Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert.-butyl ester [CAS-No. 335255-88-4] according to the general procedure M. Obtained as a light yellow solid (427 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9](I)[C:8]([O:12][CH2:13][O:14][CH3:15])=[C:7](Br)[CH:6]=1)[CH3:2].C(O[C:21](=O)[C:22]1[CH:27]=[C:26](Br)[C:25](OCOC)=[C:24](Br)[CH:23]=1)C>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH3:4])[CH:6]=2)[C:8]([O:12][CH2:13][O:14][CH3:15])=[C:7]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:21])[CH:27]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(OCOC)c(Br)c1
Reactant: CCOC(=O)c1cc(Br)c(OCOC)c(I)c1
Product: CCOC(=O)c1cc(-c2cccc(C)c2)c(OCOC)c(-c2cccc(C)c2)c1

Procedure:
3,5-Bis-(3-methylphenyl)-4-methoxymethoxybenzoic acid ethyl ester was prepared as a white solid (4.2 g, 30%) in a similar manner to Step 1 of Example 143 from a 2:1 mixture of 3-bromo-4-methoxymethoxy-5-iodobenzoic acid ethyl ester and 3,5-dibromo-4-methoxymethoxybenzoic acid ethyl ester. 1H NMR (CDCl3) δ 1.17 (t, J=8.18 Hz, 3H); 2.4 (s, 6H); 2.66 (s, 3H); 4.36 (quartet, J=8.18 Hz, 2H); 4.40 (s, 2H); 7.11–7.20 (m, 2H); 7.20–7.40 (m, 6H); 8.00 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]1)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.BrC1C=CC=[C:39]2[C:35]=1[C:36]1([C:52]3=[CH:53][C:54]4OCO[C:55]=4[CH:59]=[C:51]3OC1)C(=O)[N:38]2CCCCC.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:38]1[C:53]2[C:52](=[CH:51][CH:59]=[CH:55][CH:54]=2)[CH:36]=[C:35]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:25]4=[CH:26][C:27]5[O:31][CH2:30][O:29][C:28]=5[CH:32]=[C:24]4[O:23][CH2:22]2)[C:5](=[O:21])[N:6]3[CH2:11][C:12]2[O:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)[CH:39]=1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1cnc2ccccc2c1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(-c3cnc4ccccc4c3)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1H)-one, quinolin-3-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (50%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.52 (d, 1H), 8.09 (d, 1H), 7.74-7.68 (m, 1H), 7.56-7.50 (m, 1H), 7.42-7.39 (m, 2H), 7.32 (s, 1H), 7.09 (d, 1H), 7.01 (d, 1H), 6.78-6.77 (m, 1H), 6.45 (d, 1H), 6.26 (s, 1H), 5.94 (d, 1H), 5.91 (s, 1H), 5.89 (d, 1H), 5.03 (ABq, 2H), 4.52 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 177.4, 156.0, 151.8, 150.0, 149.3, 147.0, 142.4, 141.8, 136.8, 135.8, 131.1, 130.2, 129.9, 129.3, 129.0, 128.8, 128.0, 127.1, 127.0, 126.4, 126.0, 120. 4, 112.7, 109.5, 108.8, 102.5, 101.7, 93.7, 78.3, 58.5, 37.1; MS (ES+) m/z 557.4 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6](F)=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:4]=1[CH3:20])#[N:2].C(N(CC)CC)C.[CH3:28][N:29]([CH3:35])[C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([N:32]2[CH2:33][CH2:34][C@H:30]([N:29]([CH3:35])[CH3:28])[CH2:31]2)=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:4]=1[CH3:20])#[N:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: COC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1N1CC[C@H](N(C)C)C1
Temperature: 90 °C
Reaction time: 10 h
Yield: 86.6 %

