Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)=[O:6])[CH3:3].[Sn].C(=O)=O>C(O)C>[CH2:2]([O:4][C:5]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[CH:13]=2)[NH:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Agent: Cl
Agent: O=C=O
Agent: [Sn]
Solvent: CCO
Product: CCOC(=O)C1Cc2cc(OC)ccc2N1
Reaction time: 1 h

Procedure:
A three neck 3-liter round bottom flask equipped with a mechanical stirrer, water condenser, and a gas inlet tube was charged with 500 ml. of absolute ethanol and chilled in a dry ice-acetone bath. Dry hydrogen chloride gas was added at a rapid rate for 0.5 hours. Fifty grams of 5-methoxyindole-2-carboxylic acid ethyl ester (B. Heath-Brown and P. G. Philpott, J. Chem. Soc. 1965, 7185) followed by 100 g. of tin metal (30 mesh) were added to the solution with stirring. With the dry ice bath in place, but with no additional cooling the reaction mixture was stirred gently for 6 hours. The crystalline solid that separated was removed by filtration. The mother liquor was evaporated under reduced pressure to give an oil. The oil dissolved in 500 ml. of absolute ethanol, was placed in a 3-liter round bottom flask equipped with a stirrer and thermometer, and chilled to 10°. Gaseous ammonia was bubbled into the mixture until the pH was 9 (by wet pH paper) and the mixture was allowed to stand at 10° for one hour. The while precipitate was filtered and the filtrate was evaporated on a rotary evaporator to dryness. The initial white precipitate and the residue from the evaporation were combined and triturated repeatedly with warm ether. The combined ether triturates were washed with a sodium chloride solution (a water:saturated salt solution, 1:1) with vigorous shaking; whereupon most of the basic tin salts were suspended and separated in the aqueous phase. Both phases were filtered through Celite and separated. The ether solution was dried over magnesium sulfate and evaporated under reduced pressure on the rotary evaporator. The oily residue was dried in vacuo to give 22 g. of d,1-2,3-dihydro-5-methoxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [Na].C(O)C.[CH:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][CH2:11][C:12](OCC)=[O:13]>C(OCC)C>[Cl:10][CH:11]([CH:12]=[O:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCl
Reactant: CCOC=O
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(Cl)C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
To a flask was added sodium (4.45 g, 194 mmol) and ethanol (56.5 mL, 968 mmol) and the mixture was stirred at room temperature for 4 hours until all of the metal had dissolved. Diethyl ether (100 mL) was added, followed by the slow addition of a solution of ethyl formate (17.20 mL, 213 mmol) and ethyl chloroacetate (22.79 mL, 213 mmol) in diethyl ether (100 mL). The reaction solution was stirred at room temperature for 16 hours. The resulting precipitate that formed was filtered and washed with ether, and dissolved in water. The aqueous layer was acidified with HCl (1N) to pH 4 and the product was extracted with diethyl ether (3×). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give ethyl 2-chloro-3-oxopropanoate (4.5 g, 29.9 mmol, 15.44% yield).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])=[O:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1.C([Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[CH2:25][NH:24][C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][NH:4][CH2:62][C@H:60]([OH:61])[CH2:59][O:58][C:55]3[CH:56]=[CH:57][C:52]([OH:51])=[CH:53][CH:54]=3)[CH2:11][CH2:10]2)(=[O:13])=[O:14])=[CH:20][CH:19]=1)=[O:23]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCC1CCN(S(=O)(=O)c2ccc(NC(=O)NCc3cc(F)ccc3F)cc2)CC1
Solvent: O=CO
Product: O=C(NCc1cc(F)ccc1F)Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3ccc(O)cc3)CC2)cc1
Yield: 13 %

