Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:35])([F:34])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:34])([F:33])[F:35])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:28]([F:30])([F:31])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoate (400 mg, 0.75 mmol, 1.00 equiv) in methanol (5 mL), a solution of sodium hydroxide (400 mg) in water (5 mL). The resulting solution was stirred for 2 h at 50° C. The pH value of the solution was adjusted to 5 with hydrogen chloride (2 mol/L). The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 380 mg (crude) of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([C:11]1[N:12]=[C:13]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Cl/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].O1[CH2:40][CH2:39][CH2:38][CH2:37]1>C(OCC)(=O)C.Cl>[CH2:9]([O:8][C:6]([C:5]([C:11]1[N:12]=[C:13]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[S:14][CH:15]=1)([C:4]([O:3][CH2:1][CH3:2])=[O:27])[CH:31]=[CH:32][C:33]([O:35][CH:37]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:38]1[CH:6]=[CH:5][CH:4]=[CH:40][CH:39]=1)=[O:34])=[O:7])[CH3:10]
Reactant: C1CCOC1
Reactant: O=C(O)/C=C/Cl
Reactant: CCOC(=O)C(C(=O)OCC)c1csc(NC(=O)OCc2ccccc2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C=CC(=O)OC(c1ccccc1)c1ccccc1)(C(=O)OCC)c1csc(NC(=O)OCc2ccccc2)n1
Reaction time: 12.5 h

Procedure:
To a solution of 2-(2-benzyloxycarbonylamino-4-thiazolyl)malonic acid diethyl ester in tetrahydrofuran (20 parts) are added sodium hydride (2.35 equivalents) and a solution of trans-3-chloroacrylic acid diphemylmethyl ester (1.2 equivalents) in tetrahydrofuran (8 parts) under ice cooling. After stirring at 35° to 40° C. for 12.5 hours, the mixture is diluted with ethyl acetate and diluted hydrochloric acid, washed with water, dried, and concentrated. The residue is chromatographed over silica gel. The fraction eluted with a mixture of benzene and ethyl acetate (15:1) is crystallized from ethyl acetate to give 3-diphenylmethoxycarbonyl-1-(2-benzyloxycarbonylamino-4-thiazolyl)-2-propene-1,1-dicarboxylic acid diethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[S:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([S:20](Cl)(=[O:22])=[O:21])=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.N1C=CC=CC=1>CC(C)=O.O>[CH3:1][O:2][C:3]1[C:8]2[S:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([S:20](=[O:22])(=[O:21])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c2c1sc1ccc(S(=O)(=O)Cl)cc12
Reactant: COc1ccc(N)cc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(NS(=O)(=O)c2ccc(OC)c3sc4ccc(S(=O)(=O)Cl)cc4c23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-methoxy-dibenzo[b,d]thiophene-1,8-disulfonylchloride (0.2 g, 0.49 mmols) from step 1 in dry acetone (10 ml) was added p-anisidine (0.6 g, 0.49 mmols) and pyridine (0.06 g, 0.73 mmols). The reaction mixture was stirred at room temperature for 18 hrs. Acetone was evaporated and reaction mixture was diluted with water and extracted in ethyl acetate. Ethyl acetate layer on concentration gave crude product which was purified by silica gel column chromatography to get the pure product.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[C:6]([N:11]2[C:15]([C:16]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[C:27](=O)[C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[O:17])=[CH:14][C:13]([C:36]([F:39])([F:38])[F:37])=[N:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1.C([O-])(=O)C.[Na+]>O.C(O)C>[Cl:4][C:5]1[C:6]([N:11]2[C:15]([C:16]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3/[C:27](=[N:2]/[OH:3])/[C:28]([N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])=[O:29])=[O:17])=[CH:14][C:13]([C:36]([F:38])([F:37])[F:39])=[N:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCN(CC)C(=O)C(=O)c1cc(C)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)/C(=N\O)c1cc(C)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C

