Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:2]2[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=2)[NH2:5])[CH:18]=1
Reactant: Cc1c[nH]cn1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 120 °C

Procedure:
A suspension of 3-bromo-5-(trifluoromethyl)aniline (4.8 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), potassium carbonate (3.04 g, 22 mmol), Cul (0.57 g, 3 mmol), and 8-hydroxyquinoline (0.44 g, 3 mmol,) in dry DMSO (20 mL) in a pressure tube was degassed by bubbling N2 into the suspension for 10 minutes while stirring. The tube was sealed tightly. The mixture was heated at 120° C. (oil bath temperature) for 15 h. The mixture was cooled down to 45-50° C. and 14% aq. NH4OH (20 mL) was added. The mixture was maintained at this temperature for 1 h. After cooling to rt, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were passed through a short silica gel column to remove most of green/blue Cu salts. The filtrate was dried over sodium sulfate and concentrated on a rotavap. The crude product was recrystallized from EtOAc/hexanes, giving pure pale yellow needles. The mother liquor was concentrated and the residue was purified on silica gel column (5% methanol/methylene chloride), yielding a second crop as pale yellow needles.
Reaction SMILES: Cl[N:2]1C(=O)CCC1=O.CN1CC[O:15][B:14]([C:18]2[CH:19]=[C:20]([S:24]([O-:26])=[O:25])[CH:21]=[CH:22][CH:23]=2)[O:13]CC1.[Li+].[OH-].[NH4+]>C(Cl)Cl>[S:24]([C:20]1[CH:19]=[C:18]([B:14]([OH:15])[OH:13])[CH:23]=[CH:22][CH:21]=1)(=[O:26])(=[O:25])[NH2:2]
Reactant: CN1CCOB(c2cccc(S(=O)[O-])c2)OCC1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li+]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Step 2) N-Chlorosuccinimide (1.015 g, 7.6 mmol) was added to a suspension of the above prepared lithium 3-(6-methyl-[1,3,6,2]dioxazaborocan-2-yl)-benzenesulfinate (2 g, 7.27 mmol) in CH2Cl2 (14 mL) and the mixture was stirred for 2 h at rt. A solution of 25% ammonium hydroxide (1.09 mL, 14.5 mmol) was added and the mixture was stirred again for 2 h at rt, then completely evaporated to give the title compound as an off-white solid (1.38 g, 94%) (according to Bioorg. Med. Chem. 2005, 13, 2305-2312). MS (ISP) 200.4 [(M−H)−].
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]>O>[CH3:1][NH:2][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]
Reactant: CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: O
Product: CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
To a stirred solution of 40% aqueous methylamine was added, in small portions, 30.Og (0.144 mole) of 4-chloro-3-nitroquinoline. The reaction mixture was heated at its reflux temperature for about 0.75 hour. After cooling, the mixture was poured into 300 ml of water. The solid was separated by filtration, and was then suspended in 300 ml of water. Acidification with 6N hydrochloric acid to pH 3 to 4 effected dissolution of most of the solid. Filtration was followed by basification of the filtrate with concentrated ammonium hydroxide to pH 8 to 10 to provide a yellow precipitate. The solid was separated by filtration, washed with water, and recrystallized from ethanol to provide yellow 4-methylamino-3-nitroquinoline, m.p. 168-170° C. Analysis: Calculated for C10H9N3O2 %C, 59.1; %H, 4.5: %N, 20.7: Found: %C, 59.0; %H, 4.2; %N, 20.8.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:44]([O:51][C:52]([N:54]1[CH2:58][CH2:57][CH2:56][C@H:55]1[C:59](=[O:73])[NH:60][C:61]1[S:62][CH:63]=[C:64]([C:66]2[CH:71]=[CH:70][C:69]([NH2:72])=[CH:68][CH:67]=2)[N:65]=1)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C>[CH2:44]([O:51][C:52]([N:54]1[CH2:58][CH2:57][CH2:56][CH:55]1[C:59](=[O:73])[NH:60][C:61]1[S:62][CH:63]=[C:64]([C:66]2[CH:67]=[CH:68][C:69]([NH:72][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[CH:70][CH:71]=2)[N:65]=1)=[O:53])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-Chlorobenzoic acid (0.017 g, 0.11 mmol), HATU (0.042 g, 0.11 mmol), and DIEA 0.09 mL, 0.67 mmol) in DMF (2 mL) was stirred at room temperature for 1 h. (S)-2-[4-(4-Amino-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (FW=422.5096 , 0.029 g, 0.054 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered to afford the crude product. The mixture was filtered and separated by reverse phase HPLC (20-100% of buffer B; buffer A: water containing 0.1% TFA; buffer B: MeCN containing 0.1 TFA). The combined fraction was evaporated to dryness to furnish the desired product. MS: 562.1(M+H+).