Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([N:9]([CH2:13]CO)[CH2:10][CH2:11]O)([CH3:8])([CH3:7])[CH3:6].CO.C(OCC)C.[CH:23]([Cl:26])(Cl)Cl>>[Cl:3][CH2:11][CH2:10][N:9]([CH2:13][CH2:23][Cl:26])[C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)N(CCO)CCO
Reactant: ClC(Cl)Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)N(CCCl)CCCl
Temperature: 20 °C
Yield: 81 %

Procedure:
Thionyl chloride (30 mL, 409.2 mmol) was diluted in chloroform (40 mL) and stirred at 20° C. 2,2′-(Tert-butylazanediyl)diethanol (30 g, 186 mmol) in chloroform (20 mL) was added dropwise over 45 minutes. The resulting mixture was stirred for 18 hours at 20° C. and refluxed for 2 hours. The mixture was cooled and methanol (˜10 mL) was added, followed by ethyl ether (˜50 mL). The resulting precipitate was filtered, washed with ethyl ether and dried under vacuum to give the title material (35 g, 81%) as the HCl salt. 1H NMR (400 MHz, CDCl3) δ ppm: 1.60 (9H, s), 3.20 (2H, s), 3.68 (2H, s), 4.12-4.19 (2H, m), 4.21-4.28 (2H, m), 12.66 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=2[F:21])[CH2:8][CH2:7]1)=[O:5].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[F:21][C:13]1[CH:14]=[C:15]([C:18](=[O:20])[CH3:19])[CH:16]=[CH:17][C:12]=1[N:9]1[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C:3]2[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:2]=2[N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:7][CH2:8]1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3Cl)CC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example 1 from 1-{4-[4-(2-Chloro-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone (example K) and morpholine (57%, white solid), MS (m/e): 490.2 (M+H, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[H-].[Na+].COC1C=C2C(=CC=1OC)N=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:45]=[CH:44][C:43](NC(NC2CCNCC2)=O)=[CH:42][CH:41]=1.[C:56](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:32][CH2:31][CH2:30][O:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=2[CH3:56])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCNCC4)cc3)c2cc1OC
Reactant: O=C([O-])O
Reactant: COc1cc2nccc(Oc3ccc(O)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(OCCCOc4ccccc4C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenol (100 mg) was dissolved in dimethylformamide (2 ml) to prepare a solution. Sodium hydride (16 mg) was then added to the solution, and the mixture was stirred at room temperature for 10 min. A solution of the compound (1) (85 mg) in dimethylformamide was added thereto, and the mixture was further stirred at room temperature for 2 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing three times with saturated brine. The extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (148 mg, yield 98%).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][N:3]([C:12](=[O:14])[CH3:13])[CH2:2]1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C.S(=O)(=O)(O)O>[N+:15]([C:10]1[CH:9]=[CH:8][C:7]2[CH2:1][CH2:2][N:3]([C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][C:6]=2[CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCc2ccccc2CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
1-(1,2,4,5-Tetrahydrobenzo[d]azepin-3-yl)ethanone (3.8 g) was dissolved in a 2:1 mixture of acetic acid and 96% sulphuric acid (15 ml), then the mixture was cooled to 0° C. and a 3:2 mixture of 65% nitric acid and 96% sulphuric acid (2.5 ml) was added dropwise, while the temperature was maintained below 5° C. The mixture was stirred for additional 30 min, then poured into crushed ice (300 g) and extracted with ethyl acetate. The organic phase was washed with 5% aqueous NaHCO3, dried over Na2SO4 and concentrated to afford a crude material (4.3 g). Filtration through a silica gel pad (DCM/MeOH, 98/2) yielded the title compound as a yellow solid (4.0 g, 85% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[N:3]=1
Reactant: Cc1n[nH]c2ncccc12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nn(C(=O)OC(C)(C)C)c2ncccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 692 mg (5.20 mmol) of 3-methyl-1H-pyrazolo[3,4-b]pyridine in 25 mL of acetonitrile under nitrogen was cooled to 0° C. in an ice bath, and was treated with 635 mg (5.20 mmol) of DMAP and 761 μL (5.46 mmol) of triethylamine. A solution of 1.36 g (6.24 mmol) of (BOC)2O in 5 mL acetonitrile was then added dropwise using an addition funnel. Upon completion of addition, the ice bath was removed and the mixture was stirred for an additional 18 hours at room temperature. Solvent was removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to an orange oil. This crude material was purified by flash chromatography over silica gel with 1:1 ethyl acetate/hexanes to give the title product as a clear oil. 1H NMR (CDCl3): 1.74 (s, 9H), 2.60 (s, 3H), 7.29 (m, 1H), 8.02 (dd, 1H), 8.74 (dd, 1H).
Reaction SMILES: [H-].[Na+].C1COCC1.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][CH2:13][C:12]2[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=2[NH:10]1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32]Br>CCOC(C)=O>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32][N:10]1[C:11]2[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=2[CH2:13][CH2:14][CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:9]1=[O:8]
Reactant: CC(C)(C)OC(=O)NC1CCc2ccccc2NC1=O
Reactant: Fc1cc(F)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCc2ccccc2N(Cc2cc(F)cc(F)c2)C1=O
Yield: 137.3 %

