Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[OH:22][N:23]=[C:24](Br)[Br:25]>CN(C=O)C.O.C(OCC)(=O)C>[Br:25][C:24]1[CH2:3][CH:2]([CH2:1][O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[O:22][N:23]=1
Reactant: ON=C(Br)Br
Reactant: C=CCOc1ccc2c(c1)CCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OCC3CC(Br)=NO3)ccc2N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a solution of 6-(allyloxy)-3,4-dihydroquinolin-2(1H)-one (1.85 g, 9.10 mmol) in DMF (20 mL) and water (5 mL), K2CO3 (3.77 g, 27.3 mmol) were added and the reaction mixture was cooled to 0° C. Hydroxycarbonimidic dibromide (3.69 g, 18.21 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over Na2SO4. The organic layer was concentrated and the crude material purified by flash chromatography on silica gel using ethyl acetate/hexane as eluant to give 6-((3-bromo-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as a white solid (1.8 g, 59.6%). 1HNMR: 400 MHz, DMSO-d6: δ 2.40 (q, J=7.20 Hz, 2H), 2.83 (t, J=8.00 Hz, 2H), 3.18 (dd, J=7.60, 17.60 Hz, 1H), 3.50 (dd, J=10.80, 17.40 Hz, 1H), 4.01-4.09 (m, 2H), 4.98-5.03 (m, 1H), 6.72-6.81 (m, 3H), 9.92 (s, 1H). LCMS: RT 1.408 min; LCMS (ES-API), m/z 327 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=O.Cl.[OH:13][NH2:14].C([O-])(=O)C.[Na+].C(O)C>O>[CH3:1]/[C:2](/[NH:14][OH:13])=[C:4]1/[CH:5]=[CH:6][C:7]([CH:8]=[C:9]/1[OH:10])=[O:11]
Reactant: NO
Reactant: CC(=O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C/C(NO)=C1/C=CC(=O)C=C1O
Yield: 93.4 %

Procedure:
A mixture of 306 g of 2,4-dihydroxyacetophenone, 164 g of hydroxyamine hydrochloride, 328 g of sodium acetate, 1,000 ml of ethanol and 500 ml of water was refluxed by heating for 4 hours. The reaction solution was poured into 10 l of water to precipitate crystals and these crystals were collected by filtration. 314 g of 2,4-dihydroxyacetophenoneoxime was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:12][B-:13]([F:16])([F:15])[F:14].[N:17]#[O+].[K+].[Br-]>C(#N)C.C(Cl)Cl>[F:12][B-:13]([F:16])([F:15])[F:14].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N+:9]#[N:17])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)c1ccc([N+]#N)cc1
Yield: 78 %

Procedure:
The 4-tert-butylaniline was dissolved in a 1:1 mixture of acetonitrile and dry methylene chloride prior to addition to the nitrosonium tetrafluoroborate. Yield: 78%. MP 91° C. IR (KBr) 3364.8, 3107.3, 2968.6, 2277.2, 1579.2, 1482.0, 1418.0, 1373.5, 1269.8, 1056.9, 841.1, 544.6, 621.4 cm−1. 1H NMR (400 MHz, CD3CN) δ 8.16 (ABq, J=9.0 Hz, Δv=298.7 Hz, 4H), 1.30 (s, 12H). 13C NMR (100 MHz, CD3CN) δ 168.85, 133.67, 130.43, 111.88, 37.86, 30.84.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[NH2:29][C:30]1[C:38]2[C:33](=[N:34][CH:35]=[C:36]([Br:53])[C:37]=2[N:39]2[CH2:44][CH2:43][CH2:42][C@@H:41]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:40]2)[NH:32][CH:31]=1>CC#N.O.O.CN1C(=O)CCC1>[Br:53][C:36]1[C:37]([N:39]2[CH2:44][CH2:43][CH2:42][C@@H:41]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])[CH2:40]2)=[C:38]2[C:30]([NH:29][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:31][NH:32][C:33]2=[N:34][CH:35]=1
Reactant: N#CCC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(N)c23)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CC#N)c23)C1
Reaction time: 18 h
Yield: 25.8 %

