Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.CO.N1C=CC=C[CH:28]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH3:28])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: c1ccncc1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Br)cc12
Solvent: CO
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Yield: 47 %

Procedure:
The product was prepared from 3-{[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]-amino}benzoic acid (20.4 mg, 0.048 mmol) (Example 41) and MeOH (50 μL, 1.23 mmol) according to the General Procedure 8, described in Example 119, using different amounts of pyridine (7.5 μL, 0.092 mmol) and a slightly modified reaction volume (0.80 mL). The title compound was obtained in 47% yield (9.9 mg). 1H NMR (500 MHz, CDCl3) δ ppm 2.44 (s, 3H) 3.87 (s, 3 H) 6.94 (s, 1 H) 7.36 (dd, J=8.10, 7.66 Hz, 1 H) 7.41 (ddd, J=8.10, 2.35, 1.26 Hz, 1 H) 7.57 (dd, J=8.63, 1.86 Hz, 1 H) 7.66 (dd, J=8.63, 0.54 Hz, 1 H) 7.73 (dd, J=2.35, 1.51 Hz, 1 H) 7.84 (ddd, J=7.66, 1.51, 1.26 Hz, 1 H) 7.87 (dd, J=1.86, 0.54 Hz, 1 H). MS (ESI+) m/z 440 [M+H]+.
Reaction SMILES: OC1C=CC(C(N[C@H](C(N[C@H](C(O)=O)CC2C=CC=CC=2)=O)C)=O)=CC=1.C(N(CC)CC)C.[CH2:34]([O:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH2:39])[CH3:35].Cl.[C:49]([NH:59][C@H:60]([C:62](O)=[O:63])[CH3:61])([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50]>ClCCl>[CH2:34]([O:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH:39][C:62](=[O:63])[C@H:60]([CH3:61])[NH:59][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])[CH3:35]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C[C@H](NC(=O)c1ccc(O)cc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
Synthesis of p-hydroxybenzoyl-L-alanyl-L-phenylalanine: 0.1 g (0.1 mol) of triethylamine was added to a suspension of 23.0 g (0.1 mol) of L-phenylalanine ethyl ester·HCl in 500 ml of dichloromethane, and to this mixture in an ice bath was added 22.3 g (0.1 mol) of carbobenzoxy-L-alanine, and then 19.2 g (0.1 mol) of 1-ethyl-3(3-dimethyaminopropyl) carbodiimide·HCl was added to the mixture. This mixture was stirred for three hours. This reaction mixture was washed with a 0.1% aqueous solution of Na2CO3 three times and with a 0.1 N HCl solution three times, and then with distilled water three times. Thereafter, the mixture was dried over anhydrous sodium sulfate, and dichloromethane was removed from the mixture under reduced pressure to obtain carbobenzoxy-L-alanyl-L-phenylalanine ethyl ester. This ester was dissolved in 260 ml of 25% HBr in glacial acetic acid, and this solution was stirred for one hour. To this solution was added 5 l of absolute ethyl ether to produce a precipitate. The precipitate was filtered and washed with ethyl ether to obtain L-alanyl-L-phenylalanine ethyl ester·HBr.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[N:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][N:16]=1>CN(C=O)C.O>[CH2:21]([C:18]1[CH:17]=[N:16][C:15]([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)=[N:20][CH:19]=1)[CH2:22][CH3:23]
Reactant: OC1CCNCC1
Reactant: CCCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cnc(N2CCC(O)CC2)nc1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
To a stirring solution of piperidin-4-ol (2.33 g, 23.0 mmol, Aldrich) and potassium carbonate (6.36 g, 46.0 mmol, EMD) in DMF (15 mL) at room temperature was added 2-chloro-5-propylpyrimidine (4.33 g, 27.6 mmol, Wako). The reaction mixture was heated at 100° C. for 3 h then diluted with H2O. The resulting mixture was extracted with EtOAc (2×). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to a brown oil. The oil was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 5.01 g of desired product as a white solid. MS (ESI) 222 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]([O:21][CH3:22])=[CH:19][C:6]([C:7]([C:9]2[NH:13][N:12]=[N:11][C:10]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:8])=[C:5]([N+:23]([O-:25])=[O:24])[CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:38]([O:40][CH2:41]OCC)[CH3:39]>C(Cl)Cl>[CH2:38]([O:40][CH2:41][N:12]1[N:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:7](=[O:8])[C:6]2[CH:19]=[C:20]([O:21][CH3:22])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:23]([O-:25])=[O:24])=[N:13]1)[CH3:39]
Reactant: CCOC(=O)c1nn[nH]c1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Reactant: CCOCOCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCOCn1nc(C(=O)OCC)c(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (Synthesis Example 2) (210 mg) and p-toluenesulfonic acid monohydrate (62 mg) were suspended in methylene chloride (5 ml) under an argon atmosphere. Diethoxymethane (0.5 ml) was added to the suspension. The mixture was stirred at 80° C. for 2 hr. The mixture was post-treated by a conventional method and subjected to separation and purification to give ethyl 2-(ethoxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (242 mg, 99%) as a yellow powder.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[N:35]=[C:34]([C:36]([O:38]C(C)(C)C)=[O:37])[CH:33]=[CH:32][CH:31]=3)[CH:28]=2)[N:23]([CH3:43])[CH2:22][CH2:21]1)=[O:19]>C(Cl)Cl>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[N:35]=[C:34]([C:36]([OH:38])=[O:37])[CH:33]=[CH:32][CH:31]=3)[CH:28]=2)[N:23]([CH3:43])[CH2:22][CH2:21]1)=[O:19]
Reactant: CN1CCN(C(=O)Nc2nc3ccccc3s2)c2cc(-c3cccc(C(=O)OC(C)(C)C)n3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C(=O)Nc2nc3ccccc3s2)c2cc(-c3cccc(C(=O)O)n3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 87 %