Procedure:
N-(4-{[4-(aminomethyl)-1-piperidinyl]sulfonyl}phenyl)-N′-(2,5-difluorobenzyl)urea formate (0.433 g, 1.00 mmol) was reacted with t-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.404 g, 1.00 mmol) according to example 37 to give the title compound (0.084 g, 0.13 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[Li]CCCC.[C:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C1COCC1>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: Cc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
Amine preparation: To a solution of 2-picoline (333 mg) in dry THF (5 mL) at −78° C. was added nBuLi (2.5M solution in hexanes, 1.50 mL). The reaction mixture was warmed to room temperature over 30 min and then cooled to −78° C. 1-BOC-4-piperidone (713 mg) was then added, and the reaction mixture was raised to 0° C. over 20 min. The reaction mixture was stirred overnight and then quenched with water. The organics were extracted into ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to give crude product. The residue was purified using flash chromatography to yield 4-hydroxy-4-pyridin-2-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester (290 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3]([O:5][CH2:6][O:7][C:8](SCC)=[O:9])=[O:4].S(Cl)([Cl:17])(=O)=O>>[CH3:1][CH:2]([CH3:13])[C:3]([O:5][CH2:6][O:7][C:8]([Cl:17])=[O:9])=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCSC(=O)OCOC(=O)C(C)C
Product: CC(C)C(=O)OCOC(=O)Cl
Reaction time: 0.33 h

Procedure:
The compound (400 mg) obtained in Step 2 of this Example was cooled to −30° C. Sulfuryl chloride (159 μL) was added thereto, and the mixture was stirred at the same temperature for 20 minutes. The mixture was in turn stirred for 20 minutes in an ice bath and further at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dried to obtain a crude product of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)([CH3:6])[CH3:5].O>C(O)C>[Cl:13][C:11]1[CH:12]=[C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:15])=[O:2])[CH:8]=[C:9]([Cl:14])[CH:10]=1
Reactant: COC(=O)C(C)(C)c1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: CCO
Product: CC(C)(C(=O)O)c1cc(Cl)cc(Cl)c1
Yield: 98.9 %

Procedure:
To a solution of 9.0 g (36 mmol) 2-(3,5-dichloro-phenyl)-2-methyl-propionic acid methyl ester in 40 ml ethanol 40 ml 2 N sodium hydroxide solution was added. After stirring for 4 hrs at RT 150 ml water was added and the solution washed twice with 200 ml Et2O. The aqueous phase was acidified with 25% hydrochloric acid solution and three times extracted with 150 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated to yield 8.3 g (97%) 2-(3,5-dichloro-phenyl)-2-methyl-propionic acid as a off-white solid.
Reaction SMILES: C[O:2][P:3]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:4][CH3:5].[C:12]([C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[CH2:19]Cl)([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:5][O:4][P:3]([CH2:19][C:18]1[CH:17]=[C:16]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:23]([OH:24])=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1)([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:2]
Reactant: COP(OC)C1CCCCC1
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C1CCCCC1
Yield: 51.2 %

Procedure:
A mixture of 10.47 grams (59 mmol) of dimethylcyclohexylphosphonite with 15.14 grams (59 mmol) of 3,5-di-tert-butyl-4-hydroxybenzyl chloride (CAS REG # 955-01-1) in 45 mL of toluene is refluxed for 2 hours and is cooled. The resultant precipitated crystals are collected by filtration, washed with toluene, then hexane and are dried under vacuum to obtain 11.5 grams (51% yield) of (3,5-di-tert-butyl-4-hydroxy-benzyl)-cyclohexyl-phosphinic acid methyl ester as a white solid mp 149-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]1[C:23]([CH3:24])=[N:22][N:21]=[C:20]1[CH2:25]O.P(Br)(Br)[Br:29]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]1[C:23]([CH3:24])=[N:22][N:21]=[C:20]1[CH2:25][Br:29]
Reactant: BrP(Br)Br
Reactant: Cc1nnc(CO)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cc1nnc(CBr)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 5, 2'-chloro-5-(trifluoromethyl)-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is treated with phosphorus tribromide in chloroform to give 2'-chloro-5-(trifluoromethyl)-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl] -benzophenone.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][C:18]([C:22]([OH:24])=O)=[C:19]([CH3:21])[N:20]=3)[CH:14]=2)[C:9](=[O:25])[N:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:7]=1[CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:2][CH2:3][CH3:4].Cl.C[N:41](C)CCCN=C=N.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:35]([O:34][C:32](=[O:33])[NH:31][CH2:30][C:7]1[N:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:9](=[O:25])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([C:16]1[S:17][C:18]([C:22]([NH2:41])=[O:24])=[C:19]([CH3:21])[N:20]=1)=[CH:12][CH:11]=2)([CH3:38])([CH3:36])[CH3:37]
Reactant: CN(C)CCCN=C=N
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(=O)O)s3)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(N)=O)s3)cc12
Yield: 97.2 %

