Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].[N+:23]([O-])([N+]([O-])=O)=[O:24]>>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 62.3 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-mannopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-cyclopropylmethyl-3-(D-mannopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][O:12][C:13]([C:15]1[NH:16][C:17]([CH:21]=O)=[C:18]([CH3:20])[CH:19]=1)=[O:14]>>[CH3:11][O:12][C:13]([C:15]1[NH:16][C:17]([CH:21]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[C:18]([CH3:20])[CH:19]=1)=[O:14]
Reactant: O=C1Cc2ccccc2N1
Reactant: COC(=O)c1cc(C)c(C=O)[nH]1
Product: COC(=O)c1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Yield: 81 %

Procedure:
Oxindole (105 mg, 0.79 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid methyl ester (110 mg, 0.67 mmol) using method E to give 153.2 mg (81%) of the title compound.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>N1C=CC=CC=1>[C:22]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C@@H:18]([O:19][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4ccc(OC(=O)c5cccnc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(=O)c1cccnc1
Temperature: 0 °C
Yield: 90 %

Procedure:
Estradiol (2 g, 0.0073 mol) was added to nicotinoyl chloride hydrochloride (5.3 g, 0.029 mol) in dry pyridine (30 ml) at 0° C. The mixture was refluxed for 1 hour and then poured over 100 ml of ice water, filtered and dried over P2O5 under vacuum. Yield 90% (3.18 g), m.p. 148°-150° C. Anal. calculated for C30H31N2O4 : C, 74.50; H, 6.47; N, 5.79. Found: C, 74.40; H, 6.32; N, 5.75. The product has the formula: ##STR91##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[N:8]=2
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2ncccc2C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4ncccc4C(F)(F)F)cc3)C2=N1
Temperature: 70 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
A mixture of 5-chloro-3-(4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyridin-2-amine (450 mg) in THF (dry) (10 mL) was added to a mixture of NaH (60%, 246 mg) and 2-chloroethanesulfonyl chloride (602 mg) in THF (dry) (10.0 mL) at room temperature. The mixture was stirred at 70° C. for 3 hr. Water was added and the mixture was concentrated in vacuo. The residue was washed with water and Et2O to give an off-white solid. The solid was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (315 mg) as a white solid. The solid was crystallized from CH3CN-IPE to give a white solid.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[C:7]([CH2:11][CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=2)[CH2:2]1.C(Cl)Cl.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[O:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[C:7]([CH2:11][CH2:12][O:13][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH:8]=[CH:9][CH:10]=2)[CH2:2]1
Reactant: OCCc1cccc(C2COC2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2cccc(C3COC3)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.9 %

Procedure:
4.9 g of 2-(3-Oxetan-3-yl-phenyl)-ethanol were dissolved using 30 ml of CH2Cl2 and 9.5 ml of pyridine added. Then, 6.3 g of p-toluenesulfonyl chloride was added at 0° C. and the reaction mixture stirred for 6 h at room temperature. The reaction mixture was then evaporated, re-dissolved using 100 ml of EA and washed using 100 ml of a saturated aqueous NaHCO3-solution. The aqueous layer was then extracted twice using 100 ml of EA each. The combined organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:1 yielded 2.0 g of the title compound, colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[CH3:20][O:21][CH2:22][CH2:23]Br>C(#N)C>[CH3:20][O:21][CH2:22][CH2:23][N:2]([C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1)[CH3:1]
Reactant: CNc1ccc(OC)cc1
Reactant: COCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)c1ccc(OC)cc1
Temperature: 80 °C
Yield: 84.3 %

Procedure:
To a stirred solution of 1.00 g (7.29 mmol) N-methyl-p-anisidine in 15 ml acetonitrile at 0° C. were added dropwise 1.36 ml (8.02 mmol) N-ethyldiisopropylamine and 1.01 g (7.29 mmol) 2-bromoethyl methyl ether. The mixture was heated at 80° C. for 2 days and then concentrated in vacuo. Flash chromatography (1/9 ethyl acetate/hexane) afforded 1.20 g (84%) (2-methoxy-ethyl)-(4-methoxy-phenyl)-methyl-amine as an orange oil. ES-MS m/e (%): 196 (M+H+, 100).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[C:18]([Br:19])=[CH:17][C:16]2[C:11](=[C:12]([Cl:21])[CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1>C1COCC1.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>[C:1]([Si:5]([O:8][C:9]1[C:18]([Br:19])=[CH:17][C:16]2[C:11](=[C:12]([Cl:21])[CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2c(Cl)cc(Br)cc2cc1Br
Reactant: COc1ccc([Mg]Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2c(O[Si](C)(C)C(C)(C)C)c(Br)cc3cccc(Cl)c23)cc1
Yield: 68.8 %

