Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Br.[N+:22]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][NH:28][CH2:29]2)([O-:24])=[O:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:22]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][N:28]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:29]2)([O-:24])=[O:23]
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 46.8 %

Procedure:
185 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 176 mg of 4-nitroisoindoline hydrobromide, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 131 mg of the target compound.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:17][C:16]3=[CH:18][NH:19][C:14]4[C:15]3=[C:10]([CH:11]=[CH:12][N:13]=4)[C:9]2=[O:20])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:28]([CH2:30][C:31](ON1C(=O)CCC1=O)=[O:32])#[N:29]>CCO>[CH3:1][C:2]1([N:8]2[CH2:17][C:16]3=[CH:18][NH:19][C:14]4[C:15]3=[C:10]([CH:11]=[CH:12][N:13]=4)[C:9]2=[O:20])[CH2:7][CH2:6][N:5]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:4][CH2:3]1
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: CC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCN(C(=O)CC#N)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
4-(4-Methylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one (21 mg, 0.078 mmol) and triethylamine (0.032 mL, 0.233 mmol) were dissolved in EtOH (4 mL) and cooled to 0° C. and allowed to stir for 10 min. Then 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (17 mg, 0.093 mmol) dissolved in EtOH (1 mL) was added dropwise and the mixture was allowed to stir for 30 min at 0° C. The solution was concentrated in vacuo and purified via preparative HPLC 10% to 40% B in A and gave 13 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.61 (m, 1H), 7.43 (m, 1H), 5.08 (s, 2H), 3.90 (m, 2H), 3.72 (m, 1H), 3.61-3.62 (m, 1H), 3.51-3.52 (m, 2H), 2.65-2.69 (m, 1H), 2.51-2.57 (m, 1H), 2.22-2.26 (m, 1H), 2.10-2.12 (m, 1H), 1.66 (s, 3H). [M+H] found 338.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:22]=[S:23]>C1COCC1.CO>[NH2:8][C:7]1[C:2]([NH:1][C:22]([NH:21][C:15]2[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])=[S:23])=[CH:3][C:4]([C:9]([O:11][CH3:12])=[O:10])=[N:5][CH:6]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: COC(=O)c1cc(N)c(N)cn1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=S)Nc2c(Cl)cccc2Cl)c(N)cn1

Procedure:
Prepared analogously to example 360f from methyl 4,5-diamino-picolinate and 1,3-dichloro-2-isothiocyanato-benzene in THF and methanol.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[C:9]([O:13][CH2:14][C@@H:15]([OH:21])[CH2:16][C:17](OC)=[O:18])([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+].C(OCC)C>C(=O)=O.CC(C)=O.O1CCCC1>[C:9]([O:13][CH2:14][C@@H:15]([OH:21])[CH2:16][C:17](=[O:18])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)C[C@H](O)COC(C)(C)C
Reactant: CC(=O)OC(C)(C)C
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC[C@@H](O)CC(=O)CC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
After completion of the dropwise addition, the mixture was stirred for 15 minutes to synthesize a lithium enolate of t-butyl acetate. The reaction mixture was cooled to -50° C. in dry ice-acetone, and a solution of 3.3 g (16.5 mmole) of methyl (3S)-4-t-butoxy-3-hydroxybutanoate as prepared in Example 1 in 15 ml of tetrahydrofuran was added to the mixture through the dropping funnel over 20 minutes, followed by stirred for an additional 1.5 hours. After confirming the completion of the reaction by gas chromatography, 30 ml of a saturated aqueous solution of ammonium chloride and 100 ml of diethyl ether were added to the reaction mixture to conduct extraction. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (diethyl ether/hexane: 1/1 by volume) to obtain 2.3 g (yield: 46%) of t-butyl (5S)-6-t-butoxy-5-hydroxy-3-oxohexanoate.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)=[O:28])[CH3:25].CO.C(O)(=O)C.C([BH3-])#N.[Na+]>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:31]2[CH2:32][CH2:33][CH2:34][C@@H:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH2:30]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CCCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (500 mg, 2 mmol) was combined with (R)-piperidine-3-carboxylic acid ethyl ester (0.51 g, 3.2 mmol) in methanol (10 mL, 200 mmol) and acetic acid (9.2 μL, 0.16 mmol). Sodium cyanoborohydride (0.25 g, 4.0 mmol) was then added and the reaction was stirred overnight at room temperature. The reaction was then quenched with water and extracted three times with ethyl acetate. Organics were combined and dried over MgSO4. Solids were removed via filtration and 10 g of silica gel was added. All solvent was then removed and the resulting silica gel was loaded onto a 24 g column and the product was eluted using a gradient of 0-60% ethyl acetate/hexanes and then dried under vacuum to give the title compound as a colorless oil. EDI-MS: 438.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[C:4](=[O:15])[C:3]=1[CH:16]=O.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:14])[C:4](=[O:15])[C:3]=1[CH:16]=[N:19][OH:20]
Reactant: NO
Reactant: CC1CCCCC1n1ccc(Cl)c(C=O)c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1CCCCC1n1ccc(Cl)c(C=NO)c1=O
Temperature: 75 °C
Yield: 92.1 %

