol) and cyanomethyl 3-((tert-butoxycarbonyl) (2-(tert-butyldisulfanyl)ethyl)amino)propanoate (Compound 6g-B, 236 mg, 0.628 mmol) were dissolved in DMF under ice-cooling, followed by addition of triethylamine (0.088 ml, 0.628 mmol). After stirring at room temperature for 1 hour, the reaction solution was purified by column chromatography (0.05% aqueous TFA solution:0.05% TFA-acetonitrile solution=70:30). TFA (1.5 ml) was added to the resulting residue, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (0.05% aqueous TFA solution:0.05% TFA-acetonitrile solution=80:20) to afford the title compound (66.9 mg, 25%).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:2]=1.O.[NH2:27][NH2:28]>CCO>[NH:27]([C:14]([C:13]1[CH:18]=[CH:19][C:10]([NH:9][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:2][CH:3]=2)=[O:8])=[CH:11][CH:12]=1)=[O:15])[NH2:28]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 66 %

Procedure:
To a suspension of methyl 4-[([1,1′-biphenyl]-4-ylcarbonyl)amino]benzoate (880 mg, 2.66 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.8 mL). After stirring for 7 days at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (3×2 mL) and water (3×2 mL), and drying under vacuo at rt for 6 hrs gave 585 mg of the title compound (66%) as a white solid in 96.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:10][NH:11][C:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:13]=2)[CH2:9][CH2:8]1>C1COCC1>[CH:7]1([CH2:10][NH:11][C:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:21][NH2:22])=[CH:23][CH:24]=3)[N:13]=2)[CH2:9][CH2:8]1
Reactant: N#Cc1ccc(-n2ccc(NCC3CC3)n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(-n2ccc(NCC3CC3)n2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Add a solution of 1M lithium aluminum hydride in THF (1.4 mL, 1.4 mmol) to a solution of 4-[3-(cyclopropylmethyl-amino)-pyrazol-1-yl]-benzonitrile (136 mg, 0.57 mmol) in THF (10 mL) at room temperature under a nitrogen atmosphere. Stir the mixture for 1 h at 60° C. Cool the mixture to room temperature and quench slowly with water, 1N NaOH and additional water. Dilute with EtOAc, stir vigorously for 20 min and filter through Celite®. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the residue by SCX chromatography to obtain the desired intermediate that was used without further purification (130 mg, 94%). MS (ES+) m/z: 243 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:13])[CH3:12]>C1C=CC=CC=1>[CH2:11]([NH:13][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCN
Solvent: c1ccccc1
Product: CCNC(=O)Cc1ccccc1

Procedure:
Dissolved 15 g (0.1 mol) of phenylacetyl chloride in 100 ml of benzene. While stirring on a magnetic stirrer, added 25 g of ethylamine (0.5 mol) into the benzene solution at 20°-30° C. After reaction, the solution was washed with water, dehydrated with anhydrous magnesium sulfate. The solvent was removed by rotary evaporator and the residue was purified by column chromatography as compound 3-1 to yield N-ethyl phenylacetamide as yellowish crystal. Yield, 14 g (85%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.Cl.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][N:18]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccccn1
Reactant: NNc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(NN=Cc2ccccn2)cc1

Procedure:
2.2 g of 2-pyridinecarbaldehyde was added to a mixture of 3.6 g of p-chlorophenylhydrazine hydrochloride and 9.8 g of sodium acetate in 60 ml of 50% by volume aqueous ethyl alcohol. The mixture was refluxed for 10 minutes, cooled and the precipitate crystallized from ethyl alcohol to give 2, as yellow crystals, mp 184°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:12]([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:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][CH2:29]SC)[N:9]=2)[CH:7]=1.BrCCN1[CH:43]=[C:42](NC(C2C=NN3C=CC=NC=23)=O)[C:41]([C:56]2C=C(Cl)C=C[C:57]=2OC(F)F)=N1.C1(CN)C=CC=CC=1>>[CH2:28]([NH:27][CH2:26][CH2:25][N:10]1[CH:11]=[C:12]([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:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:32][CH:33]([F:35])[F:34])=[N:9]1)[C:29]1[CH:57]=[CH:56][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: CSCCNCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Solvent: NCc1ccccc1
Product: O=C(Nc1cn(CCNCc2ccccc2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12

