Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f2) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:7]([NH:17][CH2:18][C:19](O)=[O:20])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C=O>[C:11]1([CH2:10][O:9][C:7](=[O:8])[NH:17][CH2:18][C:19](=[O:20])[NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Nn1cccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccccc1)Nn1cccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 18.8 %

Procedure:
To a solution of 1-aminopyrrole (2.46 g) and carbobenzyloxyglycine (6.28 g) in 120 ml of dry DCM and 10 ml of dry dimethylformamide was added DCC (8.00 g). The reaction mixture was stirred at room temperature over a period of 64 hours. The precipitate was removed by filtration and stirred in boiling ethyl acetate. The mixture was filtered and the filtrate was combined with the filtrate of the reaction mixture and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, DCM/methanol 20:1) yielding a first fraction (2.97 g) which was contaminated by DCU. A second fraction recrystallized from ethyl acetate afforded 1.54 g of the product as crystals, m.p. 146°-147° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[C:36]([CH:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.C[O-].[Na+]>C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[C:35]([CH3:34])[C:36]([CH:44]4[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:49]4)=[CH:37][C:38]=3[O:42][CH3:43])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 150 °C
Yield: 43.6 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (200 mg, 0.43 mmol), 5-methyl-2-(methyloxy)-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}aniline (Example 163, step D) (127 mg, 0.39 mmol), and p-toluenesulfonic acid (197 mg, 1 mmol) were weighed into a 20 mL microwave vial. 7 mL of trifluoroethanol was added and the mixture was heated in the microwave to 150° C. for 1 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2.5 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 2 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (135 mg, 0.17 mmol, 43%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 9.41 (d, J=6.04 Hz, 1H), 8.47 (s, 1H), 8.32 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.04 (d, J=7.69 Hz, 1H), 7.80 (d, J=7.87 Hz, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.59 (t, J=7.69 Hz, 1H), 7.53 (s, 1H), 7.43-7.49 (m, 1H), 7.39 (t, J=8.06 Hz, 1H), 7.19 (t, J=8.06 Hz, 2H), 6.98 (t, J=6.87 Hz, 1H), 6.88 (s, 1H), 6.51 (d, J=5.13 Hz, 1H), 3.80 (s, 3H), 3.27-3.30 (m, 2H), 3.05 (s, 3H), 2.98-3.03 (m, 2H), 2.73 (t, J=6.87 Hz, 2H), 2.59-2.68 (m, 1H), 2.18 (s, 3H), 2.03-2.14 (m, 2H), 1.64-1.74 (m, 4H). MS (ESI): 752 [M+H]+.
Reaction SMILES: C[O-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][OH:20])=[CH:13][CH:12]=1.C(OCC)(=O)C.I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCCCC1.Cl>O1CCCC1.[Br-].[Zn+2].[Br-].O.CO>[Br:10][C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:18]/[CH2:19][OH:20])=[CH:15][CH:16]=1
Reactant: OCC#Cc1ccc(Br)cc1
Reactant: Ic1ccccc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[O-]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: OC/C=C(\c1ccccc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (0.27 g, 0.5 mmol) was added to 1M solution of lithium aluminum hydride in tetrahydrofuran (12 mL, 12 mmol). The mixture was cooled to 0° C. and a solution of 3-(4-bromophenyl)prop-2-yn-1-ol (0.422 g, 2.0 mmol) in tetrahydrofuran (50 mL) was slowly added. The reaction was stirred for at 0° C. for 3 h, ethyl acetate (2.6 mL, 30 mmol) was added and the mixture was stirred for further 10 min without cooling. Iodobenzene (2.7 g, 13 mmol), anhydrous zinc bromide (1.4 g, 6 mmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (0.50 g, 0.5 mmol) were added and the mixture was evacuated and kept under nitrogen. A solution of tri-tert-butylphosphine in cyclohexane (6.7 mL, 1 mmol) was added and the mixture was heated at 60° C. for 16 h. Methanol (10 mL) was added and the resulting mixture was stirred for additional 1 h. The reaction mixture was poured into water, acidified with hydrochloric acid and extracted with ethyl acetate (3×100 mL). Organic layers were combined, dried with anhydrous sodium sulphate, evaporated in vacuo and the residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 98:2-70:30) affording (E)-3-(4-bromophenyl)-3-phenylprop-2-en-1-ol.
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:55][C@@H:56]([N:58]2[CH2:63][CH2:62][C@H:61]([OH:64])[C@@H:60]([CH3:65])[CH2:59]2)[CH3:57])CC1>>[ClH:1].[ClH:1].[OH:64][C@H:61]1[CH2:62][CH2:63][N:58]([C@@H:56]([CH3:57])[CH2:55][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:59][C@@H:60]1[CH3:65]
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCc5coc6cc(F)cc(F)c56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized from 4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (115, see example 66) and amine 56 analogously to the method described in example 1.
Reaction SMILES: N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.[CH3:19][C:20](=[O:25])[CH2:21][C:22](=O)[CH3:23].BrN1C(=O)CCC1=O.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH2:40]>C(Cl)(Cl)Cl.CCOC(C)=O.CO>[CH3:23][C:22]1[N:40]=[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]2[C:21]=1[C:20](=[O:25])[CH3:19]
Reactant: Nc1ccccn1
Reactant: CC(=O)CC(C)=O
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)nc2ccccn12
Reaction time: 1 h
Yield: 35.5 %

