Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([O:29]CC1C=CC=CC=1)=[CH:5][C:6]([C:13](=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:7]2.FC(F)(F)C(O)=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:29])[CH:5]=[C:6]([C:13](=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[NH:7]2
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)Nc1ccccc1C(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Reaction time: 24 h

Procedure:
Combine 5,7-dichloro-2-[2-(t-butoxycarbonylamino) benzoyl]-4-benzyloxyquinoline (4 mmol) and trifluoroacetic acid (55 mL) and heat to 80° C. After 4 hours evaporate the reaction mixture in vacuo to give a residue. Add dichloromethane and evaporate several times to completely remove residual trifluoroacetic acid. Dissolve the crude reaction mixture in dichloromethane (20 mL) and add di-t-butyl dicarbonate (4 mmol). Allow to stir for 24 hours. Evaporate in vacuo. Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[CH3:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][N:68]1[CH2:73][CH2:74][CH2:75][NH2:76]>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:76][CH2:75][CH2:74][CH2:73][N:68]5[CH2:69][CH2:70][CH2:71][CH2:72][CH:67]5[CH3:66])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1CCCCN1CCCN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCCN2CCCCC2C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 71.7 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.019 g (0.12 mmole) 3-(2-Methyl-piperidin-1-yl)-propylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.042 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-[3-(2-methyl-piperidin-1-yl)-propyl]-benzamide as a white solid.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:9]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1C(NCc2ccccc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(CNC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 77 (200 mg, 0.47 mmol) in EtOAc (10 mL) for 1 min, and the solution is stirred at RT overnight. The solvent is removed by rotary evaporation, and the residue is crystallized from dichloromethane and Et2O to give 130 mg of the product 78. 1H NMR (DMSO-d6) δ 9.80-8.30 (m, 3H), 7.60-7.30 (m, 5H), 7.20-7.00 (m, 6H), 7.00-6.85 (m, 4H), 5.49 (s, 2H), 4.59 (d, 2H); MS: m/z 328 (M++1).
Reaction SMILES: [BH4-].[Na+].[N:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=[O:18])=[CH:11][CH:10]=2)[CH:4]=1>C(O)C>[N:6]1[CH:7]=[CH:8][N:3]=[CH:4][C:5]=1[C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[CH:16][CH2:17][OH:18])=[CH:13][CH:14]=1
Reactant: O=C/C=C/c1ccc(-c2cnccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC=Cc1ccc(-c2cnccn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
Sodium borohydride (90 mg, 2.38 mmol) was added to a suspension of (2E)-3-[4-(3-pyrazinyl)phenyl]-2-propenal (400 mg, 1.90 mmol, prepared as described in Reference Example 18) in ethanol (5 mL) maintained in a room temperature water bath. After 20 min, the reaction was quenched with water (10 mL), allowed to stir for 10 min, and then concentrated to remove the ethanol. The solids were removed by filtration, washed with water, and dried in vacuo to provide 360 mg (89%) of the title compound. MS 213 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[CH3:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[CH:17]=[N+:18]([CH3:20])[CH3:19].COC1C=CC=CC=1C=O.CNC>>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH:17]([N:18]([CH3:19])[CH3:20])[C:16]1[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=1[O:14][CH3:13])[CH3:2]
Reactant: CCc1cccc2cc[nH]c12
Reactant: COc1ccccc1C=[N+](C)C
Agent: CNC
Agent: COc1ccccc1C=O
Agent: [Cl-]
Product: CCc1cccc2c(C(c3ccccc3OC)N(C)C)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethyl-1H-indole and (2-methoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-methoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26]C)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC[C@H]3C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of (R)-methyl 2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (95 mg, 0.26 mmol) in methanol (50 mL) was added sodium hydroxide (95 mg, 2.38 mmol) and water (2 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with HCl (3N), and filtered to give (R)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (29.2 mg, 32%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CC(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:18][CH2:17][CH2:16][CH2:15][Cl:14])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1CCN(CCCCCl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