Procedure:
Using synthetic method analogous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and phenylmethanamine. LCMS (Method 20) [M+H]+=538.2, RT=2.70 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.84 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.67 (dd, 1H, J=1.6, 4.4 Hz), 8.67 (s, 1H), 8.37 (s, 1H), 7.64-7.59 (m, 2H), 7.46-7.42 (m, 1H), 7.32-7.19 (m, 6H), 7.06 (t, 1H, J=73.2 Hz), 4.25 (t, 2H, J=6.4 Hz), 3.73 (s, 2H), 2.93 (t, 2H, J=6.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)[N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:19]=[C:20]([CH:25]=[C:26]([F:28])[CH:27]=3)[C:21]([NH:23][NH2:24])=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[C:37](Cl)(Cl)=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:19]=[C:20]([C:21]4[O:22][C:37](=[O:38])[NH:24][N:23]=4)[CH:25]=[C:26]([F:28])[CH:27]=3)[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)[C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[C:35]#[N:36])=[CH:6][CH:7]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(C(=O)NN)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: CC(C)(F)[C@H](c1cc(F)cc(-c2n[nH]c(=O)o2)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 44 mg (0.86 mmol) of 3-((1S)-1-{1-[(S)-(4-chlorophenyl)(3-cyanophenyl) methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzohydrazide (Preparation 19) in 2 mL CH2Cl2 was added 11.3 uL(0.215 mmol) of phosgene solution (20% in toluene) at 0° C., followed by stirring at rt. After 1.5 h, the solution was concentrated in vacuo to remove solvents and 2 mL of 2N NH3 in MeOH was added and the solution was concentrated again. The residue was purified by silica gel chromatography with CH2Cl2/acetone to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 1.22(d, 3H, J=22 Hz), 1.28(d, 3H, J=22 Hz), 2.36 (t, 1H, J=8 Hz), 2.91 (t, 1H, J=8 Hz), 2.96 (m, 1H), 3.12 (t, 1H, J=7 Hz), 3.27 (m, 1H), 3.64 (t, 1H, J=6 Hz), 4.30 (s, 1H), 7.06-7.71 (m, 12H); Mass Spectrum: m/e=535 (M+1, 35Cl), 537 (M+1, 37Cl).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:23])/[CH:14]([O:21][CH3:22])[CH2:15][C:16]([O:18]CC)=[O:17])=[C:9]([O:24][CH3:25])[C:8]([CH3:26])=[C:7]2[C:3]=1[C:4](=[O:27])[O:5][CH2:6]2>CCCCCC.C(Cl)Cl>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:23])/[CH:14]([O:21][CH3:22])[CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:24][CH3:25])[C:8]([CH3:26])=[C:7]2[C:3]=1[C:4](=[O:27])[O:5][CH2:6]2
Reactant: CCOC(=O)CC(OC)/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)C(CC(=O)O)OC)C(=O)OC2

Procedure:
By following the procedure of Example ZA-6A and substituting methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) 2,4-dimethyl-4-hexenoate with ethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-methoxy-4-methyl-4-hexenoate and the corresponding compounds of Formula I-ZA-M1 prepared as described in Part A above, there are obtained (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-methoxy-4-methyl-4-hexenoic acid, m.p. 133°-135° C. (hexane/methylene chloride) and the corresponding compounds of Formula I-ZA-M2 as identified in the following table.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:45])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[C:11]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[N:23]([CH2:38][CH2:39][N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[CH:24]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=4)[N:26]=3)[CH2:18][CH2:17]2)[N:10]=[CH:9][N:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:45])[CH2:5][NH:6][C:7]1[C:12]([NH2:13])=[C:11]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[N:23]([CH2:38][CH2:39][N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[CH:24]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=4)[N:26]=3)[CH2:20][CH2:21]2)[N:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCCC3)CC2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CNc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCCC3)CC2)c1N
Reaction time: 2 h
Yield: 82.7 %

Procedure:
The mixture of (6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-nitro-pyrimidin-4-ylamino)-acetic acid ethyl ester (30.00 mg; 0.05 mmol; 1.00 eq.), and Pd/C (100 mg) in MeOH (10 mL) was hydrogenated under 20 psi for 2 hours. After filtration, the solvent was removed to yield (5-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamino)-acetic acid ethyl ester (25 mg, 87% yield), which was used for the next reaction; LC/MS: 605 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[C:15]1([N:6]2[C:5]3[CH:21]=[CH:22][C:2]([N:1]([S:31]([C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=4)(=[O:33])=[O:32])[S:31]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)(=[O:33])=[O:32])=[CH:3][C:4]=3[N:8]=[C:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)N(c2ccc3c(c2)nc(-c2ccccc2)n3-c2ccccc2)S(=O)(=O)c2ccc(OC)cc2)cc1

Procedure:
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with 4-methoxybenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:20][CH:19]=[CH:18][CH:17]=2.O.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH2:2]([C:1]1[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[C:22]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(OC)(OC)OC
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cccnc12
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc2cnc3cccnc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Freshly distilled trimethyl orthovalerate (41 mL, 0.24 mole) was added to a mixture of 1,1-dimethylethyl N-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate (39 g, 0.12 mole) in warm xylene (500 mL). The reaction mixture was heated at reflux overnight. Thin layer chromatography showed that at least half of the starting material was still present. p-Toluenesulfonic anhydride monohydrate (6 g) was added. After a short time thin layer chromatography showed that the reaction was complete. The reaction mixture was allowed to cool to ambient temperature and then it was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was concentrated under vacuum to provide an oily residue. The residue was triturated with hexane to provide a dark pink solid. This solid was recrystallized from acetonitrile to provide 1,1-dimethylethyl N-[4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a pale peach solid, m.p. 96.0-98.0° C. Analysis: Calculated for C22H31N5O2: %C, 66.47; %H, 7.86; %N, 17.62; Found: %C, 66.29; %H, 7.78; %N, 17.76.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13]>N1C=CC=CC=1>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[Cl:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccccc1Cl
Solvent: c1ccncc1
Product: O=P(Cl)(Cl)Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a reaction vessel there is added 113 g..phosphoryl chloride and 0.8 g. pyridine. Over a period of one hour, a total of 64 g. o-chlorophenol is added and the pot temperature is raised from 100° to 110°C. and held at 110°C. for one hour and then allowed to gradually cool to room temperature. The reaction mixture is stripped and there is obtained 108 g. product which affords, on distillation, 93.7 percent o-chlorophenyl phosphorodichloridate and 7.3 percent di-o-chlorophenyl phosphorochloridate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH2:42])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH:42][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]2)=[O:28])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCNC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2)cc1OC
Yield: 45.1 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with 2-(3,4-dimethoxy-phenyl)ethyl amine (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) to at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-(3,4-dimethoxy-phenyl)ethyl amide (53.6 mg, 45.07%).