Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[F:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH:43]2[CH2:48][CH2:47][N:46]([C:49]3[C:55]([O:56][CH3:57])=[CH:54][C:52]([NH2:53])=[C:51]([O:58][CH3:59])[CH:50]=3)[CH2:45][CH2:44]2)[CH2:39][CH2:38]1.N>CC(O)C.Cl.CO>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:53][C:52]3[CH:54]=[C:55]([O:56][CH3:57])[C:49]([N:46]4[CH2:45][CH2:44][CH:43]([N:40]5[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][F:34])[CH2:42][CH2:41]5)[CH2:48][CH2:47]4)=[CH:50][C:51]=3[O:58][CH3:59])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(OC)cc1N
Agent: Cl
Agent: N
Solvent: CO
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(OC)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 32.1 %

Procedure:
In a 5 mL microwave vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2,5-bis(methyloxy)-aniline (0.190 g, 0.520 mmol) were taken up in iPrOH (3 mL) and concentrated HCl (4 drops) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo. The resulting residue was taken up in DCM and purified by column chromatography using basic alumina followed by silica gel flash chromatography. The desired fractions were concentrated and the resulting solid was triturated with DCM and hexane, filtered and vacuum dried to give the title compound (0.110 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=5.1 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.26-7.53 (m, 3H), 7.13-7.27 (m, 2H), 6.84-7.08 (m, 1H), 6.66 (s, 1H), 6.50 (d, J=5.1 Hz, 1H), 4.56 (t, J=4.9 Hz, 1H), 4.45 (t, J=4.9 Hz, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 3.36-3.53 (m, 2H), 2.37-2.74 (m, 12H), 2.13-2.36 (m, 1H), 1.70-1.94 (m, 2H), 1.39-1.69 (m, 2H). MS (M+H, ES+) 792.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C[O-].[Na+]>COCCO.C([O-])(O)=O.[Na+]>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][C@@H:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]([OH:37])=[O:36])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), L-phenylalanine (296 mg, 1.8 mmol) and NaOMe (73 mg, 1.3 mmol) in 2-methoxyethanol (10 mL) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (5-60% EtOAc/hexanes+2% AcOH) to give a crude solid. The solid was dissolved in saturated NaHCO3 and washed with ether. 1 M HCl was added to the aqueous layer until pH was about 1, and the resulting precipitate was isolated by filtration to give 25 mg of the title compound as an off-white solid. MS: (+) m/z 469.26 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)(=[O:10])=[O:9]>CO.Cl>[Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(=O)c2ccc3c(c2)OCO3)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2c(C(=O)c3ccc4c(c3)OCO4)sc3ncccc23)c1Cl
Temperature: 25 °C

Procedure:
A solution of N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxy-methyl)-2-[3,4-(methylenedioxy)benzoyl]thieno[2,3-b]pyridine-3-sulfonamide (0.15 g, 0.26 mmoles) in methanol (5 ml) and 4N HCl (2 ml) was heated to reflux for 3 hours then cooled to ambient temperature and concentrated. The residue was diluted with EtOAc (50 ml) and washed with saturated NaCl (2×50 ml). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.10 g (81%) of the title compound as a foamy yellow solid, m.p. 75-90° C.
Reaction SMILES: C([N:8]1[C:20]2[C:19]([O:21][CH2:22][CH2:23]Br)=[C:18]3[N:25](C(OC(C)(C)C)=O)[C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][C:31]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:40])[CH:13]=2)(OC(C)(C)C)=O.[NH:41]1[CH:45]=[CH:44][N:43]=[N:42]1>>[N:41]1[N:42]([CH2:23][CH2:22][O:21][C:19]2[C:18]3[NH:25][C:26]4[C:31](=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[C:17]=3[CH:16]=[C:15]3[C:14]4[CH:13]=[C:12]([Cl:40])[CH:11]=[CH:10][C:9]=4[NH:8][C:20]=23)[N:43]=[CH:44][CH:45]=1
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(OCCBr)c21
Product: Clc1ccc2[nH]c3c(OCCn4nccn4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1
Yield: 70 %

