Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:6]=1)=O.[OH-].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[OH:2][CH2:3][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[N:6]=1
Reactant: COC(=O)c1nn(S(=O)(=O)c2ccc(C)cc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2nc(CO)c3ccccc32)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
To a stirred suspension of ester of Step 1 (31.0 g, 94 mmol) in dry THF (600 mL) cooled at 5° C. and under nitrogen was added dropwise and at this temperature a solution of Red-A1 (sodium dihydro-bis (2-methoxyethoxy)aluminate--70% in toluene) (34 mL, 114 mmol) in dry THF (30 mL). After stirring 2 hours at 5° C., and then 1 hour at room temperature the mixture was cooled at 10° C. and treated dropwise with 2N NaOH (100 mL) to effect hydrolysis of the intermediate complex. The organic phase was separated and the solvent in vacuo evaporated. The residue was chromatographed over silica gel using MeOH/CH2Cl2 5:95 (v/v) as eluant to give the required alcohol (13.5 g, 54%) as a yellow oil which solidified upon standing, m.p. 95°-98 ° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:17][CH3:18]>CC(C)=O.C(OCC)(=O)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=1[O:8][CH2:17][CH3:18]
Reactant: Nc1ncnc(Cl)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOc1c(N)ncnc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A reaction mixture of 4-amino-6-chloro-pyrimidin-5-ol (1000.0 mg; 6.8 mmol; 1.0 eq.), cesium carbonate (2686.3 mg; 8.24 mmol; 1.2 eq.), and iodoethane (1285.9 mg; 8.24 mmol; 1.2 eq.) in acetone (10 ml) was stirred at 50° C. overnight. The reaction solution was diluted with ethyl acetate (50 ml), washed with water, then brine, dried and concentrated. The residue was treated with ether, stirred for 30 min, filtered, collected white off solid as title compound (1165 mg in yield 98%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1)C=C.C1(O)C=CC=CC=1.N1CCCCC1>C(O)C>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][C:13](=[O:24])[C:14]2[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:15]=2[N:16]=1
Reactant: C=CCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: Oc1ccccc1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3O)nc12

Procedure:
A mixture of 5-(2-allyloxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (0.25 g, 0.0008 mol), phenol (0.145 g, 0.0015 mol), piperidine (0.131 g, 0.0015 mol) and tetrakis-(triphenylphosphine)palladium(0) (0.046 g, 0.00004 mol) in absolute ethanol (5 ml) was refluxed overnight under nitrogen. The mixture was allowed to cool, the solvent evaporated under vacuum and the residue dissolved in ethyl acetate (40 ml). This solution was washed with water (3×10 ml), 1M HCl (3×10 ml) and brine (1×10 ml). After drying (Na2SO4) and filtration, the filtrate was evaporated under vacuum to give the crystallisation from ethyl acetate/pentane, m.p 233-238° C. Found: C, 63.17; H, 5.65; N, 19.52. C15H16N4O2 requires C, 63.36; H, 5.67; N, 19.71%.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=2[O:18][CH3:19])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>ClCCl>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:35])[NH:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=2[O:18][CH3:19])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COc1cc(C)cc(OC)c1C1=NC(N)C(=O)N(C)c2ccccc21
Solvent: ClCCl
Product: COc1cc(C)cc(OC)c1C1=NC(NC(=O)Nc2ccccc2Cl)C(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To 56 mg of 3-amino-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one in 10 ml of dichloromethane is added 0.022 ml of 2-chlorophenyl isocyanate and the reaction mixture is then stirred at room temperature overnight. It is concentrated under vacuum and the residue is crystallized from isopropyl ether to give 3-(2-chlorophenylureido)-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one; m.p.=260° C.; Yield=91%.
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[CH2:6][CH2:5][CH2:4][CH:3]1[CH:7](O)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.S(Cl)([Cl:25])=O>O1CCOCC1>[Cl:25][CH:7]([CH:3]1[CH2:4][CH2:5][CH2:6][S:2]1(=[O:22])=[O:1])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)c1ccc(C(O)C2CCCS2(=O)=O)cc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CCOC(=O)C(C)c1ccc(C(Cl)C2CCCS2(=O)=O)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Ethyl 2-{4-[(1,1-dioxotetrahydro-1λ6-thiophen-1-yl)hydroxymethyl]phenyl} propionate (400 mg) obtained in Example 38 was dissolved in 1,4-dioxane (5.0 ml), and then to the solution was added thionyl chloride (0.2 ml), and the mixture was stirred at 70° C. overnight. The reaction mixture was quenched with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (420 mg, 99%).
Reaction SMILES: [NH2:1][C@H:2]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[CH:3]=[O:4].[N+]([O-])([O-])=O.[Ag+:18]>[OH-].[K+].O>[NH2:1][C@H:2]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])[OH:8])[OH:6])[CH:3]=[O:4].[Ag+:18]
Reactant: N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Product: N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)C(=O)[O-]
Yield: 80 %

