Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[CH:8]=[C:9]3[CH2:17][O:16][CH2:15][CH2:14][C:10]3=[N+:11]([O-:13])[CH:12]=2)=[N:2]1.C(Cl)(Cl)Cl.[N+:22]([O-])([OH:24])=[O:23]>>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:8]([N+:22]([O-:24])=[O:23])=[C:9]3[CH2:17][O:16][CH2:15][CH2:14][C:10]3=[N+:11]([O-:13])[CH:12]=2)=[N:2]1
Reactant: [O-][n+]1cc(Nc2ccon2)cc2c1CCOC2
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1c(Nc2ccon2)c[n+]([O-])c2c1COCC2
Temperature: 55 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 653 mg of Compound 5 obtained in the above step (1) as crystals in 3.2 ml of fuming nitric acid is stirred at 55° C. for 3 hours. The reaction mixture is chilled, poured onto ice water and shaken with chloroform. The extract is washed with water, aqueous disodium hydrogen phosphate and saturated saline in this order, dried over anhydrous magnesium sulfate and concentrated to remove the solvent. The resultant residue is washed with methanol to give 551 mg of the titled compound as light yellow crystals. Yield: 70% mp.: 174° to 176° C. (dec.)
Reaction SMILES: [C:1]([Si:5]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[O:6][CH2:7][CH:8]([CH3:35])[O:9][C:10]1[CH:11]=[C:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15]2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[OH-].[Na+]>[C:42]([Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[O:6][CH2:7][CH:8]([CH3:35])[O:9][C:10]1[CH:11]=[C:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)CO[Si](c3ccccc3)(C(C)(C)C)C(C)(C)C)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
Ethyl 7-(2-{[di-tert-butyl(phenyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.4 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-ethanol (10 mL), 1M aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at 50° C. for 1 hr. 1M Aqueous sodium hydroxide solution (1 mL) was added to the reaction solution, and the mixture was stirred at 50° C. for 40 min. 1M Aqueous sodium hydroxide solution (1 mL) was added again, and the mixture was further stirred at 50° C. for 30 min. The reaction solution was allowed to cool to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid, and subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (1.9 g, yield 83%) as a pale-red amorphous solid. MS 644 (MH+).
Reaction SMILES: Br[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:20]#[N:21].Cl>CN(C)C=O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[S:10][C:6]3[C:7](=[C:2]([C:20]#[N:21])[CH:3]=[CH:4][CH:5]=3)[N:8]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2nc3c(Br)cccc3s2)cc1
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(C#N)cccc3s2)cc1

Procedure:
To a solution of EXAMPLE 1C (5 g) in N,N-dimethylformamide (1.6 mL) was added copper(I) cyanide (2.1 g) and the mixture heated at reflux for 6 hours. The mixture was cooled, poured into 1N hydrochloric acid and extracted with ethyl acetate. The solid that precipitated out of the organic layer was filtered, washed with water and dried to afford the title compound.
Reaction SMILES: [N:1]1([C:6]2[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[CH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:21]C(=O)C)(=[O:20])[CH3:19]>[Cl-].[Zn+2].[Cl-]>[C:18]([O:21][CH:4]1[C:5]2=[N:12][C:11]3[C:6](=[N:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=3)[N:1]2[CH2:2][CH2:3]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cnc(N2CCCC2)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)OC1CCn2c1nc1cc([N+](=O)[O-])cnc12
Temperature: 0 °C