Procedure:
A solution of hydroxylamine hydrochloride (50 mg, 0.71 mmol) in water (0.5 mL) was added to a solution of 1-(3-chloro-2-pyridinyl)-N-[2-[(diethylamino)oxoacetyl]-4,6-dimethylphenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (i.e. the title product of Example 2, 124 mg, 0.24 mmol) in ethanol (5 mL) at 25° C. The resulting mixture was treated with a solution of sodium acetate (200 mg) in water (2 mL). The resulting mixture was heated at reflux for 3 days and then cooled to 25° C., diluted with ethanol (30 mL) and concentrated onto silica gel (0.5 g). The residue was purified by flash chromatography on silica gel eluted with 35% ethyl acetate in hexanes to give 50 mg of the title product, a compound of the present invention, as a yellow glassy solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:35]([O:39][C:40](=[O:70])[CH2:41][N:42]([CH2:56][C:57]1[N:58]([CH2:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH:59]=[CH:60][N:61]=1)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](O)=[O:54])([CH3:38])([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:66]([O:65][C:63](=[O:64])[CH2:62][N:58]1[CH:59]=[CH:60][N:61]=[C:57]1[CH2:56][N:42]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](=[O:54])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:41][C:40]([O:39][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:70])([CH3:69])([CH3:67])[CH3:68]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN(CCCCCCCCCCC(=O)O)Cc1nccn1CC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCCCCCN(CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 64.8 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (85 mg, 0.175 mmol), 11-((2-tert-butoxy-2-oxoethyl)((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)undecanoic acid (89 mg, 0.175 mmol), EDCI (38 mg, 0.20 mmol), HOBt (26 mg, 0.20) and DIPEA (0.30 mL) in DCM (5.0 mL) was stirred at rt for 3 days. The reaction mixture was purified by biotage eluting with 1% to 10% MeOH in DCM to afford (19S,23S)-tetra-tert-butyl 2-((1-(2-tert-butoxy-2-oxo ethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylate (111 mg, 65%) as a yellow oil. MS (ESI), 490.5 (M/2+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].I[CH:11]([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:13])[CH3:12]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of commercially available 3-hydroxybenzaldehyde (3.000 g; 24.60 mmol), 2-iodopropane (12.528 g; 73.70 mmol), K2CO3 (6.790 g; 49.10 mmol), and Cs2CO3 (1.601 g; 4.91 mmol) in anh. DMF (60 ml) was stirred at rt, under nitrogen, for 17 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 3-isopropoxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.76 min.; [M+H]+: 165.24 g/mol.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O[C:21]1C=CC(C(OC)=O)=C[CH:22]=1.C1(CCO)CCCC1>>[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)[CH2:3][CH2:2][CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Agent: OCCC1CCCC1
Product: O=C(O)CNC(=O)c1ccc(OCCC2CCCC2)cc1
Yield: 79 %

Procedure:
Reactions similar to those described in Example 1 (1a) and (1b) were conducted using methyl 4-hydroxybenzoate (6.09 g, 40.0 mmol) and 2-cyclopentylethanol (4.57 g, 40.0 mmol) to give 9.20 g of the title compound (white solid, yield: 79%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[N:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:33][N:34](C)C=O.C(N(CC)C(C)C)(C)C.CN>O1CCCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:23][CH2:24][N:25]([CH2:28][C:29]([NH:34][CH3:33])=[O:30])[CH2:26][CH2:27]5)=[N:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCN(CC(=O)O)CC3)nc1OCC2
Reactant: CN(C)C=O
Agent: CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN1CCN(c2ccc3c(n2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 25 °C

Procedure:
2-(4-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetic acid (0.050 g, 0.00011 mol) was dissolved in N,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine (0.119 mL, 0.000686 mol) 2.00 M of Methylamine in Tetrahydrofuran (0.228 mL) then N,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.0521 g, 0.000137 mol). Stir at r.t. 2 h. Add sat. sodium bicarbonate, extract with ethyl acetate. Dry organics over sodium sulfate and concentrate to give 334, analyzed by rHPLC. MS: (ESI+)=452.2
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[CH:27]([NH2:28])[C:26](=[O:29])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24])(=[O:14])[CH3:13].F[C:31]1[NH:32][CH:33]=[CH:34][N:35]=1>CN(C=O)C>[C:12]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[CH:27]([NH:28][C:31]3[NH:32][CH:33]=[CH:34][N:35]=3)[C:26](=[O:29])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24])(=[O:14])[CH3:13]
Reactant: Fc1ncc[nH]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.9 %

