Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([C:21]1[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>O1CCCC1>[C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]4[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C(Cl)Cc1ccc(Nc2ccccc2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(Nc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 81.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenylamino-phenyl)-acetohydroximoyl chloride (150 mg, 0.576 mmol) described in Manufacturing Example 69-1-4 and 3-ethynyl-pyridin-2,6-diamine (48.9 mg, 0.367 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (201 μL, 1.44 mmol). This mixture was stirred for 6.5 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (107 mg, 52%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][P:34]([CH3:38])(=[O:37])[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]3[CH2:32][CH2:33][P:34]([CH3:38])(=[O:37])[CH2:35][CH2:36]3)=[CH:30][C:24]=2[O:23][CH3:22])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].B(Br)(Br)Br.CO>ClCCl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(Nc2nc3c(-c4ccc(S(C)(=O)=O)cc4)cccn3n2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(O)cc4)nc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of [8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methoxy-phenyl)-amine (150.0 mg, 0.3803 mmol) in dichloromethane (10 mL, was added dropwise 1.0 M of boron tribromide in dichloromethane (1.2 mL, 1.2 mmol). The mixture was stirred for 1 hour at room temperature then methanol (5 mL) was added slowly. The mixture was evaporated to dryness. Additional methanol (10 mL) was added and the mixture was evaporated to dryness. The brown solid was suspended in saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to a solid. 4-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenol was isolated without further purification as a light brown solid (0.115 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (dd, J=6.7, 0.9 Hz, 1H), 8.22 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.5 Hz, 2H), 7.64 (dd, J=7.4, 0.8 Hz, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.00 (dd, J=7.1, 7.1 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.73 (s, 1H), 4.72 (br s, 1H), 3.09 (s, 3H). MS=381 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH:8]=2)=[CH:5][N:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][C:15]=23)[N:3]=1.CO.[BH4-].[Na+]>[Pd]>[CH3:1][C:2]1[C:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH:9]([OH:13])[CH2:8]2)=[CH:5][N:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[CH:21]=[CH:22][C:15]=23)[N:3]=1
Reactant: Cc1nn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cc1C1=CC(=O)CCC1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cc1C1CCCC(O)C1
Reaction time: 8 h
Yield: 26 %

Procedure:
A mixture of 3-[3-methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]cyclohex-2-en-1-one (0.019 g, 0.000045 mol) and palladium on carbon (Pd/C) (0.018 g, 0.000017 mol) in methanol (2 mL, 0.05 mol) was degassed and was stirred under a hydrogen atmosphere overnight. An additional 48 mg of 10% Pd/C was added and stirred under a hydrogen atmosphere for 8 h. The palladium was filtered and the filtrate was stirred with sodium tetrahydridoborate (0.032 g, 0.00084 mol) for 5 h. The reaction was purified by prep-HPLC to give 5 mg of the desired product. MS (M+H)+: 427.
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[C:10]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:9]3[N:19]=[C:20]([C:22]4[C:31]([CH3:32])=[N:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:21]=[C:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>[Pd].ClCCl.CO>[CH:1]1([C:6]2[CH:11]=[C:10]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:9]3[N:19]=[C:20]([C:22]4[C:31]([CH3:32])=[N:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:21]=[C:8]3[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(C3=CCCC3)cc(NC3CCOCC3)n2n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2ccccc2nc1-c1cc2nc(C3CCCC3)cc(NC3CCOCC3)n2n1
Reaction time: 3 h