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the staring material is 5,7-diBOC-2,10-dichloro-6-(2-bromoethoxy)indolo[2,3-b]carbazole and the reagent is 1,2,3-triazole. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.29 (s, 2H), 8.70 (s, 1H), 8.16 (d, J=2.0 Hz, 2H), 7.88 (s, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.37 (dd, J=8.4, 2.0 Hz, 2H), 4.98 (t, J=6.4 Hz, 2H), 4.71 (t, J=6.0 Hz, 2H); MS (ESI) m/z 434.0 (M−H)−; MS (ESI) m/z 436.0 (M+H)+
Reaction SMILES: Cl[C:2]1[C:3]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][S:14][C:4]=2[N:5]=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[N:7]=1.Cl.[CH3:24][O:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C(O)C>[CH3:24][O:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:3]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][S:14][C:4]=3[N:5]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[N:7]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)Cc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reactant: COCC1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCC1CCN(c2nc(CC(=O)O)nc3scc(-c4ccccc4)c23)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
Ethyl 2-(4-chloro-5-phenyl-thieno[2,3-d]pyrimidin-2-yl)acetate (100 mg, 0.285 mmol), 4-(methoxymethyl)piperidine hydrochloride (52 mg, 0.314 mmol) and triethylamine (0.12 mL, 0.85 mmol) were dissolved in ethanol (4 mL) and heated to 65° C. for 6 hrs. The reaction was then heated to 150° C. in a microwave for 10 min. The reaction was poured over ice and extracted with DCM. The extracts were combined and concentrated in vacuo. The residue was dissolved in non-dry THF (2 mL) and lithium hydroxide monohydrate (48 mg) was added. The reaction was stirred at room temperature overnight then another portion of lithium hydroxide monohydrate was added (10 mg) and the reaction stirred for a further 2 hrs. The reaction mixture was purified on an Isolute NH2 SPE column (eluting ammonia in methanol) to give 2-[4-[4-(methoxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]acetic acid (107 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:26]([Cl:27])=[C:25]([S:28][CH3:29])[CH:24]=[CH:23][C:14]=1[C:15]([C:17]1[CH:18]=[N:19][O:20][C:21]=1[CH3:22])=[O:16]>ClCCl>[Cl:12][C:13]1[C:26]([Cl:27])=[C:25]([S:28]([CH3:29])=[O:9])[CH:24]=[CH:23][C:14]=1[C:15]([C:17]1[CH:18]=[N:19][O:20][C:21]=1[CH3:22])=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C(=O)c2cnoc2C)c(Cl)c1Cl
Solvent: ClCCl
Product: Cc1oncc1C(=O)c1ccc(S(C)=O)c(Cl)c1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
3-Chloroperbenzoic acid (85%, 0.99 g) was added portionwise to a stirred solution of 4-(2,3-dichloro-4-methylsulphenylbenzoyl)-5-methylisoxazole (1.5 g) in dichloromethane (50 ml) whilst naintaining the temperature below -20° C. The mixture was stirred at -20° C. for 1 hour. Dichloromethane (50 ml) was added and the solid was removed by filtration. The filtrate was evaporated to dryness and the residue was chromatographed on silica eluted with a mixture of ethyl acetate and cyclohexane (1:5) to give 4-(2,3-dichloro-4-methylsulphinylbenzoyl)-5-methylisoxazole (compound 46, 0.8 g) as a white solid, mp 125°-126.4° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=O)[CH2:9][C:8](=[O:13])[CH2:7]1.Cl.[NH2:15][CH2:16][C:17]#[C:18][CH3:19].O1CCCC1>C(N(CC)CC)C>[CH3:19][C:18]1[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:11][C:10]=2[N:15]=[CH:16][CH:17]=1
Reactant: CC#CCN
Reactant: O=C1CC(=O)CC(c2cccs2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1cccs1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a mixture of 5-(2-thienyl)cyclohexane-1,3-dione (1.5 g), 1-amino-2-butyne hydrochloride (0.82 g), molecular sieves 4A (3 g) and tetrahydrofuran (30 ml) was added triethylamine (0.78 g). The mixture was stirred at room temperature for 1 hour, refluxed for refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and to the residue was added diphenylether (80 ml), and the mixture was stirred at 250° C. for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 4-methyl-7-(2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (0.67 g).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:37]1[S:38][C:39]2[C:44](=[O:45])[NH:43][N:42]=[CH:41][C:40]=2[N:46]=1.C(O)(C)C>C(N(CC)CC)C>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:37]3[S:38][C:39]4[C:44](=[O:45])[NH:43][N:42]=[CH:41][C:40]=4[N:46]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[O:11])=[CH:32][CH:33]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=c1[nH]ncc2nc(Cl)sc12
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3cn[nH]c(=O)c3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Yield: 92.7 %

