Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]([Cl:22])([Cl:21])[CH:7]([OH:20])[CH:8]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>CN(C)C=O>[Cl:22][C:6]([Cl:5])([Cl:21])[CH:7]([O:20][C:1](=[O:3])[CH3:2])[CH:8]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)C(=O)C(C(O)C(Cl)(Cl)Cl)n1cncn1
Solvent: CN(C)C=O
Product: CC(=O)OC(C(C(=O)C(C)(C)C)n1cncn1)C(Cl)(Cl)Cl
Yield: 40.1 %

Procedure:
8.0 g (0.1 mol) of acetyl chloride were added to 31.5 g (0.1 mol) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one in 100 ml of dimethylformamide at room temperature. Thereafter, the mixture was heated under reflux for 4 hours. It was left to cool and concentrated by distilling off the solvent in vacuo. The residue was taken up in methylene chloride and the methylene chloride solution was washed with aqueous sodium bicarbonate solution and dried over sodium sulphate. The solvent was distilled off and the residue was taken up in 100 ml of diisopropyl ether. After the diisopropyl ether mixture had stood for several hours, colorless crystals precipitated. 14.3 g (40% of theory) of 1,1,1-trichloro-2-acetoxy-3-(1,2,4-triazol-1-yl)-5,5-dimethylhexan-4-one were obtained as the pure diasteromer of the A* form of melting point 128°-130° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:9][CH3:10])[CH3:7].[O:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1.[Cl-].[NH4+]>O1CCCC1>[CH2:6]([C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:31]2([OH:34])[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[C:13]([CH3:19])[CH:12]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:9][CH3:10])[CH3:7]
Reactant: O=C1CCOCC1
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCOCC2)c(C)c1
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
n-Butyllithium (2.71 M solution in hexane, 3.15 mL, 8.55 mmol) was added to a solution of 4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol (Example 1-(3); 1.0 g, 3.42 mmol) in tetrahydrofuran (30 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred for 15 minutes. Then, tetrahydropyran-4-one (685 mg, 6.84 mmol) was added to the reaction mixture, which was further stirred at 0° C. for 30 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 30:70) to give the target compound as a colorless oil (0.97 g, 72%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C#N)c3)C2=O)cn1
Yield: 21 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-(bromomethyl)benzonitrile. Yield 21%. MS M+H calculated 411.1; found 411.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1 uM.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1.Br[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[I:9])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1I
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Temperature: 45 °C
Yield: 95.5 %

Procedure:
To a solution of 4-chloro-2-iodoaniline (16.5 g, 65.1 mmol) in DMF (250 mL) at rt were added □-bromodiphenylmethane (21.5 g, 84.6 mmol) and iPr2NEt (23 mL, 130 mmol) and the reaction mixture was heated at 45° C. overnight. After the volatile was removed under reduced pressure, the residue was dissolved in EtOAc, washed with water (3×) and brine and dried over MgSO4. Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes) gave the desired Benzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g, 97% yield) as a yellowish solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])=[CH:10][CH:9]=1
Reactant: Clc1ccccc1I
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2Cl)cc1
Yield: 96.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (637 mg, 0.551 mmol), Na2CO3 (5 mL, 1M) and 4-methylbenzene boronic acid (1.5 g, 11.0 mmol) were added to a solution of 2-chloroiodobenzene (1.315 g, 5.514 mmol) in toluene (98 mL) and EtOH (20 mL). The reaction mixture was heated at reflux for 3 h. The cooled solution was diluted with EtOAc, and the organic solution was washed with water (2×) followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (hexanes to 10% EtOAC/hexanes) to afford 4′-methyl-2-chlorobiphenyl (1.08 g). 1H NMR (CDCl3 400 MHz) δ 7.49-7.21 (m, 8H), 2.39 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.BrC1C=CC(C(CCCCCCC(OCC)=O)=O)=CC=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].S1C=CC(B(O)O)=C1>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: Brc1ccc(Br)nc1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: CCOC(=O)CCCCCCC(=O)c1ccc(Br)cc1
Agent: OB(O)c1ccsc1
Product: COc1ccc(-c2ccc(Br)cn2)cc1OC
Yield: 78 %