Procedure:
2.31 Grams of 2-amino-2-deoxy-glucuronic acid was dissolved in a solution of 0.85 g of KOH in 200 ml of water. A solution of 2.035 g of AgNO3 in 100 ml of water was added to the former solution to precipitate the silver salt (Yield about 80%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][O:13][CH3:14])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:25])[N:5]([C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:6]2=[O:15].CN(CCN(C)C)C.[I:34]I>C1COCC1>[Cl:1][C:2]1[C:10]([O:11][CH2:12][O:13][CH3:14])=[CH:9][C:8]([I:34])=[C:7]2[C:3]=1[CH:4]([OH:25])[N:5]([C:16]([CH3:17])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:24])[C:6]2=[O:15]
Reactant: COCOc1ccc2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Reactant: II
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1cc(I)c2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 96.1 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-chloro-5-methoxymethoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.01 g, 8.32 mmol) was dissolved in THF (110 mL), and the solution was treated with TMEDA (4.00 mL, 26.5 mmol), sec-butyl lithium-hexane solution (0.95 mol/L, 28.0 mL, 26.6 mmol) and iodine (2.53 g, 9.98 mmol), followed by purification by slurry using diisopropylether to obtain 4-chloro-5-methoxymethoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (3.90 g, yield 96%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([C:15](OC)=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([CH2:15][OH:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CN1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reaction time: 6 h

Procedure:
Methyl(2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidine-2-carboxylate 3c (2.50 g, 9.10 mmol) was dissolved in 50 mL of dichloromethane in an ice-water bath. Diisobutyl aluminium hydride (18 mL, 18 mmol) was added dropwise slowly, and the mixture was stirred for 6 hours. The reaction mixture was quenched with 1 mL of methanol, diluted with 200 mL of dichloromethane, added with anhydrous sodium sulfate, and stirred for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure and the resulting residue was purified by alkaline alumina column chromatography with elution system A to obtain the title compound [(2S,4R)-4-(tert-butyl(dimethyesilyl)oxy-1-methyl-pyrrolidin-2-yl]methanol 3d (570 mg, yield 50.0%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]([OH:32])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:15]([CH3:17])[CH:16]=1)=[O:9].[CH2:33]([O:40][P:41]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([O:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([CH3:51])[C:45]=1[C:52]([CH3:58])([CH3:57])[CH2:53][C:54](O)=[O:55])=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:60]([O:59][P:41]([O:40][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([O:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([CH3:51])[C:45]=1[C:52]([CH3:58])([CH3:57])[CH2:53][C:54]([O:32][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:16][C:15]=2[CH3:17])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]1=2)=[O:55])=[O:42])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reactant: Cc1cc(C)c(C(C)(C)CC(=O)O)c(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(C(C)(C)CC(=O)OC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)c(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
Tolvaptan (0.63 g), 3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyric acid (0.70 g), and 4-dimethylaminopyridine (DMAP) (24 mg, 0.22 mmol) were suspended in dichloromethane (10 ml). N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (WSC) (383 mg) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=70:30→35:65). The purified product was concentrated under reduced pressure to obtain 0.92 g of 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyrate as white amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:35]([CH2:36][O:37]CC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][CH2:26][CH2:25][CH2:24][C:21]1[N:20]2[C:15]3[CH:14]=[C:13]([C:6]4[C:5]5[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=5)[N:8]([CH3:12])[CH:7]=4)[N:35]([CH2:36][OH:37])[C:16]=3[N:17]=[CH:18][C:19]2=[CH:23][N:22]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CCCNC(=O)OC(C)(C)C)n43)n1COCC[Si](C)(C)C)cn2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CCCN)n43)n1CO)cn2C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 3-(7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)propylcarbamate (0.347 g, 0.574 mmol, prepared using J.1 from Preparation #I.1 with 4-(tert-butoxycarbonylamino)butyric acid and L.1 with mercury(II) trifluoroacetate) in DCM (5 mL) at rt was added TFA (1.10 mL, 14.3 mmol). After about 16 h, the mixture was concentrated in vacuo to provide (1-(3-aminopropyl)-7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-6-yl)-methanol (0.232 g, 100%): LC/MS (Table 2, Method c) Rt=1.26 min; MS m/z 405 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:19].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:19][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:20]
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCO
Reactant: COC(=O)CCCCCCCBr
Product: COC(=O)/C=C/c1c(C#CCCCCO)cccc1OCCCCCCCC(=O)OC
Yield: 67 %