Procedure:
2-Cyanoacetic acid (0.332 g, 3.90 mmol), BOP-Cl (0.993 g, 3.90 mmol), and triethylamine (1.02 mL, 7.31 mmol) were added to an NMP solution (2 mL) of (R)-tert-butyl 1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.200 g, 0.487 mmol; Example 98, Step A). The reaction was then stirred for 18 hours, then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95% CH3CN/water) to give (R)-tert-butyl 1-(5-bromo-3-(2-cyanoacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.06 g, 26% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:30][CH2:31][C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])[C:5]2[N:6]([C:8]([C:12]([NH:14][CH:15]([CH3:29])[C@@H:16]([NH:18]C(=O)OCC3C=CC=CC=3)[CH3:17])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1>C(O)C.[Pd]>[NH2:18][C@@H:16]([CH3:17])[CH:15]([NH:14][C:12]([C:8]1[N:6]2[CH:7]=[CH:2][CH:3]=[C:4]([O:30][CH2:31][C:32]3[C:33]([F:39])=[CH:34][CH:35]=[CH:36][C:37]=3[F:38])[C:5]2=[N:10][C:9]=1[CH3:11])=[O:13])[CH3:29]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)NC(C)[C@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)[C@H](C)N
Reaction time: 3 h

Procedure:
155 mg of benzyl {(2S)-3-[({6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]butan-2-yl}carbamate (Example 191A, 0.28 mmol, 1 equivalent) were dissolved in 50 ml of ethanol, and 40 mg of palladium on activated carbon (5%) were added. The mixture was hydrogenated at RT and standard pressure for 3 h. After the reaction had ended, the mixture was filtered through silica gel, the residue was washed with ethanol and the mother liquor was concentrated under reduced pressure. The crude product obtained was purified by preparative HPLC (Method 9).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][O-:13].[Na+].O>CO>[CH3:12][O:13][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A roundbottom flask was charged with a solution of 6-chloro-2-methyl-3-nitropyridine (12.0 g, 69.36 mmol) in methanol (100 ml). Sodium methanolate (5.6 g, 103.70 mmol) was added and the resulting solution was stirred at room temperature for 24 hours. The mixture was poured into 100 ml of water and the solids that formed were collected by filtration to afford the title compound.
Reaction SMILES: N1C=CN=C1.[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12]/[C:13]/2=[N:16]/[OH:17])=[CH:9][CH:8]=1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>C(Cl)Cl>[CH:18]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:17]/[N:16]=[C:13]1/[CH2:12][CH2:11][C:10]2[C:14]/1=[CH:15][C:7]([Br:6])=[CH:8][CH:9]=2)([CH3:20])[CH3:19]
Reactant: O/N=C1/CCc2ccc(Br)cc21
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)[Si](O/N=C1/CCc2ccc(Br)cc21)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of imidazole (11 g, 162 mmol) in 100 mL of dry DCM was added dropwise to a solution of (Z)-6-bromo-2,3-dihydro-1H-inden-1-one oxime (1C) (18.2 g, 81 mmol) and triisopropylsilyl chloride (23.3 g, 121.5 mmol) in solution in 40 mL of dry DCM. The reaction mixture was stirred for 16 hours at rt. It was then filtered to remove the precipitate and the filtrate was concentrated under vacuum. The crude material was purified by column chromatography on silica gel to provide (Z)-6-bromo-2,3-dihydro-1H-inden-1-one O-triisopropylsilyl oxime (1D). The crude product was taken on to the next step immediately.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[CH:4][S:5][C:6]=1[CH2:7][CH3:8].[ClH:12].[CH:13](O)([CH3:15])[CH3:14]>>[ClH:12].[CH:13]([O:10][C:9]([C:3]1[C:2]([NH2:1])=[C:6]([CH2:7][CH3:8])[S:5][CH:4]=1)=[O:11])([CH3:15])[CH3:14]
Reactant: CCc1scc(C(=O)O)c1N
Reactant: CC(C)O
Agent: Cl
Product: CCc1scc(C(=O)OC(C)C)c1N