Procedure:
A suspension of anhydrous toluene-p-sulphonic acid (0.74 g.) and 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid (1.17 g.) in dry DMF (17.5 ml.) was stirred for 15 minutes at room temperature to effect partial solution. One portion of 2-fluoroimidazole (0.74 g.) was then added and the mixture stirred at 90° for 2 hours. The solvent was evaporated at ambient temperature, 2% v/v aqueous HOAc (20 ml.) was added to the residue and the mixture was extracted with EtOAc (20 ml.). The aqueous layer was concentrated to 15 ml., filtered and the filtrate purified by preparative HPLC on Whatman "Partisil 10" using water/MeOH/HOAc 80:20:1 v/v/v as solvent. The product was further purified by trituration with acetone and washing with acetone and ether to give 3-acetoxymethyl-7-(imidazol-2-yl)aminoceph-3-em-4-carboxylic acid (0.42 g.) as a hydrated mixed acetate/toluene-p-sulphonate salt having m.p. >160° (decomp.) and the following n.m.r. in D2O: 2.28 (s, 3H); 3.58 (d, 1H); 3.89 (d, 1H); 4.92 (d, 1H); 5.13 (d, 1H); 5.42 (d, 1H); 5.70 (d, 1H); 7.08 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]([CH3:30])([CH3:29])[CH:26]([OH:28])[CH3:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:24][C:25]([CH3:30])([CH:26]([OH:28])[CH3:27])[CH3:29])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(O)C(C)(C)N
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)C(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), 3-amino-3-methylbutan-2-ol (0.05 g, 0.49 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), HOBT (0.041 g, 0.3 mmol) and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF was stirred at room temperature overnight. The solvent was removed under reduced pressure at 70° C., the residue was triturated with water and then purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 15% acetonitrile/75% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(3-hydroxy-2-methylbutan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.025 g, 28%) as a yellow solid. MS: (M+H)+=413; 1H NMR (300 MHz, DMSO): δ 12.85 (s, 1H), 9.12 (s, 1H), 8.66 (d, 1H, J=8.7 Hz), 8.41 (s, 1H), 8.00-7.96 (m, 1H), 7.33 (dd, 1H, J=8.7, 1.5 Hz), 5.17 (d, 1H, J=5.7 Hz), 4.20 (s, 1H), 4.04-4.00 (m, 1H), 1.48 (s, 6H), 1.17 (d, 3H, J=6.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[N:7]([C:15]1[C:20]([CH3:22])([CH3:21])[S:19](=[O:24])(=[O:23])[C@H:18]2[CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][C:29]=3[C@@:17]2([CH3:37])[N:16]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:38])[N:7]([C:15]1[C:20]([CH3:22])([CH3:21])[S:19](=[O:24])(=[O:23])[C@H:18]2[CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=3[C@@:17]2([CH3:37])[N:16]=1)[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3CCC[C@@H]2S(=O)(=O)C1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3CCC[C@@H]2S(=O)(=O)C1(C)C
Yield: 97.8 %

Procedure:
A solution of tert-butyl-N-((4aS,11bR)-10-nitro-3,3,11b-trimethyl-4,4-dioxido-3,4a,5,6,7,11b-hexahydrobenzo[3,4]cyclohepta[1,2-b][1,4]thiazin-2-yl)-N-tert-butoxycarbonyl-carbamate (125 mg, 0.227 mmol) in THF (2 ml) was hydrogenated in the presence of palladium (10% wt.) on activated carbon (48.2 mg, 0.045 mmol) for 1 h (hydrogen balloon). The mixture was filtered through plug of celite, filter cake was washed with EtOAc, filtrate was concentrated to afford tert-butyl-N-((4aS,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxido-3,4a,5,6,7,11b-hexahydrobenzo[3,4]cyclohepta[1,2-b][1,4]thiazin-2-yl)-N-tert-butoxycarbonyl-carbamate (116 mg, 0.222 mmol, 98% yield), which was used without further purification. LC/MS (ESI+) m/z=522 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]([OH:9])[C:4]([CH3:11])([CH3:10])[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:14]=1[CH2:21][Br:22]>CN(C)C=O>[BrH:22].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]([O:9][CH2:21][C:14]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])[C:4]([CH3:11])([CH3:10])[N:3]=1
Reactant: CC1(C)N=C(N)N=C(N)N1O
Reactant: Clc1cc(Cl)c(CBr)cc1Cl
Solvent: CN(C)C=O
Product: Br
Product: CC1(C)N=C(N)N=C(N)N1OCc1cc(Cl)c(Cl)cc1Cl
Yield: 63.7 %

Procedure:
A solution of 0.6 gram (0.004 mole) of 4,6-diamino-1,2-dihydro-1-hydroxy-2,2-dimethyl-1,3,5-triazine and 1.6 grams (0.006 mole) of 2,4,5-trichlorophenylmethyl bromide in 5 ml of dimethylformamide was stirred in a closed reaction vessel during about an 18 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residual solid. The solid was washed with 50 ml of acetone. The dried solid was recrystallized from 125 ml of water, yielding 1.1 grams of 4,6-diamino-1,2-dihydro-1-(2,4,5-trichlorophenylmethoxy)-2,2-dimethyl-1,3,5-triazine hydrobromide, m.p. 247°-248° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16](=[O:23])[CH:17]=[C:18]([CH2:21][OH:22])O[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[OH:26][N:25]1[CH:20]=[C:15]([O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:16](=[O:23])[CH:17]=[C:18]1[CH2:21][OH:22]
Reactant: O=c1cc(CO)occ1OC(c1ccccc1)c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1cc(CO)n(O)cc1OC(c1ccccc1)c1ccccc1
Yield: 44 %

