Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14].C(N1C=CN=C1)([N:23]1C=CN=C1)=O.C([O-])(=O)C.[NH4+]>CN(C=O)C>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH2:23])=[O:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cccc(-c2ccccc2OC(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(-c2ccccc2OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.94 g (3.36 mmol) of 3-(2-trifluoromethoxyphenyl)-benzoic acid in 17 mL of DMF was added 0.55 g (3.36 mmol) of carbonyldiimidazole (CDI) and the reaction was stirred at RT for 4 h. To the reaction mixture was added 2.6 g (33.6 mmol) of ammonium acetate and the reaction mixture was stirred over night at RT. The reaction mixture was partitioned between ethyl acetate and water and the organic fraction was washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 30%, 50% successively EtOAc: hexanes) to give the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=2)[C:31](O)=[O:32])[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:23]1([C:28]2[CH:29]=[C:30]([C:31]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]3[CH2:16][O:15][C:14]3[C:4]4[C:3]([NH2:2])=[N:8][S:7](=[O:9])(=[O:10])[NH:6][C:5]=4[CH:11]=[CH:12][CH:13]=3)=[O:32])[CH:34]=[CH:35][N:36]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: O=C(O)c1ccnc(-n2ccnc2)c1
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)c3ccnc(-n4ccnc4)c3)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(1H-imidazol-1-yl)isonicotinic acid (Example 52a) (22% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.47-1.91 (m, 6H), 3.02 (m, 1H), 3.35 (m, 1H), 4.28 (dd 1H, J=10.4, 4.4 Hz), 4.65 (t, 1H, J=10.4 Hz), 5.24 (m, 1H), 6.63 (d, 1H, J=8.2 Hz), 6.90 (d, 1H, J=8.5 Hz), 7.31 (d, 1H, J=5.2 Hz), 7.48 (d, 1H, J=8.2 Hz), 7.77 (s, 1H), 7.84 (br s, 1H), 8.00 (s, 1H), 8.44 (br s, 1H), 8.52-8.59 (m, 2H), 10.95 (br s, 1H). MS 482 (MH+).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[N+:17]([C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[C:1](=[O:11])[NH:5][C:4]2=[O:6])([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Product: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
In a dried 50 mL two necked round-bottom flask equipped with an addition funnel and CaCl2 drying tube was placed 2.0 g (13.6 mmol) of phthalimide. The flask was then cooled to 0° C. in a salt and ice bath. An ice cold mixture of concentrated sulfuric acid and fuming nitric acid (1:1 v/v) 8 mL was gradually added with constant stirring. The mixture was then stirred for 30 min. at 0° C. and allowed to slowly warm to room temperature with stirring over a period of 1 h. The reaction mixture was then poured into ice. The resulting solid product was filtered and dried to give 1.6 g (61.3%) of 5-nitro-1H-isoindole-1,3(2H)-dione as a yellow colour solid.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:12][C:11]2[C:13]3[C:18]([C:19](=[O:22])[C:20](=[O:21])[C:10]=2[S:9][CH2:8]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)(=O)=O.[N:23]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>CS(C)=O>[O:21]=[C:20]1[C:10]2[S:9][CH2:8][CH:7]([CH2:6][N:26]3[CH2:25][CH2:24][N:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27]3)[O:12][C:11]=2[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:22]
Reactant: CS(=O)(=O)OCC1CSC2=C(O1)c1ccccc1C(=O)C2=O
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(CC2CSC3=C(O2)c2ccccc2C(=O)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
To a solution of (5,6-dioxo-2,3,5,6-tetrahydronaphtho[1,2-b][1,4]oxathiin-2-yl)methyl methanesulfonate (0.15 g, 0.44 mmol) in DMSO (1.5 mL) was added ethyl piperazine-1-carboxylate (0.065 mL, 0.88 mmol) and triethylamine (0.12 mL, 0.88 mmol). The reaction mixture was shaken at 50° C. for 2 hours. The crude product was purified by reverse phase HPLC to give the desired product as a purple solid (0.015 g, 5%). M.p.=185-187° C.; 300 MHz 1H NMR (CDCl3) δ: 8.04 (d, J=7.2 Hz, 1H), 7.66 (m, 2H), 7.48 (t, J=7.2 Hz, 1H), 4.66 (m, 1H), 4.15 (m, 2H), 3.51 (m, 4H), 3.23 (m, 1H), 3.03 (m, 1H), 2.83 (m, 2H), 2.54 (m, 4H), 1.27 (m, 3H); LCMS: 403 [M+H].
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[C:34]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH:45]([CH3:48])[CH:46]=O)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([CH2:44][CH:45]([CH3:48])[CH:46]=[CH:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:42][CH:43]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C=CCc1ccccc1)Cc1ccc(C(C)(C)C)cc1
Yield: 68.8 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.00 g, 6.71 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.2 mL, 6.71 mmol, 1.0 equiv.) and 3-(4-tert-butylphenyl)-2-methylpropanal (2.05 g, 10.1 mmol, 1.5 equiv.), 1.35 g (69%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: C([NH:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:10]=1)C1C=CC=CC=1.Cl>[C].[Pd].CO>[NH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:10]=1
Reactant: CC(C)(C)Nc1nc(NCc2ccccc2)c(F)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)Nc1nc(N)c(F)cc1F
Reaction time: 24 h
Yield: 44.7 %