In a 2 L three-necked round bottomed flask was added N-methyl-piperazine (100.16 g, 1.0 mol), acetone (1000 mL), and anhydrous potassium carbonate (276.42 g, 2.0 mol, 2.0 equiv.). The flask was equipped with a mechanical stirrer and a condenser. 4-chloro-1-bromo-butane (188.6 g, 1.1 mol, 1.1 equiv.) was added dropwise under continuous stirring at room temperature over a period of 30 min. The suspension mixture was then stirred at 40° C. The progress of the reaction was monitored by TLC, which confirmed the reaction was completed after 4 hours. The mixture was cooled to room temperature and the insoluble materials were removed by filtration and washed with dichloromethane (2×100 mL). The combined filtrates were concentrated under vacuum until they became dry. The residue was then mixed with dichloromethane (500 mL). Insoluble materials were removed by filtration and washed by dichloromethane (2×100 mL). The combined filtrate and washings were concentrated and purified through a flash silica gel column, which gave the expected product as light yellow oil. (92.5 g, 48.5% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.C(O)(=O)C.[C-:14]#[N:15].[K+]>CS(C)=O>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:14]#[N:15]
Reactant: [C-]#N
Reactant: OCc1ccccc1O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: N#CCc1ccccc1O
Temperature: 125 °C
Reaction time: 2 h

Procedure:
29.8g of 2-hydroxybenzyl alcohol are dissolved in 250 ml of dimethylsulfoxide, together with 18g of potassium cyanide, and the mixture is heated to 125°C. 16g of glacial acetic acid are then added dropwise over the course of 1 hour and the mixture is stirred for a further 2 hours at 125°C. The dimethylsulfoxide is removed in vacuo and the residue is stirred with 200 ml of water and 150 ml of chloroform. The chloroform phase is separated off and the aqueous phase is re-extracted with 150 ml of chloroform. The combined chloroform phases are extracted by shaking with water and dried with sodium sulfate. After distilling off the chloroform, an oil remains, which solidifies on cooling. Yield: 19.8g = 60.5% of theory. Recrystallization from benzene/ligroin: melting point 118°C.
Reaction SMILES: ClC1C=C(C#N)C2C=[CH:7][N:8]([C:11]3[N:12]([CH2:22][CH3:23])[C:13](=[O:21])[NH:14][C:15](=[O:20])[C:16]=3[CH:17]([CH3:19])[CH3:18])[C:9]=2[CH:10]=1.[NH:26]1C=CN=C1>>[CH2:22]([N:12]1[C:11]([N:8]2[CH:9]=[CH:10][N:26]=[CH:7]2)=[C:16]([CH:17]([CH3:18])[CH3:19])[C:15](=[O:20])[NH:14][C:13]1=[O:21])[CH3:23]
Reactant: CCn1c(-n2ccc3c(C#N)cc(Cl)cc32)c(C(C)C)c(=O)[nH]c1=O
Reactant: c1c[nH]cn1
Product: CCn1c(-n2ccnc2)c(C(C)C)c(=O)[nH]c1=O

Procedure:
This compound was made by a procedure similar to that used to prepare 6-chloro-1-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-1H-indole-4-carbonitrile (90), except that imidazole was used instead of 6-chloro-1H-indole-4-carbonitrile. LC-MS shows 249.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 9.03 (br, 1H), 7.60 (m, 1H), 7.32 (m, 1H), 7.00 (m, 1H), 3.40 (m, 2H), 2.08 (m, 1H), 1.19 (m, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=3[F:20])[C:5]2=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)(=[O:29])=[O:28]>CN(C=O)C>[F:20][C:12]1[C:13]([F:19])=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[C:10]1[C:5]2[C:6](=[N:7][C:2]([NH:36][CH:33]3[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]3)=[N:3][CH:4]=2)[NH:8][N:9]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1ccc(F)c(F)c1-c1n[nH]c2nc(Cl)ncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)c(F)c1-c1n[nH]c2nc(NC3CCN(S(C)(=O)=O)CC3)ncc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 6-chloro-3-(2,3-difluoro-6-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 3, 148 mg, 0.50 mmol) in DMF (2.5 mL), sodium bicarbonate (100 mg) and 1-methanesulfonyl-piperidin-4-ylamine, 125 mg, 0.70 mmol) were added and the mixture was stirred at 100° C. for 4 hours. The solvent was removed under reduced pressure and the residue was treated with water. The solid was filtered and dried. Recrystallization from 2% MeOH/CH2Cl2 gave 92 mg off-white solid. 42%. MS (M+H)+, 439.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[OH:13][C@@H:14]([CH3:28])[CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCCCCC>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:16][CH2:15][C@@H:14]([OH:13])[CH3:28])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@H](C)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)Cc1cccc(OCC[C@H](C)O)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester (0.93 g, 0.0056 mole) and toluene-4-sulfonic acid-(S)-3-hydroxy-butyl ester (1.5 g, 0.0061 mole) in anhydrous DMF (10 mL) was added Cs2CO3 (2.0 g, 0.006 mole). The reaction was heated to 100° C. and stirred for 4 hours. The mixture was cooled to RT and filtered. The filtrate was poured into H2O (50 mL) and extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography over silica gel (silica gel 60, EM Science) using 30% EtOAc:hexane as eluent to afford 0.59 g (44% yield) of the title compound as an oil: MS (ESI) 239.0 (M+H+).
