Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[CH3:15])=[O:4]>C(OCC)(=O)C>[NH2:12][C:10]1[CH:9]=[CH:8][C:7]([CH3:15])=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:16])[F:17])[CH:11]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1NC(=O)C(F)(F)F
Reaction time: 12 h
Yield: 95 %

Procedure:
2,2,2-Trifluoro-N-(2-methyl-5-nitro-phenyl)-acetamide-(3.91 g, 15.78 mmol) was taken up in ethyl acetate in a Paar vessel and flushed with argon. Palladium on carbon (400 mg) was added and the argon atmosphere was replaced with hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen was then replaced with argon and the catalyst was removed by filtration through celite. The solvent was removed under reduced pressure to yield 3.27 g of the desired amine. C9H9F3N2O MS m/e=219.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].O>S1(=O)(=O)CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][N:17]=3)[CH2:20][CH2:21]2)[N:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reactant: COc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COc1ccnc(N2CCN(c3ccc([N+](=O)[O-])cn3)CC2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A mixture of 2-chloro-4-methoxypyrimidine (29 g) and 1-(5-nitro-2-pyridinyl)piperazine (35 g) in tetrahydrothiophene 1,1-dioxide (50 ml) was stirred at 130° C. for 1 hour. The mixture was poured into sodium carbonate and water, stirred for 30 minutes and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and evaporated. The residue was triturated in diisopropyl ether, yielding 23 g (43%) of 4-methoxy-2-[4-(5-nitro-2-pyridinyl)-1-piperazinyl]pyrimidine (interm. 10).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][N:7]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].C1(=O)O[CH2:28][CH2:27][O:26]1.[OH-].[K+].C(=O)=O>CN(C)C=O.O>[C:1]([C:4]1[C:5](=[O:24])[N:6]([CH2:28][CH2:27][OH:26])[N:7]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: O=C1OCCO1
Reactant: CC(=O)c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)n[nH]c1=O
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)nn(CCO)c1=O
Temperature: 5 °C
Yield: 68 %

Procedure:
4-Acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one (3.1 g), ethylene carbonate (2.0 g), and potassium hydroxide (powdered) were dissolved in dimethylformamide (50 ml) and the flask placed in an oil bath (110°-120° C.) until CO2 evolution ceased (ca. 3.5 hours). The reaction mixture was poured into water (400 ml) and chilled at 5° C. for 1 hour. The resulting precipitate was separated by filtration and recrystallized from methanol (85 ml) to afford 4-acetyl-5,6-bis(p-chlorophenyl)-2-(2'-hydroxyethyl)-2H-pyridazin-3-one (68 percent yield) as pale yellow crystals, m.p. 191°-193° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]=[CH:12][C:11]([O:14][C:15]2[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=[C:17]([C:26]([O:28][CH3:29])=[O:27])[CH:16]=2)=[CH:10][N:9]=1)=[O:7])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:29][O:28][C:26]([C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[N:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:27]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)OC(C)(C)C)nc2)c2c(c1)OC(C)(C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2cnc(C(=O)O)nc2)c2c(c1)OC(C)(C)C2

Procedure:
A solution of 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyrimidine-2-carboxylic acid tert-butyl ester (171b) (83 mg, 0.21 mmol) in 2 mL CH2Cl2 and 1 mL TFA was stirred at room temperature for 2 hr. The mixture was concentrated, dried under vacuum, and taken to the next step as it is.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]([C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:8])#[N:2].C([Sn]([N:47]=[N+:48]=[N-:49])(CCCC)CCCC)CCC.Cl.CO>O1CCCC1>[CH2:24]([O:23][C:22]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:8])=[CH:5][C:4]=1[CH2:3][C:1]1[NH:49][N:48]=[N:47][N:2]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1CC#N
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1Cc1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A mixture of 1.0 g of the product from Example 1 and 2.2 g of tri-n-butylstannylazide in 30 ml of tetrahydrofuran was heated at reflux for 10 days. The reaction was allowed to cool to ambient temperature. A mixture of hydrochloric acid and methanol was added, and after stirring for 30 minutes, the mixture was concentrated in vacuo. The residue was purified by chromatography over silica gel eluting with a 30-75% ethyl acetate in hexane gradient which additionally contained 0.05% acetic acid. The appropriate fractions were cooled and concentrated to provide 592 mg of product. Recrystallization from hexane/ethyl acetate provided 580 mg of the desired title product.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[O:22]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[CH:2]1[N:1]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:30]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)ccc2ccccc12
Product: COc1ccc2ccccc2c1C1CCCC(=O)N1Cc1cccc(Oc2ccccc2)c1