Procedure:
72 mg of sodium hydride in suspension at 60% in oil (1.81 mmol) are introduced, at AT, into a 100 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of THF and 0.5 g of 2 (1.81 mmol). The medium is stirred for 1 h and then 0.75 g (3.62 mmol) of 3,5-difluorobenzyl bromide is added. The medium is left stirring at AT overnight. 50 ml of EtOAc are added and the organic phase is washed with 50 ml of water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 1 g of a white solid is obtained. After trituration with 20 ml of isopropyl ether and filter-drying, 0.62 g of product 3 (white solid) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][C:17]3=[O:18])=[CH:12][CH:11]=2)=[O:9])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:31](Br)[CH3:32]>CN(C)C=O>[CH2:31]([N:7]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][C:17]2=[O:18])=[CH:12][CH:11]=1)=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=1)[CH3:32]
Reactant: CCBr
Reactant: COc1ccc(NC(=O)c2ccc(N3C(=O)CCc4ccccc43)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ccc(N2C(=O)CCc3ccccc32)cc1)c1ccc(OC)cc1
Yield: 55.8 %

Procedure:
To a solution of 1-[4-(4-methoxyanilinocarbonyl)phenyl]-3,4-dihydrocarbostyril (0.2 g) in dimethylformamide (15 ml) is added 60% sodium hydride (24 mg) with stirring under ice cooling and the mixture is stirred at room temperature for 0.5 hour. Then, thereto is added a solution of ethyl bromide (64 mg) in dimethylformamide (DMF, 1 ml) and the mixture is refluxed with heating for 1 hour. DMF is distilled off under reduced pressure and water is added to the residue and the mixture is extracted with dichloromethane. The extract is washed with water and dried with magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography to give 1-[4-(N-ethyl-4-methoxyanilinocarbonyl)phenyl]-3,4-dihydrocarbostyril (0.12 g).
Reaction SMILES: CCCCC.[H-].[Na+].[ClH:8].[NH:9]1[CH2:13][CH2:12][N:11]=[CH:10]1.[Cl:14][C:15]1[C:16]2[N:17]([CH:21]=[CH:22][N:23]=2)[CH:18]=[CH:19][N:20]=1.CN(C)[CH:26]=[O:27]>C(OCC)C>[ClH:14].[OH2:27].[ClH:8].[ClH:14].[NH:11]1[CH2:12][CH2:13][N:9]=[C:10]1[CH2:26][O:27][C:15]1[C:16]2[N:17]([CH:21]=[CH:22][N:23]=2)[CH:18]=[CH:19][N:20]=1.[NH:11]1[CH2:12][CH2:13][N:9]=[C:10]1[CH2:26][O:27][C:15]1[C:16]2[N:17]([CH:21]=[CH:22][N:23]=2)[CH:18]=[CH:19][N:20]=1.[ClH:14].[ClH:14]
Reactant: C1=NCCN1
Reactant: CN(C)C=O
Reactant: Clc1nccn2ccnc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCC
Product: O
Product: c1cn2ccnc2c(OCC2=NCCN2)n1
Reaction time: 0.5 h