Procedure:
Following the procedure described in Example 67, step 1, but substituting respectively 2,5-dibromopyridine for 49d and 3,4-dimethoxyphenyl boronic acid for 3-thiophene boronic acid, the title compound 147 was obtained in 78% Yield. 1H NMR (300 MHz, CDCl3): δ 8.65 (dd, J=2.4, 0.9 Hz, 1H), 7.77 (dd, J=8.4, 5.4 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.53 (dd, J=8.4, 0.9 Hz, 1H), 7.73 (dd, J=8.4, 2.1 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.95 (s, 3H), 3.90 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 55.92, 55.93, 109.64, 111.01, 118.46, 119.25, 120.92, 131.05, 139.09, 149.28, 150.21, 150.3 6, 155.40.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[C:25]=1I>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[C:25]=1[C:17]1[CH:18]=[CH:19][C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: Nc1nccc(Cl)c1I
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1nccc(Cl)c1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A mixture of sodium carbonate (122 mg), tetrakis(triphenylphosphine)palladium(0) (33.2 mg), 4-phenoxyphenylboronic acid (160 mg) and 4-chloro-3-iodopyridin-2-amine (146 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (111 mg) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13].C(OCCO)C>>[CH:8]1([C:6]2[CH:7]=[C:2]([NH:12][NH2:13])[N:3]=[CH:4][N:5]=2)[CH2:10][CH2:9]1
Reactant: Clc1cc(C2CC2)ncn1
Reactant: NN
Solvent: O
Solvent: CCOCCO
Product: NNc1cc(C2CC2)ncn1

Procedure:
1.6 g (6.9 mmol) 4-chloro-6-cyclopropylpyrimidine [FR 1 519 069 (1966); Chem. Abstr. 71, 49965y, 1969] and 3.4 ml (3.5 g, 69.0 mmol) hydrazine hydrate are stirred at a bath temperature of 90° C. for 16 h. Ethylene glycol monoethyl ether is added to the cooled reaction mixture and the mixture is concentrated in vacuo. This operation is repeated once. The residue is then chromatographed over silica gel 60 (mobile phase: acetonitrile/water 8:2).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C=O>[Si:27]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 93.1 %

Procedure:
To a solution of 1.0 g of 3β-hydroxyandrost-5-en-17-one (Coffey S. in Rodd's Chemistry of Carbon Compounds, 1970, IID, 257) in 10 ml of dimethylformamide, 1.7 g of imidazole and 1.95 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 1.3 g of crude 3β-tert-butyldimethylsilyloxy-androst-5-en-17-one
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].[CH3:44][NH:45][CH2:46][C@@H:47]([C@H:49]([C@@H:51]([C@@H:53]([CH2:55][OH:56])[OH:54])[OH:52])[OH:50])[OH:48]>ClCCl>[CH3:34][O:33][C:31]([C:30]1[CH:35]=[CH:36][C:27]([CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:16]([C:15]3[C:14]4[CH2:37][CH2:38][CH2:39][CH2:40][C:13]=4[S:12][C:11]=3[NH:10][C:8]([C:7]3[CH:6]=[C:5]([S:2]([N:45]([CH3:44])[CH2:46][C@@H:47]([C@H:49]([C@@H:51]([C@@H:53]([CH2:55][OH:56])[OH:54])[OH:52])[OH:50])[OH:48])(=[O:4])=[O:3])[CH:43]=[CH:42][CH:41]=3)=[O:9])=[O:17])=[CH:20][CH:21]=2)=[CH:28][CH:29]=1)=[O:32]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 153 mg of N-methyl-D-glucamine, and 2.5 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was washed with water to obtain 256 mg of 1-deoxy-1-[{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}(methyl)amino]-D-glucitol as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CC(C)=O.[CH2:38]([OH:41])[CH:39]=[CH2:40]>CN(C)C=O.C(N(C(C)C)C(C)C)C>[NH2:8][C:6]1[CH:7]=[C:2]([CH2:40][CH2:39][CH:38]=[O:41])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Reactant: C=CCO
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(CCC=O)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 3 h
Yield: 18.3 %

