Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([CH3:28])[N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:25]2[CH:26]=[C:21]([Cl:20])[N:22]=[C:23]([CH3:28])[N:24]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1
Reactant: Cc1ccn(-c2cc(Br)ccc2[C@@H](O)C(F)(F)F)n1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(Cl)nc(C)n2)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of 1(R)-1-[4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol (15.7 g, 46.3 mmol, Intermediate 1) in dioxane (200 mL) was added 4,6-dichloro-2-methylpyrimidine (30.6 g, 51 mmol) and Cs2CO3 (61.2 g, 187 mmol). The reaction mixture was heated to 80° C. for 30 h, then cooled to RT, and filtered. The residue was concentrated in vacuo and purified by normal phase column chromatography on silica gel (CH2Cl2/heptane) to provide (R)-4-(1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-chloro-2-methylpyrimidine as a white solid.
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Br:32][C:33]1[C:34]([N:57]2[CH2:62][CH2:61][CH:60]([O:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:59][CH2:58]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:56]=[CH:55][C:45]([CH2:46][NH:47]C(=O)OC(C)(C)C)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:32][C:33]1[C:34]([N:57]2[CH2:62][CH2:61][CH:60]([O:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:59][CH2:58]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:43]=[CH:44][C:45]([CH2:46][NH2:47])=[CH:55][CH:56]=3)[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCC(Oc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(-c2nc3c(N4CCC(Oc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Yield: 93.7 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl 4-(6-bromo-7-(4-phenoxypiperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzylcarbamate (17 mg, 0.029 mmol), TFA (0.25 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (13 mg, 93%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.84-1.90 (m, 2H, 2× piperidine CHAHB), 2.17-2.19 (m, 2H, 2× piperidine CHAHB), 3.61 (ddd, J=12.4, 9.7, 1.8 Hz, 2× piperidine NCHAHA), 3.80 (s, 3H, OCH3), 3.86-3.91 (m, 2H, 2× piperidine NCHAHA), 4.70 (septet, J=4.0 Hz, 1H, piperidine CH), 6.94 (t, J=7.3 Hz, 1H, phenyl H-4), 7.04 (d, J=7.8 Hz, 2H, phenyl H-2 & H-6), 7.30 (dd, J=8.6, 7.4 Hz, 2H, phenyl H-3 & H-5), 7.50 (d, J=8.6 Hz, 2H, phenyl H-3′ & H-5′), 8.11 (d, J=8.4 Hz, 2H, phenyl H-2′ & H-6′), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5);
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([OH:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N1C=CC=CC=1.Cl>C1C=CC=CC=1.CCOCC>[C:1]([O:23][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:3])[CH3:2]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCCOC(C)=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
a solution of 2.8 g of acetyl chloride in 10 ml of dry benzene was added dropwise, with stirring, to an ice-cold solution of compound III (5.0 g) and 2.8 g of pyridine in 20 ml of dry benzene. Following addition, stirring was maintained at room temperature for 30 minutes and the mixture was then refluxed for 2 hours. The cooled mixture was diluted with 30 ml of ether and treated with sufficient cold 5% HCl to make the mixture strongly acid. The layers were separated and the aqueous layer was shaken once with 20 ml of ether; the combined organic layers were washed with three 10-ml portions of cold H2O and dried over Na2SO4. Evaporation of the solvent and distillation of the residue gave 5.1 g (85%) of compound IV as a colorless liquid boiling at 139°-143° (0.1 mm), nD25 1.4493.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:42])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:12]=[CH:11][N:10]=[C:9]2[NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[C:29]([Cl:41])[CH:28]=1)=[O:4].[C:43](Cl)(=[O:46])[CH:44]=[CH2:45].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:41][C:29]1[CH:28]=[C:27]([NH:26][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:6]([NH:5][C:3]([C@@H:2]([NH:1][C:43](=[O:46])[CH:44]=[CH2:45])[CH3:42])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1
Reactant: C=CC(=O)Cl
Reactant: C[C@H](N)C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)N[C@@H](C)C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Yield: 33 %

Procedure:
500 mg of (2S)-2-amino-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(3-morpholin-4-ylpropoxy)-quinazolin-6-yl}-propionamide as a starting material was dissolved in 12 ml of THF and 4 ml of water, and reacted with 0.08 ml of acryloylchloride at room temperature for 1.5 hours after adding 213 mg of sodium bicarbonate. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=15:1) to obtain the title compound (180 mg, 33%).