Procedure:
Prepared according to general procedure 1 (GP1) using methyl 5-amino-5-(2-methoxynaphthalen-1-yl)pentanoate and commercially available 3-phenoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.99 min.; [M+H]+: 438.14 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[C:18]([N:26]=C=O)(=[O:25])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[OH:11][C:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:18]([NH2:26])=[O:25])[CH:7]=1
Reactant: CC(O)(Cc1ccnc(N)c1)c1ccccc1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CC(O)(Cc1ccnc(NC(N)=O)c1)c1ccccc1
Temperature: 50 °C
Yield: 47 %

Procedure:
The crude 1-(2-Amino-pyridin-4-yl)-2-phenyl-propan-2-ol (120 mg) is dissolved in methylene chloride (4 mL). Then benzoyl isocynate (155 mg, 1.1 mmol) is added. The reaction mixture is sealed and heated at 50° C. for 16 hour. The solvent is then carefully removed and to the residue are added ethanol (5 mL) and potassium carbonate (73 mg, 0.53 mmol). The resulting mixture is heated at 85° C. for 2 hrs. Then solvent is removed to give the crude product which is purified by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) to give 67 mg of the titled product.
Reaction SMILES: [N:1]1([C:80]([O:82][CH2:83][C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)=[O:81])[CH2:79][CH2:78][CH2:77][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([NH:19][C@H:20]([C:36]([NH:38][C@H:39]([C:50]([NH:52][C@H:53]([C:69]([NH:71][CH2:72][C:73]([O:75]C)=[O:74])=[O:70])[CH2:54][CH2:55][CH2:56][CH2:57][NH:58][C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])=[O:51])[C@@H:40]([CH3:49])[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:37])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4].[OH-].[Na+]>CN(C=O)C.CO>[N:1]1([C:80]([O:82][CH2:83][C:84]2[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=2)=[O:81])[CH2:79][CH2:78][CH2:77][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([NH:19][C@H:20]([C:36]([NH:38][C@H:39]([C:50]([NH:52][C@H:53]([C:69]([NH:71][CH2:72][C:73]([OH:75])=[O:74])=[O:70])[CH2:54][CH2:55][CH2:56][CH2:57][NH:58][C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:60])=[O:51])[C@@H:40]([CH3:49])[O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:37])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4]
Reactant: COC(=O)CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of compound (i) (0.87 g, 0.0007 M) in 50% DMF/methanol (30 ml) was treated with 1 N NaOH solution (1.7 ml) and stirred at R.T. for 2 hours. Acidification precipitated the product (0.43 g) in 50% yield. T.L.C. 2:1 CHCl3 :MeOH (I2 stain) showed one spot at Rf 0.77. [α]D25° =-4.1° (C=1, AcOH). The NMR was consistent with structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11].C(O)(=O)C.[Br:17]Br>ClCCl>[Br:17][C:8]1[C:9]([OH:10])=[C:4]([C:5]([OH:11])=[CH:6][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1c(O)cccc1O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1c(O)ccc(Br)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a mixture of methyl-2,6-dihydroxybenzoate (1.68 g, 10.0 mmol) in dichloromethane (10 mL) was added acetic acid (1 mL), followed by drop-wise addition of bromine (515 μL, 10.0 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at ambient temperature for 1 hour, concentrated under reduced pressure, co-evaporated with ethyl acetate (2×). The resulting solid was triturated with hexane/ethyl acetate and re-crystallized from hot hexane/ethyl acetate to provide the titled compound (1.45 g). MS ESI(−,) m/e 244, 246 (M−H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 10.19 (s, 1H), 7.46 (d, 1H), 6.41 (d, 1H), 3.84 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:23]([O:14][C:12]1[C:11]([C:15]#[N:16])=[CH:10][C:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)nc1OCc1ccccc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-nitrile (200 mg, 0.65 mmol) from Example 1, Step B in DMF (3 mL) was added benzyl bromide (0.10 mL, 0.85 mmol) and then cesium carbonate (276 mg, 0.85 mmol). The reaction was stirred at 55° C. for 3 h and was then diluted with water and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The products were separated by preparative TLC (30% ethyl acetate in hexanes) to give the desired higher Rf O-alkylation title product.
Reaction SMILES: C([O:8][C:9](=[O:59])[CH2:10][CH2:11][C:12]([O:14][C:15]1([CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:51][C@H:50]([CH2:52][NH:53][C:54](=[O:56])[CH3:55])[O:49][C:48]3=[O:57])=[CH:43][C:42]=2[F:58])[CH2:20][CH2:19][N:18]([C:21]2[C:30]([F:31])=[CH:29][C:28]3[C:27](=[O:32])[C:26]([C:33]([OH:35])=[O:34])=[CH:25][N:24]([CH:36]4[CH2:38][CH2:37]4)[C:23]=3[N:22]=2)[CH2:17][CH2:16]1)=[O:13])C1C=CC=CC=1>[OH-].[Pd+2].[OH-].O1CCCC1.CO>[C:54]([NH:53][CH2:52][C@@H:50]1[O:49][C:48](=[O:57])[N:47]([C:44]2[CH:45]=[CH:46][C:41]([O:40][CH2:39][C:15]3([O:14][C:12](=[O:13])[CH2:11][CH2:10][C:9]([OH:59])=[O:8])[CH2:16][CH2:17][N:18]([C:21]4[C:30]([F:31])=[CH:29][C:28]5[C:27](=[O:32])[C:26]([C:33]([OH:35])=[O:34])=[CH:25][N:24]([CH:36]6[CH2:38][CH2:37]6)[C:23]=5[N:22]=4)[CH2:19][CH2:20]3)=[C:42]([F:58])[CH:43]=2)[CH2:51]1)(=[O:56])[CH3:55]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)O)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 3 step 5 with 22 mg succinic acid 4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-1-(6-carboxy-8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-yl)-piperidin-4-yl ester benzyl ester (MW: 817.80, 0.026 mmol) and 2 mg of palladium hydroxide 20% on activated carbon in 20 ml of a 1/1 tetrahydrofuran/methanol mixture. Yield: 16 mg, 81%. MS: 729 (M+H)+, 727 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][CH:18]1[O:20][CH2:19]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:17][CH:18]1[O:20][CH2:19]1
Reactant: ClCC1CO1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc(OCC2CO2)c(Cl)c1