Procedure:
A solution of tert-butyl[(3,6-dibromo-8-chloro-2-naphthyl)oxy]dimethylsilane (1.95 g, 4.32 mmol), 4-methoxyphenylmagnesium bromide (13.8 mL of 0.5 N solution, 6.9 mmol), and tetrakis(triphenylphosphine)palladium (0.25 g, 0.21 mmol) in THF (10 mL) were stirred at reflux for 8 hr. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water, dried with sodium sulfate, filtered, evaporation of the solvent, and purified on a silica column (5% ethyl acetate-hexanes) to yield 1.42 g (69%) of the title compound as a white solid: 1H NMR (CDCl3): δ 0.36 (6H, s), 1.10 (9H, s), 3.87 (3H, s), 7.01 (2H, d, J=8.78 Hz), 7.33(1H,d, J=1.36 Hz), 7.58 (2H, d J=8.75 Hz), 7.73 (1H, s), 7.78 (1H, d, J=1.62 Hz), 8.10 (1H, s).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].CN([Sn:13]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])C.CNC>>[C:4]1([S:2]([CH2:1][Sn:13]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N(C)C
Reactant: CS(=O)c1ccccc1
Agent: CNC
Product: CCCC[Sn](CCCC)(CCCC)CS(=O)c1ccccc1
Yield: 65 %

Procedure:
Phenyl methyl sulfoxide (7.0 g.; 0.05 moles) and dimethylamino tributyltin (16.7 g.; 0.05 moles) were admixed in a 50 ml round bottom flask, under a positive pressure argon atmosphere, for 20 hours at 100° C. During the reaction, liberated dimethylamine gas exited from the reaction flask through an open port with the moving argon gas. The crude product was distilled through a semi-micro distillation apparatus. The main fraction (13 g; 65% yield) distilled at 160°-170° C at 0.05 mm Hg. The product was identified by 'H NMR and infra red spectra as (phenylsulfinylmethyl) tributyltin.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([NH:13][CH2:14][CH3:15])[CH:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH2:14]([NH:13][C:5]1[CH:4]=[C:3]([C:1]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16](=[O:24])[N:2]=2)[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH3:15]
Reactant: CCNc1cc(C#N)ccc1C(=O)OC
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CCNc1cc(-c2nc(=O)c3ccccc3s2)ccc1C(=O)OC
Temperature: 145 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
A mixture of methyl 4-cyano-2-(ethylamino)benzoate (1.23 g, 6.02 mmol), methyl thiosalicylate (1.52 g, 9.04 mmol), triethylamine (1.7 mL, 12 mmol) and xylene (6 mL) was stirred at 145° C. for 18 hours under a nitrogen flow. After the reaction mixture was allowed to cool, the crystals were taken by filtration and recrystallized from methanol to give the title compound (450 mg, 22%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.CN(OC)[C:14]([CH:16]1[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH2:17]1)=[O:15].Cl>O1CCCC1>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:14]([C@H:16]1[CH2:17][N:18]([C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[C:19](=[O:21])[CH2:20]1)=[O:15]
Reactant: Brc1nccs1
Reactant: CON(C)C(=O)C1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2nccs2)CC1=O
Reaction time: 0.17 h
Yield: 36 %

