Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].O>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][Si:17]([C:15]#[C:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:20])[CH3:19]
Reactant: Brc1ccccn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)C#Cc1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A flask was charged with 2-bromopyridine (1.21 mL, 12.66 mmol) and triethylamine (40 mL) and sparged with nitrogen for 15 min. To this was added ethynyltrimethylsilane (1.97 mL, 13.92 mmol) and the reaction was purged 15 min longer. To this was added copper(I) iodide (0.121 g, 0.633 mmol), and Pd(PPh3)2Cl2 (0.444 g, 0.633 mmol). Reaction stirred at room temperature for 72 h. The reaction was diluted with ethyl acetate (60 mL) and poured into water. The black heterogeneous emulsion was filtered through a plug of celite and the layers separated. The organics were washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (5%-->15% EtOAc/Hex) gave 1.73 g (78%) as a dark oil. 1H-NMR (CDCl3, 500 MHz) δ 8.58 (m, 1H), 7.66 (ddd, J=7.9, 7.9, 1.8, 1H), 7.47 (m, 1H), 7.24 (ddd, J=7.6, 4.9, 1.2, 1H), 0.29 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 150.1, 143.2, 136.1, 127.4, 123.1, 103.8, 94.9, −0.2. Mass spec.: 176.14 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3].[H-].[Na+].F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.O.O.C(O)(=O)C(O)=O>CS(C)=O.C(OCC)(=O)C.O>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([O:13][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])=[CH:18][CH:19]=1)#[N:22]
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCC(Oc1ccc(C#N)cc1)c1ccccc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A mixture of N,N-dimethyl-3-hydroxy-3-phenylpropylamine (3.58 g, 20 mM), 50% sodium hydride dispersion (1 g) and DMSO (50 ml) was heated at 80° until homogenous, cooled to ambient temperature and treated dropwise with a solution of 4-fluorobenzonitrile (2.42 g, 20 mM) in DMSO with cooling (exothermic). After 1 h the reaction mixture was poured on to water (200 ml) and extracted with ether (2×200 ml). The ether extract was extracted with 1 N hydrochloric acid (2×50 ml), the acid extract basified and then extracted with ether (2×200 ml). The ether was dried and the solvents removed under reduced pressure to give an oil which was dissolved in ethyl acetate and treated with an excess of a solution of oxalic acid dihydrate in ethyl acetate. Removal of the resultant precipitate by filtration followed by recrystallisation from ethyl acetate gave the title compound (4.8 g) as the oxalate quarter hydrate m.p. 80° (decomp). Found: C, 64.1; H, 6.05; N, 7.7% C18H20N2O.C2H2O4 requires: C, 64.1; H, 6.1; N 7.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)cnc1Cc1ccc(F)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(4-fluorobenzyl)nicotinic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 9.15 (1H, d, J=7.7 Hz), 8.63 (1H, d, J=2.4 Hz), 7.96–7.92 (3H, m), 7.50 (2H, d, J=8.4 Hz), 7.15–6.96 (4H, m), 5.19–5.09 (1H, m), 4.17 (1H, d, J=14.0 Hz), 4.08 (1H, d, J=14.0 Hz), 3.85 (3H, s), 1.42 (2H, d, J=7.0 Hz); MS (ESI) m/z 427 (M+H)+, 425 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][C:25]([CH3:34])([CH3:33])[CH2:26][NH:27][C:28](=[O:32])[CH2:29][C:30]#[N:31])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:35]1([CH:38]=O)[CH2:37][CH2:36]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][C:25]([CH3:34])([CH3:33])[CH2:26][NH:27][C:28](=[O:32])[C:29]([C:30]#[N:31])=[CH:38][CH:35]3[CH2:37][CH2:36]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=CC1CC1
Reactant: CC(C)(CNC(=O)CC#N)Cn1nc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(CNC(=O)C(C#N)=CC1CC1)Cn1nc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21

