Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH3:12][N:13]([CH3:30])[S:14]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]=[C:28]=[O:29])(=[O:26])=[O:25])(=[O:16])=[O:15]>C(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:28]([NH:27][S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][S:14]([N:13]([CH3:30])[CH3:12])(=[O:15])=[O:16])(=[O:25])=[O:26])=[O:29])[N:7]=1
Reactant: CN(C)S(=O)(=O)Oc1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2OS(=O)(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
To a suspension of 0.46 g (0.003 mole) 2-amino-4,6-dimethoxypyrimidine in 5 ml methylene chloride was added 1.2 g (0.004 mole) 2-(dimethylaminosulfonyloxy)-benzenesulfonyl isocyanate. The reaction exothermed (18°-26° C.) and was then stirred at room temperature 3 hours. The solvent was evaporated under reduced pressure. The resultant mixture was triturated with diethyl ether and filtered to give 1.2 g of a white solid, m.p. 165°-168° C. The infrared spectrum shows absorption bands at 1710, 1380, 1170 cm-1.
Reaction SMILES: [CH:1]1([C:5]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:8](N)=[C:7]([I:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.N([O-])=O.[Na+].S(=O)(=O)(O)O.C(O)C>C(#N)C.C(Cl)(Cl)Cl.O>[CH:1]1([C:5]2[CH:6]=[C:7]([I:16])[CH:8]=[CH:10][C:11]=2[C:12]([F:15])([F:13])[F:14])[CH2:2][CH2:3][CH2:4]1
Reactant: Nc1cc(C(F)(F)F)c(C2CCC2)cc1I
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: FC(F)(F)c1ccc(I)cc1C1CCC1
Yield: 62.9 %

Procedure:
To a suspension in acetonitrile (60.0 mL) of the compound (2.08 g) obtained in step (3) above and sodium nitrite (2.10 g), conc. sulfuric acid (6.00 mL) was added at 0° C. over a period of 15 minutes. After stirring the mixture at that temperature for an hour, ethanol (24.0 mL) was added. After being stirred at 100° C. for two hours, the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into iced water and two extractions were conducted with chloroform. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure and the residue was purified twice by NH silica gel column chromatography (with n-hexane only) to give 2-cyclobutyl-4-iodo-1-(trifluoromethyl)benzene as a colorless oil (1.25 g).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:27]=1)[C:18]1[C:17]([Br:19])=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].CN(C=O)C.Br[CH2:42][C:43]1([CH3:47])[CH2:46][O:45][CH2:44]1>O.C(OCC)(=O)C>[Br:19][C:17]1[C:18]2[C@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:27]3)[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:7]=3)[O:12][C:13]=2[CH:14]=[CH:15][C:16]=1[O:20][CH2:42][C:43]1([CH3:47])[CH2:46][O:45][CH2:44]1
Reactant: CC1(CBr)COC1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ccc(O)c(Br)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(COc2ccc3c(c2Br)[C@]2(COC(N)=N2)c2cc(-c4cccnc4)ccc2O3)COC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a slurry of (S)-2-amino-1′-bromo-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (710 mg, 1.674 mmol), cesium carbonate (1091 mg, 3.35 mmol) and potassium iodide (306 mg, 1.841 mmol) in DMF (6694 μL, 1.674 mmol) at 0° C. was added 3-(bromomethyl)-3-methyloxetane (304 mg, 1.841 mmol). The reaction was removed from the ice bath and allowed to warm to rt. Reaction was allowed to stir at rt overnight before being diluted with water (250 mL) and poured into a separatory funnel containing ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a red oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-100% CH2Cl2 to 10:1 methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-1′-bromo-2′-((3-methyloxetan-3-yl)methoxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off white solid. MS m/z=508.0 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.C(O[C:45]([N:47]1[CH2:53][CH2:52][CH2:51][N:50]([C:54](=O)[CH2:55]Cl)[CH2:49][CH2:48]1)=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:55][CH2:54][N:50]1[CH2:51][CH2:52][CH2:53][N:47]([CH3:45])[CH2:48][CH2:49]1)[CH2:5][N:7]([CH:33]([CH3:34])[CH3:35])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:17][CH2:18][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:24]=2[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)CCl)CC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCN(C)CC3)c(F)c2)C(C)C)c1
Yield: 59.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 4-(2-chloroacetyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (26 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (16 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1.[C:11]([C:13]([C:19]#[N:20])=[C:14](SC)[NH:15][CH3:16])#[N:12]>>[C:11]([C:13]([C:19]#[N:20])=[C:14]([NH:15][CH3:16])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1)#[N:12]
Reactant: CNC(SC)=C(C#N)C#N
Reactant: NCCSCc1ccsn1
Product: CNC(NCCSCc1ccsn1)=C(C#N)C#N