Procedure:
1,1′-Azobis(cyclohexanecarbonitrile) (catalytic amount) was added to a solution of pentane-2,4-dione (1.00 g, 9.99 mmol) and N-bromosuccinimide (1.96 g, 10.99 mmol) in CHCl3 (20 mL). The reaction mixture was stirred for 1 hour, filtered and the filtrate was concentrated under reduced pressure. The residue was re-dissolved in a 1:1 mixture of THF/Et2O (20 mL), then pyridin-2-amine (723 mg, 7.68 mmol) was added and the reaction mixture was refluxed overnight. After cooling the solvent was removed under reduced pressure and the residue was purified by column chromatography, eluents EtOAc, then EtOAc-MeOH (96:4), to afford the title compound (475 mg 35% yield). 1H NMR (DMSO-d6) δ (ppm): 9.59 (dt, J=6.8, 1.4 Hz, 1H), 7.68 (dt, J=8.8, 1.2 Hz, 1H), 7.56 (ddd, J=8.8, 6.8, 1.4 Hz, 1H), 7.17 (td, J=6.8, 1.4 Hz, 1H), 2.72 (s, 3H), 2.58 (s, 3H). MS (m/z): 174.20 (calc) 175.1 (MH+) (found).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].[N:29]#[C:30]Br.C([O-])(O)=O.[Na+]>O1CCOCC1.O.CCOC(C)=O>[NH2:29][C:30]1[O:24][C:23]([C:22]2[CH:27]=[CH:28][C:19]([C:18]3[CH:17]=[N:16][N:13]4[CH:14]=[CH:15][C:10]([N:5]5[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]5=[O:9])=[N:11][C:12]=34)=[CH:20][CH:21]=2)=[N:25][N:26]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)NN)cc3)c2n1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nnc(N)o4)cc3)c2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 49 %

Procedure:
To a suspension of (S)-4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide (50 mg, 0.131 mmol) in 3 mL of p-dioxane was added cyanogen bromide (30.6 mg, 0.289 mmol) followed by a solution of NaHCO3 (13.3 mg, 0.158 mmol) in 1.5 mL of water. The resulting mixture became a clear tan solution within 3 minutes, and was allowed to stir at ambient temperature for 17 hours. The reaction was diluted with EtOAc, and the organic layer was washed with water and brine. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude was purified by silica gel flash column chromatography (0-8% MeOH in dichloromethane) to afford 26 mg (49%) of (S)-3-(3-(4-(5-amino-1,3,4-oxadiazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one. 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, 1H), 8.79 (s, 1H), 8.26 (d, 2H), 7.91 (d, 1H), 7.82 (d, 2H), 7.23 (s, 2H), 4.97 (m, 1H), 4.52 (d, 2H), 2.76 (m, 1H), 1.06 (d, 3H), 0.86 (d, 3H); LCMS (APCI+) m/z 406.4 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[F:10].[Na].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>O1CCCC1>[F:10][C:4]1[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][CH:13]([C:14](=[O:15])[CH3:16])[C:12]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(C)=O
Reactant: Fc1cccc(CBr)c1F
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cccc(F)c1F)C(C)=O
Yield: 78.8 %