Procedure:
A mixture of 4-chloro-1-(2-methylcyclohexyl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step C (1.22 g), hydroxylamine hydrochloride (667 mg) and sodium acetate (787 mg) in methanol/water (4:1, 6.0 mL) was heated at 75° C. for 1 hr, and cooled to room temperature. The reaction mixture was poured into ice water, and the resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (1.19 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([F:11])[CH:5]=[CH:4][C:3]=1[CH:12](OC)[O:13]C.O.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([F:11])[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: CCCc1c(F)ccc(C(OC)OC)c1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(F)ccc(C=O)c1Cl
Yield: 99.4 %

Procedure:
2-Chloro-1-(dimethoxymethyl)-4-fluoro-3-propylbenzene (1.20 g) was dissolved in a mixed solvent of tetrahydrofuran (16 mL)-1 mol/L hydrochloric acid (8 ml), and the mixture was heated under reflux for 2 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate. The ethyl acetate solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=30:1→3:1) to give the title compound as a colorless oil (yield: 970 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1C(OC(C)(C)C)=O)=[O:13].FC(F)(F)C(O)=O>>[CH3:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[N:3]1[CH2:9][CH2:10][NH:11][C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]1)=[O:13]
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1

Procedure:
The title compound was prepared by a similar method to Preparation 8 from tert-butyl (2S)-2-[(2-[(cis)-2,6-dimethyl-1-piperidinyl]ethylamino)carbonyl]-1-piperidinecarboxylate [see Preparation 14] and trifluoroacetic acid, to afford (2S)-N2 -2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-2-piperidinecarboxamide as a gum.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:18]([O-])=O)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt]=O.C1COCC1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:18])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN(Cc1ccccc1)C2
Agent: O=[Pt]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)CCN(Cc1ccccc1)C2
Reaction time: 72 h

