Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:11].[SH:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[N:14]=1.C(N(CC)CC)C.CCOCC>C(O)C>[Cl:11][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH2:9][CH3:10])[C:3]=1[CH2:2][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([C:20]([F:23])([F:21])[F:22])[N:14]=1
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: CCc1cncc(Cl)c1CBr
Solvent: CCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCc1cncc(Cl)c1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a mixture of crude 4-(bromomethyl)-3-chloro-5-ethylpyridine (2.5 g, 10.66 mmol), 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (1.35 g, 6.92 mmol) in anhydrous ethanol (50 mL) at 0° C. was added triethylamine (3.77 g, 37.31 mmol). The reaction mixture was allowed to stir overnight at room temperature. The solvent was evaporated to provide a crude residue. Ether was added to precipitate the triethylamine hydrochloride salt. The solid was filtered and washed with ether several times. The combined ether layers were evaporated to provide a crude residue, which was purified by Combiflash using 0-10% MeOH in dichloromethane to provide 2-{[(3-chloro-5-ethylpyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol as a white solid (1.5 g, 40% yield); 1H NMR (400 MHz, CDCl3): δ 1.17 (t, 3H), 2.24 (s, 3H), 2.84 (q, 2H), 4.65 (s, 2H), 6.72 (s, 1H), 8.41 (s, 1H), 8.50 (s, 1H); M+ 350.1
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[H-].[Na+].[C:9](#[N:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)Cl>CN(C)C=O.O>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[C:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5]
Reactant: N#Cc1ccccc1
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CSC(=C(N)c1ccccc1)S(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
1.815 Grams of methyl methylthiomethyl sulfoxide was dissolved in 20 ml of dimethylformamide, and the solution was added with 380 mg of sodium hydride under cooling with ice, and then stirred for 1.5 hours at room temperature. Thereafter, upon addition of 1.515g of benzonitrile, the mixture was stirred for 1.5 hours at room temperature and for 10 hours at 50° C., followed by addition of 70 ml of methylene chloride and 2 ml of water and stirring for 20 minutes at room temperature. After drying with Glauber's salt and filtration, the filtrate was concentrated under reduced pressure. The resulting product was crystallized from methylene chloride-carbon tetrachloride-cyclohexane to obtain 2.332 g of 1-methylsulfinyl-1-methylthio-2-amino-2-phenylethylene. The isolation yield was 70%.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]2[NH:12][C:13](=[O:15])[N:14]=[C:7]2[C:6]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2C=[CH:27][CH:26]=[CH:25][C:24]=2C#N)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4].[OH-:31].[Na+].Cl.[CH2:34]([OH:37])[CH2:35]O>O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]2[NH:12][C:13](=[O:15])[N:14]=[C:7]2[C:6]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:35]([C:34]([OH:37])=[O:31])=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: OCCO
Reactant: CCCCc1nc(C)n2[nH]c(=O)nc2c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCc1nc(C)n2[nH]c(=O)nc2c1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
8 g of 7-n-butyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidin-2(3H)-one, prepared in Example 111, are heated to reflux for 10 hours in a solution of 6 g of sodium hydroxide in 30 ml of ethylene glycol and 2 ml of water. This solution, after cooling is acidified with hydrochloric acid to pH 5, and the crystals formed are drained and dried and then washed with acetone to give 5 g of 4'-[(7-n-Butyl-5-methyl-2-oxo-2,3-dihydro-1,2,4-triazolo[1,5-c]pyrimidin-8-yl}methyl]-2-biphenylcarboxylic acid in the form of crystals of melting point 210°-211° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c2cccnc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(F)c2cccnc12
Yield: 67.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-fluoro-quinolin-8-ylamine (Intermediate 50) (350 mg, 2.0 mmol), 2-nitro-benzenesulfonyl chloride (575 mg, 2.59 mmol), pyridine (0.35 ml, 4.3 mmol) and DCM (12 ml) gave the title compound (470 mg, 63%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@H:18]2[O:22][N:21]=[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH2:19]2)=[O:17])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=CC=CC=2C[C:43]([O:45][CH3:46])=[O:44])=CC=1.CC(N(C(C)C)CC)C.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:20]2[CH2:19][CH:18]([C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([CH:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:43]([O:45][CH3:46])=[O:44])=[CH:10][CH:11]=3)=[O:17])[O:22][N:21]=2)[CH:24]=1
Reactant: COC(=O)Cc1ccccc1-c1ccc(N)cc1
Reactant: O=C(c1ccccc1)c1ccc(NC(=O)[C@@H]2CC(c3cccnc3)=NO2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 0 °C
Yield: 34.4 %

