Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]([S:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[O:15]>C(Cl)Cl>[CH3:12][N:13]([S:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:9])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[O:15]
Reactant: CN(SC(C)(C)C)C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)S(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
4.3 g of 80% m-chloroperbenzoic acid dissolved in 50 ml of methylene chloride were added dropwise to a solution of 6.15 g of N-methyl-N-tert.-butylthio-N'-(3,4-dichlorophenyl)-urea in 60 ml of methylene chloride cooled to 0° C. and after stirring the mixture at 0° C. for 20 minutes, the insolubles were removed by filtration. The organic phase was washed with an aqueous saturated solution of sodium bicarbonate, then with water and dried. The solvent was distilled off under reduced pressure and the residue was crystallized from isopropyl ether to obtain 5.5 g of N-methyl-N-tert.-butylsulfinyl-N'-(3,4-dichlorophenyl)-urea melting at 118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[F:25][C:26]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:27]=1[CH:28]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:28][C:27]2[CH:30]=[C:31]([C:34]([F:35])([F:37])[F:36])[CH:32]=[CH:33][C:26]=2[F:25])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Product: Fc1ccc(C(F)(F)F)cc1CNc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2-fluoro-5-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 507.9.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:27][C:26]=2[C:36]([OH:38])=[O:37])[C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[C:15]([N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:25]1[CH:29]=[C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:27][C:26]=1[C:36]([OH:38])=[O:37])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2ccc(Cl)cc2Cl)c2cc(-c3ccccc3)sc2C(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C1CCNCC1
Reaction time: 4 h
Yield: 107.2 %

Procedure:
A solution of 4-[(2-Carboxy-5-phenyl-thiophen-3-yl)-(2,4-dichloro-benzoyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (240 mg, 0.42 mmol) in dioxane (4 ml) at 21° C. under nitrogen was treated with anhydrous 4M HCl (3 ml, 12.6 mmol, 30 eq). After 4 h the reaction was stripped off solvent and the residue triturated with ether to give 3-[(2,4-Dichloro-benzoyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid as a pale yellow powder (214 mg, 100%) 1H NMR (Acetone, 400 MHz) 7.76-7.73 (m, 2H), 7.64 (s, 1H), 7.45-7.38 (m, 3H), 7.30 (bs, 1H), 7.28-7.24 (m, 1H), 4.93-4.84 (m, 1H), 3.56-3.49 (m, 2H), 3.25-3.14 (m, 2H), 3.05-2.55 (bs, 1H), 2.50-2.37 (m, 2H), 2.13-1.83 (m, 1H). Similarly prepared were Compound #366, Compound #553, Compound #543
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:27](=[O:28])[CH2:26][Cl:25])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (see reference WO 2000039125, prep 27)(25 g, 103 mmol) was dissolved in dichloromethane (300 ml) and 4-methylmorpholine (12.5 ml, 113 mmol) was then added. The mixture was cooled using an ice bath and chloroacetyl chloride (8.2 ml, 103 mmol) was added dropwise. The reaction was then allowed to warm to room temperature and was stirred for 4 hours. The reaction mixture was partitioned with aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate, filtered and the filtrate was evaporated to give the title compound as an off white solid (29.6 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[C:6]([O:13][CH3:14])[CH:5]=1)([OH:3])=O.[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[CH:15]([NH:18][C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[O:3])([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: COc1cc(C(=O)O)ccc1B(O)O
Product: COc1cc(C(=O)NC(C)C)ccc1B(O)O

