Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4](Cl)[N:3]=1.[CH3:12][SH:13].C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4]([S:13][CH3:12])[N:3]=1
Reactant: CS
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1nc(N)c(C=O)nc1Cl
Reaction time: 0.5 h

Procedure:
In 3 ml of dimethylformamide there was dissolved 2-amino-5,6-dichloro-3-formylpyrazine (384 mg; 0.002 M), and the solution was cooled in an ice bath. Through the solution there was then bubbled methanethiol gas for 2 minutes. Triethylamine was added, and more methanethiol gas was bubbled through the solution for 3 minutes. The reaction mixture was stirred in the ice bath for 30 minutes and then at room temperature for 30 minutes. The solvent and methanethiol were then removed under nitrogen atmosphere, and the residue was treated with water. The product precipitated, was filtered, and washed with water (333 mg). Elemental Analysis for C6H6N3OSCl.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Pt](=O)=O>[CH2:1]([CH:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2cnccn2)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: c1ccc(CC2CNCCN2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A solution of 2-benzylpyrazine (8 g) in acetic acid (60 cc) is treated with platinum dioxide (0.8 g) and hydrogenated under a pressure of 1 atmosphere at approximately 20° C. When the absorption of hydrogen is complete, the catalyst is removed by filtration through diatomaceous silica. The solution is concentrated to dryness under reduced pressure (20 kPa) at approximately 60° C. The dry extract is suspended in ethanol (40 cc) and treated at approximately 20° C. with a solution of sodium ethylate prepared from sodium (1.49 g) in ethanol (40 cc). After 2 hours' stirring at approximately 20° C., the suspension is concentrated to dryness under reduced pressure (20 kPa) at approximately 30° C. The dry extract is taken up with ethyl ether (60 cc). The insoluble matter is removed by filtration through diatomaceous silica. The filtrate is concentrated to dryness under reduced pressure under the same conditions as above. The dry extract is taken up with isopropyl ether (20 cc), drained and washed with the same solvent (2×5 cc). (RS)-2-Benzylpiperazine (5.32 g) is obtained in the form of a light beige solid, m.p. 90° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])([O-])=O.[OH-].[Na+]>>[NH2:2][C:5]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccc(N)cc1N
Yield: 79.9 %

Procedure:
To a stirred solution of 45.12 grams (0.2 moles) of stannous chloride dihydrate in 100 ml. of concentrated HCl is added, gradually, 5.44 grams (0.0282 moles) of 2,4-dinitrobenzonitrile. An exothermic reaction takes place with the temperature rising to about 80°. The solution is stirred and allowed to come to room temperature over the course of 2 hours. The mixture is made strongly basic by the addition of a 50% sodium hydroxide solution, with cooling, and extracted with methylene chloride. The CH2Cl2 extracts are dried over anhydrous MgSO4 and the solvent removed. There is obtained 3.0 grams (80%) of a yellow solid melting at 102°-3°. Infrared (mull): 3500, 3350, (NH), 2200 (CN) cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:20]([C:21]([OH:23])=O)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[Cl-].[NH4+]>ClCCl>[N:24]1([C:21]([C@@H:20]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[O:23])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C([C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5 g of (3S)-2-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (16 mmol) in 160 mL of dichloromethane there are added 1.5 mL of morpholine (17.6 mmol) and then 9 mL of N,N,N-triethylamine (64 mmol), 3.3 g of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDC) (19.2 mmol) and 2.6 g of hydroxybenzotriazole (HOBT) (19.2 mmol). The reaction mixture is stirred at ambient temperature overnight and is then poured onto a solution of ammonium chloride and extracted with ethyl acetate. The organic phase is subsequently dried over magnesium sulphate and then filtered and evaporated to dryness. The crude product so obtained is then purified by chromatography over silica gel (dichloromethane/methanol gradient). The product is obtained in the form of a foam.
Reaction SMILES: [CH3:1][C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[C:40]([N:44]=[C:45]=[O:46])([CH3:43])([CH3:42])[CH3:41].[OH-].[Na+]>C(#N)C.O>[C:40]([NH:44][C:45]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:3]2[N:4]=[C:5]3[N:11]([CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[CH:6]3[O:16][CH:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[C:2]=2[CH3:1])=[CH:25][CH:26]=1)=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1c(-c2ccc(N)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Reactant: CC(C)(C)N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2ccc(NC(=O)NC(C)(C)C)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 80 °C

