Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=S)[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>P(Cl)(Cl)(Cl)=O>[Cl:15][C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=2[N:9]=1
Reactant: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2oc(Cl)nc2c1
Temperature: 100 °C

Procedure:
To a solution of 5-nitrobenzo[d]oxazole-2(3H)-thione (2.52 g, 12.86 mmol) in phosphorous oxychloride (21 mL) was added phosphorous pentachloride (2.68 g, 12.86 mmol) in one portion. The mixture was then heated to 100° C. for 2.5 h. After cooling, the excess of phosphorous oxychloride was removed in vacuo and the resulting mixture was used crude without characterisation.
Reaction SMILES: C([NH:6][C@H:7]([C:9](O)=[O:10])[CH3:8])(=O)C(C)=C.N[C@H](C(O)=O)C.Cl.[NH2:19][C@H:20]([C:24]([NH:26][C@H:27]([C:29]([O:31][CH3:32])=[O:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[NH2:6][C@H:7]([C:9]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:29]([O:31][CH3:32])=[O:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:10])[CH3:8]
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C
Reactant: C=C(C)C(=O)N[C@@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@H](N)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](C)N)C(C)C

Procedure:
Using the Schotten-Bauman method of acylation, N-methacryloylalanine was prepared. Coupling of MA-Ala-OH (5.35 g; 0.034 mol) with HCl.Val-Ala-OMe (8.1 g) was performed in dimethylformamide by means of dicyclohexylcarbodiimide (7.0 g) in the presence of triethylamine (3.4 g). Recrystalization from CH2Cl2 /pentene gave 9.5 g of MA-Ala-Val-Ala-OMe.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@H:6]([C:10](O)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].S(Cl)([Cl:17])=O>>[F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@H:6]([C:10]([Cl:17])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C)[C@H](NC(=O)C(F)(F)F)C(=O)O
Product: CC(C)[C@H](NC(=O)C(F)(F)F)C(=O)Cl
Reaction time: 0.25 h

Procedure:
A solution of 1 g. of N-trifluoroacetyl-L-valine in 5 ml. of thionyl chloride was cooled to 5°C. and stirred for 15 minutes. The excess thionyl chloride was removed under reduced pressure under a stream of dry nitrogen gas, affording N-trifluoroacetyl-L-valyl chloride as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1CC[CH2:22][CH2:21][N:20]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].F[C:38](F)(F)C(O)=O.C[C@H](OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCC1CCN(C(OCC2C=CC=CC=2)=O)CC1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][C@@H:12]([CH3:38])[CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:19][CH2:18]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt and phenylmethyl 4-(bromomethyl)-1-piperidinecarboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]2[N:15]=[CH:16][S:17][CH:18]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClCc1cscn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2cscn2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 60.8 %

Procedure:
A mixture of 4-nitrophenol (3.92 g), 4-chloromethyl-1,3-thiazole hydrochloride (4.0 g), potassium carbonate (8.13 g) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 40 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-[(4-nitrophenoxy)methyl]-1,3-thiazole as colorless crystals (3.38 g, yield 61%). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 175-176° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][N:36](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15])=[O:11].Cl.[NH+]1C=CC=CC=1>CO>[CH:26]1([CH2:25][C@H:17]([NH:16][C:14]([C@@H:13]([NH:12][C:10]([C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)=[O:11])[CH2:32][C:33]2[N:34]=[CH:35][NH:36][CH:37]=2)=[O:15])[C@@H:18]([OH:24])[C@H:19]([CH:21]2[CH2:22][CH2:23]2)[OH:20])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1)c1nc2ccccc2[nH]1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1)c1nc2ccccc2[nH]1
Yield: 55.5 %

Procedure:
A mixture of 375 mg (0.39 mmol) of (S)-α-2-benzimidazolecarboxamido-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-1-tritylimidazole-4-propionamide and 1.8 g (15.6 mmol) of pyridinium hydrochloride in 40 ml of methanol is heated to reflux for 3.5 hours. Thereafter, the reaction mixture is evaporated and the residue is partitioned between 100 ml of ethyl acetate and 50 ml of water. The organic phase is washed with 100 ml of semi-saturated ammonium chloride solution and 100 ml of 2N potassium bicarbonate solution, thereafter dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue is chromatographed on 40 g of silica gel using a 6:1 mixture of methylene chloride and methanol as the eluent. There are obtained 110 mg of N-[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]-2-benzimidazolecarboxamide as an amorphous solid; MS: 509 (M+H)+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[CH:29]=[C:30]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[CH:31]=[CH:32][CH:33]=1>[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>[N:34]1([C:30]2[CH:29]=[C:28]([C:6]3[N:10]4[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]4=[N:8][CH:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: Brc1cccc(-n2ccnc2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1ccn2c(-c3cccc(-n4ccnc4)c3)cnc2n1
Yield: 21.3 %