Procedure:
By the procedure of Example 1(ii), reacting 3-[(2-aminoethyl)thiomethyl]isothiazole with 1,1-dicyano-2-methylthio-2-methylaminoethylene gives the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=[CH2:6].C(OC)(OC)OC.[CH3:19][C:20]([CH3:22])=O>S(=O)(=O)(O)O>[CH2:4]([C:3]1([CH2:7][CH:8]=[CH2:9])[CH2:10][O:11][C:20]([CH3:22])([CH3:19])[O:1][CH2:2]1)[CH:5]=[CH2:6]
Reactant: CC(C)=O
Reactant: C=CCC(CO)(CO)CC=C
Agent: O=S(=O)(O)O
Solvent: COC(OC)OC
Product: C=CCC1(CC=C)COC(C)(C)OC1

Procedure:
There were put 15.2 g of 4,4-bis(hydroxymethyl)-1,6-heptadiene prepared above, 42.5 mL of trimethyl orthoformate manufactured by Tokyo Chemical Industry Co., Ltd., and 97 mL of dry acetone manufactured by Kanto Chemical Co., Inc. in a 200 mL round-bottom flask. To the resultant mixture, a few drops of concentrated sulfuric acid were added gradually, and the mixture was refluxed for 4 hours. The reaction mixture was extracted with ether, and the extract was washed with saturated aqueous sodium bicarbonate, and was further washed with a saturated sodium chloride solution. The washed extract was dried over anhydrous magnesium sulfate manufactured by Nacalai Tesque, Inc. The dried ether solution was subjected to evaporation to remove ether contained therein. The obtained liquid was distilled in vacuo, thereby obtaining 16.2 g of 5,5-diallyl-2,2-dimethyl-1,3-dioxane as a colorless and oily fraction at 45° C. under a pressure of 4 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCCOc1cc2ncnc(Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 4-chloro-6-methoxyquinazolin-7-ol (compound 5, 3.0 g, 14.25 mmol) and ethyl 4-bromobutanoate (4.53 g, 28.49 mmol) in tetrahydrofuran (30 mL) was added potassium carbonate (5.90 g, 42.74 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (100 mL×2). The combined organic phases were concentrated to give the crude product as a yellow solid. The crude product was purified by silica gel column (gradient of hexane:ethyl acetate 10:1 to 2:1) to give Compound 6 (3.7 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.C([O-])([O-])=O.[K+].[K+].[CH3:20][O:21][C:22](=[O:47])[C@H:23]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](OS(C(F)(F)F)(=O)=O)=[CH:35][CH:34]=1)[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CCOC(C)=O>[CH3:20][O:21][C:22](=[O:47])[C@H:23]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH3:10])=[CH:37][CH:38]=1)[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26]
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reactant: COc1cccc(OC)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 97.7 %

Procedure:
2,6-Dimethoxybenzeneboronic acid (0.5 g) was dissolved in DME (10 mL). To the solution was added K2CO3 (0.7 g), N-(tert-butoxycarbonyl)-O-(trifluoromethane-sulfonyl)-L-tyrosine methyl ester (0.4 g), Pd(Ph3P)4 (0.6 g) and water (0.2 mL). The resulting mixture was heated to 80° C. overnight. Subsequently EtOAc and water were added to the mixture. The EtOAc layer was dried (MgSO4) and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexane 1:2) to give N-(tert-butoxycarbonyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (380 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH:17]([O:19]C)Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([CH:17]=[O:19])=[CH:5][CH:4]=1
Reactant: COC(Cl)Cl
Reactant: COc1cccc2c1oc1ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)c2c1oc1ccccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-Methoxydibenzofuran (25 g, 0.12 mol) was dissolved in DCM (300 ml) at room temperature and cooled to 0° C. To this solution TiCl4 (22.2 ml, 0.20 mol) was added drop wise at 0-2° C. The reaction mass was allowed to stir for 10 min and to that solution dichloromethyl methylether (9.7 ml, 0.107 mol) was added drop wise at 0° C. The reaction mass was stirred for 10 min and the reaction was monitored by TLC. Once the reaction was completed, the reaction mass was quenched with water and the organic layer was washed with NaHCO3 solution and brine. The organic layer was dried with sodium sulfate and concentrated under vacuum. 4-methoxy-dibenzofuran-1-carbaldehyde was isolated by column chromatography obtaining a white solid. Yield 13.5 g (48%)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:31])[C@@H:5]([NH:8][C:9]([C:11]1[S:12][C:13]([C:18](=[O:30])[NH:19][CH2:20][C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[N:24][NH:25]3)=[CH:14][C:15]=1[C:16]#[N:17])=[O:10])[CH2:6][NH2:7].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C[O:74][C:75]1[CH:76]=[C:77]([CH:81]=[C:82]([O:84]C)[CH:83]=1)[C:78](O)=[O:79]>CN(C=O)C.CCOC(C)=O>[CH3:2][O:3][C:4](=[O:31])[C@@H:5]([NH:8][C:9]([C:11]1[S:12][C:13]([C:18](=[O:30])[NH:19][CH2:20][C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[N:24][NH:25]3)=[CH:14][C:15]=1[C:16]#[N:17])=[O:10])[CH2:6][NH:7][C:78](=[O:79])[C:77]1[CH:76]=[C:75]([OH:74])[CH:83]=[C:82]([OH:84])[CH:81]=1
Reactant: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C#N
Reactant: COc1cc(OC)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1cc(O)cc(O)c1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a solution of (S)-3-Amino-2-({3-cyano-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester hydrochloride (0.40 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.17 mL, 1.20 mmol), HBTU (0.18 g, 0.048 mmol), HOBt (0.065 g, 0.048 mmol), and 3,5-Dimethoxybenzoic acid (0.062 g, 0.40 mmol). The mixture was stirred at room temperature 1 h, treated with EtOAc (40 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (50-100% EtOAc in hexane) to give 0.1241 g (55%) colorless oil. MS m/e 563.0 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]2[N:12]=[N:13][N:14]=[C:7]2[C:6]=1[N+:15]([O-])=O.CO>C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]2[N:12]=[N:13][N:14]=[C:7]2[C:6]=1[NH2:15]
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c2nnnn12
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(NCC(C)C)c(N)c2nnnn12
Reaction time: 2 h
Yield: 88.5 %