Procedure:
A solution of N-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,2-dimethylpropyl)-2-cyanoacetamide (0.12 g, 0.26 mmol, 1.0 eq.), cyclopropanecarbaldehyde (56 mg, 0.78 mmol, 3.0 eq.) and a drop of piperidine in ethanol (15 mL) was refluxed overnight. The volatile phase was removed under reduced pressure. The residue was applied on silica gel eluting with petroleum: ethyl acetate (1:1). This provided 50 mg (38%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 508 (M+1) H-NMR (300 MHz, DMSO-d6, ppm): 8.59 (t, 1H), 8.29 (s, 1H), 7.69-7.66 (d, J=9.6 Hz, 2H), 7.46-7.41 (t, J=6.6, 7.5 Hz, 2H), 7.21-7.11 (m, 5H), 7.05-7.02 (d, 10.4 Hz, 1H), 4.18 (s, 2H), 3.04-3.02 (d, J=6.3 Hz, 2H), 1.98-1.93 (m, 1H), 1.21-1.26 (m, 2H), 1.0-0.92 (m, 2H), 0.91 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:16](=[O:18])[CH3:17])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(N)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Cl)nc(C)n1
Temperature: 40 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
A mixture of 6-chloro-2-methylpyrimidin-4-amine (500 mg, 3483 μmol), pyridine (568 μl, 6965 μmol), and acetic anhydride (493 μl, 5224 μmol) was stirred at 40° C. for 24 h. The mixture was cooled down to rt. The reaction mixture was diluted with saturated NaHCO3 (30 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (about 2 mL), dried over Na2SO4, filtered, concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give N-(6-chloro-2-methylpyrimidin-4-yl)acetamide (458 mg, 71% yield). 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H); 7.90 (s, 1H); 2.58 (s, 3H); 2.23 (s, 3H). m/z (ESI, +ve ion) 186 (M+H)+.
Reaction SMILES: C[C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].C[CH2:19][OH:20]>>[CH3:19][O:20][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]([OH:5])=[O:4])=[CH:15][CH:14]=1
Reactant: CCO
Reactant: CCOC(=O)C(C)(C)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(OCC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-methyl-2-phenoxypropanoate (210 mg, 1 mmol) in EtOH (10 ml) was added 10% NaOH aqueous solution (10 mL) at 26° C. The mixture was stirred for 30 min and then concentrated before the addition of water (20 mL) and washing with ethyl acetate (2×20 mL). The aqueous layer was acidified with 2N HCL until pH 3 and extracted with ethyl acetate (2×20 ml). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:33]([CH3:35])[N:34]=2)[N:31]=1.C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:33]([CH3:35])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c(C)nc2ccc(Cl)nn12
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(C)nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 120 °C
Reaction time: 40 h
Yield: 12.8 %

Procedure:
1.98 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.46 g of ethyl (6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl]carboxylate were dissolved in 15 ml of 1-methyl-2-pyrrolidone; 1.05 ml of N-ethyldiisopropylamine was added, followed by stirring at 120° C. for 40 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated; ethyl ether-hexane (1:2) was added to the residue; the crystal precipitated was collected by filtration, washed with hexane and dried to yield 412 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)[CH3:13].[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21].CO>O1CCCC1>[CH2:26]([O:25][C:23]([CH2:22][NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)[CH3:13])=[O:24])[CH3:27]
Reactant: CC(=C1C(=O)Nc2ccc(N)cc21)c1ccc[nH]1
Reactant: CCOC(=O)CN=C=O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CNC(=O)Nc1ccc2c(c1)C(=C(C)c1ccc[nH]1)C(=O)N2
Reaction time: 8 h

