Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9]C)=O.O.[NH2:12][NH2:13]>CC(O)C>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH:12][NH2:13])=[O:9]
Reactant: COC(=O)[C@@H]1CCC[C@H]1O
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: NNC(=O)[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a 200-mL four-necked flask were added 18.47 g (128.1 mmol) of methyl (R,R)-2-hydroxycyclopentanecarboxylate and 75 mL of 2-propanol and stirring was started. Hydrazine monohydrate (12.83 g; 256.2 mmol) was dropped thereinto at 20° C. taking 1 hour and 30 minutes. After the dropping, the mixture was stirred at 85° C. for 15 hours. After the reaction, heating was stopped and the mixture was cooled to room temperature to precipitate the crystals. The crystals were filtered and washed with small amount of 2-propanol. The resulting crystals were dried to give 10.89 g of the title compound. The yield was 59%. Ratio of anti-form to syn-form of the compound was measured by a high-performance liquid chromatography (column: Inertsil ODS-3V) and found that the anti/syn ratio was more than 99/1.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH3:4].C.O.NN>CO>[CH3:1][O:2][CH:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH3:4]
Reactant: COC(C)C1CCCN1Cc1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: CO
Solvent: O
Product: COC(C)C1CCCN1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(1-Methoxy-ethyl)-1-(4-nitro-benzyl)-pyrrolidine (250 mg, 0.95 mmol) is dissolved in MeOH (10 mL). To this solution is added FeCl3.6H2O (25 mg, 0.09 mmol) and active charcoal (12 mg, 1.0 mmol). The suspension is heated to reflux. Hydrazine hydrate (1.0 mL) is added, and reflux is continued for 4 h. After the mixture is cooled to room temperature, the active charcoal is filtered off through Celite, and the MeOH is removed under reduced pressure. The residue (200 mg, 90%) is used directly in the next step.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:40])[CH:26]=[C:27]([CH:28]([CH3:30])[CH3:29])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:43][N:42]=[N:41][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:40])[CH:26]=[C:27]([CH:28]([CH3:29])[CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C(C)C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C(C)C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-isopropyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2- cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:39])=[CH:27][C:28]([O:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35])=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1.[OH-].[Na+]>FC(F)(F)C(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:39])=[CH:27][C:28]([O:31][CH2:32][C:33]([CH3:37])([CH3:38])[C:34]([OH:36])=[O:35])=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[NH:12][C:11]([C:13]([F:14])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 63.9 %

Procedure:
In trifluoroacetic acid (1.0 mL) and water (0.05 mL) was dissolved 3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid (268 mg), and the solution was stirred at room temperature for 10 hours. The solution was neutralized by adding 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with a saturated brine, and the organic layer was separated and concentrated under reduced pressure. Ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 3-[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid (133 mg).
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:14])[C:5](=[O:15])[O:4]1)[CH3:2].[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1)#[N:19]>>[CH2:16]([C:3]1([CH2:1][CH3:2])[O:4][C:5](=[O:15])[N:6]([CH3:14])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:22]3[CH:21]=[C:20]([CH:25]=[C:24]([F:26])[CH:23]=3)[C:18]#[N:19])=[CH:9][C:8]1=2)[CH3:17]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(O)cc21
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Oc3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared from 4,4-diethyl-6-hydroxy-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-cyano-5-fluorobenzeneboronic acid according to the coupling procedure described in example 69. A white solid, 1H NMR (DMSO-d6): δ 7.61 (m, 1H), 7.29 (s, 1H), 7.23 (dt, J=10.3, 2.3 Hz, 1H), 7.17 (m, 2H), 7.13 (m, 1H), 3.30 (s, 3H), 2.02 (m, 2H), 1.89 (m, 2H), 0.79 (t, J=7.2 Hz, 6H). MS (ESI) m/z 355 ([M+H]+); HRMS: calcd for C20H19FN2O3, 354.1380. found (ESI+), 355.14578.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[CH3:25][O:26][C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:31]3[CH2:30][CH2:29][C:28]4[C:33](=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:27]=4[O:26][CH3:25])[CH2:32]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(C(F)(F)F)cc3)nc3ccccc13)C2
Yield: 13 %

