Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[C:9]1(=O)[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(OC(=O)C)(=O)C.O>[C:9]1(=[O:14])[N:7]([CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[C:12](=[O:13])[CH:11]=[CH:10]1
Reactant: CCOC(=O)CN
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
In a separable flask, glycine ethyl ester hydrochloride (reagent grade) (279 g, 2 mol) was mixed into acetic anhydride (reagent grade) (800 ml). Then, to the mixture was added dropwise over 3 hours a solution of maleic anhydride (reagent grade) (196 g. 2 mol) in acetic anhydride (600 ml), with stirring at room temperature. After the dropwise addition, stirring was carried out for another 1 hour, and the resulting precipitate was collected by suction filtration, washed with ion-exchanged water, and dried. The product obtained (382 g), triethylamine (reagent grade) (404 g, 4 mol), and toluene (1200 ml) were charged into a separable flask equipped with a Dean-Stark trap. Then, the mixture was subjected to reaction at 120° C. for 2 hours with stirring. During the reaction, the water formed was removed with the Dean-Stark trap. After the reaction, toluene (300 ml) was added and the mixture was washed three times with ion-exchanged water. Then, the organic phase obtained was collected and subjected to removal of the toluene by evaporation using an evaporator and a vacuum dryer to give ethyl maleimidoacetate (165 g). (Yield: ca. 38%. The production of ethyl maleimidoacetate was verified by GPC measurement. The presence of ethyl maleimidoacetate was verified by 1H-NMR measurement using DMSO-d6. This compound is referred to hereinafter as Compound A4).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20]>>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([N+:1]([O-:4])=[O:2])[C:16]([F:19])=[CH:15][C:14]=1[F:20]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Fuming nitric acid 90% (8.5 mL, 0.19 mol) was added with gentle stirring to concentrated sulfuric acid 98% (125 mL) in a 1 L beaker. After stirring for 10 minutes at room temperature, 2,4-difluorobenzoic acid methyl ester (21.9 g, 0.127 mol) was added dropwise. After the addition, the reaction mixture was allowed to stir gently for 40 minutes at room temperature. The reaction mixture was then poured into ice-H2O (1 L) and stirred for 10 minutes. The mixture was extracted with EtOAc. The layers were separated, and the organic layer was washed sequentially with 1N NaCl, saturated NaHCO3, H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow residue. This residue was washed with 10% EtOAc/hexane, filtered, and dried to yield a pale yellow solid, 29.0 g (0.133 mol, 82%). mp 78-80° C. Analysis for C8H5F2NO4: Calcd: C, 44.25; H, 2.32; N, 6.45. Found: C, 44.18; H, 2.39; N, 6.14.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([N:33]4[CH2:34][CH2:35][N:30]([C:25]5[N:24]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:31][CH2:32]4)[C:12]=3[C:14]([F:16])([F:15])[F:17])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(N3CCN(c4ncccn4)CC3)c(F)cc2c1=O
Temperature: 105 °C
Reaction time: 3 h
Yield: 47.5 %

Procedure:
In 20 ml of pyridine were dissolved 1.0 g (0.003 mole) of 1-cyclopropyl-6,7-difluoro-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1.23 g (0.0075 mole) of 1-(2-pyrimidinyl)piperazine, and the mixture was stirred at 105° C. for 3 hours. Then, the solvent was removed by evaporation under reduced pressure, and the residue was applied to silica gel column chromatography (eluent; a chloroform:methanol=9.5:0.5 mixed solution) to obtain 0.68 g of 1-cyclopropyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-7-[4-(2-pyrimidinyl)piperazin-1-yl]quinoline-3-carboxylic acid as yellow powder.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]#[CH:22].CN(C)C=O>O>[CH3:1][O:2][N:3]=[C:4]([O:13][CH2:22][C:21]#[CH:20])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12]
Reactant: C#CCBr
Reactant: CONC(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOC(=NOC)c1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 29.8 %

