Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH:13]=[C:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]1=O)C>>[CH2:1]([N:8]1[C:15]2[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[C:14]=2[CH:13]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNCc1ccccc1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Product: O=C1CCCc2c1cnn2Cc1ccccc1

Procedure:
Prepared analogously to Example 1 starting from benzylhydrazine and 2-(dimethylaminomethylene)-cyclohexane-1,3-dione.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.O>CC(N(C)C)=O>[NH2:19][C:20]1[N:21]=[C:22]([Cl:27])[CH:23]=[C:24]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:25]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(Cl)cc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 90 °C

Procedure:
356 mg (1.52 mmol) 2,2,2-trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 3 mL dry dimethylacetamide under argon atmosphere, and 73.1 mg (3.1 mmol) NaH is added. 250 mg-(1.54 mmol) 2-amino-4,6-dichloropyrimidine is then added and the solution stirred at 90° C. over night. 1 mL water is added carefully to quench all excess NaH and the mixture poured into 50 mL 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (gradient ethyl acetate:cyclohexane from 1:1 to 3:1). Yield: 254 mg (46%). ESI-MS m/z 361.1 [M+H]+.
Reaction SMILES: C([NH:4][CH2:5][CH2:6][N:7]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[N+:22]([O-:24])=[O:23])=[N:10][N:9]=[N:8]1)(=O)C.[ClH:25]>C(O)C>[ClH:25].[NH2:4][CH2:5][CH2:6][N:7]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[N+:22]([O-:24])=[O:23])=[N:10][N:9]=[N:8]1
Reactant: CC(=O)NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
A mixture of 6.5 g (0.02 mol) of 1-(2-acetamidoethyl)-5-(2,4-dinitrophenylthio)tetrazole, 100 ml of 12 N hydrochloric acid and 100 ml of 95% ethanol was refluxed for 4.5 hours. The mixture was evaporated to dryness to give a gummy residue which crystallized upon addition of ethanol to give 1-(2-aminoethyl)-5-(2,4-dinitrophenylthio)tetrazole hydrochloride, mp 217°-219° (d).
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([C:14]#[C:15][Si](C(C)C)(C(C)C)C(C)C)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[C:14]([N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:27][CH2:26][C:5]1=2)#[CH:15]
Reactant: Cc1ccc2c(c1)c1c(n2C#C[Si](C(C)C)(C(C)C)C(C)C)CCN(C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 177.6 %

Procedure:
To a cooled solution of 2,8-dimethyl-5-((triisopropylsilyl)ethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (10 g, 0.0236 mol) in THF (100 mL) was added tetrabutylammonium fluoride solution (1.0M in THF, 49 mL, 0.0526 mol) at 0° C. over 15 min. The reaction mixture was stirred for 1 h at 0° C., and the reaction monitored by TLC. After completion of reaction, the mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure to obtain product as a brown colored oil (9.4 g).
Reaction SMILES: [O:1]=[C:2]([CH3:21])[CH2:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:5].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1COCC1>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][CH:3]([C:2](=[O:1])[CH3:21])[C:4]([C@H:6]2[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[O:5])=[CH:27][CH:26]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(=O)CC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of (R)-benzyl 2-(3-oxobutanoyl)pyrrolidine-1-caboxylate (670 mg, 2.32 mmol) in anhydrous THF (20 mL) was added sodium hydride (111 mg, 60 wt. % in mineral oil, 2.78 mmol). The mixture was stirred at room temperature for 30 min and added to a solution of 4-chlorobenzyl bromide (715 mg, 3.48 mmol) in THF (10 mL). The reaction mixture was stirred at 60° C. for 18 h and then the solvents were removed in vacuo. Purification of the resulting residue by silica gel column chromatography (ethyl acetate/hexane gradient, 10-100% EtOAc) afforded the desired product (812 mg, 86%). MS: calculated: 413.14, found (MH+): 414.3.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C@H:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19](=[O:21])[NH2:20]>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:5]=1[C:10](=[O:11])[N:15]([CH:16]([CH2:17][CH2:18][C:19](=[O:21])[NH2:20])[C:22]([OH:24])=[O:23])[C:7]2=[O:9])([O-:3])=[O:2]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CN(C)C=O
Product: NC(=O)CCC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 87.5 °C
Yield: 72.6 %