Procedure:
Using the procedure of example 122, (E)-3-[(2-hydroxy-6-(6-hydroxy-1-hexynyl)phenyl]-2-propenoic acid methyl ester (example 176) was alkylated with methyl 8-bromo-octanoate giving the title compound, in 67% yield, as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[C:27](=[O:28])[N:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[N:25]=[CH:24][C:23]=3[N:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>CN(C1C=CN=CC=1)C.ClCCl.N1C=CC=CC=1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[C:27](=[O:28])[N:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[N:25]=[CH:24][C:23]=3[N:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)=[O:6]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(-n2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccc(-c4ccc(O)cc4)cc3)c2=O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-n2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccc(-c4ccc(OC(=O)C(C)(C)C)cc4)cc3)c2=O)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
0.66 ml of pivaloyl chloride are added dropwise to a suspension of 728 mg (1.18 mmol) of tert-butyl 4-[5-[(4′-hydroxy-1,1′-biphenyl-4-yl)oxy]-1-(4-methyl-phenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-1-piperazinecarboxylate (Example 46) and a catalytic amount of 4-DMAP in a mixture of dichloromethane (4.0 ml) and pyridine (0.4 ml) at room temperature. The heterogeneous reaction mixture is stirred at about 40° C. overnight. The slightly cloudy suspension is diluted with dichloromethane and washed with 0.2 N hydrochloric acid solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is purified by chromatography on silica gel.
Reaction SMILES: [C:1]([C:3]([CH3:34])([CH3:33])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13]3[C:16]([C:27]([O:29]CC)=O)=[N:17][N:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:12]=3[C:11]2=[O:32])=[CH:6][CH:5]=1)#[N:2].[NH3:35]>C(O)CO>[C:1]([C:3]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13]3[C:16]([C:27]([NH2:35])=[O:29])=[N:17][N:18]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[C:12]=3[C:11]2=[O:32])=[CH:6][CH:5]=1)([CH3:33])[CH3:34])#[N:2]
Reactant: N
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(C(C)(C)C#N)cc1)C2=O
Solvent: OCCO
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(C(C)(C)C#N)cc2)CC3)cc1
Temperature: 80 °C
Yield: 88 %

Procedure:
Ethyl 6-[4-(cyano-dimethyl-methyl)phenyl]-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboylate (0.38 g, 0.83 mmol) obtained in Example 96 was placed in a sealed tube containing 10% ammonia in ethylene glycol (3 mL) and heated 80° C. for 2 h. The reaction was cooled, quenched with H2O, extracted with EtOAc, and dried (MgSO4). Recrystallization from CH2Cl2/Hexanes afforded 0.31 g (88%) of the title amide. High Resolution Mass Spec (M+H)+. for C24H24N5O3 430.1898.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[Na].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[N:9]=1>CCOC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:4][CH2:3][CH:2]([CH3:5])[CH3:1])[N:9]=1
Reactant: CC(C)CO
Reactant: Brc1cccc(Br)n1
Agent: [Na]
Solvent: CCOC(C)=O
Product: CC(C)COc1cccc(Br)n1
Reaction time: 0.25 h

