Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([N:3]([CH2:16][CH3:17])[CH2:1][CH3:2])(=[O:6])=[O:5])=[CH:8][CH:9]=1
Reactant: CCN(CC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)S(=O)(=O)c1ccc(N)cc1
Reaction time: 2 h
Yield: 106.5 %

Procedure:
A 250 mL Parr shaker bottle was charged with N,N-Diethyl-4-nitro-benzenesulfonamide (617 mg, 2.39 mmol), ethyl acetate (50 mL), and 10% palladium on activated carbon (100 mg). The bottle was place on a Parr shaker apparatus and charged with hydrogen to a pressure of 52 psi. The reaction mixure was shaken for two hours, filtered through celite, and concentrated to provide 4-Amino-N,N-diethyl-benzenesulfonamide as a green solid (581 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:10][CH3:9])[CH:7]=1
Reactant: CN
Reactant: Clc1cc(Cl)ncn1
Solvent: CCO
Product: CNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4,6-dichloro-pyrimidine(3.53 g, 23.7 mmol) and methylamine (33 wt % in ethanol, 10 ml, 80 mmol) in ethanol is kept stirring overnight at room temperature. The reaction mixture is concentrated, triturated with water and filtered. The crude product is washed with water, a small amount of ethanol and ethyl ether sequentially, and air-dried to give (6-Chloro-pyrimidin-4-yl)-methyl-amine as white powder: 1H NMR 400 MHz (d6-DMSO) δ 8.36-8.16 (m, 1H), 7.69 (s, 1H), 6.50 (s, 1H), 2.90-2.68 (m, 3H); MS m/z 144.00 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[Cl:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([NH:6][S:21]([C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([Cl:11])[S:13][C:14]=2[CH:20]=1)(=[O:22])=[O:23])[CH:7]([CH3:9])[CH3:8]
Reactant: O=S(=O)(Cl)c1ccc2nc(Cl)sc2c1
Reactant: COC(=O)[C@H](N)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](NS(=O)(=O)c1ccc2nc(Cl)sc2c1)C(C)C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
(D)-valine methylester hydrochloride (0.33 g, 2.0 mmol) was dispersed in dichloromethane (5 mL) and cooled down to 0° C. 2-Chloro-6-benzthiazolsulfonyl chloride (0.5 g, 1.0 equi.) prepared in Example 13 was dissolved in dichloromethane (3 mL) to give a dichloromethane solution. Triethylamine (0.83 mL, 3 equi.) and the dichloromethane solution were added while maintaining the temperature of 0° C. When starting material was exhausted after 5 hours, the organic phase was washed with 1N HCl, dried over MgSO4 and distilled under reduced pressure. Then, the product was eluted and purified on silica gel chromatography using ethylacetate/n-hexane (1/3) solvent to prepare the titled compound, (2R)-3-methyl-2-[(2-chlorobenzthiazol-6-sulfonyl)amino] butanoic acid methylester (0.65 g, 90%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[N:5]=[C:6]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:7]2[S:12][C:11]([C:13]3([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][C:8]=2[N:9]=1.[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:3][C:4]1[N:5]=[C:6]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:7]2[S:12][C:11]([C:13]3([OH:19])[CH2:14][CH2:15][N:16]([CH2:31][C:27]4[S:26][CH:30]=[CH:29][N:28]=4)[CH2:17][CH2:18]3)=[CH:10][C:8]=2[N:9]=1
Reactant: O=Cc1nccs1
Reactant: OC1(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: OC1(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN(Cc2nccs2)CC1

Procedure:
4-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)piperidin-4-ol dihydrochloride salt (250 mg) and 2-thiazole-carboxaldehyde (0.08 ml) were stirred together in 1,2-dichloroethane (3 ml) and triethylamine (0.18 ml) with sodium triacetoxyborohydride (187 mg) at room temperature overnight. Dichloromethane/brine extraction and purification on silica yielded 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-1-thiazol-2-ylmethyl-piperidin-4-ol (119 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(N(CC)CC)C.[Cl:29][CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>O1CCCC1>[Cl:29][CH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:11][N:10]=3)[CH:7]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (2.83 g, 8.29 mmol) was dissolved in tetrahydrofuran (20 ml), triethylamine (1.4 ml, 9.95 mmol) was added thereto, and the mixture was stirred for 30 minutes. 4-Chloromethyl benzoyl chloride (2.03 g, 10.78 mmol) was added and the whole mixture was reacted under reflux for 4 hours. The mixture was filtered, and the filtrate was concentrated and crystallized from water to give N-(5-(4-chloromethylbenzoylamino)-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (3.12 g).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:38])[CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:17][CH:18]=2)[C:13]1=[O:39])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:38])[CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:17][CH:18]=2)[C:13]1=[O:39]
Reactant: COC(=O)CCC(=O)Nc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC(=O)Nc1ccc2c3c(n(CCCN)c(=O)c2c1)-c1ccccc1C3=O

