Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C(N(CC)CC)C.[CH:39](=O)[CH2:40][CH3:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH2:39][CH2:40][CH3:41])[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: CCC=O
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCN1CC(CC#N)(n2cc(-c3nc(-c4cnn(C)c4)cc4nccn34)cn2)C1
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
In a 2 mL flask, 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 15 mg, 0.035 mmol) was suspended in acetonitrile (350 μL, 0.035 mmol). To this was added triethylamine (19 μL, 0.14 mmol), followed by propionaldehyde (25 μL, 0.35 mmol). After stirring for 30 minutes, NaBH(OAc)3 (37 mg, 0.17 mmol) was added. After the reaction was complete, it was quenched with saturated bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC using a 0-100% acetonitrile/water gradient to afford 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo-[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-propylazetidin-3-yl)acetonitrile (7.1 mg, 51% yield) as a white solid. MS (apci) m/z=402.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([OH:19])=[O:18])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:9]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[C:17]([OH:19])=[O:18])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[C@@H:11]12[C:9](=[O:10])[O:19][C:17](=[O:18])[C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16]2
Reactant: O=C(c1cc(F)cc(F)c1)[C@H]1CCCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H]1CCCC[C@H]1C(=O)c1cc(F)cc(F)c1
Product: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Cis-2-(3,5-difluorophenylcarbonyl)cyclohexanecarboxylic acid was dissolved in 10% NaOH (250 mL) and the solution was stirred at 20° C. for 16 h. The aqueous solution was extracted with diethyl ether (100 mL), and then acidified with IM hydrochloric acid. The resulting precipitate was collected, and recrystallized from CH2Cl2/hexanes, to give (1S,2R)-2-(3,5-difluorophenyl-carbonyl)cyclohexanecarboxylic acid as a white solid (4 g, 30% from cis-1,2-cyclohexanedicarboxylic anhydride).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]3[N:9]([C:13]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[N:25]=4)=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=4)[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([NH:6][C:7]2[C:8]3[N:9]([C:13]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[N:25]=4)=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=4)[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.4 %

Procedure:
To a solution of N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)imidazo[1,2-α]pyridin-8-amine (0.4 g, 0.9 mmol) in dichloromethane (10 mL) at −78° C. was added boron tribromide (2.6 mL, 1.0 M in dichloromethane, 2.6 mmol) dropwise. The resulting solution was allowed to warm to room temperature. After stirring for 15 hours at room temperature, the mixture was cooled to 0° C. and quenched by the addition of water and aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to give a solid residue which was purified by silica gel chromatography (95:5 chloroform-methanol) to give 4-{8-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-α]pyridin-2-yl}phenol as a solid (280 mg, 70%). 1H NMR (DMSO-d6): δ 9.63 (s, 1H), 8.86 (broad s, 1H), 8.07 (d, 1H), 7.37 (d, 2H), 7.30 (d, 1H), 6.80 (m, 3H), 6.30 (m, 2H), 5.60 (d, 1H), 4.19 (m, 1H), 3.89 (m, 1H), 1.9–2.1 (m, 4H), 1.4–1.9 (m, 12H); MS m/z 455 (M+1).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[C:1]([NH:3][C:4]([NH:22][CH2:21][CH2:20][O:19][CH3:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: COCCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Product: COCCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
N-Cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (4.05 g) was dissolved in 2-methoxyethylamine (15 ml) and heated under reflux for 6 hours. Evaporation of the solvent and chromatographic purification of the residue on a column of silica gel with elution by chloroform and then with chloroform/methanol (20:1) yielded the title compound as a pale yellow oil (2.7 g).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[C:16]([CH2:20][C:21](Cl)=[O:22])([CH3:19])([CH3:18])[CH3:17].[F:24][C:25]([F:36])([F:35])[CH2:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:20][C:21]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:34]([C:31]3[CH:32]=[N:33][C:28]([O:27][CH2:26][C:25]([F:36])([F:24])[F:35])=[CH:29][CH:30]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)=[O:22]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Nc1ccc(OCC(F)(F)F)nc1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCC2(CC1)CCN(c1ccc(OCC(F)(F)F)nc1)C2=O

