Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[H-].[Na+].[CH2:19](I)[CH3:20]>C(OCC)(=O)C>[CH2:19]([O:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH3:20]
Reactant: CCI
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(F)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a DMF (10 mL) solution of 4-fluoro-3-nitro-phenol (628 mg), sodium hydride (purity: 55% or higher, 209 mg) was added in small portions at room temperature. After 30 minutes, ethyl iodide (0.38 mL) was added thereto at room temperature. After 2 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to obtain the title compound (685 mg, 93%) as a yellow solid.
Reaction SMILES: C(O)(=O)C.[CH3:5][N:6]([C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)[N:7]=[C:8]1[CH2:13][CH:12]2[C:14]([CH3:16])([CH3:15])[CH:9]1[CH2:10][CH2:11]2.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:5][N:6]([C:17]1[N:18]=[N:19][C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:21][CH:22]=1)[N:7]=[C:8]1[CH2:13][CH:12]2[C:14]([CH3:16])([CH3:15])[CH:9]1[CH2:10][CH2:11]2
Reactant: C1COCCN1
Reactant: CN(N=C1CC2CCC1C2(C)C)c1ccc(Cl)nn1
Solvent: CC(=O)O
Product: CN(N=C1CC2CCC1C2(C)C)c1ccc(N2CCOCC2)nn1
Temperature: 145 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A mixture of 33.9 g (0.1 moles) of 1,7,7-trimethyl-2-bicyclo(2,2,1)heptylidene-(6-chloro-3-pyridazinyl)-hydrazine acetate and 43.5 g /0.5 moles/ of morpholine is reacted while stirring at 145° C. for 8 hours. Then the excess of morpholine is removed under vacuum, the residue is triturated with 100 ml of water, filtered and dried to give 30.5 g (92.6%) of the title compound; m.p. 188°-190° C. (after recrystallization from ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=1.[O:21]1[C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=[N:22]1>>[ClH:20].[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[NH:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:26]([C:25]3[O:21][N:22]=[CH:23][CH:24]=3)=[O:27])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: Nc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Reactant: O=C(Cl)c1ccno1
Product: Cl
Product: O=C(Nc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1)c1ccno1
Yield: 87 %

Procedure:
Using an analogous procedure to that described in Example 18, 6-amino-4-(3-chloro-4-fluoroanilino)quinazoline was reacted with 5-isoxazolecarbonyl chloride to give 4-(3-chloro-4-fluoroanilino)-6-(isoxazole-5-carboxamido)quinazoline hydrochloride salt in 87% yield, m.p.>250° C.;
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([C@@H:15]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:16]([O:18]CC2C=CC(OC)=CC=2)=[O:17])[CH2:4]1)=O.[CH2:33]([C:40]1[S:41][C:42]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[C:43]([CH2:45][CH3:46])[N:44]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([C:40]1[S:41][C:42]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[CH2:6][N:5]([C@@H:15]([CH:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[C:16]([OH:18])=[O:17])[CH2:4]3)[CH2:49][CH2:48]2)=[C:43]([CH2:45][CH3:46])[N:44]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCc1nc(Cc2ccccc2)sc1C1CCNCC1
Reactant: CCC(CC)[C@@H](C(=O)OCc1ccc(OC)cc1)N1C[C@H](c2cccc(F)c2)[C@@H](C=O)C1
Product: CCc1nc(Cc2ccccc2)sc1C1CCN(C[C@H]2CN([C@H](C(=O)O)C(CC)CC)C[C@@H]2c2cccc(F)c2)CC1
Yield: 26.3 %

Procedure:
Reductive amination of 20 mg (0.045 mmol) of 2(S)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-ethylvaleric acid, 4-methoxybenzyl ester with 15 mg (0.42 mmol) of 4-(2-benzyl-4-ethyl-thiazol-5-yl)piperidine as described in example 527 step D, and removal of 4-methoxybenzyl ester according to example 527 step E furnished 7 mg of the title compound. Mass spec. 592.4 (M+1), HPLC A 2.36 min.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][C:15]1[O:19][N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[N:16]=1.O>CN(C)C=O>[CH:20]([C:17]1[N:16]=[C:15]([CH2:14][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[O:19][N:18]=1)([CH3:22])[CH3:21]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)c1noc(CCl)n1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1noc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C

