Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:43])[O:21][NH:22][C:23](=[O:42])[C@@H:24]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=[O:31])[CH2:25][C:26]([NH2:28])=[O:27])[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:45]([C:48]1[CH:61]=[CH:60][C:51]2[NH:52][C:53]([NH:55][C:56](=[O:59])[O:57][CH3:58])=[N:54][C:50]=2[CH:49]=1)(=[O:47])=[O:46].C(N(C(C)C)CC)(C)C>O1CCCC1.CO>[CH2:1]([C@H:8]([NH:19][C:20](=[O:43])[O:21][NH:22][C:23](=[O:42])[C@@H:24]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=[O:31])[CH2:25][C:26]([NH2:28])=[O:27])[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)[S:45]([C:48]1[CH:61]=[CH:60][C:51]2[NH:52][C:53]([NH:55][C:56]([O:57][CH3:58])=[O:59])=[N:54][C:50]=2[CH:49]=1)(=[O:47])=[O:46])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)NOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCC1
Reactant: COC(=O)Nc1nc2cc(S(=O)(=O)Cl)ccc2[nH]1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1nc2cc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc3ccccc3)NC(=O)ONC(=O)[C@H](CC(N)=O)NC(=O)c3ccc4ccccc4n3)OC3CCCC3)ccc2[nH]1
Reaction time: 24 h
Yield: 18.9 %

Procedure:
(2S)-4-Amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanamido N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)-amino]-2-hydroxypropylcarbamate (Step 1, above), (44 mg, 0.0825 mmcl), methyl N-[5-(chlorosulfonyl)-1H-benzimidazol-2-yl]carbamate (24 mg, 0.0825 mmol), and anhydrous diisopropylethylamine (0.05 mL, 0.280 mmol) were combined in anhydrous tetrahydrofuran (3 mL) in a 25 mL round bottomed flask under nitrogen. The reaction was stirred for 24 hours and concentrated in vacuo. Ethyl acetate (30 mL) and water (10 mL) were added and the layers were separated. The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative silica gel TLC using 90:10 chloroform: methanol as an eluent to provide the desired product as a white solid (11 mg, 0.014 mmol, 17%). 1HNMR (d6-DMSO) δ: 8.86 (d, J=8.4 Hz, 1H), 8.62 (d, J=8.4 Hz, 1H), 8.22-6.94 (m, 12H), 5.19 (d, J=6.2 Hz, 1H), 4.77-4.72 (m, 2H), 4.02-1.35 (m, 17H), 3.80 (s, 3H). MS(ES): 787 (M+1), 785 (M-1).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O.C1(C)C=CC=CC=1>[N:17]1[CH:16]=[CH:15][C:14]([C:13]2[O:20][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3)nc2c1
Reaction time: 1.3 h
Yield: 27.8 %

Procedure:
To a mixture of 1.69 g of N-(2-hydroxy-5-trifluoromethylphenyl)isonicotinamide, 25 ml of tetrahydrofuran and 2.36 g of triphenylphosphine, 3.91g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. After 1.3 hours, 0.6 g of triphenylphosphine and 1.0 g of 40% toluene solution of diethyl azodicarboxylate were added and stirred for further 40 minutes. Water was poured into the mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was washed with diethyl ether, and 10 ml of methanol and 10 ml of 1 M aqueous solution of sodium hydroxide were added and stirred for two hours at room temperature. After concentrated hydrochloric acid was added to the reaction mixture while ice-cooling so as to make it acidic, the reaction mixture was washed with ethyl acetate. To the aqueous layer, 1 M aqueous solution of sodium hydroxide was added so as to make the solution alkaline, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.44 g of 2-(pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 13”).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1.Br[C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:19][N:2]([CH2:3][C:4]1[CH:9]=[C:8]([C:21]2[CH:22]=[C:23]3[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=2)[NH:26][CH:25]=[C:24]3[CH:33]2[CH2:34][CH2:35][N:36]([S:39]([CH2:42][CH3:43])(=[O:40])=[O:41])[CH2:37][CH2:38]2)[CH:7]=[N:6][CH:5]=1)[CH3:1]
Reactant: CN(C)Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CN(C)C)c4)cc23)CC1