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=O.N[N:15]1[CH:19]=[N:18][N:17]=[CH:16]1>C1(C)C(C)=CC=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[C:19]2[N:15]([CH:16]=[N:17][N:18]=2)[N:2]=[CH:3][CH:4]=1
Reactant: Nn1cnnc1
Reactant: CN(C)C=CC(=O)c1ccccn1
Solvent: Cc1ccccc1C
Product: c1ccc(-c2ccnn3cnnc23)nc1

Procedure:
As for Example 16, a mixture of 3-dimethylamino-1-(2-pyridyl)-2-propen-1-one, 4-amino-1,2,4-triazole and xylene is refluxed for 16 hours to give the product of the Example.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH3:17])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)(=[O:32])=[O:31]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH3:17])=[O:9])=[CH:6][N:5]=[C:4]([NH:39][CH:36]2[CH2:37][CH2:38][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:34][CH2:35]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)ccc2C)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methyl-phenyl)-methanone (Example 198) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C18H23N5O3SF [(M+H)+] 408.1500, observed 408.1504.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:14])[O:8][C@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH2:2]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=2)[N:19]=[C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[F:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])[N:17]=[C:16]2[N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:14])[O:8][C@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH2:2]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: O=C(N[C@@H]1CCNC1)O[C@H]1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A mixture of (S)-tetrahydrofuran-3-yl(R)-pyrrolidin-3-ylcarbamate (225 mg, 1.12 mmol), 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (250 mg, 0.86 mmol), and triethylamine (0.240 mL, 1.72 mmol) in CH2Cl2 (10 mL) was stirred at room temperature. The reaction was complete in one hour. The reaction was quenched with water, the aqueous layer was extracted twice with CH2Cl2, and the combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc/CH2Cl2 gave (S)-tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate (250 mg, 66%). LC/MS: m/z 439.5 (M+H)+ at 2.40 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J=7.8, 1.5 Hz, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.87-7.91 (m, 1H), 7.74-7.79 (m, 1H), 7.70 (d, J=6.2 Hz, 1H), 7.35-7.39 (m, 1H), 6.91-6.96 (m, 2H), 5.15 (s, 1H), 4.21-4.25 (m, 2H), 4.12-4.14 (m, 1H), 4.01-4.06 (m, 1H), 3.87-3.89 (m, 1H), 3.65-3.78 (m, 4H), 2.02-2.26 (m, 3H), 1.82-1.89 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][C:3]=1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[F:24][C:25]([F:64])([F:63])[C:26]1[CH:27]=[C:28]([C@H:36]2[O:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[CH:45][C:44]=3B3OC(C)(C)C(C)(C)O3)[C@H:37]2[CH3:62])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:64][C:25]([F:24])([F:63])[C:26]1[CH:27]=[C:28]([C@H:36]2[O:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:46]=[CH:45][C:44]=3[C:5]3[C:6]([O:8][CH3:9])=[CH:7][C:2]([F:1])=[C:3]([CH:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH:4]=3)[C@H:37]2[CH3:62])[CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(F)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Product: COc1cc(F)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of tert-butyl 4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidine-1-carboxylate (58 mg; 0.133 mmol) and (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (111 mg, 0.187 mmol) was treated with 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (˜10 