Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.C([Li])CCC.[CH3:44][C:45]([CH3:47])=[O:46].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[C:13]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([C:45]([OH:46])([CH3:47])[CH3:44])=[CH:7][N:6]=3)[N:17]=[CH:16][N:15]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)=O
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(C)(C)O)cn2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 30.4 %

Procedure:
To a solution of N-[6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (300 mg) in tetrahydrofuran (10 ml) is added a 1.6M solution of n-butyl lithium in n-hexane (0.75 ml) at -78° C. The mixture is stirred at -78° C. for 5 minutes, and thereto is added a solution of acetone (58 mg) in tetrahydrofuran (1 ml), and the mixture is warmed to room temperature. The mixture is treated with aqueous ammonium chloride solution, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=2:1~1:1), and recrystallized from ethyl acetate/n-hexane to give 4-tert-butyl-N-[6-{2-(5-(1 -hydroxy- 1 -methylethyl)primidin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl]benzenesulfonamide (88 mg) as crystals.
Reaction SMILES: C[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.Br([O-])(=O)=O.[Na+]>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[CH:5][CH:6]=1
Reactant: COCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Product: O=Cc1ccc(Cl)cc1

Procedure:
In the same manner as in Example 3, the operation was conducted, except that 0.63 g (4 mmols) of p-chlorobenzyl methyl ether was used in place of m-methoxybenzyl alcohol and also 0.2 g (1.35 mmols) of sodium bromate was used. With respect to the components in the reaction solution, the intended p-chlorobenzaldehyde was produced in an area ratio, as determined by gas chromatography, of 91.0%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[C:33]([C:37]1[CH:45]=[CH:44][C:40]([CH:41]=[N:42][OH:43])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:43]/[N:42]=[CH:41]/[C:40]2[CH:44]=[CH:45][C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:38][CH:39]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
To a solution of 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-(3-bromo-propoxy)-benzoic acid methyl ester (0.53 g, 1.00 mmol) and 4-tert-butyl-benzaldehyde oxime (0.20 g, 1.10 mmol) in acetone (35 mL) was added cesium carbonate (1.30 g, 4.00 mmol). The mixture was heated to reflux overnight and then allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and brine and the layers were then separated. The aqueous layer was extracted with two additional portions of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 5/95) to give 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.30 g, 48%) as an off-white solid. 1H NMR (400 MHz, CDCl3); δ 12.52 (s, 1H), 8.51 (d, 1H), 8.48 (s, 2H), 8.06 (s, 1H), 8.04 (s, 1H), 7.99 (d, 1H), 7.47-7.35 (AA′BB′, 4H), 6.67 (dd, 1H), 4.34 (t, 2H), 4.22 (t, 2H), 3.92 (s, 3H), 2.23 (m, 2H), 1.28 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14]O>C(Cl)(=O)C>[Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:14])=[O:8]
Reactant: COc1cc(O)c(Cl)cc1C(=O)O
Reactant: CO
Solvent: CC(=O)Cl
Product: COC(=O)c1cc(Cl)c(O)cc1OC
Temperature: 60 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of 5-chloro-4-hydroxy-2-methoxybenzoic acid (intermediate 52; 4.17 g; 13.69 mmol) in 123 ml of anhydrous methanol, 2.2 ml of acetyl chloride were added. The solution was stirred at 60° C. under nitrogen atmosphere for 18 hrs. The solution was evaporated under reduced pressure and the residue purified by preparative reversed-phase HPLC (Cl2CH2/EtOAc from 100/0 to 80/20), affording 2.2 g (75%) of a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH2:8][N:9]([CH2:11][CH2:12][CH:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])[CH:7]=1.[H-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:20][CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:9]([CH3:10])[CH2:8][C:6]=2[CH:7]=1
Reactant: CN(CCC(O)c1ccccc1)Cc1cc(Cl)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCC(c2ccccc2)Oc2ccc(Cl)cc2C1
Yield: 55.2 %