Procedure:
A mixture of 3-nitrophthalic anhydride (1.5 g, 7.8 mmol) and L-glutamine (1.14 g, 7.8 mmol) in DMF (15 mL) is heated at 85-90° C. for 4 hours. The mixture is concentrated in vacuo and the residue is slurried with water (30 mL). The resulting slurry is filtered and the solid is washed with water (10 mL), dried (60° C., <1 mm Hg) to give 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid (1.82 g, 73%); mp 182-184° C.; 1H NMR (DMSO-d6) δ8.33 (d, J=7.7 Hz, 1H), 8.22 (d, J=7.0 Hz, 1H), 8.11 (t, J=7.8 Hz, 1H), 7.19 (s, 1H), 6.73 (s, 1H), 4.82-4.77 (dd, J=4.6 and 9.8 Hz, 1H), 2.36-2.11 (m, 4H); 13C NMR (DMSO-d6) δ173.21, 170.03, 165.43, 162.75, 144.45, 136.70, 132.98, 128.83, 127.25, 122.52, 51.87, 31.31, 23.87; Anal. Calcd. For C13H11N3O7: C, 48.60; H, 3.45; N, 13.08. Found: C, 48.52; H, 3.28; N, 13.05.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][CH:9]=2)[CH:2]=1.[NH2:18][NH2:19]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:18][NH2:19])=[O:13])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: NN
Reactant: COC(=O)c1ccc(Oc2cccnc2)cc1
Solvent: CCO
Product: NNC(=O)c1ccc(Oc2cccnc2)cc1
Yield: 100 %

Procedure:
Methyl 4-(pyridine-3-yloxy)benzoate (4.8 g, 20.94 mmol) was dissolved in ca. 150 mL of EtOH and anhydrous hydrazine (4.08 g, 4.0 mL) was added via a syringe. The resulting yellow solution was refluxed for 24 hrs. Then solvent was removed in vacuo to give the title product (4.8 g, 100% yield) as yellow viscous oil, which upon standing slowly solidified.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1)=[O:8].[CH3:22][CH2:23][O-:24].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:24][CH2:23][CH3:22])[N:10]=1)=[O:8]
Reactant: COc1ccc(OC)c(CNC(=O)c2cccc(Br)n2)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cccc(C(=O)NCc2cc(OC)ccc2OC)n1
Temperature: 150 °C
Yield: 69.5 %

Procedure:
A mixture of bromide from Example 156A (35 mg, 0.1 mmol) and NaOEt (21% w/w ethanol soulution, 56 μL, 0.15 mmol) in ethanol (500 μL) was heated in a microwave oven at 150° C. for 10 minutes. It was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel column using ethyl acetate:hexane (1:1) to provide the titled compound (22 mg, 70%). MS (ESI(+)) m/e 317 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.89 (t, J=6.4 Hz, 1H), 7.89-7.84 (m, 1H), 7.63-7.60 (m, 1H), 7.02-6.74 (m, 4H), 4.46 (d, J=6.4 Hz, 2H), 4.45 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 3.65 (s, 3H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=2)[CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.[OH-].[Li+].CO>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=2)[CH2:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(C2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(C2CC2)c1

Procedure:
The title compound was synthesized from methyl 4-(3-cyclopropylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.020 g, 0.068 mmol) and lithium hydroxide (0.030 g, 0.71 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound: 2.2 mg, 12% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.61-0.66 (m, 2H), 0.92 (s, 2H), 1.86 (s, 1H), 2.06 (s, 1H), 2.49 (s, 1H), 2.59 (s, 2H), 2.72 (d, J=7.03 Hz, 2H), 3.23 (s, 1H), 6.30 (s, 1H), 6.84 (s, 1H), 6.96 (s, 1H), 7.12 (s, 1H); LCMS-MS (ESI−) 280.1 (M−H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[C:38]2=[CH:39][N:40]=[N:41][C:42](=O)[C:37]2=[N:36][CH2:35]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)[Cl:56]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Cl:56][C:42]1[N:41]=[N:40][CH:39]=[C:38]2[N:34]([C@@H:11]3[O:12][C@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:14]([O:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C@H:10]3[O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:35]=[N:36][C:37]=12
Reactant: ClP(Cl)Cl
Reactant: O=C1N=NC=C2C1=NCN2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)c1ccccc1
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nncc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
A solution containing the compound from Step B (1.32 g, 2.27 mmol), the N,N-diethylaniline (365 μL), tetrabutylammonium chloride (1.2 g), freshly distilled phosphorus chloride (1.3 μL) and anhydrous acetonitrile (17 mL) was stirred at 90° C. for 1 hour. The reaction mixture was poured over cracked ice/water. The aqueous layer was extracted with dichloromethane (3×60 mL). The organic layer was washed with sodium hydrogenocarbonate 5%, water and was evaporated to dryness. The crude product was purified on silica gel using n-hexane/ethyl acetate (3/1) as eluant to give the title compound (404 mg) as a yellow powder.
Reaction SMILES: O[CH2:2][C@H:3]([N:8]([CH3:19])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCOCC1>[CH3:19][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:3](=[CH2:2])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@H](CO)N(C)S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C(=O)O)N(C)S(=O)(=O)c1ccc(C)cc1
Temperature: 60 °C
Yield: 64.3 %

