Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: BrCc1ccccc1Br
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3Br)CC2)cc1

Procedure:
A solution of EXAMPLE 1B (23.43 g, 100.0 mmol), 2-bromobenzyl bromide (26.24 g, 105.0 mmol) and diisopropylethylamine (20.94 mL, 120 0 mmol) in acetonitrile (200 mL) was stirred at room temperature for two hours. The resulting precipitate was collected by filtration to give the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:8][CH2:7][C:6]2=[O:23].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:24](=[C:7]1[C:6](=[O:23])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:8]1)[CH:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH2:30]1
Reactant: COc1ccc2c(c1)C(=O)CCN2S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccccc1
Product: COc1ccc2c(c1)C(=O)C(=CC1C=CC=CC1)CN2S(=O)(=O)c1ccc(C)cc1
Yield: 62.8 %

Procedure:
By the method of Example 146, 25.0 g (75.5 mmol) of 6-methoxy-1-(p-toluenesulfonyl)-2,3-dihydro-4(1H)-quinolinone (J. Am. Chem. Soc., Vol. 71, p. 1901, 1949) and 12.0 g (113 mmol) of benzaldehyde were converted to 20.0 g (63%) of present title product recrystallized from ether-hexane, m.p. 131-132° C.
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=2CC(CC)C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=[O:21].[Al+3].[Cl-].[Cl-].[Cl-].Cl.[C:29]1([CH3:35])[CH:34]=CC=[CH:31][CH:30]=1>>[CH2:30]([CH:29]1[CH2:35][C:8]2[C:16](=[CH:17][CH:18]=[CH:19][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:34]1=[O:21])[CH3:31]
Reactant: O=S(Cl)Cl
Reactant: CCC(Cc1ccccc1-c1ccccc1)C(=O)O
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC1Cc2c(cccc2-c2ccccc2)C1=O
Temperature: 80 °C
Yield: 85 %

Procedure:
A solution of 236 g (0.93 mol) of 13 in 81 cm3 (1.2 mol) of thionyl chloride was stirred at room temperature for 18 hours. Excess thionyl chloride was removed at 10 mbar and the oily residue was freed from adhering residues of thionyl chloride by repeated dissolution in 200 cm3 of toluene in each case and stripping off in vacuo. The acid chloride was taken up in 400 cm3 of toluene and added dropwise at 10° C. to a suspension of 133 g (1.0 mol) of AlCl3 in 2000 cm3 of toluene. The reaction mixture was heated at 80° C. for 1 hour, poured into 2000 g of ice and acidified to pH 1 by means of concentrated aqueous HCl. The organic phase was separated off, and the aqueous phase was then extracted three times with 200 cm3 of Et2O in each case. The combined organic phases were washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution and subsequently dried (MgSO4), giving 187 g (85%) of 14, which was reacted further without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[S:27][C:28]([CH:31]=O)=[CH:29][N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:31][C:28]2[S:27][C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:30][CH:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cnc(-c2ccccc2)s1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cnc(-c2ccccc2)s1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 2-phenylthiazole-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 409.16 g/mol.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[P:23](Cl)(Cl)([O:25][CH2:26][CH3:27])=[O:24].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1C[O:43]CC1>>[P:23]([OH:43])([O:25][CH2:26][CH3:27])([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)=[O:24]
Reactant: CCOP(=O)(Cl)Cl
Reactant: C1CCOC1
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOP(=O)(O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1