Procedure:
A mixture of N-(5-chloro-2-fluorophenyl)methyl-N-methyl-3-hydroxy-3-phenylpropylamine (3.1 g), 50% sodium hydride dispersion (480 mg) and DMSO (100 ml) was maintained at 50° under nitrogen for 12 h. The mixture was poured onto water (500 ml) and extracted with ether (3×300 ml) The combined organic extracts were washed, dried and evaporated. Chromatography of the residue on silica (Woelm Grade 1) using ethyl acetate as eluant gave the title compound (1.6 g). This was converted to the tosylate in ether/IPA, m.p. 219°-221°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[CH2:13][C:14]1[C:15]([CH3:20])=[N:16][O:17][C:18]=1[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:20][C:15]1[C:14]([CH2:13][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=2)=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: Cc1noc(C)c1CCl
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc(OCc2c(C)noc2C)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A mixture of 4-hydroxyphenyl acetone (1.5 g), 4-chloromethyl-3,5-dimethylisoxazole (1.6 g) and potassium carbonate (1.5 g) in dimethylformamide (10 ml) was heated and stirred at 60° C. for 18 h. After cooling, the mixture was poured into water and extracted twice with ethyl acetate. The combined solvent phase was washed twice with brine, dried (magnesium sulphate) and then evaporated. The resultant oil was chromatographed on silica using isohexane to 20% ethyl acetate in isohexane mixtures to give the title compound (2.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]([C@H:24]([C:26]3[CH:43]=[CH:42][C:29]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])=[O:31])=[CH:28][CH:27]=3)[CH3:25])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]([C@H:24]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:42][CH:43]=3)[CH3:25])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: C[C@@H](c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1cnc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](c1ccc(C(=O)NCCC(=O)O)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the intermediate from step F (128 mg) in CH2Cl2(2 mL) was added TFA (2 mL). After the reaction was stirred at room temperature for 30 minutes, it was concentrated in vacuo and azeotroped with toluene (3×). The resulting light yellow solid was dissolved in 1,4-dioxane and lyophilized overnight to afford the title compound as a white solid. 1H NMR (CD3OD, 500 MHz) 8.82 (d, J=1.8 Hz, 1H), 8.42 (s, 1H), 8.12 (d, J=8.5 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.93 (t, J=7.3 Hz, 1H), 7.90 (d, J=1.6 Hz, 2H), 7.77 (t, J=7.5 Hz, 2H), 7.71 (d, J=8.3 Hz, 2H), 7.4 (s, 1H), 7.24 (d, J=8.3 Hz, 2H), 7.06 (s, 1H), 5.71 (q, J=6.8 Hz, 1H), 3.66 (t, J=6.9 Hz, 2H), 2.63 (t, J=7.1 Hz, 2H), 2.01 (d, J=6.8 Hz, 3H). LC-MS: 3.68 min; (M+H)=559.1.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=O.[F:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]3[C:20](=[O:33])[C:21]([CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[C:22]([OH:25])[C:23]([OH:24])=[C:16]3[C:15]2=[O:34])=[CH:11][CH:10]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CN(C=O)C>C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]3[C:20](=[O:33])[C:21]([CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([C:2](=[O:1])[C:4]([F:7])([F:6])[F:5])[CH2:31][CH2:32]4)=[C:22]([OH:25])[C:23]([OH:24])=[C:16]3[C:15]2=[O:34])=[CH:35][CH:36]=1
Reactant: O=C1c2c(O)c(O)c(CC3CCNCC3)c(=O)n2CCN1Cc1ccc(F)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1c2c(O)c(O)c(CC3CCN(C(=O)C(F)(F)F)CC3)c(=O)n2CCN1Cc1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 2-(4-fluorobenzyl)-8,9-dihydroxy-7-(piperidin-4-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione mono TFA salt [50 mg, 0.125 mmol; Example 31 (Step 3)] in methylene chloride (2 mL), pyridine (12 μL, 0.149 mmol), trifluoroacetic anhydride (26 mg, 0.149 mmol) and a couple drops of DMF were added. After one hour, the reaction mixture was concentrated under vacuum, and the residue was purified by prep HPLC [Gilson semi preparative HPLC system using a Waters Nova Pak column (10×40 mm I.D. cartridge, C18, 6 μM pore size) eluting with 95-5% water (0.10% TFA)/acetonitrile (0.10% TFA) gradient at 35 mL/min]. The product fractions were collected and lyophilized to provide the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]([NH2:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.N1([S:19](N2C=C[N+](C)=C2)(=[O:21])=[O:20])C=CN=C1.FC(F)(F)S([O-])(=O)=O>CC#N>[CH2:2]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[NH:13][S:19](=[O:21])(=[O:20])[NH:1]1
Reactant: NCc1ccc2cccnc2c1N
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: O=S1(=O)NCc2ccc3cccnc3c2N1
Yield: 6 %