Procedure:
To 60 ml of methanol were added 10.7 g of the crude 2-benzylamino-6-(t-butylamino)-3,5-difluoropyridine as described above together with 1.10 g of 10% palladium carbon and 3.8 g of concentrated hydrochloric acid, and the mixture was hydrogenated for one day. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. To the residue was added 150 ml of chloroform, and the mixture was washed with 80 ml of 10% aqueous solution of sodium carbonate, and the washings were extracted again with 50 ml of chloroform. The chloroform layers were combined, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography (silica gel, 100 g; eluent:chloroform:n-hexane, 2:1, and then, chloroform) to obtain 3.3 g of the title compound as a pale brown oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].[F:14]C1C(F)=C(F)C=CC=1N.FC1C=CC([N+]([O-])=O)=C(F)C=1F.OCC(=O)C>>[OH:9][CH2:8][CH:7]([NH:6][C:5]1[CH:11]=[CH:12][C:2]([F:1])=[C:3]([F:13])[C:4]=1[F:14])[CH3:10]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: CC1COc2c(ccc(F)c2F)N1
Agent: CC(=O)CO
Agent: O=[N+]([O-])c1ccc(F)c(F)c1F
Product: CC(CO)Nc1ccc(F)c(F)c1F

Procedure:
A method for the preparation of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine either as the optically active s-(-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine or the racemic mixture. The process of the invention comprises the reaction of 2,3,4-trifluoroaniline or trifluoronitrobenzene with hydroxyacetone or a hydroxyacetone derivative under reducing condition to yield N-(3-hydroxy-2-propyl)-2,3,4-trifluoroaniline derivative. The N-(3-hydroxy-2-propyl)-2,3,4-trifluoroaniline is treated with base to yield the benzoxazine intermediate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:15]([N:17](C(C)C)C(C)C)[CH3:16].BrCC#N>C1COCC1>[C:15]([CH2:16][NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:17]
Reactant: CCOC(=O)c1cc(N)c(C)c(F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(F)c(C)c(NCC#N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-amino-5-fluoro-4-methyl-benzoic acid, ethyl ester (Example 169b, 1.2 g) in THF (10 mL) at room temperature was added N-ethyldiisopropylamine (1.28 mL) followed by bromoacetonitrile (0.51 mL) and the reaction was heated at reflux for 14 h. Additional bromoacetonitrile (0.21 mL) was added and the mixture was heated at reflux for 6 h. Further bromoacetonitrile (0.21 mL) was added and heating was continued for a further 12 h. After cooling to room temperature the reaction was concentrated. Aqueous HCl (30 mL, 1N) and ethyl acetate (30 mL) were added. The layers were separated and the organic fraction was dried (Na2SO4), filtered and concentrated to give the subtitle product (1.43 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:31]1([CH3:41])[C:32]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[CH3:41][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:23])=[O:24])(=[O:39])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)Nc1ccc(N2CCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
2-Methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and o-toluenesulfonylchloride is (46 mg, 0.239 mmol) according to general method 3 to give before Boc-deprotection 160 mg of a purple solid. MS (posES-FIA) m/z=Found 487.1; Calcd 487.14; 1H-NMR δ 7.74-7.16 (m, 8H), 6.78-6.52 (m, 4H), 3.27-3.16 (m, 8H), 2.58 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:20]([OH:22])=O)[CH3:19])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[S:23]1[CH2:27][CH2:26][NH:25][CH2:24]1>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:20]([N:25]2[CH2:26][CH2:27][S:23][CH2:24]2)=[O:22])[CH3:19])=[O:16])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C1CSCN1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](C)C(=O)N1CCSC1