Procedure:
N-(2-Methylpropyl)-5-methyl-8-nitrotetraazolo[1,5-a]pyridin-7-amine (9.60 g, 43.6 mmol) was dissolved in warm anhydrous toluene (900 mL) and methanol (100 mL) and then added to a 2 L stainless steel Parr vessel. The vessel was flushed several times with nitrogen, and 5% platinum on carbon (2.0 g) was added to the solution. The vessel was flushed multiple times with hydrogen, and then placed under hydrogen pressure (50 psi, 3.4×105 Pa). After two hours, no further hydrogen was consumed. The reaction mixture was filtered through a layer of filter agent (available from Aldrich, Milwaukee, Wis. under the trade name CELITE), and the filter cake was washed with hot toluene (1 L). The filtrate was concentrated under reduced pressure to yield 8.5 g N7-(2-methylpropyl)-5-methyltetraazolo[1,5-a]pyridine-7,8-diamine as a light orange solid, m.p. 159–162° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]4[CH2:37][CH2:36][C:31]5(OCC[O:32]5)[CH2:30]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:38][CH3:39])[CH:6]=1.Cl.CC(C)=O>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]4[CH2:37][CH2:36][C:31](=[O:32])[CH2:30]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:38][CH3:39])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N4CCC5(C4)OCCO5)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3c(c(N4CCC(=O)C4)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Temperature: 60 °C
Yield: 5.3 %