Procedure:
Reaction of 2-(4-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 39 (13% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.72 and 2.99 (2t, 2H), 3.50 and 4.04 (2t, 2H), 3.68-3.82 (4s, 6H), 4.43 and 4.94 (2s, 2H), 6.62 and 7.01 (2d, 1H), 6.81 and 7.08 (2d, 1H), 7.82-7.85 (m, 1H), 7.93-8.04 (m, 3H), 8.12-8.24 (m, 2H), 8.70-8.76 (m, 2H); MS (ESI) m/z 494 ([M+H]+).
Reaction SMILES: CO[CH:3]([O:14]C)[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([N+:11]([O-])=O)[CH:5]=1.[C:16]1([NH:22][C:23](=O)[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:24][C:23]1[N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]2[CH:8]=[CH:9][C:4]([CH:3]=[O:14])=[CH:5][C:6]=2[N:11]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: COC(OC)c1ccc(I)c([N+](=O)[O-])c1
Product: Cc1nc2cc(C=O)ccc2n1-c1ccccc1
Yield: 66.9 %

Procedure:
Method A applied to 4-dimethoxymethyl-1-iodo-2-nitrobenzene (155 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) yielded the title compound as pale yellow oil (79 mg, 67% yield). 1H NMR (DMSO) δ 2.50 (s, 3H), 7.31 (d, J=8.3Hz, 1H), 7.61-7.68 (m, 5H), 7.82 (d, J=8.3Hz, 1H), 8.25 (s, 1H), 10.10 (s, 1H); 13C NMR δ 13.6, 111.4, 120.1, 124.2, 127.0, 129.8, 130.2, 132.3, 139.1, 154.7, 158.3, 192.4. HRMS (FAB): cal. for C15H13N2O [M+H+]: 237.1028; found: 237.1024.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[CH2:11]([C:18]1[N:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[N:26][OH:27])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[CH2:11]([C:18]1[N:23]=[CH:22][C:21]([CH2:24][C:25]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:27][N:26]=2)=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ON=C(Cl)Cc1ccc(Cc2ccccc2)nc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Cc4ccccc4)nc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a tetrahydrofuran (5 mL) solution of 3-ethynyl-pyridin-2,6-diamine (20 mg, 0.15 mmol) described in Manufacturing Example 13-1-3 and 2-(6-benzyl-pyridin-3-yl)-acetohydroximoyl chloride (79 mg, 0.30 mmol) described in Manufacturing Example 210-1-7 was added triethylamine (46 mg, 0.45 mmol), which was stirred for 30 minutes at 50° C. The reaction solution was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate, then ethyl acetate:methanol=20:1) to obtain the title compound (43 mg, 80%).
Reaction SMILES: Br[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[CH2:3].[Li]C(C)(C)C.[CH:19]([CH:21]=[CH2:22])=[O:20]>>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([C:2]([CH:19]([OH:20])[CH:21]=[CH2:22])=[CH2:3])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: C=CC=O
Reactant: C=C(Br)c1ccc(OC)c(OC)c1
Agent: [Li]C(C)(C)C
Product: C=CC(O)C(=C)c1ccc(OC)c(OC)c1
Yield: 42.3 %

Procedure:
According to the General Procedure C, 1-bromo-1-(3,4-dimethoxyphenyl)ethene (1.00 g, 4.11 mmol), t-BuLi (6.05 ml, 10.28 mmol) and acrolein (691 mg, 12.33 mmol) are converted to give after workup and chromatography (SiO2, PE/EE=2:1, Rf=0.25) the title compound (382 mg, 1.74 mmol, 42%) as a yellow oil; C13H16O3 (220.26).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:19])[CH2:9][C:10]2[NH:14][C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([C:9]1[CH:25]=[CH:24][C:23](=[O:26])[N:14]2[C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[NH:11][C:10]=12)=[O:19]
Reactant: C#CC(=O)OC
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1cccc(Cl)c1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 559.9 mg (2.03 mmol) of 1-(3-Chlorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXIX), 220.2 mg (4.08 mmol) of sodium methylate and 171.3 mg (2.03 mmol) methyl propiolate.
Reaction SMILES: [NH:1]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][CH2:19][C:20](OC)=[O:21])=[O:17])[CH3:15])=[O:12])=[O:8])=[O:4].O.[NH2:32][NH2:33]>CO>[C:27]([O:26][C:24]([NH:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:32][NH2:33])=[O:21])=[O:17])[CH3:15])=[O:12])=[O:8])=[O:4])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Reactant: NN
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)NN