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](O)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.P(Cl)(Cl)([Cl:25])=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:25][C:13]1[N:14]2[C:18]([N:19]=[C:11]3[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=13)=[CH:17][CH:16]=[N:15]2.[ClH:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(O)c2CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: Clc1c2c(nc3ccnn13)CCNCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 5 g (16.43 mmol) 10-hydroxy-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester was added 15.2 mL (160.8 mmol) of phosphorus oxychloride followed by 2.85 mL (16.43 mmol) of DIPEA. The reaction mixture was stirred at room temperature for 10 minutes, then heated at 90° C. for 1 hour, and allowed to cool to room temperature. 30 mL DCM was added to the mixture and the solid was collected by filtration and washed with DCM (2×10 mL) to give the desired product as a HCl salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:4][N:3]=1.[CH3:17][C:18]([O:21][C:22]([NH:24][C@@H:25]([CH2:30][C:31]#[CH:32])[C:26]([O:28][CH3:29])=[O:27])=[O:23])([CH3:20])[CH3:19].C(NCC)C>C(OCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:18]([O:21][C:22]([NH:24][C@@H:25]([CH2:30][C:31]#[C:32][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:4][N:3]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:23])([CH3:17])[CH3:19]
Reactant: Fc1ccccc1COc1ccc(Br)nc1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOCC
Solvent: CCNCC
Product: COC(=O)[C@H](CC#Cc1ccc(OCc2ccccc2F)cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
To a solution of 2-bromo-5-{[(2-fluorophenyl)methyl]oxy}pyridine (D82, 0.60 g, 2.13 mmol), methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (D64, 1.20 g, 5.30 mmol), synthesized with an analogous procedure to the one described hereinabove, and diethylamine (1.10 ml, 10.65 mmol) in diethyl ether (20 ml) were added copper iodide (0.042 g, 0.22 mmol) and PdCl2(PPh3)2 (0.077 g, 0.11 mmol) and the mixture was stirred for three hours at room temperature. The reaction was quenched with a saturated solution of ammonium chloride diluted with water and extracted with diethyl ether. The organic layer was dried (Na2SO4) filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (9:1 to 8:2) to afford the title compound as a yellow solid (0.36 g, 40%). Rt (HPLC): 5.64 min; MS: (ES/+) m/z: 429 [MH]+ C23H25FN2O5 requires 428; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.28-8.39 (m, 1H); 7.44-7.53 (m, 1H); 7.32-7.41 (m, 2H); 7.16-7.25 (m, 2H); 7.08-7.16 (m, 1H); 5.37-5.55 (m, 1H); 5.19 (s, 2H); 4.46-4.66 (m, 1H); 3.81 (s, 3H); 2.91-3.07 (m, 2H); 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])[CH3:2].[OH-].[Na+]>C1COCC1.CCO>[CH2:1]([O:3][C:4](=[O:24])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCOC(=O)CCC(C(=O)OCC)(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(CCC(=O)O)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
2-Ethoxycarbonyl-2-phenylpentanedioic acid diethyl ester (670 mg) was dissolved in THF (2 mL) and EtOH (2 mL), and thereto was added 1N sodium hydroxide (2 mL). The solution was stirred at room temperature for 1 hour and concentrated. The residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and concentrated to give 2-ethoxycarbonyl-2-phenylpentanedioic acid 1-ethyl ester (517 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7](=O)[CH2:8][C:9]3([O:13]2)[CH2:12][CH2:11][CH2:10]3)=[C:5]([CH3:17])[C:4]=1[OH:18])[CH3:2].Cl.[CH3:20][O:21][NH2:22].C([O-])(=O)C.[Na+].O>CO>[CH3:20][O:21][N:22]=[C:7]1[C:6]2[C:14](=[CH:15][C:3]([CH2:1][CH3:2])=[C:4]([OH:18])[C:5]=2[CH3:17])[O:13][C:9]2([CH2:12][CH2:11][CH2:10]2)[CH2:8]1
Reactant: CON
Reactant: CCc1cc2c(c(C)c1O)C(=O)CC1(CCC1)O2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1cc2c(c(C)c1O)C(=NOC)CC1(CCC1)O2
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of 7-ethyl-6-hydroxy-5-methylspiro[chroman-2,1′-cyclobutan]-4-one (0.8 g), methoxyamine HCl salt (500 mg) and sodium acetate (300 mg) in MeOH (20 mL) was stirred at 80° C. overnight. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was dried and evaporated. The residue was purified by silica gel column eluting with 10% ethyl acetate in hexane, giving 7-ethyl-6-hydroxy-5-methylspiro[chroman-2,1′-cyclobutan]-4-one O-methyl oxime (530 mg).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32]>>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:8]3[C:7]4[CH2:6][CH2:5][O:4][C:12]=4[CH:11]=[CH:10][N:9]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:32]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(Cl)cc1Cl