Procedure:
A THF (184 mL) solution of compound (17) (4.6 g, 17 mmole) with platinum oxide (230 mg) was hydrogenated for 18 hrs. at 50 psi. The catalyst was filtered off and platinum oxide (230 mg) was added and the hydrogenation continued for 72 hrs. The completed hydrogenation was filtered to provide a THF solution of the intermediate, 2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl amine (18). Triethylamine was added to the THF solution of (18) followed by the dropwise addition of 4'-trifluoromethylbiphenyl-2-carbonyl chloride (4.88 g., 17 mmole) from Example 3. The contents were stirred subsequently for 17 hrs. The solvent was removed under vacuum, water (50 mL) was added, the contents stirred for 3 hr., the product filtered off and dried under vacuum to yield 5.93 g (71%) of compound (19) as a white solid.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[Br-].[CH:10]1([CH2:16][Zn+])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[CH3:8][S:7][C:4]1[N:3]=[C:2]([CH2:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[S:6][N:5]=1
Reactant: CSc1nsc(Cl)n1
Reactant: [Zn+]CC1CCCCC1
Agent: [Br-]
Solvent: C1CCOC1
Product: CSc1nsc(CC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.00 g of 5-chloro-3-methylthio-1,2,4-thiadiazole and 244 mg of {1,1′-bis(diphenylphosphino)ferrocene} dichloro palladium(II) dichloromethane complex were dissolved in 12 ml of tetrahydrofuran under nitrogen atmosphere, 13.2 ml of solution of (cyclohexyl)methyl zinc bromide in tetrahydrofuran (0.5 mol/l) was added thereto under ice-cooling taking for about 10 minutes, and the reaction mixture was stirred for 30 minutes under ice-cooling and for 8 hours at room temperature. Then, the reaction mixture was concentrated, and the residue subjected to silica gel column chromatography to give 1.29 g of 3-methylthio-5-(cyclohexyl)methyl-1,2,4-thiadiazole.
Reaction SMILES: C[O:2][CH2:3][PH:4]([O:6][C@@H:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:8]([NH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=[O:9])=[O:5].C(O)(C)C.N.O>CC(C)=O>[OH:2][CH2:3][PH:4]([O:6][C@@H:7]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:8]([NH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=[O:9])=[O:5]
Reactant: COC[PH](=O)O[C@@H](Cc1ccccc1)C(=O)Nc1ccc(C(=O)OC)cc1
Agent: N
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(NC(=O)[C@H](Cc2ccccc2)O[PH](=O)CO)cc1
Reaction time: 8 h

Procedure:
The methyl ester product from part (b) (2.3 g., 5.88 mmole) is suspended in acetone (7 ml.) at room temperature. Trimethylamine is bubbled in for about 20 minutes to saturate the mixture. The reaction vessel is sealed, and the mixture is heated to about 95° and is stirred overnight. The volatiles are evaporated, and the residue is partitioned between ethyl acetate and 5% potassium bisulfate. The organic layer is washed once with brine, dried (Na2SO4), filtered, and the volatiles are evaporated to give 1.86 g. of 4-[[(S)-2=[(hydroxymethylphosphinyl)oxy]-1-oxo-3-phenylpropyl]amino]benzoic acid, methyl ester. TLC (silica gel; isopropanol:ammonia:water, 7:2:1) Rf =0.62.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22]([NH:24][NH2:25])=[O:23]>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:25]/[NH:24][C:22]([C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)=[O:23])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NNC(=O)c1ccc2ccccc2c1
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCCCN1C(=O)/C(=N\NC(=O)c2ccc3ccccc3c2)c2ccccc21
Yield: 86 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and 2-naphthhydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 86%. 1H NMR (DMSO-d6): δ 0.85 (t, J=6.9 Hz, 3H), 1.22-1.38 (m, 6H), 1.66 (m, 2H), 3.79 (t, J=7.2 Hz, 2H), 7.19 (t, J=7.5 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.63-7.73 (m, 3H), 7.94 (dd, J=1.8 Hz, J=8.4 Hz, 1H), 8.05 (d, J=7.5 Hz, 1H), 8.13-8.17 (m, 2H), 8.55, (s, 1H), 14.01 (br s, 1H). 13C NMR (DMSO-d6): δ 14.32 (CH3), 22.44 (CH2), 26.39 (CH2), 27.43 (CH2), 31.33 (CH2), 39.79 (CH2), 110.66 (CH), 119.69 (C), 121.27 (CH), 123.68 (CH), 127.74 (CH), 128.24 (CH), 129.03 (CH), 129.38 (CH), 129.70 (CH), 129.74 (C), 132.21 (CH), 132.63 (C), 135.22 (C), 143.45 (C═N), 161.58 (C═O). HRMS (ES+) calcd for C25H26N3O2 (M+H+), m/e, 400.2031. found, 400.2020.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[C:6]([NH2:15])[CH:5]=1.[NH2:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1.[C:32](N1C=CN=C1)(N1C=CN=C1)=S.C(Cl)CCl>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH2:12][O:13][CH3:14])[C:32]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:31])([F:29])[F:30])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:15][C:6]=2[CH:5]=1)=[O:16]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COCCNc1ccc(C(=O)OC)cc1N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)OC)ccc21
Yield: 49.8 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (829.0 mg) was prepared by following General Procedure D starting from 3-amino-4-(2-methoxy-ethylamino)-benzoic acid methyl ester (800.0 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (930.0 mg), 1,1′-thiocarbonyldiimidazole (700.0 mg), and EDC (770.0 mg) in DMF (8.0 mL).
Reaction SMILES: [Cl:1]CCl.[OH-].[Na+].Cl.C[O:8][C:9]1[CH:10]=[C:11](/[C:15](=[CH:22]\[CH2:23][CH3:24])/[CH:16]([CH3:21])[CH2:17][N:18]([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1>>[ClH:1].[CH3:20][N:18]([CH3:19])[CH2:17][CH:16](/[C:15](/[C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)=[CH:22]/[CH2:23][CH3:24])[CH3:21]
Reactant: ClCCl
Reactant: CC/C=C(\c1cccc(OC)c1)C(C)CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC/C=C(\c1cccc(O)c1)C(C)CN(C)C
Yield: 86 %