Procedure:
A solution of 5-amino-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one (360 mg, 1.5 mmol) in tetrahydrofuran (15 mL) was treated with ethyl isocyanatoacetate (195 mg, 1.5 mmol) at ambient temperature. After stirring overnight, methanol (5 mL) was added and the reaction was concentrated. Chromatography on SiO2 (7.2 g) using 1:2 hexane/ethyl acetate afforded 5-(N′-(ethoxycarbonylmethyl)ureido)-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, 3H), 2.82 (s, 3H), 3.96 (d, 2H), 4.22 (q, 2H), 6.44 (m, 2H), 6.88 (d, 1H), 7.16 (m, 1H), 7.28 (d, 1H), 7.40 (m, 1H), 7.96 (m, 1H), 8.76 (s, 1H), 11.02 (s, 1H) ppm; (200 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13](=O)[N:12]=[C:11]([CH3:15])[N:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:13]1[NH:12][C:11]([CH3:15])=[N:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C2=NC(C)=NC2=O)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc(C)[nH]c2Cl)cc1

Procedure:
A stirred solution of 10.0 grams (0.049 mole) of 4-(4-methoxyphenyl)-2-methyl-imidazol-5-one in 50 mL of phosphorous oxychloride is heated at reflux for about three hours. After this time, the reaction mixture is concentrated under reduced pressure, yielding 5-chloro-4-(4-methoxyphenyl)-2-methylimidazole.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26]1([CH2:32][CH2:33][SH:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>O1CCOCC1.O>[CH2:33]([S:34][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: SCCc1ccccc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(SCCc3ccccc3)nn2)CC1
Temperature: 105 °C
Yield: 44.1 %

Procedure:
A mixture of [4-(6-chloro pyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.089 g, 0.240 mmol), 2-phenylethanethiol (0.049 g, 0.36 mmol) and sodium hydroxide (9.6 mg) in 5 mL 1,4-dioxane was heated at 100-110° C. overnight. The reaction mixture was cooled to room temperature, diluted with 20 mL of water, and then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate, then concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (50 mg, 43.7% yield). 1H NMR (400 MHz, CDCl3) δ 7.65, 7.52-7.55, 7.47-7.48, 7.27, 7.12-7.22, 7.03, 6.76, 3.89-3.94, 3.79-3.84, 3.54-3.61, 3.49-3.51, 3.45, 3.17-3.25, 2.97.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:32])[C@@H:24]([NH:25][C:26](=[S:31])[CH2:27][CH:28]([F:30])[F:29])[C@H:21]3[S:20][CH2:19][C:18]=2[S:33][CH2:34][S:35][C:36]2[N:37]=[N:38][NH:39][CH:40]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl.C1(OC)C=CC=CC=1>[F:29][CH:28]([CH2:27][C:26]([NH:25][C@@H:24]1[C:23](=[O:32])[N:22]2[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:33][CH2:34][S:35][C:36]3[N:37]=[N:38][NH:39][CH:40]=3)[CH2:19][S:20][C@H:21]12)=[S:31])[F:30]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SCSc2c[nH]nn2)CS[C@@H]2[C@H](NC(=S)CC(F)F)C(=O)N12
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=C(SCSc2c[nH]nn2)CS[C@@H]2[C@H](NC(=S)CC(F)F)C(=O)N12
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 7β-difluoromethylthioacetamido-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (451 mg: 0.710 mMol.) in a mixture of dichloromethane (3 ml) and anisole (1.2 ml) under ice cooling is added trifluoroacetic acid (3 ml), and the mixture is stirred under ice cooling for 1 hour. The reaction mixture is concentrated to dryness and the residue is pulverized with ether, washed, and dried to give 7β-difluoromethylthioacetamido-3-(1,2,3- triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid (257 mg) white powder. Yield: 77%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]2[CH:13]=[C:12]([C:15]3[O:19][C:18]([CH3:20])=[N:17][N:16]=3)[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[C@H:2]1[O:4][CH2:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:31]2[CH2:32][CH2:33][N:34]([CH2:3][C@H:2]([OH:4])[CH2:1][O:5][C:6]3[C:14]4[CH:13]=[C:12]([C:15]5[O:19][C:18]([CH3:20])=[N:17][N:16]=5)[O:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:35][CH2:36]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C2CCNCC2)cc1OC
Reactant: Cc1nnc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)o1
Product: COc1ccc(C2CCN(C[C@H](O)COc3cccc4oc(-c5nnc(C)o5)cc34)CC2)cc1OC
Yield: 49 %

