Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([OH:12])=O)=[O:7])(C)(C)C.C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.[NH2:36][C@H:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][C@H:38]1[OH:46].C(OC(=O)NC(C(=O)NC1C2C(=CC=CC=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:80][C:81]([C:83]1([NH:88][C:89]([CH:91]2[CH2:95][CH:94]([O:96][C:97]3[C:106]4[C:101](=[CH:102][C:103]([O:107][CH3:108])=[CH:104][CH:105]=4)[N:100]=[C:99]([C:109]4[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=4)[CH:98]=3)[CH2:93][N:92]2C(=O)NC(C(=O)NC2C3C(=CC=CC=3)CC2O)C(C)(C)C)=[O:90])[CH2:85][CH:84]1[CH:86]=[CH2:87])=[O:82])C>>[CH:14]1([CH2:13][C@H:9]([NH:8][C:6]([N:92]2[CH2:93][C@H:94]([O:96][C:97]3[C:106]4[C:101](=[CH:102][C:103]([O:107][CH3:108])=[CH:104][CH:105]=4)[N:100]=[C:99]([C:109]4[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=4)[CH:98]=3)[CH2:95][C@H:91]2[C:89]([NH:88][C@:83]2([C:81]([OH:82])=[O:80])[CH2:85][C@H:84]2[CH:86]=[CH2:87])=[O:90])=[O:7])[C:10](=[O:12])[NH:36][C@H:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][C@H:38]2[OH:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Agent: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: O=C([O-])NCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@@H](CC1CCCCC1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(=O)O
Yield: 25 %

Procedure:
(2S)-tert-Butoxycarbonylamino-3-cyclohexylpropanoic acid was attached to the resin as described for the preparation of compound 16 followed by reaction with (1S,2R)-1-amino-2-indanol as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (12.3 mg, 25% yield), Purity by HPLC >95% M+H+802.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]([C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:12][O:13][C:5]=2[CH:4]=1)=[O:10].[CH3:21][O:22]C1C=CC(C2C(=O)C3C=CC(O)=CC=3OC=2)=C(O)C=1.C[O:43]C1C=CC(C2C(=O)C3C=CC(O)=CC=3OC=2)=CC=1O.C1OC2C=C(C3C(=O)C4C=CC(O)=CC=4OC=3)C=CC=2O1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C@H:9]3[O:10][C:15]4[C:14](=[CH:19][C:18]5[O:22][CH2:21][O:20][C:17]=5[CH:16]=4)[C@@:11]3([OH:43])[CH2:12][O:13][C:5]=2[CH:4]=1
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1O
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)c(O)c1
Reactant: COc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1
Agent: O=c1c(-c2ccc3c(c2)OCO3)coc2cc(O)ccc12
Product: COc1ccc2c(c1)OC[C@]1(O)c3cc4c(cc3O[C@H]21)OCO4

Procedure:
Isoformononetin, 2′-hydroxyformononetin, 3′-hydroxyformononetin (calycosin) and pseudobaptigenin were purchased from Apin (Abingdon, UK). Maackiairi and pisatin were kindly provided by Dr. H. D. VanEtten, (University of Arizona, Tucson). Maackiain glucoside and maackiain glucose malonate standards were gifts from Dr. S. Tebayashi (Kochi University, Japan). Medicarpin was from a lab collection. Other isoflavonoids were from Indofine Chemical Company (Somerville, N.J.). CO was obtained from Aldrich and all other chemicals were from Sigma (St. Louis, Mo.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([CH2:13][C:14]([NH:16]C2C=CC=CC=2)=O)=[O:12])[N:4]=1.Cl.[OH-].[Na+]>CO>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([C:11]([C:13]2[CH:14]=[CH:13][CH:11]=[CH:5][C:14]=2[NH2:16])=[O:12])[N:6]=1
Reactant: COc1cc(OC)nc(C(=O)CC(=O)Nc2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)nc(C(=O)c2ccccc2N)n1

