Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: C#C[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(F)cc(C#N)c1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-5-fluorobenzonitrile (2.5 g, 12.5 mmol), (trimethylsilyl)acetylene (2.86 ml, 20 mmol), bis(acetate)bis(triphenylphoshpino) Palladium(II) (936 mg, 1.25 mmol) and triethylamine (35 ml) in toluene (35 ml) was 15 degassed by bubbling nitrogen through the solution and then stirred at 95° C. for 30 minutes. Filtration and concentration to yield a crude product. It was diluted with EtOAc (150 ml). The organic phase was washed with saturated NaHCO3 solution (50 ml), brine (50 ml) and the organic layer was dried over sodium sulfate. Filtration and concentration to yield a product A293.1 (2.4 g, 88%). HPLC: 95%, retention time: 4.05 minute (condition A). LC/MS (M+H)+=218.2.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[CH:20]=[CH:19][C:9]2[S:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][NH:14][C:8]=2[CH:7]=1.C(N(CC)CC)C>O1CCCC1>[Cl:5][C:6]1[CH:20]=[CH:19][C:9]2[S:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]([C:1]([Cl:4])=[O:2])[C:8]=2[CH:7]=1
Reactant: Clc1ccc2c(c1)NCc1ccccc1S2
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)N1Cc2ccccc2Sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold (ice-H2O bath), stirred solution of phosgene (1.93M in toluene; 8.6 mL) in anhydrous tetrahydrofuran (40 mL) under a nitrogen atmosphere is added, dropwise, a solution of the product of Example 104 (8-chloro-10,11-dihydrodibenzo[b,f][1,4]thiazepine) (2.00 g) and triethylamine (1.3 mL) in anhydrous tetrahydrofuran (30 mL). The resulting mixture is stirred at room temperature for 90 minutes, and the solvent is then evaporated in vacuo to provide the title product.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:32]=[CH:31][C:23]2[O:24][C@H:25]([C:28](O)=[O:29])[CH2:26][O:27][C:22]=2[CH:21]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:11][C:10]1[CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH3:17])=[CH:6][C:5]=1[C@H:3]([NH:2][C:28]([C@H:25]1[O:24][C:23]2[CH:31]=[CH:32][C:20]([C:19]([F:34])([F:18])[F:33])=[CH:21][C:22]=2[O:27][CH2:26]1)=[O:29])[CH3:4]
Reactant: O=C(O)[C@@H]1COc2cc(C(F)(F)F)ccc2O1
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](C)NC(=O)[C@@H]2COc3cc(C(F)(F)F)ccc3O2)c(F)cc1NS(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (48 mg, 0.17 mmol) in N,N-dimethylformamide (3 mL) was stirred for 5 mins. (S)-6-trifluoromethyl-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxylic acid (40 mg, 0.1 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (200 mg, 0.4 mmol) and N,N-diisopropylethylamine (50 μL, 0.3 mmol) was added and the reaction was stirred at 50° C. overnight. Purification by HPLC afforded the final compound. m/z=477.1 (M+H)+. 1H NMR (400 MHz; DMSO-d6) δ 9.16 (s, 1H), 8.66 (t, 1H, J=8.3 Hz), 7.38 (d, 1H, J=2.2 Hz), 7.28-7.21 (m, 2H), 7.05-7.01 (m, 1H), 6.88 (d, 1H, J=8.5 Hz), 5.17-5.08 (m, 1H), 5.04-5.01 (m, 1H), 4.45-4.41 (m, 1H) 4.37-4.31 (m, 1H), 2.99 (s, 3H), 2.09 (s, 3H), 1.37 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:13][O:12][CH:11]([CH2:14][CH:15]=[O:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][CH:9]1[CH2:13][O:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCC1CC(OCc2ccccc2)CO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCC1CC(OCc2ccccc2)CO1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a stirred solution of 2-(4-(benzyloxy)tetrahydrofuran-2-yl)acetaldehyde (2.46 g, 11.17 mmol) in methanol (50 mL) was added NaBH4 (0.423 g, 11.17 mmol), in small portions, at room temperature. After 2 h, the reaction mixture was concentrated and the residue was taken up in sat. Na2CO3 (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give 2-(4-(benzyloxy)tetrahydrofuran-2-yl)ethanol (2.3847 g, 10.73 mmol, 96% yield) as a colorless oil consisting of a ˜4:1 mixture of diastereomers. 1H NMR (500 MHz, CDCl3) δ: 7.23-7.38 (5 H, m), 4.49 (1.6 H, s), 4.42 (0.4 H, d, J=1.5 Hz), 4.17-4.29 (1 H, m), 3.99-4.11 (2 H, m), 3.74-3.82 (2 H, m), 3.70 (0.8 H, dd, J=9.8, 4.9 Hz), 3.61 (0.2 H, dd, J=9.9, 5.0 Hz), 2.52 (0.8 H, t, J=5.6 Hz), 2.48 (0.2 H, t, J=5.6 Hz), 2.30 (0.8 H, dt, J=13.6, 7.2 Hz), 2.16-2.25 (0.2 H, m), 1.61-1.99 (3 H, m). LCMS (M+H) calcd for C13H19O3: 223.13; found: 223.07.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:62]=[CH:61][C:53]2[NH:54][C:55]([C@@H:57]([NH2:60])[CH2:58][OH:59])=[N:56][C:52]=2[CH:51]=1.BrBr.ClCl>O1CCCC1.ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([NH:60][C@H:57]([C:55]1[NH:54][C:53]2[CH:61]=[CH:62][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][OH:59])=[O:7]
Reactant: N[C@@H](CO)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)c(Br)c1
Agent: BrBr
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H](CO)c1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCCC2)c(Br)c1
Yield: 90 %