Procedure:
A solution of 2-(4-butoxy-3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylic acid (0.60 g, 1.1 mmol), 1-ethyl,-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.42 g, 2.2 mmol) and 1-hydroxybenzotriazole ammonium salt (0.33 g, 2.2 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl{6-[5-(-aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.58 g, 96.7%) as crystals.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)C>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=2[C:17]#[N:18])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2C#N)CC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 77.7 %

Procedure:
To a solution of N-Boc-piperazine (2.02 g, 11.0 mmol) in DMSO (20 mL) was added 2-fluoro-6-chlorobenzonitrile (1.55 g, 10 mmol) and potassium carbonate (1.52 g, 11 mmol). The mixture was stirred at 80° C. for about 48 hours. The mixture was cooled to r.t. and diluted with diethyl ether (200 mL). The solution was washed with 1N HCl (2×20 mL), H2O (3×20 mL) and brine (20 mL) and then dried over sodium sulfate and concentrated to a yellow oil. Purification by flash chromatography (4:1 hexanes/ethyl acetate) gave the title compound (2.5 g, 86%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH:12]1([C:15](=[N:17]O)[NH2:16])[CH2:14][CH2:13]1>C(O)C>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[O:6][N:17]=[C:15]([CH:12]2[CH2:14][CH2:13]2)[N:16]=1
Reactant: NC(=NO)C1CC1
Reactant: COC(=O)c1ccccc1N
Solvent: CCO
Product: Nc1ccccc1-c1nc(C2CC2)no1

Procedure:
Methyl 2-amino-benzoate (6 g, 40 mmol) and cyclopropylcarboxamid oxime (5 g, 50 mmol) was refluxed for 10 h in dry ethanol containing 0.25 g sodium and 2 g molecular sieves. The mixture was filtered while hot, and cooled precipitating 2.8 g of the desired product as white needles. Upon additionof water to the flitrate, a further amount of 3.2 g white crystals could beisolated. M.p. 84.4°-84.9° C.
Reaction SMILES: C([C@H:3]([S:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[CH3:42][NH:43][CH2:44][CH2:45][OH:46]>>[CH3:34][N:33]1[C:29]([C:27]([NH:26][C:22]2[CH:21]=[C:20]([C:19]#[C:18][C:16]3[CH:15]=[N:14][CH:13]=[C:12]([CH:17]=3)[C:10]([N:9]=[S@@:7]([CH2:3][C:4]([N:43]([CH2:44][CH2:45][OH:46])[CH3:42])=[O:5])(=[O:8])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:11])[CH:25]=[CH:24][CH:23]=2)=[O:28])=[CH:30][C:31]([CH3:35])=[N:32]1
Reactant: CNCCO
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@](=O)(CC(=O)N(C)CCO)c4ccccc4)c3)c2)n(C)n1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate and 2-methylaminoethanol were reacted to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH2:26][CH3:27])=[C:17]3[N:22]([CH:23]=2)[CH:21]=[C:20]([O:24][CH3:25])[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([C:34]([O:36][CH3:37])=[O:35])#[C:29][C:30]([O:32][CH3:33])=[O:31]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3=[C:28]([C:34]([O:36][CH3:37])=[O:35])[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:21]4[C:20]([O:24][CH3:25])=[CH:19][CH:18]=[C:17]([N:22]34)[C:16]=2[CH2:26][CH3:27])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cc(OC)ccc12
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)OC)c(C(=O)OC)c3c(OC)ccc1n32
Yield: 80 %