Procedure:
To a solution of potassium phthalimide (72 g, 0.39 mol) in dry N,N-dimethylformamide (300 mL) was added 5-(chloromethyl)-3-isopropyl-1,2,4-oxadiazole (50 g, 0.31 mol) gradually with stirring. The reaction mixture was maintained at ambient temperature for 2 h and then poured into cold water (1.2 L). The resulting yellow precipitate was collected by filtration, washed with water, and dried in the air to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][C:36]#[N:37].O>CC(C)=O>[Br:1][C:2]1[C:3]2[C:8](=[CH:7][C:6]([C:13]3[O:14][C:15]4[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=4[C:17]=3[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:35][C:36]#[N:37]
Reactant: N#CCBr
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
The mixture of 1-[2-(5-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.46 g, 3.45 mmol) and cesium carbonate (2.36 g, 7.23 mmol) in acetone (16 mL) was stirred at room temperature for 15 minutes. Bromoacetonitrile (0.50 mL, 7.2 mmol) was then added and the mixture was stirred for 4 hours at room temperature then poured into excess water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified by flash chromatography (Biotage apparatus) using 5-20% tert-butyl methyl ether in hexane as an eluant to afford 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy} acetonitrile as a yellow solid (0.989 g), mp 100-102° C. Mass spectrum (−ESI, [M−H]−) m/z 460. 1HNMR (400 MHz, DMSO-d6): δ8.55 (d, 1H, J=0.98 Hz), 8.25 (d, 2H, J=9.3 Hz), 8.0-8.05 (m, 2H), 7.7-7.75 (m, 2H), 7.4-7.5 (m, 2H), 5.5 (s, 2H), 2.75 (t, 2H, J=7.2 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.2 Hz). Elemental Analysis for C25H20BrNO3: Calculated: C, 64.95; H, 4.36; N, 3.03. Found: C, 64.71; H, 4.32; N, 2.86.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]([O-])=[CH:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].Cl.[Cl:27][C:28]1[CH:29]=[C:30]([NH:34][NH2:35])[CH:31]=[CH:32][CH:33]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(OCC)=O)=N2)C=CC=1F>>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=3)[N:35]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:24])[F:23])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NNc1cccc(Cl)c1
Agent: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Product: CCOC(=O)c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 19A and 3-chlorophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 2.42 g (62% of theory) of the title compound are obtained.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[C:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[C:9]([C:19]([OH:21])=O)[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([F:18])[CH:13]=1)#[N:6].C1(C)C=CC=CC=1.C(Cl)Cl.Cl.[CH3:41][NH:42][O:43][CH3:44]>>[C:5]([C:7]1[C:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[C:9]([C:19]([N:42]([O:43][CH3:44])[CH3:41])=[O:21])[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([F:18])[CH:13]=1)#[N:6]
Reactant: CNOC
Reactant: N#Cc1c(-c2ccnc(F)c2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
Thionyl chloride (6.2 mL, 85 mmol) was added to a mixture of 4-cyano-3-(2,4-dichlorophenyl)-5-(2-fluoropyridin-4-yl)thiophene-2-carboxylic acid (2.94 g, 7.48 mmol) in Toluene (22 mL, 210 mmol) and the mixture was heated at 90° C. for 1 h. The reaction mixture was evaporated and the residue was coevaporated with toluene twice to thick oil. This oil in DCM (20 g, 200 mmol) was added to a mixture of N,O-Dimethylhydroxylamine Hydrochloride (2.92 g, 29.9 mmol) and TEA (7.0 mL, 5.0E1 mmol) in DCM (100 mL, 2000 mmol) in a ice bath. After 2 h, the mixture was washed by water and brine. The DCM layer was collected and dried and evaporated in vacuum to afford crude intermediate, which was purified by column chromatography to afford the title compound (2.41 g, 73.9%). LCMS: (FA) ES+, 436, 438. 1H NMR (400 MHz, d1-chloroform) δ: 8.41 (1H, d, J=5.26 Hz), 7.72-7.63 (1H, m), 7.54 (1H, d, J=1.96 Hz), 7.39 (2H, dd, J=7.70, 1.99 Hz), 7.29 (1H, d, J=8.26 Hz), 3.76 (3H, s), 3.27 (3H, s)
Reaction SMILES: ClC(OCC(C)C)=O.O[C:10](=[O:27])[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CCN(CC)CC.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=1>C(Cl)Cl.O>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([NH:35][C:10](=[O:27])[CH2:11][N:12]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:37][CH:38]=1)(=[O:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Reactant: CC(=O)c1ccc(N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(NC(=O)CN(Cc2ccccc2)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 61.9 %