Procedure:
The title compound, white solid (92 mg, 73%), MS (ISP) m/z=503.2 [(M+H)+], mp 203.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 2,4-dichloro-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][C:28]([C:32]([O:34]C)=[O:33])=[CH:29]4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][C:28]([C:32]([OH:34])=[O:33])=[CH:29]4)=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1
Reactant: COC(=O)c1ccc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3ccc(C(=O)O)cc3c2)cc1
Temperature: 100 °C
Yield: 77 %

Procedure:
A solution of methyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-naphthalenecarboxylate (0.126 g, 0.2 mmol) in tetrahydrofuran (2.0 mL) was placed in a microwave reaction tube. Methanol (1.0 mL) was added followed by 1 N sodium hydroxide (0.3 mL, 0.3 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 600 seconds. The solution was neutralized and concentrated. Water was added and the mixture was filtered. The resulting solid was dried in a vacuum oven at 45° C. with P2O5 to yield the title compound (0.082 g, 73.9% as 0.30 tetrahydrofuran) 1H NMR (DMSO-d6): 13.3-12.6 (broad s, approximately 1H), 8.61 (s, 1H), 8.29 (s, 1H), 8.02-7.87 (m, 4H), 7.68 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.54 (dd, J=7, 9 Hz, 1H), 6.91 (d, J=9 Hz, 2H), 4.86 (s, 2H), 3.44 (septet, J=7 Hz, overlapping H2O, 1H), 1.33 (d, J=7 Hz, 6H). HRMS C30H23NO4Cl2 m/z 532.1082, (M+H)+Cal; 532.1087 (M+H)+Obs.
Reaction SMILES: [CH3:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[C:16]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH2:27][C:28]#[CH:29])=[O:24])[CH2:19][C:17]=3[S:18][C:5]=2[NH:4][C:3]1=O.C(=O)([O-])O.[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:37].ClCCl>C(COC)OC.CO>[CH3:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[C:16]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH2:27][C:28]#[CH:29])=[O:24])[CH2:19][C:17]=3[S:18][C:5]=2[NH:4][C:3]1=[S:37]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: C#CCCOC(=O)N1CCc2c(sc3c2C(c2ccccc2Cl)=NC(C)C(=O)N3)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: ClCCl
Product: C#CCCOC(=O)N1CCc2c(sc3c2C(c2ccccc2Cl)=NC(C)C(=S)N3)C1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
0.21 g of 3-methyl-5-(2-chlorophenyl)-8-(3-butynyloxycarbonyl)-6,7,8,9-tetrahydro-1H,3H-pyrido[4',3':4,5]thieno[3,2-f][1,4]diazepin-2-one was dissolved in 10 ml of dimethoxyethane, to which 0.11 g of sodium hydrogencarbonate and 0.22 g of phosphorus pentasulfide were added, followed by heating at 80° C. for 3 hours. After completion of the reaction, dichloromethane and methanol were added, and the mixture was filtered, followed by addition of silica gel to the resultant filtrate and evaporating the solvent to dryness. Silica gel column chromatography (elution solvent: dichloromethane:methanol=99:1) was used for purification, thereby obtaining 0.15 g of the intended compound.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:31])[CH2:13][C@H:14]([N:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:15]([OH:17])=[O:16])=[O:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[N-:39]=[N+:40]=[N-].[Na+]>CC(C)=O.O>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:31])[CH2:13][C@H:14]([N:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]([OH:17])=[O:16])=[O:7])=[CH:32][CH:33]=1)=[N+:39]=[N-:40]
Reactant: Nc1ccc(C(=O)OCCOC(=O)C[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C(=O)OCCOC(=O)C[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
To a stiffed solution of 19 (0.115 g, 0.260 mmol) in acetone (6 mL) was added 5% HCl (6 mL) at 0° C. and the solution was stiffing for 5 min NaNO2 (0.020 g, 0.28 mmol) in 1 mL water was added dropwise to the above solution causing an immediate color change from colorless to orange. After 20 min of stirring at 0° C., NaN3 (0.034 g, 0.52 mmol) in 1 mL water was added dropwise to the reaction mixture causing an immediate color changed from orange to colorless to pale yellow. The reaction mixture was stiffed for additional 20 min and extracted with ethyl acetate (50 mL), washed with water (20 mL) and brine (20 mL). The final organic layer was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to obtain (S)-4-(2-(4-azidobenzoyloxy)ethoxy)-2-(9H-carbazol-9-yl)-4-oxobutanoic acid 20 (0.117 