Procedure:
The general synthetic pathway outlined in example 23, step 1-5, have been applied to proper starting materials in the preparation of 2-(4-benzyloxyphenyl)-1-ethyl-6-methoxyindolizine, which was reacted with dimethyl acetylene dicarboxylate by the general synthetic principle outlined in example 23, step 6, to afford dimethyl 3-(4-benzyloxyphenyl)-4-ethyl-7-methoxypyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate as a red oil in 80% yield. 1H-NMR (CDCl3, 200 MHz) δ: 1.36 (t, 3H); 3.02 (q, 2H); 3.60 (s, 3H); 3.98 (s, 3H); 4.14 (s, 3H); 5.15 (s, 2H); 7.04-7.52 (m, 10H); 7.81 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:4][N:5]=[N:6][C:7]=1[Cl:8].[CH3:19][CH:20]([NH2:22])[CH3:21]>O1CCCC1>[Cl:1][C:2]1[C:3]([NH:9][C:10]([NH:22][CH:20]([CH3:21])[CH3:19])=[O:18])=[CH:4][N:5]=[N:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1cnnc(Cl)c1Cl)Oc1ccccc1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1cnnc(Cl)c1Cl
Yield: 10 %

Procedure:
A stirred solution of 1.0 gram (0.004 mole) of phenyl N-(5,6-dichloro-4-pyridazinyl)carbamate and 0.27 gram (0.005 mole) of 1-methylethylamine in tetrahydrofuran is heated under reflux for 18 hours. The reaction mixture is filtered and the filtrate concentrated under reduced pressure to a residue. The residue is purified by column chromatography to yield 0.1 gram of N-(5,6-dichloro-4-pyridazinyl)-N'-(1-methylethyl)urea.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:39]=[CH:40][N:41]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:25][C:26]4[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=4)=[O:24])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:39]=[CH:40][N:41]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:25][C:26]4[CH:38]=[CH:37][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)=[O:24])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(N3CCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nn3ccnc23)nc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N3CCC(C(=O)Nc4ccc(C(=O)O)cc4)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.3 %

Procedure:
A mixture of tert-butyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-carboxamido)benzoate (200 mg, 0.36 mmol) and TFA (2 mL) in dichloromethane (2 mL) was stirred at room temperature for 2 h. The residue was concentrated in vacuo. The crude product was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 25% acetonitrile/75% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-carboxamido)benzoic acid (6 mg, 4%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.54 (s, 1H), 8.88 (brs, 2H), 7.95-7.82 (m, 4 h), 7.49-6.69 (m, 3H), 4.06-3.57 (m, 6H), 3.19-3.02 (m, 5H), 2.05 (brs, 2H). LC-MS: [M+H]+, 504, tR=1.269 min, HPLC: 96.47% at 214 nm, 97.69% at 254 nm, tR=4.72 min.
Reaction SMILES: [SH:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.Br[CH:16]([CH3:23])[C:17](=O)[C:18]([O:20][CH3:21])=[O:19]>C([O-])(=O)C.[Na+].O.C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:13][N:5]1[C:4](=[O:14])[C:3]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH3:23])[S:1][C:2]=2[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]1=[O:12]
Reactant: CC(C)Cn1c(S)cc(=O)n(C)c1=O
Reactant: COC(=O)C(=O)C(C)Br
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(C)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Temperature: 0 °C
Yield: 59.2 %