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxyethylamine in tetrahydrofuran. Yield: 90%; Rf value: 0.40 (silica gel: dichloromethane/methanol=9:1); C21H20BrClN4O3 (491.77); mass spectrum: (M+H)+=491/493/495 (bromine/chlorine isotope).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([NH2:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:24]2)=CC=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[S:24])[NH2:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)CCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: NC(=S)CCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
A mixture of 3-(4-nitrophenyl)propanamide (0.50 g), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.81 g) and pyridine (5 mL) was stirred at 50° C. for 15 hrs. The reaction mixture was concentrated, and 1N hydrochloric acid was added to the obtained residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-(4-nitrophenyl)propanethioamide as colorless crystals (0.40 g, yield 73%) from a fraction eluted with hexane-ethyl acetate (2:1-1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 157-158° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[N:9]=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1.[NH2:23][CH2:24][CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH2:14][NH:23][CH2:24][CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[N:9]=[C:8]([C:19]([F:22])([F:20])[F:21])[CH:7]=1
Reactant: O=Cc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCNCc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of crude 122 (1.522 g, 4.97 mmol) in MeOH (20 mL) was added a solution of tert-butyl 2-aminoethyl(methyl)carbamate (1.732 g, 9.94 mmol, E. Atherton et al, J. Chem. Soc. C, 1971, 3393-3396) in MeOH (5 mL) followed by acetic acid (1.1 mL, 20 mmol). The reaction was stirred at room temperature for 1 hour then sodium cyanoborohydride (0.625 g, 9.94 mmol) was added and the resulting mixture was stirred for 16 hours. After the usual work-up crude 123 (2.30 g, 4.95 mmol, 100% yield) was obtained as yellow oil. LRMS(ESI): (calc.) 464.5 (found) 465.2 (MH)+, 487.2 (MNa)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>CO.[Ni]>[NH2:13][C:12]1[C:3]([O:2][CH3:1])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1OC
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cccc(N)c1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.8 %

Procedure:
To a solution of methyl 2-methoxy-3-nitrobenzoate (28.4 g, 134 mmol) in MeOH (150 mL) was added Raney Ni (3 g). The mixture was stirred under H2 atmosphere (50 psi/25° C.) for 3.5 h. The catalyst was filtered, and the filtrate was concentrated under the reduced pressure to dryness to give the crude product, which was purified by recrystallization in EtOAc to afford the title compound of Step C, methyl 3-amino-2-methoxybenzoate (23.5 g, 96.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.80-6.93 (m, 3H), 5.10-5.25 (br, 2H), 3.78 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:23][S:20]([NH:19][C:17]([CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:18])(=[O:21])=[O:22]
Reactant: CS(=O)(=O)NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)NC(=O)C1CCNCC1
Yield: 41 %