Procedure:
To a solution of 4-[1-methyl-4-(1-methyl piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine (example 173) (50 mg, 0.124 mmole) in ACN (1 mL) are added DIEA (65 μL, 0.372 mmole) and tertbutylisocyanate (21 μL, 0.182 mmole). The reaction mixture is heated overnight at 80° C. Water is added as well as 1N NaOH to pH 10. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over MgSO4, filtered, and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography eluting with (CH2Cl2:MeOH:NH4OH) from (98:2:0.2) to (95:5:0.5), and the residue is submitted to a preparative TLC on silica gel eluting with (CH2Cl2:MeOH:NH4OH) from (9:1:1) to give 1-tert-butyl-3-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-urea melting at 173° C.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:35])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([NH:26][CH2:27][CH2:28][O:29]C(=O)C(C)=C)=[O:25])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[K+]>CO.O>[C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:35])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([NH:26][CH2:27][CH2:28][OH:29])=[O:25])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C=C(C)C(=O)OCCNC(=O)COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)c2cc(OCC(=O)NCCO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
2-Methyl-acrylic acid 2-[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetylamino]-ethyl ester (Compound A9-13, 40 mg, 0.085 mmol) was dissolved in a mixture solvent of methanol (2 mL) and water (2 mL), added with potassium hydroxide (48 mg, 0.85 mmol), and then stirred at room temperature for 18 hr. After the neutralization with 1 N hydrochloric acid, the reaction solution was concentrated under reduced pressure. The resulting residues were purified by amino silica gel to obtain the title compound (white solid, 8.9 mg, 26%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(OC([N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=2)[C:30](=[O:38])[NH:29]1)=O)(C)(C)C.O>CN1C(=O)CCC1>[CH:18]([C:16]1[CH:17]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:37][C:34]3[CH:35]=[C:36]4[C:31]([C:30](=[O:38])[NH:29][NH:28]4)=[CH:32][CH:33]=3)[N:11]=2)[NH:14][N:15]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Reactant: CC(C)c1cc(Nc2nc(Cl)nc3ccccc23)[nH]n1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1cc(Nc2nc(Nc3ccc4c(=O)[nH][nH]c4c3)nc3ccccc23)[nH]n1
Temperature: 130 °C