Procedure:
Compound 19 (0.060 g, 0.112 mmol) was treated with trifluoroacetic acid (0.5 mL) in chloroform (5 mL) for 2 h at room temperature. The solvent was removed on a rotary evaporator and the residue was then basified with 2 N NH3 in in methanol to get the free amine, which was purified by silica gel column chromatography, eluting with chloroform-methanol, 8.8:1.2, to yield the product 24 (0.028 g, 60%) as a brown solid: mp 272-274° C. IR (KBr) 2952, 1735, 1690, 1656, 1572, 1532, 1510, 1160, 765, 455 cm−1; 1H NMR (CD3OD, 300 MHz) δ 8.28 (s, 1 H), 7.92 (m, 1 H), 7.31 (m, 3 H), 7.20 (s, 2 H), 4.30 (t, J=4.8 Hz, 2H), 3.71 (s, 3 H), 2.83 (m, 2 H), 2.68 (m, 4 H), 2.00 (m, 2 H); 13C NMR (CD3OD, 125 MHz) δ 191.8, 174.9, 172.6, 164.4, 155.6, 139.2, 138.2, 135.9, 134.8, 131.9, 129.3, 127.1, 125.0, 124.9, 124.0, 123.8, 122.9, 118.5, 114.8, 109.5, 57.6, 57.4, 57.2, 43.6, 36.3, 32.2, 30.3, 29.7; ESIMS m/z (relative intensity) 434 (MH+, 100); HRESIMS calcd for C24H23N3O5 434.1852 (MH+), found 434.1835 (MH+); HPLC purity: 98.0% (1% TFA in MeOH).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH2:24]([N:26]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28]([CH3:34])=[N:27]1)[CH3:25]>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:31]([C:29]3[C:28]([CH3:34])=[N:27][N:26]([CH2:24][CH3:25])[CH:30]=3)=[O:32])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: CCn1cc(C(=O)O)c(C)n1
Product: CCn1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(C)sc2-c2cccc(F)c2)c(C)n1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.79 min; [M+H]+=468.2.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:5]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:4]=2[N:3]=1.[C:21]([C:27](OC)=[O:28])#[C:22][C:23]([O:25][CH3:26])=[O:24]>CO>[C:23]([C:22]1[N:3]2[C:4]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:5]=3[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])=[N:7][CH2:8][C:2]2=[N:1][C:27](=[O:28])[CH:21]=1)([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C#CC(=O)OC
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Solvent: CO
Product: COC(=O)c1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 21, 2-amino-7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepine was heated in methanol with dimethyl acetylenedicarboxylate to give 1-carbomethoxy-9-chloro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1[C:18]([O:20]C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.S(=O)(=O)(O)O>[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[S:11][C:10]=1[C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(C(F)(F)F)cc1OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1sc(C(F)(F)F)cc1OCc1ccccc1
Yield: 88.7 %

Procedure:
A mixture of 5E (3.80 g) and tetrahydrofuran (12 ml) was heated to reflux in 2N sodium hydroxide (12 ml) for 12 hours. Then the mixture was poured on ice and acidified with 6N sulfuric acid (pH=1-2). The mixture is extracted with diethyl ether twice. The combined organic phases were washed with water and dried. The mixture was concentrated and the residue is distilled under reduced pressure to yield the product as a white solid (3.22 g, 89 %) with a melting point of 142-144° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C@H:11]([CH2:14][NH2:15])[O:10][C:9]=2[CH:16]=1)(=[O:4])=[O:3].[F:17][C:18]([F:23])([F:22])[CH2:19][CH2:20]I>C(#N)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C@H:11]([CH2:14][NH:15][CH2:20][CH2:19][C:18]([F:23])([F:22])[F:17])[O:10][C:9]=2[CH:16]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)CCI
Reactant: CS(=O)(=O)c1ccc2c(c1)O[C@@H](CN)CO2
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)O[C@@H](CNCCC(F)(F)F)CO2
Temperature: 120 °C

