Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([O:22][CH2:23][C:24]([O:26]CC=C)=[O:25])=[O:21])=[C:9]2[CH3:30])=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1>[Pd].C1(C)C=CC=CC=1>[CH3:30][C:9]1[N:8]([C:6]([C:5]2[CH:31]=[CH:32][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:7])[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH3:18])=[CH:12][C:11]=2[C:10]=1[CH2:19][C:20]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21]
Reactant: C=CCOC(=O)COC(=O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1

Procedure:
31.9 g of acemetacin allyl ester, 100 ml of toluene, 2.3 g of triphenylphosphine and 0.75 g of palladium on charcoal (5% strength) are taken as an initial charge, under nitrogen. 11.9 g of piperidine are added dropwise, with stirring, and the mixture is then stirred for a further 3 hours at 90° C. It is filtered hot and the catalyst is rinsed with hot toluene. The filtrate is evaporated, the residue is taken up in methylene chloride (about 300 ml) and this solution is washed with half-concentrated hydrochloric acid (100 ml) and then with water. After removal of the solvent in vacuo, the residue is recrystallized from toluene.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH2:14]([N:21]1[C:1](=[O:13])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Solvent: O
Product: O=C1Cc2ccccc2C(=O)N1Cc1ccccc1

Procedure:
A mixture consisting of homophthalic acid (25 g, 0.139 mol) and benzylamine (15.2 ml, 14.91 g, 0.139 mol) was heated at 165°-180° C. for two hours, producing a vigorous release of water vapor. Cooling afforded a hard green solid which was pulverized, triturated with diethyl ether, and isolated by filtration to afford the title compound as a light-green granular solid (29.4 g) used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=CC=1.[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]2[S:16][CH:10]=[CH:15][CH:14]=2)[N+:3]=1[O-:9]
Reactant: Sc1ccccc1
Reactant: [O-][n+]1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: [O-][n+]1c(Cl)cccc1-c1cccs1

Procedure:
The 1.64 g (0.010 moles) of 2,6-dichloropyridine N-oxide and 1.11 g (99%) (0.010 moles) of thiophenol was reacted with 0.400 g (0.010 moles) of ground sodium hydroxide of 16.4 ml of DMSO at 80° C. for 5 hours to give 2-chloro-6-thiophenylpyridine N-oxide. It was reacted with 1.20 g (0.030 moles) of ground sodium hydroxide at 80° C. for 2.5 hours to give 1-hydroxy-6-thiophenylpyridine-2(1H)-one. After cooling, it was added 148 ml of water and was adjusted with 6N HCl to pH 3. The precipitate was filtered, washed with water and washed with hexanes to give 1.64 g (75%). It was recrystallized from ethanol: mp 180°-181° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)[CH:3]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cc1cccc(Br)c1
Product: Cc1cccc(C2(O)CCC3(CC2)OCCO3)c1

Procedure:
The title compound was prepared as a white solid from 3-bromotoluene (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]([CH3:20])[CH:9]([CH:17]([CH3:19])[CH3:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([F:23])[CH:4]=1)#[N:2].[NH2:24][OH:25]>C(O)C.O>[NH2:2][C:1](=[N:24][OH:25])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]([CH3:20])[C@H:9]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH:17]([CH3:19])[CH3:18])=[C:5]([F:23])[CH:4]=1
Reactant: NO
Reactant: CC(C)C(C(=O)OC(C)(C)C)N(C)Cc1ccc(C#N)cc1F
Solvent: CCO
Solvent: O
Product: CC(C)[C@@H](C(=O)OC(C)(C)C)N(C)Cc1ccc(C(N)=NO)cc1F
Temperature: -20 °C
Reaction time: 12 h

Procedure:
To a stirred solution of tert-butyl 2-[(4-cyano-2-fluorobenzyl)(methyl)amino]-3-methylbutanoate (3.4 g, 0.011 mol), in ethanol (30 mL), was added 50% aqueous. hydroxylamine (1.4 mL, 0.021 mol). The mixture was stirred at −20° C., for 12 h. The reaction mixture was diluted with water and extracted in dichloromethane (100 mL), dried over Na2SO4 and concentrated under reduce pressure. The solid was recrystallised with ethyl acetate (5 mL), filtered and dried under vacuum, affording the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.73 (s, 1H), 7.49 (m, 1H), 7.38 (m, 2H), 5.85 (s, 2H), 3.71 (d, J=14.2 Hz, 1H), 3.57 (d, J=14.2 Hz, 1H), 2.66 (d, J=10.7 Hz, 1H), 2.18 (s, 3H), 1.99-1.93 (m, 1H), 1.45 (s, 9H), 0.91-0.81 (m, 6H). LC/MS (Method B) 354.3 (M+H)+. HPLC (Method A) Rt: 2.66 min (Purity 98.6%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][C:6](=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.COC(=O)CN.CN1CCOCC1.[F:31]C1C=CC(C=CC(O)=O)=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>O1CCCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][C:6](=[O:15])[CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([F:31])=[CH:13][CH:14]=1
Reactant: COC(=O)CNC(=O)C=Cc1ccccc1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COC(=O)CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)C=Cc1ccc(F)cc1
Temperature: 0 °C