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(5-isopropyl-2H-pyrazol-3-yl)-amine (50 mg, 0.17 mmol) in NMP (1 mL) was added 6-amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (65 mg, 0.26 mmol). The mixture was heated at 130° C. for 3 hrs, cooled to room temperature, and then poured into water. The crude material was collected by filtration and treated with TFA in CH2Cl2 for 30 min.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]#[C:18]C(C)(O)C)=[CH:13][N:12]=2)[CH2:7][CH2:6]1.[H-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]#[CH:18])=[CH:15][N:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)(O)C#Cc1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#Cc1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)nc1
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
Into a 50-mL round-bottom flask equipped with a magnetic stirbar was added 4-{2-[4-(2-Bromo 5-fluorophenoxy)piperidin-1-yl]pyrimidin-5-yl}-2-methylbut-3-yn-2-ol (300 mg, 0.69 mmol) and toluene (10 mL). The reaction mixture was treated with sodium hydride (3 mg, 0.07 mmol, 60 wt % in mineral oil) and the contents of the flask heated to 110° C. without attaching a reflux condenser in order to remove the acetone formed during the deprotection stage. After 2.5 h, complete conversion of starting material was observed by TLC analysis. The reaction mixture was cooled to room temperature and then quenched with dropwise addition of a saturated aqueous NH4Cl solution (10 mL). The mixture was poured into a 125-mL separatory funnel containing water (50 mL) and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. Purification by column chromatography through silica gel, eluting with 0% EtOAc in hexanes to 20% EtOAc in hexanes as a gradient gave the desired product as a clear oil.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.[CH3:19][C:20]1[C:21](=[O:49])[N:22]([C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[C:39]([C:45]([F:48])([F:47])[F:46])[CH:38]=2)[C:23](=[O:36])[C:24]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O1CCCC1.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]([S:15]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]3[C:23](=[O:36])[N:22]([C:37]4[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[C:39]([C:45]([F:46])([F:47])[F:48])[CH:38]=4)[C:21](=[O:49])[C:20]=3[CH3:19])[CH2:31][CH2:32]2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: CC1=C(CCCCCN2CCNCC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1=C(CCCCCN2CCN(S(=O)(=O)c3cccc(F)c3)CC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.2 ml of a solution of triethylamine in tetrahydrofuran (1.5 mol/l) and 8 mg of 3-fluorophenylsulfonyl chloride in 0.4 ml of tetrahydrofuran were added to a solution of 9 mg of 4-[2,5-dihydro-3-methyl-2,5-dioxo-4-[5-(piperazin-1-yl)pentyl]-1H-pyrrol-1-yl]-2-(trifluoromethyl)benzonitrile in 0.4 ml of tetrahydrofuran, and the mixture was stirred for 8 hours at room temperature. For working-up, the reaction mixture was diluted with ethyl acetate and washed with semi-saturated sodium bicarbonate solution. After the organic phase was concentrated by evaporation, it was chromatographed with methanol/dichloromethane on silica gel, and 6 mg of the title compound was thus obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:35])[C:11](C(O)=O)=[CH:12][N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C([N:45](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:15]([C:14]1[N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:12]=[C:11]([NH2:45])[C:10](=[O:35])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: COC(Cn1cc(C(=O)O)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(Cn1cc(N)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1 g) obtained in Example 161, Step 4 in tetrahydrofuran (15 ml)-toluene (15 ml) were added triethylamine (0.61 ml) and diphenylphosphoryl azide (0.47 ml) and the mixture was stirred at room temperature for 30 min. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran (8 ml). Triethylamine (0.61 ml) and diphenylphosphoryl azide (0.47 ml) were added again and 2 hr later, and 3 hr later, triethylamine (1.22 ml, 0.61 ml) and diphenylphosphoryl azide (0.94 ml, 0.47 ml) were respectively added, and stirring was continued. After confirmation of disappearance of the starting material, 9-fluorenylmethanol (7.7 g) and toluene (10 ml) were added, and the mixture was stirred under reflux with heating. After 20 min, triethylamine (2.5 ml) was added, and stirring was continued with heating for 1.5 hr. The mixture was concentrated, water was added to the residue and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-chloroform:methanol=15:1) to give 5-amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (886 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH2:11][CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:24]([N:31]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:37]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[NH2:1][C:2]1[C:7]2=[C:8]([C:35]3[CH:36]=[CH:37][C:38]4[C:33]([CH:34]=3)=[N:32][N:31]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:39]=4)[CH:9]=[C:10]([CH2:11][CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(Cc2cc(Br)c3c(N)ncnn23)C1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 110 °C
Yield: 94.3 %

Procedure:
To a stirred, degassed mixture tert-butyl 3-[(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]azetidine-1-carboxylate (397 mg, 1.04 mmol), Intermediate C (521 mg, 1.56 mmol), Na2CO3 (330 mg, 3.12 mmol) and H2O (1.6 mL) in DMF (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol). The reaction was heated (110° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (50 mL) and H2O (50 mL). The layers were separated and the aqueous was further extracted with ethyl acetate (1×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude material was purified via ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 500 mg (80%) of the desired product, which contained trace impurities.
Reaction SMILES: [CH:1]1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15]CC(O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:34][C:35](=[O:45])[CH:36](SC1SC(N)=NC=1)[CH3:37])C>>[CH:1]1([N:7]([C@H:21]2[CH2:22][CH2:23][C@H:24]([O:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:25][CH2:26]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:37][CH2:36][C:35]([OH:45])=[O:34])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Product: CC(C)CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared as described for the synthesis of {2-[3-cyclohexyl-3-(trans-4-isobutoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-acetic acid ethyl ester in the coupling step.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]([C:11]([C@@H:13]([C@H:24]([CH2:37][OH:38])[O:25][CH2:26][P:27]([O:33][CH:34]([CH3:36])[CH3:35])([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])OC(OC3C=CC=CC=3)=S)=[O:12])[CH:6]=[N:7]2)=[N:3][CH:2]=1.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]([C:11]([CH2:13][C@H:24]([CH2:37][OH:38])[O:25][CH2:26][P:27]([O:33][CH:34]([CH3:36])[CH3:35])([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[O:12])[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: CC(C)OP(=O)(CO[C@@H](CO)[C@@H](OC(=S)Oc1ccccc1)C(=O)n1cnc2c(N)ncnc21)OC(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: CC(C)OP(=O)(CO[C@@H](CO)CC(=O)n1cnc2c(N)ncnc21)OC(C)C
Yield: 23 %