Procedure:
A solution of bromoarene 2 (1.544 g, 7.11 mmol) (or any haloarene of choice); tri-o-tolyl-phosphine (280 mg; 0.9 mmol) and trkdibenzylidene acetone)dipalladium(0) (280 mg; 0.3 mmol) in N,N-dimethylformamide (6 mL) and ethyl diisopropyl amine (3 mL) was treated with prop-2-en-1-ol (3 mL, 40 mmol) (or any alken-1-ol of choice, 6 eq.) and the solution was stirred at 120° C. for 3 h under nitrogen. The reaction mixture was concentrated under high vacuum and the residue was purified by flash chromatography (eluent 5% MeOH in dichloromethane) to afford the aldehyde 80 (253 mg, 18% yield).
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:7][CH2:6]1)=O.[C:28]([NH2:36])(=[S:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>CCO>[C:29]1([C:28]2[S:35][CH:2]=[C:3]([CH:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH:15]4[C:27]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[C:21]5[C:16]4=[CH:17][CH:18]=[CH:19][CH:20]=5)=[O:12])[CH2:9][CH2:10]3)[N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C(CBr)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2csc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
To a stirred solution of (9H-fluoren-9-yl)methyl 4-(bromoacetyl)piperidine-1-carboxylate (3 g, 7.03 mmol) in EtOH (20 mL) was added thiobenzamide (0.96 g, 7.03 mmol). This reaction mixture was stirred at RT for 24 h. NaHCO3 (3 g) was added and the reaction mixture was further stirred for 5 d. The reaction mixture was concentrated to afford the crude material which was chromatographed over silica gel eluting with a gradient (0-10% EtOAc:hexanes) to afford (9H-fluoren-9-yl)methyl 4-(2-phenylthiazol-4-yl)piperidine-1-carboxylate (2 g, 61%) as an off white solid.
Reaction SMILES: CC1[CH:7]=[CH:6][C:5]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])=[CH:4][N:3]=1.[Se](=O)=[O:14].[O:16]1[CH2:21][CH2:20]OCC1>C(OCC)(=O)C>[Cl:12][C:8]([C:5]1[CH:6]=[CH:7][C:20]([C:21]([OH:16])=[O:14])=[N:3][CH:4]=1)=[C:9]([Cl:11])[Cl:10]
Reactant: Cc1ccc(C(Cl)=C(Cl)Cl)cn1
Reactant: C1COCCO1
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C(Cl)=C(Cl)Cl)cn1

