Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C(F)=CC([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](CCS(C)(=O)=O)[C:16](=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=C(OC)C=1.[F:40][C:41]([F:54])([F:53])[CH2:42][O:43][C:44]1[C:49](B(O)O)=[CH:48][CH:47]=[CH:46][N:45]=1>>[CH3:16][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:49]1[C:44]([O:43][CH2:42][C:41]([F:54])([F:53])[F:40])=[N:45][CH:46]=[CH:47][CH:48]=1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: OB(O)c1cccnc1OCC(F)(F)F
Product: CNc1cnccc1-c1cccnc1OCC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-N-methylpyridin-3-amine (example 98, intermediate b) and 2-(2,2,2-trifluoroethoxy)pyridin-3-ylboronic acid after a reaction time of 5 hours at 90° C. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless oil (76%). MS (ESI): m/z=284.10 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].[Br:42]Br>ClCCl>[Br:42][C:15]1[C:14]([NH2:17])=[CH:13][CH:12]=[C:11]2[C:16]=1[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[N:9][N:10]2[C:18]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrBr
Reactant: Nc1ccc2c(c1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccc2c(c(-c3cccc(F)c3)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1Br

Procedure:
A total of 1.04 g of. 3-(3-fluoro-phenyl)-1-trityl-1H-indazol-5-ylamine was dissolved in 22.3 ml of dichloromethane, and 375 mg of sodium hydrogencarbonate was added. Under ice-cooling and stirring, a solution of 0.12 ml of bromine in 50 ml dichloromethane was added dropwise over 50 minutes. After stirring for 2 hours while ice-cooling, saturated aqueous sodium thiosulfate solution and the mixture was extracted with diethyl ether. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:5), to give 1.18 g of the title compound as a white foam.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[C:19]([NH2:27])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:27]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:26][CH:15]=2)[CH:9]=1
Reactant: NC(=O)c1ccccc1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Product: O=C(O)COc1ccc(Br)cc1-c1coc(-c2ccccc2)n1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and benzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.6 min, m/z 374/376 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH3:2].[H-].[Na+].[F:12][C:13]1[C:27]([F:28])=[CH:26][C:25](F)=[C:24]([N+:30]([O-:32])=[O:31])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].O>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:6][C:25]1[C:24]([N+:30]([O-:32])=[O:31])=[C:14]([C:13]([F:12])=[C:27]([F:28])[CH:26]=1)[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])[CH3:2]
Reactant: CCOC(CO)OCC
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-])OCC
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 54.3 %

Procedure:
For large scale synthesis, 2,2-diethoxyethanol was added dropwise into a suspension of 60% sodium hydride in 5 L of THF at 1-2° C. over 30 minutes and then stirred at 0-5° C. for 1.5 hours. A solution of 750 g of 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitroaniline in 2.25 L of THF was then added dropwise into the above suspension at 0-5° C. After the addition, the purple solution was stirred at room temperature for 2 days and 17 hours. HPLC analysis showed 4.1% remaining of 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitroaniline. 150 mL of water was added very slowly (gas generated) into the pre-cooled solution at 10° C. The solution was then concentrated to dryness. The resultant oil was then suspended in 5 L of heptanes and seeded with pure 3-(2,2-diethoxyethoxy)-5,6-difluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline crystal and stirred for 30 minutes. After 1 hour of stirring, the precipitate was filtered and dried to yield 520 g (54.3%) of product with 96.4% purity. Further product was available in the mother liquor. 1H NMR (CDCl3, 400 MHz): δ 7.42 (dd, 1H), 7.34 (d, 1H), 6.87 (bs, 1H), 6.56-6.67 (m, 2H), 4.79 (t, 1H), 4.06 (d, 2H), 3.74-3.82 (m, 2H), 3.59-3.66 (m, 2H); 1.24 (t, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.C(OC([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])=[CH:21][CH:20]=1)=O)(C)(C)C>>[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCC#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCCCc1ccc(N)cc1
Reaction time: 0.5 h
Yield: 117.5 %

