Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.CN(C)CCCN=C=NCC.[F:23][CH:24]([F:40])[O:25][C:26]1[C:31]2[N:32]=[C:33]([CH2:35][CH3:36])[O:34][C:30]=2[C:29]([C:37](O)=[O:38])=[CH:28][CH:27]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:37]([C:29]2[C:30]3[O:34][C:33]([CH2:35][CH3:36])=[N:32][C:31]=3[C:26]([O:25][CH:24]([F:23])[F:40])=[CH:27][CH:28]=2)=[O:38])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
para-Nitrophenol (0.95 g), 4-dimethylaminopyridine (80 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.4 g) were added to a stirred suspension of 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (1.6 g) in dry dichloromethane (60 ml) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 18 hours. Water (20 ml) was added and the aqueous layer extracted with dichloromethane (400 ml). The organic layer was washed with water (80 ml), separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 1:4 ethyl acetate/heptane to 1:1:2 ethyl acetate/dichloromethane/heptane afforded the title compound as a pale yellow solid (1.9 g)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C@@H:8]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@H:7]12)C.[NH3:18].C(OCC)C>CO>[O:11]=[C:10]1[N:6]([CH2:5][C:4]([NH2:18])=[O:3])[C@H:7]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:8]2[CH2:9]1
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCCCC[C@@H]21
Reactant: N
Solvent: CCOCC
Solvent: CO
Product: NC(=O)CN1C(=O)C[C@@H]2CCCCC[C@@H]21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of cis-octahydro-2-oxo-cyclohepta[b]pyrrole-1(2H)-acetic acid ethyl ester (3.0 g, 0.0125 mole) in methanol (50 ml) is saturated with anhydrous ammonia. The solution is stirred at ambient temperature for 72 hours. the solution is concentrated at reduced pressure to yield a solid. Trituration with anhydrous diethyl ether yields pure cis-octahydro-2-oxo-cyclohepta[b]pyrrole-1(2H)acetamide with mp 140°-142° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([C:35]([O:37]CC)=[O:36])=[CH:4]1)[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c(F)c21
Temperature: 90 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a suspension of ethyl 1-ethyl-8-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (32 g, 59.8 mmol) in a mixture of Methanol (250 mL) and Water (125 mL) was added KOH (6.70 g, 120 mmol) portionwise. The resulting mixture was stirred at 90° C. for 3 h. LCMS indicated completion of the reaction. The mixture was cooled down to r.t. and concentrated. Water was then added, and the mixture was adjusted to pH ˜1 using 6 N aq. HCl. The precipitate was collected by filtration and dried to afford 1-ethyl-8-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (28 g, 55.2 mmol, 92% yield) as a yellow solid. LCMS (M+H)+: 508.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[C:21]([F:23])[C:7]([CH2:8][N:9]2[C:13]([OH:14])=[C:12]([CH3:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10]2)=[C:6]([F:24])[CH:5]=1)[CH3:2].IC.[C:27](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:24])[C:7]([CH2:8][N:9]2[C:13]([O:14][CH3:27])=[C:12]([CH3:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10]2)=[C:21]([F:23])[CH:22]=1)[CH3:2]
Reactant: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(O)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(OC)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.95 g of ethyl 1-(4-ethoxy-2,6-difluorobenzyl)-5-hydroxy-4-methyl-1H-pyrazole-3-carboxylate 1-1-1 (11.6 mmol, 1.0 eq.) were dissolved in 50 mL of acetone. 1.45 mL of iodomethane (23.2 mmol, 2.0 eq.) and 5.78 g (41.8 mmol, 3.6 eq.) of potassium carbonate were added and stirred over for 24 hours at rt. 1.45 mL of iodomethane (23.2 mmol, 2.0 eq.) were added and the mixture was stirred for further 24 hours at rt. The suspension was filtered off over sea sand and the filtrate was concentrated in vacuo. The residue was extracted by DCM and water. