Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][S:3][CH2:4][CH2:5][CH:6]1[NH:11][C:10](=[O:12])[CH:9]([CH2:13][CH2:14][S:15][CH3:16])[NH:8][C:7]1=[O:17].[OH2:18]>>[NH2:8][C@H:9]([C:10]([NH:11][C@H:6]([C:7]([OH:17])=[O:18])[CH2:5][CH2:4][S:3][CH3:2])=[O:12])[CH2:13][CH2:14][S:15][CH3:16]
Reactant: CSCCC1NC(=O)C(CCSC)NC1=O
Reactant: O
Agent: Cl
Product: CSCC[C@H](NC(=O)[C@@H](N)CCSC)C(=O)O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
500 l of water were introduced into a 500 l enameled tank with stirrer, 32 l of concentrated hydrochloric acid and 78.6 kg of 3,6-bis[2-(methylthio)ethyl]-2,5-piperazinedione (III) (DKP) were added, and the apparatus was closed tightly. It was then heated at 110° C. while stirring for 2 hours, during which the pressure rose to 2.5 bar and the DKP (III) virtually completely dissolved. After the reaction was complete, the mixture was cooled to 20° C., and the unreacted DKP was spun down in a centrifuge. The solid was washed with 10 l of water. The filtrate and washing water were then collected in an 800 l container and subsequently introduced into a 500 l tank with stirrer again. Addition of 2 kg of activated carbon was followed by stirring at 20° C. for 30 min. The suspension was then filtered through a filter press into a further 500 l tank with stirrer. About 28 l of concentrated ammonia solution were then added to precipitate at pH 6 the DD/LL/DL/LD-methionylmethionine (I). During this there was an initial preferential precipitation of the less soluble racemic pair of diastereomers DL/LD-methionylmethionine (DL/LD-I). This was spun down and the mother liquor was concentrated together with washing water to one quarter of the original volume in vapor pump vacuum at an internal temperature not exceeding 40° C. During this, the more soluble racemic pair of diastereomers DD/LL-methionylmethionine (DD/LL-I) crystallized together with small amounts of the slightly soluble DL/LD-I. Completion of the distillation was followed by cooling to 20° C. and centrifugation. The separated mother liquor and washing water were discarded. Both fractions were dried in vacuo at 70° C. In total, it was possible to obtain 64.2 kg (78%) of DD/LL/DL/LD-methionyl-methionine (I) as mixture of diastereomers. Purity >98% (HPLC).
Reaction SMILES: [NH2:1][C:2]1[C:27]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])=[CH:26][C:25]([F:37])=[CH:24][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][NH:9][S:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:12])=[O:11].[CH:38]1([S:41](Cl)(=[O:43])=[O:42])[CH2:40][CH2:39]1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:38]1([S:41]([NH:1][C:2]2[C:27]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=3[F:36])=[CH:26][C:25]([F:37])=[CH:24][C:3]=2[O:4][C:5]2[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=2)[CH2:8][NH:9][S:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:12])=[O:11])(=[O:43])=[O:42])[CH2:40][CH2:39]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1
Reaction time: 16 h
Yield: 79.2 %

Procedure:
864 mg of crude tert-butyl [(3-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}benzyl)sulfamoyl]carbamate (1.37 mmol, 1 eq.) were dissolved in 13 mL pyridine and 250 mg cyclopropyl sulfonyl chloride (1.78 mmol, 1.3 eq.) and stirring was continued at that temperature for 16 h. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the aqueous layer was reextracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo. The residue was further purified by flash column chromatography (hexan to hexan/ethyl acetate 1:1 gradient) to yield 814 mg of the target compound (70% UV-purity), which was used for the subsequent transformation.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:12]=[N:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=2)/[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19][C:20]1[S:24][C:23]([NH2:25])=[N:22][CH:21]=1>>[Br:19][C:20]1[S:24][C:23]([NH:25][C:8](=[O:10])/[C:7](/[C:11]2[CH:12]=[N:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=2)=[CH:6]/[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:22][CH:21]=1
Reactant: CSc1ccc(/C(=C\C2CCCC2)C(=O)O)cn1
Reactant: Nc1ncc(Br)s1
Product: CSc1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(Br)s2)cn1

Procedure:
Condensation of (E)-3-cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)acrylic acid (Preparation 3, 64 mg, 0.24 mmol) with 5-bromothiazol-2-ylamine (218 mg, 1.22 mmol), by the protocol described in EXAMPLE 5, yielded (E)-N-(5-bromothiazol-2-yl)-3-cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)acrylamide: RTA=4.28 min; m/z (ES+)=426.2 [M+H]+. This compound (61 mg, 144 μmol) was oxidised, employing the procedure described in EXAMPLE 35, to give the title compound: RTA=3.91 min; m/z (ES+)=499.2 [M+MeCN+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:14]=[C:13]([OH:15])[C:12]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:11][C:9]=2[OH:10])[CH2:3][CH2:2]1.[H-].[Na+].[N+:25]([C:28]1[CH:33]=[C:32]([S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])[CH:31]=[CH:30][C:29]=1Cl)([O-:27])=[O:26]>C1COCC1>[N:17]1([CH2:16][C:12]2[C:13]([O:15][C:29]3[CH:30]=[CH:31][C:32]([S:34]([C:37]([F:39])([F:40])[F:38])(=[O:36])=[O:35])=[CH:33][C:28]=3[N+:25]([O-:27])=[O:26])=[CH:14][C:8]([CH2:7][N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[C:9]([O:10][C:29]3[CH:30]=[CH:31][C:32]([S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[CH:33][C:28]=3[N+:25]([O-:27])=[O:26])[CH:11]=2)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: Oc1cc(CN2CCOCC2)c(O)cc1CN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Oc1cc(CN2CCOCC2)c(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,5-bis-(morpholinomethyl)-hydroquinone (100 mg, 0.324 mmol) in THF was added sodium hydride (26 mg of 60% dispersion in mineral oil) followed by 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (188 mg, 0.648 mmol). The mixture was stirred at room temperature for overnight. The reaction was extracted with ethyl acetate, the organic layer was washed with water and brine, dried, concentrated and purified to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.81 (d, J=2.2 Hz, 2H), 8.23 (m, 2H), 7.60 (s, 2H), 7.27 (m, 2H), 3.4 (m, 4H, 2×CH2), 3.06 (m, 8H, 4×CH2), 2.18 (m, 8H, 4×CH2). MS 815 [M++1].
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)[CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CO.[OH-].[K+:31]>O1CCCC1>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)[CH:14]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[K+:31]
Reactant: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)no2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)[O-])cc3)no2)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Methyl 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate (16.4 kg), tetrahydrofuran (164 L), methanol (25 L) and 19% aqueous potassium hydroxide (25 L) were put into a 1500 L glass-lined reaction chamber, heated to 50 to 60° C., and stirred for 2 hours. Tetrahydrofuran (328 L) was added to this reaction mixture for 30 minutes to 1 hour. The mixture was then cooled to 35 to 40° C. and stirred further for 1 hour. The product was isolated by a centrifugal separator and washed with tetrahydrofuran (164 L) to obtain rough potassium 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate (which was used in the next step in a wet state).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])=[N:24][CH:25]=1>>[OH:29][CH2:28][C:27]([NH:26][C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1)([CH3:30])[CH3:31]
Reactant: CC(C)(CO)Nc1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CC(C)(CO)Nc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-hydroxy-1,1-dimethyl-ethylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-(5-Amino-pyridin-2-ylamino)-2-methyl-propan-1-ol. LCMS calcd for C20H19F3N4O3 (m/e) 420, obsd 421 (M+H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[C:20]([CH3:27])[N:21]=[CH:22]3)=[O:15])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.ClCCl>[CH3:27][C:20]1[N:21]=[CH:22][C:23]2[C:18]([CH:19]=1)=[C:17]([NH:16][C:14]([NH:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:15])[CH:26]=[CH:25][CH:24]=2
Reactant: Cc1cc2c(NC(=O)NC3CCN(Cc4ccccc4)C3)cccc2cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2c(NC(=O)NC3CCNC3)cccc2cn1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A solution of (D3) (2.30 g, 6.40 mmol), ammonium formate (2.02 g, 32.10 mmol) and 10% palladium on carbon (1 g) in methanol (100 mL) was heated at 70° C. for 3 h, then cooled to 25° C. and filtered through Celite. Evaporation in vacuo gave an oil which was suspended in dichloromethane and washed with saturated sodium carbonate solution. The organic layer was removed, dried (Na2SO4), and the solvents evaporated in vacuo to give the title compound as a yellow oil (1.2 g). 1H NMR (CDCl3) δ: 2.05-2.20 (2H, m), 2.68 (3H, s), 2.85-2.95 (2H, m), 3.00-3.15 (2H, m), 4.35-4.45 (1H, m), 5.85-5.90 (1H, m), 7.40-7.50 (2H, m), 7.62 (1H, s), 7.72 (1H, d, J=8.2 Hz), 7.91 (1H, d, J=7.6 Hz), 9.14 (1H, s).