Procedure:
The 197 mg of the product from Step A was taken up in 5 mL of methanol and hydrogenated at 40 psi over 60 mg of 10% Pd/C for 16 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to afford 49 mg of title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)[CH2:11][CH:12]([CH3:14])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: CC(C)CCOc1ccccc1B(O)O
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)CCOc1ccccc1-c1cc(Cl)nc(Cl)n1
Temperature: 60 °C

Procedure:
To a solution of 2,4,6-trichloropyrimidine (7.32 g, 40 mmol) in 40 mL of THF was added 2-(isopentyloxy)phenylboronic acid (4.1 g, 20 mmol), Pd(OAc)2 (0.4 mmol), PPh3 (0.8 mmol), and Na2CO3 solution (40 mL, 1M). The reaction was heated to 60° C. for 3 hours with stirring. The resulting mixture was cooled down to room temperature then partitioned between EtOAc and water. Layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to result in 4.3 g (70%) of 2,4-dichloro-6-(2-(isopentyloxy)phenyl)pyrimidine as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.18-8.14 (m, 2H), 7.45 (dd, 1H), 7.09 (t, 1H), 7.01 (t, 1H), 4.10 (t, 2H), 1.90-1.75 (m, 3H), 1.02 (s, 6H).
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:37]2[C:38]([C:43]3[CH:44]=C(C)C=CC=3)=[N:39][O:40][C:41]=2C)=NC=1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:39][CH:38]2[CH2:43][CH2:44][O:40][CH2:41][CH2:37]2)=[O:25])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(C)cc3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(C)c3)noc2C)nc1
Product: Cc1ccc(-c2noc(C)c2COc2ccc(C(=O)NC3CCOCC3)cn2)cc1
Yield: 84 %

Procedure:
As described for example 249f, 6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (250 mg, 0.73 mmol) was converted, instead of 6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (260 mg, 84%) which was obtained as a white solid. MS: m/e=408.4 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH:9]=[CH:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=2[F:28])=[O:19])[C@H:14]([CH3:29])[CH2:13]1)#[N:8].[NH:30]1[CH:34]=[C:33]([C:35]2[C:36]3[CH:43]=[CH:42][N:41](COCC[Si](C)(C)C)[C:37]=3[N:38]=[CH:39][N:40]=2)[CH:32]=[N:31]1>CN(C=O)C>[C:7]([CH2:9][CH:10]([N:30]1[CH:34]=[C:33]([C:35]2[C:36]3[CH:43]=[CH:42][NH:41][C:37]=3[N:38]=[CH:39][N:40]=2)[CH:32]=[N:31]1)[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=2[F:28])=[O:19])[C@H:14]([CH3:29])[CH2:13]1)#[N:8]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: C[C@@H]1CN(CC=CC#N)CCN1C(=O)c1ccc(C#N)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(CC(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CCN1C(=O)c1ccc(C#N)cc1F
Reaction time: 8 h