Procedure:
7-Aminomethyl-quinolin-8-amine (Intermediate 211) (50 mg, 0.29 mmol) and 1-(1H-imidazole-1-sulfonyl)-3-methyl-1H-imidazol-3-ium; trifluoromethanesulfonate (157 mg, 0.43 mmol) in MeCN (5 ml) was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The crude residue was purified by preparative HPLC (basic conditions) to give the title compound (4.5 mg, 6%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:32]([N:40]2[CH2:51][CH2:50][N:49]3[C:42](=[CH:43][C:44]4[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=43)[C:41]2=[O:54])=[N:33][CH:34]=[CH:35][C:36]=1B(O)O)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:26]([O:29][CH2:30][C:31]1[C:32]([N:40]2[CH2:51][CH2:50][N:49]3[C:42](=[CH:43][C:44]4[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=43)[C:41]2=[O:54])=[N:33][CH:34]=[CH:35][C:36]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOC[C@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 29.4 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 249a (407 mg, 1.0 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (800 mg, 2.0 mmol), K3PO4 (424 mg, 2.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (73 mg, 0.1 mmol), sodium acetate (164 mg, 2.0 mmol), acetonitrile (8 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 1.5 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (20 mL). The aqueous layer was separated and extracted with dichloromethane (20 mL×3). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 249b (200 mg, 29%) as yellow solid. MS-ESI: [M+H]+ 680.1
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([O:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([O:37][CH2:38][CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)=[CH:29][CH:28]=2)=[O:6])[N:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[N:11]=1)([CH3:22])([CH3:23])[CH3:21]
Reactant: Nc1ccc(OCCCc2ccncc2)c2ccccc12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCCc3ccncc3)c3ccccc23)cc1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26 mmol), 1-amino-4-(3-pyridin-4-ylpropoxy)naphthalene (26 mmol), diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:12])[CH3:11])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[C:4]=1[NH:9][C:10](=[O:12])[CH3:11])[CH3:2]
Reactant: CCc1ccccc1NC(C)=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCc1cccc([N+](=O)[O-])c1NC(C)=O
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To a mixture of N-(2-ethylphenyl)acetamide (6.2 g, 38 mmol) in acetic acid (50 mL) was added dropwise fuming HNO3 (13 mL, 310 mmol) at a temperature of 50° C. to 55° C. The mixture was allowed to react at 55° C. for 2 hours and was subsequently cooled to RT, poured onto ice, and extracted with DCM. The organic layer was washed with water until the pH of the aqueous phase was >7. The organic layer was washed again with water, dried over Na2SO4, and the solvent evaporated. The residue was purified using flash chromatography eluting with MeOH/DCM (1:400) to give the title compound as a yellow solid (2.4 g, 30%; 48% purity). 1H NMR (400 MHz, CD3OD) δ 7.75 (1H, d, J=7.6 Hz), 7.62 (1H, d, J=7.6 Hz), 7.43 (1H, t, J=7.6 Hz), 2.71 (2H, q, J=7.6 Hz), 2.14 (3H, s), 1.21 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:68][CH:69]=[CH2:70].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:70][CH:69]=[CH2:68])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CC1OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (820 mg in 9 ml 33% methylene chloride in cyclohexane) allyl trichloroacetimidate (366 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (16 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 17 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×15 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ether:hexane (2:3)) gave the title compound (800 mg). (1H NMR was consistent with the desired structure).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].C[N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1C=O>>[CH2:17]([N:13]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:10]=[C:14]1[CH3:15])[CH3:16]
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: Cn1cccc1C=O
Agent: [Na+]
Product: CCn1c(C)cc2ccccc21
Yield: 94 %