Procedure:
By the reactions in the same manner as in Example 1 using (S)-5-(4-glycidyloxybenzo(b)furan-2-yl)-2-methyl-1,3,4-oxadiazole (0.90 g) and 4-(3,4-dimethoxyphenyl)piperidine (0.90 g); the title compound (0.80 g) was obtained as a brown oil.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].C[O:9][C:10](=O)[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([N:19]([CH3:23])[C:20](=[O:22])[CH3:21])=[C:13]([O:24][CH3:25])[CH:12]=1.Cl>O.CS(C)=O>[CH3:18][O:17][C:15]1[CH:16]=[C:11]([C:10](=[O:9])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:12]=[C:13]([O:24][CH3:25])[C:14]=1[N:19]([CH3:23])[C:20](=[O:22])[CH3:21]
Reactant: CS(C)(=O)=O
Reactant: COC(=O)c1cc(OC)c(N(C)C(C)=O)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(C(=O)CS(C)(=O)=O)cc(OC)c1N(C)C(C)=O
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
A suspension of 35.7 g. of dimethylsulfone and 12.0 g. of sodium hydride (50% dispersion in oil) in 100 ml. of absolute dimethylsulfoxide was stirred at 50° C. for 3 hours with the exclusion of moisture and subsequently treated with 34.0 g. of 3,5-dimethoxy-4-(N-methyl-acetamido)-benzoic acid methyl ester. After stirring at room temperature for 2.25 hours, the mixture was diluted with 1 liter of water. The resulting solution was made acidic with 3N hydrochloric acid and extracted with two 1 liter portions of ethyl acetate. The ethyl acetate extracts were washed with two 200 ml. portions of water, combined, dried over magnesium sulfate and evaporated in vacuo. Recrystallization of the residue from ethyl acetate gave 2',6'-dimethoxy-N-methyl-4'-[(methylsulfonyl)-acetyl]-acetanilide having a melting point of 141°-142° C.
Reaction SMILES: O(C([N:10]1[CH2:15][CH2:14][C:13]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:16]2)[CH2:12][CH2:11]1)=O)C1C=CC=CC=1.[OH-].[K+]>C(O)CO.O>[C:24]1([CH:17]2[S:16][C:13]3([CH2:12][CH2:11][NH:10][CH2:15][CH2:14]3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=3)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1ccccc1)c1ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: c1ccc(C2SC3(CCNCC3)c3ccccc32)cc1
Temperature: 155 °C

Procedure:
A mixture of 3.0 g of 1,3-dihydro-1'-phenoxycarbonyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine], Example 3, 8.0 g of potassium hydroxide pellets in 50 ml of ethylene glycol is stirred at 155° C. until a clear solution results. The solution is permitted to cool, diluted with water and the biphasic mixture extracted thrice with chloroform. The combined chloroform extracts are washed carefully with water and dried and the chloroform removed leaving a solid residue. The residue is recrystallized from an acetone-hexane to give prisms, mp 142°-144° C. of 1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: [CH3:1][N:2]([CH2:10][C@:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][C@H:12]1[CH2:14][O:15]CC1C=CC=CC=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>[Pd].C(O)C>[OH:15][CH2:14][C@@H:12]1[CH2:13][C@:11]1([CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CN(C[C@]1(c2ccccc2)C[C@H]1CO)C(=O)OC(C)(C)C
Yield: 92.6 %