Procedure:
) Intermediate (3) (0.007 mol) was added to a solution of methyl [(4-aminophenyl) phenyl]acetate (0.007 mol), N,N-bis(1-methylethyl)ethanamine (0.014 mol) and N,N-dimethyl-4-pyridinamine (catalytic quantity) in CH2Cl2 (100 ml), stirred at 0° C. The reaction mixture was stirred overnight at RT. Water was added. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated under reduced pressure. The residue was crystallized from EtOAc. The precipitate was filtered off, washed with EtOAc, and dried, yielding 1.0 g (35%) of (±)-methyl 4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]-α-phenylbenzeneacetate (compound 56).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH:4]=[N:3]1.C(N(C(C)C)CC)(C)C.[NH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12]([NH:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:14])[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccccc3)cc2C(=O)N2CCCCC2)cn1
Reactant: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1cc(-c2cc(C(=O)Nc3cccnc3)c(OCc3ccccc3)cc2C(=O)N2CCCCC2)cn1
Reaction time: 3 h

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-2-[(phenylmethyl)oxy]-4-(1-piperidinylcarbonyl)benzoic acid (may be prepared as described in Description 38; 80 mg, 0.19 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.13 ml, 0.76 mmol), 3-aminopyridine (32.3 mg, 0.34 mmol), 1-hydroxy-7-azabenzotriazole (46.7 mg, 0.34 mmol) and EDC (91 mg, 0.48 mmol). The solution was stirred for 3 hours. The solvent was removed in vacuo and the residue purified by MDAP to give the title compound as a white solid. 33 mg.
Reaction SMILES: C[Si]([O:5][P:6]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])(=[O:12])[O:7][Si](C)(C)C)(C)C.[O-]CCC.[O-]CCC.[O-]CCC.[O-]CCC.[Zr+4:34]>C(Cl)(Cl)(Cl)Cl>[Zr:34].[C:16]([CH2:15][CH2:14][CH2:13][P:6](=[O:5])([O-:12])[O-:7])#[N:17]
Reactant: C[Si](C)(C)OP(=O)(CCCC#N)O[Si](C)(C)C
Reactant: [Zr+4]
Agent: CCC[O-]
Solvent: ClC(Cl)(Cl)Cl
Product: N#CCCCP(=O)([O-])[O-]
Product: [Zr]
Temperature: 60 °C

Procedure:
A 2.5 ml portion of the above prepared bistrimethylsilyl-3-cyanopropylphosphonate solution in CCl4 was added dropwise 0.049 g of zirconium tetra propoxide. The reaction mixture was heated to 60° C. and filtered. The filtrate was saved. About 0.058 g of zirconium-3-cyanopropylphosphonate was formed.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.Cl.[C:9]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH2:17])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([N:50]=[C:51]=[S:52])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(NCC)C>>[C:9]([O:13][C:14](=[O:18])[CH2:15][CH2:16][N:17]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:51]([NH2:50])=[S:52])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=Cc1cccs1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCNCC
Product: CC(C)(C)OC(=O)CCN(Cc1cccs1)C(N)=S

Procedure:
3-(1-Thiophen-2-ylmethyl-thioureido)-propionic acid tert-butyl ester was prepared (750 mg) following general procedure D using thiophene-2-carbaldehyde (0.466 mL, 5 mmol), beta-alanine tert-butyl ester hydrochloride (905 mg, 5 mmol), sodium triacetoxyborohydride (1.27 g, 6 mmol), Fmoc isothiocyanate (1.4 g, 95.3%, 5 mmol), and diethyl amine (2 mL). LCMS m/z: 301 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:10]=O.[ClH:12].[CH3:13][NH:14][CH3:15].Cl>C(O)C.CC(C)=O>[ClH:12].[CH3:13][N:14]([CH3:10])[CH2:15][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CNC
Reactant: CC(=O)c1ccccc1
Reactant: C=O
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: CN(C)CCC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Acetophenone (29.1 ml, 0.25 mol), para-formaldehyde (12.0 g, 0.40 mol) and dimethyl amine hydrochloride (28.5 g, 0.35 mol) are suspended in ethanol (50 ml). Concentrated hydrochloric acid (0.5 ml) is added and the mixture is heated to reflux for 4 h. Then acetone (200 ml) is added and the resulting clear solution is allowed to cool to ambient temperature. The precipitate is collected by filtration and crystallized from ethanol yielding the title compound (40.7 g, 76.0% of theoretical yield) as colorless crystals with mp. 158° C.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([CH2:11][O:12][CH3:13])[CH:3]=1>C(O)(=O)C.[Ni]>[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:11][O:12][CH3:13]
Reactant: COCc1cc(C)[nH]c(=O)c1C#N
Agent: [Ni]
Solvent: CC(=O)O
Product: COCc1cc(C)[nH]c(=O)c1CN