Procedure:
A solution of Boc-Gly-Gly-Gly-Ala-Gly-OMe (1.0 g, 2.32 mmole, described in Example 16) and hydrazine hydrate (1 ml, 23.2 mmole) in methanol (30 ml) is stirred at 0° C for 4 hr. After evaporation the residue is triturated with diethyl ether and dried to give the title compound, mp 221° - 223° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCCOC)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][C:15]4[CH2:31][CH2:30][CH2:29][CH2:28][C:16]=4[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.C(O)C>CCOCC>[O:27]=[C:19]1[C:18]2[C:13](=[CH:14][C:15]3[CH2:31][CH2:30][CH2:29][CH2:28][C:16]=3[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[NH:20]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)n2COCCOC)CCCC4)c1
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCCC4)c1
Yield: 48.3 %

Procedure:
Preparation of 1-(4-oxo-3,4,6,7,8,9-hexahydro-benzo[g]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester. HCl (4M in dioxane, 2.1 mL, 8.3 mmol) was added to a solution of 1-[3-(2-methoxy-ethoxymethyl)-4-oxo-3,4,6,7,8,9-hexahydro-benzo[g]quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.254 g, 0.596 mmol) and ethanol (2.0 mL). The reaction mixture was stirred at room temperature for 4 h, at which point ether (2 mL) was added and the precipitate was collected. The precipitate was triturated three times with ethanol, once with ethanol/THF (1:1), and once with DMSO. The filter cake was rinsed with ethanol and dried to yield the titled compound (89.4 mg, 44% yield). MS (ESI/Cl): mass calcd. for C18H18N4O3, 338.1; m/z found, 339.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 12.66 (s, 1H), 8.98 (s, 1H), 8.30 (s, 1H), 7.84 (s, 1H), 7.40 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 2.95-2.83 (m, 4H), 1.82-1.74 (m, 4H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[CH3:14][Si:15]([CH3:30])([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]1[CH2:23][O:22]1>C(O)C>[CH3:14][Si:15]([CH3:30])([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:22])[CH2:23][N:2]([CH3:1])[CH2:3][CH:4]([OH:5])[CH:6]([OH:7])[CH:8]([OH:9])[CH:10]([OH:11])[CH2:12][OH:13]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: CN(CC(O)COCCC[Si](C)(C)CC[Si](C)(C)C)CC(O)C(O)C(O)C(O)CO
Temperature: 70 °C

Procedure:
N-methyl-D-glucamine (1.42 g; 7.28 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20](O)=[O:21])=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:34][C:35]1([CH2:38][OH:39])[CH2:37][CH2:36]1.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[OH:39][CH2:38][C:35]1([NH:34][C:20]([C:19]2[C:13]3[C:14](=[N:15][CH:16]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=3)[NH:17][CH:18]=2)=[O:21])[CH2:37][CH2:36]1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Reactant: NC1(CO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(CO)CC5)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 8.1 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), EDCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) in 6 mL of DMF was added (1-aminocyclopropyl)methanol (59 mg, 0.68 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was 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: 25% acetonitrile/75% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(1-(hydroxymethyl)cyclopropyl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (10 mg, 8.1%) as a yellow solid. MS: (M+H)+=363; 1H NMR (300 MHz, DMSO): δ 13.36 (s, 1H), 12.81 (s, 1H), 9.16 (s, 1H), 8.75 (s, 1H), 8.40-8.38 (m, 2H), 7.43 (s, 1H), 7.16 (d, 1H, J=8.7 Hz), 4.89 (brs, 1H), 3.59 (brs, 2H), 2.54 (s, 3H), 0.92-0.83 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1.CCOC(C)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cncc(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To a solution of 3,5-dimethylpyridine (85 g, 0.8 mol) in CHCl3 (1500 mL) was added m-CPBA (180 g, 0.88 mol) in portions at 0° C. Then the mixture was stirred at room temperature for 18 hr. TLC (petroleum ether:EtOAc=1:1) showed the starting material was consumed almost. After diluting with CH2Cl2 (1200 mL), the solution was washed with Na2S2O3(aq.) (600 mL), NaHCO3(aq.) (600 mL) and brine (600 mL). The resulting material was dried over Na2SO4 and concentrated in vacuo to give crude material which was purified by chromatography on silica gel with EtOAc:CH2Cl2=4:1 to afford 3,5-dimethylpyridine 1-oxide (92 g, 93%) as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[CH3:21][C:22](=O)[CH2:23][C:24](=O)[CH3:25].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:21])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Solvent: CCO
Solvent: O
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1
Yield: 84 %