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to give 2.29 g (6.46 mmol, 55.7%) of analytically pure target compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([Br:32])[CH:31]=1)[NH:28][C:27](=[O:33])[CH2:26]2>>[Br:32][C:30]1[CH:31]=[C:23]([F:22])[CH:24]=[C:25]2[C:29]=1[NH:28][C:27](=[O:33])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Product: Cc1c(C=C2C(=O)Nc3c(Br)cc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 87 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-7-bromo-1,3-dihydro-indol-2-one as starting materials to give 2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (57 mg, 87.0%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14]([N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][N:19]2[CH:27]=[CH:28][CH:29]=[C:18]2[CH2:17]1)=[O:15].[Br:30]N1C(=O)CCC1=O>ClCCl>[Br:30][C:27]1[N:19]2[C:18]([CH2:17][N:16]([C:14]([C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]4)=[CH:7][C:2]=3[Cl:1])=[O:15])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20]2)=[CH:29][CH:28]=1
Reactant: Cc1ccn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4ccc(Br)n4Cc4ccccc43)c(Cl)c2)n1
Temperature: -40 °C
Yield: 76.4 %

Procedure:
To a stirred pre-cooled solution of [2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.61 g) in dichloromethane (25 ml) was added solid N-bromosuccinimide (0.712 g) over 10 minutes at −78° C. The reaction was allowed to warm to −40° C. over thirty minutes. The mixture was diluted with dichloromethane, and extracted sequentially with saturated aqueous sodium bicarbonate (2×100 ml) and water (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered through a plug of silica gel, and evaporated in vacuo to a residue. Crystallization from diethyl ether yielded 1.47 g of the title compound as a colorless solid, m.p. 148-149° C. (dec); MS (EI), m/z: 480 (M)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:29]=[N:28][C:13]3[N:14]([CH2:26][CH3:27])[C:15]4[N:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:16]=4[N:17]([CH3:20])[C:18](=[O:19])[C:12]=3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[I-:30].[Na+]>>[Cl:25][C:23]1[CH:22]=[CH:21][C:16]2[N:17]([CH3:20])[C:18](=[O:19])[C:12]3[CH:11]=[C:10]([CH2:9][CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([I:30])[CH:3]=4)[CH:29]=[N:28][C:13]=3[N:14]([CH2:26][CH3:27])[C:15]=2[N:24]=1
Reactant: CCN1c2ncc(CCc3cccc(N)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: [I-]
Agent: [Na+]
Product: CCN1c2ncc(CCc3cccc(I)c3)cc2C(=O)N(C)c2ccc(Cl)nc21

Procedure:
In a manner analogous to the procedure described for Example 23, 8-[2-(3-aminophenyl)ethyl]-2-chloro-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.15 g, 0.37 mmol) was diazotized and treated with sodium iodide to provide 9 mg of the pure product, m.p. 143°-145° C. (petroleum ether).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[NH3:15].CO>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH2:15])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: N
Solvent: CO
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
6-bromo-2-naphthoic acid (2 g, 7.97 mmol) was stirred in thionyl chloride (13.28 ml) at 70° C. for 16 h. After concentration in vacuo, the residue was rediluted in CH2Cl2 and concentrated again. To the acid chloride intermediate was added ammonia in MeOH (7 M, 13.66 ml, 96 mmol) and the mixture was stirred at room temperature for 3 h. The mixture was then concentrated. The residue was taken up in AcOEt, filtered, rinsed with AcOEt and then dried over MgSO4, filtered and concentrated in vacuo. The title compound (1.802 g, 90%) was isolated as a beige solid. LC-MS (M+1) 251.9, t=1.34 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C:13]1[CH:14]=[C:15]([C:19]23[CH2:26][CH2:25][C:22]([CH2:27][CH2:28][CH2:29][CH2:30][OH:31])([CH2:23][CH2:24]2)[CH2:21][O:20]3)[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl>[CH3:1][S:2]([O:31][CH2:30][CH2:29][CH2:28][CH2:27][C:22]12[CH2:23][CH2:24][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH:7]4[CH2:8][CH2:9][CH2:10][CH2:11][O:6]4)[CH:14]=3)([CH2:26][CH2:25]1)[O:20][CH2:21]2)(=[O:4])=[O:3]