Procedure:
Brown crystalline solid. MS (ESI): 428.4 (MH+). This example was prepared in analogy to example 7 step A) to B) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), tert-butyl acetyl chloride and 6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:14]1[C:13]([CH3:12])=[CH:17][N:16]=[CH:15]1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1F
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1-n1cncc1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 1 %

Procedure:
To a DMF (50 mL) solution of 4-fluoro-3-methoxybenzaldehyde (3.00 g) and 4-methylimidazole (3.307 g), potassium carbonate (4.05 g) was added and the reaction mixture was agitated at 100° C. overnight. The obtained reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:hexane-ethyl acetate system), and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (856 mg) and 3-methoxy-4-(5-methyl-1H-imidazol-1-yl)benzaldehyde (44 mg) were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:24])=[C:4]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8](Cl)[CH3:9])[CH:7]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.CCOCC>[N:25]([CH:8]([C:6]1[C:5]([O:11][CH3:12])=[C:4]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:3]([F:24])=[C:2]([Cl:1])[CH:7]=1)[CH3:9])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1c(C(C)Cl)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1c(C(C)N=[N+]=[N-])cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate (0.070 g, 0.18 mmol) and sodium azide (0.036 g, 0.56 mmol) in DMF (0.66 mL) was stirred at room temperature overnight. After diluting with ether, the mixture was washed with water, dried over MgSO4 and concentrated to give the crude azide which was used in the next step without further purification. LCMS calculated for C17H22ClFN4O3Na (M+Na)+: m/z=407.1. found: 407.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][S:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)([C:14]([NH:16][OH:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:31]O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][S:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)=[O:31])([C:14]([NH:16][OH:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCOc1ccc(SCC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: OO
Solvent: CO
Product: CC#CCOc1ccc(S(=O)CC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a slurry of tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl}methyl)-4-[(hydroxyamino) carbonyl]-1-piperidinecarboxylate (0.24 g, 0.55 mmol) at 0° C. in 7 mL of MeOH was added dropwise 3.5 mL of 30% hydrogen peroxide. The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was cooled to 0° C. and quenched with 3.5 mL of a saturated solution of Na2SO3. The organaics were removed and the aqueous solution was extracted with CH2Cl2. The organics were washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether to provide 0.166 g (67%) of the desired product as an off white solid. Electrospray Mass Spec: 451.3 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].CN(C)C=O.Cl.CN(C)CCCN=C=NCC.[Br:36][C:37]1[CH:38]=[C:39]([NH2:44])[C:40]([NH2:43])=[CH:41][CH:42]=1>C(OCC)(=O)C.N1C=CC=CC=1>[Br:36][C:37]1[CH:42]=[CH:41][C:40]2[NH:43][C:15]([CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)=[N:44][C:39]=2[CH:38]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3cc(Br)ccc3[nH]2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.8 %

Procedure:
In a round-bottomed flask, 1.3 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate are introduced into 10 ml of dimethylformamide and then 10 ml of pyridine, 1.44 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 1.87 g of 4-bromobenzene-1,2-diamine are added. The reaction mixture is stirred at ambient temperature overnight and is then concentrated to dryness under reduced pressure. The residue is taken up in 40 ml of acetic acid and brought to reflux for 4 hours, then concentrated under reduced pressure. 100 ml of water are then added and a saturated aqueous solution of sodium bicarbonate is added until a pH in the region of 7 is obtained. 200 ml of ethyl acetate are then added and the resulting mixture is stirred for 1 hour. The precipitate formed is filtered then purified by silica gel column chromatography, elution being carried out with a gradient of the eluent CH2Cl2/MeOH: 80/20 in dichloromethane of 0% to 100% in 25 minutes. 560 mg of 2-[(5-bromo-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[O:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>CS(C)=O>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([NH:35][CH:32]5[CH2:33][CH2:34][O:29][CH2:30][CH2:31]5)[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(F)n1
Reactant: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(NC2CCOCC2)n1
Temperature: 160 °C
Yield: 46.7 %