Procedure:
A sample of 1.02 g. (4.610 mmols) of 4-amino-5-ethyl-3-thiophenecarboxylic acid was dissolved in 50 ml. of isopropanol which had been previously saturated with gaseous hydrogen chloride. The resulting reaction was heated under reflux for 48 hours, cooled and evaporated to afford 0.927 g. (81%) of pure 4-amino-5-ethyl-3-thiophenecarboxylic acid isopropyl ester hydrochloride, m.p. 159° C. (dec.) after recrystallization from isoprpopanol/ether.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13](Cl)[N:12]=2)=[CH:7][C:6]=1[CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([NH2:29])[CH:28]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[Cl:17][C:16]1[CH:15]=[N:14][C:13]2[NH:29][C:27]3[CH:26]=[N:25][CH:24]=[C:23]([CH:28]=3)[CH2:22][CH2:21][C:6]3[CH:7]=[C:8]([CH2:9][NH:10][C:11]=1[N:12]=2)[CH:19]=[CH:20][C:5]=3[NH2:4]
Reactant: Nc1cncc(CCc2cc(CNc3nc(Cl)ncc3Cl)ccc2N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)NC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.3 %

Procedure:
Into a reaction flask were added N-{4-amino-3-[2-(5-aminopyridin-3-yl)ethyl]benzyl}-2,5-dichloropyrimidin-4-amine trihydrochloride (0.29 g, 0.74 mmol), 1,4-dioxane (5 mL), and triethylamine (0.31 mL, 2.2 mmol). The mixture was stirred at rt under N2 for 5 minutes, followed by an addition of palladium acetate (5 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (12.9 mg, 0.02 mmol), and cesium carbonate (500 mg, 2.0 mmol). The reaction mixture was degassed with N2 bubbling. The tube was then sealed and heated at 160° C. for 2 hours. After concentration, the crude product was purified by silica gel column chromatography to give the desired product as a white powder (100 mg, 42%). LCMS for C18H18ClN6 (M+H)+: m/z=353.0. 1H NMR (400 MHz, DMSO-d6): δ 9.65 (s, 1H), 8.44 (d, J=1.6 Hz, 2H), 8.16 (d, J=2.3 Hz, 1H), 8.01 (s, 1H), 7.11 (m, 2H), 7.03 (m, 2H), 6.69 (s, 1H), 4.14 (d, J=5.8 Hz, 2H), 2.88 (m, 4H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH:11]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:10]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:36][N:37](C)C=O>ClCCl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[C:21]([O:20][C:18](=[O:19])[NH:17][CH:11]1[CH2:12][CH2:13][C:14]2[C:9](=[CH:8][C:7]([C:36]#[N:37])=[CH:16][CH:15]=2)[CH:10]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Diphenylphosphinoferrocene (100 mg, 0.18 mmol) and dipalladium trisdibenzylideneacetone (41 mg, 0.045 mmol) were suspended under an atmosphere of argon in dry dimethylformamide (5 mL). After stirring at room temperature for 40 min 7-[(tert-butoxycarbonyl)amino]-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (0.5 g, 0.902 mmol) was added and the reaction mixture was heated to 90° C. Over 30 min zinc cyanide (159 mg, 1.353 mmol) was added in small portions. After complete addition stirring was continued at 90° C. for 2 h. The reaction mixture was cooled to room temperature diluted with dichloromethane (50 mL), washed with saturated NaHCO3 (3×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane, silica gel). Yield: 97 mg (0.225 mmol, 25%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=[O:32])[NH:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)[C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([S:36]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=2)[CH2:41][CH2:40]1)(=[O:38])=[O:37])[CH2:34][CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=[O:32])[NH:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:24]=[CH:25][C:26]([C:29](=[O:30])[NH:52][C:49]3[CH:50]=[CH:51][C:46]([CH2:45][N:42]4[CH2:41][CH2:40][N:39]([S:36]([CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])[CH2:44][CH2:43]4)=[CH:47][CH:48]=3)=[CH:27][CH:28]=2)[C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)[C@H]5CCCCN5C(=O)OC(C)(C)C)ccc4Cl)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(4′-Carboxy-6-chloro-biphenyl-3-ylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (73 mg), 4-(4-(propane-1-sulfonyl)-piperazin-1-ylmethyl)-phenylamine (118 mg) and HBTU (91 mg) in dry DMF (4 ml) containing N-methylmorpholine (52 μl) was stirred at room temp for 18 h.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[N:3]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[C:4]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccsc2)[nH]c1C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(-c2ccsc2)n(S(=O)(=O)c2ccccc2)c1C
Yield: 40 %