Procedure:
In an atmosphere of nitrogen and at −78° C., n-butyl lithium (20.4 ml, 30.0=mol, 1.47 M hexane solution) was added dropwise to a tetrahydrofuran solution (200 ml) of 2-bromothiazole (4.92 g, 30.0 mmol) spending 10 minutes, and the mixture was stirred at the same temperature for 1 hour. To this was added dropwise a tetrahydrofuran solution (50 ml) of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-carboxamide (6.91 g, 25.0 mmol) spending 10 minutes, and the mixture was stirred at −78° C. for 30 minutes and then under ice-cooling for 1 hour. The reaction solution was mixed with 1 mol/l hydrochloric acid (150 ml) under ice-cooling and extracted with ethyl acetate (100 ml×2), and the resulting organic layer was washed with saturated brine (300 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the residue was applied to a silica gel column chromatography. By eluting with n-hexane:ethyl acetate (1:1), 2.70 g (36%) of the title compound was obtained as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH:26]([CH3:28])[CH3:27])=[C:23]([CH:25]=1)[NH2:24]>>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH:26]([CH3:28])[CH3:27])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: CC(C)c1ccc(O)cc1N
Product: CC(C)c1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol) and 5-hydroxy-2-isopropylaniline (26 mg, 0.173 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.75 (d, J=1.2 Hz, 1H), 8.77 (t, J=1, 8 Hz, 1H), 8.72 (d, J=2.7 Hz, 1H), 7.29 (brs, 1H), 7.27 (s, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 6.79 (d, J=2.7 Hz, 1H), 6.70 (s, 1H), 4.13 (sep, J=6.9 Hz, 1H), 1.20 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:18]=1[C:19]([NH2:21])=[O:20]>>[CH2:1]([N:8]1[C:12]([C:13]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[C:18]=2[C:19](=[O:20])[NH2:21])=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1c(N)cccc1N1CCOCC1
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Product: NC(=O)c1c(NC(=O)c2nnnn2Cc2ccccc2)cccc1N1CCOCC1

Procedure:
In a manner similar to Example I, 1-benzyl-1H-tetrazole-5-carbonyl chloride is condensed with 2-amino-6-(4-morpholinyl) benzamide to give 1-benzyl-N-[2-carbamoyl-3-(4-morpholinyl)phenyl]-1H-tetrazole-5-carboxamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[C:9]([OH:18])(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[SH:12].N1C2C(=CC=CC=2)C=CC=1.Cl>N1C=CC=CC=1>[Br:8][C:4]1[CH:3]=[C:2]([S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]([OH:18])=[O:17])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1Sc1cccc(Br)c1

Procedure:
A mixture consisting of 179 g. m-dibromobenzene (0.758 mole); 46.6 g. thiosalicyclic acid (0.303 mole); 25.9 g cuprous oxide (0.181 mole); 212 cc. quinoline; and 24 cc. pyridine is mechanically stirred and heated in an oil bath at 200° C. to 210° C. for three hours. The internal temperature remains constant at 145° C. The reaction mixture is then poured into 1500 cc. of 5N aqueous HCl. The oily solid is filtered, then dissolved in 750 cc. 1N aqueous NaOH solution; this solution is filtered through celite, then extracted three times with ether. The aqueous fraction is acidified with concentrated HCl and the resulting grayish solid filtered, washed well with water and dried. The crude yield obtained is 65 g. (69.4%). It is used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:34])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:32])[C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][O:27]5)[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:33]=1.C[O-].[Na+].C([NH2:40])=O>>[Br:1][C:2]1[C:3]([F:34])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:20]([OH:32])[C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][O:27]5)[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([NH2:40])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:33]=1
Reactant: COC(=O)c1nc2n(c1C(O)c1ccnn1C1CCCCO1)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: NC(=O)c1nc2n(c1C(O)c1ccnn1C1CCCCO1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-9-fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford the crude title compound which was carried forward without further purification.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.[CH:28]12[CH2:35][CH2:34][CH:31]([CH:32]=[CH:33]1)[CH2:30][CH:29]2[S:36]([CH2:39][C:40]1[C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:50][CH3:51])[C:43](Br)=[CH:42][CH:41]=1)(=[O:38])=[O:37]>>[CH:28]12[CH2:35][CH2:34][CH:31]([CH:32]=[CH:33]1)[CH2:30][CH:29]2[S:36]([CH2:39][C:40]1[C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:50][CH3:51])[C:43]([C:23]2[CH:27]=[CH:26][O:25][CH:24]=2)=[CH:42][CH:41]=1)(=[O:38])=[O:37]
Reactant: COC(=O)c1c(CS(=O)(=O)C2CC3C=CC2CC3)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CS(=O)(=O)C2CC3C=CC2CC3)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 6-(bicyclo[2.2.2]oct-5-ene-2-ylsulphonylmethyl)-3-bromo-2-methoxybenzoate.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)=[O:11])=[N:27][CH:28]=1
Reactant: Clc1ccc(Br)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 447 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:12][CH2:13][C:14]([N:16]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][CH:17]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[NH:12][CH2:13][C:14]([N:16]2[CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:25][CH:17]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CN
Reactant: COc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.9 cm3 of 3-methoxyphenyl isocyanate is added to a solution of 2 g of tert-butyl (2RS,5SR)-1-(2-aminoacetyl)-5-phenylprolinate in 20 cm3 of anhydrous tetrahydrofuran. The reaction mixture is stirred for 20 hours at a temperature in the vicinity of 25° C. After evaporation of the solvent under reduced pressure at a temperature in the vicinity of 45° C., the crude product obtained is purified by chromatography on silica [eluent: dichloromethane/methanol (95/5 by volume)]. The fractions containing the expected product are combined, then concentrated to dryness under reduced pressure. After recrystallization in acetonitrile, 1.9 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-methoxyphenyl)ureido]acetyl}-5-phenylprolinate melting at 174° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=1>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:23]=[CH:22][N:21]=1
Reactant: COc1cc(Br)ccn1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COc1cc(-c2ccc(C)nc2)ccn1
Yield: 95.3 %

