Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C:4]1[C:9]([OH:10])=[C:8]([CH2:11]O)[C:7]([CH2:13][OH:14])=[CH:6][N:5]=1)=[CH2:3].[OH-].[Na+].C(=S)=[S:18]>>[CH:2]([C:4]1[C:9]([OH:10])=[C:8]([CH2:11][SH:18])[C:7]([CH2:13][OH:14])=[CH:6][N:5]=1)=[CH2:3]
Reactant: C=Cc1ncc(CO)c(CO)c1O
Reactant: S=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=Cc1ncc(CO)c(CS)c1O

Procedure:
The product from Step F is treated with sodium hydroxide and carbon disulfide as described in Example 1, Step C, to produce 2-vinyl-3-hydroxy-4-mercaptomethyl-5-hydroxymethylpyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[C:11]([CH3:24])[C:12]([F:23])=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:21][OH:22])[N:14]=2)[C:9](=[O:25])[C:8]([C:26]([O:28]CC)=[O:27])=[CH:7]1.[OH-].[Li+].O.Cl>CO>[CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[C:11]([CH3:24])[C:12]([F:23])=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:21][OH:22])[N:14]=2)[C:9](=[O:25])[C:8]([C:26]([OH:28])=[O:27])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC[C@H]3CO)c(F)c(C)c2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(C)c(F)c(N4CCC[C@H]4CO)nc32)c(OC)c1

Procedure:
A mixture of EXAMPLE 3A (312 mg) and 1M lithium hydroxide (1.9 mL) in methanol (6 mL) at 25° C. was stirred for 24 hours, treated with water (100 mL), adjusted to pH 3 with 1M hydrochloric acid, and filtered.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:1][C:2]2[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:3]=2)=[CH:41][CH:40]=1
Reactant: CCOC(=O)CCc1cc(O)nn1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
A mixture of ethyl 3-(3-hydroxy-1-phenyl-1H-pyrazol-5-yl)propionate (500 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (600 mg), potassium carbonate (530 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (980 mg, yield 95%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCCC.[I:26]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([I:26])=[CH:4][CH:3]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
To a solution of N-(6-chloropyridin-2-yl)-2,2-dimethylpropionamide (20 g, 94 mmol) in dry THF (500 mL) at −78° C., 1.3 M t-BuLi in hexane (220 mL, 282 mmol) is added dropwise. The reaction mixture is stirred for 30 min and a solution of iodine (29 g, 114 mmol) in dry THF is added. The reaction mixture is stirred for 3 h at −78° C. then is warmed to ambient temperature and stirred for another 1 h. The reaction mixture is quenched with 1N HCl and is extracted with ethyl acetate (2×250 mL). The organic layers are separated and washed with Na2S2O3 solution and saturated NaHCO3 solution, respectively. The combined organic layers are dried (Na2SO4) and evaporated under reduced pressure. The crude residue is purified by flash column chromatography using 20% EtOAc/petroleum ether to afford the title compound as a pale yellow solid (15 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Reaction time: 1.5 h

Procedure:
Ethyl 5-chloroindole-2-carboxylate (1.4 g) was dissolved in N,N-dimethylformamide (30 ml), and potassium carbonate (2.9 g) and benzyl chloride (2.4 ml) were added. The mixture was heated and stirred for 1.5 hours on a hot bath controlled to 100° C. The reaction mixture was concentrated under reduced pressure, and the residue was poured into ice water and extracted with ethyl acetate. The resultant organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatagraphy on silica gel (ethyl acetate:hexane=1:19) and crystallized from diethyl ether-hexane to obtain the title compound (1.6 g).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:40]([O:44][C:45](=[O:56])[NH:46][CH2:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][NH2:55])=[CH:50][CH:49]=1)([CH3:43])([CH3:42])[CH3:41].CN1CCOCC1>CN(C)C=O>[C:40]([O:44][C:45](=[O:56])[NH:46][CH2:47][C:48]1[CH:49]=[CH:50][C:51]([CH2:54][NH:55][C:9]([C:8]2[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:11])=[CH:52][CH:53]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
2-(4-Fluoro-phenoxy)-nicotinic acid (see reference Patent application WO 98/45268) (6.20 g, 26 mmol), 1-hydroxybenzotriazole (5.39 g, 40 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.62 g, 34 mmol) were disolved in N,N-dimethylformamide (50 ml) at room temperature and (4-aminomethyl-benzyl)-carbamic acid tert-butyl ester (6.28 g, 26 mmol) (see Preparation 1) added followed by addition of N-methyl morpholine (4.4 ml, 40 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at room temperature for 18 hours, and then partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic layer separated. The organic phase was then washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residue was triturated with diethylether (15 ml) giving [4-({[2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (9.52 g) as an off-white solid.
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:23]([O:26][C:27]1[N:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30])[CH2:24][CH3:25]>FC(F)(F)C(O)=O>[CH2:23]([O:26][C:27]1[N:35]=[CH:34][C:33]([I:1])=[CH:32][C:28]=1[C:29]([OH:31])=[O:30])[CH2:24][CH3:25]
Reactant: NC(=O)CCC(=O)NI
Reactant: CCCOc1ncccc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCOc1ncc(I)cc1C(=O)O