Procedure:
To a slurry of 530 mg (22 mmol) of pentane-washed sodium hydride in 50 ml of dry dimethylformamide (DMF) was added 1.37 g (10.0 mmol) of 2-hydroxymethyl)-4,5-dihydroimidazole hydrochloride. After 30 minutes at room temperature, 1.55 g (10.0 mmol) of 8-chloroimidazo[1,2-a]pyrazine in 30 ml of DMF was added dropwise. After 1 hour at room temperature, the mixture was concentrated to dryness. The residue was dissolved in 30 ml of water and extracted with 2×50 ml of chloroform. The combined organic extracts were dried (Na2SO4), filtered, and concentrated. The oily residue was purified by flash chromatography (230-400 mesh SiO2 ; 10% MeOH/CHCl3 saturated with NH3 as eluent) to afford the product. Treatment with ethanolic HCl and excess diethyl ether afforded the crystalline dihydrochloride hemihydrate salt of the product, m.p. 162°-165° C. (dec).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:11])=[C:2]=[S:3].[OH-].[NH4+:13]>>[CH3:11][N:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[CH2:5][CH2:4][NH:1][C:2]([NH2:13])=[S:3]
Reactant: [NH4+]
Reactant: CN1CCCC1CCN=C=S
Agent: [OH-]
Product: CN1CCCC1CCNC(N)=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The 2-(2-isothiocyanatoethyl)-1-methylpyrrolidine and concentrated ammonium hydroxide (3 mL) were heated at 100° C. for 30 minutes. Additional ammonium hydroxide (1 mL) was added and heating was continued for an additional 30 minutes. The reaction mixture was allowed to cool to room temperature and then it was lyophilized to give [2-(1-methylpyrrolidin-2-yl)ethyl]thiourea as a very viscous colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]([CH3:17])=[N:15][NH:14][N:13]2[CH3:18])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:20]([O:22][CH2:23][CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[N:34]1[CH2:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][C:43]2([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:47][CH2:46][NH:45][CH2:44]2)[CH2:36][CH2:35]1)[CH3:21]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]([CH3:17])=[N:15][NH:14][N:13]2[CH3:18])=[CH:8][C:4]=1[C:5]([N:45]1[CH2:46][CH2:47][C:43]([CH2:42][CH2:41][N:37]2[CH2:38][CH2:39][CH2:40][N:34]([C:26]3[N:25]([CH2:24][CH2:23][O:22][CH2:20][CH3:21])[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=3)[CH2:35][CH2:36]2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:44]1)=[O:7]
Reactant: COc1ccc(C2C(C)=NNN2C)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(C5C(C)=NNN5C)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:9]1[CH2:12][CH:11]([NH:13][C:14](=[O:31])[CH2:15][NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:9]2[CH2:10][CH:11]([NH:13][C:14](=[O:31])[CH2:15][NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:12]2)[CH2:4][CH2:3]1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of 4-methylcyclohexanone with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29].[C:30]1(C)[C:31]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=1.Cl.O.N1C=CC=C[CH:44]=1>>[S:36]([O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])([C:31]1[CH:30]=[CH:35][C:34]([CH3:44])=[CH:33][CH:32]=1)(=[O:37])=[O:38]
Reactant: c1ccncc1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCO
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: O
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1