Yield: 16 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution of dimethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 23 mg of crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 5.4 mg of the title compound (16%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[Cl:12].CCN(CC)CC.CS(C)=[O:22]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Ag+]>[Cl:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]=[O:22]
Reactant: O=[N+]([O-])c1cccc(CBr)c1Cl
Reactant: CS(C)=O
Agent: [Ag+]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Product: O=Cc1cccc([N+](=O)[O-])c1Cl
Yield: 20 %

Procedure:
2-Chloro-3-nitrobenzaldehyde (150 mg, 20%) was prepared by reaction of 1-bromomethyl-2-chloro-3-nitrobenzene (1.0 g, 3.9 mmol) with silver p-toluenesulfonate (1.94 g, 1.75 equiv.) in DMSO in the presence of Et3N (4 mL, 7 equiv.) at rt for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:33])=[C:19]([NH:23][S:24]([C:27]3[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:35]>>[ClH:1].[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:33])=[C:19]([NH:23][S:24]([C:27]3[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Cn1ccc(S(=O)(=O)Nc2cccc(-c3nc(C(C)(C)C)sc3-c3ccnc(Cl)n3)c2F)n1
Agent: [OH-]
Product: Cl
Product: Cn1ccc(S(=O)(=O)Nc2cccc(-c3nc(C(C)(C)C)sc3-c3ccnc(N)n3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 282 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-3-sulfonamide (760 mg, 1.50 mmol) and ammonium hydroxide (15 ml), the title compound was obtained as a white solid (130 mg, 54%). 1HNMR (MEOD-d4): δ ppm 7.94-7.96 (d, J=6.4 Hz, 1H), 7.60-7.60 (d, J=2.4 Hz, 1H), 7.44-7.49 (dd, J1=7.7 Hz, J2=1.2 Hz, 1H), 7.27-7.30 (t, J=6.4 Hz, 1H), 7.15-7.19 (t, J=8.0 Hz, 1H), 6.56-6.56 (t, J=2.4 Hz, 1H), 6.41-6.43 (d, J=6.8 Hz, 1H), 3.81 (s, 3H), 1.39 (s, 9H); MS: 488 [M+H]+:
Reaction SMILES: C([O:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([C:11]2[CH:29]=[CH:28][C:14]([CH2:15][S:16][C:17]3[N:18]([CH3:27])[C:19](=[O:26])[C:20]4[S:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].O>C1COCC1>[OH:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([C:11]2[CH:29]=[CH:28][C:14]([CH2:15][S:16][C:17]3[N:18]([CH3:27])[C:19](=[O:26])[C:20]4[S:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(CSc3nc4ccsc4c(=O)n3C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(SCc2ccc(C(=O)c3ccc(O)cc3)cc2)nc2ccsc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
To a solution of 2-[4-(4-acetoxybenzoyl) benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (3.51 g) in THF (20 ml) was added 1N-sodium hydroxide/water (10 ml) and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was concentrated, the residue was dissolved in water, and 1N-hydrochloric acid was added. The resulting crystals were collected by filtration, rinsed with water, and dried to provide the title compound as colorless solid (3.22 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4](Cl)[N:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4]([NH:23][CH:20]2[CH2:22][CH2:21]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Reactant: NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(NC2CC2)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1

Procedure:
