Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[CH3:7].[NH2:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:3]1[C:2]([C:14]2[CH:15]=[C:10]([CH:11]=[CH:12][CH:13]=2)[NH2:9])=[C:6]([CH3:7])[O:5][N:4]=1
Reactant: Cc1noc(C)c1I
Reactant: Nc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1cccc(N)c1
Yield: 85 %

Procedure:
To a solution of 4-iodo-3,5-dimethylisoxazole (for a preparation see intermediate 1, 142 g, 640 mmol, 1 eq.) and (3-aminophenyl)boronic acid (100 g, 640 mmol, 1 eq.) in DME (600 ml) were added tetrakis(triphenylphosphine) palladium(0) (18.5 g, 16 mol) and a solution of Na2CO3 (203.5 g, 192 mmol, 3 eq.) in water (750 ml). The mixture was heated under reflux for 24 h. To complete the reaction intermediate 1 (0.2 eq.) and tetrakis(triphenylphosphine) palladium(0) (5 g) were added and the mixture was refluxed overnight. The cooled mixture was poured into water and extracted with DCM. The organic phase was washed with water, dried over Na2SO4 and filtered. Evaporation of the solvent in vacuo gave a crude oil which was precipitated with iPr2O to afford the title compound as a beige solid (102 g, 85%). [ES-MS] m/z: 189 MH+, Rt 2.20 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2-].[Na+].N.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][N:11]=1>O1CCOCC1>[N:1]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Clc1ncc(C2CCCCC2)c2ccccc12
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc2c(-n3ccnc3)ncc(C3CCCCC3)c2c1

Procedure:
3.4 g (50 mmoles) of imidazole were allowed to react with 1.9 g (49 mmoles) of sodium amide in 50 ml of absolute dioxane until the evolution of ammonia was finished. Then 9 g (37 mmoles) of 1-chloro-4-cyclohexyl-isoquinoline were added and the solvent was evaporated. The reaction mixture was heated for 3 hours to 140° C, distributed between methylene chloride and water and the organic phase was evaporated after having been dried over magnesium sulfate. The oily crude product was taken up in 30 ml of ether and crystallized upon trituration. M.p. 92° to 93° C, hydrochloride M.p. 228° to 229° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:14])[CH2:10][CH2:11][C:12]=1[CH3:13].N1C=CC=CC=1.[C:21]1([CH3:33])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[S:29](Cl)(=[O:31])=[O:30].Cl>C(Cl)Cl>[C:21]1([CH3:33])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[S:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:14])[CH2:10][CH2:11][C:12]=1[CH3:13])(=[O:30])=[O:31]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC1=C(c2ccccc2N)C(=O)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(c2ccccc2NS(=O)(=O)c2c(C)cc(C)cc2C)C(=O)CC1

Procedure:
0.500 g (2.67 mmol) of 2-(2-aminophenyl)-3-methyl-2-cyclopenten-1-one, 0.253 g (3.204 mmol) of pyridine, 0.584 g (2.67 mmol) of 2-mesitylenesulfonyl chloride), and 2 mL of M.C (methylene chloride) were loaded to a 20 mL vial, and then reacted for 12 hours. 10 mL of M.C and 4 mL of 2 N HCl were added to the reaction product. The resultant organic layer is collected and then dried over MgSO4 to remove water. The solvent contained in the dried product was removed using a rotary vacuum evaporator. The obtained solid was washed with 10 mL of diethyl ether and filtered using a glass filter. The filtered product was dried in vacuum to remove the solvent that had remained therein (0.790 g, 80%).
Reaction SMILES: CN(CCN(C)C)C.[C:9]1([CH3:22])[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C([Li])CCC.[CH:28]1([P:34]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)Cl)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CCCCCC.O>[C:9]1([CH3:22])[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[P:34]([CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: Cc1cc(C)c(-n2ccnc2)c(C)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(C)c(-n2ccnc2P(C2CCCCC2)C2CCCCC2)c(C)c1
Reaction time: 1 h

