Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]3[C:22]4[CH:21]=[C:20]([C:23]([O:25]C)=[O:24])[NH:19][C:18]=4[CH2:17][CH2:16]3)[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].CO>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]3[C:22]4[CH:21]=[C:20]([C:23]([OH:25])=[O:24])[NH:19][C:18]=4[CH2:17][CH2:16]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(O)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(O)cc2)c1
Yield: 51 %

Procedure:
The title compound was synthesized from methyl 4-((4′-hydroxybiphenyl-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.044 g, 0.13 mmol) and lithium hydroxide (0.055 g, 1.31 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford a light pink solid: 21.7 mg, 51% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.13 (s, 1H), 2.48-2.62 (m, 3H), 2.80 (dd, J=7.05, 3.78 Hz, 2H), 3.25-3.29 (m, 1H), 6.39 (s, 1H), 6.81-6.86 (m, 2H), 7.09 (d, J=7.52 Hz, 1H), 7.25-7.30 (m, 2H), 7.33-7.37 (m, 1H), 7.38-7.42 (m, 2H); LCMS ESI− 332.2 (M−H); HPLC (UV=98.1%), (ELSD=100%).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Br[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[N:16][CH:17]=1.CC(C)([O-])C.[Na+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[N:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)(C)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)N1CCN(c2ccc(F)nc2)CC1
Temperature: 80 °C
Yield: 71 %

Procedure:
1-tert-Butylpiperazine (1.61 g, 11.4 mmol) is placed in 35 ml of toluene under nitrogen, 5-Bromo-2-fluoropyridine (2 g, 11.4 mmol), sodium t-butoxide (1.6 g, 17 mmol), tris(dibenzylideneacetone)dipalladium (0.52 g, 0.57 mmol), and S-Phos (0.93 g, 17 mmol) are then added. The reaction medium is heated at 80° C. for 18 h. After hydrolysis, and extraction with ethyl acetate, the organic phase is washed with water and then with a saturated aqueous sodium chloride solution. After drying over MgSO4, and concentrating to dryness, the crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of methanol in dichloromethane ranging from 0% to 5%. 1.92 g of 1-tert-butyl-4-(6-fluoropyridin-3-yl)piperazine are obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:33]=[CH:32][C:27]([CH2:28][NH:29][CH2:30][CH3:31])=[CH:26][CH:25]=1>>[CH2:30]([N:29]([CH2:28][C:27]1[CH:26]=[CH:25][C:24]([F:23])=[CH:33][CH:32]=1)[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)[CH3:31]
Reactant: CCNCc1ccc(F)cc1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: CCN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)Cc1ccc(F)cc1
Yield: 14 %

Procedure:
The title compound was prepared in 14% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-fluoro-N-ethylbenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 0.90 (3H, t, J=6.9 Hz), 2.74 (2H, t, J=6.4 Hz), 3.58 (2H, s), 4.08 (2H, t, J=5.9 Hz), 7.03 (2H, t, J=8.9 Hz), 7.23 (2H, dd, J=7.0 Hz and 2.6 Hz), 7.43 (1H, d, J=5.2 Hz), 7.66 (1H, d, J=4.4 Hz), 8.21 (1H, s), 8.35 (1H, d, J=4.5 Hz), 8.54 (1H, s). [M+H] Calc'd for C20H21FN4O2, 369. Found, 369.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]([F:47])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:32]OS(C(F)(F)F)(=O)=O>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:32][C:31]([F:47])([F:30])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:15]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4]
Reactant: O=S(=O)(OCC(F)(F)c1ccccc1)C(F)(F)F
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)CCCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCC(F)(F)c3ccccc3)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.7 %

Procedure:
To a mixture of 1-(3-hydroxy-4-methoxy-benzoylamino)-cycloheptanecarboxylic acid methyl ester (80 mg, 0.249 mmol) and potassium carbonate (83 mg, 0.60 mmol) in 0.5 ml of acetone and 0.5 ml of DMF was added slowly a solution of the compound of step 1 (0.22 g, 0.374 mmol) as solution in acetone. The mixture was stirred for 3 d at room temperature and then evaporated. The residue was purified by preparative RP HPLC (water/ACN gradient) to give the title compound (87 mg).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[C:18](OC)=O.[N+:22]([C:25]1[CH:26]=C(B(O)O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].ClCCl>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[C:18]([C:9]2[CH:8]=[CH:17][CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cccc([N+](=O)[O-])c2)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 151.8 %