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate K from 4-carboxy-2-methoxyphenyl boronic acid and isopropylamine. The solvent was removed and then water and EtOAc were added. The phases were separated and the aqueous one was extracted twice with EtOAc. The organic extracts were combined and dried (Na2SO4), and concentrated. The residue was triturated in acetonitrile to give the title compound. tR: 0.63 min (LC-MS 2); ESI-MS: 238.5 [M+H]+ (LC-MS 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: CCOC(=O)C1=C(Nc2cccc(Cl)c2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2cccc(Cl)c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a solution of ethyl 2-[(3-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.051 g, 0.35 mmol) in ethanol (3.0 mL), piperidine (0.0035 mL, 0.035 mmol) was added at ambient temperature. The mixture was refluxed for 6 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound (0.061 g, y. 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C.O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([I:11])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Clc1ccn2ccnc2c1
Reactant: O=C1CCC(=O)N1I
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccn2c(I)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 7-Chloro-imidazo[1,2-a]pyridine (30.9 g, 186 mmol, 1.0 equiv) in DMF (280 ml) was added N-iodosuccinimide (43.6 g, 194 mmol, 1.05 equiv) and the resulting mixture was stirred overnight at RT. The thin brown slurry was diluted with water (840 ml), brine (280 ml) and extracted with EtOAc (560 ml). The aqueous layer was further extracted with EtOAc (3×280 ml). The combined organic phases were washed with water (2×280 ml), 10% w/v sodium thiosulfate (280 ml), brine (280 ml), dried (MgSO4), filtered and concentrated in vacuo to give a brown residue. The residue was triturated with ether (200 ml), filtered and the solid was washed with ether (2×50 ml) and dried on the filter to give 39 g of product. MS: [M+H]+=279.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]CC)=O)[CH:3]=1.[NH3:13]>>[OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:13])=[O:10])[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1cc(O)ncn1
Product: NC(=O)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
Ethyl 6-hydroxy-4-pyrimidinecarboxylate (Intermediate 6, 0.995 g, 5.92 mmol) was treated with 0.88 ammonia solution (9.95 mL, 460 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The resulting solid was collected by filtration, taken up in toluene and the solvent removed under reduced pressure to give the title compound as a yellow solid (563 mg);
Reaction SMILES: [NH2:1][C@H:2]([C:14]([O:16][CH3:17])=[O:15])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:1][C@H:2]([C:14]([O:16][CH3:17])=[O:15])[CH2:3][C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)=[O:36])=[CH:38][CH:39]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1ccc(C[C@H](N)C(=O)OC)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C[C@H](NC(=O)c2ccc(C(C)(C)C)cc2)C(=O)OC)cc1
Reaction time: 2 h
Yield: 44.6 %

Procedure:
Prepared using General Procedure 3: To the solution of (S)-methyl 4-(2-amino-3-methoxy-3-oxopropyl)benzoate (425.0 mg, 1.79 mmol) in DCM (10 mL) and DIEA (463.0 mg, 3.58 mmol) was added 4-(tert-butyl)benzoyl chloride (556.6 mg, 2.83 mmol) at RT. The reaction was stirred for 2 h and the reaction was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 317 mg (45%) of (S)-methyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate. LCMS-ESI (m/z) calculated for C23H27NO5: 397.2; found 398.1 [M+H]+, tR=2.31 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 7.97-7.75 (m, 2H), 7.67-7.51 (m, 2H), 7.46-7.26 (m, 2H), 7.14 (d, J=8.3 Hz, 2H), 6.60 (d, J=7.4 Hz, 1H), 5.03 (dt, J=7.4, 5.7 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 3.28 (dd, J=13.7, 5.8 Hz, 1H), 3.18 (dd, J=13.7, 5.5 Hz, 1H), 1.24 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19].N1CCCCC1>COCCO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:17]2[S:13][C:14](=[O:19])[NH:15][C:16]2=[O:18])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: COCCO
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A solution of 4-formyl-benzoic acid methyl ester (1.0 g, 6.7 mmol), thiazolidine-2,4-dione (0.78 g, 6.7 mmol) and piperidine (0.66 ml, 6.7 mmol) in 2-methoxy-ethanol (20 ml) was refluxed for 2 hrs, cooled to the room temperature and evaporated. The residue was triturated with CH2Cl2 to produce a crystalline material which was collected by filtration to afford the title compound (620 mg, 35% yield). LRMS: 263.3 (calcd.), 264.1 [MH]+ (found).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:10][CH:9]=1)C.[NH2:24][C:25]([NH2:27])=[S:26].CC(C)([O-])C.[K+].Cl>C(O)CCC.O>[C:18]([O:17][C:15](=[O:16])[NH:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]2[CH:5]=[C:4]([OH:3])[N:27]=[C:25]([SH:26])[N:24]=2)=[CH:9][CH:10]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)CC(=O)Cc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: NC(N)=S
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(O)nc(S)n2)cc1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-(4-tert-butoxycarbonylamino-phenyl)-3-oxo-butyric acid ethyl ester (10.5 g, 32.7 mmol), thiourea (2.5 g, 32.7 mmol) and potassium tert-butoxide (8.3 g, 71.9 mmol, 2.2 equiv) in butan-1-ol (30 mL) is heated to 50° C. (oil bath temperature) for 23 h, under an argon atmosphere. The resulting yellow suspension is diluted with butan-1-ol (30 mL), neutralized by addition on 1N HCl (65 mL), diluted with H2O (20 mL) and extracted with CHCl3 (2×100 mL). The organic phase is dried (Na2SO4), filtered (washing the filter cake with copious amount of CHCl3) and concentrated in vacuo. After silica gel (300 g) column chromatography purification (CHCl3/MeOH, 90/10), the product is treated with CH2Cl2 (200 mL). The resulting suspension is allowed to stir at rt for 20 min, then diluted with hexane (200 mL) and filtered through a glass sintered funnel. The white residue is washed with a mixture (120 mL) of CH2Cl2/hexane (11, v/v) and dried in vacuo to afford the title compound: ES-MS: 334.0 [M+H]+; single peak at tR=7.04 min (System 2); Rf=0.34 (CHCl3/MeOH, 90/10).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1CCC(c2ccccc2)(c2ccccc2)CC1
Yield: 98.1 %