Procedure:
1.6 ml of TMEDA (15 mmol.) are added to a suspension of 1.86 g (10 mmol.) of N-mesitylimidazole in 30 ml of hexane. 6.25 ml of 1.6 molar n-butyllithium solution (10 mmol.) are added at room temperature. The mixture is then heated for 2.5 hours at reflux temperature (solution 1). In another flask, 2.2 ml (10 mmol.) of dicyclohexylchlorophosphane are mixed with 20 ml of hexane and heated to 60° C. (solution 2). The boiling solution 1 is then slowly transferred into solution 2, which is at 60° C., by means of a cannula. The mixture is then boiled for a further 1 hour at reflux, the solution is cooled, and 20 ml of degassed water are added thereto. The organic phase is filtered off over magnesium sulfate. The solution is concentrated in vacua; 30 ml of pentane are added thereto, and the mixture is boiled for 1 hour at reflux. The product precipitates in crystalline form at −30° C. and is filtered off while cold. Yield: 2.48 g (65%)
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[CH2:15]([O:22][C@H:23]1[C@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:26]([CH3:45])[O:25][C:24]1=[O:46])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:15]([O:22][C@H:23]1[C@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@H:26]([CH3:45])[O:25][C@@:24]1([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[OH:46])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@H]1OC(=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CCOP(C)(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(C[C@@]1(O)O[C@@H](C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 0.64 mL, 1.59 mmol, commercially available from Sigma Aldrich) was added to a stirred solution of diethyl methylphosphonate (0.23 mL, 1.59 mmol, commercially available from Sigma Aldrich) in THF (1.5 mL) at −78° C. under an argon atmosphere. The mixture was stirred for 15 min before a solution of (3 S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one (0.275 g, 0.636 mmol) in THF (1 mL) at −78° C. was added. The reaction mixture was removed from the cooling bath, and the mixture was allowed to warm to room temperature while stirring for 1 h. The reaction mixture was next concentrated in vacuo. The resulting oil was purified by silica gel chromatography (0 to 75% EtOAc/hexanes gradient) to give diethyl (((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)methyl)phosphonate as a colorless oil (0.251 g, 67.5% yield). 1H NMR (400 MHz, CDCl3): δ ppm 1.09 (d, J=6.65 Hz, 3 H) 1.26 (q, J=6.85 Hz, 6 H) 1.76 (dd, J=18.49, 15.16 Hz, 1 H) 2.33 (dd, J=17.41, 15.26 Hz, 1 H) 3.68 (br. d, J=1.60 Hz, 1 H) 3.72 (d, J=9.98 Hz, 1 H) 3.92-4.02 (m, 2 H) 4.06-4.17 (m, 4 H) 4.69 (dd, J=11.54, 4.11 Hz, 2H) 4.77 (dd, J=16.43, 11.74 Hz, 2 H) 4.99 (dd, J=11.54, 9.39 Hz, 2 H) 7.26-7.41 (m, 15 H).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:14](=[O:15])[C:5]=2[CH2:4][C:3]2[NH:16][C:17]4[C:22]([C:23](=[O:24])[C:2]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3.[OH-].[K+].S(=O)(=O)(O)O>CS(C)=O>[CH:20]1[CH:21]=[C:22]2[C:23]([C:2]3[C:3]([NH:16][C:17]2=[CH:18][CH:19]=1)=[CH:4][C:5]1[C:14]([C:13]2[C:8]([NH:7][C:6]=1[CH:1]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:15])=[O:24]
Reactant: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12

Procedure:
The oxidation of 6,13-dihydroquinacridone is carried out as described in the Japanese Patent Disclosure JP 54-135821, Example 5. Thus, 10 grams 6,13-dihydroquinacridone are stirred into a mixture of 100 ml dimethyl sulfoxide and 20 grams 33% aqueous potassium hydroxide solution at 110° to 120° and air is then introduced into the vessel at a rate of 90-96 ml/min. for a period of 5 hours. The reaction mixture is cooled and 33% aqueous sulfuric acid is introduced dropwise. The precipitated pigment is filtered and the presscake washed dimethyl sulfoxide-free with water to pH 6 and dried yielding 9.1 grams of a quinacridone pigment. A spectrophotometric analysis shows the product to consist of 0.8% 6,13-dihydroquinacridone, 17.2% of undesirable quinacridonequinone and 78.3% quinacridone. When incorporated into paints or plastics, the pigment shows a dirty red color. Its X-ray diffraction pattern shows the main peaks of known gamma quinacridone and quinacridonequinone.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]([CH3:28])[C:12]1=[O:29].[OH-].[Na+]>CO>[C:22]1([C:14]2[N:13]([CH3:28])[C:12](=[O:29])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(-c2ccccc2)c(-c2ccccc2)n(CCCCCCCC(=O)O)c1=O

Procedure:
The product is produced as described in example 18 from 17.5 g of 8-(4.5-diphenyl-3-methyl-2-oxo-4-imidazolin-1-yl) caprylic acid methyl ester and 2.1 g of NaOH in 100 cc. of methanol. Further purification by chromatography on silicic acid gel using chloroform as eluant.
Reaction SMILES: [NH2:1][C@H:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[Cl:19])=[CH:7][N:6]([CH2:20][C:21]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=2[F:31])[C:5]1=[O:32].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50]>CN(C=O)C>[CH2:52]([O:51][C:49]([CH2:48][CH2:47][CH2:46][NH:1][C@H:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[Cl:19])=[CH:7][N:6]([CH2:20][C:21]2[C:26]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:24]=[CH:23][C:22]=2[F:31])[C:5]1=[O:32])=[O:50])[CH3:53]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2Cl)cn(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 95 °C
Yield: 53.4 %