Procedure:
Methyl 4-cyano-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-6-carboxylate (I-183) (100 mg, 0.37 mmol) was dissolved in dimethyl, then at room temperature, triethylamine (76 μl, 0.55 mmol) and (3S)-3-(dimethylamino)pyrrolidine (56 μl, 0.44 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 10 hours, then cooled to room temperature. This was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=92:8) to obtain the entitled compound (118 mg) as a roughly-purified product. This was washed with diisopropyl ether to obtain the entitled compound (109 mg, 81%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])C.CO.[OH-].[Na+].Cl>O>[CH2:13]([CH:5]([CH2:6][S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[C:4]([OH:20])=[O:3])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 299 mg of 2-benzyl-3-dimethylaminosulphonyl-propionic acid ethyl ester, 1 ml of methanol, 2 ml of water and 0.42 ml of 1H NaOH is stirred for 16 hours at room temperature, then neutralise with 0.42 ml of 1N HCl and extracted with ethyl acetate. The organic extracts are washed with water, dried, concentrated by evaporation and purified by chromatography on silica gel with eluant I. Rf (J)=0.48.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:16][CH2:17][CH:18]([N:21]2[CH2:25][CH2:24][CH2:2][NH:23][C:22]2=[O:26])[CH2:19][CH2:20]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNC2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 1-(1-t-butoxycarbonylpiperidin-4-yl)imidazolidin-2-one (20 mg, 0.07 mmol) in dichloromethane (2 mL) and the reaction stirred at room temperature overnight. The reaction was concentrated in vacuo to give the title compound as its trifluoroacetic acid salt (12 mg).
Reaction SMILES: Cl[O-:2].[Na+].[OH-].[Na+].[C:6]([C:8]1[CH:9]=[C:10]([C:18](=[O:20])C)[CH:11]=[CH:12][C:13]=1[CH2:14][CH:15]([CH3:17])[CH3:16])#[N:7].Cl>CO>[C:6]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[CH2:14][CH:15]([CH3:16])[CH3:17])[C:18]([OH:20])=[O:2])#[N:7]
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc(CC(C)C)c(C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cc1ccc(C(=O)O)cc1C#N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Subsequently, 10% aqueous sodium hypochlorite solution (370 ml) containing sodium hydroxide (8 g) and methanol (5 ml) was heated to 60° C. 3′-Cyano-4′-isobutylacetophenone (20 g) was added thereto by portions and the mixture was stirred for 1 h. The reaction mixture was cooled to room temperature and dilute hydrochloric acid was added, which was followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give 3-cyano-4-isobutylbenzoic acid (8.5 g), melting point: 118° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[N:9][N:10]=2)[CH:7]=1.Cl.Cl.[Cl:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:29]3[CH2:28][CH2:27][CH:26]([C:20]4[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=4[Cl:18])[CH2:31][CH2:30]3)=[O:13])=[N:9][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Reactant: Fc1cccc(C2CCNCC2)c1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cccc(F)c2Cl)CC1
Reaction time: 0.33 h
Yield: 48.1 %

Procedure:
To a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (102 mg, 0.38 mmol) in THF (3.1 mL) was added a solution of LiOH monohydrate (16 mg, 0.38 mmol) in H2O (2.0 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (4.0 mL) under an atmosphere of N2. To this mixture was added 4-(2-chloro-3-fluorophenyl)piperidine hydrochloride (14, 94 mg, 0.38 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (334 mg, 0.76 mmol), and diisopropylethylamine (0.20 mL, 1.1 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL) and the resulting precipitate was collected by filtration. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0 to 50% EtOAc in hexanes) to provide (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-3-fluorophenyl)piperidin-1-yl)methanone as a white solid (80 mg, 48%): 1H NMR (300 MHz, DMSO-d6) δ 9.11 (br s, 1H), 8.03-7.95 (m, 1H), 7.71 (dd, J=9.6, 1.8 Hz, 1H), 7.43-7.23 (m, 3H), 5.27-5.17 (m, 1H), 4.80-4.69 (m, 1H), 3.48-3.34 (m, 2H), 3.12-2.96 (m, 1H), 2.02-1.59 (m, 4H); ESI MS m/z 438 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)=[CH:9][N:8]([C:14]1[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=1)[N:7]=3.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][CH2:31][CH2:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:19]([N:15]1[C:14]([N:8]2[N:7]=[C:6]3[C:10]([CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:32][CH2:31][O:30][CH:25]6[CH2:26][CH2:27][CH2:28][CH2:29][O:24]6)[CH:37]=5)[CH:23]=[CH:22][C:5]=43)=[CH:9]2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(-c3cnn(CCOC4CCCCO4)c3)cc1OCC2
Temperature: 85 °C
Yield: 63.7 %