Procedure:
A mixture containing 81.5 g of 2,4-dichlorophenol in 120 g of 1-chloro-2,3-epoxypropane and 138 g of potassium carbonate is refluxed for 10 hours.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[CH2:22]([N:13]1[CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:11]=[CH:12]1)[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)CBr
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)Cn1cnc(-c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-nitrophenyl)-1H-imidazole (0.500 g, 2.64 mmol) in N,N-dimethylformamide (10 ml) was added cesium carbonate (1.292 g, 3.96 mmol) followed by 1-bromo-2,2-dimethylpropane (0.366 ml, 2.91 mmol). After heating at 85° overnight, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Normal phase chromatography provided the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH2:21][OH:22])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13][CH2:12]1.I[CH3:32]>O1CCCC1>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH2:21][O:22][CH3:32])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:13][CH2:12]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CO)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 25.0 mg, 0.61 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (160 mg, 0.41 mmol) and iodomethane (51.0 μL, 0.81 mmol) in tetrahydrofuran (2 mL) at 0° C. After 3 h, the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (75 mg). MS 408.2 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[C:11](O)(=[O:14])[CH2:12][CH3:13]>O>[C:11]([C:7]1[CH:8]=[CH:9][C:4]2[NH:3][C:2](=[O:10])[O:1][C:5]=2[CH:6]=1)(=[O:14])[CH2:12][CH3:13]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CCC(=O)O
Solvent: O
Product: CCC(=O)c1ccc2[nH]c(=O)oc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1000 g polyphosphoric acid are taken at 50° C., 100 g (740 mmol) 2-benzoxazolinone and 80 mL (1.07 mol) propionic acid are added and then the mixture is stirred for 2 h at 90° C. The reaction mixture is cooled to 50° C. and while being cooled it is combined with 1500 mL cold H2O. H2O phase is decanted off and the whole process is repeated twice more with 1500 mL H2O. Then the solid is suction filtered, triturated with diethyl ether/EtOH, suction filtered and washed with diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18](O)=[O:19].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:43]1([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]([F:15])([F:16])[F:17])=[CH:11][CH:12]=2)[C:3]=1[C:18]([N:46]1[CH2:45][CH2:44][N:43]([C:49]2[CH:50]=[CH:51][C:52]([OH:55])=[CH:53][CH:54]=2)[CH2:48][CH2:47]1)=[O:19]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 68.5 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (566 mg, 1.26 mmol, 69%) was obtained.
Reaction SMILES: [BrH:1].[CH:2]1([NH:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[C:14]=3[OH:18])[C:9]2=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3]1>[Pd].O>[BrH:1].[CH:2]1([NH:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[C:14]=3[OH:18])[CH:9]2[OH:20])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2ccc(O)c(O)c2CCC1NC1CCCC1
Agent: [Pd]
Agent: Br
Solvent: O
Product: Oc1ccc2c(c1O)CCC(NC1CCCC1)C2O