Procedure:
Potassium carbonate (0.170 g, 1.23 mmol) was added to a mixture of 4-({(2R)-4-[3-cyanoprop-2-en-1-yl]-2-methylpiperazin-1-yl}carbonyl)-3-fluorobenzonitrile (0.12 g, 0.38 mmol, mixture of E- and Z-isomers from Step 2) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.12 g, 0.38 mmol, prepared as described in WO 2007/070514 Example 65) in DMF (0.59 mL) and the mixture was stirred overnight. The reaction mixture was then filtered and the filtrate was diluted with EtOAc. The filtrate was then washed with water (thrice), followed by brine, dried over sodium sulfate, decanted and concentrated. A portion of the crude product was dissolved in a 1:1 mixture of DCM:TFA, stirred at RT for 1 h, and concentrated. The residue was dissolved in methanol (1 mL) and 0.2 mL of aqueous ammonium hydroxide was added. After stirring for 2 h, the reaction mixture was concentrated. Preparative HPLC-MS (C18, eluting with a gradient of H2O/MeCN containing 0.15% NH4OH) afforded product as a mixture of two diastereomers. 1H NMR (300 MHz, DMSO-d6, diastereomers, rotamers): δ 12.11 (br s, 2H), 8.84-8.79 (m, 2H), 8.68-8.66 (m, 2H), 8.37-8.35 (m, 2H), 8.02-7.93 (m, 2H), 7.80-7.73 (m, 2H), 7.64-7.53 (m, 4H), 6.99-6.94 (m, 2H), 5.07-4.85 (m, 2H), 4.71-4.51 (m, 1H), 4.34 (t, 1H), 3.58-1.94 (m, 20H), 1.19 (d, 1.5H), 1.12 (d, 1.5H), 1.05 (d, 1.5H), 0.94 (d, 1.5H); 19F NMR (300 MHz, DMSO-D6): −114.54 to −115.75 (m, 2F); LCMS (M+H)+: 498.2.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=[C:7]([O:19][CH3:20])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:21]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH:33]=O)[CH2:26][CH2:25]1)([CH3:23])[CH3:22].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CN(C)C(=O)C>[CH2:12]([O:11][C:10]1[CH:9]=[CH:8][C:7]([O:19][CH3:20])=[C:3]2[C:2]=1[N:1]=[C:33]([C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([N:27]3[CH2:26][CH2:25][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:29][CH2:28]3)[CH:31]=1)[NH:6][C:4]2=[O:5])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(OCc2ccccc2)c(N)c1C(N)=O
Reactant: CC(C)N1CCN(c2cccc(C=O)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(OCc2ccccc2)c2nc(-c3cccc(N4CCN(C(C)C)CC4)c3)[nH]c(=O)c12
Temperature: 110 °C
Yield: 22.5 %

Procedure:
A solution of 2-amino-3-(benzyloxy)-6-methoxybenzamide (11, 0.267 g, 0.98 mmol) and 5-(benzyloxy)-2-methoxybenzaldehyde (3, 0.152 g, 0.65 mmol) in N,N-dimethylacetamide (10 mL) was treated with p-TsOH (0.30 g, 1.57 mmol) and NaHSO3 (0.204 g, 1.96 mmol) and then heated at 110° C. for 15 h. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% 95:4.5:0.5 CH2Cl2/MeOH/concentrated NH4OH in CH2Cl2 to afford the title compound (71 mg, 22%) as a light yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.79 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.3 Hz, 2H), 7.42-7.33 (m, 5H), 7.14 (d, J=7.6 Hz, 1H), 6.92 (d, J=9.0 Hz, 1H), 5.24 (s, 2H), 3.83 (s, 3H), 3.34-3.31 (m, 4H), 2.80-2.60 (m, 5H), 1.05 (br s, 6H); ESI MS m/z 485 [M+H]+.
Reaction SMILES: Br[CH2:2][CH3:3].[Cl:4][C:5]1[C:10]2[O:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=2[N:8]=[C:7]([CH2:16][CH3:17])[N:6]=1>>[Cl:4][C:5]1[C:10]2[O:11][CH2:12][C:13](=[O:15])[N:14]([CH2:2][CH3:3])[C:9]=2[N:8]=[C:7]([CH2:16][CH3:17])[N:6]=1
Reactant: CCBr
Reactant: CCc1nc(Cl)c2c(n1)NC(=O)CO2
Product: CCc1nc(Cl)c2c(n1)N(CC)C(=O)CO2