Procedure:
A 0.25 M solution of trifluoroacetic acid in dichloromethane (5 mL, 1.25 mmol) was added to 4-[4-(t-Butoxycarbonylamino)phenyl]butanenitrile (98) (0.22 g, 0.85 mmol). After 30 min, reaction was quenched with 1 N NaOH solution. The mixture was partitioned with ethyl acetate (30 mL) and water (20 mL). The organic layer was dried over MgSO4, concentrated to give 4-(4-Aminophenyl)butanenitrile (97) (0.16 g, 99%) which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:10][C:9]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[O:13][CH2:14][C:8]=2[C:7](=[O:19])[CH:6]=1)=[O:4].[OH-].[K+:21]>CO>[K+:21].[O:19]=[C:7]1[CH:6]=[C:5]([C:3]([O-:4])=[O:2])[O:10][C:9]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[O:13][CH2:14][C:8]1=2
Reactant: COC(=O)c1cc(=O)c2c(o1)-c1ccccc1OC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1cc(=O)c2c(o1)-c1ccccc1OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-oxo-4H,5H-[1]benzopyrano[4,3-b]pyran-2-carboxylic acid methyl ester (0.292 g, 1.1 moles, described in Example 6) in methanol (15 ml) containing potassium hydroxide (0.2 g) is stirred at room temperature overnight. The solution is evaporated under reduced pressure and the residue is crystallized from methanol to give 4-oxo-4H,5H-[1]benzopyrano[4,3-b]pyran-2-carboxylic acid potassium salt; m.p. > 280° C, νmaxnujol 1650 cm-1. The latter compound is dissolved in water and the resulting solution is added to dilute hydrochloric acid. The precipitate is collected and crystallized from methanol to give the title compound; m.p. 253°-254° C (dec.), νmaxnujol 2500, 1735 and 1650 cm-1.
Reaction SMILES: [CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21](O)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[NH:25]1[CH2:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([N:25]3[CH2:28][CH2:27][CH2:26]3)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:2])[CH3:3]
Reactant: C1CNC1
Reactant: CC(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 84 h
Yield: 94.6 %

Procedure:
A mixture of 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 213 μmol), azetidine (71.6 μl, 1.07 mmol), propylphosphonic anhydride (50% in ethyl acetate, 314 μl, 533 μmol) and diisopropylethylamine (112 μl, 640 μmol) in tetrahydrofuran (4 ml) was stirred for 3.5 days (weekend) at 25° C. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (74 mg, 94.5%) as a white solid. mp: 226-227° C., MS: m/z=366.1 (M−H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[CH2:9][O:8]1.Cl.[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23]2=[O:31])[CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:8][CH:7]([CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[CH2:9][N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23]2=[O:31])[CH2:16]1
Reactant: COc1ccccc1OCC1CO1
Reactant: O=c1[nH]c2ccccc2n1CC1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1OCC(O)CN1CCCC(Cn2c(=O)[nH]c3ccccc32)C1
Yield: 22 %

Procedure:
A mixture of 3.6 parts of 2-(2-methoxyphenoxymethyl)oxirane, 5.3 parts of 1,3-dihydro-1-(3-piperidinylmethyl)-2H-benzimidazol-2-one monohydrochloride, 6 parts of sodium carbonate and 80 parts of ethanol is stirred and refluxed for 6 hours. The reaction mixture is cooled, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and recrystallized from 4-methyl-2-pentanone, yielding 1.8 parts (22%) of 1,3-dihydro-1-{1-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3-piperidinylmethyl}-2H-benzimidazol-2-one; mp. 158.1° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:21][S:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:33][CH:32]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-methylsulphonylbenzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:2].[NH2:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19].C([BH3-])#N.[Na+]>>[CH2:1]([O:3][C:4]([CH:5]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:16])[CH3:2]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)C(CCc1ccc(F)cc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in Example 26, ethyl-2-oxo-4-(4-fluoro-phenyl)butyrate and L-alanyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-[1-ethoxycarbonyl-3-(4-fluorophenyl)-propyl]-L-alanyl-L-proline. The mass spectrum shows a molecular ion at 394, and strong peaks at 376 (M-18, H2O) and 375 (M-19, F). The nmr spectrum is consistent with the proposed structure. Elemental analysis indicates a hydrate.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[CH3:18])[CH2:6]1)=[O:4].[NH:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:13]1[C:12]([CH3:18])=[C:11]([N:7]2[C:8](=[O:10])[CH2:9][N:5]([C:3](=[O:4])[CH2:2][N:20]3[CH:21]=[C:22]4[C:23]([N:24]=[CH:25][CH:26]=[CH:27]4)=[N:19]3)[CH2:6]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CCl)CC1=O
Reactant: c1cnc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1N1CN(C(=O)Cn2cc3cccnc3n2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2-Chloro-acetyl)-3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (230 mg, 0.8 mmol, 1 eq), 1H-Pyrazolo[3,4-b]pyridine (96 mg, 0.8 mmol, 1 eq), Cesium carbonate (653 mg, 2.0 mmol, 2.5 eq) in DMF (6 ml) was stirred at room temperature overnight. It was diluted with ethyl acetate, washed with water and purified with HPLC to give the desired product. LCMS observed for (M+H)+: 370.1
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([O:8]CC)=O)[C:3]([C:11]([O:13]CC)=O)=[CH:2]1.[O-][CH2:17]C.[Na+].C(OCC)(=O)C.S(=O)(=O)(O)O>O>[CH:5]1[S:1][CH:2]=[C:3]2[C:11](=[O:13])[CH2:17][C:6](=[O:8])[C:4]=12
Reactant: CCOC(=O)c1cscc1C(=O)OCC
Reactant: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CC(=O)c2cscc21