Procedure:
Isobutyl chloroformate (35.1 g, 0.26 mol) was added (15 min) to an ice-cold solution of tert-butyl N-(2-hydroxy-2-oxoethyl)-N-(phenylmethyl)carbamate (65.0 g, 0.24 mol), described in preceding section a), and Et3N (31.0 g, 0.31 mol) in CH2Cl2 (610 mL). The mixture was stirred at 0° for 45 min. Solid 4′-aminoacetophenone (34.8 g, 0.26 mol) was added portion wise to the reaction mixture. The reaction mixture was stirred at 0° for 1.5 h and then at room temperature for 16 h. H2O (10 mL) was added. The resulting solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (1 L). The solution was washed successively with 1 N aqueous HCl (2×300 mL), a saturated aqueous solution of NaHCO3 (2×300 mL) and brine (200 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting brownish solid was crystallized (EtOAc: Hex) to give the title compound (56.8 g, 61% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ9.72 (broad s, 1H), 7.90 (d, J=8.6 Hz, 2H), 7.40-7.54 (m, 2H), 7.26-7.39 (m, 5H), 4.55 (s, 2H), 3.96 (s, 2H), 2.56 (s, 3H), 1.51 (s, 9H); MS (FAB) m/z383 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.CC(C)=O.C(O)C.[C-:28]#[N:29].[Na+]>O>[C:28]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1)#[N:29]
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: N#CCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reaction time: 2 h

Procedure:
A solution of 5-bromomethyl-2-nitro-3-phenylbenzofuran (5 g., 0.015 mole) in 95 ml. of acetone is treated with 20 ml. of ethanol, and the mixture is heated to its reflux temperature. To this mixture is added 0.015 mole of sodium cyanide dissolved in 9 ml. of water, and refluxing is continued for about two hours. The mixture is evaporated under vacuum, then dichloromethane and water are added to the residue. The organic layer is separated, washed with water and dried. The organic layer is then evaporated under vacuum. The residue is purified by eluting twice with benzene through a silica gel column, followed by refluxing in 30 ml. of diethyl ether. The yellow precipitate is separated by filtration and recrystallized twice from benzene to provide 5-cyanomethyl-2-nitro-3-phenylbenzofuran, m.p. 166°-168° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:15]#[CH:16])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:7]=1.I[C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:19]=1.BrCl>>[Br:1][C:2]1[C:3]([C:15]#[C:16][C:18]2[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:19]=2)=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: OCCOc1ccc(I)cc1
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1Br
Agent: ClBr
Product: OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2Br)cc1

Procedure:
The product was prepared analogously to Example 7.1e starting from 3-bromo-5-(4-chlorophenyl)-2-ethynylpyridine and 2-(4-iodophenoxy)ethanol. Yield: 0.18 g (28% of theoretical); C21H15BrClNO2 (M=428.706); calc.: molpeak (M+H)+: 428/430/432 (BrCl); found: molpeak (M+H)+: 428/430/432 (BrCl).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[CH2:4][C@H:3]1[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12]1)=[O:10].C1([O:31][C:32](=O)[NH:33][C:34]2[S:35][C:36]([C:40](=[O:42])[CH3:41])=[C:37]([CH3:39])[N:38]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:40]([C:36]1[S:35][C:34]([NH:33][C:32]([NH:1][C@@H:2]2[C@@H:3]([C:9]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH2:12]3)=[O:10])[CH2:4][S:5](=[O:7])(=[O:8])[CH2:6]2)=[O:31])=[N:38][C:37]=1[CH3:39])(=[O:42])[CH3:41]
Reactant: N[C@@H]1CS(=O)(=O)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1
Reactant: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1sc(NC(=O)N[C@H]2CS(=O)(=O)C[C@@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)nc1C
Temperature: 25 °C
Reaction time: 94 h
Yield: 54.2 %