Procedure:
A mixture of [(2S)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methylamine (0.31 g, 1.27 mmol), 1,1,1-trifluoro-3-iodopropane (0.16 ml, 1.4 mmol) K2CO3 (0.35 g, 2.5 mmol) and ACN (4 ml) was heated under microwave radiation at 120° C. for 40 min. The product was evaporated to dryness and was purified by preparative HPLC (MeOH/NH3 buffer). Yield: 0.19 g, 44%. The amine was converted to the hydrochloric acid salt and was crystallized from MeOH/Et2O. M.p. 204° C. MS m/z (rel. intensity, 70 eV) 339 (M+, 3), 127 (5), 126 (bp), 79 (4), 51 (4). [α]=−52° (MeOH).
Reaction SMILES: COC(=O)[NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:6]=1[C:14]#[C:15][CH2:16][CH2:17][CH2:18]Cl.C(OC1C=CC2[N:29]3CC[CH2:35][C:28]3=[CH:27]C=2C=1)C.[OH-].[K+]>C(#N)C.[Pd](Cl)Cl>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]2[N:4]3[CH2:18][CH2:17][CH2:16][C:15]3=[C:14]([CH2:27][C@@H:28]([NH2:29])[CH3:35])[C:6]=2[CH:7]=1)[CH3:13]
Reactant: CCOc1ccc2c(c1)cc1n2CCC1
Reactant: CCOc1ccc(NC(=O)OC)c(C#CCCCCl)c1
Agent: Cl[Pd]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCOc1ccc2c(c1)c(C[C@H](C)N)c1n2CCC1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 53.8 %

Procedure:
Iodoethane (15.8 mL, 220.64 mmol) and potassium carbonate (28.4 g, 220.05 mmol) were added to [2-(5-Chloro-pent-1-ynyl)-4-hydroxy-phenyl]-carbamic acid methyl ester (39 g, 145.68 mmol) in N,N-dimethylformamide (300 mL). The mixture was stirred 3 h at room temperature. The mixture was poured into 1M pH7 phosphate buffer and the organic phase extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated to dryness. The oily residue was purified by column chromatography on silica gel (6:1 to 5:1 hexane/ethyl acetate eluant) to afford the product as an oil (29 g, 67% over two steps) which solidified upon standing in the refrigerator. m.p. 55-56° C. 6-Ethoxy-2,3-dihydro-1H-3a-aza-cyclopenta[a]indene [2-(5-Chloro-pent-1-ynyl)-4-ethoxy-phenyl]-carbamic acid methyl ester (28.5 g, 96.36 mmol) was dissolved in acetonitrile (600 mL). Palladium (II) chloride (0.9 g, 5.08 mmol) was added and the mixture was heated 2 h at 70° C. The dark mixture was cooled to room temperature and filtered through a small pad of celite, while washing the pad with acetonitrile. The solvent was evaporated to dryness and the brown residue (30 g) taken up in tert-butanol (600 mL). Powdered potassium hydroxide (22 g, 392.09 mmol) was added and the mixture stirred 40 min in an oil-bath at 105° C. The mixture was cooled, poured onto ice and extracted twice with ethyl acetate. The combined organic phases were washed with water, brine, dried over sodium sulfate and evaporated. The brown residue was purified by column chromatography on silica gel (5:1 hexane/ethyl acetate) to afford the product as an off-white solid (13.4 g, 69%). m.p.101-102° C.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:31])=[C:11]([CH3:30])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:18]=3[O:26][CH3:27])[C:13]=2[C:28]=1[CH3:29])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[C:13]3[C:28]([CH3:29])=[C:9]([NH2:8])[C:10]([CH3:31])=[C:11]([CH3:30])[C:12]=3[O:16][CH2:15]2)=[C:18]([O:26][CH3:27])[CH:19]=1)([CH3:25])[CH3:24]
Reactant: COc1cc(C(C)C)ccc1C1COc2c(C)c(C)c(NCc3ccccc3)c(C)c21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C(C)C)ccc1C1COc2c(C)c(C)c(N)c(C)c21
Yield: 87 %