(+)-(1S, 2R, 4R)-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl) cyclopentanol (425 mg, 1.5 mmol), cyclopropylamine (Aldrich, 1.4 mL), and ethanol (4 mL) were refluxed for 3 hours. To the cooled solution was added 1N sodium hydroxide (1.5 mL). The residual oil left on evaporation of volatiles under vacuum was chromatographed on silica gel. Title compound was eluted with methanol ethyl acetate/15:85 as a white solid foam which solidified to white powder in methanol-acetonitrile (309 mg, 68%); m.p. 174°-176° C.; mass spectrum (Cl,CH4)305 (M+1); 1H-NMR(DMSO-d6) δ: 7.79 (s, 1, H-8); 7.25 (d, J=2.9 Hz, 1, NH), 5.79 (s, 2, NH2), 4.90-4.75 (m, 1, CH-N), 4.73 (d, J=4.0 Hz, 1, OH), 4.63 (t, J=5.3 Hz, 1, CHOH), 4.08-4.00 (m, 1, CHO), 3.58-3.38 (m, 2, CH2O), 3.05-2.95 (m, 1 CH-NH), 2.35-2.20(m, 1, CH), 2.18-2.0 (m, 1, 1/2CH2), 2.0-1.9 (m, 2, methylene), 1.7-1.5 (m, 1, 1/2CH2),0.70-0.50 m, 4, 2CH2 of cyclopropyl); [α]20589 +7.72°, [α]20 578 +7.87°, [α]20546 +8.77°, [α]20436 +14.4°, [α]20365 +20.1°(c=0.65, methanol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:4][C:3]=1[O:15][CH3:16].C(N(CC)CC)C.[C:24](Cl)(=[O:28])[O:25][CH2:26][CH3:27].[CH2:30]([NH2:35])[CH:31]=[C:32]([CH3:34])[CH3:33]>C(Cl)Cl>[CH2:30]([NH:35][C:12](=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:24]([O:25][CH2:26][CH3:27])=[O:28])=[C:3]([O:15][CH3:16])[CH:4]=1)[CH:31]=[C:32]([CH3:34])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: COc1cc(C=CC=CC(=O)O)ccc1O
Reactant: CC(C)=CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(C=CC=CC(=O)NCC=C(C)C)cc1OC
Temperature: -10 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
In 50 ml of methylene chloride is suspended 2.20 g of 5-(4'-hydroxy 3'-methoxyphenyl)pentadienoic acid under an argon atmosphere. To the suspension cooled to -10° C. are added 2.92 ml of triethylamine and 2.16 g of ethyl chlorocarbonate. To the mixture, after stirred for one hour, is added a solution of 1.28 g of prenylamine in 10 ml of methylene chloride, and the resulting mixture is stirred at -10° C. to 0° C. for 3 hours. The reaction mixture is poured onto water and extracted with chloroform. The organic layer is washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel. From the fraction eluted with methylene chloride-methanol (99:1) is obtained 2.91 g of 5-(4'-ethoxycarbonyloxy-3'-methoxyphenyl)pentadienoic acid prenylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[N:12]=[C:13]=[O:14].[CH2:15]([NH2:17])[CH3:16].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:10])([CH3:11])[CH3:9])[C:3]=1[NH:12][C:13]([NH:17][CH2:15][CH3:16])=[O:14]
Reactant: CCN
Reactant: C[Si](C)(C)c1cccc(Cl)c1N=C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1c(Cl)cccc1[Si](C)(C)C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of the compound of Example h (4 mmol) in 50 mL toluene was added 70% ethyl amine (4 mL). The solution was stirred for 0.5 h and then stood overnight. Ethyl acetate was added and the mixture was washed with water. The organic layer was concentrated to a semisolid, which was triturated with hexane. The title compound was collected by filtration as 0.9 g of crystals, an 83% yield. m.p. 161°-163° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]([N:19]1[C:23]2[N:24]=[C:25](F)[N:26]=[C:27]([O:28][C:29]3[C:36]([CH3:37])=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=3[CH3:38])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[N:26]=[C:27]([O:28][C:29]3[C:30]([CH3:38])=[CH:31][C:32]([C:33]#[N:34])=[CH:35][C:36]=3[CH3:37])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(F)nc2c1ccn2Cc1ccccc1
Reactant: N#Cc1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To a solution of 4-aminobenzonitrile (54 mg, 0.46 mmol) in 1-methyl-2-pyrridone (1 mL) was added NaH (18 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 4-(7-benzyl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile (34 mg, 0.091 mmol) in 1-methyl-2-pyrridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water, and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 28 mg (65%) of 4-[7-benzyl-2-(4-cyano-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3,5-dimethyl-benzonitrile.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17].[OH-].