Procedure:
As shown in FIG. 9, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene 106 (160 mg, 0.43 mmol), 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole 43 (165 mg, 0.51 mmol), cesium carbonate (279 mg, 0.85 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (17 mg, 5 mol %) were combined in a reaction vial, the atmosphere evacuated and back-filled with nitrogen. THF (5 mL) and water (1 mL) were added and the reaction mixture heated at 85° C. for 4 h. The reaction mixture was diluted with ethyl acetate and water, the organic layer separated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 30% ethyl acetate in cyclohexane) to give 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene 45 (134 mg, 64%).
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH:8]([C:10]1[C:20]2=[C:21]3[C:16](=[CH:17][CH:18]=[CH:19]2)[CH2:15][CH2:14][CH2:13][N:12]3[N:11]=1)[CH3:9]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:8]([C:10]1[C:20]2=[C:21]3[C:16](=[CH:17][CH:18]=[CH:19]2)[CH2:15][CH2:14][CH2:13][N:12]3[N:11]=1)(=[O:7])[CH3:9]
Reactant: CC(O)c1nn2c3c(cccc13)CCC2
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1nn2c3c(cccc13)CCC2
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
19.7 g (0.25 mol) of pyridine were dissolved in 335 ml of methylene chloride. 15.2 (152 mmol) of chromium trioxide were added in portions under an atmosphere of nitrogen at temperatures below 35° C., and the mixture was stirred for 30 minutes. 4.0 g (0.02 mol) of 2-(1-hydroxyethyl)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline (obtained by reaction of 2-formyl-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline with 2.5 equivalent of methylmagnesium bromide), dissolved in 40 ml of methylene chloride were then added. The mixture was stirred for a few minutes, decanted and evaporated in vacuum. The residue was chromatographed over silicagel using methylene chloride/ethyl acetate (3/1) as a eluent. 3.5 g of the desired product were obtained after evaporation of the desired fractions. Melting point 101°-102° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11][NH2:12]>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(Cl)c1cccc(Br)n1
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(Br)n1
Reaction time: 0.25 h

Procedure:
A solution of 6-bromopicolinoyl chloride (Example 69A, 350 mg, 1.6 mmol) in tetrahydrofuran (4 mL) was added in portions via a pipette over 2 minutes to a solution of methylamine (40 wt. % in water, 4 mL, 46.2 mmol) in tetrahydrofuran (6 mL). The mixture was stirred for 15 minutes and partitioned between water (5 mL) and CH2Cl2 (25 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (25 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered and concentrated to provide the desired product, 6-bromo-N-methylpicolinamide. 1H NMR (300 MHz, CDCl3) δ ppm 3.03 and 3.04 (s and s, 3H), 7.45 and 7.60 (dd and dd, J=8.1, 1.0 Hz, 1H), 7.71 and 7.82 (t, J=7.8 Hz, 1H), 7.75-7.88 (bs, 1H), 8.11-8.18 (m, 1H); MS (DCI/NH3) m/z 215 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:5]=1[C:6](OC)=[O:7])(=[O:3])[CH3:2].[CH3:17][NH2:18]>C(O)C>[OH:3][C:1]1([CH3:2])[C:4]2[C:5](=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[C:6](=[O:7])[N:18]1[CH3:17]
Reactant: COC(=O)c1c(C(C)=O)cccc1[N+](=O)[O-]
Reactant: CN
Solvent: CCO
Product: CN1C(=O)c2c([N+](=O)[O-])cccc2C1(C)O
Yield: 85 %