Procedure:
In a dry 3-neck flask with an argon inlet and a water condenser, diethyl thiophene-3,4-dicarboxylate (3.7 g, 16.2 mmol) is mixed with sodium ethoxide (1.1 g, 16.2 mmol). After heating to 100° C. ethyl acetate (1.4 g, 16.2 mmol) is added through syringe pump over one hour. The mixture was further heated for a few hours. The residue was redissolved in water at 70° C. and concentrated sulfuric acid is added (1 mL). The mixture is heated at this temperature for one hour to ensure complete decarboxylation.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1>>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][C:2]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1Nc1nc(Cl)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-4-nitro-benzamide was prepared from 2-Amino-N-methyl-4-nitro-benzamide and 2,4,5-Trichloro-pyrimidine in an analogous manner to Example 1223b. Product was isolated as an orange solid (711 mg, 81%) MP 241 (dec), LCMS 344.10, HPLC purity 80%, 1H-NMR (CDCl3, 400 MHz) δ: 11.72 s, 1H), 9.73 (s, 1H), 8.33 (s, 1H), 7.98 (8.6 Hz, 1H), 7.69 (8.5 Hz, 1H), 6.37 (m, 1H), 3.11 (d, J=4.8 Hz, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8](=[O:22])[C@@H:9]1[CH2:13][CH:12](OS(C)(=O)=O)[CH2:11][N:10]1[C:19](=[O:21])[CH3:20])[CH3:6]>CN(C=O)C>[CH2:5]([O:7][C:8](=[O:22])[C@@H:9]1[CH2:13][CH:12]([N:1]=[N+:2]=[N-:3])[CH2:11][N:10]1[C:19](=[O:21])[CH3:20])[CH3:6]
Reactant: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)CN1C(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CC(N=[N+]=[N-])CN1C(C)=O
Temperature: 0 °C
Yield: 99.1 %

Procedure:
243 g of sodium azide was added to a solution of 802 g of N-acetyl-4-mesyloxy-L-proline ethyl ester and 2.4 L of DMF, and the mixture was reacted at an inner temperature of 70° C. for 7 hours. The reaction solution was cooled, poured into ice water (4.8 L), and extracted with chloroform (3.2 L). The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to obtain 644 g of N-acetyl-4-azido-L-proline ethyl ester as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16](=[O:18])[CH3:17])=[N:11]2)[CH2:2][CH2:3][CH3:4].[CH3:24][Mg]Br>O1CCCC1>[CH2:1]([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16]([OH:18])([CH3:24])[CH3:17])=[N:11]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nccc2nc(C(C)=O)c3ccc(F)cc3c12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCCCOc1nccc2nc(C(C)(C)O)c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(1-butoxy-9-fluorobenzo[c]-1,6-naphthyridin-6-yl)ethanone (59 mg, 0.19 mmol) in tetrahydrofuran (2.0 ml) was added methylmagnesium bromide (1.4 M in toluene/THF 75:25; 0.202 ml, 0.283 mmol) dropwise at −78° C. The cooling bath was removed, and the resulting suspension was allowed to warm to room temperature. The reaction mixture was stirred for 30 minutes, and then quenched with saturated aqueous ammonium chloride (5 mL). Water was added, and the mixture extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated to a crude solid that was adsorbed on to silica gel and purified by column chromatography on silica gel eluting with an EtOAc/hexanes gradient to afford 2-(1-butoxy-9-fluorobenzo[c]-1,6-naphthyridin-6-yl)propan-2-ol. LRMS (ESI) calc'd for (C19H21FN2O2) [M+H]+, 329.2; found 329.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([N:21]3[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[CH3:27])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]([C:30]1[O:34][C:33]([C:35](Cl)=[O:36])=[CH:32][CH:31]=1)#[N:29].CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:35]([C:33]3[O:34][C:30]([C:28]#[N:29])=[CH:31][CH:32]=3)=[O:36])=[C:16]([N:21]3[C:22]([CH3:27])=[CH:23][CH:24]=[C:25]3[CH3:26])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: Cc1ccc(C)n1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C)n1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)c1ccc(C#N)o1
Yield: 19 %