Procedure:
A solution of 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol), ethyl dichlorophosphate (0.13 mL, 1.1 mmol), and lithiumhexamethyldisilazide (0.183 g, 1.1 mmol) in 10 mL of THF was stirred for 1 hour at ambient temperature. The reaction mixture was quenched with H2O and concentrated in vacuo. The residues were purified by reversed phase HPLC (Column: HS Hyperprep C18 8 u ID 22 mm; solvent gradient 40% to 100% acetonitrile (0.1% TFA) in H2O; flowrate 10 mL/min) to give 0.065 g of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH2:8]P(=O)(OCC)OCC)=[O:7])[CH3:4].C[CH2:18][CH2:19][CH:20]([CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)C.O1CC[CH2:33][CH2:32]1>>[CH2:3]([O:5][C:6](=[O:7])[CH:8]=[C:32]([C:28]1[CH:27]=[CH:26][C:25]([CH2:23][CH2:22][CH2:20][CH2:19][CH3:18])=[CH:30][CH:29]=1)[CH3:33])[CH3:4]
Reactant: CCCC(C)CC(=O)c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCCCCc1ccc(C(C)=CC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (28.6 g, content: 63%) was suspended in tetrahydrofuran (1000 ml). Diethyl ethoxycarbonylmethylphosphonate (168 g) dissolved in tetrahydrofuran (500 ml) was added dropwise into the mixture with cooling in an ice-bath over 30 mins. 4-Pentylacetophenone (95 g) in tetrahydrofuran (500 ml) was added to the solution. The solution was stirred overnight at room temperature and then refluxed at 8 hrs. Tetrahydrofuran was evaporated from the reaction mixture. Dilute hydrochloric acid was added to the residue. The acidic solution was extracted with ethyl acetate. The extract dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=99:1→98:2→95:5) to give the title compound (128 g) having the following physical data:
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[C:15]([NH2:31])=[CH:14][N:13]=2)=[C:7]([O:32][CH3:33])[CH:6]=1)([CH3:4])=[O:3].C1C[O:37][CH2:36]C1>>[CH3:4][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]3[C:15]([NH:31][C:36](=[O:37])[N:18]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH:28]([CH3:29])[CH3:30])(=[O:27])=[O:26])=[CH:14][N:13]=2)=[C:7]([O:32][CH3:33])[CH:6]=1)([CH3:1])=[O:3]
Reactant: C1CCOC1
Reactant: COc1cc(P(C)(C)=O)ccc1Nc1ncc(N)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Product: COc1cc(P(C)(C)=O)ccc1Nc1ncc2[nH]c(=O)n(-c3ccccc3S(=O)(=O)C(C)C)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4,5-triamine (as prepared in Example 28: 40 mg, 0.082 mmol) in THF was added N,N′-Carbonyldiimidazole (40 mg, 0.25 mmol). The solution was stirred at room temperature overnight. The solution was concentrated under reduced pressure and diluted with water and extracted with Ethyl Acetate. The combined organic layer was washed with brine and dried over Magnesium Sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by RP Prep-HPLC to obtain the desired product as an off white solid. MS/ES+: m/z=516
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.N([O-])=[O:35].[Na+]>CC(O)=O.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C@:19]2([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([OH:35])[N:7]=4)=[CH:13][CH:12]=3)[CH3:15])[CH2:21][CH2:20]2)=[CH:27][CH:28]=1
Reactant: C[C@@H](c1ccc(-c2ccnc(N)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](c1ccc(-c2ccnc(O)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 8 %

Procedure:
To a solution of (R)-3-((S)-1-(4-(2-aminopyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (40 mg, 0.089 mmol) in CH3COOH (0.3 mL) and H2O (0.13 mL) was added an aqueous solution of NaNO2 (2 mol/L, 0.5 mL) dropwise at 0° C. The reaction was stirred for 10 min at this temperature before heating at 60° C. for 3 h. After the mixture was evaporated to dryness, the mixture was adjusted pH 9 with aqueous NaHCO3 solution. The mixture was extracted with EtOAc, and the organic layer was dried and concentrated to give the residue, which was purified by preparative TLC to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-hydroxypyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one (3.18 mg, 8%). LC-MS Method 2 tR=0.87 min, m/z=452. 1H NMR (CD3OD): 1.19-1.23 (m, 2H), 1.48 (d, 3H), 1.82-1.86 (m, 2H), 2.05-2.41 (m, 3H), 3.01-3.10 (m, 1H), 3.37 (t, 2H), 5.50 (q, 1H), 6.90 (d, 1H), 6.95-7.02 (m, 4H), 7.18-7.22 (m, 2H), 7.00-7.05 (m, 3H), 7.21-7.24 (m, 2H), 7.80 (d, 2H).
Reaction SMILES: BrC1C=CC=C[N+]=1C.[CH2:9]([OH:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:19](O)(=[O:21])[CH3:20].C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:19]([O:18][CH2:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:21])[CH3:20]
Reactant: OCC=Cc1ccccc1
Reactant: CC(=O)O
Agent: C[n+]1ccccc1Br
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CC(=O)OCC=Cc1ccccc1
Yield: 82 %

Procedure:
To a suspended CH2Cl2 (2 ml) solution of 2-bromo-1-methylpyridinium (720 mg, 2.4 mmol) was added a mixture of cinnamyl alcohol (268 mg, 2.0 mmol), acetic acid (120 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and cinnamyl acetate was isolated in 82% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]([CH3:22])[CH3:21])[C:12]2=[O:23])=[O:10])[CH2:3][CH2:2]1.[Cl:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](F)=[CH:31][CH:30]=1)=[O:28]>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH:20]3[CH2:21][CH2:22]3)[C:12]2=[O:23])=[O:10])[CH2:3][CH2:2]1.[Cl:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Product: O=C(CCCl)c1ccccc1
Product: O=C(NCC1CCNCC1)n1c(=O)n(C2CC2)c2ccccc21

