Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8](C)([CH2:47][CH2:48][CH3:49])[NH:7][C:6]=1O)=[O:4].[C:52](OCC)(=[O:54])C>C1COCC1.O=[Mn]=O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:28]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:47][CH2:48][CH3:49])=[N:7][C:6]=1[CH:52]=[O:54])=[O:4]
Reactant: CCCC1(C)NC(O)=C(C(=O)OC)N1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCCc1nc(C=O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
A suspension of 10.00 g (14.82 mmole) of 5-methoxycarbonyl-4-hydroxy-methyl-2-propyl-1-[(2'-(N-trityltetrazol-5-yl)biphen-4-yl)methyl]imidazole (Example 101, Part A) in 200 mL THF was added to a stirring slurry of 12.88 g (148.2 mmole) of MnO2 at room temperature. The mixture was stirred at room temperature for 2 days. 3.22 g (37.0 mmole) of additional MnO2 was added to the mixture and stirred at room temperature for 5 hours after which TLC (ethyl acetate) showed no starting material. The product was filtered through Celite™, and the cake was washed with ethyl acetate and methylene chloride; the filtrate was evaporated under reduced pressure to give 8.10 g (81%) of the title compound as a light-yellow-colored solid. 1H NMR (300 MHz, CDCl3): δ0.89 (t, J=7.3 Hz, 3H); 1.74 (m, 2H); 2.58 (t, J=7.7 Hz, 2H); 3.81 (s 3H); 5.49 (s, 2H); 6.74-7.92 (m, 23H); 10.38 (s, 1H). MS (NH3 --DCI): m/z 673 (M+H, 10%); 617 (M+H-N4, 100%); 243 (Tr, 20%). Calculated mass for C42H37N6O3 (M+H): 673.292714; found: 673.292470.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([CH:14]=1)[CH:12]=[O:13].P([O-])(O)(O)=[O:34].[Na+].Cl[O-].[Na+].OO>C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([CH:14]=1)[C:12]([OH:34])=[O:13]
Reactant: O=P([O-])(O)O
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C=O)c2)c(OC)c(OC)c1OC
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC#N
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Yield: 89.8 %

Procedure:
To a solution of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (5.60 g, 0.0128 mol) in acetonitrile (30.0 ml) were added an aqueous solution (10.0 ml) of sodium dihydrogen phosphate (12.0 g, 0.100 mol), an aqueous solution (30.0 ml) of sodium hypochlorite (5.19 g, 0.0577 mol) and an aqueous hydrogen peroxide (1.701 ml, 30%) and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrosulfite (Na2S2O4) and a saturated saline, dried and concentrated to give the title compound (5.20 g, 0.0115 mol, 90%).
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1>ClCCl>[CH:37]1([C:40]([N:34]2[CH2:35][CH2:36][N:31]([C:30]3[C:2]([F:1])=[CH:3][C:4]4[N:8]=[C:7]([CH2:9][O:10][C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[N:6]([CH2:17][C:18]5[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=5)[C:5]=4[CH:29]=3)[CH2:32][CH2:33]2)=[O:41])[CH2:39][CH2:38]1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: O=C(C1CC1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.019 ml cyclopropanecarbonyl chloride (0.2 mmol). After 2 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 89 mg yellow solid (98%). MS (ISP) 569.4 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][CH2:17][CH:16]([O:19][CH3:20])[O:15][CH3:14])=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(OC2CCCC2)cc1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CNc1ccc(OC2CCCC2)cc1)OC
Temperature: 100 °C