Procedure:
6-Fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (100 mg, 0.27 mmol) and tetrahydro-2H-pyran-4-amine (55 mg, 0.54 mmol) were dissolved in DMSO (1.5 ml) in a microwave vial. DIPEA (0.282 ml) was added and the mixture was heated at 160° C. for 3 h under microwave irradiation. The reaction mixture was concentrated under a stream of nitrogen and redissolved in methanol. This solution was loaded onto a 2 g aminopropyl column, which was been preconditioned with methanol. The column was eluted with methanol (2 column volumes) and the desired fraction was blown to dryness under nitrogen. The sample was then purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound (57 mg) as a white solid.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH:16]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[C@H:17]([C:25]([NH:27][C@H:28]([C:33](O)=[O:34])[C@H:29]([CH2:31][CH3:32])[CH3:30])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23].[NH2:53][C@H:54]([C:58]([NH:60][C@H:61]([C:69]([NH:71][C@H:72]([C:77]([O:79][CH2:80][C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=1)=[O:78])[C@H:73]([CH2:75][CH3:76])[CH3:74])=[O:70])[CH2:62][CH2:63][CH2:64][NH:65][C:66](=[NH:68])[NH2:67])=[O:59])[CH:55]([CH3:57])[CH3:56].C1C=C2C(N(O)N=NC2=CC=1)=O>CN(C)C=O>[NH:16]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[C@H:17]([C:25]([NH:27][C@H:28]([C:33]([NH:53][C@H:54]([C:58]([NH:60][C@H:61]([C:69]([NH:71][C@H:72]([C:77]([O:79][CH2:80][C:81]1[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=1)=[O:78])[C@H:73]([CH2:75][CH3:76])[CH3:74])=[O:70])[CH2:62][CH2:63][CH2:64][NH:65][C:66](=[NH:67])[NH2:68])=[O:59])[CH:55]([CH3:57])[CH3:56])=[O:34])[C@H:29]([CH2:31][CH3:32])[CH3:30])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)C(C)C)C(=O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)CC)C(C)C

Procedure:
3.3 g of DCC are added, at 0° C., to a stirred solution of 7.4 g (15 mmol) of Fmoc-Arg-Ile-OH, 7.15 g of H-Val-Arg-Ile-OBzl and 2.44 g of HOObt in 150 ml of dimethylformamide. The working-up is carried out in analogy to Example 2b. The dried residue is triturated with ethyl acetate, filtered off with suction and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([NH:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=3)[S:17][C:13]=2[C:12]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][O:36][CH2:37][CH2:38][NH:39][CH3:40]>>[CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([NH:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:39]([CH2:38][CH2:37][O:36][CH3:35])[CH3:40])=[CH:22][CH:21]=3)[S:17][C:13]=2[C:12]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc2c(OCc3ccccc3)ccc(N3CCOCC3)c2s1)c1ccc(CCl)cc1
Reactant: CNCCOC
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OCc4ccccc4)ccc(N4CCOCC4)c3s2)cc1

Procedure:
Using N-(4-benzyloxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-chloromethyl-benzamide and (2-methoxy-ethyl)-methyl-amine the title compound was prepared using the general procedure C as white solid (69%), MS: m/e=547 (M+H+).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:28])=[CH:20][N:21]=[C:22]([Cl:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C(OC([NH:36]C1CCNC1)=O)(C)(C)C.C(OC(N([C@H]1CCNC1)C)=O)(C)(C)C>>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:28])=[CH:20][N:21]=[C:22]([NH2:36])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Product: Cl
Product: Nc1ncc(Br)c2c(S(=O)(=O)N3CCC(N)C3)cccc12