Procedure:
Following General Procedure C and using N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7 above) and thiazolidine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.25 in 9:1 CHCl3/MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[C:24]4[N:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH2:18][CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cccnc21
Product: CC1c2ncccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1.[CH2:26]([OH:29])[C:27]#[CH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:28]#[C:27][CH2:26][OH:29])=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1
Reactant: C#CCO
Reactant: O=C1Cc2cnc(Nc3ccc(I)cc3)nc2-c2ccc(Cl)cc2N1
Product: O=C1Cc2cnc(Nc3ccc(C#CCO)cc3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for Method O, 9-chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-36) and prop-2-yn-1-ol were converted to I-54 (86%): HRMS Calcd. for C21H11ClN4O2: 391.0961, Found 391.0960.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(O)=O.[CH3:27][C:28]1[CH:32]=[C:31]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]2=[O:46])[S:30][C:29]=1[C:47]([OH:49])=O.[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>>[CH3:27][C:28]1[CH:32]=[C:31]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]2=[O:46])[S:30][C:29]=1[C:47]([NH:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)=[O:49]
Reactant: Cc1cc(N2CCN(CCc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(CCc3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 74 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 3-methyl-5-(2-oxo-3-phenethylimidazolidin-1-yl)thiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 74% yield: mp 95-97° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (d, J=2.2 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.35-7.18 (m, 6H), 6.12 (t, J=5.6 Hz, 1H), 6.05 (s, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.77-3.70 (m, 2H), 3.54 (t, J=7.4 Hz, 2H), 3.46-3.39 (m, 2H), 2.88 (t, J=7.4 Hz, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.6, 155.8, 149.2, 148.8, 142.6, 141.8, 138.4, 135.5, 134.1, 128.6, 126.6, 123.6, 118.7, 112.2, 45.5, 42.8, 42.6, 41.2, 34.1, 16.0; MS (ES+) m/z 421.3 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([O:20][C@@H:21]([CH3:24])[CH2:22][OH:23])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[OH:23][CH2:22][C@@H:21]([O:20][C:18]1[CH:17]=[C:12]([CH:11]=[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])[CH3:24]
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)CO)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.3 %

Procedure:
Bromomethylbenzene (1.89 g, 7.20 mmol) was added to a mixture of methyl 3-hydroxy-5-[(2S)-1-hydroxypropan-2-yl]oxy-benzoate (1.55 g, 6.86 mmol) and potassium carbonate (1.89 g, 0.014 mol) in DMF (16 mL) and the reaction stirred at RT for 20 hours. Ethyl acetate (40 mL) was added and the mixture washed with water (40 mL), saturated sodium bicarbonate solution (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give the desired compound (1.7 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:36]1[CH:41]=[N:40][CH:39]=[C:38]([CH3:42])[N:37]=1>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:41]=[N:40][CH:39]=[C:38]([CH3:42])[N:37]=2)[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1cncc(Cl)n1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Product: Cc1cncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)n1
Yield: 83 %

Procedure:
The title compound was synthesized as described for Intermediate example I-28 in 83% yield starting from (S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-amine and 2-chloro-6-methylpyrazine (1.1 equiv); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (s, 1 H), 8.54-8.56 (m, 1 H), 7.24-7.34 (m, 8 H), 7.16-7.22 (m, 3 H), 6.99 (dd, 1 H), 6.86 (dd, 1 H), 4.31-4.37 (m, 1 H), 4.07 (t, 1 H), 3.64-3.73 (m, 4 H), 3.12-3.21 (m, 1 H), 2.92-3.02 (m, 1 H), 2.64-2.73 (m, 1 H), 2.55 (s, 3 H); MS (APPI/APCI) m/z 422[M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1c(=O)ccc2cc(Br)ccc21
Yield: 100 %

Procedure:
6-Bromoquinolin-2(1H)-one (5.03 g, 22.5 mmol) was subjected to protocol K with ethyl bromoacetate instead of methyl bromoacetate to afford 6.96 g (100% yield) of ethyl 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetate as a white solid. Method [7] Retention time 4.79 min by HPLC (M+=310 and 312) and (M+Na=332 and 334). The acetate (318 mg, 1.03 mmol) was subjected to the protocol in Example 1.53.4 to afford 228 mg (83% yield) of 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetic acid as a white solid. Method [8] Retention time 4.79 min by HPLC (M+=282 and 282) and (M+Na=304 and 306).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]4[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([O:32][CH3:33])[CH:25]=4)[N:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CO>O>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]3[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([O:32][CH3:33])[CH:25]=3)[N:20]=2)=[CH:11]1
Reactant: COc1cc2nc(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)cc(C(=O)O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc2nc(-c3c[nH]c4ccccc34)cc(C(=O)O)c2cc1OC