Procedure:
A suspension of 5-cyclopent-1-en-1-yl-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (30 mg, 0.0703 mmol) and palladium on carbon (5%, 30 mg) in dichloromethane (2.0 mL) and methanol (2.0 mL) was stirred for 3 h under hydrogen atmosphere. Then reaction mixture was filtrated with chloroform, and the filtrate was concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 1:1) to give 5-cyclopentyl-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (the compound of Example 1.012 listed in the Table of Examples as described hereinafter). 1H-NMR (400 MHz, CDCl3): δ 1.67-1.95 (8H, m), 2.08-2.20 (4H, m), 3.05 (3H, s), 3.11-3.23 (1H, m), 3.60 (2H, ddd, J=11.8, 11.8, 2.4 Hz), 3.74-3.85 (1H, m), 4.10 (2H, ddd, J=11.5, 3.3, 3.3 Hz), 5.94 (1H, s), 6.32 (1H, d, J=7.9 Hz), 7.02 (1H, s), 7.71-7.79 (2H, m), 8.04-8.08 (1H, m), 8.16-8.20 (1H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.[H-].[Na+].Br[CH2:35][CH3:36]>CN(C=O)C>[CH2:35]([O:1][CH2:2][CH2:3][CH:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)[CH3:36]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)C(CCO)CC4)CC1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCC1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
To a 25-mL round-bottom flask was added a solution of intermediate 18.3 (125 mg, 0.28 mmol, 1.00 equiv) in distilled DMF (10 mL) followed by sodium hydride (60% dispersion in mineral oil, 96 mg, 2.80 mmol) at 0° C. and the reaction mixture was stirred for 30 min. Then bromoethane (305 mg, 2.80 mmol) was added and the resulting solution was stirred overnight at room temperature. The reaction was then quenched with water and extracted with 100 mL of ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with EtOAc/petroleum ether (1:5). Purification afforded tert-butyl N-(4-[[3-(2-ethoxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (19.1, 19 mg, 14%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:15]([OH:21])([CH3:20])[CH2:16][C:17](=[NH:19])[NH2:18].C(=O)(O)[O-].[K+].Br[CH2:28][C:29](=O)[C:30]([CH3:33])([CH3:32])[CH3:31]>O1CCCC1.O>[C:30]([C:29]1[N:19]=[C:17]([CH2:16][C:15]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=3)=[CH:7][C:2]=2[F:1])([OH:21])[CH3:20])[NH:18][CH:28]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(O)(CC(=N)N)c1ccc(-c2ccc(F)cn2)cc1F
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1c[nH]c(CC(C)(O)c2ccc(-c3ccc(F)cn3)cc2F)n1

Procedure:
A solution of the di(trifluoroacetate) salt of (±)-3-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanimidamide (50 mg, 0.10 mmol), potassium bicarbonate (19 mg, 0.19 mmol) and 1-bromo-3,3-dimethylbutan-2-one (52 mg, 0.29 mmol) in tetrahydrofuran (1 mL) and water (0.25 mL) were stirred at ambient temperature overnight. Volatiles were removed in vacuo and the residue was purified by HPLC (Gilson; KR100-5C18 100×21.2 mm column; 10-100% MeCN/H2O) over 12 min to afford the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.51 (d, J=2.8 Hz, 1H), 7.90 (dd, J=4.3, 8.8 Hz, 1H), 7.76-7.58 (m, 4H), 6.99 (s, 1H), 3.45 (AB, J=14.9 Hz, 2H), 3.30 (bs, 1H), 1.732 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5](I)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5]([C:14]#[N:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cnc2cccc(I)c2n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1cnc2cccc(C#N)c2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
A suspension of 2-methyl-8-iodoquinoxaline (730 mg), Zn(CN)2 (423 mg) and Pd(PPh3)4 (313 mg) in DMF (5 mL) was stirred at 60° C. for 5 hours. The reaction solution was cooled, and thereto was added water (10 mL), and the mixture was extracted twice with a mixture of toluene and ethyl acetate (1:1) (50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→4/1) to give 2-methyl-8-cyano-quinoxaline (422 mg, 93%) as red brown solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][O:18][CH2:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1.O[C:23]1[CH:27]=[C:26]([CH3:28])[O:25][N:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:28][C:26]1[O:25][N:24]=[C:23]([O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH2:16][CH2:17][O:18][CH2:19][CH:20]=4)=[C:11]([F:21])[CH:10]=3)[CH2:4]2)[CH:27]=1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCOCC2)c(F)c1
Reactant: Cc1cc(O)no1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC[C@H]2CN(c3ccc(C4=CCOCC4)c(F)c3)C(=O)O2)no1
Yield: 46.1 %

Procedure:
5(R)-hydroxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one (300 mg, 1.02 mmol), 3-hydroxy-5-methylisoxazole (120 mg, 1.21 mmol), triphenylphosphine (270 mg, 1.03 mmol) and diisopropylazodicarboxylate (204 mg, 1.01 mmol) were reacted in THF (8.0 ml) using the general method of Example 1. The resultant product was purified by flash chromatography (Merck 9385 silica, EtOAc/isohexane (7:3) eluant) to give the title product (176 mg, 46%) as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]1C(C)=NOC=1C.Cl.ClCC[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[H-].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][CH2:16][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:11][N:12]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1noc(C)c1CN1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN1C(=O)CCN(CCN2CCOCC2)c2nc(Cl)ncc21