Procedure:
N-Iodosuccinamide (18.22 g, 0.08 mol), trifluoroacetic acid (100 ml) and trifluoroacetic anhydride (25 ml) were added to 2-propoxynicotinic acid (0.054 mol). The mixture was refluxed for 2.5h, cooled and the solvents evaporated. The residue was extracted from water with ethyl acetate and the organics washed with water (twice) and brine (twice), dried (MgSO4) and concentrated. The red residue was redissolved in ethyl acetate washed with sodium thiosulfate solution (twice), water (twice), brine (twice), redried (MgSO4) and concentrated to give the desired product as a solid; 1H NMR (300 MHz, CDCl3): δ=1.05 (t, 3H), 1.85-2.0 (m, 2H), 4.5 (t, 2H), 8.5 (s, 1H), 8.6 (s, 1H), Analysis: found C, 35.16; H, 3.19; N, 4.46. Calcd for C9H10INO3: C, 35.19; H, 3.28; N, 4.56%; LRMS (TSP): 529.5 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl.[NH2:14][OH:15].C(=O)(O)[O-].[Na+]>CO>[OH:15][N:14]=[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[CH:4]2)[NH2:12]
Reactant: NO
Reactant: Cn1ncc2cc(C#N)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cn1ncc2cc(C(N)=NO)ccc21
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A solution of 1-methyl-1H-indazole-5-carbonitrile (205 mg, 1.304 mmol), hydroxylamine hydrochloride (363 mg, 5.22 mmol) and sodium bicarbonate (548 mg, 6.52 mmol) in Methanol (6 mL) was heated to 60 degrees for 90 min. The reaction mixture was cooled to ambient temperature and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organics washed with brine, dried (Na2SO4) and concentrated to afford the crude N′-hydroxy-1-methyl-1H-indazole-5-carboximidamide (174 mg, 0.915 mmol, 70% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15-1.38 (m, 6H) 2.13 (s, 3H) 4.18 (dq, J=19.59, 7.15 Hz, 4H) 4.98 (br. s., 1H) 8.90 (br. s., 1H). LC/MS (m/z) ES+=191 (M+1).
Reaction SMILES: Cl[C:2]1C=CC(C2C=CN3C(=O)NN=C3C=2C2C=CN=CC=2)=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]3[C:37](=[O:51])[N:38]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[CH:43][CH:42]=4)[N:39]=[C:33]3[C:32]=2[C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]3[C:37](=[O:51])[N:38]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([S:47]([CH2:50][CH3:2])(=[O:48])=[O:49])=[CH:43][CH:42]=4)[N:39]=[C:33]3[C:32]=2[C:52]2[CH:53]=[CH:54][N:55]=[CH:56][CH:57]=2)=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)c1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)cc1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Product: CCS(=O)(=O)c1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)cc1

Procedure:
The title compound was prepared by coupling 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one with the requisite benzyl halide in a manner analogous to that in which 7-(4-chlorophenyl)-2-(4-(methylsufonyl)benzyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared. HPLC/MS: retention time=2.428 min, [M+H]+=505.
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cc(Br)ccc1OCc1ccccc1
Reactant: C1CNCCN1
Agent: COc1ccc(Br)cc1C
Product: Clc1cc(N2CCNCC2)ccc1OCc1ccccc1
Yield: 65.2 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-(2-phenethyl)piperazine were replaced with 1-benzyloxy-4-bromo-2-chlorobenzene (7.138 g) and piperazine (12.404 g), respectively. Thus obtained crude product was purified on silica gel column chromatography (eluent, chloroform: methanol=5:2) to provide 1-(4-benzyloxy-3-chlorophenyl)piperazine (4.739 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[CH:15][CH:14]=[C:13]([F:23])[CH:12]=2)[C:5]([O:7][CH3:8])=[O:6].[CH3:25][O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:24])[C:4]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[CH:15][CH:14]=[C:13]([F:23])[CH:12]=2)([CH3:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[O-]
Reactant: COC(=O)C(C(=O)OC)c1[nH]c2cc(F)ccc2c1CCN=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C(=O)OC)c1[nH]c2cc(F)ccc2c1CCN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[3-(2-azidoethyl)-6-fluoro-1H-indol-2-yl]-propanedioic acid dimethyl ester (37 mmol) in dry MeOH (0.25 L) at 0° C. under argon was added a solution of 25% NaOMe in MeOH (8.56 mL, 37.4 mmol). The mixture was stirred for 30 min at 0° C. Mel (3.56 mL, 56.6 mmol) was added. The mixture was refluxed for 42 h, cooled, and concentrated. The residue was partitioned between H2O and Et2O. The Et2O extracts were washed with H2O , dried, and concentrated to an oil. This oil was purified by silica chromatography to give the title compound: TLC Rf=0.50 (CH2Cl2); MS (ESI+) m/z 371.1; 1H NMR (CDCl3, 300 MHz) δ 9.63 (1H), 7.44 (1H), 7.05 (1H), 6.97 (1H), 3.82 (6H), 3.44 (2H), 2.94 (2H), 1.93 (3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH:9]([CH3:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:28](Br)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C)C=O>[CH2:32]([O:31][C:29]([CH:28]1[O:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[CH3:8])[CH3:19])=[CH:12][C:13]=2[O:18]1)=[O:30])[CH3:33]
Reactant: CC(Cc1ccc(O)c(O)c1)N(C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2ccc(CC(C)N(C)C(=O)OC(C)(C)C)cc2O1
Temperature: 100 °C
Yield: 34.2 %