Procedure:
To a degassed solution of 3-tributylstannyl-7-trifluoromethyl-imidazo[1,2-a]pyrimidine (1.4 mmol) was added 1-(3-bromophenyl)-1H-imidazole (0.60 g, 2.7 mmol) (prepared by the method of A. Johnson et al., J. Med. Chem., 1969, 12(5), 1024-8) and tetrakis(triphenylphosphine)-palladium(0) (218 mg, 0.18 mmol) and the mixture heated at reflux for 18 h. The crude reaction was adsorbed onto silica and chromatographed on silica, eluting on a gradient of 1 to 5% methanol in dichloromethane, to give a yellow oil. Crystallisation from ethyl acetatelisohexane afforded 3-[3-(imidazol-1-yl)phenyl]-7-trifluoromethylimidazo[1,2-a]pyrimidine (0.098 g) as a white solid: δH (400 MHz; DMSO) 7.15 (1H, s), 7.53 (1H, d, J 7.4), 7.73 (1H, dd, J 3.1 and 1.6), 7.74 (1H, d, J 0.8), 7.78-7.81 (1H, m), 7.89 (1H, t, J 1.4), 8.08 (1H, dd, J 1.6 and 1.2), 8.39 (2H, d, J 7.0), 9.44 (1H, d, J 6.7); m/z (ES+) 330 (M++H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])([CH3:4])([CH3:3])[CH3:2].[I-].[CH3:25][S+](C)(C)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-].[Na+].C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:25][CH2:15]2)[C:11]([C:16]([F:18])([F:19])[F:17])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Reactant: C[S+](C)(C)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [I-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(C2CC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 48 h

Procedure:
A mixture of (2-nitro-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example A27) (1.66 g, 5 mmol), trimethylsulfoxonium iodide (2.75 g, 12.5 mmol) and benzyltriethylammonium chloride (200 mg, 0.878 mmol) in NaOH 50% (15 ml) and DCM (25 ml) was stirred at 23° C. for 2 days. The mixture was diluted with EtOAc and washed with 1N HCl, water and brine, dried over MgSO4. Removal of the solvent invacuum left a dark brown oil, which was purified by silica gel column chromatography to give the title compound a yellow solid (659 mg). Residual starting material was removed as follows: To a solution of the obtained material (659 mg, 1.9 mmol) in EtOAc (11.5 ml) and MeCN (11.5 ml), a solution of RuCl3 (30 mg, 0.133 mmol) and NaIO4 (610 mg, 2.85 mmol) in H2O (3.8 ml) was added under vigurous stirring at 0° C. The mixture was being stirred for a further 3 min and then quenched with a sat. sol. of Na2S2O3 (19 ml). The mixture was diluted with EtOAc, the aqueous layer was separated, extracted once with EtOAc. The combined EtOAc layers were washed with brine, dried over MgSO4 and charcoal, filtered over dicalite, evaporated and purified by column chromatography on silica gel (heptane/ethyl acetate 9:1) to yield a yellow solid (630 g, 36%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.[Al].Cl.[N+](C1C=CC(OC(=O)[NH:53][C:54]2[CH:59]=[CH:58][C:57]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[CH:56][CH:55]=2)=CC=1)([O-])=O>>[N:60]1([C:57]2[CH:56]=[CH:55][C:54]([NH:53][C:6]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:12][CH2:13]3)=[O:7])=[CH:59][CH:58]=2)[CH2:61][CH2:62][O:63][CH2:64][CH2:65]1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCNS(C)(=O)=O)ccc23)CC1
Agent: Cl
Agent: [Al]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCCCOc1ccc2c(C3CCN(C(=O)Nc4ccc(N5CCOCC5)cc4)CC3)ncnc2c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 38.5 %

Procedure:
4-[7-(3-methanesulfonylamino-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (7.4 mg, 16 μmol), as prepared in Example 65c, and TFA (100 μL, 1.35 mmol) was capped tightly and stirred at 100° C. (aluminum block) for 5 min. The reaction was then concentrated, and pyridine (100 μL) was added to give a homogeneous solution. (4-Morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (7.5 mg, 20 μmol) was then added in one portion at rt, and the solution was stirred at 80° C. for 10 min, then at rt overnight. The reaction was then concentrated and subjected to silica flash chromatography (4:3→3:5 DCM/acetone) to afford the title compound as an off-white semisolid (3.5 mg, 39%). 1H-NMR (400 MHz, 95:5 v/v CDCl3:CD3OD) δ 9.10 (s, 1H), 8.09 (d, 1H), 7.33-7.25 (m, 4H), 6.89 (m, 2H), 4.27 (m, 4H), 3.87 (m, 4H), 3.70 (m, 1H), 3.38 (t, 2H), 3.17-3.07 (m, 6H), 2.96 (s, 3H), 2.20-2.05 (m, 4H), 2.01-1.92 (m, 2H). LC/MS (ESI): calcd mass 568.2, found 569.1 (MH)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34](Cl)[N:33]=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:33]=[CH:32][N:31]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COc1cccc(Cc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cccc(Cc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)c1
Yield: 57.4 %

