Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH3:5])=[CH:7][CH:8]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNCCC(O)c1ccccc1
Agent: Cl
Product: CNCCC(Oc1ccc(C)cc1)c1ccccc1

Procedure:
Under stirring, while maintaining the temperature between about 15° and about 25° C. with an ice-water bath, 14.25 g of 36 percent aqueous hydrogen chloride are dropped on the filtered organic phase. 4-ATM Hydrochloride (mw 291.82) crystallizes in bulk, and 40 ml of n-butyl acetate are added to allow stirring. The resulting suspension is stirred at about 20° C. for 1 hour, the solid is collected by filtration, washed twice with 40 ml of n-butyl acetate, and dried for 18 hours under vacuum at about 50° to about 60° C., yielding 23.5 g of product, having a melting point of about 164° to about 167° C., for a 33 percent yield, based on the N-methyl-3-hydroxy-3-phenylpropylamine starting material. The 4-ATM HCl is found by chiral HPLC as a mixture of enantiomers, with a relative ratio of 58:42.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:30][C:31](=[O:34])[CH2:32][CH3:33]>C(Cl)Cl>[O:34]=[C:31]([CH2:32][CH3:33])[CH2:30][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: CCC(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)CSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice bath cooled solution containing 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole prepared as in Example 16 and 0.5 ml (3.6 mmole) of triethylamine in 10 ml of methylene chloride is added 0.36 ml (3.5 mmole) of 1-bromo-2-butanone. The reaction is allowed to warm to room temperature and stirred at room temperature for several hours. Workup and chromatography in a manner analogous to that outlined in Example 18 affords the desired titled compound.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:12]C1C=CN=C(C(O)=O)C=1.FC1N=C(C(O)=O)C=CC=1>>[CH3:12][C:4]1[CH:3]=[CH:2][N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=1
Reactant: NNC(=O)c1cccc(F)n1
Reactant: Cc1ccnc(C(=O)O)c1
Agent: O=C(O)c1cccc(F)n1
Product: Cc1ccnc(C(=O)NN)c1

Procedure:
4-Methyl-2-pyridinecarbohydrazide was prepared in a manner analogous to that described above for 6-fluoro-2-pyridinecarbohydrazide (I23) but using 4-methyl-2-pyridinecarboxylic acid (CAS [4021-08-3], commercially available e.g. from Sigma-Aldrich or Fluorochem) in the place of 6-fluoro-2-pyridinecarboxylic acid.
Reaction SMILES: [NH2:1][C:2]([CH3:10])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[K+].[K+].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>O1CCCC1.O>[C:21]([O:20][C:18]([NH:1][C:2]([CH3:10])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4])=[O:17])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)CC(C)(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(C)(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a stirred solution of 2-amino-2,4-dimethylpentanoic acid (1 g, 6.89 mmol) in tetrahydrofuran (15 mL) and water (15 mL) was added K2CO3 (3.81 g, 27.5 mmol) and the reaction mixture was stirred at room temperature for 10 min. To the resultant mixture (BOC)2O (3.20 mL, 13.77 mmol) was added dropwise and the reaction mixture was allowed to stir at room temperature for 14 h. The reaction mixture was then concentrated under reduced pressure. The aqueous layer was washed with ethyl acetate (3×15 mL) and acidified with a saturated aqueous solution of citric acid (25 mL) then extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (2×15 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 2-((tert-butoxycarbonyl)amino)-2,4-dimethylpentanoic acid (1.6 g, 6.89 mmol, quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.36 (bs, 1 H), 2.10 (m, 1 H), 1.77 (m, 2 H), 1.74-1.65 (m, 3 H), 1.59 (s, 9 H), 0.89 (m, 3 H), 0.94 (m, 3 H).
Reaction SMILES: C(OC([N:8]([C:34]1[C:43]([N+:44]([O-:46])=[O:45])=[CH:42][CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]=[N:24][N:23]=2)=[CH:12][CH:11]=1)=O)(C)(C)C>CO>[CH2:27]([N:26]1[C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:13]2[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:34]3[C:43]([N+:44]([O-:46])=[O:45])=[CH:42][CH:41]=[CH:40][C:35]=3[C:36]([O:38][CH3:39])=[O:37])=[CH:11][CH:12]=2)=[N:23][N:24]=[N:25]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2-c2nnnn2Cc2ccccc2)cc1)C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2-c2nnnn2Cc2ccccc2)cc1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of methyl 2-(N-tert-butoxycarbonyl-N-{(2′-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl}amino)-3-nitrobenzoate (compound 20b, 11.93 g, 19.2 mmol) in methanol (15 mL) was added 2NHCl-MeOH (30 mL) under ice-cooling, and the mixture was stirred at the same temperature for 2 hr, and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and to the residue were added methanol and diisopropyl ether. The resulting crystals were collected by filtration, washed with diisopropyl ether and hexane, and dried under reduced pressure to give methyl 2-[({2′-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-nitrobenzoate (compound 21b) (8.64 g, 86%) as yellow crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:54]([O:58][C:59]([NH:61][C@H:62]([C:64](O)=[O:65])[CH3:63])=[O:60])([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[C:54]([O:58][C:59]([NH:61][C@H:62]([C:64]([NH:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:65])[CH3:63])=[O:60])([CH3:56])([CH3:57])[CH3:55]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](N)CC(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 90 %