Procedure:
Tetrakis(triphenylphosphine) palladium(0) (1.04 g, 0.90 mmol, 0.03 equiv.) and sodium carbonate (4.8 g, 45.28 mmol, 1.52 eqiuv.) were added to a stirred mixture of dimethyl 4-bromoisophthalate (1.26 g, 4.61 mmol) and 3-nitrophenylboronic acid (5.16 g, 30.91 mmol, 0.03 eqiuv.) in 1,4-dioxane (50 mL). The mixture was stirred at about 85° C. for about 16 hours, and then was cooled to ambient temperature. Standard extractive workup with dichloromethane (3×100 mL) gave a crude residue was then purified by silica gel column chromatography (ethyl acetate/petroleum ether) to afford the title product as a white solid (1.8 g; yield=23%). 1H NMR (300 MHz, CDCl3) δ: 8.52 (s, 1H), 8.33 (s, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.14 (d, J=2.7 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.67 (m, 2H), 4.00 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([NH:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)[CH2:13][CH3:14]
Reactant: CCCNC1(c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCNC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 75.6 %

Procedure:
Using General Procedure D; [1-(4-bromophenyl)-cyclopropyl]-propylamine (Intermediate 118, 100.0 mg, 0.39 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (13.0 mg, 0.06 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (48.0 mg, 0.06 mmol). The resulting reaction mixture was heated to 70° C. for Sdays. The title compound (80.0 mg, 75%) was isolated by chromatography (0-10% EtOAc-hexanes) as an orange oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:15][CH:14]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1NCc1ccc(Cl)cc1
Yield: 57.6 %

Procedure:
25 g of 2,5-dichloronitrobenzene and 36.9 g of 4-chlorobenzylamine are heated for two hours at 135° C., it being necessary for the temperature always to be kept below 140° C. After cooling, the mixture is taken up with water and extracted with ethyl acetate. After drying over magnesium sulfate and evaporation under vacuum, the residue is taken up with ether and the crystals obtained are filtered off and washed with ether to give 22.3 g of 2-(4-chlorophenylmethylamino)-5-chloronitrobenzene in the form of crystals melting at 120° C.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=[O:10])[C:4]2=[N:3][CH:2]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O)([O-:20])=[O:19].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[C:17]1[C:6]2[N:5]3[CH:1]=[CH:2][N:3]=[C:4]3[C:9](=[O:10])[NH:8][C:7]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]1=2)([O-:20])=[O:19]
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1[nH]c2c3ccccc3c(=Cc3cccc([N+](=O)[O-])c3)c2n2ccnc12
Yield: 62.6 %

Procedure:
10 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one and 27.1 g of 3-nitrobenzaldehyde are refluxed for 15 hours in the presence of 13.79 g of ammonium acetate in 600 ml of acetic acid. The precipitate formed is filtered off, washed with water and dried under reduced pressure (1 mmHg; 0.13 kPa) at 45° C. 10 g of 10-(3-nitrobenzylidene)-5H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a yellowish powder, the melting point of which is greater than 260° C. (Analysis, C20H12N4O3 ; % calculated C: 67.42; H: 3.39; N: 15.57; O: 13.47; % found C: 67.4; H: 3.2; N: 15.6; O: 13.5).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:38])[N:4]([CH2:22][C@H:23]([NH:30]C(OC(C)(C)C)=O)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5](=[O:21])[N:6]([CH2:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:20])[C:7]=1[CH3:8]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3](=[O:38])[N:4]([CH2:22][C@H:23]([NH2:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5](=[O:21])[N:6]([CH2:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=2[F:20])[C:7]=1[CH3:8]
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Br)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-pyrimidine-2,4(1H,3H)-dione 1e was dissolved in 20 mL/20 mL CH2Cl2/TFA. The resulting yellow solution was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue was partitioned between EtOAc/sat. NaHCO3. The organic phase was dried over Na2SO4. Evaporation gave 2a as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1ccc(Cl)c(CBr)c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3cc(F)ccc3Cl)c2c1