Procedure:
2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.5 g, 16 mmol) and 4-bromo-2-methoxypyridine (2.0 g, 11 mmol) were reacted according to Example 6 (step a) to provide the title compound (2.1 g, 98%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 8.75 (d, J=2.1 Hz, 1H), 8.23 (d, J=5.4 Hz, 1H), 7.78 (dd, J=8.0, 2.4 Hz, 1H), 7.24 (d, J=8.1, 1H), 7.08 (dd, J=5.4, 1.5 Hz, 1H), 6.84 (d, J=1.0, 1H), 3.98 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[NH2:26][O:27][CH2:28][CH2:29][OH:30]>CO>[OH:30][CH2:29][CH2:28][O:27][N:26]=[C:22]([C:19]1[N:20]=[C:21]2[N:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[F:1])[N:9]=[CH:8][CH:7]=[CH:6]4)[N:14]=[N:15][C:16]2=[N:17][CH:18]=1)[CH3:23]
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Reactant: NOCCO
Agent: Cl
Solvent: CO
Product: CC(=NOCCO)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Temperature: 45 °C
Yield: 74.7 %

Procedure:
To a solution of 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (190.0 mg, 0.59 mmol) in MeOH (40 mL) was added 2-(aminooxy)ethanol hydrochloride (134.0 mg, 1.18 mol). The mixture was heated at 45° C. overnight. The solvent was removed under reduced pressure. The residue was purified by column chromatography with gradient (DCM:MeOH=10:1) to give the title compound as a white solid (168.0 mg, 71%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.30 (s, 1H), 8.93 (d, 1H), 8.41 (d, 1H), 8.19 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.24 (s, 2H), 4.78 (t, 1H), 4.31 (t, 2H), 3.72 (m, 2H), 2.29 (s, 3H). LCMS (method A): [MH]+=382, tR=4.99 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[F:35][CH:36]1[CH2:39][NH:38][CH2:37]1.C(Cl)(Cl)Cl>CN(C=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH:36]([F:35])[CH2:37]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: FC1CNC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CC(F)C4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-fluoro-azetidine hydrochloride in DMF. [α]D20=+19.7° (c=0.17, CHCl3), ES-MS m/e (%): 445 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=O)[CH:17]=1.CC1ON=C(C2C=CC=CC=2)C=1C1N=C[N:42]([C:44]2[CH:52]=[CH:51][C:47](C(O)=O)=CC=2)C=1>>[CH:52]1([CH2:44][NH:42][C:21](=[O:23])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([N:16]3[CH:17]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[CH:15]3)[CH:19]=2)[CH2:47][CH2:51]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)NCC3CC3)c2)cn1
Yield: 43 %

Procedure:
As described for Example 71c, 3-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol), instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid was converted to the title compound (50 mg, 43%) which was obtained as an off-white solid. MS: m/e=399.1 [M+H]+.