g, 96%) as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[NH2:12][C:13]1[C:14]([C:20](O)=[O:21])=[N:15][C:16]([Br:19])=[CH:17][N:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:12][C:13]1[C:14]([C:20]([N:6]([C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])=[O:5])[NH2:7])=[O:21])=[N:15][C:16]([Br:19])=[CH:17][N:18]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: NNC(=O)c1ccccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncc(Br)nc1C(=O)N(N)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-fluorobenzohydrazide (2 g, 12.98 mmol), 3-amino-6-bromo-pyrazine-2-carboxylic acid (2.830 g, 12.98 mmol), and TBTU (5.002 g, 15.58 mmol) in DMF (20.00 mL) was added DIPEA (3.691 g, 4.974 mL, 28.56 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL), the combined organic extracts were washed with water (3×20 mL) and brine (1×20 mL), dried over MgSO4 and concentrated in vacuo. The residue was then triturated with acetonitrile and filtered and dried to give 3-amino-6-bromo-N-(2-fluorophenylcarbonyl)pyrazine-2-carbohydrazide as an orange solid. This was taken up in MeCN (20.00 mL) and added bromo(triphenyl)phosphonium (5.331 g, 15.58 mmol) was added followed by DIPEA (3.691 g, 4.974 mL, 28.56 mmol). The reaction mixture was stirred for 30 min, and then filtered. The solid was washed with acetonitrile to give the product as a yellow solid (1.46 g, 67%); 1H NMR (400 MHz, DMSO) d 7.48-7.54 (m, 2H), 7.75 (m, 3H), 8.12 (m, 1H) and 8.45 (m, 1H) ppm; MS (ES+) 338.03
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[O:23][CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[Br:44][C:45]1[CH:46]=[C:47]([C@H:51]([NH2:53])[CH3:52])[CH:48]=[CH:49][CH:50]=1>C(Cl)(Cl)Cl>[Br:44][C:45]1[CH:46]=[C:47]([C@H:51]([NH:53][C:36]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:17]([O:23][CH3:24])[CH:18]=2)=[O:42])[CH3:52])[CH:48]=[CH:49][CH:50]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3OC)c2cc1OC
Reactant: C[C@@H](N)c1cccc(Br)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4cccc(Br)c4)cc3OC)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyaniline (79 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(3-bromophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (39 mg, yield 29%).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[CH2:11]([NH:15][C:16](=[O:49])[C@H:17]([CH3:48])[CH2:18][C@H:19]([OH:47])[C@@H:20]([NH:39]C(OC(C)(C)C)=O)[CH2:21][C@@H:22]([CH:36]([CH3:38])[CH3:37])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][C:34]#[N:35])[CH:25]=1)[CH2:12][CH2:13][CH3:14]>ClCCl>[CH2:11]([NH:15][C:16](=[O:49])[C@H:17]([CH3:48])[CH2:18][C@H:19]([OH:47])[C@@H:20]([NH2:39])[CH2:21][C@@H:22]([CH:36]([CH3:37])[CH3:38])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][C:34]#[N:35])[CH:25]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCC#N)c1)C(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)C[C@H](Cc1ccc(OC)c(OCC#N)c1)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.5 ml of a mixture of trifluoroacetic acid/dichloromethane=1:3 are added at 0° C., with stirring, to a solution of 35 mg of N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-cyanomethoxy-4-methoxy-phenyl)-octanoic acid (N-butyl)amide in 1 ml of dichloromethane, and the mixture is stirred for a further 3 hours at 0° C. and then concentrated by evaporation. The residue is purified by FC (5 g of silica gel, dichloromethane/methanol=9:1). This yields the title compound: Rf (dichloromethane/methanol=9:1)=0.19; Rt (I)=19.59 minutes; FAB-MS(M+H)+ =448.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:12][C@H:11]([N:13]([CH2:21][C:22]3[C:23]4[N:24]([CH:28]=[CH:29][N:30]=4)[CH:25]=[CH:26][CH:27]=3)C(=O)OC(C)(C)C)[CH2:10]2)=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39]>>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39].[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:12][C@H:11]([NH:13][CH2:21][C:22]3[C:23]4[N:24]([CH:28]=[CH:29][N:30]=4)[CH:25]=[CH:26][CH:27]=3)[CH2:10]2)=[CH:4][C:3]=1[C:31]([F:33])([F:32])[F:34]
Reactant: CC(C)(C)OC(=O)N(Cc1cccn2ccnc12)[C@H]1C[C@@H](Oc2ccc(F)c(C(F)(F)F)c2)C1
Agent: O=C(O)/C=C\C(=O)O
Product: Fc1ccc(O[C@H]2C[C@@H](NCc3cccn4ccnc34)C2)cc1C(F)(F)F

Procedure:
Prepared similarly to Example 16 by acidic deprotection of 1,1-dimethylethyl (cis-3-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}cyclobutyl)(imidazo[1,2-a]pyridin-8-ylmethyl)carbamate followed by conversion of the product into the maleate salt with maleic acid.