Procedure:
To 2.5 g (8.8 mmol) of 1C was added 20 mL of anhydrous N, N-dimethylformamide (DMF) followed by 3.68 g (26 mmol) of anhydrous K2CO3 and 3 mL (23 mmol) of ethyl dibromoacetate. The reaction mixture was heated to 100° C. for 4.5 hours and then allowed to cool to room temperature. This was concentrated to dryness under reduced pressure, and 50 mL of water was added to the residue. The mixture was adjusted to pH 3 using 1N HCl and extracted with 4×50 mL of dichloromethane. Organic layers were combined, dried (anhydrous Na2SO4), and concentrated to dryness. The residue was purified by flash column silica gel chromatography using 15% ethyl acetate in hexane to give 1.1 g (3.01 mmol, 34%) of 1D as a colorless oil (M+Na, 388).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][N:5]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[C:6](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)SC>C(O)C>[CH3:1][N:2]([CH3:3])[C:6]([N:5]([CH3:4])[N:16]1[C:24](=[O:25])[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:18]2[C:17]1=[O:26])=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNC
Reactant: CSC(=Nc1ccccc1)N(C)N1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: CN(C)C(=Nc1ccccc1)N(C)N1C(=O)c2ccccc2C1=O

Procedure:
To a saturated solution of anhydrous dimethylamine in 80 ml. of ethanol was added 4.53 g. (0.01 mol) of 2-(1,2-dimethyl-3-phenylisothioureido)-1H-isoindole-1,3-(2H)-dione, and the resulting solution was heated to 50° C. for 30 minutes. Evaporation and treatment with heptane gave 3.5 g. of crystalline product, m.p. 146°-8° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH3:11])[S:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:11][CH:10]1[C:3]2[C:2]([N:22]3[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][S:9]1
Reactant: CC1SCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC1SCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Yield: 70.8 %

Procedure:
A solution of 4-chloro-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidine (4 g, 21 mmol) and 1-Boc-piperazine (8.5 g, 46 mmol) in NMP (20 mL) was heated to 120° C. overnight. After cooling, the mixture was diluted with ethyl acetate (500 mL) and washed with water (6×300 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (2:1) to provide tert-butyl 4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (5 g, 69%). The crude material was purified by chiral separation on chiral HPLC (ODH, 250×20 mm, 100% acetonitrile, 15 mL/min) to give (R)-tert-butyl 4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (retention time: 4.016 min) and (S)-tert-butyl 4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (retention time: 4.551 min). 1H NMR (CDCl3, 400 MHz) δ 8.53 (s, 1H), 4.83 (m, 1H), 4.18 (m, 2H), 3.73-3.56 (m, 4H), 3.51-3.43 (m, 4H), 1.50 (m, 9H). MS (APCI+) [M+H]+ 337.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[CH:10]([CH:24]3[O:28][CH2:27][CH2:26][O:25]3)[CH2:9][CH2:8][C@@:7]4([OH:29])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.N1C=CN=C1.[C:35]([Si:39]([CH3:42])([CH3:41])Cl)([CH3:38])([CH3:37])[CH3:36].O>CN(C=O)C>[Si:39]([O:20][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][C@H:6]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:23][CH2:22][C@:12]45[C:13]=2[C:14]=1[O:21][C@H:11]4[CH:10]([CH:24]1[O:25][CH2:26][CH2:27][O:28]1)[CH2:9][CH2:8][C@@:7]35[OH:29])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reaction time: 0.67 h
Yield: 80 %