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 156, on a 0.3 mmol scale, utilising N-(2-chloroethyl)morpholine hydrochloride (Aldrich; 67 mg, 0.36 mmol) and Sodium Hydride (60% mineral oil dispersion; 36 mg, 0.75 mmol), as a solid (95 mg, 97%).
Reaction SMILES: I[C:2]1[C:3]([O:25]C)=[CH:4][C:5]([O:23]C)=[C:6]([C:8]2[N:12]([C:13]3[CH:22]=[CH:21][C:16]4[O:17][CH2:18][CH2:19][O:20][C:15]=4[CH:14]=3)[N:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)=[CH2:28]>CCOCC>[CH3:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:27][CH2:28][C:2]2[C:3]([OH:25])=[CH:4][C:5]([OH:23])=[C:6]([C:8]3[N:12]([C:13]4[CH:22]=[CH:21][C:16]5[O:17][CH2:18][CH2:19][O:20][C:15]=5[CH:14]=4)[N:11]=[CH:10][CH:9]=3)[CH:7]=2)=[CH:30][CH:31]=1
Reactant: C=Cc1ccc(C)cc1
Reactant: COc1cc(OC)c(-c2ccnn2-c2ccc3c(c2)OCCO3)cc1I
Solvent: CCOCC
Product: Cc1ccc(CCc2cc(-c3ccnn3-c3ccc4c(c3)OCCO4)c(O)cc2O)cc1

Procedure:
12.6 Analogous reaction of 5-[5-iodo-2,4-dimethoxyphenyl]1-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1H-pyrazole with 4-vinyltoluene, hydrogenation and ether cleavage gives the compound 5-{5-[2-(4-methylphenyl)ethyl]2,4-dihydroxyphenyl}-1-(2,3-dihydrobenzo-1,4-dioxin-6-yl)-1H-pyrazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([I:13])[CH:7]=1)[CH3:2].[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][C:17]([CH3:19])=O>C1C=CC=CC=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH2:22]([O:21][C:15](=[O:20])[CH:16]=[C:17]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])=[CH:7][C:8]=1[I:13])[CH3:19])[CH3:23]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)Cc1ccc(N)c(I)c1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C=C(C)Nc1ccc(CC(=O)OCC)cc1I
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of (4-amino-3-iodo-phenyl)acetic acid ethyl ester (9.85 g, 32.3 mmol), ethyl acetoacetate (4.2 g, 32.3 mmol), and toluenesulfonic acid monohydrate (0.3 g, 1.6 mmol) in benzene (150 mL) is refluxed under Dean-Stark conditions overnight. The solution is then cooled to room temperature and washed with sodium bicarbonate (NaHCO3) (2×50 mL) and concentrated in vacuo to give the desired product (12.5 g, 93%). The product is used without further purification in Step 3. MS: 418 (M+1)+.
Reaction SMILES: [CH2:1]([SH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)[C:18]=1[CH3:39])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.C[O-].[Na+].CO.C1COCC1>[CH2:9]([O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH2:27][S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:18]=1[CH3:39])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)OCc2nc3ccccc3c(OCc3ccccc3)c2C)cc1
Reactant: CCCCCCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCSCc1nc2ccccc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
1-Heptanethiol (250 mg) was dissolved in methanol (5 mL), to which a solution of 28% sodium methoxide in methanol (0.37 mL) was then added, followed by stirring at room temperature for 15 minutes. The reaction mixture was added to a solution of p-toluenesulfonic acid [4-(benzyloxy)-3-methylquinolin-2-yl]methyl ester (464 mg) in methanol-THF (1:1, 10 mL), followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and water (100 mL) was added to the resulting residue, followed by extraction with ethyl acetate (100 mL). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain 4-(benzyloxy)-2-[(heptylsulfanyl)methyl]-3-methylquinoline (380 mg).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([NH2:9])=[C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Cl)cc1Oc1ccccc1
Yield: 143.8 %