Procedure:
6-Mercapto-3-methyl-1-(isobutyl)-pyrimidine-2,4(1H,3H)-dione (50 g) was dissolved in a solution of sodium acetate (95.6 g) in water (1.5 L), and methyl 3-bromo-2-oxo-butanoate (44.6 g) was added dropwise with stirring. After stirring 1 h at room temperature the mixture was extracted into ethyl acetate. The organic solution was washed with brine, dried (MgSO4) and evaporated to leave an oil. The oil (75.1 g) was dissolved in methylene chloride (800 ml) and cooled in an ice-bath under an atmosphere of nitrogen. With efficient stirring titanium tetrachloride (43.3 ml) was slowly added dropwise. The reaction mixture was stirred 1 h in the ice-bath and then 3 h at room temperature. The reaction mixture was poured slowly into vigorously stirred ice-water (2 L), and then the resulting suspension was extracted into methylene chloride. After drying, the organic solvent was removed in vacuo, and the residue was chromatographed (SiO2/1:1 ethyl acetate-isohexane) to afford the sub-title compound 42 g. Trituration with isohexane gave a white powder. δ 1HCDCl3—0.98(6H,d), 2.23-2.41 (1H,m), 2.46 (3H,s), 3.4 (3H,s), 3.75 (2H,d), 3.96 (3H,s).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2([CH3:21])[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([CH3:20])[C:11]([CH3:19])=[C:12]([OH:18])[C:13]=3[CH3:17])[O:8]2)=[O:6])[CH2:3][CH2:2]1.[O:22]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]([OH:22])([CH3:21])[CH2:16][CH2:15][C:14]2[C:9](=[O:8])[C:10]([CH3:20])=[C:11]([CH3:19])[C:12](=[O:18])[C:13]=2[CH3:17])[CH2:3][CH2:2]1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NC1CC1)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NC2CC2)=C(C)C1=O
Yield: 37.9 %

Procedure:
Oxidation as described in protocol B, using 100 mg (0.346 mmol) of N-cyclopropyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 417 mg CAN (0.762 mmol) yielded 40 mg of N-cyclopropyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH:16]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C>C(#N)C>[CH:16]([C:19]1[N:20]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH:21]=[CH:22][N:23]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ncc[nH]1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1ccc(-n2ccnc2C(C)C)c([N+](=O)[O-])c1
Yield: 81.7 %

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate 4.26 g, 2-isopropylimidazole 2.20 g, N,N-diisopropylethylamine 5.2 mL and acetonitrile 40 mL was heated under reflux for 24 hours. After distilling the solvent off, water was added to the residue and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and removed of the solvent by distillation, to provide 4.95 g of the title compound.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]1[Cl:11].[NH3:13]>CCOCC>[Cl:11][C:6]1[N:5]([CH2:4][C:3]([NH2:13])=[O:2])[C:9]([Cl:10])=[CH:8][CH:7]=1
Reactant: N
Reactant: COC(=O)Cn1c(Cl)ccc1Cl
Solvent: CCOCC
Product: NC(=O)Cn1c(Cl)ccc1Cl

Procedure:
A mixture of methyl(2,5-dichloro-1H-pyrrol-1-yl)acetate (0.5 g), in ether (3 cm3), and concentrated aqueous ammonia solution (3 cm3) was stirred at room temperature overnight in a stoppered flask. The precipitated crystalline product was collected by filtration and washed with ether to give 0.07 g of title compound. The ethereal washings were dried and evaporated. The crystalline residue was triturated with diisopropyl ether to give a further 0.13 g of title compound, m.p. 183°-4° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]=[CH:6]2.[Mg].[C:20](=[O:22])=[O:21].[Cl-].[NH4+]>C(OCC)C>[C:13]1([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][C:20]([OH:22])=[O:21])[CH:4]=3)[N:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccc2nc(-c3ccccc3)ccc2c1
Reactant: O=C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: O=C(O)Cc1ccc2nc(-c3ccccc3)ccc2c1

Procedure:
The Grignard compound is prepared in the customary manner from 5 g of 6-bromomethyl-2-phenyl-quinoline and magnesium in 30 ml of diethyl ether. It is added to a solution of solid carbon dioxide in 100 ml of diethyl ether. At the same time a further quantity of solid carbon dioxide is added in portions to the reaction solution. Thereafter, aqueous ammonium chloride solution is added to the reaction mixture and the whole is extracted with ethyl acetate. The organic phases are extracted with 2 N sodium carbonate solution. The sodium carbonate extracts are adjusted to pH 6 and extracted with ethyl acetate. These ethyl acetate layers are dried and evaporated. The residue, after recrystallisation from methanol-pentane, yields 2-phenyl-6-quinolineacetic acid of melting point 176-179°C.