Procedure:
(S)-2-(1-Aminoethyl)-5-(3-methoxybenzyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.29 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (49 mg, 0.32 mmol), and N,N-diisopropylethylamine (152 μl, 0.87 mmol) in tert-butanol according to the method described in Example 17. The crude was purified by reverse phase using SP1® Purification System to give 82 mg (57% yield) of the title compound as solid. Purity 99%.
Reaction SMILES: [Mg].[CH3:2][O-:3].[Mg+2].C[O-].[CH2:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>C1(C)C=CC=CC=1.N1C=CC=CC=1.C(O)(=O)C.CO>[CH2:7]([C:16]1[CH:17]=[C:18]([CH:2]=[O:3])[C:19]([OH:22])=[CH:20][CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: C[O-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: c1ccncc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A 2-liter round-bottomed flask was charged with magnesium (12 g, 0.49 mol), methanol (285 ml), toluene (120 ml) and magnesium methoxide (10 ml solution of 7.4% by weight magnesium methoxide in methanol). The reaction mixture was heated to reflux and the magnesium dissolved. Para-nonyl phenol (112.4 g) was added in one portion to the reaction mixture. The flask was then rigged for a fractional vacuum distillation and an azeotrope of methanol/toluene was distilled off to an internal temperature of 70° C. at a pressure of 350 mm Hg. Glacial acetic acid (28.5 ml, 0.5 mole) was added to the reaction mixture over a 1 hour period while maintaining the reaction temperature at 70° C. and the pressure at 350 mm Hg. When the addition of glacial acetic acid was complete, pyridine (79 ml) and toluene (250 ml) were added. An azeotrope of methanol and toluene was distilled at a pot temperature of 100° C. The reaction mixture was then cooled to 95° C. and solid paraformaldehyde (46 g, a commercial sample containing 5-7% by weight water) was added over a 45 minute period. The reaction mixture was maintained at a temperature of 95-100° C. during the addition of paraformaldehyde and volatile reaction by-products were continually removed by distillation. When the paraformaldehyde addition was complete, the reaction temperature was maintained at 95-100° C. for an additional 2 hours. Sulfuric acid (300 ml, 10% w/w) was added to the reaction mixture, which was then stirred for 1 hour. After phase separation, the organic phase was washed twice with 200 ml portions of water. The washed organic phase was then separated, dried and rendered free of the solvent to yield crude 5-nonyl salicylaldehyde. A 78% yield was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].ClC1C=CC(C)=CC=1.ClCl.[Na].[C:20](=[O:22])=[O:21]>C(Cl)(Cl)(Cl)Cl.O1CCOCC1.C1(C)C=CC=CC=1>[C:3]1([CH2:8][C:20]([OH:22])=[O:21])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C=O
Reactant: Cc1ccccc1Cl
Agent: ClCl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: Cc1ccc(Cl)cc1
Solvent: C1COCCO1
Product: O=C(O)Cc1ccccc1
Temperature: 100 °C
Yield: 96.3 %