Procedure:
A mixture of 1 g (4.2 mmol) of 2-(pyrrolidin-1-yl)-3,5-dinitropyridine (Org. & Biomol. Chem. 2003, 1(6), 1004-1011) and 0.584 g (4.2 mmol) of zinc chloride in 10 ml of acetic anhydride is heated at reflux for six hours. After this time a further 0.584 g (4.2 mmol) of zinc chloride are added and the stirring at reflux is maintained for eighteen hours. After this time the mixture is poured onto 100 g of ice and then extracted with three times 50 ml of ethyl acetate. The organic phases are combined and then washed with twice 20 ml of saturated sodium hydrogen carbonate solution, once with 20 ml of water and then once with 50 ml of saturated sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. The product obtained is purified by chromatography on a silica column, eluting with a mixture of ethyl acetate and n-heptane. The resulting product is recrystallized from a mixture of diisopropyl ether and isopropanol. This gives 0.29 g of the expected compound.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:25]3[CH2:27][CH2:26]3)[CH2:19][CH2:18]2)=[O:16])=[C:9]([CH3:35])[CH:8]=1.[OH-].[Na+]>C1COCC1.O>[C:31]([O:30][C:28]([N:24]([CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:36])=[O:5])=[CH:8][C:9]=2[CH3:35])[CH2:18][CH2:19]1)[CH:25]1[CH2:27][CH2:26]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)c1ccc(CCC(=O)N2CCC(CN(C(=O)OC(C)(C)C)C3CC3)CC2)c(C)c1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)C2CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
Lithium hydroxide monohydrate (142 mg, 3.4 mmol) was added to a solution of 4-(3-{4-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic acid methyl ester from Example E86.1 (1.41 g, 3.1 mmol) in THF (20 ml) and water (2 ml). The mixture was stirred for 16 h at room temperature then 1M NaOH solution (5 ml) was added. The mixture was heated at 60° C. for 3 h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1M HCl then brine, dried and concentrated in vacuo to yield the title compound (1.25 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=1)[C:5]2=[O:53].[CH:54]([N:57]=[C:58]=[O:59])([CH3:56])[CH3:55]>C(Cl)Cl.CCOC(C)=O>[CH2:12]([C:7]1[N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=2)[C:5](=[O:53])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:58](=[O:59])[NH:57][CH:54]([CH3:56])[CH3:55])[CH:3]=2)[N:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)N=C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc2ccc(NC(=O)NC(C)C)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 72 h
Yield: 70 %

Procedure:
To solution of 0.069 g (0.1 mmol) of the aminoquinazolinone from Example 40 in 1 mL of CH2Cl2 was added 12.7 mg (0.15 mmol) of isopropylisocyanate. The reaction mixture was stirred for 3 days. The mixture was diluted with 20 mL of EtOAc, washed with water (2×5 mL), brine (1×5 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo and the residue was purified by MPLC over a silica Lobar B column eluting with 50% EtOAc/hexanes to give 59.5 mg (0.07 mmol) of an oil, 76% yield. 1H-NMR (CDCl3 300 MHz): 0.86 (t, 3H, J=7.3 Hz), 1.07 (d, 6H, J=6.5 Hz), 1.29 (m, 2H), 1.68 (m, 2H), 2.59 (3 line m, 2H, J=7.06 Hz), 3.95 (m, 1H), 5.18 (d, 1H,J=7.7 Hz), 5.28 (bs, 2H), 7.12 (m, 6H), 7.07 (d, 2H), 7.19-7.32 (m, 11H), 7.43 (m, 2H), 7.57 (m, 2H), 7.90 (m, 2H), 8.13 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.C1COCC1.[Li]CCCC>C1(C)C=CC=CC=1>[CH3:19][C:17]1[CH:18]=[C:2]([B:24]([OH:25])[OH:23])[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2ccc(C(F)(F)F)cn2)cc(B(O)O)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 121.2 %

Procedure:
2-(3-Bromo-5-methylphenoxy)-5-(trifluoromethyl)pyridine (2 g, 0.006 mol) and triisopropylborate (1.66 mL, 0.0072 mol) were dissolved in toluene (40 mL) and THF (20 mL) and cooled to −78° C. n-BuLi (5.38 mL, 0.006 mol) was added while maintaining the reaction at −70° C. The reaction was stirred for 1 h at −40° C. Gradually the temperature was increased to −20-0° C. and the reaction was quenched with 2NHCl. The reaction mixture was warmed to RT, concentrated and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (2.16 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[CH2:17]([OH:23])[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:23][CH2:17][C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1ccco1
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccco3)c21
Yield: 12.2 %

Procedure:
The title compound (cis/trans=15/85) was prepared as a flesh-colored powder in 12.2% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=20/80) and furfuryl alcohol.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:3]1.[CH2:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][CH2:24][C:25]#[CH:26]>CCCCCCC.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:4]([C:26]#[C:25][CH2:24][CH2:23][CH2:22][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:3]1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)n(C)n2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cn1nc(C#CCCCc2ccccc2)cc1C(F)(F)F