Procedure:
In a reactor were placed 0.57 g (1.9 m moles) of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)acetanilide, 10 ml of methanol and 5 ml of 6 N hydrochloric acid, followed by refluxing for 1 hour with heating. After the completion of the reaction, the reaction mixture was made alkaline with sodium hydroxide, after which extraction with ethyl acetate was made. The ethyl acetate layer was concentrated. The residue was subjected to gas chromatography. As a result, formation of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)aniline was confirmed. Conversion: 1000 (in terms of total area ratio in gas chromatography)
Reaction SMILES: CI.[F:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8]N(C)C(=S)C)=[CH:6][CH:5]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][CH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH2:32])[CH:30]=2)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].[N:34]1[CH:39]=CC=[CH:36][CH:35]=1>CCOCC>[C:16]([O:20][C:21](=[O:33])[NH:22][CH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([N:32]=[C:35]([NH:34][CH2:39][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:15][CH:14]=3)[CH3:36])[CH:30]=2)[CH2:25][CH2:24]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: c1ccncc1
Reactant: CC(=S)N(C)Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(N)cc21
Solvent: CI
Solvent: CCOCC
Product: CC(=Nc1ccc2c(c1)C(NC(=O)OC(C)(C)C)CC2)NCCc1ccc(F)cc1
Reaction time: 3 h

Procedure:
Add MeI (0.623 g, 4.4 mmol) to a solution of N-4-fluorobenzyl-N-methylthioacetamide (0.662 g, 3.4 mmol) in 10 mL of ether at rt. Stir the mixture for 3 h and evaporate the ether under vacuum. Add (6-aminoindan-1-yl)carbamic acid tert-butyl ester (0.7 g, 2.28 mmol) followed by 5 mL of pyridine. Stir the resulting mixture for 12 h. Evaporate pyridine and purify the residue by column chromatography (silica gel, 3% MeOH in CH2Cl2) to give 1.26 g of (6-(1-((4-fluorobenzyl)methylamino)ethylideneamino)indan-1-yl)carbamic acid tert-butyl ester as a light yellow solid; MS 412 (MH+); 1H NMR (CD3OD) d 7.35-7.29 (2H, m), 7.18-7.10 (3H, m), 6.70 (1H, s), 6.65 (1H, d, J=7.6 Hz), 5.06 (1H, t, J=6.8 Hz), 4.69 (2H, s), 3.05 (3H, s), 2.97-2.91 (1H, m), 2.84-2.77 (1H, m), 2.55-2.48 (1H, m), 1.97 (3H, s), 1.52 (9H, s).
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[CH2:4][C:3](=[O:8])[CH2:2]1.[Na].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:7][C:5]1[CH2:6][O:1][CH2:2][C:3](=[O:8])[CH:4]=1)[CH3:16]
Reactant: O=C1COCC(=O)C1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CCOC1=CC(=O)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of 2H-pyran-3,5(4H,6H)-dione, sodium salt (1.36 g, 10 mmol) in 50 mL of ethanol were added 1.5 mL of concentrated sulphuric acid and the reaction mixture was stirred at room temperature overnight. Most of the solution was evaporated under vacuum, the residue was neutralized with saturated sodium bicarbonate, product extracted with ethyl acetate (4×50 mL), organics combined dried with sodium sulfate, filtered and concentrated. Residue purified by column chromatography (silica gel. 200-300 mesh, eluting with ethyl acetate/petroleum ether=1/1) to afford 5-ethoxy-2H-pyran-3(6H)-one (641 mg, 45%) as yellow solid. LCMS: (M+H)+=143; 1H NMR (300 MHz, CDCl3): δ 5.44 (s, 1H), 4.25 (s, 2H), 4.06 (s, 2H), 3.98 (q, 2H, J=6.9 Hz), 1.38 (t, 3H, J=6.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[NH:4][CH:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[NH:37][C:38]([CH:41]5[CH2:45][CH2:44][CH2:43][NH:42]5)=[N:39][CH:40]=4)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:13])[CH2:6][CH2:7][C:8]([F:11])([F:10])[F:9].[F:47][C:48]([F:61])([F:60])[CH2:49][CH2:50][CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:52](O)=[O:53].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:59][O:58][C:56](=[O:57])[NH:55][CH:51]([C:52]([N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[C:38]1[NH:37][C:36]([C:33]2[CH:34]=[CH:35][C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:21]4[NH:20][C:19]([CH:15]5[CH2:16][CH2:17][CH2:18][N:14]5[C:12](=[O:13])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:46])[CH2:6][CH2:7][C:8]([F:9])([F:11])[F:10])=[N:23][CH:22]=4)=[CH:29][CH:28]=3)=[CH:31][CH:32]=2)=[CH:40][N:39]=1)=[O:53])[CH2:50][CH2:49][C:48]([F:47])([F:61])[F:60]
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(CCC(F)(F)F)NC(=O)OC)[nH]4)cc3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
To a solution of crude [4,4,4-Trifluoro-1-(2-{5-[4′-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-butyl]-carbamic acid methyl ester (115 mg, 0.18 mmol) in dimethylformamide (0.5 mL) was added a solution of 5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoic acid (44 mg, 0.19 mmol) and HATU (72 mg, 0.19 mmol) in dimethylformamide (0.5 mL). Diisopropylethylamine (65 μL, 0.37 mmol) was then added and the reaction was stirred at room temperature for 16 hours. The solution was concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield (4,4,4-Trifluoro-1-{2-[5-(4′-{2-[1-(5,5,5-trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-butyl)-carbamic acid methyl ester (35 mg, 23%). LCMS-ESI+: calculated for CoH44F6N8O6: 846.82; observed [M+1]+ : 847.34. 1H-NMR: 400 MHz, (CD3OD) δ: 7.81-7.72 (m, 4H), 7.67-7.64 (m, 4H), 7.38-7.32 (m, 2H), 5.20-5.16 (m, 2H), 4.55-4.51 (m, 2H), 3.91-3.86 (m, 4H), 3.67 (s, 6H), 2.38-2.20 (m, 8H), 2.18-1.79 (m, 8H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:12]=3)=[C:4]2[CH:3]=1.C([Li])CCC.[CH2:36]([S:38]SCC)[CH3:37].O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:38][CH2:36][CH3:37])[N:5]2[N:8]=[C:9]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:12]=3)=[C:4]2[CH:3]=1
Reactant: CCSSCC
Reactant: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(Nc3ccccc3)n2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCSc1cc(Cl)cc2c(-c3ccnc(Nc4ccccc4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.1 %