Reaction SMILES: C1(C[O:8][C:9](=[O:67])[C@@H:10]([CH3:66])[NH:11][C:12](=[O:65])[C@@H:13]([CH2:40][CH2:41][CH2:42][CH:43]([C:55]([O:57]CC2C=CC=CC=2)=[O:56])[NH:44]C(OCC2C=CC=CC=2)=O)[NH:14][C:15]([O:17][CH:18]([CH3:39])[CH:19]([NH:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:20](=[O:29])[O:21]CC2C=CC=CC=2)=[O:16])C=CC=CC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[C:55]([CH:43]([NH2:44])[CH2:42][CH2:41][CH2:40][C@H:13]([C:12]([NH:11][C@@H:10]([C:9]([OH:67])=[O:8])[CH3:66])=[O:65])[NH:14][C:15]([O:17][CH:18]([CH3:39])[CH:19]([C:20]([OH:29])=[O:21])[NH:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:16])([OH:57])=[O:56]
Reactant: CCCCCCC(=O)NC(C(=O)OCc1ccccc1)C(C)OC(=O)N[C@H](CCCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCC(=O)NC(C(=O)O)C(C)OC(=O)N[C@H](CCCC(N)C(=O)O)C(=O)N[C@H](C)C(=O)O
Reaction time: 5.5 h

Procedure:
A solution of 1a-1 (140 mg, 0.15 mmol) in EtOAc/EtOH (5 mL:15 mL) is hydrogenated over Pd(OH)2 (Pearlman's catalyst, 20% on C, 100 mg) using a Parr apparatus at an initial pressure of 70 psi. After 5.5 h, filtration and evaporation gives a colorless glass. The latter is triturated with ether and the sides of the flask are scraped to provide a white crystalline powder. The ether solution is removed with a syringe and the solid is washed with two more portions of ether, dried, and characterized as 1a-11: NMR (CH3OD) δ 0.89 (m, 3 H), 1.22 (d, J=6.5, 3 H), 1.24-1.39 (m, 6 H), 1.42 (d, J=7.3, 3 H), 1.45-1.99 (m, 8 H), 2.26 (t, J≃7.5, 2 H), 3.62 (m, 1 H), 4.06 (m, 1 H), 4.41 (m, 1 H), 4.89 (br s for OH, NH; one hidden CH signal), 5.14 (m, 1 H); MS (HR-FAB) m/z 519.2671 (M+H calcd. for C22H39N4O10, 519.2666).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.Cl.[CH3:18][NH:19][NH:20][CH3:21].[OH-].[Na+]>O1CCOCC1.O>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:19]([CH3:18])[NH:20][CH3:21])[N:3]=1)[CH2:14][CH3:15]
Reactant: CNNC
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCNc1nc(NCCC)nc(N(C)NC)n1
Temperature: 60 °C
Yield: 42.4 %

Procedure:
A mixture of 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (2.50 g, 10.88 mmol), N,N′-dimethyl-hydrazine dihydrochloride (2.89 g, 21.76 mmol) and NaOH (2.18 g, 54.40 mmol) in 1,4-dioxane (40 mL) and water (20 mL) was heated at 60° C. for 18 h. The volatiles were removed under reduced pressure. Saturated NaHCO3 solution (100 mL) was added to the residue, the mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (75 mL), brine (75 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution (CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5)) to yield N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N,N′-dimethyl-hydrazine (1.17 g, 42%). 200 MHz 1H NMR (DMSO-d6, ppm): 6.81-6.44 (2H, m), 5.31 (1H, br s), 3.24-3.08 (4H, m), 3.05 (3H, s), 2.47-2.40 (3H, m), 1.57-1.37 (4H, m), 0.84 (6H, t, J=7.4 Hz). ESI-MS (m/z): 254 [M+H]+.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.Cl.[NH2:49][C:50]1[N:51]=[C:52]([CH2:55][C:56]2[S:60][C:59]([C:61](=[O:63])[CH3:62])=[CH:58][CH:57]=2)[S:53][CH:54]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:61]([C:59]1[S:60][C:56]([CH2:55][C:52]2[S:53][CH:54]=[C:50]([NH:49][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[N:51]=2)=[CH:57][CH:58]=1)(=[O:63])[CH3:62]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(=O)c1ccc(Cc2nc(N)cs2)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(Cc2nc(NC(=O)c3ncoc3-c3ccccc3)cs2)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-phenyl-1,3-oxazole-4-carboxylic acid (40 mg, 0.21 mmol) in CH2Cl2 (2.0 mL) was treated sequentially with DMAP (6 mg, 0.05 mmol), HOBt (34 mg, 0.25 mmol), EDC.HCl (101 mg, 0.53 mmol) and DIPEA (0.14 mL, 0.85 mmol) and the resulting mixture was stirred at rt for 15 min. This solution was then added to a solution of 1-[5-(4-amino-thiazol-2-ylmethyl)-thiophen-2-yl]-ethanone hydrochloride (58 mg, 0.21 mmol) in dry CH2Cl2 (0.5 mL) and the reaction mixture was stirred for 2 days at rt. CH2Cl2 (20 mL) was then added and the org. phase was washed with brine (15 mL). The org. phase was then dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept:EA) followed by HPLC gave the title compound as a yellow solid. LC-MS-conditions 05: tR=0.98 min, [M+H]+=410.16.