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 7:3; yield (86 mg, 60%); 1H NMR δ (CDCl3): 7.31-7.25 (m, 2H), 7.22-7.16 (m, 3H), 6.64 (s, 1H), 3.98 (s, 3H), 2.78 (t, J=7.44 Hz, 2H), 2.42 (t, J=7.04 Hz, 2H), 1.95 (p, J=7.33 Hz, 2H); LCMS m/z: 292.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[F:18][C:19]1[C:24]([CH:25]=[O:26])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:20]4[C:19]([F:18])=[C:24]([CH:23]=[CH:22][CH:21]=4)[CH:25]=[O:26])=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(B(O)O)c1F
Reactant: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1F
Temperature: 70 °C
Yield: 56.8 %

Procedure:
500 mg of 6-bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridine, 473 mg of 2-fluoro-3-formylbenzeneboronic acid and 93 mg of tetrakis(triphenylphosphine)palladium are placed under a stream of argon in a round-bottomed flask comprising a mixture, degassed beforehand under a stream of argon, of 5 ml of acetonitrile, 5 ml of toluene and 6 ml of a 2M sodium carbonate solution. The reaction mixture is heated at 70° C. for 21 h. After cooling, the reaction mixture is diluted with ethyl acetate and water and then the organic phase is separated, dried and evaporated under reduced pressure. The residue is purified by chromatography on silica gel, elution being carried out with a dichloromethane/ethyl acetate 98/02 mixture. 324 mg of compound are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])[CH:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])[CH:21]=2)[N:7]=1)[CH3:4]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)ccn1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccnc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 4-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethyl]-1H-pyrazol-4-yl]propionate (640 mg, yield: 87%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([NH:20][CH:21]=[O:22])[CH:6](O)[C:7](=[CH2:18])[CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].S(Br)([Br:26])=O.O>ClCCl>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([NH:20][CH:21]=[O:22])[CH:6]=[C:7]([CH2:18][Br:26])[CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCOCc1ccccc1)C(O)C(NC=O)C(=O)OCC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C=C(CBr)CCOCc1ccccc1)NC=O
Reaction time: 2 h

Procedure:
7.0 g (21.8 mmol) of 6-benzyloxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 70 ml of dichloromethane, and 2.0 ml (26.1 mmol) of thionyl bromide are added dropwise at room temperature. After 2 hours, 40 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, N-KHCO3 solution and again with water, dried over MgSO4, filtered and concentrated by evaporation. 6-benzyloxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil which can be reacted further without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22]I.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(=O)OC[C@H]1CC[C@H](CCNC(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To an ice-cooled and stirred solution of the crude 26.0 g trans-acetic acid 4-(2-tert-butoxycarbonylamino-ethyl)-cyclohexylmethyl ester and 5.77 ml (92.6 mmol) methyliodide in 300 ml of N,N-dimethylformamide was added within 15 minutes 4.04 g (92.58 mmol) sodium hydride (55% in oil). After stirring over night at room temperature, additional 1.65 ml (26.5 mmol) methyliodide and 1.16 g (26.5 mmol) of sodium hydride were added and the reaction-mixture was then stirred for another 1 hour at room temperature. It was then partitioned between Et2O, 1N hydrogen chloride solution and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the residue then chromatographed on silica gel with a 4:1 v/v mixture of hexane and ethylacetate as the eluent giving 18.7 g (68% over 3 steps) of pure trans-acetic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester as colorless viscous oil, MS: 214 [(M-(tert-butoxycarbonyl)) H+].
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[F:24]NS(C1C=CC=CC=1)(=O)=O>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][C:3]=1[F:24]
Reactant: O=S(=O)(NF)c1ccccc1
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Solvent: CN(C)C=O
Product: Nc1nc2[nH]c(-c3ccc(F)cc3)c(-c3ccncc3)c2cc1F
Reaction time: 48 h

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (250 mg, 0.822 mmol), N-fluorobenzenesulphonamide (259 mg, 0.822 mmol), and DMF (4 mL) were warmed to 90° C. behind an explosion shield. After 48 h, the reaction was concentrated in vacuo and the residue was purified by flash chromatography (ethyl acetate:hexane 1:1) to afford 6-Amino-5-fluoro-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (28): Mass Spectrum (CI) 323 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([F:12])=[CH:4][C:3]=1[N+:13]([O-])=O.C(N(CC)CC)C>C(O)C.[Pd]>[F:12][C:5]1[CH:4]=[C:3]([NH2:13])[CH:2]=[C:7]([C:8]([F:10])([F:11])[F:9])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(F)cc(C(F)(F)F)c1Br
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cc(F)cc(C(F)(F)F)c1