Procedure:
The mixture of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (Example 205) (37 mg, 0.068 mmol) and HCl (272 μL, 0.272 mmol) in THF (339 μL) was heated at 60° C. overnight. Concentrated to remove THF and added Acetone (339 μL) and HCl (272 μL, 0.272 mmol) to the mixture. The mixture was heated at 60° C. for 6 h. The crude product was purified by Prep-HPLC (Solvent A=10% MeOH−90% H2O−0.1% TFA, Solvent B=90% MeOH−10% H2O−0.1% TFA. Column. PHENOMENEX LUNA 30×100 mm, S10, Flow rate: 40 ml/min, 35-100% B, 40 min) and then was purified by Prep-HPLC (Column: PHENOMENEX LUNA C18 30×100 mm, Solvent A=10 mM Ammonium Acetate in 95:5 H2O/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 H2O/ACN. Flow rate: 40 ml/min, 30-100% B, 35 min) to get 1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-one (2.0 mg, 3.59 μmol, 5.29% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([C@H:44]([N:46]=[C:47]=[O:48])[CH3:45])=[CH:40][CH:39]=1.C(O)(C(F)(F)F)=O>O1CCOCC1.C(Cl)Cl>[F:37][C:38]1[CH:39]=[CH:40][C:41]([C@@H:44]([NH:46][C:47]([NH:17][C:15]2[N:14]=[CH:13][C:12]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[N:9][NH:10][C:11]=3[CH:16]=2)=[O:48])[CH3:45])=[CH:42][CH:43]=1
Reactant: C[C@@H](N=C=O)c1ccc(F)cc1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(N)ncc23)ccn1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2n[nH]c3cc(NC(=O)N[C@@H](C)c4ccc(F)cc4)ncc23)ccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
A mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (intermediate 5a; 50 mg, 0.107 mmol) and 1-fluoro-4-[(1R)-1-isocyanatoethyl]-benzene (75 mg, 0.454 mmol) in 1,4-dioxane (1 mL) was heated to 60° C. overnight, then cooled down to RT and concentrated in vacuo. The residue was suspended in DCM and purified by chromatography on silica gel (0-50% MeOH/DCM) to yield a solid, which was directly dissolved in DCM (1 mL) and treated with TFA (1 mL). The mixture was stirred at RT for 3 h, then concentrated in vacuo and purified via reverse phase HPLC over a gradient of 20-55% MeCN with 0.1% TFA. The collected fractions were then partitioned between DCM/MeOH and 1N NaOH. The organic layer was dried (Na2SO4) and concentrated in vacuo to provide 1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]urea as a solid (13 mg, 0.033 mmol, 31%). MS ESI calc'd. for C21H20N6OF. [M+1]+ 391, found 391.
Reaction SMILES: 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.[O:34]=[C:35]([CH3:46])[CH2:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([OH:42])=O.[CH3:47][O:48][C:49]1[CH:50]=[C:51]([NH:55][C:56]2[C:65]3[C:60](=[C:61]([CH3:83])[CH:62]=[C:63]([S:66]([C:69]4[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([N:77]5[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]5)=[O:76])[CH:70]=4)(=[O:68])=[O:67])[CH:64]=3)[N:59]=[CH:58][C:57]=2[C:84]([NH2:86])=[O:85])[CH:52]=[CH:53][CH:54]=1>CN(C=O)C.C(Cl)Cl.CO.O>[CH3:47][O:48][C:49]1[CH:50]=[C:51]([NH:55][C:56]2[C:65]3[C:60](=[C:61]([CH3:83])[CH:62]=[C:63]([S:66]([C:69]4[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([N:77]5[CH2:78][CH2:79][N:80]([C:40](=[O:42])[C:39]6[CH:43]=[CH:44][CH:45]=[C:37]([CH2:36][C:35](=[O:34])[CH3:46])[CH:38]=6)[CH2:81][CH2:82]5)=[O:76])[CH:70]=4)(=[O:68])=[O:67])[CH:64]=3)[N:59]=[CH:58][C:57]=2[C:84]([NH2:86])=[O:85])[CH:52]=[CH:53][CH:54]=1
Reactant: CC(=O)Cc1cccc(C(=O)O)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCNCC5)c4)cc23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(C(=O)c6cccc(CC(C)=O)c6)CC5)c4)cc23)c1
Reaction time: 0.67 h
Yield: 59.9 %

Procedure:
HATU (82 mg, 0.217 mmol), DIEA (0.103 mL, 0.59 mmol), and 3-(2-oxopropyl)benzoic acid (39 mg, 0.217 mmol) were added to a stirring solution of Intermediate 96 (110 mg, 0.197 mmol) in DMF (2 mL) at rt. The reaction mixture was stirred for 40 min then pour into H2O (50 mL). The resulting precipitate was filtered, washed with H2O, and dried to give crude di-amide (256 mg). Chromatography (9:1, CH2Cl2/MeOH) afforded the title compound (85 mg, 64%) as a yellow solid. ES/MS calcd. for C39H38N5O7S+ 720.3. Found m/z=720.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17](=[O:29])[CH2:18][C@@H:19]1[C:23]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=2[O:21][CH2:20]1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:26]3[CH:25]=[CH:24][C:23]4[C@@H:19]([CH2:18][C:17]([OH:29])=[O:16])[CH2:20][O:21][C:22]=4[CH:27]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: COC(=O)C[C@H]1COc2cc(O)ccc21
Product: O=C(O)C[C@H]1COc2cc(OCc3cccnc3SC3CCCC3)ccc21
Yield: 77.8 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (11 mg, 0.05 mmol) obtained in Step C of Preparation Example 8 and ((R)-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (10 mg, 0.05 mmol) obtained in Preparation Example 55 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (15 mg, 89%).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7](=[O:16])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:5]1[NH:6][C:7](=[O:16])[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ncc(C(=O)O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 40 h
Yield: 85.4 %

Procedure:
Ethyl 2-tert-butyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (43.9 g) was dissolved in ethanol (200 ml), 2M aqueous sodium hydroxide solution (330 ml) was added and the mixture was stirred at room temperature for 40 hr. The reaction mixture was concentrated under reduced pressure, and aqueous layer of the mixture was adjusted to pH 8 with 6M hydrochloric acid. The mixture was concentrated under reduced pressure and azeotroped with 2-propanol. The residue was suspended in acetone, and insoluble powder was collected by filtration. The obtained powder was suspended in 1M hydrochloric acid and the mixture was adjusted to pH 3, and concentrated under reduced pressure. The residue was azeotroped with 2-propanol, and the insoluble material was suspended in acetone and filtered off. The filtrate was concentrated under reduced pressure to give the object product (32.8 g) as a powder.