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Na+].[CH3:31]I.[Cl-].[NH4+]>CN(C=O)C>[C@H:1]1([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:31])[C:20]3=[O:28])[CH2:17][CH2:18]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CI
Reactant: O=c1[nH]c2ncccc2n1C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2cccnc21
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
(R)-1-[1-(Acenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.78 g) was dissolved in DMF (20 ml), 60% sodium hydride (90 mg) was added, and the suspension was stirred for 20 min. Then, methyl iodide (340 mg) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.58 g) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[C:17]([N+:25]([O-:27])=[O:26])[CH:16]=1>CN(C1C=CN=CC=1)C>[N+:25]([C:17]1[CH:16]=[C:15]([O:14][CH3:13])[CH:20]=[CH:19][C:18]=1[S:21]([NH:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)(=[O:23])=[O:22])([O-:27])=[O:26]
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Cc1ccc2cccc(N)c2n1
Agent: CN(C)c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cccc3ccc(C)nc23)c([N+](=O)[O-])c1
Yield: 51.8 %

Procedure:
In a similar fashion using route 14 general procedure 27, 2-methyl-quinolin-8-ylamine (Intermediate 22) (500 mg, 3.1 mmol) and 4-methoxy-2-nitrobenzenesulfonyl chloride (826 mg, 3.4 mmol) and DMAP (19 mg, 1.5 mmol) gave the title compound (600 mg, 51%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[N:12]=[C:13]([C:42]([F:45])([F:44])[F:43])[N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:41])[CH2:21][C@H:22]([NH:33]C(OC(C)(C)C)=O)[CH2:23][C:24]3[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=3[F:32])[CH2:16][C:15]=12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:46]>C(OCC)(=O)C>[ClH:46].[CH2:1]([O:8][C:9]([C:11]1[N:12]=[C:13]([C:42]([F:44])([F:45])[F:43])[N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:41])[CH2:21][C@H:22]([NH2:33])[CH2:23][C:24]3[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=3[F:32])[CH2:16][C:15]=12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)OCc3ccccc3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)OCc3ccccc3)c2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid benzyl ester 33a (0.056 g, 0.087 mmol) and a solution of 2.7 N hydrochloric acid in 2 mL of ethyl acetate were added into the reaction flask. The reaction mixture was stirred at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid benzyl ester hydrochloride 33 (0.043 g, yield 86%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+]>Br>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(C2CCCN2Cc2ccccc2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cccc(C2CCCN2Cc2ccccc2)c1
Temperature: 25 °C
Yield: 61 %

Procedure:
1-Phenylmethyl-2-(3-methoxyphenyl)pyrrolidine in 48% hydrobromic acid (65 ml), was warmed to 110° C. for 2.5 hrs, and cooled to ambient temperature. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted into dichloromethane (2 times). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 1:1 ethyl acetate/dichloromethane). The appropriate fractions were collected and concentrated. The residue was flushed through alumina with ether to give 2.5 g (61%) of product, mp 113°-115° C.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].Cl.O>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C(OCCCC)CCC>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCCCOCCCC
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-keto-L-gulonic acid (125 g, 0.584 mol, content: 90.7%, water: 8.5%) and trimethylcetylammonium chloride (0.084 g) was stirred in dibutyl ether (500 ml), and 36% conc. hydrochloric acid (18.0 g) was added. At this time, the amount of water in the reaction system was calculated as 2.1 mol per mol of 2-keto-L-gulonic acid. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (17.2 g) in dibutyl ether (91 g) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 900 g of the solvent was distilled away under reduced pressure while continuously introducing toluene (1000 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by HPLC showed that the solution contained L-ascorbic acid (92.4 g, yield: 90.0%) and no residual starting compound, i.e. 2-keto-L-gulonic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.NC1C=CC(OC)=CC=1C(NC)=O.ClC1N=C(Cl)C(Cl)=CN=1.[NH2:44][C:45]1[CH:58]=[CH:57][C:48]2[N:49]([CH2:55][CH3:56])[C:50](=[O:54])[CH2:51][CH2:52][CH2:53][C:47]=2[C:46]=1[O:59][CH3:60]>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:44][C:45]2[CH:58]=[CH:57][C:48]3[N:49]([CH2:55][CH3:56])[C:50](=[O:54])[CH2:51][CH2:52][CH2:53][C:47]=3[C:46]=2[O:59][CH3:60])=[N:3][CH:4]=1
Reactant: CNC(=O)c1cc(OC)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Agent: CNC(=O)c1cc(OC)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccc(OC)cc3C(=O)NC)n1)c2OC

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-methoxy-N-methyl-benzamide, prepared in a similar manner as Example 601a from known 2-amino-5-methoxy-N-methyl-benzamide reacted with 2,4,5-trichloropyrimidine was reacted with 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, in a similar manner as Example 601b, to yield crude product 2-[5-Chloro-2-(1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-5-methoxy-N-methyl-benzamide. The crude material was semi-purified by preparative HPLC, and the purest fractions were partitioned between NaHCO3 and CH2Cl2. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a clear oil. This material was dissolved in Et2O and treated with 1N ethereal HCl. The resulting solid was filtered, then dissolved in CH3CN. A solid precipitated with scratching, which was filtered and rinsed with a small amount of ice cold CH3CN to give desired product as a solid HCl salt (4%); 1H NMR (400 MHz, DMSO-d6) δ 11.3 (bs, 1H), 8.74 (bs, 1H), 8.5 (bs, 1H), 8.42 (bd, 1H) 8.18 (s, 1H), 7.74 (d, J=8.84 Hz, 1H), 7.28 (s, 1H), 7.16 (d, J=9.85 Hz), 6.94 (d, J=11.12 Hz, 1H), 3.80 (s, 3H), 3.69 (s, 3H), 2.80 (bs, 3H), 2.23 (bs, 4H), 1.24 (bs, 2H), 1.0 (m, 3H); MS (m/e) 525.49 (M+H).