Procedure:
To a solution of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-phenyl-2-pyrimidinamine (80 mg, 0.19 mmol) in tetrahydrofuran (5 mL) was added n-butyllithium (0.43 mL of 1.6M solution in hexane, 0.67 mmol) at −78° C. The resulting dark solution was stirred for 10 minutes, then quenched by the addition of ethyl disulfide (0.08 mL, 6.5 mmol). The reaction mixture was allowed to warm to room temperature, then water and ethyl acetate were added. The phases were separated and the ethyl acetate phase was washed with water, dried (magnesium sulfate), filtered and concentrated. The resulting residue was crystallized from acetonitrile to give N{4-[5-chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-phenylamine (20 mg, 22%) as a solid. 1H NMR (CDCl3): δ 8.30 (d, 1H), 8.22 (d, 1H), 7.66 (m, 3H), 7.40 (t, 2H), 7.1-7.24 (m, 4H), 6.75 (d, 1H), 6.52 (d, 1H), 3.20 (q, 2H), 1.54 (t, 3H); 19F-NMR (CDCl3): δ −112.55; MS m/z 476 (M+1).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Si:17]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH:15]=[CH2:16].C([O:31]OC(C)(C)C)(C)(C)C.P.C([SiH3])C=C>>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:16][CH2:15][CH2:14][Si:17]([O:24][CH2:25][CH3:26])([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])=[O:31])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CC[Si](OCC)(OCC)OCC
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: CC(C)(C)OOC(C)(C)C
Agent: C=CC[SiH3]
Agent: P
Product: CCO[Si](CCCP(=O)(c1ccccc1)c1ccccc1)(OCC)OCC
Reaction time: 1 h
Yield: 216.6 %