Procedure:
The procedure given in Example 135 was followed using 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 3-chloro-4′-fluoropropiophenone as a reactant, instead of 3-cyclopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 3-chloropropiophenone, to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH:14]([CH3:16])[CH3:15].Cl.[CH:19]([O:22][NH2:23])([CH3:21])[CH3:20].Cl.CON>C(O)C>[CH:19]([O:22][N:23]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[C:13]1[CH:14]([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cnc2ccccc2c1Cl
Reactant: CC(C)ON
Agent: CON
Agent: Cl
Solvent: CCO
Product: CC(C)On1c(C(C)C)nc2cnc3ccccc3c21
Yield: 56.3 %

Procedure:
The method of Part B of Example 25 was followed using N-(4-chloroquinolin-3-yl)-2-methylpropanamide (3.6 g, 14.5 mmol), O-isopropylhydroxylamine hydrochloride (1.8 g, 16 mmol) in lieu of O-methylhydroxylamine hydrochloride, and ethanol (60 mL). 1-Isopropoxy-2-isopropyl-1H-imidazo[4,5-c]quinoline (2.2 g) was obtained as a dark oil.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[C@H:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].N1C=CC=CC=1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1>C(Cl)Cl>[CH3:1][C@@H:2]1[N:8]([C:34]([CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[O:35])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[C@H:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(Cl)C1CCOCC1
Reactant: C[C@@H]1Nc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2ccccc2N1C(=O)C1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a 0° C. solution of tert-butyl(2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (prepared as in Example 1, 330 mg, 1.13 mmol) in methylene chloride (10 ml) was added pyridine (277 μl, 3.4 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (185 mg, 1.25 mmol). It was stirred at 0° C. for one hour and then warmed to room temperature and stirred overnight. After this time another portion of tetrahydro-2H-pyran-4-carbonyl chloride (252 mg, 1.70 mmol) was added and the reaction mixture was stirred at room temperature another 3 h. After this time the reaction mixture was diluted with methylene chloride (30 mL), washed with a saturated aqueous sodium bicarbonate solution (30 mL), and saturate aqueous sodium chloride solution (30 mL), the organic layer was then dried over sodium sulfate, filtered to remove the drying agent, and concentrated in vacuo. The crude material was then purified on an Intelliflash 280 system (12 g silica gel column, 20-65% ethyl acetatehexanes) to afford tert-butyl(2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (210 mg, 46%) as a white foam: LC-MS m/z 426 [M+Na]+.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]1([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)(=O)C>[ClH:2].[C:7]1([C:13]2[CH:14]=[CH:15][N:16]=[C:17]([CH2:3][CH2:4][CH2:5][NH2:6])[CH:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(-c2ccncc2)cc1
Reactant: NCCCCl
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCCc1cc(-c2ccccc2)ccn1
Temperature: 70 °C
Yield: 70.4 %