Procedure:
A suspension of 4-cyclopentyloxyphenylamine (8.86 g), bromo-acetaldehyde dimethyl acetal (12.2 g), potassium carbonate (13.8 g) and dimethylformamide (100 ml) was heated at 100° C. for 5 hours. Cooling was followed by filtration and concentration of the filtrate. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 4:1). The product with the molecular weight of 265.36 (C15H23NO3); MS (ESI): 266 ([M+H]+), was obtained in this way.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[N:32][CH:33]=4)=[C:14]([CH2:16][O:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[NH:36]1[C:34]([C:31]2[N:32]=[CH:33][C:28]([C:13]3[N:9]4[N:10]=[CH:11][CH:12]=[C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:8]4=[N:15][C:14]=3[CH2:16][O:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:29][CH:30]=2)=[N:35][N:38]=[N:37]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(-c2c(COc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccc2nc(OCc3nc4c(N5CCOCC5)ccnn4c3-c3ccc(-c4nnn[nH]4)nc3)ccc2c1

Procedure:
A solution of compound 83c (200 mg, 0.430 mmol), sodium azide (85 mg, 1.31 mmol) and triethylamine hydrochloride (300 mg, 2.17 mmol) in N,N-dimethylformamide (3 mL) was stirred for 2 h at 110° C. The reaction was quenched by the addition of 10 mL of water. The solids were collected by filtration. The crude product was purified by flash column chromatography on silica gel (methanol/DCM, 1:200-1:10) to afford title compound 33 as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.13 (s, 1H), 8.52-8.50 (m, 1H), 8.38-8.36 (m, 1H), 8.26-8.22 (m, 2H), 7.88 (d, J=7.6 Hz, 1H), 7.64-7.59 (m, 2H), 7.43-7.39 (m, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.49-6.48 (m, 1H), 5.68 (s, 2H), 4.05-3.98 (m, 4H), 3.85-3.75 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C26H22N10O2: 507.2 (M+H). Found: 507.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[S:23][C:24]=1[C@H:25](O)[CH3:26].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C@H:25]([C:24]3[S:23][C:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=4)=[N:21][C:20]=3[CH3:19])[CH3:26])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@@H](C)O
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@H](C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with (R)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol [ee=79%; PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to obtain (S)-(6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless liquid. The configuration was tentatively assigned as S according to R. Cadilla et al., PCT Int. Appl. (2002), WO 02/062774 A1 and the generally accepted SN2-type mechanism of the Mitsunobu reaction.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:6]1[O:8][CH2:7]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:7][CH:6]([OH:8])[CH2:5][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: NCCO
Reactant: CCCCCCC(O)CCCCCCCCCCCOCC1CO1
Solvent: CCO
Product: CCCCCCC(O)CCCCCCCCCCCOCC(O)CNCCO
Temperature: 80 °C
Yield: 76.3 %

Procedure:
A 200-ml flask equipped with a stirrer, reflux condenser and dropping funnel was charged with 35.0 g (0.57 mol) of ethanolamine and 35 g of ethanol, and the mixture was heated to 80° C. with stirring in a nitrogen atmosphere. To this mixture, 13.0 g (38 mmol) of 12-hydroxyoctadecyl glycidyl ether were added dropwise over 3 hours. After the resultant mixture was stirred further for 3 hours, it was concentrated under reduced pressure and purified by column chromatography on silica gel, thereby obtaining 11.7 g (yield: 77%) of the title compound (Ia-1).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][S:5]([Cl:8])(=[O:7])=[O:6].Cl.Cl.[CH2:16]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:8].[CH2:16]([N:25]1[CH2:30][CH2:29][N:28]([S:5]([CH2:4][C:3]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:2]=2[F:1])(=[O:7])=[O:6])[CH2:27][CH2:26]1)[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: O=S(=O)(Cl)Cc1ccc(F)cc1F
Reactant: O=C(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCN(S(=O)(=O)Cc2ccc(F)cc2F)CC1)c1ccccc1

Procedure:
A mixture of 2,4-difluorobenzylsulfonylchloride (3.5 mmol), N-phenacyl piperazine dihydrochloride (3 mmol), and K2CO3 (10.5 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-22), 0.81 g (71%), M+ 412.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(OC(=O)[NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[C:28]([Br:29])=[CH:27][N:26]=[C:25]([Cl:30])[N:24]=1)(C)C>C(#N)C.Cl.O>[ClH:30].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[C:28]([Br:29])=[CH:27][N:26]=[C:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)[N:24]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CC#N
Solvent: O
Product: NCCCNc1nc(Nc2ccc(S(N)(=O)=O)cc2)ncc1Br
Yield: 74.3 %