Procedure:
A solution of 1-(bromomethyl)-2,3-difluorobenzene (1.6 g) and ethyl acetoacetate sodium salt (2.36 g) in tetrahydrofuran (20 mL) was stirred for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.56 g, 79%) as a colorless viscous oil.
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[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:66][CH2:67][CH2:68][CH2:69][N:70]1[CH2:74][CH2:73][CH2:72][C:71]1=[O:75]>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[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:66][CH2:67][CH2:68][CH2:69][N:70]5[CH2:74][CH2:73][CH2:72][C:71]5=[O:75])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCN1CCCC1=O
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCCN2CCCC2=O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 78.7 %

Procedure:
A mixture of 0.045 g (0.1 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-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.017 g (0.12 mmole) 1-(3-amino-propyl)-pyrrolidin-2-one was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.045 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)-3-methoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide (I-113) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1/[CH:31]=[CH:32]/[C:33](Cl)=[O:34])([O-:24])=[O:23]>C(Cl)Cl>[CH3:21][C:5]1([CH3:20])[C:4]2[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH:1][C:33](=[O:34])/[CH:32]=[CH:31]/[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N+:22]([O-:24])=[O:23])[CH:3]=2)[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Reactant: O=C(Cl)/C=C/c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)/C=C/c3ccccc3[N+](=O)[O-])c([N+](=O)[O-])cc21

Procedure:
To a solution of A8 (0.6 g) is added freshly prepared (E)-3-(2-nitro-phenyl)-acryloyl chloride (0.7 g; 3,31 mmol). The mixture is stirred for 2 h at RT in dry CH2Cl2 (15 ml). After an aqueous work-up the compound is obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O.CO>CN(C=O)C>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: CN(C)C=O
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4-1) (1.53 g, 10.0 mmol) in DMF (20 mL) was added N-bromosuccinimide (1.78 g, 10.0 mmol) in DMF (10 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 1 h. Methanol (25 mL) was added, and the reaction mixture was stirred for an additional 1 h. The solvent was evaporated and the residue was crystallized from methanol to give the title compound as white solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]2)=[O:23])=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)cc1)N1CCN(C2CCC2)CC1
Yield: 56 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (56%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:30][CH2:31][CH2:32][CH2:33][F:34])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([O:27][CH3:28])=[CH:19][C:18]3=[O:29])=[N:15][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)(=O)C>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:30][CH2:31][CH2:32][CH2:33][F:34])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([O:27][CH3:28])=[CH:19][C:18]3=[O:29])=[N:15][C:11]=2[CH:10]=1
Reactant: COc1cc(=O)n(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCF)c2ccccc12
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(=O)n(Cc2nc3cc(CN)ccc3n2CCCCF)c2ccccc12
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of [1-(4-fluoro-butyl)-2-(4-methoxy-2-oxo-2H-quinolin-1-ylmethyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (20 mg, 0.039 mmol) in DCM (1 mL) was added TFA (91 μL, 1.2 mmol). The solution was allowed to reach room temperature and stirred for 3 hrs. The volatiles were removed in vacuo and the residue was stripped with DCM and methanol. The TFA salt was dissolved in methanol followed by the addition of acetyl cloride (28 μL, 0.39 mmol) and concentrated. The product was dissolved in methanol and dichloromethane and concentrated (twice) then the resiude was triturated in diethyl ether to give 1-[5-aminomethyl-1-(4-fluoro-butyl)-1H-benzoimidazol-2-ylmethyl]-4-methoxy-1H-quinolin-2-one; HCl salt (11 mg, 65%) as an off white solid:
Reaction SMILES: Cl.[N:2]1([C:6]([C:8]2[CH:41]=[CH:40][C:11]([O:12][C:13]3[CH:14]=[C:15]([CH:25]=[C:26]([O:28][C@@H:29]([CH3:39])[CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH:27]=3)[C:16]([NH:18][C:19]3[S:23][N:22]=[C:21]([CH3:24])[N:20]=3)=[O:17])=[C:10]([F:42])[CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+]>CO>[N:2]1([C:6]([C:8]2[CH:41]=[CH:40][C:11]([O:12][C:13]3[CH:14]=[C:15]([CH:25]=[C:26]([O:28][C@@H:29]([CH3:39])[CH2:30][OH:31])[CH:27]=3)[C:16]([NH:18][C:19]3[S:23][N:22]=[C:21]([CH3:24])[N:20]=3)=[O:17])=[C:10]([F:42])[CH:9]=2)=[O:7])[CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nsc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
10% Hydrochloric acid (2 mL) was added to a solution of 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide (950 mg, 1.58 mmol) in methanol (20 mL). The reaction was stirred at ambient temperature for 1 hour, saturated sodium bicarbonate solution added and the methanol evaporated. The aqueous residue was taken to pH2 and extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with ethyl acetate, to give the desired compound (400 mg) which was recrystallised from ethyl acetate (mpt 173° C.-175° C.).
Reaction SMILES: CP(C)C.[N:5]([CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[O:16])[S:12][CH:13]=1)=[N+]=[N-].[ClH:26]>C1COCC1>[ClH:26].[NH2:5][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[O:16])[S:12][CH:13]=1
Reactant: [N-]=[N+]=NCc1csc(NC(=O)NCc2cccc(F)c2)n1
Agent: CP(C)C
Agent: Cl
Solvent: C1CCOC1
Product: NCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reaction time: 22 h