Procedure:
Using the procedure of Example 80, except that 1-bromoethane was used instead of methyl iodide, 4-chloro-6,7-dihydro-2-ethyl-8H-pyrimido[5,4-b][1,4]oxazin-7-one was alkylated providing 4-chloro-2,8-diethyl-6,7dihydropyrimido[5,4-b ][1,4]oxazin-7-one.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=CC=1.[OH-].[Na+]>OS(O)(=O)=O>[F:18][C:15]([F:16])([F:17])[C:14]1[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(CNc2ncccc2C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncccc1C(F)(F)F
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To conc. H2SO4 (230 mL) at 5° C. was dropwise added (4-methoxy-benzyl)-(3-trifluoromethyl-pyridin-2-yl)-amine (83.76 g, 297 mmol) keeping the internal temperature below 20° C. Stirring was continued at 23° C. for 30 min, poured onto ice, made alkaline with 32% NaOH-sol. (ca. 800 mL) [external ice cooling necessary!!!], saturated with solid NaCl, extracted twice with THF/TBME/DCM, dried over Na2SO4. Removal of the solvent in vacuum gave the product as a white solid (44.27 g, 92%). MS (ISP) 163.2 [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][C@H:12]1[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:13][C@H:12]1[CH3:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNC(=O)CCN1C(=O)OCc1ccccc1
Reactant: ClCCCN1CCCCC1
Product: C[C@@H]1CN(CCCN2CCCCC2)C(=O)CCN1C(=O)OCc1ccccc1

Procedure:
The title compound could be prepared from (R)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester and 1-(3-chloropropyl)piperidine in analogy to example 33A. MS: 388.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21]>C(O)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[N:20][OH:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2ccc(OC)cc2)cc1
Reaction time: 3 h

Procedure:
4,4′-Dimethoxybenzophenone (25 g, 103 mmol) is suspended in ethanol (150 ml) and pyridine (30 ml). Hydroxylamine hydrochloride (21.50 g, 310 mmol) is added and the reaction mixture is refluxed. The reaction is shown to be complete by TLC after 3 hours. The reaction mixture is allowed to cool and the solvent is removed in vacuo. The residue is partitioned between ethyl acetate (500 ml) and water (500 ml). The organic layer dried is over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained following crystallisation from ethylacetate/cyclohexane. 1H nmr (CDCl3, 400 MHz); 7.70(s, 1H), 7.40(d of d, 4H), 6.95(d, 2H), 6.85(d, 2H), 3.85(s, 3H), 3.80(s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:12]=[N:13][CH:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cncc1-c1ccc([N+](=O)[O-])cc1
Yield: 62.6 %

Procedure:
Reaction of 4-(4-nitrophenyl)-1H-imidazole (160 mg, 0.85 mmol), NaH (60%, 33 mg, 0.82 mmol), and SEMCl (158 uL, 0.89 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (170 mg, 65%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ0.00 (s, 9H), 0.94 (t, 2H, J=7.5 Hz), 3.55 (t, 2H, J=7.5 Hz), 5.33 (s, 2H), 7.50 (s, 1H), 7.69 (s, 1H), 7.94 (d, 2H, J=6.0 Hz), 8.26 (d, 2H, J=6.0 Hz).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C:15]4[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1>>[CH3:22][N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([C:28]4[CH:27]=[N:26][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:30][CH:29]=4)=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=2)[C:13]1=[O:21]
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: Cn1nccc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cn1nccc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(C(F)(F)F)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate E, 58 mg, 0.163 mmol) and 2-trifluoromethylpyridine-5-boronic acid (Frontier Scientific, Logan, USA, 40.5 mg, 0.212 mmol) to give the title compound as a red solid. (HPLC: tR 2.87 min (Method A); M+H=425 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.08 (s, 1H), 8.82 (d, 1H), 8.27-8.16 (m, 2H), 8.10-7.98 (m, 2H), 7.82 (d, 1H), 7.18-7.16 (m, 1H), 6.72 (s, 1H), 3.72 (s, 3H), 3.63 (s, 3H))
Reaction SMILES: COC(=O)C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=NC=1OC.Cl[C:25]1[N:30]=[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[C:28]([CH3:44])=[CH:27][C:26]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1.[CH3:55][N:56]1[CH:60]=[C:59](B2OC(C)(C)C(C)(C)O2)[CH:58]=[N:57]1>>[CH3:44][C:28]1[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])=[N:30][C:25]([C:59]2[CH:58]=[N:57][N:56]([CH3:55])[CH:60]=2)=[C:26]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[CH:27]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cnn(C)c2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 5C, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give the title compound as colorless solid. MS: 498.2 (MH+).