Procedure:
To a solution of nonaethylene glycol monomethyl ether (2.0 g. 4.7 mmol) in pyridine (15 mL) at 0° C. was added toluenesulfonyl chloride (1.35 g). After stiring at room temperature ovemight, the mixture was cooled to 0° and adjusted to pH 2 by addition of 12N HCl. Water (200 mL) was added and the solution was washed with methylene chloride (3×50 mL). The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated to provide nonaethylene glycol methyl tosyl ether as a colorless oil (2.7 g); 1H-NMR (DMSO-d6) δ: 7.85 and 7.55 (2d, 4, C6H4), 4.18 (m, 2, CH2OTos), 3.7-3.45 (m 34, 17 CH2), 3.2 (s, 3, OCH3) 2.40 (s, 3, CH3).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][O:31][CH2:30]1>>[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][O:31][CH2:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCC1CCCOC1
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 243 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(2-bromoethyl)tetrahydro-2H-pyran.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.O>ClCCl>[OH:3][CH:2]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH3:12])[C:1]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C=O
Reactant: C=CCCCC
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC=CCC(O)C(=O)OC
Temperature: 25 °C
Yield: 67 %

Procedure:
Methyl glyoxalate (8.80 g, 0.1 mol, 1.0 eq) and 1-hexene (16.80 g, 0.2 mol, 2.0 eq) are dissolved in dry dichloromethane (150 ml, freshly distilled from calcium hydride) under a nitrogen atmosphere. Stannic chloride (3.51 ml, 0.03 mol, 0.3 eq) is added dropwise with stirring and cooling at 0° C. (ice/water bath). After half an hour the reaction mixture is allowed to warm to room temperature and stirred for a further 21 hours before being neutralised with triethylamine (4.2 ml, 0.03 mol, 0.3 eq) with a further 5 minutes stirring. Water (50 ml) and dichloromethane (100 ml) are added, the organic layer is separated, washed in turn with water (50 ml) and brine (50 ml), dried over anhydrous magnesium sulphate and evaporated. The crude oil is purified by short path distillation (b p 120-130° C./0.7 mm Hg) to furnish the ester product (23) as a colourless liquid, 11.49 g (67% yield).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][S:4][CH:3]1[C:8]([O:10]CC)=O.[OH-].[K+].Br.[CH3:16][S:17][C:18](=[NH:20])[NH2:19]>C(O)(=O)C>[OH:10][C:8]1[C:3]2[S:4][CH2:5][CH2:6][CH2:7][C:2]=2[N:19]=[C:18]([S:17][CH3:16])[N:20]=1
Reactant: CCOC(=O)C1SCCCC1=O
Reactant: CSC(=N)N
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CSc1nc(O)c2c(n1)CCCS2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
20 g of ethyl 3-oxotetrahydrothiopyran-2-carboxylate was added to 120 ml of a methanolic solution containing 9 g of potassium hydroxide at room temperature while stirring. Then, a small amount of S-methylisothiourea hydrobromide was added to the mixture and the stirring was continued for 2 hours. The reaction solution was then poured into ice-water, and the mixture was made acidic with acetic acid. The precipitated crystals were separated by filtration and recrystallized from acetic acid to obtain 4-hydroxy-2-methylthio-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine as colorless needles having a melting point of 248° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])OC(C)(C)C)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:22]1([NH2:32])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1.[CH2:33]([N:36]([CH2:50][CH2:51][CH3:52])[C:37]([C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([CH2:48]C)[CH:47]=1)C(O)=O)=[O:38])[CH2:34][CH3:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([F:1])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[C:41]1[CH:45]=[C:46]([CH3:48])[CH:47]=[C:39]([C:37]([N:36]([CH2:33][CH2:34][CH3:35])[CH2:50][CH2:51][CH3:52])=[O:38])[CH:40]=1)[C@H:11]([OH:12])[CH2:13][NH:32][C@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: NC1CCCc2ccccc21
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CN[C@@H]2CCCc3ccccc32)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3), 1,2,3,4-tetrahydro-1-naphthalenylamine (VI) and “5-Me-PHTH” (IX), the title compound is obtained, MH+=588.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:15]=1)=O.F[C:30]1[C:35](C(F)(F)F)=[CH:34][CH:33]=[CH:32][C:31]=1[C:40]([C:42]1C=CC=C(OC2C=CC(OC)=CC=2)[CH:43]=1)=O>>[CH2:40]([C:42]1[CH:43]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH:15]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=1
Reactant: COc1ccc(Oc2cccc(C(=O)c3cccc(C(F)(F)F)c3F)c2)cc1
Reactant: COc1ccc(Oc2cccc(C(=O)c3cccc(C(F)(F)F)c3N)c2)cc1
Product: COc1ccc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
[2-amino-3-(trifluoromethyl)phenyl][3-(4-methoxyphenoxy)phenyl]methanone: The title compound was prepared from (2-fluoro-3-trifluoromethylphenyl)-[3-(4-methoxy-phenoxy)-phenyl]methanone (0.64 g, 0.0015 mole) following the procedure of Example 457, Step 3: MS (ESI) m/z 388;
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[H][H].[Pd]>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]4)=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3oc(-c4ccc(C(F)(F)F)cc4)nc3c2)CC1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3oc(-c4ccc(C(F)(F)F)cc4)nc3c2)CC1
Yield: 56 %