Procedure:
1,1-dimethylethyl methyl[((1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]carbamate (3.1 g, 8.1 mmol), accessed via the method of Preparation 12B, was combined with 10% palladium on activated carbon (0.50 g) in ethyl alcohol and hydrogenated under 1 atm H2(g) for 0.5 h at ambient temperature. The catalyst was filtered off through celite and the filtrate concentrated to a colorless oil. The crude material was purified by flash chromatography (SiO2, eluted with EtOAc/hexanes (4:6)) to give the title compound (2.2 g, 7.5 mmol, 95%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.32-7.20 (m, 5H), 3.70-3.54 (m, 1H), 3.34-3.18 (m, 3H), 2.76-2.60 (m, 3H), 1.41-1.22 (m, 11H), 1.00 (m, 1H), 0.87-0.85 (m, 1H). ES-LCMS m/z 314.1 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:10]([O:11][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)CBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncccc3O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccnc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
60 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxypyridine and 20 mg of methyl bromoacetate were dissolved in 2 ml of acetonitrile, to this was added 20 mg of potassium carbonate, and the mixture was stirred for 2 hours at 60° C. This reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 60 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-(methoxycarbonyl)methoxypyridine [present compound 2-7].
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:15][C@@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]1.[NH3:18]>>[NH2:18][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:15][C@@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]1
Reactant: OC[C@H]1C=C[C@@H](n2cnc3c(Cl)ncnc32)C1
Reactant: N
Product: Nc1ncnc2c1ncn2[C@@H]1C=C[C@H](CO)C1
Yield: 87 %

Procedure:
(1R,cis)-4-(6-Chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (from part e of this example, 2.00 g, 7.98 mmol) was stirred in liquid ammonia (50 mL) in a Parr bomb at 25° C. for 18 hours. Evaporation of volatiles and crystallization of the residual solid from methanol-acetonitrile gave title compound as white prisms (1.61 g, 87%), m.p. 195–200° C.; 1H-NMR (DMSO-d6) δ 8.15 (s, 1H), 8.06 (s, 1H), 7.21 (br s, 2H), 6.15 and 5.95 (two m, 2H), 5.61 (m, 1H), 4.76 (t, J=5.4 Hz, 1H), 3.48 (t, J=5.5 Hz, 2H), 2.92 (m, 1H), 2.71 (m, 1H), 1.67 (m, 1H); [α]58920+4.5° (c 0.5, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([C@@H:18]2[CH2:20][C@H:19]2[C:21](=[O:41])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][N:31](C(OCCCC)=O)[CH2:30][CH2:29]3)[CH:23]=2)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([C@@H:18]2[CH2:20][C@H:19]2[C:21](=[O:41])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[CH:23]=2)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCCOC(=O)N1CCN(c2cccc(C(=O)[C@@H]3C[C@H]3c3ccc(OCC(=O)OC(C)(C)C)c(OC)c3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc([C@@H]2C[C@H]2C(=O)c2cccc(N3CCNCC3)c2)ccc1OCC(=O)O

Procedure:
Cyclopropyl adduce 300a was deprotected with TFA/CH2Cl2 in the usual way to provide a pale grey solid. IR(KBr): cm-1 3200-2500(br), 1738, 1680. HR-MS: Calc'd 411.1920, Found 411.1925.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH:12]=[CH2:13])[CH2:11][O:10][CH2:9][O:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH:12]([C:6]1([C:4]([OH:5])=[O:3])[CH2:7][O:8][CH2:9][O:10][CH2:11]1)=[CH2:13]
Reactant: C=CC1(C(=O)OCC)COCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1(C(=O)O)COCOC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
A solution of 5-vinyl-[1,3]dioxane-5-carboxylic acid ethyl ester (397.7 mg, 2.136 mmol) in tetrahydrofuran/methanol/water (15 mL, 2:2:1) was treated with lithium hydroxide monohydrate (269 mg, 6.408 mmol). After stirring at room temperature for 1.5 h, the volatiles were removed in vacuo and the residue was cooled to 0° C. and quenched with hydrochloric acid (1 M). The aqueous layer was saturated with sodium chloride, extracted with dichloromethane (3×). The combined organics were filtered through a phase separator and the volatiles were removed in vacuo to provide the title compound (320.3 mg, 95%) as a colourless solid. 1H NMR (300 MHz, CDCl3) δ 3.72 (d, J=11.6 Hz, 2H), 4.50 (d, J=11.4 Hz, 2H), 4.73 (d, J=6.2 Hz, 1H), 5.02 (d, J=6.0 Hz, 1H), 5.27-5.39 (m, 2H), 5.69 (dd, J=17.6, 10.9 Hz, 1H).