Procedure:
To diphenylphosphine (18.0 g, 0.097 mol) heated to 140° C under a nitrogen atmosphere, a mixture of allyl triethoxysilane (19.8 g, 0.97 mol) and di-t-butyl peroxide (1.86 g) is added during 3/4 hour. Heating is continued for 1 hour after the addition is complete. Analysis of the liquid shows the presence of unreacted phosphine and allyl silane, so di-t-butyl peroxide (2.0 g) is added and heating continued 2 hours more. This analysis, addition, and heating is repeated once more, after which only a trace of diphenylphosphine is present. The liquid reaction mixture is distilled giving the product (11.2 g, 30 percent yield), b.p. 180- 184° C/0.7 mm, nD27 1.5340.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12](=[O:14])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].Br[C:16]1C=C(C=CC=1C)C(=N)NO.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:16])[C:12](=[O:14])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2noc(=O)[nH]2)cc1Br
Reactant: Cc1ccc(C(=N)NO)cc1Br
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2noc(=O)n2C)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step-2: 3-(3-Bromo-4-methylphenyl)-1,2,4-oxadiazol-5(4H)-one: To a 0° C. cooled solution of 3-bromo-N-hydroxy-4-methylbenzimidamide (500 mg, 2.18 mmol, 1.0 eq) in DCM (10 mL) was added triphosgene (250 mg, 0.87 mmol, 0.4 eq) followed by diisopropylethylamine (0.76 mL, 4.46 mmol, 2 eq). The resulting mixture was stirred at room temperature for 3 h. The reaction was cooled back down to room temperature and quenched with water (5 mL) followed by dilution with DCM. The layers were separated and the organic layer was washed with brine (10 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under vacuum to afford 250 mg of the title product as white solid. 1HNMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H, D2O exchangeable), 8.01 (d, J=1.5 Hz, 1H), 7.74 (dd, J=8.0, 1.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H) 2.42 (s, 3H); ESI-MS (m/z) 255, 257 [(MH)+, Br79,81]
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]#[C:12][Si](C)(C)C)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1.[C:23](C1C=C2C(=CC=1)N(C1CCCCO1)N=C2)#[CH:24].C(C1C=C2C(=CC=1)N(C1CCCCO1)N=C2)#CCC>>[C:11]([C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[N:5]=[CH:4]2)#[C:12][CH2:23][CH3:24]
Reactant: C#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: Cc1c(C#C[Si](C)(C)C)ccc2c1cnn2C1CCCCO1
Agent: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Product: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1C

Procedure:
The title compound was prepared from 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethynyl)-1H-indazole following the procedures outlined for Intermediate 2 (step 2) and Intermediate 3. 1H NMR (300 MHz, DMSO-d6): δ 7.97 (s, 1H), 7.27 (d, 1H), 7.11 (d, 1H), 5.59 (dd, 1H), 3.58 (m, 1H), 3.50 (m, 1H), 2.38 (s, 3H), 2.17 (q, 2H), 2.13 (m, 1H), 1.77 (m, 2H), 1.50 (m, 1H), 1.36 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:25])=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[NH:26]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][NH2:38])[CH2:27]1>>[NH2:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH:28]1[CH2:29][CH2:30][N:26]([C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:24])[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]3[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[C:3]([CH3:25])[C:2]=2[F:1])[CH2:27]1
Reactant: NCc1ccccc1C1CCNC1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Product: Cc1c(F)c(N2CCC(c3ccccc3CN)C2)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 72 %

Procedure:
Starting from 6,7-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid (0.40 g, 1.1 retool) and 2-(3-pyrrolidinyl)benzenemethanamine, a procedure analogous to that given in Example 1, provided the title compound (0.40 g, 72%) as a beige solid, mp 283°-285° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([OH:14])=O)=[C:7]([Cl:15])[CH:6]=[CH:5][C:4]=2[N:3]=1.[F:16][C:17]1([F:25])[CH2:22][CH2:21][CH:20](NC)[CH2:19][CH2:18]1.Cl.[CH3:27][N:28](C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:28][CH2:27][CH:20]3[CH2:19][CH2:18][C:17]([F:16])([F:25])[CH2:22][CH2:21]3)=[O:14])=[C:7]([Cl:15])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C(O)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCN=C=NCCCN(C)C
Reactant: CNC1CCC(F)(F)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A mixture of 2,6-dichloro-quinoline-5-carboxylic acid (1500.00 mg; 6.20 mmol; 1.00 eq.), (4,4-difluoro-cyclohexyl)-methylamine (1380.48 mg; 7.44 mmol; 1.20 eq.), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (1425.53 mg; 7.44 mmol; 1.20 eq.) (EDCI), benzotriazol-1-ol (1004.81 mg; 7.44 mmol; 1.20 eq.) (HOBt) and ethyl-diisopropyl-amine (2402.70 mg; 18.59 mmol; 3.00 eq.) in DMF (10.0 mL) was stirred at room temperature overnight. The mixture was poured into water, the solid was collected by filtration and washed with ethyl acetate, then dried over. The product, 2,6-dichloro-N-((4,4-difluorocyclohexyl)methyl)quinoline-5-carboxamide (1.78 g, 77% yield) was used for the next reaction without further purification. m/z: 374 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[C-:12]#[N:13].[Na+].C(Cl)Cl>CS(C)=O>[C:12]([CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)#[N:13]
Reactant: ClCc1cc2ccccc2o1
Reactant: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#CCc1cc2ccccc2o1
Reaction time: 1 h