Procedure:
1.0 g of N-methoxy-2,4-dichlorobenzamide, 0.75 g of potassium carbonate and 0.65 g of propargyl bromide were added to 10 ml of N,N-dimethylformamide, and the mixture was stirred for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 0.35 g of propargyl N-methoxy-2,4-dichlorobenzimidate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]3[C:22](Cl)=[N:21][C:20]([S:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:19][C:18]=3[N:32]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:33][C@@H:34]([CH2:39][OH:40])[CH2:35][CH:36]([CH3:38])[CH3:37]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]3[C:22]([NH:33][C@@H:34]([CH2:39][OH:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[N:21][C:20]([S:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:19][C:18]=3[N:32]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](N)CO
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3nc(SCc4ccccc4)nc(Cl)c3s2)CC1
Solvent: C1CCOC1
Product: CC(C)C[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)sc12
Temperature: 100 °C
Yield: 76.8 %

Procedure:
The product from step (a) (50 mg, 0.1 mmol) and D-leucinol (60 mg, 0.5 mmol) were dissolved in anhydrous tetrahydrofuran (3 mL). The solution was heated in a capped reaction tube at 100° C. for 7 days. The crude product was flash chromatographed on silica (gradient eluent—ammonia:ethyl acetate:chloroform, 1:9:90 to 1:49:50). The product was dried in vacuo at room temperature resulting in 44 mg (76% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2].[H-].[Na+].[CH2:25](I)[CH3:26]>C1(C)C(C)=CC=CC=1>[CH2:25]([O:22][C@@H:4]1[C@:3]2([CH2:1][CH3:2])[C@H:7]([C@@H:8]3[CH2:19][CH2:18][C:17]4[CH:16]=[C:15]([O:20][CH3:21])[CH:14]=[CH:13][C:12]=4[C@H:9]3[CH2:10][CH2:11]2)[CH2:6][CH2:5]1)[CH3:26]
Reactant: CCI
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCO[C@H]1CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12CC

Procedure:
Reflux a suspension of 5.0 g. of dl-13-ethyl-3-methoxygona-1,3,5(10)-trien-17β-ol and 3.83 g. of sodium hydride (50% in oil) for 1.5 hours in xylene (100 ml). Add 14.5 ml. of ethyl iodide and reflux for 22 hours. Acidify with 2N hydrochloric acid and extract the material with benzene. Chromatograph the residue on alumina (Grade I neutral). Elute the product with benzene-ether (1:1). Recrystallize the product from 60 ml. of methanol to obtain dl-17β-ethoxy-13-ethyl-3-methoxygona-1,3,5(10)-triene (2.3 g); m.p. 74°-77°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:4]=1[O:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)C(=Cc1ccc(OC)c(OCCc2ccccc2)c1)C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OC)c(OCCc2ccccc2)c1)C(=O)OC
Yield: 99.5 %

Procedure:
The methyl 3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-methoxycarbonylacrylate (66.50 g) was dissolved in 330 ml of ethyl acetate at 40° C. To the solution, 3.33 g of 5% Pd/C was added to hydrogenate at 40° C. until hydrogen absorption was stopped. 5% Pd/C was separated by filtration through a powder magnesium sulfate plate under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 66.51 g of crude methyl 3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-methoxycarbonylpropionate. This crude compound was used in the subsequent step without purification.
Reaction SMILES: [CH:1]1([N:4]([CH:30]2[CH2:32][CH2:31]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=O)[CH3:23])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][N:34](C(OC(C)(C)C)=O)[NH2:35].C(O)=O>C(O)(=O)C>[CH:1]1([N:4]([CH:30]2[CH2:31][CH2:32]2)[C:5]([C:7]2[N:27]([CH2:28][CH3:29])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:21]=[C:22]([CH3:23])[N:34]([CH3:33])[N:35]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(C)=O)SC)nc21
Solvent: O=CO
Solvent: CC(=O)O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C)n(C)n3)nc21
Temperature: 35 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
A mixture of (Z)—N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 72B, 70 mg, 0.155 mmol) and tert-butyl 1-methylhydrazinecarboxylate (0.046 mL, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35° C. for 4 h (monitored by LC/MS until no starting material left). Formic acid (0.5 mL) was added and stirred at 60° C. for 6 h. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane). The impure product was further purified by preparative HPLC to give N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (45 mg, 63.9% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([OH:16])[CH:9]=2.[I-].[CH3:24][N:25]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:26](N1C=C[N+](C)=C1)=[O:27]>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([O:16][C:26](=[O:27])[N:25]([CH3:24])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:9]=2
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(O)ccc12
Agent: [I-]
Product: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(OC(=O)N(C)c3ccccc3)ccc12