Procedure:
A stirred solution of (0.547 g) of 2-(N-phenylsulfonylindol-3-yl)-4-carboxy-6,7-dimethoxyquinoline, K2CO3 (0.380 g), MeOH (40 ml) and H2O (10 ml) are heated to reflux. The MeOH is evaporated in vacuo, and the aqueous residue diluted with more H2O, and acidified with 0.1N HCl to pH between 6-7 while contained in an ice-bath. An orange solid precipitates. This is collected, washed with ether then dried under vacuum (0.1 mm at 22° C.) for a few hours to obtain 2-(indol-3-yl)-4-carboxy-6,7-dimethoxyquinoline (m.p. 286° C. dec).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[CH:10][CH:9]=2)[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[CH3:2].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:66]=[N+:67]=[N-:68])(C2C=CC=CC=2)=O)C=CC=CC=1>>[CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:66]=[N+:67]=[N-:68])=[CH:10][CH:9]=2)[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCc1nc2ccccc2n1-c1ccc(CCO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1nc2ccccc2n1-c1ccc(CCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100.9 %

Procedure:
A mixture of 2-[4-(2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (914 mg, 3.4 mmol) in TUF (40 mL) was added diethyl azodicarboxylate (DEAD) (1.2 mg, 7 mmol), triphenylphosphine (1.8 g, 7 mmol) and diphenylphosphoryl azide (DPPA) (1.9 g, 7 mmol). The mixture was stirred at room temperature for 4.5 h. After removal of solvent, the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) to afford 1000 mg (74%) of the title compound as a brown oil: MS (EI) m/z 291 (M+)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](F)=[O:9])=[CH:6][CH:5]=1.[N-:15]=[N+:16]=[N-:17].[Na+].C1OCCOCCOCCOCCOCCOC1.C(#N)C>C(OCC)C>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:15]=[N+:16]=[N-:17])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(F)c1ccc(OC(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: [N-]=[N+]=NC(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
A mixture of 5 grams (24 mmol) of 4-(trifluoromethoxy)benzoyl fluoride, 1.87 grams (29 mmol) of sodium azide, 0.2 grams of 18-Crown-6 ether, and 20 ml. of acetonitrile was stirred at room temperature for two hours under an atmosphere of dry nitrogen. The reaction mixture was diluted with diethyl ether, filtered and concentrated under reduced pressure, with a bath temperature of 40° C., to give the title compound as a turbid oil. IR showed adsorptions at 2280, 2240 and 1695 cm-1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Ca+2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(Cl)Cl.C(Cl)Cl.CO>[N+:29]([C:26]1[CH:25]=[CH:24][C:23]([O:22][C:20](=[O:21])[NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)=[CH:28][CH:27]=1)([O-:31])=[O:30]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A mixture of 4-morpholinoaniline (1.01 g, 5.68 mmol) and CaCO3 (743 mg, 7.42 mmol) (10 micron powder) was treated with a solution of 4-nitrophenyl chloroformate (1.49 g, 7.39 mmol) in DCM (7.5 mL) in one portion under air on an ice bath. The thick, easily stirred reaction slurry was stirred for 1-2 min on the ice bath before stirring at rt for 1 h. The slurry was then diluted with 9:1 DCM/MeOH (7.5 mL) and directly applied to a flash silica column (95:5 DCM/MeOH) to provide 0.7 g of material. This was further purified by trituration with hot toluene (25 mL) to afford the title compound as a light olive green powder (444 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 8.28 (m, 2H), 7.42-7.31 (m, 4H), 6.95-6.85 (m, 3H), 3.86 (m, 4H), 3.13 (m, 4H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[N:16]=[C:15]2[NH:20][N:21]=[CH:22][C:14]=12.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C1COCC1.C(Cl)Cl>[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[N:16]=[C:15]2[N:20]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[N:21]=[CH:22][C:14]=12
Reactant: Clc1nc(Cl)c2cn[nH]c2n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Clc1nc(Cl)c2cnn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
p-Toluene sulfonic acid (p-TsOH, 30.2 mg, 0.159 mmol) was added to a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.587 mmol) and 3,4-dihydro-2H-pyran (200 mg, 2.381 mmol) in a mixture of THF:CH2Cl2 (1:1, 10 mL). The reaction mixture was stirred for 12 h at room temperature after which the solvent was removed in vacuo. The residue was taken up in CH2Cl2 (20 mL) and poured in water (20 mL). The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (20 mL). The combined organic phases were washed with water (40 mL), then washed with brine (40 mL), dried over Na2SO4 and concentrated. The resulting crude material was purified by flash chromatography (CH2Cl2/CH3OH, 99/1 increasing) to yield the title compound (397 mg, 1.454 mmol, 92% yield) as a pale white oil which was used without further purification.