Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc(Br)cc1
Product: BrCCCCOc1ccc(Br)cc1

Procedure:
The procedure is as for Example 53 using as substrate 4-bromophenol and 1,4-dibromobutane.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]1.[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CC(C)([O-])C.[K+]>CS(C)=O.CCOC(C)=O>[Cl:10][C:11]1[C:12]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]2)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: O=C1CCCC(CO)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCCC(=O)C2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.8 %

Procedure:
To a solution of 3-(hydroxymethyl)cyclohexanone (575 mg) and tert-butyl 5-chloro-2,4-difluoro-benzoate (1.23 g) in DMSO (13.5 mL) at 14° C. (bath) was added potassium tert-butoxide (604 mg) gradually. After 5 min, the mixture was stirred at rt for 30 min. Diluted with EtOAc, the contents were washed with dilute NaHCO3 (3×) and brine, and dried (Na2SO4). After filtration and concentration, the crude was purified with flash chromatography (0->40% EtOAc/heptane) to give the product (445 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].[CH2:32]([CH:34]1[O:36][CH2:35]1)Br.O>CN(C)C=O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:32][CH:34]1[CH2:35][O:36]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (130 mg) was dissolved in N,N-dimethylformamide (4 ml) to prepare a solution. Potassium carbonate (162 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (83 mg, yield 55%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1cnn(-c2cc(Cl)nc(N)n2)c1C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2cc(NCc3ccc(OC)cc3)nc(N)n2)c1C
Temperature: 25 °C

Procedure:
A mixture consisting of 3.0 g of ethyl 1-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-4-pyrazolecarboxylate, 3.5 ml of 4-methoxybenzylamine, and 150 ml of tetrahydrofuran was heated under reflux for 99 hours. The reaction mixture was cooled to room temperature and concentrated. Water was added to the residue, and the mixture was extracted three times with chloroform. The combined organic layers were washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography using a 49:1 mixture of chloroform and methanol as a developing solvent. The fraction containing the desired product was concentrated to afford 4.08 g of the title compound (amorphous).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]1.C([Li])CCC>CCCCCC.O1CCCC1>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:17]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:16]=1)=[O:19]
Reactant: CC1CCCCN1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CCCCN1C(=O)c1nc(-c2ccccc2)nc2ccccc12

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 2-methylpiperidine (3 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 2-methyl-1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidine (1.7 g), melting at 150° C., is obtained.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[O:6][C:5]=1[NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])(=O)[CH3:2].[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>C(#N)C>[C:19]1([C@@H:16]([NH:15][C:5]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:25]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:1]=2[CH3:2])=[O:6])[CH2:17][CH3:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC[C@H](Nc1oc(=O)c2ccccc2c1C(C)=O)c1ccccc1
Reactant: Nc1cccnc1
Solvent: CC#N
Product: CC[C@H](NC(=O)c1c(C)n(-c2cccnc2)c(=O)c2ccccc12)c1ccccc1
Temperature: 170 °C
Yield: 29.9 %

Procedure:
A mixture of 4-acetyl-3-((S)-1-phenyl-propylamino)-isochromen-1-one (100 mg) and 3-aminopyridine (400 mg, excess) in acetonitrile (0.2 mL) was heated under microwave irradiation at 170° C. for 15 min. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (20 ml), and the organic phase was washed with water (3×10 ml). The product was extracted into aqueous phase with aq. 2M HCl (10 ml), the aqueous solution was neutralised with aq. 10% Na2CO3 and extracted again with ethyl acetate and evaporated. The obtained residue was purified by flash chromatography on SiO2 (5 g, gradient heptane-ethyl acetate, the product came out with 100% ethyl acetate) to give 37 mg of oil, which was precipitated from methanol (0.1 mL) and water (10 mL) with sonication for 10 min. The title compound was separated by filtration to give 10 mg of brown solid. LC-MS (m/z) 398.1 (MH+); tR=1.06. 1H NMR (250 MHz, 70° C., DMSO-d6): 0.93 (t, J=7.4 Hz, 3H, Me of Et), 1.72-1.88 (overlapping m, CH2 of Et), 1.85 (overlapping s, 3H, Me), 4.97 (q (dt), J=8 Hz, J=6.9 Hz, 1H, CHNH), 7.23 (m, 1H), 7.28-7.42 (m, 5H), 7.49 (t, J=7.6 Hz, 1H), 7.59 (dd, J=4.8 Hz, J=8.1 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 7.76 (d of dd, J=8.1 Hz, J=2.4 Hz, J=1.4 Hz, 1H), 8.21 (dd, J=8 Hz, J=0.8 Hz, 1H), 8.49 (d, J=2.4 Hz), 8.67 (dd, J=4.7 Hz, J=2.4 Hz, 1H), 8.72 (br d, J=8.2 Hz, NHCO).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Br:9]Br>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Br:9])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1ccnc(N)n1
Solvent: CC(=O)O
Product: Nc1ncc(Br)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a stirring mixture of 2,4-diaminopyrimidine (25 g, 0.23 mol, 1.0 eq) in acetic acid (375 ml) was added Br2 (36.3 g, 0.23 mol, 1.0 eq) at room temperature. The resulting mixture was stirred at room temperature (about 25° C.) for 2 hours and then filtered. The yellow solid was mixed with water (250 ml) and the pH of the resulting mixture was adjusted to 8-9 using 50% NaOH solution. Stirring was continued at room temperature for 30 min and the mixture was filtered, washed with water, and then dried under vacuum to give 38 g (87%) of 2,4-diamino-5-bromo-pyrimidine as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 6.06 (s, 2H, ex. D2O), 6.50 (br, 2H, ex. D2O), 7.76 (s, 1H); MS (+)-ES [M+H]+ m/z 191.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:17]3[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:25]N1C(=O)CCC1=O>ClCCl>[F:24][C:2]([F:1])([F:23])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:17]3[N:18]([CH3:22])[N:19]=[CH:20][C:21]=3[Br:25])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3ccnn3C)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3c(Br)cnn3C)ccc21
Reaction time: 8 h
Yield: 108.4 %