Procedure:
To a mixed solution of the compound (26 mg) obtained in Example 783, the compound (10 mg) obtained in Step 6 and isopropanol (1.0 ml) was added triethylamine (14 μl) at room temperature, and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:20, developed twice) to give the title compound (31 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].CN(C=O)C.CC#N.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:33][CH:34]1[CH2:36][CH2:35]1
Reactant: O=C(CCc1ccc(O)c(Cl)c1)C1CCCC1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(OCC2CC2)c(Cl)c1)C1CCCC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of 3-(3-chloro-4-hydroxyphenyl)-1-cyclopentylpropan-1-one ((25 g, 0.099 mol, from Step 2) in 1:1 DMF/CH3CN (200 mL) was treated with K2CO3 (15 g, 0.109 mol, 1.1 equiv), and the mixture stirred for 15 min. A solution of (bromomethyl)cyclopropane (17.4 g, 0.129 mol, 1.3 equiv) in DMF (50 mL) was added dropwise, and the reaction mixture heated to 100° C. for 1 h. The volatiles were removed in vacuo. The residue was dissolved in a minimal amount of ethyl acetate, and this solution washed with water, dried over Na2SO4, filtered, and evaporated. Chromatographic purification of the residue on silica gel using hexanes/ethyl acetate afforded 29.12 g (96%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[N+:11]([O-])([OH:13])=[O:12].C(OCC)C>C(O)(=O)CC>[N+:11]([C:7]1[C:2]([OH:1])=[C:3]2[S:10][CH:9]=[CH:8][C:4]2=[N:5][CH:6]=1)([O-:13])=[O:12]
Reactant: Oc1ccnc2ccsc12
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Solvent: CCOCC
Product: O=[N+]([O-])c1cnc2ccsc2c1O
Temperature: 110 °C

Procedure:
Commercially available 7-hydroxythieno[3,2-b]pyridine (9.9 g, 65.5 mmol) was dissolved in propionic acid (200 mL) and heated to 110° C., behind a bomb shield. 4.85 mL of fuming nitric acid (90%) was added over 2 minutes, during which time a copius precipitate formed. The thick suspension was brought to reflux (oil bath temperature ˜150° C.) for 1 h during which time an orange gas evolved (Caution: procedure should only be performed in a well ventilated hood). The reaction mixture was allowed to cool to room temperature and 200 mL of diethyl ether was added. The product was collected by filtration, washed with ˜400 mL of water, 300 mL of 1:1 diethyl ether/methanol, and dried to yield 9.5 g, (74%) of A2.1 as a tan powder. M.S. 197 (M+H)+ 100%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH2:10]([NH:17][C:18](=[O:40])[N:19]([C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][C:28]=2[OH:39])[CH:24]=[CH:25][CH:26]=1)[CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:39][C:28]1[CH:29]=[C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:31]=[CH:32][C:27]=1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([N:19]([CH3:20])[C:18]([NH:17][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:40])[CH:22]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCc2cccc(F)c2)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 300 μL (2.4 mmol, 2.6 eq) of 3-fluorobenzyl bromide and 400 mg (0.93 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 3.9 eq) of potassium carbonate at 90° C. for 3 hours, methyl 3-[2-(3-fluorobenzyloxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C(O)(=[O:17])C>O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[C:7](=[O:17])[CH2:8][CH2:9][C:10]2([CH3:14])[CH3:13]
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)C(C)(C)CCC2
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of 7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Intermediate 8, 1.65 g, 8.7 mmol) in 7.5 mL of glacial acetic acid was cooled to 0° C. and treated with a solution of chromium trioxide (2 g, 20 mmol) in 8 mL of acetic acid and 7 mL of water. The reaction mixture was then allowed to warm to ambient temperature and stirred overnight. It was diluted with water and extracted with diethyl ether (×2). The combined organic phase was washed with water (×1), saturated aqueous sodium bicarbonate (×1) and brine (×1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (1.64 g, 93%) as a yellow oil.
Reaction SMILES: Cl[CH:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]([OH:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>C1C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:25]([CH:24]([O:32][CH:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCOC(=O)C(Cl)Sc1ccccc1
Reactant: CCCCCCC=CCC(O)CCCCCCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCC=CCC(CCCCCCC)OC(Sc1ccccc1)C(=O)OCC

Procedure:
Part B. The method of Speckamp et al., Tetrahedron Letters, v. 32, p. 1491 (1991), is employed here. Thus, a solution of ethyl 2-chloro-2-(phenylthio)acetate [prepared according to the method of Bohme et al., Liebigs Annalen der Chemie, p. 51 (1977)], 7-heptadecen-10-ol, andcatalytic zinc acetate dihydrate in benzene is heated to reflux under a Dean-Stark trap until the formation of hydrogen chloride is complete. Workup according to the listed reference affords ethyl 2-(1-heptyl-3-decen-1-oxy)-2-(phenylthio)acetate.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C([Li])CCC.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>O1CCCC1.CCCCCC>[O:1]1[CH2:6][C:5](=[O:7])[N:4]([C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C1COc2cccnc2N1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1COc2cccnc2N1C(=O)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Under an anhydrous atmosphere, a solution of 10 mmol of 2H-pyrido[3,2-b][1,4]oxazin-3-one in 50 ml of tetrahydrofuran is cooled to −78° C. At that temperature, 11 mmol of a 1.6M solution of n-butyllithium in hexane are added dropwise. After 30 minutes' contact at −78° C., 11 mmol of phenyl chloroformate are added dropwise and stirring is maintained for a further 2 hours. After returning to ambient temperature, the solution is hydrolysed and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated. After purification by chromatography on silica gel (petroleum ether/ethyl acetate: 8/2), the expected product is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:34]=[C:33]4[C:13]([CH2:14][CH2:15][C:16]5[N:20]=[C:19]([CH:21]6[CH2:25][CH2:24][CH2:23][N:22]6[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1>ClCCl.C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:34]=[C:33]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([CH:21]6[CH2:25][CH2:24][CH2:23][N:22]6[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2c([nH]1)-c1cc3c(cc1CC2)-c1ccc(Cl)cc1CO3
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(Cl)ccc1-4
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.6 %