Procedure:
6-Methyl-4-[(methyloxy)methyl]-2-oxo-1,2-dihydro-3-pyridine carbonitrile (1.000 g, 5.61 mmol) was suspended in acetic acid (150 ml) and the solution passed through an H-cube instrument equipped with Raney-Ni cartridge at a rate of 1 mL/min at 50 psi and 60° C. After 18 h. the acetic acid was removed under reduced pressure and the remaining residue was dissolved in MeOH. The methanolic solution was passed through a 0.2 μm teflon syringe filter. The methanolic filtrate was purified by reverse phase HPLC (Gemini 50×100 5 μm column. Run 1: 3 min, 90-10%. Run 2, 5 min 0-10%. Run 3, 10 min, 0-20%. The product fractions were concentrated to dryness on a Genevac HT-4 instrument to afford 3-(aminomethyl)-6-methyl-4-[(methyloxy)methyl]-2(1H)-pyridinone as a pale grey waxy solid (900 mg, 70.2% yield) LCMS MH+=183.0 1H NMR (400 MHz, DMSO-d6) δ 8.40 (br. s., 1H), 6.10 (s, 1H), 4.39 (s, 2H), 3.66 (br. s., 2H), 3.32 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[S:21]1[CH:25]=[C:24](B(O)O)[C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]1=2>>[S:21]1[CH:25]=[C:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3csc4ccccc34)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and benzo[b]thiophene-3-boronic acid to give (1-benzo[b]thiophen-3-yl-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 387(MH+).
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[OH:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)=[CH:19][CH:18]=1.Cl>O1CCCC1.CCCCCC.O>[S:4]1[CH2:5][CH2:6][CH2:7][S:8][C:3]1=[C:21]([C:20]1[CH:19]=[CH:18][C:17]([OH:16])=[CH:30][CH:29]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Oc1ccc(C(=C2SCCCS2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-trimethylsilyl-1,3-dithiane (29.1 g) in dry tetrahydrofuran (600 ml) is added at -65° a 1.4M solution of n-butyllithium in hexane (108 ml). The reaction mixture is progressively warmed to 0° during 4 hours and cooled to -65°. A further 1.4M solution of n-butyllithium in hexane (108 ml) and a solution of 4-hydroxybenzophenone (30.0 g) in dry tetrahydrofuran (180 ml) are added, the temperature being maintained under -60°. The reaction mixture is progressively warmed to room temperature overnight. The suspension is slowly poured into water (2 l) and acidified to pH 2 with hydrochloric acid (32%). The compound is immediately extracted with ethyl acetate (4×500 ml). The combined organic solutions are washed with water (3×250 ml) and dried over magnesium sulphate. The solvent is evaporated in vacuo. The residue is washed with hexane (3×50 ml) and then recrystallized from carbon teytrachloride. The product is dried in vacuo to constant weight to give (1,3-dithian-2-ylidene)-(4-hydroxyphenyl)-phenylmethane, m.p. 135°-137°.
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl[C:21](OC(Cl)(Cl)Cl)=[O:22].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCCC1>[O:31]1[CH2:32][CH2:33][N:28]([C:21]([O:1][C@@H:2]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])=[O:22])[CH2:29][CH2:30]1
Reactant: O=C(OCc1ccccc1)[C@@H](O)Cc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl 2(S)-hydroxy-3-phenylpropionate (256 mg) in dry tetrahydrofuran (10 ml) was added trichloromethyl chloroformate (0.122 ml). The mixture was refluxed for 18 hours. The mixture was cooled to 0° C., and morpholine (348 mg) was added thereto. The mixture was stirred at the same temperature for 3 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (40 ml). The solution was washed with 5% hydrochloric acid, 1 M sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (25% ethyl acetate in n-hexane as eluent) to give benzyl 2(S)-morpholinocarbonyloxy-3-phenylpropionate (367 mg) as an oil.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(N2CCCC2=O)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1N1CCCC1=O
Temperature: 65 °C

Procedure:
A mixture of 1-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)pyrrolidin-2-one (40 mg, 0.1 mmol) and ammonium acetate (89 mg, 1.2 mmol) and sodium cyanoborohydride (15 mg, 0.23 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (34 mg, 80%). LCMS calculated for C19H18ClFNO (M−NH2)+: m/z=330.1. found: 330.0.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[O:17]1[CH:19]([CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:18]1.C(Cl)(Cl)Cl.CO>CN(C)C=O>[OH:17][CH:19]([CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:18][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOCC(O)Cn1cnc2c(N)ncnc21
Reaction time: 20 h
Yield: 32 %