Procedure:
The base was released with dichloromethane/sodium hydroxide solution from (15), which was prepared as in Example 13, and after drying the solution the dichloromethane was removed by distillation. Hydrochloride (18) was obtained, under the conditions given in Example 2, from the base thus obtained, in a yield of 86% theoretical and with a melting point of 120°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.B(Br)(Br)Br>ClC(Cl)C.ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(C2=NC(Cc3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)cc1
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccc(O)cc2)=NC1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.9 %

Procedure:
(Z)-7-Chloro-3-(2-chlorobenzyl)-5-(4-methoxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (74 mg, 0.174 mmol) was dissolved in dichloroethane (1 mL) under nitrogen and BBr3 (1M in dichloromethane, 0.348 mL, 0.348 mmol) was added dropwise at room temperature (there was an immediate color change from colorless to orange). The reaction mixture was stirred at room temperature for approximately 5 hours. Two more equivalents of BBr3 in dichloromethane were added (0.348 mL, 0.348 mmol) and the mixture was left stirring for another approximately 18 hours. The reaction was carefully quenched with methanol (exothermic) then diluted with dichloromethane and washed twice with water then once with brine (the last wash gelled so some methanol was added to separate the layers). The organic layer was dried (MgSO4). Chromatography eluting with 20-40% ethyl acetate in hexanes gave some starting material plus (Z)-7-chloro-3-(2-chlorobenzyl)-5-(4-hydroxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one as a yellow solid (40 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 3.59-3.89 (m, 3H), 6.30 (br s, 1H), 6.71 (d, J=8 Hz, 2H), 7.09-7.32 (m, 4H), 7.44 (dd, J=9, 2 Hz, 1H), 7.58 (d, J=7 Hz, 1H), 9.13 (s, 1H); ESI m/z 411.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](F)[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: Fc1cccc(Nc2cc(Cl)nn3ccnc23)n1
Reactant: C1CCNC1
Solvent: O
Product: Clc1cc(Nc2cccc(N3CCCC3)n2)c2nccn2n1
Temperature: 205 °C
Yield: 18.4 %

Procedure:
A suspension of 6-chloro-N-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (132 mg, 0.5 mmol) and pyrrolidine (54 mg, 0.75 mmol) in water (0.3 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=200:1) to give 6-chloro-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (29 mg, 18%) as a light yellow solid. LC-MS: [M+H]+, 315.0, tR=1.837 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[N:13](OCCCC)=[O:14].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])/[C:7](=[N:13]\[OH:14])/[CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CCCCON=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)C/C(=N/O)C2=O
Reaction time: 0.5 h