Procedure:
To a Parr hydrogenation bottle was added 4,4-diphenyl-2-cyclohexen-1-one (0.91 g, 3.66), dissolved in methanol (20 mL), followed by the addition of 10% Pd/C (0.2 g). This mixture was hydrogenated at 50 psi overnight. After the catalyst was filtered and washed with methanol, the filtrate was concentrated in vacuo to give 0.90 g of 4,4-diphenyl-cyclohexanone. MS (EI) calcd: M+H=251.1. Found: 251.1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[O:18][C:19]=2[CH3:20])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[OH:26][C:27]1[C:31]([CH:32]=[O:33])=[CH:30][N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]=1.CN(C)C=O.[H-].[Na+]>O>[CH:32]([C:31]1[C:27]([O:26][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:13][CH2:14][C:15]3[N:16]=[C:17]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[O:18][C:19]=3[CH3:20])=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])=[N:28][N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=1)=[O:33]
Reactant: COC(=O)c1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a mixture of methyl 5-(chloromethyl)-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate (1.16 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.12 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate as colorless crystals (1.07 g, yield 77%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 173-174° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C[N:18](C)C=O.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH2:18])=[O:16])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 4'methyl-[1,1'biphenyl]-2-carboxylic acid (20.0 g, 94.2 mmol) in dichloromethane (200 mL) at 0° C. was added dimethylformamide (0.5 mL) followed by oxalyl chloride (100 mL of 2.0M solution in dichloromethane, 200 mmol). The rate of addition was adjusted to maintain the internal temperature below 10° C. When the addition was complete, the mixture was allowed to warm to 25° C. and was stirred at that temperature for two hours, after which it was concentrated in vacuo. The semisolid residue was added portionwise to concentrated ammonium hydroxide solution (250 mL) at 0° C., stirred for 15 minutes, and diluted with water (200 mL). The resulting white precipitate was collected, washed with water, and dried in vacuo over phosphorus pentoxide to give the title compound (18.7 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][I:12])[CH2:10][CH2:9]O[CH2:7][CH2:6]1)=[O:4].[CH3:13]OC(C1CCCCC1)=O>>[CH3:1][O:2][C:3]([C:5]1([CH2:11][I:12])[CH2:10][CH2:9][CH2:13][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CI)CCOCC1
Reactant: COC(=O)C1CCCCC1
Product: COC(=O)C1(CI)CCCCC1
Yield: 100 %

Procedure:
Prepared according to the method for the preparation of 4-iodomethyltetrahydropyran-4-carboxylic acid methyl ester, from cyclohexane-carboxylic acid methyl ester (10 ml), to give the title compound as a brown gum (20 g, 100%).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([NH:10][NH2:11])[CH:5]=1.C(O[CH:16]=[C:17]([C:23]#[N:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[NH2:24][C:23]1[N:10]([C:6]2[CH:5]=[C:4]([O:3][CH:2]([F:1])[F:12])[N:8]([CH3:9])[N:7]=2)[N:11]=[CH:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Cn1nc(NN)cc1OC(F)F
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cc(OC(F)F)n(C)n2)c1N