Procedure:
Using N-benzyl-3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 273, the title compound was synthesized in the same manner as in Reference Example 30. Yield 87%. Melting point: 120-121° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1]S([O-])(=O)=O.[K+].[F:7][C:8]([F:25])([C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:9][CH2:10][S:11][CH2:12][C:13]#[N:14].S([O-])([O-])=O.[Na+].[Na+]>O.CO>[F:25][C:8]([F:7])([C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])[CH2:9][CH2:10][S:11]([CH2:12][C:13]#[N:14])=[O:1]
Reactant: O=S(=O)([O-])O
Reactant: N#CCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CCS(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 2 h

Procedure:
To a suspension of 15.10 g of a double salt of 2KHSO5.KHSO4.K2SO4 (Oxone, registered trade mark) in 100 ml of water was added dropwise a solution of 4.77 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylthio)acetonitrile in 100 ml of methanol at −20° C. over 60 minutes under a nitrogen atmosphere, and the mixture was stirred for 2 hours. To the reaction mixture was added 50 ml of an aqueous 10% sodium sulfite solution, followed by extraction with 100 ml of ethyl acetate twice. Organic layers were combined, washed with 50 ml of an aqueous 10% sodium sulfite solution and 50 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under rescued pressure. The residue was subjected to silica gel column chromatography to obtain 12.56 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylsulfinyl)acetonitrile represented by the formula:
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:21](OC)=[O:22]>O1CCCC1.CCCCCC>[OH:22][CH:21]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC=O
Reactant: O=C(Nc1ccccc1)c1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1c2ncccc2C(O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-phenyl-2-pyridinecarboxamide (1.00 g) in dry tetrahydrofuran (20 mL) under N2 atmosphere at -78° C., was added n-butyllithium in hexane (4.0 mL, 2.5M). This mixture was allowed to stir for one hour. Methyl formate (0.62 mL) in dry tetrahydrofuran (5 mL) was added rapidly dropwise. After addition, the cold bath was removed and the mixture warmed to room temperature over two hours. The reaction was quenched with water and the tetrahydrofuran was evaporated in vacuo. The residue was extracted with ethyl acetate and dried (K2CO3). Purification was effected by flash chromatography on silica gel using ethyl acetate/hexane (6/4) as eluant (Rf =0.1). The yield was 310 mg (27.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].C([O-])([O-])=O.[K+].[K+].[CH:17](I)([CH3:19])[CH3:18]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: CC(C)I
Reactant: COc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cc(OC(C)C)ccc1Br
Temperature: 25 °C

Procedure:
To a stirred suspension of 4-bromo-3-methoxyphenol (2.03 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) in 2-butanone (70 mL) at ambient temperature under argon is added dropwise isopropyl iodide (2.21 g, 13.3 mmol). The resulting mixture is heated and stirred under reflux for 17 hours. The mixture is allowed to cool to ambient temperature then is filtered and concentrated by evaporation of the solvent. The residue is partitioned between Et2O and H2O. The Et2O layer is extracted with 5% NaOH (2×50 mL), washed with brine, and dried over MgSO4. The solvent is evaporated and the resulting residue is purified by flash chromatography (5% EtOAc/hexane) to afford the desired compound as a pale yellow oil. 2.13 g (87%).
Reaction SMILES: [N:1]1[NH:2][C:3]([NH2:6])=[N:4][CH:5]=1.[O:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[C:14]([C:17](=O)[CH2:18][C:19](OCC)=[O:20])[CH:15]=[CH:16][C:8]1=2>C(O)(=O)C>[O:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[C:14]([C:17]3[NH:6][C:3]4[N:2]([N:1]=[CH:5][N:4]=4)[C:19](=[O:20])[CH:18]=3)[CH:15]=[CH:16][C:8]1=2
Reactant: Nc1ncn[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc2c(c1)OCCO2
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc3c(c2)OCCO3)[nH]c2ncnn12
Temperature: 120 °C
Reaction time: 24 h
Yield: 14.8 %