Procedure:
17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxy-6-(1,3-dioxolan-2-yl)morphinan (3.85 g, 10 mmol) was dissolved in 10 ml of DMF, then imidazole (0.68 g, 10 mmol) and tert-butyl dimethyl chlorosilane (1.5 g, 10 mmol) were added with stirring. The whole system was reacted at a temperature ranging from 20° C. to 25° C. for 40 min. After the reaction was complete, water was added to the system and the resultant mixture was extracted with diethyl ether for 3 times. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated for crystallization to afford a white solid of 4.0 g. Yield: 80%. Melting point: 107.7-109.3° C.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[N:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)[CH:21]=[CH:22][CH:23]=1>ClCCl.CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[C:26]([N:30]=[C:1]=[S:2])[N:27]=[CH:28][N:29]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc(-c2cccc(Cl)c2)ncn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: S=C=Nc1cc(-c2cccc(Cl)c2)ncn1
Temperature: 60 °C

Procedure:
To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.486 g, 2.091 mmol) in dichloromethane/N,N-dimethylformamide at room temperature was added 6-(3-chlorophenyl)pyrimidin-4-amine (0.43 g, 2.091 mmol). The orange mixture was heated at 60° C. for 18 hours. The LC/MS showed the desired product peak as a major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-(3-chlorophenyl)-6-isothiocyanatopyrimidine (0.12 g, 0.484 mmol, 23% yield) as an orange oil. LCMS R.T.=2.15; [M]+=248.31.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[NH2:5].F[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([NH:5][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1)[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: CC(C)C[C@H](N)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(N[C@@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cn3)cc2)nc1
Temperature: 107.5 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
A mixture of crude (S)-3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butan-1-amine (66.34 g, 192.4 mmol), methyl 6-fluoronicotinate (32.8 g, 212 mmol), and freshly pulverized and dried (150 C, vacuum oven, 12 h) tripotassium phosphate (75.6 g, 356 mmol) was purged with dry nitrogen then diluted with N,N-dimethylacetamide (320 ml). The mixture was heated to 110° C. (107-108° C. internal temperature) for 24 hours. The reaction was diluted with water (˜1.5 L) and the resulting mixture was stirred vigorously for 15 minutes. The aqueous portion was decanted, leaving behind a thick amorphous solid. This material was washed with water (2×1 L). The resulting solid was dissolved in ethyl acetate and the remaining water was removed via azeotropic distillation (rotary evaporator, approximately 2×1 L ethyl acetate). The combined aqueous layers were stirred vigorously for 12 hours resulting in the precipitation of an additional aliquot (approximately 500 mg) of the crude product that was combined with the originally recovered material. The crude material was purified via ISCO MPLC (SiO2, 0-75% ethyl acetate in heptane) to yield the product (53.0 g, 62%) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.93 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.97 (dd, J=8.5, 2.1 Hz, 1H), 7.92 (dd, J=8.9, 2.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 6.25 (d, J=8.8 Hz, 1H), 5.79 (d, J=6.5 Hz, 1H), 4.73-4.85 (m, 1H), 3.84 (s, 3H), 1.77-1.86 (m, 1H), 1.65-1.77 (m, 2H), 1.01 (d, J=6.1 Hz, 3H), 0.97 (d, J=6.1 Hz, 3H). MS (M+1): 444.5.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]3)=[CH:10][C:9]=1[CH3:29].Cl[CH2:31][C:32]1[C:33]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[N:34][O:35][C:36]=1[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[Cl:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:47])[C:40]=1[C:33]1[C:32]([CH2:31][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]4)=[CH:10][C:9]=2[CH3:29])=[C:36]([CH:37]([CH3:39])[CH3:38])[O:35][N:34]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(O)c(C)c3)ccc2n1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)c(C)c3)ccc2n1
Yield: 21.7 %

Procedure:
Cesium carbonate (54.9 mg, 168.6 μmol) was added to ethyl 6-(4-hydroxy-3-methylphenyl)-2-quinolinecarboxylate (47.1 mg, 153.3 μmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (51.3 mg, 168.6 μmol) in N,N-dimethylformamide (3.1 mL) at room temperature. The resulting suspension was stirred for twenty hours, then water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to give 19.1 mg (22%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-3-methylphenyl]-2-quinolinecarboxylate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 8.56 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.19-8.09 (m, 3H), 7.66-7.59 (m, 4H), 7.55 (dd, J=9, 7 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 4.91 (s, 2H), 4.42 (q, J=7 Hz, 2H), 3.52 (septet, J=7 Hz, 1H), 1.97 (s, 3H), 1.38 (t, J=7 Hz, 3H), 1.36 (d, J=7 Hz, 6H). ESI-LCMS m/z 575 (M+H)+.