Procedure:
[(3R,4S)-4-Amino-1,1-dioxo-tetrahydrothiophen-3-yl]-[(S)-3-(4-fluorobenzyl)-piperidin-1-yl]-methanone (50 mg, 141 μmol) and [5-acetyl-4-methylthiazol-2-yl]-carbamic acid phenyl ester (43 mg, 155 μmol) were dissolved in N,N-dimethylformamide (1 mL) and treated with triethylamine (22 μL, 155 μmol). The mixture was stirred at room temperature for 94 h, and then concentrated. The residue was purified by flash column chromatography (4% methanol/dichloromethane containing 0.4% aqueous ammonium hydroxide) to provide a white solid (41 mg, 55%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[CH3:11][O:12][Na]>CO>[CH3:11][O:12][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: CO[Na]
Reactant: O=Cc1cccc(CBr)c1
Solvent: CO
Product: COCc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
3-(bromomethyl)benzaldehyde (1.00 g, 5.02 mmol) was dissolved in MeOH (100 mL) and treated with 0.5M solution of MeONa (5 equiv.) in MeOH. The mixture was stirred overnight at RT and MeOH was evaporated under reduced pressure. The residue was acidified to pH˜6 with 1M aqueous HCl solution. DCM (100 mL) was added and the mixture was vigorously stirred overnight. The organic layer was separated, dried over Na2SO4 and the solvent was removed under reduce pressure to furnish the desired material as yellowish oil (560 mg, 3.75 mmol, 74%). 1H NMR (DMSO, 400 MHz): 3.33 (s, 3H), 4.51 (s, 1H), 7.62 (m, 2H), 7.85 (m, 2H), 10.02 (s, 1H). MS 151 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:30])[CH:21]=2)[C:9]1=[O:31])[CH2:5][CH2:6][CH3:7]>O1CCOCC1.O>[CH3:30][N:22]1[C:23]2[C:28](=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17](=[O:18])[N:8]([CH:4]([CH2:5][CH2:6][CH3:7])[C:3]([OH:32])=[O:2])[C:9]2=[O:31])=[CH:21]1
Reactant: CCCC(C(=O)OC)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Solvent: C1COCCO1
Solvent: O
Product: CCCC(C(=O)O)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-pentanoic acid methyl ester (108 mg, 0.25 mmol) in dioxane (2.5 ml) is added a solution of LiOH monohydrate (25 mg, 0.60 mmol) in H2O (2.5 mL). The solution is stirred at 60° C. for 16 hours. The reaction mixture is allowed to cool to room temperature, quenched with 4M HCl in dioxane (400 μl) and is concentrated. The resulting residue is triturated with MeoH and H2O to afford the title compound. LCMS (ESMS): m/z 420.21 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=[C:16]([C:25]([OH:27])=O)[CH:15]=1)[CH2:5][CH2:6][O:7]2.Cl.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[N:29]1([C:25]([C:16]2[CH:15]=[C:14]([O:13][CH:4]3[C:3]4[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=4[F:1])[O:7][CH2:6][CH2:5]3)[C:22]3[N:21]=[C:20]([CH3:23])[N:19]([CH3:24])[C:18]=3[CH:17]=2)=[O:27])[CH2:32][CH2:31][CH2:30]1
Reactant: C1CNC1
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2n1C
Agent: Cl
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N3CCC3)cc2n1C
Yield: 80 %

Procedure:
The title compound was prepared as a colorless amorphous in 80% yield (1.4 g) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (1.6 g, 4.2 mmol, STEP 2 of Example 19) and azetidine hydrochloride (0.79 g, 8.4 mmol) by the same manner in STEP 3 of Example 11.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][OH:17])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].CO>N1C=CC=CC=1.C(OCC)(=O)C>[Si:18]([O:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCNc1c([N+](=O)[O-])cnc2cccnc12
Reaction time: 3 h
Yield: 77.1 %