Procedure:
To a solution of N-trifluoroacetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (30 mg, 0.082 mmol) in dichloromethane (1 mL) was treated with N-bromosuccinimide (15.3 mg, 0.086 mmol) and stirred overnight at 20 C. The product mixture was absorbed on silica and purified by flash chromatography (2-5% MeOH in CH2Cl2, silica) resulting in 37 mg of a white crystalline solid. MS calculated for C17H17BrF3N3O+H: 416, observed: 416.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[C:17]([S:21]([CH3:29])(=[N:23]C(OCC)=O)=[O:22])[CH:18]=[CH:19][CH:20]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:30][CH:31]([CH3:33])[CH3:32])#[N:2].ClCCl.CO>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[C:17]([S:21]([CH3:29])(=[NH:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:30][CH:31]([CH3:33])[CH3:32])#[N:2]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC(C)C)c3cc2C#N)c1
Solvent: CO
Solvent: ClCCl
Product: CC(C)Nc1ncnc2cc(OCc3cccc(S(C)(=N)=O)c3)c(C#N)cc12
Yield: 74 %

Procedure:
According to GWP 6, the conversion of (RS)-S-[3-({[6-cyano-4-(isopropylamino)-quinazolin-7-yl]oxy}methyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (65 mg, 0.14 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 74% yield (41 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.[Br:22]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.[Fe]>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)[C:5]([Br:22])=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: BrBr
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1nc(N)nc(-c2ccc(F)c3ccccc23)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (free base, 0.100 g) in carbon tetrachloride (10 mL) was added iron powder (0.002 g) and bromine (0.074 g) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, after which time it was poured into sodium bicarbonate solution (saturated, 30 mL). The layers were separated and the aqueous layer was extracted three times with methylene chloride (3×10 mL). The combined organic layers were evaporated to dryness. The residue was purified by preparative thin layer chromatography, eluting with hexane/ethyl acetate, and recrystallized from ether/hexane to give 2-amino-5-bromo-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.072 g), m.p. 176-180° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:11][C:12]1[C:17]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:16][C:15](Br)=[CH:14][N:13]=1>C1C=CC=CC=1>[NH2:11][C:12]1[C:17]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[N:16][C:15]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][N:13]=1
Reactant: OCc1ccccc1
Reactant: Nc1ncc(Br)nc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Nc1ncc(OCc2ccccc2)nc1N1CCOCC1

Procedure:
Sodium hydride (0.1 mole) is added to benzyl alcohol (0.1 mole) in 100 ml. dry benzene and the mixture is refluxed one to two hours. The cooled solution is treated with 0.1 mole of 2-amino-3-morpholino-5-bromopyrazine in 100 ml. of benzene and the resulting mixture refluxed for 20-60 hours whereupon it is cooled, washed with water, dried and evaporated to give 2-amino-3-morpholino-5-benzyloxypyrazine.
Reaction SMILES: [CH3:1][C:2]1([CH2:12][OH:13])[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[Cl:14][C:15]1[C:16](F)=[CH:17][C:18]([F:28])=[C:19]([CH:27]=1)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:14][C:15]1[C:16]([O:13][CH2:12][C:2]2([CH3:1])[CH2:11][CH2:10][C:5]3([O:6][CH2:7][CH2:8][O:9]3)[CH2:4][CH2:3]2)=[CH:17][C:18]([F:28])=[C:19]([CH:27]=1)[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1(CO)CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCC2(CC1)OCCO2
Temperature: 70 °C
Reaction time: 96 h
Yield: 53.8 %