Procedure:
3-Chloropropylamine hydrochloride (13.0 g) and 15.5 g of 4-phenylpyridine were dissolved in dimethylacetamido and heated at 70° C. for 5 hours. Ethyl acetate was added thereto and the precipitated crystals were collected by filtration to obtain 17.5 g of 3-(4-phenylpyridyl)propylamine hydrochloride.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.[H-].[Na+]>C1COCC1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][C@H:12]([O:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
4-Fluoronitrobenzene (2.82 g, 20 mmol) was mixed with (S)-3-hydroxy-N-Boc-pyrrolidine (3.74 g, 20 mmol) in dry THF (100 mL). At 0° C., sodium hydride (1.69 g, 60% dispensed in mineral oil, 2.20 eq) was added. The mixture was stirred at 0° C. for 60 min and at room temperature overnight. Solvents were evaporated and the residue was extracted with ethyl acetate and 0.2N hydrochloric acid. The organic layer was washed with brine and dried over sodium sulfate. After the evaporation of solvents, the residue was purified through flash column chromatography using ethyl acetate and hexanes (5% to 60% ethyl acetate) to give a crystalline material as (S)-3-(4-nitro-phenyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.33 g, 70.3% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1.O.[OH-].[Li+]>N1C=CC=CC=1.C1COCC1.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(Cl)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol) in pyridine (5 mL) at 0° C. was treated dropwise with cyclopropanecarbonyl chloride (118.3 μL, 1.304 mmol). The mixture was stirred at 0° C. for 60 minutes, and then the pyridine was removed in vacuo. The residue obtained was dissolved in THF (10 mL) and treated with lithium hydroxide hydrate (109.5 mg, 2.61 mmol) in water (1 mL). After 30 minutes, the THF was removed under reduced pressure, and water (5 mL) was added to the residue. The solid formed was filtered, washed with additional water and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (165 mg, 64% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.03 (br s, 1H), 9.76 (s, 1H), 8.34 (d, 1H), 7.59 (s, 1H), 1.93-1.86 (m, 1H), 0.783 (d, 4H); LCMS (APCI+) m/z 298, 300 (M+H)+, Retention time=2.71 min (Method 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12](OCC)=[O:13])=[N:7]1.O.[NH2:21][NH2:22].CCN(CC)CC>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]([NH:21][NH2:22])=[O:13])=[N:7]1
Reactant: CCOC(=O)c1nc(C)n(Cc2cccc(Br)c2)n1
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)NN)nn1Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carboxylate (1.28 g, 3.92 mmol) in MeOH (19 mL) was added hydrazine hydrate (784 μL, 7.84 mmol) and NEt3 (2.47 mL, 17.6 mmol). The reaction was allowed to stir overnight at RT. The solvent was then removed under reduced pressure and the crude material was spun down from toluene (3×) to give a white solid, which was used directly for the next step without further purification. MS (ES+) C11H12BrN5O requires: 309, 311 found: 310, 312 [M+H]+(1:1).
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])C.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[CH3:21])[CH:15]=1.[CH2:23]1COCC1>>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH3:21])=[CH:4][C:6]([O:8][CH3:23])=[O:7])[CH:15]=1
Reactant: CC(=O)c1cccnc1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C=C(C)c1cccnc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (192 mg of a 60% wt. suspension, 4.80 mmol) was added in several portions to a stirred solution of trimethylphosphonoacetate (712 μL, 4.40 mmol) in THF (20.0 mL). After 5 min, 1-pyridin-3-ylethanone (440 μL, 4.00 mmol) was added dropwise, and the resulting mixture was heated to reflux. After 20 h, the reaction mixture was cooled to rt, poured into satd. aq. NH4Cl and extracted with EtOAc. The combined organics were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-60% EtOAc/hexanes as eluent) afforded the title compound i-7a as a separable mixture of two isomers. m/z (ES) 178 (MH)+.
Reaction SMILES: CN1C(CO)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=[CH:3]1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.[CH3:25][O:26][CH:27]([O:30][CH3:31])[CH:28]=O>>[CH3:25][O:26][CH:27]([O:30][CH3:31])[C:28]1[N:22]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH:3]=[N:4][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(C=O)OC
Reactant: COc1ccc(CN)cc1
Reactant: Cn1cnc(-c2ccccc2)c1CO
Product: COc1ccc(Cn2cnc(-c3ccccc3)c2C(OC)OC)cc1

Procedure:
The title compound was prepared by a similar process to that described for preparation of Intermediate 1, except that 4-methoxybenzylamine was used in place of methylamine and dimethoxyacetaldehyde in place of glycolaldehyde. Colourless oil (1.5 g, 74%);
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]3)[C:8]=2[CH:30]=1)(=[O:3])[CH3:2].NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([NH2:22])[CH2:20][CH2:21]3)[C:8]=2[CH:30]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: CC(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2

Procedure:
tert-Butyl {1-[2-(6-acetyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 88) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(NC(C)C)(C)C.[Na+].[I-]>CN(C=O)C.O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: COC(=O)c1ccc(N2CCN(C)CC2)nc1
Reaction time: 4 h
Yield: 76.3 %

Procedure:
To a solution of 5.15 g of methyl 6-chloronicotinate, 3.15 g of 1-methylpiperazine and 3.18 g of diisopropylamine in 50 ml of DMF was added a catalytic amount of NaI. The mixture was heated to 120°-130° C. and stirred for 4 hours. The resulting mixture was poured into 250 ml of water followed by extraction with ethyl acetate. The extract was washed twice with water, and once with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated. Purification of the concentrate by column chromatography (silica gel; chloroform:methanol=3:1) afforded 5.39 g of methyl 6-(4-methyl-1-piperazinyl)nicotinate (yield 77%).