Procedure:
Using ethyl 2-methyl-5-(3-thienyl)-1H-pyrrole-3-carboxylate (1.25 g), sodium hydride (60% in oil, 255 mg) and benzenesulfonyl chloride (1.22 mL), a procedure as in Reference Example 4 was performed to give the title compound as white crystals (yield 0.80 g, 40%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].B>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Agent: B
Solvent: C1CCOC1
Product: NCc1cccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a solution of 3-cyano-N-(3,5-dichlorobenzyl)-N-(4-fluorobenzyl)benzenesulfonamide (0.9 g, 2.00 mmol) in THF (10 mL) at rt was added dropwise a solution of borane (1 M solution in THF) (16 mL, 16.02 mmol) under nitrogen atmosphere. The reaction mixture was stirred at rt. for 3 h, acidified by dropwise addition of TEA and it was stirred for 30 min. The solvents were removed and the residue was diluted with ethyl acetate and saturated aq NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4, and the crude product was purified by flash silica gel column chromatography on silica gel (ISCO. Column: 24 g. Eluent: A: CH2Cl2. B: 10% of 2 M ammonia in MeOH of ethyl acetate. Condition: A to 40% of B (45 min gradient) to obtain the desired product as a white solid (0.29 g, 32%). 1H NMR (CDCl3): δ 7.82 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.20-7.19 (m, 1H), 7.11-7.08 (m, 2H), 6.97-6.92 (m, 2H), 6.86-6.85 (m, 2H), 4.32 (s, 2H), 4.26 (s, 2H), 4.00 (s, 2H), 1.58 (bs, 2H); MS (ESI): [M+H]+=452.9.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:26](Cl)=[O:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2>>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:26]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:27])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[O:19][C:20]2[C:25]1=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: C1COCCN1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(N1CCOCC1)C1(CCCCBr)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from morpholine and 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[CH3:34][N:35]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:39]2[N:35]([CH3:34])[N:36]=[CH:37][CH:38]=2)[CH:3]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1nccc1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Yield: 66.7 %

Procedure:
N-(4-Fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.250 g, 0.44 mmol) was reacted with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.183 g, 0.88 mmol), sodium carbonate (0.150 g, 1.41 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.10 g) to give 0.152 g (65% yield) of the title material as a white solid after chromatography on silica gel. 1H NMR 400 MHz (CDCl3) δ (ppm): 1.63 (6H, s, 2×CH3), 3.69 (3H, s, NCH3), 4.0-4.1 (4H, m, 2×CH2), 4.34 (2H, d, J=6.6 Hz, NCH2), 5.29 (2H, s, OCH2), 6.26 (1H, d, J=2.0 Hz, CH), 6.98 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.13 (1H, m, aromatic), 7.3-7.35 (3H, m, aromatics), 7.47-7.55 (4H, m, aromatics and NH), 7.57 (1H, d, J=2.0 Hz, CH). MS (ESI+) m/z 518 [M+H+].
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:14][N:13]=2)=[CH:8][CH:7]=1>CN(C)C=O.O>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CN=C=O
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Nc1ccc(C2=NN=C(C)Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.4 %