Procedure:
To a solution of (8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)methanol (4.30 g, 23 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (10.66 g, 30 mmol) in anhydrous dimethylsulfoxide (37 mL) was added cesium carbonate (14.99 g, 46 mmol). The reaction mixture was heated to 70° C. and stirred for 4 days. At this point, HPLC and TLC analysis indicated remaining starting material, but the reaction was not progressing any further. The reaction mixture was cooled to ambient temperature, filtered through a pad of diatomaceous earth and rinsed with ethyl acetate (100 mL). The filtrate was washed with 1N aqueous hydrochloric acid solution (100 mL). The organic layer was separated, washed with brine (40 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 20% ethyl acetate in hexanes) afforded the title compound (5.13 g, 54%) as a colorless oil: MS (ES+) m/z 359.1 (M−55).
Reaction SMILES: [ClH:1].[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[S:13][CH:14]=1.CCCCCC>C(OCC)(=O)C>[ClH:1].[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[S:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(F)c3F)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1cccc(-c2csc(N3CCNCC3)n2)c1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 4 N solution (50 ml) of hydrogen chloride in ethyl acetate was added to a solution of tert-butyl 4-[4-(2,3-difluorophenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (4.20 g, 11.0 mmol) in ethyl acetate (100 ml), and the mixture was stirred at room temperature for 14 hours. Hexane was added to the reaction mixture, and crystals were collected by filtration to give 1-[4-(2,3-difluorophenyl)-1,3-thiazol-2-yl]piperazine hydrochloride. The hydrochloride was dissolved in water, neutralized with a 1 N sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1.76 g (56.8%) of the desired product as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:27]=[CH:26][C:25]([N:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]6)=[CH:24][CH:23]=5)[CH:20]=4)[NH:15][CH:14]=3)[CH:10]=[N:9]2)[CH:2]=1.Cl>CCOCC.CO>[N:28]1([C:25]2[CH:26]=[CH:27][C:22]([C:19]3[CH:20]=[C:21]4[C:13]([C:11]5[CH:10]=[N:9][N:8]([CH2:7][C:3]6[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=6)[CH:12]=5)=[CH:14][NH:15][C:16]4=[N:17][CH:18]=3)=[CH:23][CH:24]=2)[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccnc6)c5)c4c3)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: c1cncc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(N6CCNCC6)cc5)cc34)cn2)c1
Yield: 11.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (100 mg, 0.186 mmol) was deprotected with HCl in ether/methanol (2/3 ml). This afforded 9 mg (11.0% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.54 (s, 1H), 8.34-8.28 (d, 1H), 8.50-8.49 (d, 1H), 8.43-8.42 (d, 1H), 8.307-8.300 (d, 1H), 8.23 (s, 1H), 7.93 (s, 1H), 7.79-7.77 (d, 1H), 7.64-7.61 (m, 3H), 7.45-7.41 (m, 1H), 7.14-7.11 (m, 2H), 5.49 (s, 2H), 3.38-3.31 (m, 4H), 3.30-3.23 (m, 4H). MS: m/z=436.2 (M+1), HPLC: 97.13% in method A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:12][C:11]1[C:10]([N+:17]([O-:19])=[O:18])=[C:9]2[C:4](=[CH:3][C:2]=1[Cl:1])[N:5]=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[N:8]2
Reactant: O=[N+]([O-])O
Reactant: COc1nc2cc(Cl)c(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)c(Cl)c([N+](=O)[O-])c2nc1OC
Temperature: 10 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
6,7-Dichloro-2,3-dimethoxyquinoxaline (25 g, 0.096 mol) was added, portionwise, to fuming nitric acid (0.113 L) which had been pre-cooled to −5° C. The solution was allowed to warm to 10° C. and stirring continued for 2 hours. The solution was then poured into an ice/water mixture (0.5 L). The slurry was filtered and the solid was washed with water and isopropanol (0.05 L) to give 6,7-dichloro-2,3-dimethoxy-5-nitroquinoxaline(27 g, 92%) as a beige solid. m.p. 184-186° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:17](Cl)(=O)C>CO>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][C:4]([O:6][CH3:17])=[O:5]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Solvent: CO
Product: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
To a stirred suspension of 3-amino-3-(3',4'-dimethoxyphenyl)propionic acid (70.1 grams, 312 mmol) in methanol (400 mL) at 0° C., was added acetyl chloride (47.6 mL, 667 mmol) dropwise. After an additional 15 minutes, the ice-water bath was removed. The resulting clear solution was stirred at room temperature for 2 hours. The system was opened and the solvent was blown off with N2 overnight. To the solid was added methanol (50 mL) and ether (300 mL). The resulting suspension was stirred at room temperature for 1 hour. The suspension was filtered and the solid was washed with ether (100 mL). The solid was dissolved in a mixture of sodium carbonate (200 mL, sat), water (200 mL), and methylene chloride (250 mL). The organic layer was separated. The aqueous layer was extracted with methylene chloride (3×250 mL). The combined organic layers were dried over magnesium sulfate. Removal of solvent gave methyl 3-amino-3-(3',4'-dimethoxyphenyl)propionate as an oil (60.2 grams, 81% yield): 1H NMR (CDCl3)δ1.77 (s, 2H, NH2), 2.65 (d, J=7 Hz, 2H, CH2), 3.68 (s, 3H, CH3), 3.87 (s, 3H, CH3), 3.89 (s, 3H, CH3), 4.39 (t, J=Hz, 1H, CH), 6.81-6.93 (m, 3H, Ar); 13C NMR (CDCl3)δ44.00, 51.48, 52.18, 55.72, 55.76, 109.20, 111.02, 118.02, 137.21, 148.11, 148.93, 172.34; Anal. Calcd for C12H17NO4 0.1 H2OC, 59.19; H, 7.19; N, 5.81. Found: C, 59.38; H, 7.09; N, 5.91.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][C:21]=1[F:29]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: N#Cc1cc(-c2ccc(Cl)c(F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (74 mg, 84%), MS (ISP) m/z=354.3 [(M+H)+], mp 221.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)[C:6]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[N+:54]([C:57]1[CH:65]=[CH:64][C:60]([C:61](O)=[O:62])=[CH:59][CH:58]=1)([O-:56])=[O:55]>C1COCC1>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@@H:10]2[CH2:11][CH2:12][C@H:13]([O:16][C:61](=[O:62])[C:60]3[CH:59]=[CH:58][C:57]([N+:54]([O-:56])=[O:55])=[CH:65][CH:64]=3)[CH2:14][CH2:15]2)[C:6]1=[O:17]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1C(Cc2ccc(Cl)cc2Cl)CCN1[C@H]1CC[C@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Reaction time: 6 h
Yield: 36.9 %