Procedure:
To a solution of compound 7h (2.0 g, 3.65 mmol) in DMF (8 mL) was added Na2CO3 (0.47 g, 4.38 mmol) followed by ethyl 4-bromobutyrate (0.83 mL, 5.48 mmol). The mixture was heated at 95° C. for 1.5 hours, cooled to room temperature, and partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel with ethyl acetate/hexanes/triethylamine 500/500/5 to afford compound 7i (1.29 g) as a white solid. MS (CI) m/z 662.2, 664.2 (MH+)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=O)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36]>>[CH3:34][S:35]([NH:38][C:23]([C:18]1[C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][N:9]3[C:8]4[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=4[N:6]=[C:5]3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:16][CH:15]=2)=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:25])(=[O:37])=[O:36]
Reactant: CS(N)(=O)=O
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)NS(C)(=O)=O)cc1

Procedure:
Prepared in analogous manner to Example 198 from 4'-[(2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid and thionyl chloride/methanesulphon-amide.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[C:38]([C:44]([NH:46][CH3:47])=[O:45])[CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[C:38]([C:44]([NH:46][CH3:47])=[O:45])[CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CNC(=O)c1ccc(OC)c(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)c1ccc(OC)c(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 67.4 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-6-methoxy-N-methyl[1,1′-biphenyl]-3-carboxamide (1.40 g) and pyridine hydrochloride (468 mg), the colorless amorphous title compound (576 mg) was obtained.
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>ClC(Cl)C>[CH3:24][CH2:23][C:22]([N:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: c1ccc(CCN2CCC(Nc3ccccc3)CC2)cc1
Reactant: CCC(=O)Cl
Solvent: CC(Cl)Cl
Product: CCC(=O)N(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
In two neck round bottom flask equipped with condenser pressure equalizing funnel and calcium chloride guard tube, a solution of 28.0 (0.10 moles) of 4-anilino N-phenethyl piperidine prepared in step II, in 100 ml of dichloroethane was taken. To this solution, 18.5 gm (0.20 moles) of propionyl chloride was added drop wise through pressure equalizing funnel with continuous stirring. After the completion of the addition, the mixture was further stirred for 1 hrs. After the completion of the reaction, the reaction mixture was washed with 20% sodium hydroxide solution. The aqueous phase was extracted with 2×100 ml of dichloromethane. The combined organic extract was dried over sodium sulphate and concentrated to give crude fentanyl. The crude product was recrystallised from petroleum ether (60 to 80° C.) to give colourless crystals of pure fentanyl having nip 82 to 83° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)[N:16]=1.C(#N)C>O>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:19]2[N:18]=[C:17]3[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=4)=[N:16]3)=[CH:21][CH:20]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(-c2ccc3ccc(N)nc3n2)cc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2ccc3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)nc3n2)cc1
Temperature: 4 °C
Yield: 57 %

Procedure:
The procedure is analogous to that described in Example 1 below but starting with 4-trifluoromethylbenzoic acid (2.7 g), N,N'-carbonyldiimidazole (2.3 g) and 2-amino-7-(4-methoxyphenyl)-1,8-naphthyridine (2.5 g). The product obtained by precipitation in water (3.3 g; m.p. 144°-146° C.) is dissolved in boiling acetonitrile (100 cc). After cooling for 3 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Methoxyphenyl)-1,8-naphthyridin-2-yl]-4-trifluoromethylbenzamide (2.4 g), m.p. 148° C., is obtained.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:31](=[O:46])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:31](=[O:46])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.21 mL, 0.64 mmol) was added to a THF (1 mL) and MeOH (0.5 mL) solution of ethyl 3-(5-(5-chloro-2-((4′-chloro-[1,1′-biphenyl]-4-yl)carbamoyl)phenyl)picolinamido)propanoate (119 mg, 0.21 mmol) and the homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][N:4]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O.C(OCC)(=O)C>C(=O)(O)[O-].[Na+]>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)=[N:4][CH:5]=2)=[N:13]1
Reactant: CC1(C)COC(c2ccc(Cl)nc2)=N1
Reactant: CN1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(c2ccc(C3=NC(C)(C)CO3)cn2)CC1
Yield: 67 %