Reactant: OCCCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
MsCl (0.036 ml, 0.462 mmol) was added to a solution of 4-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2] octan-4-yl)butan-1-ol (111 mg, 0.31 mmol) and TEA (0.129 ml, 0.92 mmol) in DCM (2 mL) at 0° C. The reaction was then stirred at rt for 2 h and concentrated in vacuo. The residue was dissolved in EtOAc (5 mL), washed with water (4×5 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (gradient from 0 to 50% EtOAc: hexanes) to afford the title compound (133 mg, 98% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J=8.0 Hz, 1H), 7.13-7.10 (m, 1H), 7.03-6.99 (m, 1H), 6.94 (ddd, J=8.2, 2.5, 0.8 Hz, 1H), 5.44 (t, J=3.2 Hz, 1H), 4.25 (t, J=6.5 Hz, 2H), 4.04-3.88 (m, 1H), 3.82 (s, 2H), 3.67-3.55 (m, 1H), 3.03 (s, 3H), 2.06-1.99 (m, 5H), 1.90-1.83 (m, 2H), 1.79-1.57 (m, 9H), 1.43-1.34 (m, 2H), 1.23-1.16 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:22][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=2
Reactant: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
2-(Butoxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (9.45 g) was dissolved in chloroform (50 mL) and cooled to 0° C. (ice-bath). To this solution was added portion wise N-bromosuccinimide (6.07 g) keeping the temperature below 3° C. This gave a dark green solution, stirred at 2.5° C. for 30 minutes before allowing to warm to room temperature and then stirring for 6 hours. The reaction mixture was then washed with water (100 mL, twice). Organic phase was dried/separated using a hydrophobic frit and evaporated to give a dark brown gum which was purified by silica chromatography (120 g) (ISCO) using a gradient elution of 0-50% ethyl acetate:cyclohexane to afford the title compound as a pale yellow solid (8.37 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([OH:18])=[C:15]([Br:17])[CH:16]=[C:11]2[N:10]=[N:9]1.[CH3:19][N:20]1[C:24]([CH2:25]Cl)=[N:23][CH:22]=[N:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:25][C:24]3[N:20]([CH3:19])[N:21]=[CH:22][N:23]=3)=[C:15]([Br:17])[CH:16]=[C:11]2[N:10]=[N:9]1
Reactant: Oc1nc2c(cc1Br)nnn2-c1ccccc1F
Reactant: Cn1ncnc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cc1Br)nnn2-c1ccccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A mixture of 3-(2-fluorophenyl)-5-hydroxy-6-bromo-1,2,3-triazolo[4,5-b]pyridine (0.91 g, 2.94 mmol), 2-methyl-3-chloromethyl-1,2,4-triazole (0.46 g, 3.53 mmol) and caesium carbonate (1.40 g, 4.29 mmol) in dry DMF (15 ml) was stirred at room temperature under nitrogen for 18 h. The mixture was poured into water (150 ml) and extracted with ethyl acetate (2×100 ml). The extracts were dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 4% methanol-dichloromethane, gave 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-bromo-1,2,3-triazolo[4,5-b]pyridine (1.05 g, 88%) as a beige solid. δH (360 MHz; CDCl3) 3.96 (3H, s), 5.59 (2H, s), 7.37-7.43 (2H, m), 7.56-7.64 (1H, m), 7.68 (1H, dd, J=7 and 7), 7.87 (1H, s) and 8.62 (1H, s); m/z (ES+) 404, 406 (M+H+).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:1]([C:14]1[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