Procedure:
The titled compound (24 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2-chloro-5-fluorobenzyl bromide according to the method of the process (7) of Example 4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([CH:8]([NH:11]C(=O)OC(C)(C)C)[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.Cl>ClCCl.O1CCOCC1>[ClH:1].[NH2:11][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:19])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(Cl)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(CO)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 160A, 1.74 g (6.01 mmol) were introduced in 20 ml of dichloromethane. A quantity of 22 ml (88.00 mmol) of 4M hydrogen chloride in dioxane was added. After stirring at RT for 1 h, the reaction mixture was evaporated to dryness on a rotary evaporator and dried in an HV. This gave 1.38 g (88% of theory) of the title compound in approximately 87% purity.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:33])=[C:11]([CH2:16][C:17]([O:19][CH:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[C:12]=3[O:14][CH3:15])[C:7](=[O:34])[C:6]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:5]2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:43][CH2:44][CH2:45][CH2:46]Br.Cl>CN(C)C=O.O.C(OCC)C.C(OCC)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:33])=[C:11]([C:16]4([C:17]([O:19][CH:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:18])[CH2:46][CH2:45][CH2:44][CH2:43]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:34])[C:6]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(CC(=O)OC(c3ccccc3)c3ccccc3)c(F)cc2c1=O
Reactant: BrCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC)c(C3(C(=O)OC(c4ccccc4)c4ccccc4)CCCC3)c(F)cc2c1=O
Reaction time: 0.75 h
Yield: 79.1 %

Procedure:
10 g of ethyl 1-cyclopropyl-7-diphenylmethoxycar-bonylmethyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quino-linecarboxylate was dissolved in 300 ml of N,N-dimethylform-amide and 1.89 g of 60% sodium hydride was added thereto under ice-cooling. After stirring for 45 minutes, 5.43 g of 1,4-dibromobutane was added thereto and the resulting mixture was stirred at room temperature for 20 hours. After regulating the pH value of the mixture to 5 with 2N hydro-chloric acid, 100 ml of ethyl acetate, 100 ml of diethyl ether and 100 ml of water were added thereto. Then the organic layer was collected, successively washed with water and a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, diisopropyl ether was added to the crystalline product thus obtained followed by the collection of the product by filtration. Thus 8.72 g of ethyl 1-cyclopropyl-7-(1-diphenylmethoxycarbonylcyclo-pentyl)-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quino-linecarboxylate was obtained (yield: 79.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH3:15])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([CH:14]([CH3:15])[N:16]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C:4]=2[CH:3]=1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2c3cc(Cl)ccc3-c3ccccc3C2C)cc1

Procedure:
The title compound was prepared from N-[1-(4′-chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethyl]-4-methoxybenzenesulfonamide (617 mg, 1.5 mmol), anhydrous N,N-dimethylformamide (2 mL), and potassium carbonate (414 mg, 3.0 mmol) according to the procedure and in the same manner as described in Example 105, step d resulting in the isolation of 607 mg (93%) of a white solid that was used without further purification;
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:21](=O)[CH:20]2[CH:16]([N:17]([CH3:23])[CH2:18][CH2:19]2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[K+]>O1CCCC1>[CH2:7]([N:14]1[CH2:21][CH:20]2[CH:16]([N:17]([CH3:23])[CH2:18][CH2:19]2)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN1CCC2C(=O)N(Cc3ccccc3)C(=O)C21
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC2CN(Cc3ccccc3)CC21
Reaction time: 3 h

Procedure:
1.52 g (40 mmol) of lithium aluminum hydride are initially introduced into 30 ml of anhydrous tetrahydrofuran, and 4.9 g (20 mmol) of 5-benzyl-4,6-dioxo-1-methyl-octahydropyrrolo[3,4-b]pyrrole are added dropwise as a solution in 15 ml of anhydrous tetrahydrofuran. The mixture is then subsequently stirred at the boiling point for 3 hours. 1.5 ml of water, 1.5 ml of 15% strength potassium hydroxide solution and 4.5 ml of water are added dropwise in succession to the batch and the precipitate is then filtered off with suction and washed with tetrahydrofuran. The filtrate is concentrated on a rotary evaporator and the residue is distilled. 3.1 g (72% of theory) of a colorless distillate of boiling point 80° C./0.07 mbar are obtained.
Reaction SMILES: C(N[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:16]([CH:19]=1)[C:17]#[N:18])(=[O:11])=[O:10])C1C=CC=CC=1.[ClH:33].Cl[O-].[Na+]>ClCCl>[C:22]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][C:15]1[CH:14]=[CH:13][C:12]([S:9]([Cl:33])(=[O:11])=[O:10])=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: Cl
Reactant: N#Cc1cc(S(=O)(=O)NCc2ccccc2)ccc1Oc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Cl)ccc1Oc1ccccc1-c1ccccc1