Procedure:
(R/S)-3-(tert-Butoxycarbonylamino)-1-(1-chloro-4-bromo-5-isoquinolinesulfonyl)pyrrolidine can be prepared by using 3-(tert-butoxycarbonylamino)pyrrolidine in the method of Example 35-1, Step A instead of (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, and then the protective group of the obtained compound can be removed according to the method described in Example 39-1, Step B to obtain the title compound as hydrochloride.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:64]2[CH2:63][CH2:62][CH:61]([NH:60][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=3[Br:53])[CH2:66][CH2:65]2)=[O:12])=[CH:5][CH:6]=1
Reactant: Brc1ccccc1NC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC(=O)N1CCC(Nc2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.071 g, 0.00028 mole) in DMF (2 mL) was added DIPEA (0.089 g, 0.0007 mole), HOBt (0.046 g, 0.00034 mole) and EDCI.HCl (0.065 g, 0.00034 mole). After 2 minutes (2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride (0.082 g, 0.00028 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, brine and concentrated. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (70% ethyl acetate in hexane) to afford 0.025 g (17%) of N-biphenyl-4-yl-3-[4-(2-bromo-phenylamino)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 492 (M+1)+, 92.2%, 1H NMR (CDCl3): δ 10.0 (s, 1H), 7.66 (d, 2H), 7.58 (m, 4H), 7.44 (t, 3H), 7.34 (t, 1H), 7.18 (t, 1H), 6.68 (d, 1H), 6.6 (t, 1H), 4.45 (d, 1H), 4.0 (d, 1H), 3.65 (bs, 1H), 3.5 (s, 2H), 3.35 (t, 1H), 3.1 (t, 1H), 2.2 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]1=[O:16]
Reactant: COCCn1cc(-c2ccccc2)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: COCCn1cc(-c2ccccc2)n(C(=O)c2ccccc2)c1=O

Procedure:
Approximately 21.8 g. of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one, 14.5 g. of benzoyl chloride and 20 g. of tri-n-butylamine are refluxed together in 60 ml of xylene for sixteen hours. The solvent is distilled off under reduced pressure and the remaining visous oil is dissolved in 300 ml. of benzene. The benzene solution is washed with water (2×100 ml.), dried over sodium sulfate, and the solvent removed to give a semisolid. Recrystallization from ether gives the title compound as a pale yellow solid; m.p. 114°-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([C:16]#N)[C:10]1=[O:18].ClC1C=C(F)C=CC=1N1C=CC(C)=C(C#N)C1=[O:36].S(=O)(=O)(O)O.[OH-:42].[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([C:16]([OH:36])=[O:42])[C:10]1=[O:18]
Reactant: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1Cl
Reactant: Cc1ccn(-c2ccc(F)cc2Cl)c(=O)c1C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1Cl
Temperature: 100 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
To a mixture of 1-(2-chloro-4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile, 1-(2-chloro-4-fluorophenyl)-4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (0.75 g, 3.80 mmol) and water (5 mL) was added conc. sulfuric acid (5 mL) at 0° C., and the mixture was stirred at 100° C. for 18 hr. After cooling to 0° C., the mixture was basified (pH 11) with 8N aqueous sodium hydroxide solution and washed with ethyl acetate. The aqueous layer was acidified (pH 4) with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diethyl ether and collected by filtration to give the title compound (588 mg, 55%) as a white solid.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.Cl.N1C=CC=CC=1.[C:18]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[N:29]=[CH:28][C:27]=1[NH2:36])(=[O:20])[CH3:19]>C1(C)C=CC=CC=1.ClCCl>[C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]1[C:26]2[C:35]3[N:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:29]=[CH:28][C:27]=2[N:36]=[CH:1]1)(=[O:20])[CH3:19]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)OCCCNc1c(N)cnc2cccnc12
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCCCn1cnc2cnc3cccnc3c21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.2 %

Procedure:
Triethyl orthoformate (1.86 mL, 17.0 mmol) and pyridine hydrochloride (0.164 g, 1.42 mrnmol) were added to a stirred suspension of 3-[(3-amino[1,5]naphthyridin-4-yl)amino]propyl acetate (prepared as described in Part C of Examples 127-135, 3.70 g, 14.2 mmol) in toluene (70 mL). The mixture was heated at reflux with a Dean-Stark trap. After 2.5 hours, additional triethyl orthoformate (1 mL) was added and heating was continued for another 2 hours. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure to afford a dark oil that was dissolved in dichloromethane (100 mL). The solution was washed with saturated aqueous sodium bicarbonate (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 3.50 g of 3-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propyl acetate as an orange oil that was used without further purification in the next step.