Procedure:
2-Chloro-5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-pyridine hydrochloride was transformed into its free base by dissolving 8.0 g (32 mmol) in saturated sodium bicarbonate solution and extracting the base into dichloromethane. The solvent was evaporated and the residue was dissolved in toluene. After addition of 11.35 g (113 mmol) N-methylpiperazine, the mixture was refluxed for 36 h. After cooling to room temperature water (50 ml) and ethyl acetate (150 ml) were added and the aqueous layer was extracted with ethyl acetate (150 ml). The combined organic layers were extracted two times with 1 N hydrochloric acid, the acidic aqueous layer was made alkaline with 28% sodium hydroxide solution and extracted two times with dichloromethane. The organic layer was dried (magnesium sulfate) and evaporated. The residue was crystallized from ethyl acetate/hexane to yield 6.0 g (67%) of a white crystalline compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:21])[N:14]([CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]=3[C:4]=2[CH:3]=1.[OH-].[Na+].[CH3:24]I>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CC1OCCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:21])[N:14]([CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=c1[nH]c2cnc3ccc(Br)cc3c2n1C1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: Cn1c(=O)n(C2CCOCC2)c2c3cc(Br)ccc3ncc21
Temperature: 45 °C
Reaction time: 17 h
Yield: 257.5 %

Procedure:
On a larger scale, 8-bromo-1-(oxan-4-yl)-3H-imidazo[4,5-c]quinolin-2-one (1300 g, 3.73 mol) was charged to the vessel along with tetrabutylammonium bromide (130 g, 0.40 mol) and 2-MeTHF (20.8 L). A solution of NaOH (240 g, 6.00 mol) in water (20.8 L) was then added over 5 minutes with an observed exotherrn from 18-24° C. The biphasic mixture was heated to 42-48° C. before the addition of methyl iodide (465 mL, 7.47 mol) as a solution in 2-MeTHF (930 mL). The reaction was stirred at 45° C. for 17 h at which point HPLC analysis showed 2.9% starting material and 97.1% product. The reaction mixture was combined with that of the other large scale batches for concentration in vacuo. The resulting aqueous suspension was then returned to the vessel and slurried for 1 h with the product material obtained from the development batches combined at this point. The product was then isolated by filtration, washing with water (2×12 L) before oven drying under vacuum at 40° C. In total 3479 g of 8-bromo-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one was isolated. Analytical data was consistent with that obtained from previous batches.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5]1)(=[O:3])[NH2:2].Cl[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[O:31][CH3:32])[CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=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.O1CCOCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[CH:23]=[CH:18][N:19]=[C:20]([NH:2][C:1]([C@@H:4]3[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:5]3)=[O:3])[CH:21]=2)=[C:25]([O:31][CH3:32])[CH:26]=1
Reactant: COc1cc(F)ccc1-c1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(F)ccc1-c1ccnc(NC(=O)[C@@H]2CC[C@H](NC(=O)OC(C)(C)C)C2)c1

Procedure:
tert-Butyl (1S,3R)-3-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-ylcarbamoyl)cyclopentylcarbamate was prepared according to Method B using tert-butyl (1S,3R)-3-carbamoylcyclopentylcarbamate (750 mg, 3.28 mmol), 2-chloro-4-(4-fluoro-2-methoxyphenyl)pyridine (930 mg, 3.94 mmol), Cs2CO3 (1.63 g, 4.92 mmol), xantphos (173 mg, 0.29 mmol), Tetrakis(triphenylphosphine)palladium (0) (150 mg, 0.13 mmol) and 1,4-dioxane (10 ml) brought to reaction at 120° C. for 4 h in a sealed tube.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:19][CH:16]([CH:17]=[CH2:18])[CH:4]([CH:5]([O:10][CH:11]([O:13][CH2:14][CH3:15])[CH3:12])[CH2:6][CH:7]=[N:8][OH:9])[O:3]1.C(N(CC)CC)C.Cl[O-].[Na+]>C(Cl)Cl.C(OCC)C>[CH3:20][C:2]1([CH3:1])[O:3][CH:4]2[CH:5]([O:10][CH:11]([O:13][CH2:14][CH3:15])[CH3:12])[CH2:6][C:7]3[CH:17]([CH2:18][O:9][N:8]=3)[CH:16]2[O:19]1
Reactant: C=CC1OC(C)(C)OC1C(CC=NO)OC(C)OCC
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(C)OC1CC2=NOCC2C2OC(C)(C)OC12
Temperature: 0 °C
Reaction time: 11 h
Yield: 53.4 %

Procedure:
One gram of 4,5- (dimethylmethylenedioxy) -3-(1-ethoxyethoxy)-6-heptenal oxime was dissolved in 15 ml of methylene chloride, and 0.2 ml of triethylamine was added at 0° C. Then, 8 ml of a 10% sodium hypochlorite aqueous solution was added, and the mixture was stirred at 0° C. for 11 hours. The reaction mixture was diluted with ethyl ether, and washed with a sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 530 mg of 4,5-(dimethylmethylenedioxy)-6-(1-ethoxyethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following properties.