Benzyl bromide (41 g, 240 mmol), 4-formylbenzeneboronic acid (28 g, 186.7 mmol), palladium tetrakis triphenyl phosphine (7.9 g, 6.84 mmol) and potassium carbonate (84.7 g, 613 mmol) were combined in tetrahydrofuran (620 mL) and heated at 80° C. under nitrogen for 8 hours. The resulting suspension was allowed to cool to ambient temperature and stirred overnight. The reaction mixture was poured into 10% citric acid (50 mL) and extracted with ethyl acetate (3-fold 50 mL). The combined organic extracts were washed with brine (100 mL) and dried (magnesium sulphate) and the solvent removed in vacuo. The resulting oil was purified by column chromatography on silica gel eluting with ethyl acetate:heptane, (0:1 changing to 1:5, by volume) to give the title compound as a colourless oil, 83% yield, 30.45 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[C:26]([CH3:43])[CH:25]=2)[N:14]=1>CCO.CN(C=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[C:26]([CH3:43])[CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate (A41) (0.248 g, 0.407 mmol) in EtOH (10 mL) was added to a solution of 10% Pd/C (53% water; 0.680 g) in DMF (6 mL). The resulting mixture was stirred at room temperature for 16 hours under an atmosphere of hydrogen then filtered through a pad of Celite, washing with EtOAc (80 mL). The volatiles were removed in vacuo to afford a yellow oil which was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to yield the title compound A42 as a clear oil (0.196 g, 79%); 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.61 (s, 1H), 7.51 (dd, J=7.9, 1.5 Hz, 1H), 7.39 (d, J=2.2 Hz, 1H), 7.29-7.19 (m, obscured by solvent), 7.17 (d, J=8.4 Hz, 1H), 4.42-4.18 (m, 2H), 3.75 (s, 2H), 3.67 (s, 3H), 3.19-3.03 (m, 4H), 2.90-2.73 (m, 3H), 2.37 (s, 3H), 1.75 (d, J=12.6 Hz, 2H), 1.62 (m, 2H), 1.50 (s, 9H). LCMS-A: rt 7.094 min; m/z 613.2 [M+H]+.
Reaction SMILES: BrBr.[S:3]([O-:7])([O-:6])(=[O:5])=[O:4].[CH3:8][C:9]1[C:10]([CH2:15][CH2:16][CH2:17][CH2:18][NH3+:19])=[N:11][CH:12]=[CH:13][CH:14]=1.CC1C(CCCC[NH3+])=NC=CC=1>OS(O)(=O)=O.O=S(=O)=O>[CH3:8][C:9]1[C:10]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[N:11][CH:12]=[CH:13][CH:14]=1.[S:3](=[O:5])(=[O:4])([OH:7])[OH:6]
Reactant: Cc1cccnc1CCCC[NH3+]
Reactant: O=S(=O)([O-])[O-]
Agent: BrBr
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Cc1cccnc1CCCCN

Procedure:
Bromine (10 g) was added dropwise with stirring to a solution of 4-(3-methyl-2-pyridyl)butylammonium sulphate (21.3 g) obtained from 4-(3-methyl-2-pyridyl)butylamine and concentrated sulphuric acid) in 65% oleum (100 ml) at room temperature. The solution was then heated to 55° C. and stirred overnight.
Reaction SMILES: [CH3:1][Si:2](Br)([CH3:4])[CH3:3].[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:8]=1[NH2:9]>C1C=CC=CC=1>[CH3:1][Si:2]([CH3:4])([CH3:3])[NH:9][C:8]1[C:7]([F:6])=[CH:13][CH:12]=[CH:11][C:10]=1[F:14]
Reactant: C[Si](C)(C)Br
Reactant: Nc1c(F)cccc1F
Solvent: c1ccccc1
Product: C[Si](C)(C)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
Trimethylsilyl bromide, 10.24 ml (77.5 mmole), was added to 6 ml (55.7 mmole) of 2,6-difluoroaniline in 70 ml of benzene. There was a slight exotherm and immediate precipitation. Triethylamine, 10.8 ml (77.5 mmole), was added and the mixture stirred at room temperature for 16 hours. The mixture was filtered and the solvent removed from the filtrate in vacuo. The product was purified as described in Example 1 to provide 8.85 g (51.1 mmole, 91.7 percent yield) of 99.3 percent pure N-trimethylsilyl-2,6-difluoroaniline as a colorless liquid, b.p. 89°-91° C. at 18 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[N:17][CH2:16][CH:15]([O:18][CH3:19])[O:14][CH3:13]
Reactant: COC(CN)OC
Reactant: COc1ccc(C=O)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(C=NCC(OC)OC)cc1OC
Yield: 99 %

Procedure:
3,4-Dimethoxybenzaldehyde (12.20 g, 73.42 mmol) was dissolved in benzene (200 mL) and aminoacetaldehyde dimethyl acetal (12.0 mL, 11.7 g, 111 mmol) was added. The mixture was stirred at reflux for 4 h using a Dean-Stark trap. The reaction mixture was then concentrated and dissolved in CHCl3 (250 mL). The solution was washed with water (4×150 mL) and brine (150 mL), dried (Na2SO4) and concentrated, and the last traces of solvent were removed under vacuum to provide the imine (18.41 g, 99.1%) as a light yellow solid: mp 50-52° C. 1H NMR (300 MHz, CDCl3) δ 8.18 (s, 1H), 7.42 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 4.65 (t, J=5.1 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.74 (d, J=5.1 Hz, 2H), 3.40 (s, 6H).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:24][CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[O:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][NH:10][CH2:11][CH2:12]1
Reactant: Cc1ccc(S(=O)(=O)N2CCOCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: C1CNCCNCCOCCNCCN1
Temperature: 100 °C
Reaction time: 70 h
Yield: 17 %

Procedure:
A mixture of 4,7,10,13-tetra(p-toluenesulfonyl)-1-oxa-4,7,10,13-tetraazacyclopentadecane prepared as in Example 17A (10.9 g, 0.0131 mole) and concentrated H2SO4 (70 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 70 h. To the resulting brown solution, ethanol (140 ml) was added dropwise with stirring at 5° C., followed by ethyl ether (340 ml). The gummy brown solid was filtered and dissolved in H2O (100 ml). The pH of the solution was adjusted to 10 with 10N NaOH and the solution was extracted with 6×100 ml CHCl3. The extracts were combined, dried (Na2SO4) and the solvent removed in vacuo. The crude product was purified by crystallization from hexane to give 0.49 g (17% yield) of the product as colorless needles: mp 80-1° C.; 1H NMR (CDCl3) δ 1.98 (br s, 4 H), 2.76 (m, 16 H), 3.61 (m, 4 H); Exact mass (M+H)+ : calcd., 217.2028; Found: 217.2051 (C10H25N4O) .
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]([N:12]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:13](=[O:38])[CH2:14][N:15]1[C:21](=[O:22])[C:20]([CH3:26])([CH2:23][CH:24]=[O:25])[C:19](=[O:27])[N:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]1=2)([CH3:11])[CH3:10].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1.Cl>[CH:9]([N:12]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:13](=[O:38])[CH2:14][N:15]1[C:21](=[O:22])[C:20]([CH3:26])([CH2:23][C:24]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:25])[C:19](=[O:27])[N:18]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]1=2)([CH3:11])[CH3:10]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)N(C(=O)CN1C(=O)C(C)(CC=O)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)CN1C(=O)C(C)(CC(=O)c2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.23 mL of 1.0M phenylmagnesium bromide in THF is added to a solution of 0.10 g (0.21 mmol) of N-Isopropyl-2-[3-methyl-2,4-dioxo-3-(2-oxoethyl)-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-phenyl acetamide, prepared as in Intermediate 9, in 2 mL of THF at 0° C. After stirring at room temperature for 60 min the reaction is diluted with 10 mL of 1N HCl and extracted with EtOAc (×3). The organic extract is washed with sat. NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to a colorless oil. The crude product is dissolved in 2 mL of CH2Cl2 and 0.092 g (0.42 mmol) of PCC added. After stirring at RT for 90 min, the reaction mixture is passed through a short plug of silica gel and concentrated in vacuo to a dark orange oil. Purification by silica gel flash chromatography (30% ethyl acetate/petroleum ether) gave 97 mg of the title compound as a white powder; 1H NMR (CDCl3 300 MHz) δ8.04 (d, 2H, J=7), 7.6-7.2 (m, 15H), 7.14 (t, 1H, J=7), 7.00 (d, 1H, J=7), 5.03 (m, 1H), 4.2 (m, 2H), 3.98 (dd, 1H, J=8,18), 3.61 (dd, 1H, J=5,18), 1.09 (dd, 1H, J=2,7); low resolution MS (FAB) m/e 546 (MH+).