mg) as described earlier. The product was purified by chiral HPLC (ChiralPak OD column, 10% IPA/heptane) to afford tert-butyl 4-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]piperidine-1-carboxylate as a colorless glass. LCMS=678.8 (M+1-100)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.86 (s, 1 H), 7.69 (s, 2 H), 7.64-7.61 (m, 2 H), 7.32 (d, J=8 Hz, 1 H), 6.96 (d, J=8.4 Hz, 1 H), 6.70 (d, J=11.9 Hz, 1 H), 5.57 (d, J=8 Hz, 1 H), 4.88 (d, J=15.8 Hz, 1 H), 4.26-4.17 (m, 2 H), 3.86 (d, J=15.8 Hz, 1H), 3.83-3.78 (m, 1 H), 3.77 (s, 3 H), 3.01-2.93 (m, 1 H), 2.84-2.75 (m, 2 H), 1.84-1.69 (m, 2 H), 1.64-1.50 (m, 2 H), 1.45 (s, 9H), 0.38 (d, J=6.7 Hz, 3 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1([CH2:14][CH2:15][CH3:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1.Cl.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[C:23]2[CH2:30][CH2:31][CH2:32][C@@H:33]1[CH2:38][CH2:37][NH:36][CH2:35][C@@H:34]1[C:39]([OH:41])=[O:40].O>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[C:23]2[CH2:30][CH2:31][CH2:32][C@@H:33]1[CH2:38][CH2:37][N:36]([CH2:16][CH2:15][CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:35][C@@H:34]1[C:39]([O:41][CH2:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:40]
Reactant: COc1ccc2nccc(CCC[C@@H]3CCNC[C@@H]3C(=O)O)c2c1
Reactant: CCCC1(Br)C=CC=CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3C(=O)OCCCc3ccccc3)c2c1
Reaction time: 17 h

Procedure:
1.75 g of potassium carbonate and then 1.15 cm3 of 1-bromophenylpropane were added with stirring, at a temperature in the region of 25° C., to a solution of 0.91 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylic acid hydrochloride in 20 cm3 of anhydrous dimethylformamide. The suspension was brought to a temperature in the region of 60° C. for 17 hours. After cooling, the mixture was poured onto 200 cm3 of water and extracted with 3 times 30 cm3 of ether. The combined ethereal extracts were washed with 2 times 20 cm3 of water. The ethereal solution was extracted with 20 cm3 of normal aqueous hydrochloric acid and twice with 20 cm3 of water. The combined aqueous extracts were rendered alkaline by addition of solid sodium hydrogencarbonate. After extracting with 3 times 20 cm3 of ether and washing the ethereal extracts with 3 times 20 cm3 of water, drying was carried out over magnesium sulfate in the presence of 0.1 g of animal charcoal. After filtering through paper and then concentrating under reduced pressure (5 kPa) at a temperature in the region of 30° C, 0.84 g of 3-phenylpropyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-3-carboxylate was obtained in the form of an oil with a light brown color.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]2[S:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:15][CH:14]=3)[C:5]=2[C:4]=1[OH:28])#[N:2].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:61][CH2:62][N:63](CC)[CH2:64][CH3:65]>CN(C=O)C>[CH2:62]([N:63]([CH2:64][CH3:65])[C:25](=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][C:20]#[C:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:5]3[C:4]([OH:28])=[C:3]([C:1]#[N:2])[C:8](=[O:9])[NH:7][C:6]=3[S:10][CH:11]=2)=[CH:18][CH:17]=1)[CH3:61]
Reactant: N#Cc1c(O)c2c(-c3ccc(C#CCCCCC(=O)O)cc3)csc2[nH]c1=O
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCCCC#Cc1ccc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-[4-(5-cyano-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)-phenyl]-hept-6-ynoic acid (24 mg, 0.06 mmol) in 0.5 mL DMF was added HOBT (trace) followed by TBTU (23 mg, 0.07 mmol). The pH of the reaction mixture was adjusted to pH>6 using Et3N, then stirred at rt overnight. Solvent was removed in vacuo, the resulting slurry was redissolved in MeOH and purified using reverse phase HPLC to afford the titled compound. MS (ESI) m/e 448 (M+H)+; 1H NMR (400 MHz, DMSO-d6): δ 1.00 (t, J=8.1 Hz, 3H), 1.10 (t, J=8.1 Hz, 3H), 1.58–1.68 (m, 4H), 2.33 (t, J=6.90 Hz, 2H), 2.45 (t, J=6.90 Hz, 2H), 3.23–3.33 (m, 4H), 6.65 (s, 1H), 7.26 (d, J=8.59 Hz, 2H), 7.42 (d, J=8.59 Hz, 2H).