Procedure:
The title compound was prepared from 3-(2,6-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=468 (M+1), Rt: 5.37 min.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:23]=[CH2:24].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[C:27]([O:26][C:22](=[O:25])[CH:23]=[CH:24][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)C=Cc1ccc(-c2ccc(OC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 24 h
Yield: 93.9 %

Procedure:
To 7.4 g (21.2 mmol) of 4-(tert-butoxycarbonyloxy)-4′-bromobiphenyl synthesized in the Example 9, were added 2.85 g (22.2 mmol) of tert-butyl acrylate, 10 ml of triethylamine, 30 ml of acetonitrile, 50 mg (2.22×10−1 mmol) of palladium acetate [Pd(OAc)2], and 116 mg (4.42×10−1 mmol) triphenylphosphine. The reaction system was purged with argon, and the reaction was conducted for 24 hours with heating and refluxing. The reaction mixture was poured into 500 ml of an iced water, and hydrochloric acid was added to the resultant mixture with stirring. The solid formed by stirring was collected by filtration, washed with water, dried, and recrystallized from methanol to give 7.9 g (19.9 mmol) of tert-butyl-4-(4′-tert-butoxycarbonyloxyphenyl)cinnamate.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([CH3:8])[CH3:7])C.Cl.[OH-].[K+].[C:15]([C:17]1[CH:18]=[C:19]([NH:24][C:25]2[C:26]3[CH:34]=[C:33]([NH:35][C:36](=[O:46])[CH2:37]P(=O)(OCC)OCC)[N:32]=[CH:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH:20]=[CH:21][C:22]=1[F:23])#[CH:16].[Li+].[Cl-]>O.C(Cl)Cl.CO.CC(N(C)C)=O.C1COCC1>[CH3:8][N:6]([CH3:7])[CH2:5]/[CH:4]=[CH:37]/[C:36]([NH:35][C:33]1[N:32]=[CH:31][C:27]2[N:28]=[CH:29][N:30]=[C:25]([NH:24][C:19]3[CH:20]=[CH:21][C:22]([F:23])=[C:17]([C:15]#[CH:16])[CH:18]=3)[C:26]=2[CH:34]=1)=[O:46]
Reactant: CCOC(CN(C)C)OCC
Reactant: C#Cc1cc(Nc2ncnc3cnc(NC(=O)CP(=O)(OCC)OCC)cc23)ccc1F
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cc(Nc2ncnc3cnc(NC(=O)/C=C/CN(C)C)cc23)ccc1F
Temperature: 45 °C
Reaction time: 25 h
Yield: 91.8 %