Procedure:
Following the general procedure described in example 1, step 2, for cinnamoyl-glycine methyl ester, glycine methyl ester hydrochloride (7.5 g) was suspended in tetrahydrofuran, cooled to 0° C., treated with N-methylmorpholine (8.4 ml, 1 equivalent), followed immediately by a precooled solution of 4-fluorocinnamic acid (10.0 g) in tetrahydrofuran, which had been pre-activated by treatment with dicyclohexylcarbodiimide (12.4 g, 1 equivalent) and 1-hydroxybenzotriazole (9.2 g). After work-up, 4-fluorocinnamoyl-glycine methyl ester was obtained as a white solid which was used for the next step without further purification.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([NH:31][C:32]1[S:33][CH2:34][C@@H:35]2[CH2:41][C@H:40]([C:42]([NH:44][CH:45]([CH3:48])[CH2:46][OH:47])=[O:43])[O:39][CH2:38][C@:36]2([C:49]2[CH:54]=[C:53]([Br:55])[CH:52]=[CH:51][C:50]=2[F:56])[N:37]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)C>[C:23]([NH:31][C:32]1[S:33][CH2:34][C@@H:35]2[CH2:41][C@H:40]([C:42]([NH:44][CH:45]([CH3:48])[CH:46]=[O:47])=[O:43])[O:39][CH2:38][C@:36]2([C:49]2[CH:54]=[C:53]([Br:55])[CH:52]=[CH:51][C:50]=2[F:56])[N:37]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(CO)NC(=O)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)ccc2F)CO1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C=O)NC(=O)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)ccc2F)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dess-Martin periodinane (1.04 g, 2.44 mmol) was added to a solution of (4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-N-(1-hydroxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxamide (C38) (0.897 g, 1.63 mmol) in dichloromethane (75 mL). The resulting solution was left stirring overnight at room temperature. The reaction mixture was diluted with diethyl ether (100 mL), a saturated aqueous solution of sodium bicarbonate (50 mL) and a 10% aqueous solution of sodium thiosulfate (50 mL). The layers were separated and the resulting aqueous layer was further extracted with diethyl ether (2×100 mL). The combined organics were then washed with water (100 mL), brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product as a white solid. Yield 747 mg, 84%. LCMS m/z 532.1 [M+H+]. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ 9.47 (d, J=6.7 Hz, 1H), 8.11 (br d, J=6.7 Hz, 2H), 7.46-7.60 (m, 4H), 7.18 (dd, J=12.1, 9.2 Hz, 1H), 4.19-4.31 (m, 2H), 4.01-4.13 (m, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:21][CH2:22][O:23][C:24]([CH2:26][CH:27]1[C:32](=O)[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:28]3[CH:27]([CH2:26][C:24]([O:23][CH2:22][CH3:21])=[O:25])[CH2:32][CH2:31][CH2:30][C:29]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(C(C)C)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-isopropylphenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared as a mixture of ethyl and isopropyl esters.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]([S:18][CH:19]([CH3:35])[CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])=[S:17])[NH:13][C:12]1=[O:36])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[C:38]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)(=[O:41])[CH:39]=[O:40]>C1C=CC=CC=1>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]([S:18][CH:19]([CH3:35])[CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=2)=[O:23])=[S:17])[N:13]([CH:39]([OH:40])[C:38]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=2)=[O:41])[C:12]1=[O:36])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 74.7 %