Procedure:
1.70 g (9.55 mmole) 5-Difluoromethoxy-3-hydrazino-1-methylpyrazole and 1.62 g (9.55 mmole) ethyl ethoxymethylenecyanoacetate in 30 ml ethanol was stirred for 1 hour at boiling point. After cooling the precipitated product was filtered off, washed with a little ethanol and dried.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C@H:10]([SH:25])[CH2:9][CH2:8][C@@:7]4([OH:26])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][CH3:21])[CH2:3][CH2:2]1.[O:27]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](Cl)=[O:35])=[CH:28]1>>[CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C@H:10]([S:25][C:34](=[O:35])/[CH:33]=[CH:32]/[C:29]3[CH:30]=[CH:31][O:27][CH:28]=3)[CH2:9][CH2:8][C@@:7]4([OH:26])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][CH3:21])[CH2:3][CH2:2]1
Reactant: COc1ccc2c3c1O[C@H]1[C@H](S)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reactant: O=C(Cl)/C=C/c1ccoc1
Product: COc1ccc2c3c1O[C@H]1[C@H](SC(=O)/C=C/c4ccoc4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Yield: 59 %

Procedure:
The procedure of Example 11 was repeated, except that 17-cyclopropylmethyl-4,5α-epoxy-14β-hydroxy-3-methoxy-6β-mercaptomorphinan(K. Kanematsu, T. Toshiyasu, M. Yoshida., Chem., Pharm. Bull., 38, 1141, (1990)) was used instead of 17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6α-(N-methylamino)morphinan 4 and trans-3-(3-furyl)acryloyl chloride was used instead of 3,4-dichlorophenylacetyl chloride, thereby preparing 17-cyclopropylmethyl-4,5α-epoxy-14β-hydroxy-3-methoxy-6β-[trans-3-(3-furyl)acryloylthio]morphinan 169 (yield: 59%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]=O>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]1[N:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:7][CH:8]=2)[C:16](=[O:15])[CH2:17][CH2:20][CH2:21]1
Reactant: NCc1ccc(N2CCCC2)cc1
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(N2CCCC2)cc1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (4-(pyrrolidin-1-yl)phenyl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.62 min.; [M+H]+: 395.25 g/mol.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH:14]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:16])[CH3:15].[C:25]1([P:31](Cl)(Cl)=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCCCCC.C1CCCCC1>[CH:14]([N:17]1[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[P:31]1(=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:16])[CH3:15]
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: CC(C)NCc1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CC(C)N1Cc2ccccc2P1(=O)c1ccccc1
Temperature: 26 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (7.87 g, 0.123 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-isopropylbenzylamine (9 g, 0.06 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2 hours at 26° C. and then cooled to -40° C. using a solid carbon dioxide-acetone bath. A solution of phenylphosphonic dichloride (12.5 g, 0.064 mol) in 60 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to 10° C. The reaction mixture was stirred for 1.5 hours at 26° C., after which time the reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 12 ml. of acetic acid. After stirring for 15 minutes, the cyclohexane was removed on a rotary evaporator, and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield an oil. This oil was distilled at 160° C. and 0.2 torr and the resulting residue was crystallized at 0° C. from diethyl ether and petroleum ether to yield 2-(1-isopropyl)-1-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (4.5 g, 28% yield) having a melting point of 92°-94° C. and the following analysis:
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([O:15]CC)=[O:14].[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1[nH]nc(-c2ccncc2)c1C(=O)O
Yield: 88.1 %

Procedure:
To a solution of ethyl 5-methyl-3-(pyridin-4-yl)-1H-pyrazole-4-carboxylate (3.1 g) in ethanol (20 mL) were added sodium hydroxide (8.0 g) and water (10 mL), and the mixture was heated under reflux overnight. The solvent was evaporated under reduced pressure, the pH of the mixture was adjusted to 5 with 2 N hydrochloric acid, and mixture was concentrated under reduced pressure. The obtained solid was collected by filtration and washed with water to give the title compound (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH:14]([CH3:16])[CH3:15])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:17]I>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:17])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CI
Reactant: COC(=O)c1cc(Cl)c(O)c(OC(C)C)c1
Product: COC(=O)c1cc(Cl)c(OC)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
Methyl 3-chloro-5-isopropoxy-4-methoxybenzoate (4) (1.06 g, 95%) was prepared from methyl 3-chloro-4-hydroxy-5-isopropoxybenzoate (3) (1.00 g, 4.09 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that methyl iodide was used instead of cyclopentyl bromide and the mixture was stirred at RT for 18 h.