Procedure:
Using a procedure similar to Example 4, step (c), 4-[4-amino-3-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (30 mg, 0.8 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (25 mg, 0.16 mmol) in the presence of DIEA (276 mg, 1.7 mmol) to afford 14.9 mg (38%) of the title compound as a yellow solid. 1H-NMR (CDCl3, 400 MHz): 8.43 (d, 1H, J=9.3 Hz), 7.25 (s, 1H), 7.10-7.13 (m, 2H), 7.03-7.06 (m, 1H), 6.89 (s, 1H), 6.06 (s, 2H), 3.62-3.61 (m, 4H), 3.18-3.17 (m, 4H), 1.96 (s, 6H), 1.48 (s, 9H); Mass spectrum (ESI, m/z): Calcd. for C27H31N5O4, 390.1 (M-BOC+2H), found 390.1.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[N:12]1[CH:13]=[CH:14][C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:10][CH:11]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccncc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.1 %

Procedure:
A solution of trimethylacetyl chloride (32.5 mL, 0.264 mol) in dry dichloromethane (50 mL) was added dropwise over 1 h to a stirred suspension of 4-aminopyridine (22.60 g, 0.240 mol) and triethylamine (41.8 mL, 0.300 mol) in dry dichloromethane (360 mL) at 0° C. under nitrogen. The ice bath was removed and the reaction allowed to warm to r.t. overnight. After 17 h, the pale brown mixture was poured into water (500 mL). The organic layer was separated and washed with a dilute aqueous solution of sodium hydrogen carbonate (400 mL). The organic layer was separated, dried over sodium sulfate, filtered and the solvent evaporated in vacuo. The crude solid was recrystallized from ethyl acetate (75 mL)/hexane (50 mL), washed with diethyl ether (2×10 mL) and air dried to yield N-(pyridin-4-yl)pivalamide (29.11 g, 68%) as colourless plate like crystals. 1H NMR: δ (CDCl3, 400 MHz) 1.33 (s, 9H), 7.50 (d, J=6 Hz, 2H), 7.56 (br. s., 1H), 8.49 (d, J=6 Hz, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([OH:10])[C:7]#[C:8][CH3:9].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[CH2:6]([O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[CH2:7][CH:8]=[CH2:9]
Reactant: C1=COCCC1
Reactant: CC#CCO
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of phosphoryl chloride (0.5 ml in 10 ml of DCM) was added with care to a solution of but-2-yn-1-ol (8.75 g, 125 mmol) and dihydropyran (10.50 g, 125 mmol) in DCM (80 ml). The reaction mixture was stirred at room temperature for 16 h, washed with sodium hydrogen carbonate solution (3 times), dried (MgSO4) and the solvent removed in vacuo to yield a colorless oil. The crude product was purified by column chromatography [silica gel, euted with hexane/ethyl acetate (4:1), Rf: 0.36] to yield a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13].[H-].[Na+].[CH3:16]I>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][CH2:12][O:13][CH3:16]
Reactant: O=[N+]([O-])c1ccc(Br)c(CCO)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Yield: 79 %

Procedure:
A solution of 2-(2-bromo-5-nitrophenyl)ethanol (12 g, 48.7 mmol) in THF (100 mL) was cooled to 0° C., then NaH (2.53 g, 60%) was added slowly, followed by stirring at 0° C. for half an hour. Then MeI (33 mL, 487 mmol) was dropwise added, followed by stirring at room temperature overnight. The solvent was evaporated, water was added. The aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give 1-bromo-2-(2-methoxyethyl)-4-nitrobenzene (10 g, yield 80%). 1H NMR: 400 MHz CDCl3 δ 8.15 (s, 1H), 7.95-7.92 (m, 1H), 7.72-7.70 (m, 1H), 3.68-3.65 (m, 2H), 3.37 (s, 3H), 3.12-3.09 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:19][CH3:20].Cl.Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:20][O:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccncc1
Temperature: 80 °C
Yield: 35 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (95 mg, 0.35 mmol), 4-chloromethyl pyridine hydrochloride (120 mg, 0.74 mmol) and potassium carbonate (200 mg, 1.4 mmol) in DMF (5 ml) were heated at 80° C. for 2 hours. The reaction mixture was allowed to cool, water was added and the mixture extracted with ethyl acetate (3×50 ml). The combined extracts were then washed with water and dried (MgSO4). The solvent was removed by evaporation and the residue trituated with an ethyl acetate/hexane mixture to give 6-methoxy-4-phenoxy-7-(4-pyridylmethoxy)quinazoline (44 mg, 35%) as a white solid.