Procedure:
A mixture of 230 mg (0.40 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-[1-methyl-2-p-nitrobenzyloxycarbonylaminoethylthio(thiocarbonyl)]thioazetidin-2-one, 182 mg (0.80 mmole) of p-nitrobenzyl glyoxylate hydrate and 5 ml of benzene was heated under reflux for 10 hours. After completion of the reaction the solvent was distilled off and the resulting residue was subjected to column chromatography through 10 g of silica gel eluted with a 7-10% v/v solution of ethyl acetate in benzene to afford 234 mg (yield 75%) of the desired product as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][N:25]4[CH2:30][C:31](O)=[O:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[CH:36]1[CH:37]=[CH:38][C:39]2[N:44](O)N=[N:42][C:40]=2[CH:41]=1.CCN=C=NCCCN(C)C.Cl.N1C=CC=CC=1CN.C([O-])(O)=O.[Na+]>CN(C=O)C>[N:42]1[CH:38]=[CH:37][CH:36]=[CH:41][C:40]=1[CH2:39][NH:44][C:31](=[O:32])[CH2:30][N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([F:14])([F:12])[F:13])=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: On1nnc2ccccc21
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)O)no2)cc1C(F)(F)F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NCc1ccccn1
Solvent: CN(C)C=O
Product: CC(Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)NCc3ccccn3)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of (4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetic acid (150 mg) and HOBt (65 mg) in DMF (1.5 ml) was added EDCI/HCl (69 mg) at 0° C., followed by stirring at room temperature for 1 hour. After cooling to 0° C. again, 1-pyridin-2-ylmethanamine (39 mg) was added thereto, followed by stirring at room temperature for 15 hours. To the reaction solution was added a saturated aqueous NaHCO3 solution to complete the reaction. It was extracted with EtOAc, the organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH 100:0 to 95:5) to obtain N-(pyridin-2-ylmethyl)-2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (157.8 mg) as a white solid. To a solution of N-(pyridin-2-ylmethyl)-2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (120 mg) in methylene chloride (2.4 ml) was added dropwise 10 equivalents of 4M HCl/dioxane, followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, and powdered/washed with IPE. The obtained solid was collected by filtration, and dried to obtain N-(pyridin-2-ylmethyl)-2-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide hydrochloride (126 mg) as a white solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]([C:12]2[NH:13][CH:14]=[CH:15][CH:16]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]([C:12]2[NH:13][C:14]([C:20]([C:19]3[C:18]([Cl:17])=[N:26][CH:25]=[CH:24][CH:23]=3)=[O:21])=[CH:15][CH:16]=2)=[O:11])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)c1ccc[nH]1)c1ccccc1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: C[C@H](NC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of 1H-pyrrole-2-carboxylic acid ((S)-1-phenyl-ethyl)-amide (800 mg, 3.7 mmol) and 2-chloronicotinoyl chloride (95 mg, 5.4 mmol) in dry benzene (10 mL) at 0° C. was added dropwise a solution of tin (IV) chloride (1.75 g) in benzene (5 mL). The mixture was allowed to warm up slowly to room temperature and stirred for overnight. The reaction was concentrated, diluted with ethyl acetate, washed with water, 1N NaOH, brine, dried and concentrated. The residue was purified on a silica gel column to give 458 mg (35%) of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid ((S)-1-phenyl-ethyl)-amide.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23](OS(C)(=O)=O)[CH2:22][C@H:21]1[C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:22][C@H:21]1[C:30](=[O:34])[N:31]([CH3:32])[CH3:33])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(CS)cc1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
151 mg of sodium hydroxide (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 532 mg of 4-methoxybenzyl mercaptan dissolved in 10 ml of dry dimethylformamide. The mixture was then stirred at room temperature for 30 minutes, after which 1.05 g of (2S, 4R)-1-(t-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)-4-methanesulfonyloxypyrrolidine [prepared as described in step (2) above] was added. The reaction mixture was then stirred at room temperature for 30 minutes and then at 40° C. for 6 hours. At the end of this time, it was treated and purified according to the procedure described in Preparation 1-(4), to afford 385 mg of the title compound as an oil.
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.C(O)(C)(C)C.[F:30][C:31]1[C:40]([CH2:41]C(O)=O)=[C:39]([F:45])[CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[N:36]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.Cl>O1CCOCC1.CCOCC.ClCCl.C(OCC)(=O)C>[F:30][C:31]1[C:40]([CH2:41][NH2:15])=[C:39]([F:45])[CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[N:36]2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)Cc1c(F)cc2ncccc2c1F
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NCc1c(F)cc2ncccc2c1F
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Diphenyl phosphoryl azide (0.5 ml, 2.32 mmol), triethylamine (0.34 ml, 2.43 mmol) and tert-butanol (1.3 ml, 13.78 mmol) were added to a solution of the product from step 1 (0.5 g, 2.24 mmol) in dioxan (6.5 ml) and heated at 110° C. for 4 h. The mixture was cooled to RT and distributed between ethyl acetate and aq, 10% citric acid. The organic layer was separated, dried over Na2SO4 and concentrated to leave a brown residue which was dissolved in dioxane (5 ml) and dichloromethane (1.5 ml) and treated with ether saturated with HCl (10 ml) and stirred at RT overnight. After removing the solvents completely, aq, NaHCO3 was added to the residue and extracted into ethyl acetate, the organic layer dried over Na2SO4 and the solvent was removed. Purification of the residue by column chromatography gave the title compound as a mixture containing ca. 35 mol % of 1,3-bis((5,7-difluoroquinolin-6-yl)methyl)urea, which was used as such in the next step. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ8.95 (d, J=3.8 Hz, 2H); 8.45 (dd, J=7.5, 5.2, 2H): 7.65 (d, J=10.9, 2H); 7.59 (dd, J=8.29, 4.2, 2H); 6.50 (t, J=5.6, 1H), 4.44 (d, J=5.6, 2H); 3.90 (s, 2H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]1([CH2:17][NH:18][C:19]2[O:20][C:21]3[CH:27]=[C:26]([O:28][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]([NH2:37])=O)[CH:30]=4)[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([CH2:17][NH:18][C:19]2[O:20][C:21]3[CH:27]=[C:26]([O:28][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:37])[CH:30]=4)[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: NC(=O)c1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Reaction time: 0.25 h