Reaction SMILES: CC1N=CC=CC=1C(N)=O.[C:11]([C:15]1[N:20]=[C:19]([CH3:21])[C:18]([CH:22]([NH2:24])[CH3:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[F:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[CH:32][N:31]([CH2:34][C:35](O)=[O:36])[C:30]=2[C:38]=1[F:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[C:11]([C:15]1[N:20]=[C:19]([CH3:21])[C:18]([CH:22]([NH:24][C:35](=[O:36])[CH2:34][N:31]2[C:30]3[C:38]([F:39])=[C:26]([F:25])[CH:27]=[CH:28][C:29]=3[N:33]=[CH:32]2)[CH3:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1nc(C(C)(C)C)ccc1C(C)N
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ncccc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(C(C)(C)C)ccc1C(C)NC(=O)Cn1cnc2ccc(F)c(F)c21

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 2-methylnicotinamide, starting from [1-(6-tert-butyl-2-methylpyridin-3-yl)ethyl]amine (intermediate 32) (31.5 mg, 0.16 mmol), 6,7-difluorobenzimidazole-1-acetic acid (35 mg 0.16 mmol) HATU (38 mg, 0.18 mmol) and DIPEA (71 μl, 0.41 mmol). Water was added and the reaction concentrated. The mixture was partitioned between ethyl acetate and water, and extracted 3 more times with ethyl acetate. The product was then purified by silica gel flash chromatography with acetone/hexanes (Yield 25 mg, 40%). 1H NMR (400 MHz, CD3OD-D4) d ppm 1.32 (s, 9 H), 1.47 (d, J=7.03 Hz, 3 H), 2.53-2.57 (m, 3 H), 5.04-5.15 (m, 2 H), 5.15-5.22 (m, 1 H), 7.16 (ddd, J=11.43, 8.79, 7.52 Hz, 1 H), 7.28 (d, J=8.20 Hz, 1 H), 7.41 (dd, J=8.89, 3.61 Hz, 1 H), 7.68 (d, J=8.20 Hz, 1 H), 8.11 (s, 1 H) MS [MH+] calc. 387.1996 found 387.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:13][CH2:14][CH2:15]1
Reactant: c1ccc2c(c1)NCCO2
Reactant: Clc1ncnc2ccc(I)cc12
Agent: c1ccc2ncncc2c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Ic1ccc2ncnc(N3CCOc4ccccc43)c2c1
Yield: 34.8 %

Procedure:
0.75 g of 4-chloro-6-iodoquinazoline, 0.39 g of 3,4-dihydro-2H-benzo-1,4-oxazine and 0.50 ml of triethylamine in 5 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is evaporated to dryness. The residue is washed by stirring with EA and filtered off with suction, giving 0.35 g of 4-(6-iodoquinazolin-4-yl)-3,4-dihydro-2H-benzo-1,4-oxazine as yellowish solid (yield 40%, content 96%); MS-FAB (M+H+)=390.0; Rf (polar method): 2.36 min.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C=Cc1ccc2nnn(O)c2c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=Cc1ccc2nnn(OS(=O)(=O)c3ccc(Cl)cc3)c2c1
Temperature: 10 °C
Yield: 83.4 %

Procedure:
In benzene (100 ml) are dissolved 1-hydroxy-6-vinyl-1,2,3-benzotriazole (8.0 g) and triethylamine (5 g) under stirring and thereto is added dropwise a solution of p-chlorobenzenesulfonyl chloride (10.6 g) in benzene (100 ml) under cooling to 10° C. The mixture is stirred at room temperature for 3 hours. The reaction mixture is poured onto ice-water (200 ml) and then extracted with ethyl acetate (150 ml, twice). The combined extracts are washed with water, dried over anhydrous magnesium sulfate, treated with charcoal and then concentrated till about 30 ml. To the mixture is added n-hexane and the mixture is allowed to stand at a cooled place. The precipitated crystals are separated by filtration to give 1-(p-chlorobenzenesulfonyloxy)6-vinyl-1,2,3-benzotriazole (13.9 g), melting point: 125° C. The filtrate is further concentrated and the resulting residue is dissolved in ethyl acetate (10 ml). To the solution is added n-hexane and the mixture is allowed to stand at a cooled place to give additionally the desired product (1.