Procedure:
To a solution of 5-(methyloxy)-2,3-dihydro-1H-inden-1-one (1.0 g, 6.2 mmol) in methanol (15 mL) at 40° C. was added n-butyl nitrite (0.8 mL, 6.25 mmol) followed by conc HCl (0.6 mL). The reaction was stirred 30 min, precipitated solid was collected by filtration, air-dried and used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.60 (br.s, 2H) 3.86 (s, 3H) 6.99 (dd, J=8.54 Hz, 2.2 Hz, 1H) 7.12 (d, J=1.71 Hz, 1H) 7.66 (d, J=8.55 Hz, 1 H) 12.45 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)SCCCS1.C(=O)([O-])[O-:28].[Ca+2]>C1COCC1.CO.O.[Hg](Cl)Cl>[N:22]1([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:2](=[O:28])[CH3:1])=[CH:17][CH:18]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C([O-])[O-]
Reactant: CC1(CCCCOCCCc2ccc(N3CCCC3)cc2)SCCCS1
Agent: Cl[Hg]Cl
Agent: [Ca+2]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)CCCCOCCCc1ccc(N2CCCC2)cc1

Procedure:
A solution of the product of stage (iv) (3.2 g) in THF (50 ml) was added to a stirred suspension of mercury (II) chloride (8.5 g) and calcium carbonate (3.2 g) in methanol-water (9:1, 50 ml) and the mixture was stirred at reflux for 1 h. The reaction was filtered through hyflo, the filtrate was concentrated in vacuo and the resulting oil was dissolved in chloroform (50 ml). The resulting precipitate was removed by filtration, the solvent was evaporated and the residue was purified by FCC (System D 19:1→4:1) to give the title compound as a crystalline mass (1.4 g) m.p. 30°-31°.
Reaction SMILES: C1COCC1.C(Cl)Cl.C([O:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:35][CH2:34][C:33]4[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:32]=4[NH:31][C:30]3=[O:42])[CH2:25][CH2:24]2)[CH:20]=[C:19]([C:43]([C:45]2[CH:55]=[C:54]([CH3:56])[C:48]3[N:49]([CH3:53])[C:50](=[O:52])[O:51][C:47]=3[CH:46]=2)=[O:44])[CH:18]=1)C1C=CC=CC=1>[Pd].CO>[CH3:53][N:49]1[C:48]2[C:54]([CH3:56])=[CH:55][C:45]([C:43]([C:19]3[CH:20]=[C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:35][CH2:34][C:33]6[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:32]=6[NH:31][C:30]5=[O:42])[CH2:25][CH2:24]4)[NH:22][C:17](=[O:16])[CH:18]=3)=[O:44])=[CH:46][C:47]=2[O:51][C:50]1=[O:52]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)cc(OCc4ccccc4)n3)CC1)C(=O)N2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)cc(=O)[nH]3)CC1)C(=O)N2
Reaction time: 1.5 h

Procedure:
30 mg palladium on charcoal (Pd/C 10%), 30 mL THF and 30 mL DCM were added to 0.13 g (0.20 mmol) 3-[6′-benzyloxy-4′-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 20 mL MeOH and the mixture was hydrogenated for 1.5 h under a hydrogen atmosphere. After filtration of the reaction mixture the solvent was evaporated down i. vac. The residue was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].C[O-].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:25])[C:21](OC)=[O:22])=[CH:16][CH:15]=1>O1CCCC1>[Cl:8][C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][C:21](=[O:22])[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[CH3:25]
Reactant: Cc1nsc(N)c1Cl
Reactant: COC(=O)C(C)c1ccc(OC)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)C(=O)Nc2snc(C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.4 %

Procedure:
5-Amino-4-chloro-3-methylisothiazole (7.4 g, 0.050 mol) was added to a suspension of sodium methoxide (6.1 g, 0.112 mol) in tetrahydrofuran (160 ml) and the mixture was stirred at room temperature for 20 minutes. A solution of methyl 2-(4-methoxyphenyl)propionate (8.8 g, 0.045 mol) in tetrahydrofuran (40 ml) was added dropwise and the mixture was stirred for 3 hours at room temperature. The reaction was quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:dichloromethane 2.5:97.5, to give N-(4-chloro-3-methylisothiazol-5-yl)-2-(4-methoxyphenyl)propionamide (12.5 g) as a colourless solid.