Procedure:
A solution of 3E (1.4 g, 4.87 mmol) in dioxane (30 mL) was added with 20% NaOH aq. solution (30 mL) and the mixture was heated at 60° C. overnight. The organic solvent was removed under reduced pressure and the aqueous phase was acidified with 10% HCl and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 4E as a pale yellow solid (0.8 g, 65% yield). 1HNMR (DMSO, 200 MHz) δ 2.81 (s, 3H), 2.88 (s, 3H), 5.46 (s, 1H), 6.02 (s, 2H), 7.41 (d, 2H, J=7.8), 7.66 (d, 2H, H=8), 13.01 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[N:7]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1>[Pd].CO>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([N:7]2[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:2]2([CH3:24])[CH3:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)C(C)(C)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
A 50-mL round-bottomed flask was purged with nitrogen and charged with 125a (1100 mg, 3.2 mmol), 10% palladium on carbon (10% wet, 110 mg), and methanol (20 mL). It was then evacuated, charged with hydrogen gas, and stirred at room temperature for 5 h. The hydrogen was evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 125b (950 mg, 94%). LCMS: [M+H]+ 307.3
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([O:13]C)=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO>O>[Br:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(Br)cccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c(Br)cccc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.7 %

Procedure:
A mixture of methyl 4-bromobenzo[b]thiophene-2-carboxylate (101 g), sodium hydroxide (63 g), methanol (1200 ml) and water (600 ml) was stirred at ambient temperature for 16 hours, the methanol was removed in vacuo, and the resulting suspension was cooled to 0° C. and acidified by dropwise addition of concentrated hydrochloric acid. The mixture was stirred for 20 minutes and the resulting solid was collected by filtration, washed with water (3×250 ml) and dried in vacuo at 110-120° C. to give 4-bromobenzo[b]thiophene-2-carboxylic acid (62 g) as a cream solid which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[C:9](F)[CH:8]=2)[CH3:2].[F:23][C:24]([F:35])([F:34])[C:25]([NH:27][CH2:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)=[O:26].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[C:9]([C:31]1[NH:32][CH:33]=[C:29]([CH2:28][NH:27][C:25](=[O:26])[C:24]([F:23])([F:34])[F:35])[N:30]=1)[CH:8]=2)[CH3:2]
Reactant: CCOC(=O)c1nc2cc(F)c([N+](=O)[O-])cc2nc1OCC
Reactant: O=C(NCc1c[nH]cn1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1nc2cc(-c3nc(CNC(=O)C(F)(F)F)c[nH]3)c([N+](=O)[O-])cc2nc1OCC
Temperature: 130 °C
Reaction time: 15 h
Yield: 37.1 %