Procedure:
In accordance with the process of Example 1, 12.7 g of chlorotoluene (a mixture of 67.03% of o-chlorotoluene and 32.97% of p-chlorotoluene) produced by reacting toluene with chlorine in carbon tetrachloride was mixed with 5.4 g of sodium dispersed in 50 ml of 1.4-dioxane. The reaction mixture was heated at 100° C for 3 hours to rearrange the product. The reaction mixture was cooled to 25° C to 28° C and carbon dioxide gas was introduced into the reaction mixture to effect carboxylation with the rearranged product. After the reaction, the post-treatment was carried out in accordance with the process of Example 1 whereby 13.1 g of phenylacetic acid (yield 96.3%) were obtained.
Reaction SMILES: Cl.C(O[C:7]([N:9](C)[NH:10][CH:11]=[C:12]1[C:17](=O)[C:16]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:15]=2[S:14][CH2:13]1)=O)(C)(C)C>CO>[Cl:23][C:20]1[CH:21]=[CH:22][C:15]2[S:14][CH2:13][C:12]3[CH:11]=[N:10][N:9]([CH3:7])[C:17]=3[C:16]=2[CH:19]=1
Reactant: CN(NC=C1CSc2ccc(Cl)cc2C1=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: Cn1ncc2c1-c1cc(Cl)ccc1SC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A solution of hydrogen chloride in methanol (225 ml) was added to a suspension of 3-(2-t-butoxycarbonyl-2-methylhydrazinomethylene)-6-chloro-2,3-dihydro-4H-1-benzothiopyran-4-one (54.14 g) in methanol (550 ml). After being stirred at ambient temperature for 8 hours, the mixture was evaporated in vacuo and the residue was extracted with ethyl acetate after an addition of water. The extract was washed with aqueous sodium bicarbonate and then water, dried over magnesium sulfate, and evaporated in vacuo to give 8-chloro-1-methyl-1,4-dihydro[1]benzothiopyrano[4,3-c]pyrazole (26.63 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[N:23][CH:24]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(N)cn1
Product: CC(C)(C)OC(=O)NCCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Yield: 62.9 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 2-(5-aminopyridin-2-yloxy)ethylcarbamate (380 mg, 1.5 mmol) to afford the desired product (332 mg, 63%) as a yellow solid: ESI MS m/z 527 [C25H27BrN4O4+H]+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:26])[CH2:13][NH:14][C:15](=[O:25])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:26])[CH2:13][N:14]1[C:15](=[O:25])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=2
Reactant: O=C(COc1ccccc1I)NCC(O)CN1CCc2ccccc2C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1COc2ccccc2N1CC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 32.5 %

Procedure:
To a solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-(2-iodophenoxy)acetamide (100 mg, 0.215 mmol) in dioxane (5 mL) was added Cs2CO3 (139 mg, 0.429 mmol), BINAP (13.3 mg, 0.0215 mmol) and Pd2(dba)3 (8.0 mg, 0.0215 mmol). The reaction mixture was heated at 120° C. for 16 h, cooled to room temperature, filtered, and concentrated. The crude produce was purified by preparative HPLC purification. (23.6 mg, yield 32.5%) MS (ESI+) e/z: 339.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.41-7.32 (m, 1H), 7.15-7.06 (m, 3H), 7.06-6.94 (m, 4H), 4.67-4.50 (m, 2H), 4.29-4.13 (m, 2H), 4.07-3.94 (m, 1H), 3.77-3.64 (m, 2H), 2.95-2.83 (m, 3H), 2.83-2.76 (m, 1H), 2.73-2.62 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.Cl[C:40]([O:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)=[O:41]>ClCCl.CCOC(C)=O>[F:49][C:46]1[CH:47]=[CH:48][C:43]([O:42][C:40](=[O:41])[N:14]([C@@H:13]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[CH:44][CH:45]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (50 mg, 0.11 mmol) in dichloromethane (1 mL) were added N,N-diisopropyl ethyl amine (29 μl, 0.17 mmol), 4-fluorophenyl chloroformate (19 μl, 0.15 mmol) and the resulting mixture was stirred for 18 h at ambient temperature. It was diluted with EtOAc (15 mL) and washed with an aqueous solution of sodium carbonate (1M, 10 mL). The aqueous layers were extracted with dichloromethane (30 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 90:10) afforded the title compound (45 mg, 68%) as a light brown oil. MS m/e: 576.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@:15]23[CH2:24][C:23]4[N:25]=[C:26]5[C:31](=[CH:32][C:22]=4[CH2:21][C@H:20]2[CH2:19][N:18](C(OC=C)=O)[CH2:17][CH2:16]3)[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O>CO.Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@:15]23[CH2:24][C:23]4[N:25]=[C:26]5[C:31](=[CH:32][C:22]=4[CH2:21][C@H:20]2[CH2:19][NH:18][CH2:17][CH2:16]3)[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=COC(=O)N1CC[C@@]2(c3cccc(OCc4ccccc4)c3)Cc3nc4ccccc4cc3C[C@H]2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc(COc2cccc([C@@]34CCNC[C@@H]3Cc3cc5ccccc5nc3C4)c2)cc1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
(4aR, 12aR)-4a-(3-benzyloxyphenyl)-2-vinyloxycarbonyl-1,2,3,4,4a,5,12,12a-octahydroquinolino[2, 3-g]isoquinoline (181 mg, 0.369 mmol) was dissolved in a 10% hydrogen chloride methanol solution (6 ml), and the resultant solution was heated under reflux for 1 hour. After the solution was cooled to 0°C., an aqueous saturated sodiumbicarbonate solution (30 ml) and water (150 ml) were added to the solution, followed by extraction with chloroform (200 ml, 2 times). The organic layers were dried, and then concentrated to obtain the target compound (155 mg). The thus-obtained compound was supplied to next reaction without purification.