Procedure:
A mixture of adenine (0.829 g, 6.10 mmol), anhydrous potassium carbonate (45 mg) and rac-1,2-epoxy-3-octadecyloxypropane (2.0 g, 6.13 mmol) in anhydrous dimethylformamide (10 mL) is stirred at 70°-75° C. for 20 hours under a nitrogen atmosphere. The reaction mixture is filtered directly without cooling, and the filtrate is concentrated in vacuo to afford a white residue. The residue is stirred with 95:5 (v/v) chloroform-methanol. The insoluble solid is filtered, purified by chromatography, and dried in vacuo to give 0.9 g (31.8%) of 9-[2'-hydroxy-3'-octadecyloxypropyl]-adenine (CPR 1148): Thin-layer Chromatography (TLC); 4×8 cm silica gel 60, 0.25 mm thickness, 10:2:0.2 (v/v/v) CHCl3 -CH3OH-30% aqueous ammonia (Rf value=0.65); mp 151°-152° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]([CH3:24])([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH3:9])(=O)=O.[CH3:25][N:26](C=O)C.[C-]#N.[Na+]>O>[CH3:9][C:8]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)([CH3:24])[CH2:7][CH2:6][C:25]#[N:26]
Reactant: CN(C)C=O
Reactant: CC(C)(CCOS(C)(=O)=O)n1cc(-c2ncnc3[nH]ccc23)cn1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CC(C)(CCC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 125 °C
Yield: 59 %

Procedure:
3-methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butyl methanesulfonate (2.97 g, 8.50 mmol), DMF (120 mL) and sodium cyanide (6.21 g, 0.127 mol) were distributed evenly into six 20 mL microwavable vessels, each of which was heated in the microwave reactor for 4000 seconds at 125° C. The contents of the vials were combined and were diluted with 400 mL water and extracted with five 150 mL portions of ethyl acetate. The combined extracts were dried over sodium sulfate, and the solvent was removed in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.40 g, 59%).
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:14][CH2:15][CH2:16][CH3:17].CI>>[C:1]([NH:5][S:6]([C:9]1([CH3:14])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1([S:6]([NH2:5])(=[O:8])=[O:7])[CH2:17][CH2:16]1
Reactant: CC(C)(C)NS(=O)(=O)CCCCl
Reactant: [Li]CCCC
Solvent: CI
Product: CC(C)(C)NS(=O)(=O)C1(C)CC1
Product: CC1(S(N)(=O)=O)CC1

Procedure:
The intermediate 1-methylcyclopropane-1-sulfonamide was prepared based on previously reported method (Synlett 2006, 5, 725-278) (Scheme 2). N-(tert-butyl)-1-methylcyclopropane-1-sulfonamide was synthesized using a one-pot procedure from N-(tert-butyl)-3-chloropropane-1-sulfonamide through n-BuLi promoted intramolecular cyclization, lithiation and alkylation with methyl iodide. The removal of the Boc protecting group with TFA afforded 1-methylcyclopropane-1-sulfonamide.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH2:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:8]=1.Cl.[N:29]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:13][N:29]=[C:14]2[S:15]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: Nc1ccc(OCCCCCl)cc1CS(=O)(=O)c1cccc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OCCCCCl)cc12
Temperature: 3 °C

Procedure:
A mixture of 4-(4-chloro-butoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (1.54 g, 3.8 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.34 g, 4.0 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.55 g, 3.75 mmoles).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.O>CN(C=O)C>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:17][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1ccc(CN2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
In DMF (108 ml) was dissolved morpholine (9.0 g). To the mixture were added at room temperature triethylamine (24 ml) and 4-bromobenzyl bromide (21.5 g), and the mixture was stirred at 80° C. for 16 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 4-(4-bromobenzyl)morpholine (17.2 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[CH:12]([N:15]=[C:16]=[O:17])([CH3:14])[CH3:13].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:1][C:16](=[O:17])[NH:15][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:7]=1
Reactant: O=C(CO)c1ccc(Cl)cc1
Reactant: CC(C)N=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)OCC(=O)c1ccc(Cl)cc1
Yield: 49.1 %

Procedure:
A mixture of 2-hydroxy-1-(4-chloro-phenyl)-ethanone (4.7914 g, 28 mmol), prepared in the previous step, isopropyl isocyanate (4.1 ml, 42 mmol) and triethylamine (2.83 ml, 28 mmol) in 100 ml of benzene was refluxed under nitrogen for approximately 24 hours. The solid formed was collected by filtration and dried under high vacuum to give 3.5184 g (49%) of isopropyl-carbamic acid 2-(4-chloro-phenyl)-2-oxo-ethyl ester as an off-white solid. Recrystallization of a portion of this solid from isopropyl alcohol gave an analytically pure sample, mp 163-164° C.