Procedure:
To 2-methylpropan-1-ol (1 mL), was added sodium (36 mg, 1.56 mmol). The mixture was stirred at 70° C. until sodium was ˜75% consumed, then 1 mL THF and the mixture was stirred an additional 15 min. To this mixture, 2,6-dibromopyridine (250 mg, 1.06 mmol). The mixture was stirred at 90° C. for 2 h, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 185 mg of Intermediate 162.1 as a colorless oil. LCMS (2 min gradient) RT=1.98 min, 230.2 (M+H)+.
Reaction SMILES: O[CH:2]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])[C:3]([Cl:7])([Cl:6])[CH2:4][Cl:5].S(Cl)([Cl:15])=O>>[Cl:15][CH:2]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])[C:3]([Cl:7])([Cl:6])[CH2:4][Cl:5]
Reactant: O=S(Cl)Cl
Reactant: CCC(=O)NC(O)C(Cl)(Cl)CCl
Product: CCC(=O)NC(Cl)C(Cl)(Cl)CCl

Procedure:
5.8 gm of N-(1-hydroxy-2,2,3-trichloropropyl)-propionamide were admixed with 20 ml of thionyl chloride, and the mixture was refluxed for 30 minutes. Subsequently, the reaction mixture was evaporated in vacuo. The crude N-(1,2,2,3-tetrachloro-n-propyl)-propionamide thus obtained was dissolved in 30 ml of tetrahydrofuran, and, while stirring, the solution was added to a solution of 1.75 gm of 1,2,4-triazole and 4.2 ml of triethylamine in 30 ml of tetrahydrofuran. After standing for 3 hours at room temperature, the reaction solution was admixed with water, and the tetrahydrofuran was distilled off in vacuo. A quickly solidifying oil was obtained, and the crystallizate was recrystallized from methanol/water. Yield: 4.6 gm; m.p. 167° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:26][C:27](O)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:26][C:27]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1CCCCC1)C2
Reaction time: 0.5 h

Procedure:
Triethylamine 0.84 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.95 g, and stirred at o@C for 30 min. Cyclohexyl acetic acid 0.72 g and WSC 1.35 g were added therein, then the reaction mixture was gradually changed to room temperature and stirred for 25 hours. The reaction mixture was washed with saturated sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-cyclohexylacetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 0.38 g and refluxed for 1 hour. The reaction mixture was cooled, then added 6N hydrochloric acid and 1N sodium hydroxide thereto, and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform acetone methanol=10:1:0.1) to obtain the product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:16]O>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:16])=[O:10])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Cl)nc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Cl)nc1

Procedure:
To a solution of 2-(6-chloropyridin-3-yl)acetic acid (2 g, 117 mmol) in methanol (40 ml) was added SOCl2 (1.38 g, 117 mmol). The reaction mixture was concentrated after two hours to give the desired product. LC-MS: m/z (M+H)=186.6
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.C1COCC1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>N1C=CC=CC=1>[C:18]([C:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:4]2[N:3]=[C:2]([NH:1][C:38](=[O:39])[O:40][CH2:41][CH3:42])[N:31]=[C:5]2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:7]=1[CH3:20])#[N:19]
Reactant: CCOC(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (25 mg, 59 μmol) was dissolved in a mixture of abs. THF (2.5 ml) and abs. pyridine (48 ml). At room temperature, ethyl chloroformate (32 mg, 297 μmol, 5 eq.) was added and the mixture was heated at 80° C. for 12 h. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (25 mg, 86% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=S)[NH2:12])[CH2:7][CH2:6]1)=[O:4].[C:14]([NH2:17])(=[S:16])[CH3:15].II>CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:17]=[C:14]([CH3:15])[S:16][N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(N)=S)CC1
Reactant: CC(N)=S
Agent: II
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](c2nsc(C)n2)CC1
Reaction time: 48 h

Procedure:
To a solution of trans-4-thiocarbamoyl-cyclohexanecarboxylic acid methyl ester (0.30 g, 1.5 mmol) and thioacetamide (0.67 g, 8.9 mmol) in methanol (7 ml) was added a solution of iodine (2.65 g, 10.4 mmol) in methanol (15 ml) at room temperature. After stirring for 48 h the reaction mixture was partitioned between 0.1 M sodium thiosulfate solution (100 ml) and ethyl acetate (100 ml). The layers were separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by Kugelrohr distillation. The distillate was purified by flash-chromatography with n-heptane/tert-butyl methyl ether as eluent to give the title compound (0.021 g, 5%) as light yellow oil, which was contaminated with 20% trans-4-(3-methyl-[1,2,4]thiadiazol-5-yl)-cyclohexanecarboxylic acid methyl ester. MS m/e: 241 ([M+H]+)