Procedure:
To a solution of ethyl 3-ethoxy-7-fluoro-6-nitroquinoxaline-2-carboxylate (308 mg, 999 μmol) and 4-(trifluoroacetamidomethyl)imidazole (1.72 g, 8.91 mmol) in acetonitrile (10 ml) was added triethylamine (3.00 ml, 21.5 mmol), and the mixture was stirred for 15 hours at 130° C. in sealed tube. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by means of silica gel column chromatography [methylene chloride] to obtain 179 mg of the title compound as light brown powder. Yield 37%.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[Cl:29][C:30]1[CH:39]=[C:38]2[C:33]([C:34]([NH:40][NH2:41])=[CH:35][CH:36]=[N:37]2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:39]=[C:38]2[C:33]([C:34]([N:40]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[C:16]([S:20]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:41]3)=[CH:35][CH:36]=[N:37]2)=[CH:32][CH:31]=1
Reactant: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1ccnc2cc(Cl)ccc12
Product: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4cc(Cl)ccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-diethyl-benzenesulfonamide (A-21) and (7-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=533.1 (M+H)+
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10]>CC(O)(C)C>[CH3:12][O:11][C:9]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C@@H:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)=[O:10]
Reactant: O=C1C=CCC1
Reactant: COC(=O)CC(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)C(C(=O)OC)[C@@H]1CCC(=O)C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
Under an atmosphere of argon, 11.0 mg (0.02 mmol, S/C=100) of Ru[(S,S)-Msdpen] (hexamethylbenzene), 168 μL (2.0 mmol) of 2-cyclopentenone, 228 μL (2.0 mmol) of dimethyl malonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 60° C. for 24 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 422 mg (99% yield) of the title compound. The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane: 2-propanol=80:20, flow rate 1.0 mL/min, detection at 210 nm) and it was found to be 98% ee.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[CH:6][O:7][CH:8]=1)([CH3:3])[CH3:2].[CH2:9]([O:11][C:12](=[O:33])[N:13]([C:22]1[CH:27]=[C:26](Br)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10]>>[CH2:9]([O:11][C:12](=[O:33])[N:13]([C:22]1[CH:27]=[C:26]([C:6]2[O:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10]
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: CC(C)c1cocn1
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2nc(C(C)C)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4-isopropyl-oxazole (54 mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg), giving the product (71 mg) as a yellow gum.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33](B2OCC(C)(C)CO2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16].Br[C:48]1[S:49][C:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:51][N:52]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33]([C:48]2[S:49][C:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:51][N:52]=2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH3:22])=[O:16]
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(B2OCC(C)(C)CO2)cc1C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cnc(Br)s1
Product: CCOC(=O)c1cnc(-c2ccc(N(CC(=O)NCCN(CC)C(=O)OC(C)(C)C)CC(=O)N(C)N3Cc4ccccc4C3)c(C)c2)s1
Yield: 13.6 %

Procedure:
Using the compound (1.69 g, 2.66 mmol) of Example 295, step A and ethyl 2-bromothiazole-5-carboxylate (754 mg, 3.19 mmol), and according to the method of Example 295, step B, the title compound (246 mg, yield 14%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=1.[H-].[Na+].[CH3:29]I>C1COCC1>[CH2:20]([N:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[N:10]([CH3:29])[C:3]3[CH:4]=[C:5]([C:8]#[N:9])[CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:13][CH:14]=1)[CH2:23][CH2:24][CH3:25])[CH2:21][CH3:22]
Reactant: CI
Reactant: CCCN(CCC)Cc1ccc(C(=O)Nc2cc(C#N)ccc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1ccc(-c2nc3ccc(C#N)cc3n2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
The compound (613 mg) obtained in Example 29-4 was dissolved in THF (18 ml) and added with 60% sodium hydride (105 mg). After that, the whole was gradually added with methyl iodide (373 mg) and stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with water, and subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (160 mg) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][CH2:12][S:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][CH2:12][S:11][C:10]([NH:14][C:23](=[O:25])[CH3:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CC1(c2cccc(Br)c2)CCSC(N)=N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1=NC(C)(c2cccc(Br)c2)CCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a 0° C. solution of 4-(3-bromo-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine (10 g, 35 mmoles, 1 equiv) and triethylamine (4.3 g, 42 mmoles, 1.2 equiv) in dichloromethane (70 mL) is added dropwise acetyl chloride (2.8 g, 35 mmoles, 1 equiv) over 5 minutes. The reaction is allowed to warm to ambient temperature. After 1 h, the reaction is diluted with dichloromethane and extracted with water. The organic layers are separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography eluting with hexane:ethyl acetate (1:1) to give the title compound (87% yield): MS (m/z): 327, 329 (M+1).
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3].[OH-].[Li+].O>CO>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:28][CH3:29]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2cccc3cccnc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2cccc3cccnc23)c1
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a mixture of methyl 3-[(dipropylamino)carbonyl]-5-(8-quinolinyl)benzoate (XLIX, step 1, 175.5 mg, 0.45 mmol) in methanol (2 mL) is added lithium hydroxide (32.3 mg, 1.4 mmol) and water (500 microliter). After stirring overnight, the reaction mixture is partitioned between ethyl acetate (10 mL) and water (10 mL). The aqueous phase is separated and acidified with hydrochloric acid (1N), and extracted with chloroform (3×40 mL). The organic phase is washed with saline, dried (sodium sulfate) and concentrated under reduced pressure to give 3-[(dipropylamino)carbonyl]-5-(8-quinolinyl)benzoic acid (IX–L, 130 mg), NMR (300 MHz, CD3OD) δ 8.84, 8.39, 8.35, 8.05, 7.96, 7.90, 7.87, 7.79, 7.68, 3.50, 3.37, 1.76–1.61, 0.99 and 0.84.