Procedure:
G. (0.0050 moles) of 2-methyl 5-trichlorovinyl pyridine is added at room temperature with stirring to 833 mg. (0.0075 moles) of selenium dioxide suspended in 5 ml. of dioxane. The reaction mixture is refluxed for 8 hours and stirred at room temperature overnight. The reaction mixture is filtered through a filtration medium (diatomaceous earth) and the filtration evaporated to dryness in vacuo affording a reddish solid. The solid is taken up in a minimum amount of hot ethyl acetate and filtered. Upon cooling, crystals are obtained which are filtered and washed with ethyl acetate and dried affording 500 mg. of a tan solid with a m.p. of 158°-159° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][N:12]([CH3:16])[CH2:13][C:14]#[CH:15]>CN(C=O)C.C(Cl)Cl.[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>[CH3:11][N:12]([CH3:16])[CH2:13][C:14]#[C:15][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a screw top tube, 8.1 mg (0.0425 mmoles) of CuI, 18 mg(0.0256 mmoles) of PdCl2(PPh3)2, and 207 mg (0.8483 mmoles) of 5-Bromo-1H-pyrrolo[2,3-b]pyridine were added. The dry solids were diluted with 1 ml of dry DMF and a stream of N2 was bubbled through the solution for 10 minutes and then 182.6 ul(1.7 mmoles) of Dimethyl-prop-2-ynyl-amine was added and the reaction was stirred in a sealed tube overnight at room temperature. The reaction was diluted with 10 ml of DCM and washed with saturated ammonium chloride solution. The organic layer was separated and dried with MgSO4, filtered, and concentrated to dryness yielding a crude material of 189 mg. MS showed a M+ ion of 200.05 which confirmed the structure above. The crude material was taken to the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7][CH:6]=1)[CH3:2].C([N:21]=[C:22]=[S:23])(=O)C1C=CC=CC=1.[O-]CC.[Na+]>C1COCC1.C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:22]([NH2:21])=[S:23])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)nc1
Reactant: O=C(N=C=S)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(N)=S)nc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
A mixture of ethyl-6-amino-nicotinate (2.5 g, 15 mmol) and benzoyl isothiocyanate (2.45 g, 15 mmol) in THF (20 mL) was heated at 40° C. for 4 h. To this mixture at RT, was added sodium ethoxide (2.04 g, 30 mmol) in ethanol (10 mL). After stirring the resulting mixture at RT for 16 h, the volatiles were removed in vacuo. The residue was suspended in aqueous NH4Cl and the solid formed was collected by filtration, rinsed with water and dried to afford 6-thioureido-nicotinic acid ethyl ester as a white solid (2.6 g, 77% yield). LC/MS; (M+H)+=226.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][CH:39]=[C:9]23)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:20][CH:21]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][CH:39]=[C:9]23)[CH2:4][CH2:3]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ccnn12
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To a solution of 4-(trans-4-hydroxycyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one (0.20 g) in methylene chloride (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.24 g), and the mixture was stirred for 18 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.091 g, 45%).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]2.[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35])[CH3:25]>C(OCC)(=O)C.C(Cl)Cl>[C:20]([O:19][C:17]([N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([NH:6][C:34]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:24][CH3:25])=[O:35])[CH:8]=2)[CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: CCOc1ccccc1N=C=O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1ccccc1NC(=O)Nc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2

Procedure:
A tetrahydrofuran (10 mL) solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (981 mg) and 2-ethoxyphenyl isocyanate (0.9 mL) was stirred at room temperature for 4 hours and then concentrated. The residue was purified by chromatography (hexane:ethyl acetate=5:1→1:1 and then methylene chloride:ethyl acetate=1:0→1:1) to obtain the title compound (1.62 g, quantitative yield) as a pale yellow solid.
Reaction SMILES: P(=O)(O)(O)O.C([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])CCC.Cl[C:20]1C=CC(C([C@]2(O)[C@](C(=O)C3C=CC(Cl)=CC=3)(O)[C@@H](COC(=O)C3C=CC(Cl)=CC=3)O[C@@H]2Cl)=O)=C[CH:21]=1.[CH2:56](C(C)=O)[CH:57](C)C>>[CH:15]1([NH:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:57][CH2:56]2)[CH2:16][CH2:17][CH2:18][CH2:21][CH2:20]1
Reactant: CCCCN(CCCC)CCCC
Reactant: CC(=O)CC(C)C
Reactant: O=C(OC[C@H]1O[C@H](Cl)[C@](O)(C(=O)c2ccc(Cl)cc2)[C@@]1(O)C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=P(O)(O)O
Product: C1CCC(NC2CCCCC2)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a mixture of 3.3 g of orthophosphoric acid in 67 mL of methyl isobutyl ketone were added 2.1 g of tri-n-butylamine and 6.6 g of molecular sieves 4A, and the mixture was cooled to 5° C. with stirring. To the mixture was added 6.6 g of 2,3,5-O-tris(4-chlorobenzoyl)-α-D-arabinofuranosyl chloride. After 1 hour, precipitation of crystals initiated and then a thick suspension was provided. After 8 hours, the ratio of α-form/β-form for compound (25) in the reaction suspension was 10:1. To the suspension was added 6.3 g of tri-n-butylamine to dissolve the precipitated crystals and molecular sieves were removed by filtration. The filtrate was washed with 55 mL of water. The organic layer was ice-cooled. To the mixture was added 2.4 g of cyclohexylamine for crystallization with stirring. After 1 hour, the precipitated crystals were collected by filtration and dried in vacuo at room temperature to provide 6.72 g of a dicyclohexylamine salt of compound (25) as a colorless powder (Yield: 70.5%; α-form:β-form=99:1).