Procedure:
A mixture of methyl 2-acetyl-6-nitrobenzoate (2 g, 8.96 mmol) and 33% methylamine in ethanol (10 mL) was stirred at reflux for 14 h. The solvents were removed under reduced pressure to afford 1.7 g of the desired product (yield: 85%). 1H NMR (CDCl3, 300 MHz): δ=1.80 (s, 3H), 3.05 (s, 3H), 7.78 (m, 2H), 7.95 (m, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([NH:7][C:8]1[N:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:11]2=[N:10][C:9]=1[C:17]1[S:18][C:19]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:21]=1)([CH3:6])([CH3:5])[CH3:4].CI.[C:32]([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CC(C)=O.CC#N.CC(=O)OCC.C1COCC1.O>[C:3]([N:7]([CH3:32])[C:8]1[N:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:11]2=[N:10][C:9]=1[C:17]1[S:18][C:19]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:21]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)Nc1c(-c2ccc(C#Cc3ccccn3)s2)nc2cnccn12
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(c1c(-c2ccc(C#Cc3ccccn3)s2)nc2cnccn12)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
43 mg (1.08 mmol, 60% in mineral oil) of sodium hydride were added to a solution of 135 mg (0.36 mmol) of tert-butyl-[2-(5-pyridin-2-ylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine (Example 77) in DMF (3 ml) and the mixture was stirred at RT for 1 h. A solution of 67 μl (1.08 mmol) of methyl iodide in DMF (500 μl) was then added dropwise thereto and the mixture stirred at RT for a further 16 h. A further 43 mg (1.08 mmol, 60% in mineral oil) of sodium hydride and a solution of 67 μl (1.08 mmol) of methyl iodide in DMF (500 μl) were then added and the mixture stirred at RT for a further 16 h. The reaction solution was combined in succession with water, a 1M aq. Na2CO3 solution and a mixture of EA/THF (3:1). The organic phase was separated off and the aq. phase was extracted with EA. The combined organic phases were dried over MgSO4, filtered and evaporated under a vacuum. 33 mg (0.09 mmol, 24%) of N-tert-butyl-N-methyl-2-(5-(pyridin-2-ylethynyl)thiophen-2-yl)imidazo[1,2-a]pyrazin-3-amine were obtained by CC (acetone/MeCN 1:1).
Reaction SMILES: [F:1][C:2]1([CH3:47])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:45][CH2:44][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:29][C:30]4[CH:42]=[CH:41][CH:40]=[CH:39][C:31]=4[C:32]([O:34]C(C)(C)C)=[O:33])[C:18]3=[O:43])[CH2:16][CH2:15]2)[C:3]1=[O:46].Cl>O1CCOCC1>[F:1][C:2]1([CH3:47])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:45][CH2:44][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:29][C:30]4[CH:42]=[CH:41][CH:40]=[CH:39][C:31]=4[C:32]([OH:34])=[O:33])[C:18]3=[O:43])[CH2:16][CH2:15]2)[C:3]1=[O:46]
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCN(CCCN3C(=O)C(C)(F)c4ccccc43)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC1(F)C(=O)N(CCCN2CCC3(CC2)C(=O)N(Cc2ccccc2C(=O)O)CN3c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 2-((8-(3-(3-fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.31 mmol) was added concentrated 4M HCl in dioxane (3 mL) and triethylsilane (0.05 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated, isolated by preparatory TLC (10% methanol/dichloromethane) and lyophilized with 4M HCl in dioxane (1 mL) to obtain the title compound as a hydrochloride salt (0.073 g, 38%); 1H NMR (DMSO-d6): δ 1.72 (d, 3H, J=23.2 Hz), 1.98-2.07 (m, 4H), 2.72 (t, 2H, J=10 Hz), 3.18 (br, 2H), 3.45-3.72 (m, 4H), 3.76 (t, 2H, J=6.8 Hz), 4.64 (s, 2H), 4.91 (s, 2H), 7.06-7.08 (m, 4H), 7.15 (t, 1H, J=7.6 Hz), 7.24 (d, 1H, J=7.6 Hz), 7.31 (d, 1H, J=7.2 Hz), 7.40-7.46 (m, 2H), 7.57 (t, 2H, J=7.6 Hz), 7.92 (d, 1H, J=8 Hz), 10.27 (br, 1H), 13.21 (s, 1H); MS for C33H34F2N4O4 m/z 589.3 (M+H)+.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2]O.[Cl:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[CH:9][CH:8]=1.Cl.N>>[Cl:6][C:7]1[N:12]=[C:11]2[NH:13][C:2]([CH2:1][OH:5])=[N:14][C:10]2=[CH:9][CH:8]=1
Reactant: O=C(O)CO
Reactant: Nc1ccc(Cl)nc1N
Agent: Cl
Agent: N
Product: OCc1nc2ccc(Cl)nc2[nH]1
Temperature: 150 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
6.60 g of glycolic acid were added to 5.00 g of 6-chloro-2,3-diaminopyridine (prepared as described in Preparation 42), and the resulting mixture was stirred at 150° C. for 4 hours. At the end of this time, the reaction mixture was treated with 3 N aqueous hydrochloric acid and subsequently made alkaline by the addition of aqueous ammonia. The aqueous mixture was evaporated to dryness, and the resulting residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent. The product was then crystallized by trituration with ethyl acetate, to give 5.33 g of the title compound, melting at 224-226° C.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][NH:18][C@H:19]1[CH2:38][N:23]2[C:24]3[C:29]([C:30]([CH2:31][C:32]([O:34]CCC)=[O:33])=[C:22]2[CH2:21][CH2:20]1)=[CH:28][CH:27]=[CH:26][CH:25]=3>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([N:18]([CH3:17])[C@H:19]2[CH2:38][N:23]3[C:24]4[C:29]([C:30]([CH2:31][C:32]([OH:34])=[O:33])=[C:22]3[CH2:21][CH2:20]2)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CN(C(=O)C(c1ccccc1)c1ccccc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from diphenylacetyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 453.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:78][N:79]([CH3:84])[CH2:80][CH2:81][CH2:82][NH2:83]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:83][CH2:82][CH2:81][CH2:80][N:79]([CH3:84])[CH3:78])=[O:28])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCCN
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 652.4 %

Procedure:
To a mixture of 0.125 g (0.257 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 9 mL of dimethylformamide was added 0.0521 g (0.386 mmole) of 1-hydroxybenzotriazole, 0.146 g (0.385 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.140 g (1.081 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0393 g (0.385 mmole) of 3-(dimethylamino)-propylamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.955 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-trifluoromethyl-benzamide (I-209) as a white solid.