Procedure:
Following a procedure similar to that described in Example 1A but employing 6.3 g. of 85% sodium p-toluenesulfinate, 2.2 g. of 98% 1-methylpyrrole-2-carboxaldehyde and 3.8 g. of 94% 1-ethyl-2-methyl-1H-indole, there was obtained 8.4 g. of 3-[(1-methyl-2-pyrrolyl)(4-methylphenylsulfonyl)methyl]-1-ethyl-2-methyl-1H-indole, m.p. 180° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1>C(OCC)(=O)C.[Br-].[Zn+2].[Br-]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH:27][C:39]3[CH:44]=[N:43][CH:42]=[CH:41][N:40]=3)[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:31]=[C:32]([CH3:37])[CH:33]=[C:34]([CH3:36])[CH:35]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Clc1cnccn1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(Nc4cnccn4)c(Cl)cc3[nH]c2=O)c1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a suspension of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (prepared essentially as described in Example 1, 100 mg in 1 mL chloropyrazine) was added 500 mg zinc bromide and the mixture heated to 150° C. on an oil bath. After 3 hours, the mixture was cooled to room temperature, diluted with ethyl acetate and filtered through diatomaceous earth. The volatile organics were removed in vacuo and the residue dissolved in ethyl acetate, washed with water and the organic portion dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 1:1) to give the title compound (12 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Br:12]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1C(=O)O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1cc(F)ccc1CBr
Temperature: 78 °C
Yield: 96.7 %

Procedure:
A suspension of 5-fluoro-2-methylbenzoic acid (500 mg, 3.24 mmol), N-bromosuccinimide (606 mg, 3.41 mmol) and benzoyl peroxide (47 mg, 0.195 mmol) in tetrachloromethane (10 mL) was heated at 78° C. for 4 h. The hot mixture was filtered and the filtrate was concentrated to provide crude 2-(bromomethyl)-5-fluorobenzoic acid as a white solid (730 mg), used without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.81 (1 H, dd, J=9.2, 2.9 Hz), 7.50 (1 H, dd, J=8.5, 5.4 Hz), 7.23-7.30 (1 H, m), 4.98 (2 H, s).
Reaction SMILES: O[CH:2]([C:4]1([O:13]C)[C:8]([O:9]C)=[CH:7][CH:6]([O:11]C)O1)[CH3:3].C(O)=O.O>CO>[CH3:3][C:2]1[O:11][CH:6]=[CH:7][C:8](=[O:9])[C:4]=1[OH:13]
Reactant: COC1=CC(OC)OC1(OC)C(C)O
Solvent: O=CO
Solvent: O
Solvent: CO
Product: Cc1occc(=O)c1O
Yield: 79.3 %

Procedure:
2(1-hydroxy ethyl)-2,3,5-trimethoxy-2,5-dihydrofuran (2.82 g, 0.015 moles) in 2 ml methanol was added to 15 ml of formic acid over 5 minutes. To the well stirred solution was then added 20 ml of water and the reaction heated to reflux for 1 hour. After cooling, the reaction was extracted with chloroform and the chloroform concentrated to yield 1.5 g maltol, which was recrystallized from methanol to yield the pure white solid, m.p. 159°-160° C. Hydrochloric acid, hydrobromic acid, p-toluene sulfonic acid and acidic ion exchange resins can be used in place of formic acid in this Example.