Procedure:
To a solution of 4-aminobenzenesulfonamide (190 mg) in acetonitrile (20 mL), hydrochloric acid solution (4M in dioxane, 0.3 mL) and water (0.3 mL) was added (3-((5-bromo-2-chloro-4-pyrimidinyl)amino)propyl)-carbamic acid-1,1-dimethylethyl ester (360 mg). The resulting mixture was refluxed overnight. The precipitate was collected and washed with acetonitrile and methanol to afford the title compound (320 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.CO.[OH-].[K+].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>CN(C)C=O>[CH3:17][S:18]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2)(=[O:20])=[O:19]
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)Oc1cccc2c1CCC(=O)N2
Yield: 38.6 %

Procedure:
10 g of 5-hydroxy-3,4-dihydrocarbostyril was added to 100 ml of methanol having dissolved therein 3.8 g of potassium hydroxide and the mixture was stirred at room temperature for 30 minutes followed by removing methanol under reduced pressure. Benzene was added to the residue to form crystals and then benzene was removed by evaporation. The residue thus-obtained was suspended in 50 ml of dimethylformamide and 10.6 g of methanesulfonyl chloride was added dropwise to the suspension while ice-cooling with stirring. After adding 3.5 g of methanesulfonyl chloride the resulting mixture was stirred at room temperature for 4 hours. After the completion of the reaction, the solvent was removed under reduced pressure and the residue was purified through silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform). Recrystallization of the elute from water-containing ethanol gave 5.7 g of 5-methanesulfonyloxy-3,4-dihydrocarbostyril as colorless prismatic crystals having a melting point of 227° to 231° C.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:10](=[O:12])[N:11]=1.[NH2:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([NH:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[C:10](=[O:12])[N:11]=1
Reactant: NC[C@H](O)COc1ccccc1
Reactant: CN(C)CCCNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Product: CN(C)CCCNC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1

Procedure:
The title compound was prepared from 1-{4-[2-(3-dimethylamino-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 33) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Intermediate 3) according to the procedure of Example 1 as a yellowish solid; mp 166-168° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 10 H), 1.60-1.80 (m, 2 H), 1.80-2.00 (m, 2 H), 2.19 (s, 6 H), 2.25 (t, J=6.8 Hz, 2 H), 2.55-3.00(m, 5 H), 3.50-4.05(m, 7 H), 6.65-6.95(m, 3 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.30 (m, 2 H), 7.40 (d, J=9.0 Hz, 2 H), 7.48 (s, 1 H); MS (ES) m/z: 269.6 (M+2H)2+, 100%), 538.1(MH+, 10%); HRMS Calcd. for C29H40N5O3S (MH): 538.2852. Found 538.2885.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].BrN1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>ClC1C=CC=CC=1.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N.O>[CH3:18][O:17][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16]
Reactant: COC(CN1C(=O)CCc2ncc(F)cc21)OC
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: Clc1ccccc1
Solvent: O
Product: COC(Cn1c(=O)ccc2ncc(F)cc21)OC
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a suspension of 5.0 g of 1-(2,2-dimethoxyethyl)-7-fluoro-3,4-dihydro-1,5-naphthyridin-2(1H)-one, 5.3 g of N-bromosuccinimide and 3.0 g of potassium carbonate in 30 mL of chlorobenzene, 0.12 g of 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) was added three times hourly at 50 to 60° C. under a nitrogen atmosphere. After stirring the reaction mixture for 1 hour at the same temperature, 10 mL of water was added thereto, and the mixture was adjusted to pH 12.6 using a 20% sodium hydroxide solution. The organic layer was separated and washed with 15 mL of water. The aqueous layer was extracted with 15 mL of toluene. The organic layer and the extract were combined to evaporate the solvent under reduced pressure. To the obtained residue, 2 mL of chlorobenzene and 6 mL of cyclohexane were added, the mixture was stirred for 30 minutes under ice cooling, and the solid product was obtained by filtration and washed with cyclohexane to give 4.1 g of 1-(2,2-dimethoxyethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29](O)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([CH3:45])[CH2:42][C@H:41]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:49]([O:48][C:47]([NH:46][C@H:41]1[CH2:42][C@@H:43]([CH3:45])[CH2:44][N:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH:32][C:29]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:40]1)=[O:53])([CH3:50])([CH3:51])[CH3:52]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Reactant: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1
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[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxylic acid (0.014 g, 0.034 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.013 g, 0.041 mmol) and HATU (0.033 g, 0.086 mmol) in DMF (0.14 mL), DIPEA (0.018 mL, 0.10 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous phase was further extracted with EtOAc. The combined organic phases were concentrated under reduced pressure. The residue was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the sub-title compound. LCMS calc. for C39H49N8O5 [M+H]+: m/z=709.4. found: 709.5.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[N:41]([CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][NH2:55])=[N+:42]=[N-:43].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](=[O:20])[NH:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][N:41]=[N+:42]=[N-:43])=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
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: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCOCCOCCOCCN=[N+]=[N-])cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
518 mg (0.92 mmol) of the compound from example 2A was dissolved in 15 ml dichloromethane. 200 mg (0.92 mmol) 2-{2-[2-(2-Azidoethoxy)ethoxy]ethoxy}ethanamine, 160 μl (0.92 mmol) N,N-diisopropylethylamine and 348 mg (0.92 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 276 mg (0.34 mmol, 37% of theory) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=1.[H-].[Na+].[CH3:22]I>CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH3:22])[CH:5]=1
Reactant: CI
Reactant: COC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN(C)C(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 57.4 %