Procedure:
from N-(2-L-leucyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-L-alanine. Yield 90%. [α]D =-8.1° (c=0.98, tetrahydrofuran).
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.C(O)C.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>[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([C:2]2[C:6](=[O:7])[C:5]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[O:4][C:3]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:33][CH:32]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)C3(CCCC3)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)c1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)OC3(CCCC3)C2=O)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 74.9 %

Procedure:
To a stirred solution of 3-bromo-2-(4-methylsulfonylphenyl)-1-oxa-spiro[4,4]non-2-en-4-one (105 mg) in 5 ml of toluene and 15 ml ethanol, were added 20 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate solution, and 50 mg of 4-isopropylbenzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. The solvent was removed under reduced pressure and the resulting residue was extracted with 20 ml water and dichloromethane (30 ml×3). The organic layer was concentrated in vacuo and the resulting crude product was purified by column chromatography (hexane/ethylacetate) to obtain 87 mg of 3-(4-isopropyl-phenyl)-2-{4-(methylsulfonyl)phenyl}-1-oxa-spiro[4,4]non-2-en-4-one as a solid. mp: 139-140° C. NMR: δ1.25 (s, 3H), 1.27 (s, 3H), 2.04 (m, 6H), 2.15 (m, 2H), 2.92 (m, 1H), 3.06 (s, 3H), 7.21 (m, 4H), 7.83 (d, J=8.7 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H). IR (cm−1): 2960, 1694, 1622, 1386, 1318, 1161, 768.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19](=O)O[CH:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)=[CH:11][CH:10]=1.[N+:25]([C:28]1[S:29][C:30]([CH:33]=C[N+]([O-])=O)=[CH:31][CH:32]=1)([O-:27])=[O:26]>C(#N)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:33]([C:30]3[S:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:32][CH:31]=3)[CH:19]=2)=[CH:11][CH:10]=1
Reactant: O=C1OC(C(F)(F)F)N=C1c1ccc(Cl)cc1
Reactant: O=[N+]([O-])C=Cc1ccc([N+](=O)[O-])s1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-c2cc(-c3ccc(Cl)cc3)[nH]c2C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.16 g, 11.3 mmol) is added to a solution of 4-(p-chlorophenyl)-2-(trifluoromethyl)-3-oxazolin-5-one (2.97 g, 11.3 mmol) and 2-nitro-5-(2-nitrovinyl)thiophene (2.26 g, 11.3 mmol) in acetonitrile near reflux. The reaction mixture is refluxed for one hour, stirred overnight at room temperature and concentrated in vacuo to obtain a red oil. Chromatography of the oil gives the title product as a tan solid, mp 166°-169° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.BrC1C2C(=NC=NC=2N)N(C(C)(C)C)N=1.[CH:39]1[C:47]2[C:46]3[CH:48]=[CH:49][CH:50]=[CH:51][C:45]=3[S:44][C:43]=2[CH:42]=[C:41](B(O)O)[CH:40]=1>>[CH:39]1[C:47]2[C:46]3[CH:48]=[CH:49][CH:50]=[CH:51][C:45]=3[S:44][C:43]=2[CH:42]=[C:41]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)[CH:40]=1
Reactant: Nc1ncnc2c1c(I)nn2[C@H]1CC[C@H](N2CCOCC2)CC1
Reactant: OB(O)c1ccc2c(c1)sc1ccccc12
Agent: CC(C)(C)n1nc(Br)c2c(N)ncnc21
Product: Nc1ncnc2c1c(-c1ccc3c(c1)sc1ccccc13)nn2[C@H]1CC[C@H](N2CCOCC2)CC1