Procedure:
The title compound 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinic acid (25) was prepared by the following procedure: Trifluoroacetic acid (2.0 mL) was added dropwise to tert-butyl 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinate (25H) (79 mg, 0.16 mmol) in DCM (2.0 mL) at 0° C. The mixture was allowed to warm up to rt and stirred for 72 hours. The mixture was concentrated, triturated with diethylether, filtered, and dried in vacuo to provide 62 mg (70%) of the desired product 6-(4-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)picolinic acid (25): 1H NMR (300 MHz, DMSO-d6), δ 8.28 (1H, s), 8.01-7.72 (5H, m), 7.45-7.30 (2H, m), 7.21 (1H, t), 6.82 (1H, d), 4.03 (2H, t), 3.45 (2H, t), 3.00 (3H, s), MS (ESI(+)): m/z 446.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O-:11].[Na+]>CO>[NH2:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ncc1N

Procedure:
A mixture of 5-amino-2,4-dichloropyrimidine (0.32 g) (obtained as described in Chem. Pharm. Bull., (JAPAN), 1958, 6, 343-346) and a solution of sodium methoxide in methanol (from sodium (0.05 g) and methanol (25 ml)) was heated at reflux for 15 minutes and allowed to cool. Volatile material was removed by evaporation and a small volume of water added. The mixture was extracted twice with ether and the combined extracts were dried (MgSO4) and evaporated to give 5-amino-2-chloro-4-methoxypyrimidine (0.2 g) as an oil; 1H NMR (d6 -DMSO): 3.92 (s, 3 H), 5.25 (s, 2 H), 7.72 (s, 1 H); mass spectrum (+ve CI): 160 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:62])[C:7]([S:25][C@@H:26]1[CH2:30][N:29](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H:28]([CH2:44][O:45][CH2:46][CH2:47][NH:48]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:27]1)=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].[H][H]>O1CCCC1.C([O-])(=O)C.[OH-].[OH-].[Pd+2]>[C:12]([OH:14])(=[O:13])[CH3:8].[NH2:48][CH2:47][CH2:46][O:45][CH2:44][C@@H:28]1[CH2:27][C@H:26]([S:25][C:7]2[C@H:6]([CH3:62])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:30][NH:29]1
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](COCCNC(=O)OCc4ccc([N+](=O)[O-])cc4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCN)C3)[C@H](C)[C@H]12
Yield: 46.5 %