Procedure:
A mixture of 5-benzylsulfamyl-2-(biphenyl-2-yloxy)-benzonitrile (Preparation 56, 6.06 g, 15.4 mmol), dichloromethane and aq HCl was stirred vigorously with cooling (ice bath). Sodium hypochlorite was added dropwise over 30 minutes and stirring continued with cooling for 1 hour. The layers were separated, the aqueous extracted with dichloromethane (2×100ml), and the organic collected, dried (MgSO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography (ethyl acetate:Heptane 10/90 to 20/80) to furnish 4.58 g of the title compound. 1HNMR (CDCl3): δ 6.7 (m, 1H), 7.2-7.6 (m, 9H), 7.85 (m, 1H), 8.15 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([NH:18][C:17](=[O:19])[C:16]3[CH:20]=[C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][O:29]C4CCCCO4)=[O:27])[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[O:19]=[C:17]1[C:16]2[CH:20]=[C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][OH:29])=[O:27])[CH:22]=[CH:23][C:15]=2[O:14][C:10]2([CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[NH:18]1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCNC1)O2)NO
Yield: 68.6 %

Procedure:
A solution of (±)-(E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (360 mg, 0.74 mmol) in DCM (14 ml) was treated with 4 M HCl in dioxane (1.9 ml) as described in Example 30, STEP C to give (±)-(E)-3-{3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide (154 mg, hydrochloride salt) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([C:18](O)=[O:19])[CH:15]=[N:14]1.S(Cl)(Cl)=O.[NH3:25]>O1CCCC1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[N:17]=[C:16]([C:18]([NH2:25])=[O:19])[CH:15]=[N:14]1
Reactant: N
Reactant: O=C(O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxylic acid (8.18 g) was treated with thionyl chloride (150 ml) to give crude acid chloride. A solution of this in tetrahydrofuran was added to ammonia with ice cooling. The mixture was stirred at room temperature for one hour, solvent was removed and the product extracted with ethyl acetate and worked up in conventional manner to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxamide, m.p. 239° (Compound 14 ).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:11][O:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:7][N:6]=1)=[O:9]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCC(F)(F)F)cn1
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
Methyl 5-aminopyridine-2-carboxylate (Intermediate 168, 200 mg, 1.31 mmol) and cesium carbonate (642 mg, 1.97 mmol) were dissolved in anhydrous DMF (2 mL) and stirred under nitrogen for 10 min. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (246 μL, 1.70 mmol) was added and the mixture was stirred at room temperature for 18 h. Further cesium carbonate (642 mg, 1.97 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (246 μL, 1.70 mmol) were added and the mixture was stirred at 85 C for 6 h. The mixture was diluted with EtOAc (50 mL) and washed with water (3×20 mL), then brine (20 mL) and then dried over sodium sulfate and evaporated under vacuum. The crude residue was purified by flash chromatography (0-10% EtOAc in heptane) to afford the title compound as a white solid (75 mg, 24%). Method B HPLC-MS: MH+ requires m/z=235. Found: m/z=235, Rt=1.76 min (84%).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:31][C@@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]1[NH:38]C(=O)OC(C)(C)C.CCN(C(C)C)C(C)C>>[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]1[NH:38][C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cn1ccc2c(Nc3nc(On4nnc5ccccc54)ncc3C(N)=O)cccc21
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)cccc21
Temperature: 80 °C
Yield: 22.1 %

Procedure:
To a solid of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (100 mg, 0.25 mmol) in vial was added tert butyl (1S, 2R)-2-aminocyclohexylcarbamate (0.3 M solution in NMP, 1.25 mL, 0.375 mmol) and DIPEA (0.09 mL, 0.5 mmol). It was heated at 80° C. for 2 h, cooled and purified by preparative HPLC to give 2-((1R,2S)-2-aminocyclohexylamino)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (21 mg). MS found for C20H25N7O as (M+H)+ 380.4. UV: λ=219.2, 241.6, 336.7.