Procedure:
To a solution of tert-butyl 2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.9 g, 3.96 mmol) in dichloromethane (35 mL) was added manganese(IV) oxide (17 g, 198 mmol). The reaction mixture was stirred at room temperature for 18 hours, diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield tert-butyl 2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.52 g, 81%). LCMS-ESI+: calculated for C27H26ClN3O3: 475.9; observed [M+1]+: 476.45.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[CH2:14](O)[CH3:15]>C(Cl)Cl>[CH2:14]([O:12][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1)=[O:13])[CH3:15]
Reactant: CCO
Reactant: Cn1ccc2ccc(C(=O)O)cc21
Solvent: ClCCl
Product: CCOC(=O)c1ccc2ccn(C)c2c1
Reaction time: 15 h
Yield: 89 %

Procedure:
A solution of 1.05 g (6.0 mmol) of 1-methyl-1H-indole-6-carboxylic acid in 15 mL of methylene chloride was added to a stirring solution of 1.905 g (10 mmole) of 1-ethyl-3-(3dimethyl-aminopropyl)carbodiimide hydrochloride, 1.20 g (10 mmole) of 4-dirmethylaminopyridine in 20 mL of methylene chloride at room temperature. Ethanol was added and the reaction stirred for 15 h. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with brine and dried on anhydrous magnesium sulfate. Chrorriatographic purification of this material gave 1.08 g (89%) of 1-methyl-1H-indole-6-carboxylic acid ethyl ester as a pale yellow oil.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.[CH3:24][O-:25].[Na+]>>[CH3:24][O:25][C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1
Reactant: C[O-]
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Agent: [Na+]
Product: CCCOc1ccccc1-c1nc2nc(OC)nnc2c(=O)[nH]1

Procedure:
In a similar manner to Example 78, 3-methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4] triazine (0.5 g) was treated for 3 hours with sodium methoxide (prepared from sodium, 0.17 g, and methanol) to afford the title compound, 0.34 g, m.p. 234-235° C. (recrystallized from methanol).
Reaction SMILES: [C:1]1([CH:7]([CH2:25][CH3:26])[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]([C:22]([OH:24])=[O:23])([CH3:21])[CH3:20])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:27]O>C(O)(=O)C>[C:1]1([CH:7]([CH2:25][CH3:26])[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:18][C:19]([C:22]([OH:24])=[O:23])([CH3:20])[CH3:21])=[O:27])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: CCC(C(=O)Oc1ccc(SCC(C)(C)C(=O)O)cc1)c1ccccc1
Solvent: CC(=O)O
Product: CCC(C(=O)Oc1ccc(S(=O)CC(C)(C)C(=O)O)cc1)c1ccccc1

Procedure:
To a solution of 4-(2'-carboxy-2'-methylpropylmercapto)phenyl 2-phenylbutyrate (745 mg, 2 mmol) in 1 mL of glacial acetic acid was added 0.25 mL of 30% H2O2. Additional 0.25 mL aliquots of 30% H2O2 were added at one-half hour intervals until TLC indicated complete consumption of the starting material. The reaction was quenched with 20 mL of H2O, extracted with Et2O (2×25 mL), dried over anhydrous MgSO4 and evaporated to give the sulfoxide containing a residual amount of acetic acid. The residue was suspended in 20 mL of H2O, the mixture was shell frozen and lyophilized to give 506 mg (65%) of the pure product sulfoxide. 1H NMR (CDCl3) δ1.00 (t, 3H, J=7.4 Hz), 1.42 (s, 3H), 1.54 (s, 3H), 1.85-1.99 (m, 1H), 2.16-2.31 (m, 1H), 3.07 (s, 2H), 3.72 (t, 1H, J=7.6 Hz), 7.17 (d, 2H, J=8.7 Hz), 7.32-7.40 (ArH, 5H), 7.70 (d, 2H, J=8.7 Hz), 11.17 (br s, --OH); 13C NMR (CDCl3) δ 11.83, 24.54, 25.71, 26.39, 41.73, 53.26, 68.81, 122.75, 125.60, 127.73, 128.10, 128.98, 138.30, 141.34, 153.11, 172.49, 180.33.