Procedure:
Compound 5 (117 g) was added dropwise to a stirring suspension of sodium cyanide (37.64 g) in dimethyl sulfoxide (100 ml). The reactor was placed from time to time into an ice bath in order to keep the reaction temperature between 20° C. and 45° C. Addition lasted 60 minutes. The reaction mixture was stirred for another 16 hours, then poured into methylene chloride (500 ml), washed with water (500 ml, then 2×250 ml), and evaporated to dryness. A small sample was purified on a silica gel column, eluting with dichloromethane/hexanes (50:50 v/v).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:12](OCC)(OCC)OCC.[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][CH:12]=[C:4]([C:3](=[O:10])[CH:2]([CH3:1])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:25][CH:24]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)C(C)C
Product: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)C(C)C
Temperature: 150 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
A mixture of ethyl 4-methyl-3-oxopentanoate (31.6 g, 0.200 mol), triethyl orthoformate (41.6 mL, 0.250 mol), and 4-bromoaniline (36.1 g, 0.210 mol) was heated at 150° C. for 2 h with a Dean Stark trap. After this time triethyl orthoformate (20.8 mL) was added and the reaction mixture was stirred for 16 h. The reaction was cooled to room temperature, diluted with 1:1 methylene chloride/hexanes (200 mL), and filtered through a plug of silica. The filtrate was concentrated, triturated with hexanes and filtered to afford the desired product (33.2 g, 53%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) δ 12.80 (d, J=11.9 Hz, 1H), 8.46 (d, J=13.0 Hz, 1H), 7.55-7.42 (m, 2H), 7.12-6.96 (m, 2H), 4.27 (q, J=7.1 Hz, 2H), 3.89-3.72 (m, 1H), 1.35 (t, J=7.1 Hz, 3H), 1.13 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (178 mg, 0.51 mmol, 1.00 equiv) in methanol (15 mL). A solution of sodium hydroxide (102.6 mg, 2.56 mmol, 5.00 equiv) in water (1.5 mL) was added. The resulting solution was stirred overnight at 50° C. in an oil bath and concentrated to dryness. The residue and diluted by 10 ml of water and pH value of the aqueous solution was adjusted to pH=3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration as product. This resulted in 130 mg (75%) of (R)-3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[Cl-].CC1C=CC(C[Zn+])=CC=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:31])=[CH:26][CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: Cc1ccc(C[Zn+])cc1
Agent: [Cl-]
Product: Cc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Yield: 45 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and (4-methylbenzyl)zinc(II) chloride in 45% yield.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4](=O)[O:5][C:6](=[O:8])[CH:7]=1.Cl.Cl.[NH2:14][NH2:15]>O>[F:1][C:2]([F:11])([F:10])[C:3]1[C:4](=[O:5])[NH:14][NH:15][C:6](=[O:8])[CH:7]=1
Reactant: O=C1C=C(C(F)(F)F)C(=O)O1
Reactant: NN
Agent: Cl
Solvent: O
Product: O=c1cc(C(F)(F)F)c(=O)[nH][nH]1
Reaction time: 4 h
Yield: 4.6 %

Procedure:
3-Trifluoromethylfuran-2,5-dione (5 g) was introduced in portions into an already boiling solution of hydrazine dihydrochloride (3.2 g) in water (50 ml). After stirring for 4 h, the mixture was left to stand overnight; the next day, the mixture was refluxed for a further 8 h and left to stand overnight. Then it was dried and the residue was purified by means of preparative chromatography (met. C). The clean fractions were combined, the ACN was drawn off and the residue was freeze-dried. 250 mg of the title compound were obtained. LC-MS rt: 0.23 min [M+H]+: 181.1 (met.b)
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2C#N.[CH3:16][S:17](Cl)(=[O:19])=[O:18].[N:21]1C=CC=C[CH:22]=1>O>[C:22]([CH2:16][S:17]([NH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2)(=[O:19])=[O:18])#[N:21]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1N)CCCC2C#N
Reactant: c1ccncc1
Solvent: O
Product: COc1ccc2c(c1NS(=O)(=O)CC#N)CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A solution of the product from Example 77 (2.5 g) in pyridine (10 ml) was treated with methanesulfonyl chloride (2 ml). After 4 hours stirring at room temperature the reaction was diluted with water and the mixture was filtered and dried affording 2.76 of product (80% yield).