Procedure:
0.8 ml (13.4 mmol) of methyl isocyanate was added to a solution containing 1.0.g (3.41 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 8 ml of dimethylformamide (DMF), then the reaction mixture was stirred at 25° C. for 24 hours. After diluting with 80 ml of water, filtering at 5° C. and drying at 60° to 100° C., 1.06 g of raw product, m.p.: 204°-207° C. (sintering from 160° C.) were obtained which, when recrystallized from 5 ml of ethanol, gave 0.85 g (71.4%) of the aimed product, m.p.: 223°-224° C. (decomp.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:3]=1[C:19](OCC)=[O:20].CC(C[AlH]CC(C)C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1>[F:18][C:14]1[CH:13]=[C:12]([C:4]2[C:3]([CH2:19][OH:20])=[CH:2][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c(-c2cccc(F)c2)nc2cccnc2c1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1cc2ncccc2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 4-chloro-2-(3-fluorophenyl)-1,5-naphthyridine-3-carboxylate (614 mg, 1.856 mmol) in toluene (10 mL) at 0° C. was added DIBAL-H (4.1 mL, 4.1 mmol) dropwise over 2 min. After this time the reaction was allowed to warm to rt for 1 h. After this time more DIBAL-H (4.1 mL, 4.1 mmol) was added and the reaction was stirred at rt overnight. After this time lithium aluminium hydride (0.92 mL, 3.68 mmol, 4.0M solution in THF) was added and the reaction was stirred at rt for 10 min. After this time the reaction was carefully quenched with water (8 mL), NaOH (5 mL, 1.0M aq. solution) and water (5 mL). To the stirred mixture was added EtOAc (50 mL) and Rochelle's salt (50 mL, satd aq. solution) and the mixture was stirred at rt for 2 h. After this time the separated organic layer was washed with water, dried over MgSO4, filtered and concentrated in vacuo. The resulting solid was purified by column chromatography on silica gel using a gradient from 1:0 to 1:2 of hexane:EtOAc to give (2-(3-fluorophenyl)-1,5-naphthyridin-3-yl)methanol: LC-MS (ESI) m/z 255.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[N:7]=[C:6]1[NH:20][C:21]1[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([C:16]([O:18][CH3:19])=[O:17])=[C:9]2[C:8]=1[N:7]=[C:6]1[N:20]([C:21]3[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=3[CH3:27])[CH2:2][CH2:3][CH2:4][N:5]21
Reactant: COC(=O)c1ccc(OC)c2nc(Nc3c(C)nc(OC)nc3C)n(CCCCl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A mixture of methyl 1-(3-chloropropyl)-4-methoxy-2-[(2-methoxy-4,6-dimethylpyrimidin-5-yl)amino]-1H-benzimidazole-7-carboxylate (878.9 mg, 2.03 mmol) and potassium carbonate (0.84 g, 6.08 mmol) in N,N-dimethylformamide (9.0 mL) was stirred at 70° C. for 16 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water (×3) and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The Precipitated pale yellow solid was collected by filtration, washed with diisopropyl ether to give the title compound (720.7 mg, 1.81 mmol, 89%) as a pale yellow solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([C:24]1([CH2:30][N:31]2[CH2:36][CH2:35][C:34]([CH2:38][NH:39][C:40](=O)[O:41]C(C)(C)C)([F:37])[CH2:33][CH2:32]2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([C:24]1([CH2:30][N:31]2[CH2:32][CH2:33][C:34]([CH2:38][NH:39][C:40]([N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]3=[O:13])=[O:41])([F:37])[CH2:35][CH2:36]2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCC1(F)CCN(CC2(C(=O)OCc3ccccc3)CCOCC2)CC1
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Product: CC(C)n1c(=O)n(C(=O)NCC2(F)CCN(CC3(C(=O)OCc4ccccc4)CCOCC3)CC2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-Butyl ({1-[(4-benzyloxycarbonyltetrahydro-2H-pyran-4-yl)methyl]-4-fluoropiperidin-4-yl}methyl)carbamate (step 5 of Example 15).