Procedure:
A solution of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-{2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl}pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene 2-carboxylate (0.45 g) in a mixture of tetrahydrofuran (25 ml) and 0.2M acetate buffer (pH 5.8) (25 ml) was stirred in the presence of 20% palladium hydroxide on carbon (0.1 g) under atmospheric pressure of hydrogen at ambient temperature for 8 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to remove tetrahydrofuran. The residual solution was washed with ethyl acetate (40 ml×2) and the organic solvent was removed by evaporation. The residual solution was subjected to a column chromatography on nonionic adsorption resin, "HP-20" (trademark, made by Mitsubishi Chemical Industries) (20 ml) and eluted with water. The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2-aminoethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid acetate (0.053 g).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[Br:8][C:9]1[C:10](O)=[C:11]([C:17]([CH3:20])=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:8][C:9]1[C:10]([O:6][CH3:7])=[C:11]([C:17]([CH3:20])=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(C)ccc(Br)c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C)ccc(Br)c1OC
Temperature: 25 °C

Procedure:
Dimethyl sulphate (2.3 ml) was added to a suspension of ethyl 3-bromo-2-hydroxy-6-methylbenzoate (Intermediate 92, 5.19 g) and potassium carbonate (5.64 g) in dry acetone (70 ml) and the resultant mixture was stirred and heated at reflux for 2 hours. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in ether and washed with NaHCO3 (saturated aqueous solution), dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give crude ethyl 3-bromo-2-methoxy-6-methylbenzoate (5.4 g) as a colourless oil.
Reaction SMILES: [C:1]([N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[N:15][C:8]=2[N:7]([CH2:16][CH3:17])[C:6]2[N:18]=[C:19]([Cl:23])[CH:20]=[C:21]([CH3:22])[C:5]1=2)(=[O:3])[CH3:2].F[B-](F)(F)F.[O:29]=[N+:30]=[O:31]>C(#N)C>[C:1]([N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[N:15][C:8]=2[N:7]([CH2:16][CH3:17])[C:6]2[N:18]=[C:19]([Cl:23])[C:20]([N+:30]([O-:31])=[O:29])=[C:21]([CH3:22])[C:5]1=2)(=[O:3])[CH3:2]
Reactant: O=[N+]=O
Reactant: CCN1c2ncccc2C(=O)N(C(C)=O)c2c(C)cc(Cl)nc21
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCN1c2ncccc2C(=O)N(C(C)=O)c2c1nc(Cl)c([N+](=O)[O-])c2C
Reaction time: 5 h
Yield: 18.6 %

Procedure:
To a solution of 5-acetyl-2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (3.36 g) in acetonitrile (20 mL) cooled on ice was added nitronium tetrafluoroborate (85%, 2.26 g). The mixture was removed from the ice bath and was stirred for 5 hours. The reaction then was quenched with 10% potassium carbonate. Ethyl acetate was added and the organic phase was separated, washed, dried, and evaporated. Chromatography over silica gel gave 0.71 g of the title compound, which crystallized from diisopropyl ether, m.p. 140-141.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[C:12]([NH:14][C:15]([NH2:17])=[NH:16])#[N:13].[CH3:18][C:19]([CH3:21])=O>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([N:6]2[C:19]([CH3:21])([CH3:18])[N:16]=[C:15]([NH2:17])[N:14]=[C:12]2[NH2:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1Cl
Reactant: N#CNC(=N)N
Reactant: CC(C)=O
Agent: Cl
Product: COc1ccc(N2C(N)=NC(N)=NC2(C)C)cc1Cl