Procedure:
2-Bromo-5-fluoro-1-nitro-3-trifluoromethyl-benzene (XVIII) (55.5 g) is dissolved in 500 mL of ethanol. Triethylamine (19.63 g) and palladium on charcoal (6 g, Pd/C 10%, Engelhard 4505) are added and the mixture is subjected to hydrogenation at 20-25° C. After 20 hours reaction time, the consumption of hydrogen had ceased. The hydrogen pressure is released and the solution is separated from the catalyst by filtration on Cellflock. The filter residue comprising the catalyst is washed with ethanol (2×100 mL). The filtrate and wash fractions are combined and the solution thus obtained is concentrated at 45° C. under reduced pressure to a final volume of ca. 400 mL. Toluene (400 mL) is added and the resulting solution is concentrated to a final volume of ca. 250 mL to obtain a suspension. The precipitate is removed by filtration and the filter cake is washed with toluene (2×100 mL). The solution is concentrated again to a final volume of 200 mL and the formed precipitate is removed again by filtration. The filter cake is washed with toluene (3×50 mL). The process of dilution with toluene, concentration and filtration is repeated until no substantial precipitation occurred in the toluene solution. Finally, the solvent is evaporated at 45-50° C. under reduced pressure and the residue is dried in vacuo at 45° C. to obtain 3-fluoro-5-trifluoromethyl-phenylamine as a yellow oil. GC-MS: m/z: 179, 160, 151, 140, 132. The product is identical in GC and HPLC to a sample of 3-amino-5-fluoro-benzotrifluoride, purchased from ABCR (ABCR F01075). Also the NMR spectra are identical to the sample purchased from ABCR.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Cl)c1cc(F)c(F)cc1Cl

Procedure:
In accordance with the above reaction scheme, a solution of 2-chloro-4,5-difluorobenzoic acid (V) in acetonitrile containing a catalytic amount of dimethylformamide is reacted under an inert atmosphere with the dropwise addition of oxalyl chloride, giving 2-chloro-4,5-difluorobenzoic acid chloride (VI) which is dissolved in diethyl ether and slowly added to a cold solution of magnesium diethylmalonate, followed by the addition to ice water and acidification to pH 2.5, giving (2-chloro-4,5-difluorobenzoyl)propanedioic acid diethyl ester (VII). A solution of compound (VII) in p-dioxane and water is heated at reflux, then evaporated and distilled, giving 2-chloro-4,5-difluoro-β-oxobenzenepropanoic acid ethyl ester (VIII). A solution of compound (VIII) and triethyl orthoformate in acetic anhydride is heated at 150° C. for 2 hours, giving 2-chloro-α-(ethoxymethylene)-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (IX). Cyclopropylamine is added to a solution of compound (IX) in ethanol, giving 2-chloro-α-[(cyclopropylamino)methylene]-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester (X). Compound (X) is reacted with sodium hydride in dry dimethylformamide under an inert atmosphere with heat, giving 1-cyclopropyl-6,7-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester (XI). Ester (XI) is then refluxed with acid, giving the desired 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (XII).
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[OH-].[Na+]>CO.O>[ClH:1].[N:2]1([CH2:7][CH2:8][NH:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: CCOC(=O)c1ccc(NCCn2ccnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(NCCn2ccnc2)cc1
Yield: 71.8 %

Procedure:
Then, a solution of 1.0 g of ethyl p-[β-(1-imidazolyl)ethylamino]benzoate hydrochloride and 1.0 g of sodium hydroxide in 30 ml of methanol-water (1:2 by volume) was stirred for 2.5 hours at room temperature. After concentration under reduced pressure, the residue was acidified with 6N hydrochloric acid to pH 1, and then concentrated under reduced pressure. To the residue was added 20 ml of tert-butanol and evaporated under reduced pressure to remove the excess of hydrochloric acid completely. The residual solid was dissolved in ethanol, the insoluble salts were filtered off, and then the filtrate was evaporated under reduced pressure. The residual solid was recrystallized from ethanol-diethyl ether to give 0.65 g of p-[β-(1-imidazolyl)ethylamino]benzoic acid hydrochloride as colorless needles. M.P.: 222° to 224° C. (dec.).