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH:9]=[CH:8][C@H:7]1[CH2:11][C:12]([O-:14])=[O:13])(=O)=O.O1CCCC1.[OH-].[Na+:21]>O>[OH:5][C@H:6]1[CH2:10][CH:9]=[CH:8][C@H:7]1[CH2:11][C:12]([O-:14])=[O:13].[Na+:21]
Reactant: CS(=O)(=O)O[C@@H]1CC=C[C@H]1CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])C[C@@H]1C=CC[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.290 g. (0.00124 mole) of racemic trans-2-methylsulfonyloxy-4-cyclopentene-1-acetate in 10 ml. of tetrahydrofuran and 4 ml. of water at 0° C. was added dropwise, 1.00 ml. (0.0020 mole) of 2 N sodium hydroxide solution. The two-phased solution was vigorously stirred at 0° C. for 1 hr. and at room temperature for 16 hrs. to form racemic sodium cis-2-hydroxy-4-cyclopentene-1-acetate in admixture with racemic cis-2-hydroxy-4-cyclopentene-1-acetic acid lactone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][C:6]=1OS(C(F)(F)F)(=O)=O)=[O:4].[CH3:19][O:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:25][C:24]=1B(O)O.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:9][CH:8]([CH3:10])[CH2:7][C:6]=1[C:25]1[CH:24]=[C:23]([O:22][CH2:21][O:20][CH3:19])[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][O:31][CH3:32])=[O:4]
Reactant: COCOc1ccc(OCOC)c(B(O)O)c1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@H](C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: COCOc1ccc(OCOC)c(C2=C(C(=O)OC)CC(C)C2)c1
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Prepare a mixture of 4-Methyl-2-trifluoromethanesulfonyloxy-cyclopent-1-enecarboxylic acid methyl ester 3a (2.5 g, 8.7 mmol), 2,5-Bis-methoxymethoxy phenylboronic acid 7 (2.31 g, 9.5 mmol), tetrakis(triphenylphosphine)palladium (485 mg, 0.435 mmol), and LiCl (1.1 g, 26.1 mmol) in DME (80 mL). Add 2.0 M solution of Na2CO3 (10 mL, 21.7 mmol) and heat the reaction to reflux and stir for 2 hours. Cool the reaction to room temperature and partitioned between CH2Cl2 and saturated aqueous NaHCO3. Separate and extract the aqueous solution with CH2Cl2 (2×). Combine the organic extracts, dry (Na2SO4), filter and concentrate in vacuo. Purify by flash chromatography (125 g SiO2, 0-30% EtOAc/hexane and 30% EtOAc/hexane) to afford 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopent-1-enecarboxylic acid methyl ester 8a (2.4 g, 7.1 mmol, 83%) as a yellow oil. 1H NMR (δ, 400 MHz, CDCl3): 7.02 (d, 1H; J=9.2 Hz), 6.90 (dd, 1H, J=9.2, 3.1 Hz), 6.80 (d, 1H, J=3.1 Hz), 5.10 (s, 2H), 5.03 (s, 2H), 3.56 (s, 3H), 3.48 (s, 3H), 3.44 (s, 3H), 3.01-2.91 (m, 2H), 2.53-2.37 (m, 3H), 1.14 (d, 3H, J=6.6 Hz). HRMS calcd. 337.1651; found (electrospray, M+1) 337.1647.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1.CC([O-])(C)C.[K+].CS(C)=O>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)=[C:6]([C:7]#[N:8])[CH:9]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: N#Cc1cc(Br)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(Nc2ccc(Br)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.9 %

Procedure:
A flask was charged with 5-bromo-2-fluorobenzonitrile (5 g, 25.00 mmol), ethyl 4-aminobenzoate (4.54 g, 27.5 mmol), and KOtBu (5.11 g, 45.5 mmol). To this was added DMSO (100 mL). After stirring at room temperature for 20 min, the reaction mixture was diluted with ethyl acetate and water. The aqueous was extracted with ethyl acetate, the combined organic was washed with water (3×), brine, dried over MgSO4 and filtered. The filtrate was concentrated. The residue was suspended in ethyl acetate, collected the solid by filtration. Repeated above procedure for several times (each collected solid was checked by LCMS) until the collected solid is pure. The mixture residue was further purified via silica gel chromatography (0-30% ethyl acetate in hexanes) to give total 7.15 g of ethyl 4-(4-bromo-2-cyanophenylamino)benzoate. MS (ESI) m/z 345.2 (M+H). 1H NMR (CDCl3) δ ppm 8.02 (2H, d, J=8.55 Hz), 7.65 (1H, d, J=2.44 Hz), 7.53 (1H, dd, J=9.00, 2.29 Hz), 7.25 (1H, d, J=9 Hz), 7.14 (2H, d, Hz), 6.47 (1H, s), 4.36 (2H, q, J=7.22 Hz), 1.38 (3H, t, J=7.17 Hz).