Procedure:
The desired product was prepared by substituting (trans)-3-iodo-1-(4-morpholin-4-yl-cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine prepared as described in WO 2005/074603 for 3-bromo-1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine and dibenzo(b,d)thiophen-3-ylboronic acid (purchased from Maybridge Chemicals) for EXAMPLE 188C in EXAMPLE 181. 1H NMR (300 MHz, methanol-d4) 8.56 (d, 1H), 8.40 (s, 1H), 8.34 (m, 1H), 8.12 (d, 1H); 7.96 (m, 1H); 7.80 (d, 1H); 7.54 (m, 2H); 4.95 (m, 1H); 4.12 (m, 2H); 3.80 (m, 2H); 3.58-3.38 (m, 4H); 2.44-2.38 (m, 2H); 2.38-2.25 (m, 4H); 1.94-1.82 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]2[C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:14][C:15]=1[NH:16]2.[NH:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:29]1>O1CCOCC1.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]>[CH2:37]([O:36][C:35]([NH:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][N:28]([C:8]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]3[C:9]=2[C:10]2[CH:11]=[CH:12][C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:14][C:15]=2[NH:16]3)[CH2:29]1)=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(N[C@@H]1CCCNC1)OCc1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C#N)ccc(Br)c12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C#N)ccc(N3CCC[C@@H](NC(=O)OCc4ccccc4)C3)c12
Temperature: 100 °C
Yield: 37 %