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:17]([O:21][C:22]([N:24]([CH2:26][CH2:27][C:28](O)=[O:29])[CH3:25])=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl.N1C=CC=C(CC(O)=O)C=1>>[C:17]([O:21][C:22]([N:24]([CH2:26][CH2:27][C:28]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:29])[CH3:25])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)Cc1cccnc1
Product: CN(CCC(=O)Nc1ncn(Cc2ccccc2)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 72 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 17, using 1.92 g (8.96 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide which was prepared in the same manner as in Reference Example 2 and 3-(N-t-butyloxycarbonyl-N-methylamino)propionic acid, instead of 3-pyridylacetic acid hydrochloride, to obtain 2.56 g of 4-(3-(N-t-butyloxycarbonyl-N-methylamino)propanoylamino)-1-benzyl-5-imidazole carboxamide (yield 72%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([O:20]C)=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[Li+].[OH-]>O.C1COCC1>[Br:1][C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([OH:20])=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: COC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1nc2n(c1C(=O)O)CCOc1cc(F)c(Br)cc1-2
Yield: 81.6 %

Procedure:
10-Bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (2 g) was subjected similar to as described in Example 6 to yield 1.22 g of methyl 10-bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate. 75 mg of methyl 10-bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate was treated with LiOH in water/THF to afford 59 mg 10-bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid. This intermediate was reacted with N-Methylamine Hydrochloride similar to as described in Example 2 to produce crude 10-bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide which was then reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 8.6 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 387 (M)+. 1H NMR (400 MHz, DMSO) δ 11.09 (q, J=4.6 Hz, 1H), 8.61 (d, J=8.5 Hz, 1H), 8.38 (s, 1H), 7.88 (s, 1H), 7.02 (d, J=10.6 Hz, 1H), 5.50 (s, 1H), 5.05-4.94 (m, 2H), 4.58-4.47 (m, 2H), 2.80 (d, J=4.6 Hz, 3H), 1.49 (s, 6H).
Reaction SMILES: [CH2:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].C([Li])CCC.CN([CH:17]=[O:18])C>CCOCC>[CH2:1]([C:4]1[O:5][C:6]([CH:17]=[O:18])=[CH:7][CH:8]=1)[CH2:2][CH3:3]
Reactant: CN(C)C=O
Reactant: CCCc1ccco1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCc1ccc(C=O)o1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a solution of 13.04 g (0.118 mol) of 2-propylfuran in 800 mL of ether cooled at 0° C. with stirring under nitrogen was added dropwise 52 mL (0.130 mol) of 2.5M n-butyllithium. The reaction mixture was allowed to warm to room temperature and then refluxed for 40 min. The reaction mixture was cooled to -60° C., 10.1 mL (0.130 mol) of DMF in 10 mL of ether was added, and the resulting mixture was stirred at -60° C. for 45 min, and warmed to room temperature. The above mixture was quenched with 10 mL of saturated aqueous ammonium chloride, diluted with water to form a clear aqueous layer, and the organic layer was washed with water, and brine. The organic layer was dried over anhydrous magnesium sulfate, treated with a small amount of a charcoal, filtered, and concentrated to yield 13.95 g of a crude oil. The kughelrohr distillation of this oil (75°-105° C.) afforded 10.5 g (64.5%) of 5-propyl-2-furancarboxaldehyde.