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@@H:12]2[CH2:16][O:15][C@@H:14]3[C@H:17](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:18][O:19][C@H:13]23)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br-:31].[Li+].O>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@@H:12]2[CH2:16][O:15][C@@H:14]3[C@@H:17]([Br:31])[CH2:18][O:19][C@H:13]23)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Temperature: 100 °C
Yield: 21.2 %

Procedure:
A stirred mixture of ditosylate (39) (16.9 g, 37.22 mmol) and lithium bromide (4.85 g, 55.84 mmol) in N,N-dimethylformamide (100 mL) was heated at 100° C. for 27 hours. The mixture was allowed to cool then water (150 mL) added before extracting with tert-butyl methyl ether (1×100 mL then 5×50 mL). The organic phase was dried (MgSO4), filtered and reduced in vacuo to give a colourless oil which solidified on standing. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 80:20 gave bromotosylate (46) as a white solid (2.86 g, 29%). TLC (Rf=0.45 diethyl ether heptane, 1:1), analytical HPLC: Rf=16.768 min; HPLC-MS: 363.1/365.0 [M+H]+, 380.1/382.1, 749.0/751.0 [2M+Na]+; [□]D18+64.7° (c=8.5, CHCl3); δH (500 MHz, CDCl3) 2.45 (3H, s, CH3), 3.74 (1H, dd, 7.05 Hz, CH2), 3.95 (1H, dd, 6.47 Hz, CH2), 4.14-4.22 (2H, m, CH2), 4.29 (1H, d, J=3.03 Hz, CHBr), 4.68 (1H, d, J=4.03 Hz, CHCH), 4.76 (1H, t, J=4.48 Hz, CHOTs), 4.87 (1H, m, CHCH), 7.36 (2H, brd, J=7.97 Hz, aromatic CH3CCH), 7.83 (2H, brd, J=8.33 Hz, aromatic OSO2CCH). δC (125 MHz, CDCl3) 21.69 (CH3), 50.06 (CHBr), 70.26 (CH2CHOTs), 76.54 (CH2CHBr), 78.27 (CHOTs), 80.17 and 88.80 (CHCHCHOTs), 127.98 and 129.94 (aromatic CH), 133.01 (CHOSO2C quaternary), 145.28 (CH3C quaternary).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:26]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([C:32]2[CH:33]=[CH:34][C:35]([C:36]([N:23]3[CH2:24][CH2:25][N:20]([CH2:19][C:17]4[CH:16]=[CH:15][N:14]=[C:13]([C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH:18]=4)[CH2:21][CH2:22]3)=[O:37])=[CH:39][CH:40]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4ccc(-c5ccccc5)cc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 4-phenylbenzoyl chloride (45 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a free base.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([NH2:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[CH3:12][C:8]([CH3:13])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([NH2:11])=[O:10]
Reactant: CC(C)(C(N)=O)c1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-hydroxy-α,α-dimethyl-benzeneacetamide (Example 198b, 15.34 g) dissolved in DMF (150 mL) was treated with potassium carbonate (11.83 g) and benzyl bromide (10.18 mL) under nitrogen. The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water (500 mL) and stirred for 30 min. The solid was filtered off and washed with water and dried in vacuo to afford the subtitle compound (19.45 g).