Procedure:
Dissolve 3-(tert-butoxycarbonylamino-methyl)-benzoic acid methyl ester (2.80 g, 10.6 mmol) in dimethylformamide (60 mL). Add 60% sodium hydride dispersion in oil (0.52 g, 13 mmol). Stir for 1 hr. Add methyl iodide (0.81 mL, 13 mmol) and stir for additional 1 hr. Quench the reaction with water and concentrate. Partition the residue between ethyl acetate and water. Separate the organic layer and dry over sodium sulfate. Filter and concentrate. Purify the residue by chromatography (silica gel) eluting with 15-25% ethyl acetate/hexane to provide the title compound (1.70 g, 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1)=[O:13].[N:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[N:16][C:17]([N:24]2[CH2:25][CH2:26][N:21]([C:27](=[O:28])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:36])[F:37])[CH2:22][CH2:23]2)=[CH:18][CH:19]=1)=[O:13]
Reactant: O=C(NCCc1ccc(F)cc1F)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCc1ccc(F)cc1F)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(2,4-difluorophenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (33% yield). m.p. 179-181° C. 1H NMR (400 MHz, CDCl3) δ 8.04, 7.91, 7.75, 7.61, 7.37, 7.30-6.89, 4.09-3.66, 3.38-3.32, 2.88. MS (ES+) m/z 520 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:30].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16]([Cl:30])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(CCC2c3c(I)nc(C)n3CCN2C(=O)OC(C)(C)C)cc1C
Reactant: ClCCl
Solvent: CO
Product: Cc1ccc(CCC2c3c(Cl)nc(C)n3CCN2C(=O)OC(C)(C)C)cc1C

Procedure:
According to the general procedure (GP12), chlorination of 8-[2-(3,4-dimethyl-phenyl)-ethyl]-1-iodo-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.061 g; 2.142 mmol) and purification by FC (DCM/MeOH=40/1) gave the product 1-chloro-8-[2-(3,4-dimethyl-phenyl)-ethyl]-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as an orange oil (157 mg; 0.388 mmol). LC-MS: tR=1.01 min.; [M+H]+=404.50 g/mol.