[Na+]>O1CCCC1>[C:15]([O:7][CH:3]1[CH2:4][CH2:5][CH2:6][S:1][CH2:2]1)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1CCCSC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCCSC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Freshly distilled tetrahydrothiopyran-3-ol (8.97 g, 75.3 mmol) and triethylamine (10.6 mL, 75.5 mmol) were dissolved in anhydrous tetrahydrofuran (THF) (40 mL) and cooled to 0° C. Methacryloyl chloride (8.1 mL, 83.2 mmol) was then added slowly, dropwise. The reaction then was warmed slowly to room temperature. After stirring overnight, 30 mL DIW were added and the mixture was made basic with 5 M NaOH. The THF then was removed by rotary evaporation and the product was extracted with diethyl ether (3×40 mL). The ether extracts were combined and washed with 0.1 M NaOH, followed by DIW before being dried over sodium sulfate and filtered. The product was then concentrated by rotary evaporation and dried in vacuo to afford tetrahydro-2H-thiopyran-3-yl methacrylate as a light orange liquid (7.63 g, 54%). 1H NMR (600 MHz, CDCl3, ppm) δ 6.08 (s, 1H), 5.54 (s, 1H), 4.94 (m, 1H), 2.78 (m, 1H), 2.62 (m, 1H), 2.49 (m, 1H), 2.47 (m, 1H), 2.14 (m, 1H), 1.99 (m, 1H), 1.91 (s, 3H), 1.85 (m, 1H), 1.49 (m, 1H). 13C NMR (150 MHz, CDCl3, ppm) δ 166.61, 136.69, 125.62, 71.21, 32.26, 31.82, 28.10, 27.43, 18.43.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([C:21]#[N:22])=[N:8][C:9]([NH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[CH:10][CH:11]=1.O.O.Cl[Sn]Cl>O.Cl>[F:19][C:17]1[CH:18]=[C:13]([NH:12][C:9]2[N:8]=[C:7]3[C:21]([NH2:1])=[N:22][NH:5][C:6]3=[CH:11][CH:10]=2)[CH:14]=[C:15]([F:20])[CH:16]=1
Reactant: N#Cc1nc(Nc2cc(F)cc(F)c2)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1n[nH]c2ccc(Nc3cc(F)cc(F)c3)nc12
Temperature: 2.5 °C
Reaction time: 0.33 h

Procedure:
A solution of 713 mg of NaNO2 (10.3 mmol) in water (5 ml) is added, drop by drop, to a stirring solution of 2.3 g of 3-amino-6-(3,5-difluorophenylamino)picolinonitrile (9.4 mmol) in 100 ml of 6 N hydrochloric acid at 0° C. The mixture is stirred for 20 minutes at 0-5° C. A solution of 5.3 g of SnCl2.2H2O (23.5 mmol, 2.5 eq) in hydrochloric acid (12 N solution, 30 ml) is then added drop by drop and the solution is stirred for 1 hour at room temperature. The reaction medium is then cooled at 0° C. and basified to pH 8 using 30% soda solution. The mixture is extracted with ethyl acetate and washed using saturated NaCl solution and the organic phase is dried on anhydrous sodium sulfate before being concentrated under vacuum. The residue is purified by silica column chromatography (AcOEt). A light yellow solid is obtained (530 mg, 22%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>CCOCC>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2ccccc2N1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C)C(=O)N1c2ccccc2CC1C(=O)OCC

Procedure:
To a chilled and stirred mixture of 2,3-dihydroindole-2-carboxylic acid ethyl ester (4.78 g., 25.0 mmole), triethylamine (2.7 g., 26.7 mmole), and anhydrous ether (500 ml) was added dropwise methacryloyl chloride (2.9 g., 27.7 mmole) dissolved in a small amount of ether. After the completion of the addition, the ice bath was removed, and the reaction mixture was stirred for 4 hours. The precipitate which separated was removed by filtration, and the filter residue was washed with ether. The combined filtrate and washing were washed with water (two 700ml portions), then with saline, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure on a rotary evaporator gave the product as an oil. The product was purified by preparative HPLC (Prep LC/System 500, Waters Associates), using a micro porasil column eluted with a mixture of hexane (95%) and ethyl acetate (5%). The crude oil may be used directly in the following reaction (Example 2).