Procedure:
A solution of 2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol (6.34 g, 27.1 mmol) dissolved in 25 mL of pyridine was treated with tert-butyldimethylsilyl chloride (4.50 g, 29.8 mmol) and N,N-dimethylaminopyridine (331 mg, 2.71 mmol) and the mixture was stirred under N2. After 3 hours, the reaction mixture was treated with 10 mL of methanol and then concentrated to give a yellow solid. The resulting solid was dissolved in 100 mL of ethyl acetate and washed with H2O (3×50 mL) and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow powder. Crystallization from 50 mL of 1:1 hexane/ethyl acetate gave 7.28 g of N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14]N(C)CC1.[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:2][CH2:3][N:9]2[CH3:10])[C:2]=1[F:1])=[O:21]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CN1CCC(Nc2cccc(N)c2F)CC1
Solvent: C1COCCO1
Product: CN1CCCCC1Nc1cccc(NC(=O)c2ccc(F)cc2Cl)c1F
Yield: 155.8 %

Procedure:
Mix 2-fluoro-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 20) (0.08 g) and 2-chloro-4-fluorobenzoyl chloride (83 mg) in 1,4-dioxane (5 mL) and heat at reflux for 2 hr. Partition the reaction mixture between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (10 g) (dichloromethane-2M NH3 in methanol, gradient) to give 0.106 g of the title compound (78% yield): mass spectrum (ion spray): m/z=380 (M+1); 1H NMR (CDCl3): 8.19 (br s, 1H), 7.83 (dd, 1H), 7.66 (dd, 1H), 7.19 (dd, 1H), 7.09 (ddd, 1H), 7.00 (dd, 1H), 6.52 (ddd, 1H), 3.76 (br d, 1H), 3.29 (m, 1H), 2.81 (br d, 2H), 2.29 (s, 3H), 2.13 (m, 2H), 2.05 (m, 2H), 1.52 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:31][NH:30][C:29](=[O:32])[C:4]=2[C:5]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15]C(=O)OC(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:7]1[N:6]=[C:5]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[C:4]2[C:29](=[O:32])[NH:30][CH2:31][C:3]=2[C:2]=1[F:1]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)NC3)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)cn1
Yield: 59.8 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (15 mg, 0.034 mmol) and TFA (0.5 mL, 6.49 mmol) in DCM (0.5 mL) was stirred at RT for 30 min. The reaction mixture was concentrated and the resulting residue was purified by preparative HPLC to give a TFA salt of the title compound (7 mg, 60.2%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.37-2.01 (m, 8 H), 3.67 (br s, 1 H), 3.89 (s, 3 H), 4.32-4.43 (m, 2 H), 4.45 (br s, 1 H), 6.77 (d, J=6.35 Hz, 1 H), 7.93 (br s, 3 H), 8.30 (s, 1 H), 8.36 (s, 1 H), 8.84 (s, 1 H). [M+H] calc'd for C17H21FN6O, 345; found, 345.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])([OH:8])=[O:7].Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]>ClCCl>[N+:6]([O:9][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])([O-:8])=[O:7]
Reactant: O=C(O)CCCCBr
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C(O)CCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
Concentrated sulphuric acid 96% (1.24 mL, 2.0 eq) was added dropwise to fuming nitric acid 100% (0.97 mL, 2.0 eq) at 0° C. After 10 minutes of stirring at 0° C., a solution of 1 (2.00 g, 1.0 eq) in dichloromethane (20.0 mL) was added dropwise. The reaction mixture was stirred from 0° C. to RT for 3 hours and quenched with water (30.0 mL). The organic layer was washed with water (20.0 mL) and brine (20.0 mL), dried over magnesium sulphate, filtered off and concentrated under vacuum. The residue was adsorbed on silica gel and purified by flash chromatography [Biotage®, dichloromethane/methanol 100/0→97/3 (10CV*), 97/3 (5CV)] affording compound 2 as a colourless liquid (1.47 g, yield=58%).