Procedure:
Trimethylphosphine (107 μL, 1.2 mmol) was added dropwise to a THF (5 mL) solution of 1-(4-(azidomethyl)thiazol-2-yl)-3-(3-fluorobenzyl)urea (307 mg, 1.0 mmol) at 0 C under a nitrogen atmosphere. The mixture was stirred for 22 hours then HCl (0.5 mL, 4M in water) was added and the stirring was continued for 22 hours. Upon evaporation of the mixture, the product was recrystallized from acetonitrile to afford 1-(4-(aminomethyl) thiazol-2-yl)-3-(3-fluorobenzyl)urea hydrochloride. 1H NMR (400 MHz, CD3OD): δ 10.3 (1H, br), 7.34 (m, 1H), 7.17-6.95 (m, 4H), 4.45 (s, 2H), 4.08 (s, 2H). MS (ES+): M/Z 281 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([OH:12])=O)=[CH:8][C:7]([CH3:13])=[N:6]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][C:47]=1[CH3:48])[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[N:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[CH:46][C:47]([CH3:48])=[C:26]([NH:25][C:10]([C:9]5[N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=[C:7]([CH3:13])[CH:8]=5)=[O:12])[CH:27]=4)=[N:35][N:34]3[CH:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: COCCn1nc(C)cc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: COCCn1nc(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1C
Yield: 75.8 %

Procedure:
In the same manner as in Example 259 and using 1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylic acid (150 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (83 μL, 0.97 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (230 mg, 77%) was obtained as a pale-green solid.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH3:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[CH2:8][CH2:7]1>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([CH3:5])[CH2:7][CH2:8]1
Reactant: CN1CCC(=O)c2ccccc21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCN(C)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxylamine hydrochloride (0.88 g, 10.6 mmol) was added to a solution of Example 17A (1.55 g, 9.6 mmol) in pyridine (20 mL) and the mixture stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure and ethyl acetate (200 mL) was added. The organic layer was washed twice with water (200 mL) and brine, dried over sodium sulfate, filtered, and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-20% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.76 (t, J=6.61 Hz, 2H), 2.83 (s, 3H), 3.11 (t, J=6.61 Hz, 2H), 3.87 (s, 3H), 6.69 (t, J=7.46 Hz, 1H), 6.75 (d, J=8.48 Hz, 1H), 7.22 (td, J=7.80, 1.70 Hz, 1H), 7.73 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z 191.07 (M+H)+.