Procedure:
Step 2 A mixture of cesium carbonate (0.960 g, 2.95 mmol), (RS)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.059 g, 0.095 mmol), tris(dibenzylideneacetone)dipalladium (0.058 g, 0.063 mmol), ethyl 5-bromo-8-cyano-9H-carbazole-2-carboxylate (0.85 g, 2.105 mmol) and (R)-benzyl piperidin-3-ylcarbamate (0.493 g, 2.105 mmol) was suspended in 1,4-dioxane (70 mL). The mixture was purged with nitrogen and heated at 100° C. for 18 h. The mixture was cooled to rt and concentrated. The residue was partitioned between EtOAc and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 to 60:40 hexane-EtOAc) to provide (R)-ethyl 5-(3-(benzyloxycarbonylamino)piperidin-1-yl)-8-cyano-9H-carbazole-2-carboxylate as a brown solid (0.68 g, 70% purity, 37% yield), used without further purification. Mass spectrum m/z 497.2 (M+H)+.
Reaction SMILES: [CH3:1]OC(C1C(O)=C2C(C=CC=N2)=CN=1)=O.[CH:16]([O:19][C:20]([C:22]1[C:27]([CH2:28][N:29]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:21])([CH3:18])[CH3:17].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OC(C1C(CO)=CC=C(C)N=1)=O)(C)C.COC(=O)CNS(C1C=CC=CC=1)(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:16]([O:19][C:20]([C:22]1[C:27]([CH2:28][N:29]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=[C:24]([CH3:1])[N:23]=1)=[O:21])([CH3:18])[CH3:17]
Reactant: COC(=O)CN(Cc1cccnc1C(=O)OC(C)C)S(=O)(=O)c1ccccc1
Reactant: COC(=O)c1ncc2cccnc2c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: COC(=O)CNS(=O)(=O)c1ccccc1
Agent: Cc1ccc(CO)c(C(=O)OC(C)C)n1
Solvent: C1CCOC1
Product: COC(=O)CN(Cc1ccc(C)nc1C(=O)OC(C)C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
According to the conditions reported by Anthony et al (WO 02/30931 A2) for the preparation of 3-[(benzenesulfonyl(methoxycarbonylmethyl)amino)methyl]pyridine-2-carboxylic acid isopropyl ester, a solution of diisopropyl azodicarboxylate (1.07 g, 5.30 mmol) in THF (5 mL) was added dropwise over 40 min to a stirred solution of 3-hydroxymethyl-6-methyl-pyridine-2-carboxylic acid isopropyl ester (739 mg, 3.53 mmol), N-(phenylsulphonyl)glycine methyl ester (810 mg, 3.53 mmol) and triphenylphosphine (1.39 g, 5.30 mol) in THF (15 mL) The resulting solution was then left to stir at room temperature overnight. The reaction mixture was concentrated to give crude 3-[(benzenesulfonyl(methoxycarbonylmethyl)amino)methyl]-6-methylpyridine-2-carboxylic acid isopropyl ester as a golden syrup. This was used in the subsequent step without further purification.—Selected 1H NMR (CDCl3): δ 4.73 (s, 2H), 4.00 (s, 2H), 3.54 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][C:10](O)([CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][CH3:12].S(=O)(=O)(O)O>CO>[CH2:11]([C:10]([C:3]1[CH:4]=[C:5]([OH:6])[C:7]([C:10]([CH3:9])([CH2:11][CH3:12])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:8][C:1]=1[OH:2])([CH3:9])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:12]
Reactant: CCC(C)(O)CCCC(C)C
Reactant: Oc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC(C)(CCCC(C)C)c1cc(O)c(C(C)(CC)CCCC(C)C)cc1O
Temperature: 0 °C
Yield: 33.8 %

Procedure:
55 g of hydroquinone and 71.5 g of 3,7-dimethyloctan-3-ol were dissolved in 100 ml of methanol. Then, 50 ml of concentrated sulfuric acid (36 N) was added dropwise thereto under stirring and cooling so as to maintain the temperature at 40° C. or less. Subsequently, the reaction mixture was maintained at 50° to 55° C. for 4 hours. The resulting reaction mixture was added to ice-water, and extracted with 500 ml of benzene. The benzene layer was washed with water and, after drying over anhydrous sodium sulfate, benzene and unreacted 3,7-dimethyloctan-3-ol were distilled off under reduced pressure. The residual oil was chromatographed on silica gel using benzene as a developing solvent. Thus, 29.8 g of 2,5-bis(1-ethyl-1,5-dimethylhexyl)hydroquinone (the same compound as obtained in Synthesis Example 1) was first eluted, and then 15.1 g of 2-(1-ethyl-1,5-dimethylhexyl)hydroquinone was eluted.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:6][CH:5]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].O>O1CCCC1.C(OCC)(=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:3])[N:9]=1)[CH3:19]
Reactant: OCCc1cccc(Br)n1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)COCCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of sodium hydride (74 mg, 1.87 mmol) in tetrahydrofuran (2 ml) was cooled to 0° C. 2-(6-Bromopyridin-2-yl)ethanol (Example 235, Step 3) (126 mg, 0.62 mmol) in tetrahydrofuran (2 ml) was added dropwise and the reaction was allowed to warm to room temperature. After 45 minutes at room temperature, the reaction was cooled to 0° C. and ethyl bromoacetate (0.14 ml, 1.25 mmol) was added. The reaction was allowed to warm to room temperature and then heated to 50° C. Upon completion, the reaction was cooled to 0° C. and water was added dropwise. Ethyl acetate was then added and the layers were separated. The organic layer was then dried over sodium sulfate, filtered and concentrated. Purification of the crude residue by silica gel chromatography afforded the title compound.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:25]=[C:24]([N+]([O-])=O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[CH:12][CH:11]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[F-:29].[K+]>>[F:29][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:11][CH:12]=2)[CH:25]=1
Reactant: [F-]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cc1
Agent: [K+]
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc(F)c3ccccc3n2)cc1