Procedure:
A stirred mixture of 3.0 grams (0.019 mole) of 90% pure 3-chloro-4-methoxyaniline and 4 mL of concentrated hydrochloric acid in 20 mL of toluene was heated to reflux using a heat gun. The reaction mixture was then concentrated under reduced pressure to a residue. The residue was triturated with 50 mL of diethyl ether, and the resultant solid was collected by filtration. The solid was dried under vacuum, yielding 3.4 grams (0.018 mole) of 3-chloro-4-methoxyaniline hydrochloride. A stirred mixture of the aniline hydrochloride and 1.8 grams (0.022 mole) of cyanoguanidine in 25 mL of acetone was then heated at reflux for about 20 hours. The mixture was cooled, and a solid was collected by filtration. The solid was dried under vacuum, yielding 4.9 grams of 1-(3-chloro-4-methoxyphenyl)-2,4-diamino-6,6-dimethyl-1,6-dihydro-1,3,5-triazine hydrochloride, mp 232 ° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[O:44][CH:43]([CH3:45])[CH2:42][NH:41][CH2:40]1>>[CH3:45][C@H:43]1[O:44][C@@H:39]([CH3:38])[CH2:40][N:41]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:42]1
Reactant: CC1CNCC(C)O1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: C[C@@H]1CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)C[C@H](C)O1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2,6-dimethylmorpholine according to conditions described in general procedure C. Mp: 118-120° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.01-1.02 (m, 6 H), 2.39 (t, J=11.7 Hz, 2 H), 3.25-3.30 (m, 4 H), 3.75-3.77 (m, 4H), 4.20 (bs, 2 H), 6.18-6.20 (m, 1 H), 7.02-7.06 (m, 1 H), 7.25-7.27 (m, 1 H), 7.42-7.44 (m, 1 H), 7.49 (s, 1 H), 7.57-7.62 (m, 3 H), 7.82-7.84 (m, 1 H), 8.00 (d, J=8.0 Hz, 1 H), 8.26-8.28 (m, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH:26](C)[CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH2:34](Cl)Cl>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([CH3:34])[CH2:31][CH2:32]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:11]
Reactant: COc1cc2c(N)ncnc2cc1OC(C)C1CCNCC1
Reactant: ClCCl
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(NC(=O)Nc3c(Cl)cccc3Cl)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,6-Dichlorophenyl isocyanate (0.075 g) was added to a solution of 4-amino-6-methoxy-7-(methylpiperidin-4-ylmethoxy)quinazoline (0.093 g) in a mixture of methylene chloride (2 ml) and DMF (0.1 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The resultant solid was isolated, redissolved in a 20:1 mixture of methylene chloride and methanol and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride, methanol and a 1% aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound as a white solid (0.029 g); NMR Spectrum: (DMSOd6) 1.3-1.4 (m, 2H), 1.7-1.8 (m, 4H), 1.85 (t, 1H), 2.1 (s, 3H), 2.8 (d, 2H), 3.9 (s, 3H), 4.0 (br d, 2H), 7.3 (br s, 1H), 7.4 (d, 1H), 7.5 (s, 1H), 7.6 (s, 1H), 8.0 (br s, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 490, 492 and 494.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[Br:19]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:19][C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH2:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:13][C:14]=1[F:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ncc(CNc2cccc(F)n2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ncc(CNc2ccc(Br)c(F)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
To (5-fluoro-6-methoxy-pyridin-3-ylmethyl)-(6-fluoro-pyridin-2-yl)-amine (24, 3.21 g, 12.8 mmol) in 100 mL of acetonitrile, N-bromosuccinimide (2.30 g, 12.9 mmol) in 30 mL of acetonitrile was added slowly at room temperature. The reaction was stirred at room temperature for 4 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (25, 3.60 g).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][C:9]([OH:11])=O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](O)[CH3:22]>O>[NH:5]1[C:9](=[O:11])[CH2:8][CH2:7][C@H:6]1[C:12]([O:14][CH2:21][CH3:22])=[O:13]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)[C@@H]1CCC(=O)N1
Temperature: 160 °C