Procedure:
Using 2 parts of 5 % palladium-on-carbon, 2 parts of 2-cyclopentylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide in 50 volume parts of water is subjected to catalytic reduction at ordinary temperature and pressure. After a stoichiometric amount of hydrogen has been absorbed, the reaction is terminated and the catalyst is filtered off. The filtrate is freeze-dried and the residue is recrystallized from a mixture of ethanol and ethyl acetate. The procedure yields 1.54 parts of 2-cyclopentylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide as colorless crystals melting at 210°-218° C (decomposition).
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:6]=[C:5]([C:12]([OH:14])=[O:13])[C:4]=1[Cl:15].[C:16](=O)(OC)OC.S(=O)(=O)(O)O.[OH-].[Na+]>O.CO>[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:6]=[C:5]([C:12]([O:14][CH3:16])=[O:13])[C:4]=1[Cl:15]
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Reactant: COC(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 70 °C
Yield: 92.3 %

Procedure:
A 500 mL multi-neck flask equipped with nitrogen bubbler, addition funnel, reflux condenser, and thermocouple was charged with 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid monohydrate (47.8 g, 0.206 mol), methanol (32 g) and dimethyl carbonate (94.5 g, 1.05 mol). Concentrated sulfuric acid (50.0 g, 0.500 mol) was added over about 30 minutes with cooling to maintain the temperature below 60° C., and then the reaction mixture was heated at 70° C. for 10 h. The resulting mixture was cooled to 15° C. and diluted with 250 mL of water. The pH of the reaction mass was raised to 5-8 by adding about 42.7 g (0.534 mol) of 50 wt % aqueous NaOH over 30 minutes with cooling to maintain the temperature in the range of 10-15° C. The resulting slurry was cooled to 5° C. and filtered. The filtered wet cake was washed with water and dried to constant weight at 50° C. to give 43.3 g (93.5% yield) of the title compound with 98% purity as a solid melting at 147-148° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[N:15][CH:16]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[CH3:25][N:17]([C:13]1[CH:14]=[N:15][CH:16]=[C:11]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=1)[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19]
Reactant: CI
Reactant: CCS(=O)(=O)Nc1cncc(-c2cc3ccccc3n2C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)c1cncc(-c2cc3ccccc3n2C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A flask is charged with ethanesulfonic acid [5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide (example 226, 100 mg, 0.317 mmol) and DMF (4 mL). The reaction is cooled to 0° C. and sodium hydride (15.85 mg, 0.396 mmol) is added. The reaction is stirred at 0° C. for 10 min, then methyl iodide (56.3 mg, 0.396 mmol) is added. The reaction is stirred for 1 hour at room temperature. The reaction is quenched with water (0.5 mL) and filtered. The filtrate is purified using Xbridge C18 eluting with a 10 to 100% acetonitrile-water gradient to afford ethanesulfonic acid methyl-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. 1H NMR (400 MHz, MeOD) δ ppm 1.39 (t, J=7.5 Hz, 3H), 3.28 (q, J=7.5 Hz, 2H), 3.49 (s, 3H), 3.84 (s, 3H), 6.74 (s, 1H), 7.14 (t, J=7.6 Hz, 1H), 7.28 (ddd, J=7.6, 1.1 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 8.13 (t, J=2.1 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H), 8.70 (d, J=2.5 Hz, 1H). HRMS (ESI) m/z 330.1281 [(M+H)+ Calcd for C17H19N3O2S 330.1270].