Procedure:
17.5 g (0.0568 mol) of the product of Step (1) was added and dissolved in a mixture of ethanol (60 ml) and water (60 ml). Then, 39.5 g (0.568 mol) of hydroxylamine hydrochloride and 77.2 g (0.568 mol) of sodium acetate trihydrate were added thereto, and the mixture was reacted at 60° C. for 18 hours under stirring. Formed precipitates were collected by filtration, washed sequentially with water, ethanol and ethyl ether, and then dried to obtain 8.1 g (yield: 44.0%) of the above identified compound.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][C:10]1[N:14]=[CH:13][NH:12][N:11]=1.[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl.O1CCCC1>[OH:8][CH2:9][C:10]1[N:14]=[CH:13][N:12]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:11]=1
Reactant: OCc1nc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.2 %

Procedure:
Triethylamine (1.13 ml, 8.08 mmol) was added to a suspension of 3-hydroxymethyl-1 H- 1, 2,4-triazole [J Am Chem Soc, 77, 1538 (1955)], (400 mg, 4.04 mmol) in dry dichloromethane (8 ml) at 0° C. A solution of trityl chloride (1.24 g, 4.44 mmol) in anhydrous tetrahydrofuran was added, and the mixture was stirred at room temperature for 3 h. The mixture was partitioned between water (75 ml) and dichloromethane (75 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give the title compound (1.547 g, >100%) which was used without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](OC)[N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CN(C)[CH:18]=[O:19]>>[CH3:18][O:19][C:5]1[C:4]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:3][CH:2]=[CH:7][CH:6]=1
Reactant: C1CNCCN1
Reactant: CN(C)C=O
Reactant: COc1cccc(Cl)n1
Product: COc1cccnc1N1CCNCC1
Temperature: 115 °C

Procedure:
To 966 mg (6.7 mmol) of 2-Chloro-6-methoxypyridine and 2.90 g (34 mmol) of piperazine in a pressure flask was added 3.3 mL dimethylformamide, and the mixture was heated at 115° C. for 5 hours. The solution was allowed to cool before opening the flask, and the resulting slurry was partitioned between ethyl acetate and water. The phases were separated, and the aqueous phase was back-extracted once with ethyl acetate. The combined ethyl acetate phases were washed once with brine, dried over Na2SO4, filtered, and the filtrate was acidified with 2M HCl in ether. The product crystallized overnight, and was isolated by filtration to give a white solid: 1H NMR (D2O, 400 MHz) 7.73 (t, 1H), 6.52 (d, 1H), 6.31 (d, 1H), 3.81 (s, 3H), 3.68 (m, 4H), 3.26 (m, 4H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]3=[CH:14][NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(-c5cccc(F)c5)cc43)cc2)CC1
Temperature: 180 °C
Yield: 28.6 %

Procedure:
To a suspension of 6-bromo-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione (221 mg, 0.5 mmol) in N,N-dimethylformamide (5 mL) is added 3-fluorobenzeneboronic acid (84 mg, 0.6 mmol), followed by 300 □L of 2M aqueous cesium carbonate and tetrakis triphenylphosphine palladium (30 mg, 0.06 mmol). The reaction mixture is subjected to microwave heating at 180° C. for 300 seconds. The reaction mixture is then diluted with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield 6-(3-Fluoro-phenyl)-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione (65.2 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.N#N.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19])=[O:15].Cl>O.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:17]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COC(=O)c1cc(N)ccc1OC
Agent: Cl
Agent: N#N
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Nc2nc(Cl)ncc2F)ccc1OC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The reaction flask equipped with a magnetic stirring bar and a rubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N2 inlet was charged with 3-methyloxycarbonyl-4-methoxyaniline (0.88 g, 4.86 mmol), MeOH (3 mL), H2O (7 mL) and 2,4-dichloro-5-fluoropyrimidine (0.81 g, 4.86 mmol). The reaction mixture was stirred at 60° C. for 30 min., diluted with H2O (50 mL), acidified with 2N HCl (6 mL) and sonicated. The solid obtained was filtered, washed with H2O and dried to produce 2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine R940302. 1H NMR (DMSO-d6): δ 10.10 (1H, s), 8.39 (1H, d, J=3.6 Hz), 8.04 (1H, d, J=2.7 Hz), 7.98–7.93 (1H, m), 7.30 (1H, d, J=9 Hz), 3.92 (3H, s), 3.89 (3H, m); purity 96%; MS (m/e): 312 (MH+).