Procedure:
To a solution of phenyl(chloro)thiocarbonate (0.25 mL, 1.8 mmol) and DMAP (426 mg, 3.5 mmol) in dried MeCN (25 mL) was added compound 15 (483 mg, 1.2 mmol) at room temperature. The reaction mixture was stirred for 12 hours. The mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH/10:1) to give 1-(adenin-9-yl)-2-O-phenoxythiocarbonyl-3-O-diisopropylphosphonomethyl-L-threose as a colorless oil. To the solution of 1-(adenin-9-yl)-2-O-phenoxythiocarbonyl-3-O-diisopropylphosphonomethyl-L-threose in dried 50 mL of toluene was added tributylinhydride (339 μL, 1.2 mmol) and AIBN (48 mg, 0.3 mmol). The reaction mixture was refluxed for 6 hours and concentrated in vacuo. The residue was purified by column chromatography (CH2Cl2:MeOH/10:1) to give compound 19 (110 mg, 0.27 mmol) as a colorless oil in 23% yield which was characterized as follows:
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:11]2[CH:15]=[C:14]([C:16]([NH2:18])=[O:17])[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:12]2)[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)#[N:2].CO.[BH4-].[Na+]>C1COCC1.CCOC(C)=O.O>[C:1]([CH2:3][C:4]1([N:11]2[CH:15]=[C:14]([C:16]([NH2:18])=[O:17])[C:13]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:12]2)[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)#[N:2]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCC(O)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[1-(cyanomethyl)-4-oxocyclohexyl]-3-[(4-fluorophenyl)amino]-1H-pyrazole-4-carboxamide (90 mg, 0.25 mmol) in a mixture of THF (1.9 mL)/MeOH (0.6 mL) at 0° C. was added NaBH4 (10 mg, 0.25 mmol), and the mixture was stirred at 0° C. for 10 minutes, then warmed to ambient temperature and stirred for another 10 minutes. The mixture was diluted with EtOAc and H2O. The organic layer was separated, washed with saturated aqueous NH4Cl, brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude residue containing a mixture of the two diasteromeric alcohols was used for next step without purification. LRMS (ESI) calc'd for C18H20FN5O2 [M+H]+: 358. Found: 358.
Reaction SMILES: [S:1](S([O-])=O)([O-:3])=[O:2].[Na+].[Na+].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.O>CN(C=O)C>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][S:1]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)(=[O:3])=[O:2])=[CH:12][CH:11]=1
Reactant: O=S([O-])S(=O)[O-]
Reactant: Fc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Cc1ccc(F)cc1)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.9 %

Procedure:
To a well-stirred suspension of 6.95 grams (40 mmol) of sodium hydrosulfite in 100 ml DMF was added 5.10 grams (35.3 mmol) of 4-fluoro benzyl chloride. The mixture was stirred at room temperature for five hours, then brought to 85° C. for 20 hours. The warm mixture was poured into 400 ml ice, and the total volume brought to 700 ml with water. The solid precipitates were isolated to give 2.3 grams (8.1 mmol; 46% yield) of bis(4-fluoro benzyl) sulfone. Recrystallization from toluene gave the pure compound as white needles (top 193° C.).