Procedure:
To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (1.56 g, 9.70 mmol) and water (1.6 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (1.62 mL, 19.3 mmol). After addition the mixture was stirred at 45° C. (bath) for 25 h. It was cooled to 0° C. (bath). This is called solution A. KOH (2.76 g, 49.3 mmol) was dissolved in water (8 mL) at room temperature under a nitrogen atmosphere. It was cooled to 0° C. (bath). This is called solution B. To a stirred heterogeneous mixture of compound 235 (1.76 g, 3.85 mmol) and THF (8 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (4 mL) to give a homogeneous solution. LiCl (163 mg, 3.85 mmol) was added and stirred at 0° C. (bath) for 15 min. The cold solution B was added and stirred at 0° C. for 2 min. Then the cold solution A was added and the final reaction mixture was continued to stir at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC (DCM-MeOH=10:1). After stirred for 30 min. it was poured into water (300 mL). Petroleum ether (300 mL) was added and stirred at room temperature for 10 min. Petroleum ether layer was decanted. More petroleum ether (300 mL) was added and stirred for 10 min. The solid was collected by suction filtration; washed with water (4×20 mL); dried under reduced pressure over silica gel/KOH to give compound 8 (1.38 g, 92%) which was found only 89.7% pure by HPLC. Thus, the sample was stirred with MeOH (ca. 40 mL) for 30 min. The insoluble material was filtered off and to the filtrates was added one volume of water to precipitate out the required product. The solid was collected, washed with water/MeOH=3:1 (3×15 mL) and dried to give (2E)-4-(dimethylamino)-N-[4-(3-ethynyl-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-2-butenamide (8) (1.28 g, 85%) as a yellow/brown solid, mp 152-155° C.; 1H NMR δ [(CD3)2SO] 10.93 (s, 1H), 10.29 (s, 1H), 9.02 (s, 1H), 8.99 (s, 1H), 8.61 (s, 1H), 8.04 (dd, J=6.4, 2.7 Hz, 1H), 7.94-7.85 (m, 1H), 7.35 (t, J=9.1 Hz, 1H), 6.87 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d, J=15.4 Hz, 1H), 4.53 (s, 1H), 3.09 (br d, J=6.0 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C21H19FN6O.0.8H2O.0.7MeOH: C, 61.00; H, 5.52; N, 19.67%. Found C, 61.26; H, 5.25; N, 19.47%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][N:12]([CH3:14])[CH3:13])[CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[N:21]([CH3:22])[N:20]=[C:19]([OH:23])[C:18]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:26][C:16]([F:15])([F:25])[C:17]1[N:21]([CH3:22])[N:20]=[C:19]([O:23][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][N:12]([CH3:14])[CH3:13])[CH:3]=2)[C:18]=1[Cl:24]
Reactant: CN(C)Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cn1nc(O)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)Nc1cc(Oc2nn(C)c(C(F)(F)F)c2Cl)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 97.4 %

Procedure:
1.98 g (0.01 mol) of the product of step (a) was mixed with 2.2 g (0.011 mol) of 5-trifluoromethyl-4- chloro-3-hydroxy-1-methylpyrazole and 1.65 g of potassium carbonate in 15 ml of DMSO and heated for 24 hours at 90° C. The mixture was poured into 400 ml of H2O and extracted with ether. The organic layer was separated, washed with H2O, brine, dried over MgSO4 and solvent removed to give 3.7 g of solid, m.p. 72°-76° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:11]=[CH:10][C:8](=[O:9])O[CH:6]=1)=[O:4].[NH2:12][CH2:13][C@H:14]([OH:16])[CH3:15]>CO>[OH:16][C@H:14]([CH3:15])[CH2:13][N:12]1[C:8](=[O:9])[CH:10]=[CH:11][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6]1
Reactant: COC(=O)c1ccc(=O)oc1
Reactant: C[C@@H](O)CN
Solvent: CO
Product: COC(=O)c1ccc(=O)n(C[C@@H](C)O)c1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of methyl coumalate (500 mg, 3.24 mmol) in MeOH (10 mL) was treated with (R)-(−)-1-amino-2-propanol (0.319 mL, 4.06 mmol) and TEA (0.790 mL, 5.68 mmol). The reaction was stirred at 23° C. under nitrogen. After 1 h, the reaction was concentrated and purified by silica gel chromatography (eluent: 55-95% EtOAc/hexane), affording (R)-methyl 1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate as a white solid. MS (ESI pos. ion) m/z: 212.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]([OH:15])=O)=[CH:5]2.[CH3:16][CH:17]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18].C(N=C=NCCCN(C)C)C>>[CH3:18][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:6]2[NH:7][C:8]3[C:4](=[CH:3][C:2]([Br:1])=[C:10]([O:11][CH3:12])[CH:9]=3)[CH:5]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:16]
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Reactant: COc1cc2[nH]c(C(=O)O)cc2cc1Br
Agent: CCN=C=NCCCN(C)C
Product: COc1cc2[nH]c(C(=O)N3CCN(c4ncccc4NC(C)C)CC3)cc2cc1Br