Procedure:
2-Fluoro-4-chloro-nitrobenzene (0.50 g), phenol (0.27 g) and potassium carbonate (0.40 g) in dry DMSO (10 ml) were stirred at RT for 2 h. The mixture was diluted with water, extracted with diethylether, dried and evaporated under reduced pressure to give a yellow oil (0.90 g). The oil was dissolved in glacial acetic acid (20 ml) and treated with reduced iron powder (0.90 g). The mixture was vigorously stirred at RT for 2 h, filtered through celite, washed with DCM and the filtrate evaporated under reduced pressure, yield 0.9 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:15][CH2:16][CH2:17][CH2:18][Cl:19])=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:12])=[CH:5][C:4]=1[O:15][CH2:16][CH2:17][CH2:18][Cl:19]
Reactant: [H][H]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCCl
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)O)c(N)cc1OCCCCl
Temperature: 40 °C
Yield: 102.1 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 2.04 g (6.90 mmol) of 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoic acid (purity: 99%) obtained in Reference Example III-8 and 40 mL of methanol. The resulting mixture was heated to 40° C. under stirring. To the mixture was added 0.2 g of 5 wt. % palladium/carbon (containing 49% water) at the same temperature. The resulting mixture was heated to the same temperature for 2 hours, while hydrogen was introduced into the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to precipitate a crystalline product. The crystalline product was dried under reduced pressure, to give 1.83 g (isolated yield: 97.0%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of 5-methoxy-4-(3-chloropropoxy)anthranilic acid as a white crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7]Br.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([CH2:7][C:6]2[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:10])([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1ccc(Cl)cc1CBr
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: OC1(Cc2cc(Cl)ccc2F)CCN(Cc2ccccc2)CC1

Procedure:
A sample of 5-chloro-2-fluorobenzyl bromide is converted to its Grignard reagent which is reacted with N-benzyl-4-piperidone to provide 1-benzyl-4-(5-chloro-2-fluorobenzyl)-4-piperidinol in the manner described in Example 4A. This product is distilled at 210° C., 0.15 mm, leaving an orange oil. The oil is dissolved in ether where it is converted to its hydrochloride salt which is recrystallized thrice from an ethyl alcohol-ether mixture to provide the product, 1-benzyl-4-(5-chloro-2-fluorobenzyl)-4-piperidinol hydrochloride, mp 217°-219° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O.[N+:24]([O-])([O-:26])=[O:25].[K+]>>[CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:14]=[CH:15][C:16]([N+:24]([O-:26])=[O:25])=[CH:17][CH:18]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)[C@H]1[C@@H](c2ccccc2)CC(=O)N1C
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)[C@H]1[C@@H](c2ccc([N+](=O)[O-])cc2)CC(=O)N1C
Reaction time: 18 h
Yield: 32 %

Procedure:
To (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-phenyl-pyrrolidin-2-one (prepared according to the procedure of Intermediate T, Method 2, 1.00 g, 4.04 mmol) was added sulfuric acid (4.0 mL). To the resulting yellow solution was added potassium nitrate (0.50 g, 4.85 mmol) in portions, keeping the reaction temperature below 30° C. The reaction mixture was stirred for 18 h, then poured onto ice water (30 mL) and extracted with CH2Cl2, dried (MgSO4) and concentrated under reduced pressure. The oily residue was diluted with EtOAc and the resulting precipitate was collected by filtration. The solid was washed with Et2O to give (±)-(4R 5R*)-5-ethoxycarbonyl-1-methyl-4-(4-nitrophenyl)pyrrolidin-2-one (374 mg, 32%) as a white solid: mp 142-143° C.; TLC (33% EtOAc/hex) Rf 0.23; HPLC ES-MS m/z 293 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH2:21]/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=[N:6][CH:7]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CSc1ccc(CC(=O)c2cncc(Br)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C(C/C=C/c2ccccc2)C(=O)c2cncc(Br)c2)cc1
Temperature: 25 °C

Procedure:
To 1-(5-bromo-3-pyridinyl)-2-[4-(methylsulfanyl)phenyl]-1-ethanone in DMF (2.5 mL) at 0° C. was added NaH (15 mg, 0.5 mmole). The reaction was stirred 30 minutes, at which point cinnamyl bromide (0.1 g, 0.5 mmole) was added and the reaction was allowed to warm to room temperature. The reaction was quenched with H2O and extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and evaporated to give the title compound.