Procedure:
(4-Chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)amine (4.15 g, 14.3 mmol) and 2,4-pentanedione (2.0 mL, 19.1 mmol) in ethanol (100 mL) were heated to reflux for 20 min. Water was added and the white crystalline compound was collected by filtration, washed with water and dried to give (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-amine (4.25 g, 84%).
Reaction SMILES: Cl.[C:2]1([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][C:24](OC(C)=O)=[O:25]>ClCCl>[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:24](=[O:25])[CH3:23])[CH2:12][CH2:11]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of phenyl(piperidin-4-yl)methanone hydrochloride (743 mg, 3.29 mmol) in dichloromethane (13.2 mL) and triethylamine (1.10 mL, 7.90 mmol) was treated with Ac2O (0.373 mL, 3.95 mmol) dropwise over 1 minute in an ice bath under argon, and the resulting translucent mixture was immediately removed from the ice bath and stirred at room temperature overnight. The reaction was then extracted with 1 M aqueous HCl (1×8 mL) and 1 M aqueous NaOH (1×8 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the title compound as a translucent beige oil that crystallized upon standing.
Reaction SMILES: [C:1]1([C:7]([F:10])([F:9])[F:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>O>[N+:16]([C:3]1[CH:2]=[C:1]([C:7]([F:10])([F:9])[F:8])[CH:6]=[CH:5][CH:4]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 97.5 %

Procedure:
To a stirred mixture of benzotrifluoride (80.0 g, 0.55 m) and concentrated sulphuric acid (200 ml) was added fuming nitric acid (95% w/w; 29.3 ml, 44.0 g, 1.2 equivalents) over 30 minutes, maintaining the temperature of the stirred reaction mixture at between 20° and 30° by means of external cooling. After completion of the addition, stirring was continued at room temperature for a further hour and then the reaction mixture was poured onto a mixture of ice (1 kg) and water (100 ml). The resultant mixture was extracted with dichloromethane (2×250 ml) and the combined extracts washed with water (2×100 ml). The organic solution was then dried (over MgSO4) and evaporated under reduced pressure at 30° to give 3-nitrobenzotrifluoride (102 g, 94.0% w/w by GLC assay, 91% yield), as a pale-yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH2:41]([NH2:44])[CH:42]=[CH2:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:41]([NH:44][C:38]([C:35]1[CH:36]=[CH:37][N:33]([S:30]([C:28]2[CH:27]=[CH:26][C:17]3[N:18]([CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])=[N:15][C:16]=3[CH:29]=2)(=[O:32])=[O:31])[CH:34]=1)=[O:39])[CH:42]=[CH2:43]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Reactant: C=CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCNC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1

Procedure:
Following the same procedure in Example 33, step A, using DIPEA (0.1 mL, 74 mg, 0.57 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (0.078 mmol) (see the step B in example 33 for preparation), allylamine (0.1 mL, 76 mg, 1.33 mmol) and HATU (100 mg, 0.31 mmol) in DMF (5 mL). The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to 32 mg (85%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.57 (m, 4 H), 1.60 (s, 9 H), 2.20-2.41 (m, 1 H), 3.24-3.38 (m, 2 H), 3.84-3.97 (m, 4 H), 4.43 (d, J=7.42 Hz, 2 H), 5.03-5.10 (m, 1 H), 5.10-5.19 (m, 1 H), 5.75-5.94 (m, 1 H), 6.67 (dd, J=3.32, 1.76 Hz, 1 H), 7.30 (dd, J=3.42, 2.25 Hz, 1 H), 7.79-7.85 (m, 1 H), 7.93 (d, J=9.0 Hz, 1H), 7.970 (dd, dd=9.0, 1.8 Hz, 1 H), 8.27 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=484.7; Anal. Calcd for C25H32N4O4S+0.90 TFA+0.20H2O (590.85): C, 54.48; H, 5.68; N, 9.48. Found: C, 54.53; H, 5.69; N, 9.57.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16](Cl)=[O:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:19])[CH:11]=2)[CH:6]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>ClCCl>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:19])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:20])[C:14]=2[CH3:15])=[O:17])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)Cl)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of (4-chlorocarbonyl-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (294 mg, 1.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (279 mg, 1.5 mmol) in dichloromethane was added triethylamine (458 μL, 3.3 mmol). The resulting mixture was stirred at room temperature overnight, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 20-40% ethyl acetate in petroleum ether) to afford 4-(7-fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalene-1-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (410 mg, 92%) as a white solid.