Procedure:
Dissolve 3-(2,4-dichloro-benzyl)-1-(trans-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (Example 15) (3.32 g, 9.70 mmol) in anhydrous THF (200 mL) and cool to −20 ° C. Add triphenyl phosphine (12.71 g, 48.48 mmol), diethyl azodicarboxylate (8.44 g, 48.48 mmol), and 4-nitro-benzoic acid (8.10 g, 48.48 mmol). Stir the reaction mixture for 6 hours at the same temperature, then warm the reaction to room temperature and continue to stir the reaction overnight. Add water (200 mL) and extract the aqueous layer with ethyl acetate (3×200 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 30-60% of EtOAc-Hexane) to give 1.76 g (100%) of the title compound as a white solid: 1H NMR (CDCl3) δ 8.28-8.32 (m, 2H), 8.17-8.24 (m, 2H), 7.38 (d, 1H), 7.23 (d, 1H), 7.18 (dd, 1H), 5.28-5.32 (m, 1H), 4.05-4.15 (m, 1H), 3.25-3.40 (m, 3H), 2.74-2.83 (m, 2H), 2.10-2.23 (m, 1H), 2.02-2.10 (m, 1H), 1.60-1.92 (m, 8H).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:5][C:6](=[O:26])[N:7]([C:15]1[CH:20]=[C:19](Br)[N:18]=[C:17]([NH2:22])[C:16]=1[N+:23]([O-:25])=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]>C1COCC1>[CH2:3]([O:5][C:6](=[O:26])[N:7]([C:15]1[CH:20]=[C:19]([NH:2][CH3:1])[N:18]=[C:17]([NH2:22])[C:16]=1[N+:23]([O-:25])=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]
Reactant: CN
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(NC)nc(N)c1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
Methylamine (40% solution in water) (0.055 ml) was added to a solution of (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (50 mg) in THF (0.5 ml) at room temperature. The reaction was stirred under nitrogen for 16 hours then the solution pre-absorbed directly onto silica gel. The mixture was purified by chromatography on an Isco Companion, eluting with ethyl acetate:heptane, increasing the gradient linearly from 20:80 to 60:40 over several column volumes. The desired fractions were combined and evaporated to provide the title compound (30 mg) as a yellow gum.