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-bromo-6-methoxyindole-2-carboxylic acid (PREPARATION 82, 0.40 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.33 g) and 1-(ethyl)-3-(dimethylaminopropyl) carbodiimide (0.34 g), the title compound is obtained, mp 202°-204°.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH:38]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:40])[CH3:39]>>[CH2:42]([N:41]([CH:38]([CH3:40])[CH3:39])[C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CC(C)NCc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NS(=O)(=O)CC(=O)N(Cc1ccccc1)C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with N-isopropyl-N-benzylamine, mp 168°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[CH2:11][NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[O:24][CH2:23][C:22]2=[O:33])[CH2:15][CH2:14]1.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:31]([C:28]1[CH:29]=[CH:30][C:25]2[O:24][CH2:23][C:22](=[O:33])[N:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][CH:13]([N:12]([CH2:11]/[CH:10]=[CH:9]/[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:14][CH2:15]3)[C:26]=2[CH:27]=1)#[N:32]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(NC/C=C/c3cc(F)ccc3F)CC1)C(=O)CO2
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)CN(C/C=C/c1cc(F)ccc1F)C1CCN(CCN2C(=O)COc3ccc(C#N)cc32)CC1
Reaction time: 72 h
Yield: 5 %

Procedure:
To a mixture of 4-[2-(4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Example 37) (120 mg, 0.265 mmol) and ethyl diazoacetate (0.09 mL) in dichloromethane (5 ml) was added rhodium(II) acetate (4 mg, 0.009 mmol) at room temperature. After 72 hrs, the product was concentrated and purified by preparative TLC to give 6.7 mg of product (5%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[N:9]([CH2:27][CH3:28])[C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[CH:13]=[C:12]([CH3:26])[N:11]=1.[CH3:29][S-:30].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([S:30][CH3:29])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:27][CH3:28])[C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[CH:13]=[C:12]([CH3:26])[N:11]=1
Reactant: C[S-]
Reactant: CCN(c1nc(C)cc(-c2ccccc2C(F)(F)F)n1)c1ccc(Br)cc1Br
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN(c1nc(C)cc(-c2ccccc2C(F)(F)F)n1)c1ccc(SC)cc1Br

Procedure:
The product from Example 15 (450 mg), dimethylsulfoxide (12 mL), tetrakis(triphenylphosphine)Pd(0) (40 mg), and sodium thiomethoxide (61 mg) were heated at reflux 18 hours. The reaction was cooled, taken up and partitioned between ethyl acetate (100 mL) and water (100 mL). The ethyl acetate was washed with brine, dried over MgSO4, and concentrated to dryness. The crude product was chromatographed on silica gel giving the title compound (90 mg). CI-HRMS calcd. for C21H20N3F3SBr (M+H)+ : 482.051340. Found: 482.051434.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:27])(=O)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[CH:9]1[CH:13]([O:14][CH3:27])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)OC(C)(C)C)CC1O
Reactant: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)CC1N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
A suspension of 6 (52 g, 0.16 mol) in tetrahydrofuran (THF, 150 mL) was stirred at room temperature for about 30 min and cooled to −10 to −15° C. A solution of potassium hexamethyldisilylamide (KHMDS, 40% solution in THF, 144 mL, 0.256 mol) was slowly added while controlling the temperature between −5 and −15° C. After 15 min, dimethyl sulfate (18.7 mL, 1.20 mol) was added dropwise to the reaction mixture while maintaining a temperature between −10 and 0° C., and the resulting reaction mixture was then stirred at this temperature for about 30 min. The reaction mixture was quenched by the addition of water (100 mL), followed by acetic acid (50 mL). The product was extracted with methyl tert-butyl ether (2×150 mL). The combined organic layer was washed with water (100 mL), brine (50 mL) and dried over anhydrous Na2SO4. Evaporation under reduced pressure gave compound 7 as an oil (54 g).