Procedure:
A mixture of 2H-1,2,4-triazol-3-amine (200 mg, 2.38 mmol, 1.00 equiv), acetic acid (3 mL), and ethyl 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopropanoate (600 mg, 2.40 mmol, 1.01 equiv) was stirred for 24 hr at 120° C. and then concentrated to dryness. The resulting solid was washed with MeOH and collected by filtration. The solid was dissolved in 15 mL of NH4OH (aq.) and filtered. The filtrate was adjusted to pH 5 with HOAc. The resulting solid was collected by filtration and washed with water. The solid was dried to get 95 mg (15%) of 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a white solid.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[NH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1.[BH4-].[Na+]>CO>[CH2:1]([NH:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH3:3]
Reactant: NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCNCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
Propanal (1.51 g) dissolved in 5 ml of methanol was added dropwise to 6.15 g of 2-aminomethyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane dissolved in 60 ml of methanol. The mixture was stirred at room temperature for 30 minutes. Then, under ice cooling, 1.03 g of sodium borohydride was added to the mixture. The resulting mixture was stirred at the same temperature for 20 minutes and then stirred at room temperature for 1 hour. After methanol was removed, water was added to the residue, and the residue was extracted with ethyl acetate. The organic layer was collected by filtration, washed with water and dried, and the solvent was removed. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol (15:1)) to obtain 5.22 g of 2-propylaminomethyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1>S(Cl)(Cl)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:7][CH2:6][CH2:5][CH3:4])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cl)n1
Solvent: O=S(Cl)Cl
Product: CCCNC(=O)c1cccc(Cl)n1
Yield: 158.6 %

Procedure:
6-chloropicolinic acid (3 g) and thionyl chloride (50 ml) was refluxed for one hour. The excess thionyl chloride was evaporated in vacuo and dichloromethane added to the residual picolinoyl chloride. This solution was poured into an excess of n-propylamine in dichloromethane. The solution was then washed with water, dried over anhydrous magnesium sulphate and the dichloromethane evaporated to give 6-chloro-2-N-n-propyl pyridine carboxamide (3 g) as a yellow oil.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][CH2:11][C:12]#[C:13][CH3:14])(=O)OC.[CH:17]([C@H:19]1[C@H:26]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][C@H:24]2[C@@H:20]1[CH2:21][C:22](=[O:36])[O:23]2)=O>>[C:28]([O:27][C@@H:26]1[CH2:25][C@H:24]2[C@H:20]([CH2:21][C:22](=[O:36])[O:23]2)[C@H:19]1/[CH:17]=[CH:7]/[C:8](=[O:16])[CH:9]([CH3:15])[CH2:10][CH2:11][C:12]#[C:13][CH3:14])(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC#CCCC(C)C(=O)CP(=O)(OC)OC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Product: CC#CCCC(C)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Yield: 85.8 %

Procedure:
Analogously to Example 1(g), 7.4 g of the title compound was synthesized from 5.4 g of 3-methyl-2-oxooct-6-inylphosphonic acid dimethyl ester and 6 g of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one [E. J. Corey et al., J. Amer. Chem. Soc. 91: 5675 (1969)].
Reaction SMILES: [CH2:1]([C:3]([OH:16])([CH2:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10])[CH3:2].[C:17](#[N:19])[CH3:18]>>[CH2:1]([C:3]([OH:16])([CH2:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]([OH:10])[CH2:18][C:17]#[N:19])[CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCC(O)(CC)COc1cccc(C=O)c1
Reactant: CC#N
Product: CCC(O)(CC)COc1cccc(C(O)CC#N)c1

Procedure:
3-(2-Ethyl-2-hydroxybutoxy)benzaldehyde was reacted with acetonitrile following the method used in Example 13. Purification by flash chromatography (30, 40, 50, 75% EtOAc-hexanes step gradient) gave 3-(3-(2-ethyl-2-hydroxybutoxy)phenyl)-3-hydroxypropanenitrile as an oil. Yield (0.17 g, 79%): 1H NMR (400 MHz, CDCl3) δ 7.23 (t, J=8.0 Hz, 1H), 6.96-6.98 (m, 2H), 6.88-6.91 (m, 1H), 5.02 (t, J=6.4 Hz, 1H), 3.83 (s, 2H), 2.76 (d, J=6.8 Hz, 2H), 1.62-1.68 (m, 4H), 0.92 (t, J=7.6 Hz, 6H).