Reaction SMILES: [SH2:1].[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1CC#N.[CH2:11]([N:13](CC)CC)[CH3:12]>N1C=CC=CC=1>[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[NH:13][C:11](=[S:1])[CH3:12]
Reactant: CCN(CC)CC
Reactant: S
Reactant: Cn1ccnc1CC#N
Solvent: c1ccncc1
Product: CC(=S)Nc1nccn1C
Temperature: 0 °C

Procedure:
Hydrogen sulfide was bubbled to a solution of 1.4 gm (11.5 mmole) of N-methyl-2-cyanomethylimidazole and 10 ml dry pyridine stirred in a medium pressure glass Carius tube at 0° C. Then 1.5 equivalents of triethylamine was added (2.50 ml) and the pressure tube was sealed and heated on a steam bath for 4 hours. It was cooled and cracked open to vent any excess hydrogen sulfide. The product crystallized out of the solution when it was cooled to 0° C. The crystals were filtered and washed with 2×5 ml of hexane to afford 1.29 gm of N-methyl-2-thioacetamidioimidazole, m.p. 155°-160° C. (decomposition).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])C(=O)[C:3]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.[CH2:56]([SH:59])[CH2:57][CH3:58].[C:60](=[O:63])([O-])[O-].[K+].[K+]>C(#N)C>[C:50]1([C:3]2[C:60](=[O:63])[N:5]([CH2:46][CH2:47][CH3:48])[C:6](=[O:45])[N:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]4[NH:22][N:23]=[N:24][N:25]=4)=[CH:11][CH:10]=3)[C:2]=2[S:59][CH2:56][CH2:57][CH3:58])[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C([O-])[O-]
Reactant: CCCn1c(=O)c(-c2ccccc2)c(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: CCCS
Agent: [K+]
Solvent: CC#N
Product: CCCSc1c(-c2ccccc2)c(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 72 %

Procedure:
A mixture of 6-chloro-5-phenyl-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g), propylmercaptan (0.08 ml) and potassium carbonate (0.14 g) in acetonitrile (10 ml) was heated under reflux for 4 hours with stirring. The reaction mixture was allowed to cool and the precipitate was removed by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and 1N hydrochloric acid (1 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.26 g, 72%).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4](=O)[CH2:5][O:6][CH2:7][CH2:8][C:9]1[C:17]([F:18])=[CH:16][C:12]2[S:13][CH:14]=[CH:15][C:11]=2[CH:10]=1)[CH3:2].Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[C:17]([F:18])=[CH:16][C:12]2[S:13][CH:14]=[CH:15][C:11]=2[CH:10]=1)[CH3:21]
Reactant: CCN(CC)C(=O)COCCc1cc2ccsc2cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)CCOCCc1cc2ccsc2cc1F
Temperature: 5 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
In 20 mL of tetrahydrofuran is dissolved 1.24 g of N,N-diethyl-2-[2-(6-fluorobenzo[b]thiophen-5-yl)ethoxy]-acetamide. The solution is cooled to 5° C., and 7.86 mL of a 1 mol/L solution of borane-tetrahydrofuran complex in tetrahydrofuran is dropwise added thereto. After stirring the resulting mixture at ambient temperature for 2 hours, 4.00 mL of 2 mol/L hydrochloric acid is dropwise added, and the resulting mixture is heated under reflux for 30 minutes. After cooling, water and ethyl acetate are added to the reaction mixture, pH is adjusted to 13 with 5 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent:chloroform:methanol=30:1 to 10:1) to obtain 0.90 g of N,N-diethyl-N-{2-[2-(6-fluorobenzo[b]thiophen-5-yl)ethoxy]ethyl}-amine as an oily product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([F:16])([F:15])[CH2:9]1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[F:15][C:10]1([F:16])[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OC1CCN(Cc2ccccc2)CC1(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: OC1CCNCC1(F)F
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar, a suspension of 1-benzyl-3,3-difluoropiperidin-4-ol (1.73 g, 7.62 mmol) and Pd(OH)2 (20% Pd, 107 mg) in dry EtOH (50 mL) was stirred at rt under a H2 atmospheric pressure until completion of the reaction. The mixture was then filtered, washed with EA/EtOH, and the filtrate concentrated under reduced pressure to give the title compound as a beige solid.