Procedure:
Following the general procedure-1, Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate (90 mg) obtained from intermediate 44 (200 mg, 0.51 mmol) and Tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (170 mg, 0.511 mmol). Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate (90 mg, 0.2 mmol) dissolved in MeOH (30 ml) and added Pd/C (90 mg). This mixture was stirred in an auto clave in hydrogen atmosphere at 55 Psi for 12 h. Reaction mixture filtered through celite and washed the cetile with MeOH. Methanol was removed on rotavapour to obtain the crude. Crude was triturated with Petether and EtOAc (1:1) to obtain the titled compound (50 mg) as an off-white solid. M.P.: 161-164° C. 1H-NMR (δ ppm, 400 MHz): 8.36 (d, J 8.2, 2H), 7.78 (d, J 8.4, 2H), 7.63 (d, J 1.5, 1H), 7.53 (d, J 8.4, 1H), 7.26-7.20 (m, 1H), 4.34-4.20 (m, 2H), 2.90-2.75 (m, 3H), 1.93-1.84 (m, 2H), 1.74-1.62 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1)=O.[C:17]1([CH:24]=[CH:23][CH:22]=[C:20]([OH:21])[CH:19]=1)[OH:18].C(N1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([OH:37])[CH:35]=2)C(C)=CC1(C)C)C.C(C1C=CC(OCC(O)=O)=CC=1)=O>CO>[OH:18][C:17]1[CH:24]=[CH:23][C:22]2[C:1]([C:3]3[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=3)=[C:31]3[C:36]([O:21][C:20]=2[CH:19]=1)=[CH:35][C:34](=[O:37])[CH:33]=[CH:32]3
Reactant: O=Cc1ccc(OCCCCC(=O)O)cc1
Reactant: CCN1c2cc(O)ccc2C(C)=CC1(C)C
Reactant: Oc1cccc(O)c1
Agent: O=Cc1ccc(OCC(=O)O)cc1
Solvent: CO
Product: O=C(O)CCCCOc1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)cc1
Yield: 26 %

Procedure:
Dye 9 (shown below) was prepared using the procedure described in Example 4 except that 5-(4-formylphenoxy)pentanoic acid and resorcinol substituted for 1-ethyl-2,2,4-trimethyl-1,2-dihydroquinolin-7-ol and 2-(4-formylphenoxy)acetic acid. Yield: 26%. λabs=486 nm (in methanol), λem=513 nm (in methanol).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].[CH2:17]=O>O1CCOCC1>[SH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][CH2:17][CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: Nc1ccccc1S
Reactant: C=O
Reactant: CC(=O)c1cccs1
Solvent: C1COCCO1
Product: O=C(CCNc1ccccc1S)c1cccs1

Procedure:
Acetylthiophene (126 mg), aminothiophenol (125 mg), and paraformaldehyde (36 mg) were reacted in dioxane (0.2 ml) at 150° C. for 2 hours.