Procedure:
Thionyl chloride (217 ml) is slowly added to a stirred suspension of L-glutamic acid (417 g) in dry ethanol (1 L), and the mixture is refluxed for 5 hours. Ethanol is removed under vaccum to give a residue, which is dissolved in water (500 ml). The water solution is made alkaline with saturated sodium carbonate solution and extracted with chloroform (4×200 ml). The chloroform extract is dried (Na2SO4) and evaporated to give crude product (178 g). This material is heated (160° C.) under vaccum (10 mm Hg) for 3 hours. Subsequent distillation gives pure ethyl L-pyroglutamate (126.6 g; b.p. 126° C./0.07 mm Hg; [α]D =-2.15°±0.01 (H2O, c=17.8).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:29][C:30]1[CH:35]=[N:34][CH:33]=[C:32](Cl)[N:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[Cl:29][C:30]1[N:31]=[C:32]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:33]=[N:34][CH:35]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cncc(Cl)n2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0499 g, 0.130 mmol) and 2,6-Dichloropyrazine (0.0311 g, 0.209 mmol) were combined then added dry N,N-Dimethylformamide (0.911 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.40 (s, 1H), 8.22 (d, J=8.8, 2H), 7.90 (s, 1H), 7.49 (d, J=8.8, 2H), 6.17 (t, J=5.5, 1H), 4.69 (d, J=16.4, 2H), 3.86 (t, J=5.1, 2H), 3.79-3.69 (m, 4 H), 3.49 (d, J=4.3, 4H), 3.18-3.06 (m, 2H), 2.80 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+495.2 (M+H)+
Reaction SMILES: [H][H].C(OC([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[CH2:22][C:23](=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=O)C1C=CC=CC=1.C(OC(N1C[C@H](OC)C[C@H]1CC(=O)CC(OCC)=O)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2]>[CH2:28]([O:27][C:25]([CH2:24][C:23](=[O:30])[CH2:22][CH:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13]1)=[O:26])[CH3:29]
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)CC1Cc2ccccc2N1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CCOC(=O)CC(=O)C[C@@H]1C[C@@H](OC)CN1C(=O)OCc1ccccc1
Agent: [OH-]
Product: CCOC(=O)CC(=O)CC1Cc2ccccc2N1

Procedure:
In a similar manner to that described in Preparative Example 1(iii)′ above, a debenzylation reaction using hydrogen gas and palladium hydroxide on carbon was performed, using 1-benzyloxycarbonyl-2-(3-ethoxycarbonyl-2-oxopropyl)indoline [obtained as described in Preparative Example 5(iii)′ above] instead of (2S, 4R)-1-benzyloxycarbonyl-2-(3-ethoxycarbonyl-2-oxopropyl)-4-methoxypyrrolidine, to give the title compound as an orange oil (yield: quantitative).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([Cl:19])=[C:14]([OH:20])[C:13]=2[NH2:21])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].Br[CH:23]([CH3:29])[C:24](OCC)=[O:25].C(=O)([O-])[O-].O>C(#N)C>[Cl:1][C:2]1[C:3]([C:12]2[C:13]3[NH:21][C:24](=[O:25])[CH:23]([CH3:29])[O:20][C:14]=3[C:15]([Cl:19])=[CH:16][C:17]=2[F:18])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: CCOC(=O)C(C)Br
Reactant: Cn1nc(-c2c(F)cc(Cl)c(O)c2N)c(Cl)c1OC(F)F
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC1Oc2c(Cl)cc(F)c(-c3nn(C)c(OC(F)F)c3Cl)c2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
Step 3 A mixture of 4-chloro-3-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole (0.88 g), ethyl 2-bromopropionate (0.70 g) and potassiun carbonate (0.711 g) in acetonitrile (30 ml) was stirred overnight at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine (×3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the oily product was subjected to silica gel chromatography eluted with ethyl acetate and hexane (1:4) to afford 4-chloro-3-(8-chloro-6-fluoro-2-methyl-2H-1,4-benzoxazine-3-one-5-yl)-5-difluoromethoxy-1-methyl-1H-pyrazole (0.054 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[S:8][C:9]([CH:12]=O)=[CH:10][N:11]=2)=[CH:4][CH:3]=1.[C:16]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[S:8][C:9](/[CH:12]=[CH:21]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cnc(Oc2ccc(Cl)cc2)s1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1cnc(Oc2ccc(Cl)cc2)s1
Temperature: 25 °C

Procedure:
A solution of 2-(4-chlorophenoxy)-5-thiazolecarboxaldehyde from above and (carboethoxymethylene)triphenylphosphorane (9.51 g, 27.3 mmol) in toluene (125 mL) was refluxed for 1 hr. It was then cooled to r.t. and concentrated in vacuo. The residue was taken up in ether and the triphenylphosphine filtered off. The filtrate was concentrated to afford ethyl trans-3-(2-(4-chlorOphenoxy)-5-thiazolyl)propenoate which was used as is.