Procedure:
tert-Butyl methyl(4-(4-fluoroquinolin-2-yl)phenyl)carbamate was prepared using general procedure M from tert-butyl methyl(4-(4-nitroquinolin-2-yl)phenyl)carbamate (10 mg, 0.026 mmol) and KF (60 mg, 1 mmol). tert-butyl (4-(4-fluoroquinolin-2-yl)phenyl)(methyl)carbamate was isolated as a clear oil (4.5 mg, 49%). 1H NMR (400 MHz, CDCl3): δ 8.16 (m, 1H), 8.12-8.07 (m, 3H), 7.78 (m, 1H), 7.59-7.54 (m, 2H), 7.41 (m, 1H), 3.32 (s, 3H), 1.48 (s, 9H); MS (ESI): 353 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:42][CH2:43][C:44]1([OH:47])[CH2:46][CH2:45]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:42][CH2:43][C:44]3([OH:47])[CH2:46][CH2:45]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)OCCC1(O)CC1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Reaction time: 24 h
Yield: 25.1 %

Procedure:
To a mixture of N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (204 mg, 0.421 mmol) and 2-(1-hydroxycyclopropyl)ethyl methanesulfonate (152 mg, 0.843 mmol) in 8 mL of DMA was added cesium carbonate (1.37 g, 4.2 mmol, Aladdin). After stirring at 40° C. for 1 day, the reaction mixture was concentrated in vacuo and the residue was chromatographed with a silica gel column (50:1 (v/v) CH2Cl2/CH3OH) to afford the title compound as a white solid (60 mg, 25%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]N2CCC(=O)CC2)[CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH2:36][C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: O=C1CCN(Cc2cccnc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(Cc2cccnc2)C3)cc1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0995 g, 0.251 mmol) in dry was added 1-(pyridin-3-ylmethyl)piperidin-4-one (0.0486 g, 0.255 mmol). The reaction mixture was then heated at 70° C. for 40 min. The reaction mixture was then cooled at 0° C. and added Sodium triacetoxyborohydride (0.1118 g, 0.5275 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred for 3 days. The reaction mixture was diluted with water, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, evaporated, chromatographed through silica gel (12 g, 0-10% MeOH in dichloromethane followed by 6:2:1:1 EtOAc:acetone:water:MeOH), and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 8.49 (d, J=1.7, 1H), 8.46 (dd, J=4.8, 1.6, 1H), 8.15 (d, J=8.8, 2H), 7.71 (d, J=7.8, 1H), 7.46 (d, J=8.8, 2H), 7.36 (dd, J=7.7, 4.8, 1H), 6.15 (t, J=5.6, 1H), 4.12 (d, J=6.5, 1H), 3.91-3.81 (m, 1H), 3.77-3.53 (m, 6H), 3.50 (s, 2H), 3.45-3.34 (m, 1H), 3.17-3.06 (m, 2H), 2.86 (d, J=11.0, 2H), 2.81-2.71 (m, 1H), 2.70-2.56 (m, 3H), 2.39 (t, J=11.3, 1H), 2.01 (t, J=10.8, 2H), 1.83 (s, 2H), 1.60-1.42 (m, 2H), 1.22 (d, J=6.6, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+571.3 (M+H)+.