Procedure:
To a solution of the methylsulfoxide (32 mg, 0.41 mmol, 6.0 eq) in 1 mL of methylene chloride was added oxalyl chloride (2M, 0.135 mL, 0.27 mmol, 4.0 eq) at −78° C. After 15 minutes, the 4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carboxamide (25 mg, 0.068 mmol, 1.0 eq) in 2 mL of methylene chloride was added to the reaction mixture. After being stirred at that temperature for 20 minutes, triethyl amine (83 mg, 0.83 mmol, 12 eq) was added to mixture. The reaction mixture was stirred at −78° C. for 2 hours, and then was quenched with aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was purified by reverse phase prep HPLC to give the title compound. MH+=349.0.
Reaction SMILES: BrC1C=CC([C:8]2[C:13]3[O:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[CH:11]=[CH:10][CH:9]=2)=CC=1.Br[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Br:32])[CH:28]=2)[CH:23]=1>>[Br:32][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C:18]1[CH:19]=[CH:20][C:15]3[O:14][C:13]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:16]=3[CH:17]=1)[CH:31]=[CH:30]2
Reactant: Brc1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: Brc1ccc2cc(Br)ccc2c1
Product: Brc1ccc2cc(-c3ccc4oc5ccccc5c4c3)ccc2c1

Procedure:
2-(6-bromonaphthalen-2-yl)dibenzofuran was synthesized in the same manner as in the synthesis of 4-(4-bromophenyl)dibenzofuran except that 2,6-dibromonaphthalene was used instead of 4-bromoiodobenzene.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C:6](=C)[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.C[OH:17]>>[OH:1][CH2:2][C@H:3]1[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:5][C:6](=[O:17])[CH2:7]1
Reactant: C=C1C[C@@H](CO)[C@H](c2cccc(F)c2)C1
Reactant: CO
Product: O=C1C[C@@H](CO)[C@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (+)-trans-1-hydroxymethyl-4-methylene-2-(3-fluorophenyl)cyclopentane from Step C (1.87 g, 9.0 mmol) in methanol (75 mL) was cooled in a dry ice/acetone bath and ozone was bubbled into the solution until the blue color persisted. The excess ozone was removed with a stream of nitrogen and then dimethylsulfide (5 mL) was added. After 10 min, the bath was removed and the reaction was allowed to warm to rt over 2 h. The mixture was treated with 10 drops of sulfuric acid (c) in water (2 mL) for 1 h before most of the methanol was removed in vacuo. The mixture was diluted with water and extracted twice with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (50% ethyl acetate in hexanes) to give the title compound (1.87 g) ), [α]D=+132 (MeOH, c=1.2),.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1)=O>Cl>[CH:13]1([CH2:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH2:5])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1
Reactant: CC(C)(C)C(=O)Nc1ccccc1CC1NCCc2ccccc21
Agent: Cl
Product: Nc1ccccc1CC1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A stirred solution of 2,2-dimethyl-N-[2-(1,2,3,4-tetrahydro-1-isoquinolinyl)methylphenyl]propanamide (12.5 g) and 6N hydrochloric acid solution (240 ml) was refluxed for 101/2 hours and then allowed to stand overnight (about 16 hours) at room temperature. On cooling to room temperature a colorless solid separated. The mixture was decanted over crushed ice, water (300 ml) was added, and the mixture was basified with 50% sodium hydroxide solution. The turbid mixture was extracted thrice with 200 ml portions of CH2Cl2, and the combined dried (Na2SO4) organic phase was filtered and concentrated to an oil (10.15 g). On standing at 5° C. for 36 hours, a small amount of crystalline material formed. The oil was triturated with hexane and the crystalline material stirred into the oil, which resulted in complete solidification of the oil. The solid was collected by vacuum filtration, washed with hexane and dried in vacuo at room temperature to give 8.94 g (72%) of 2-[(1,2,3,4-tetrahydro-1-isoquinolinyl)methyl]benzenamine as a solid, m.p. 69°-71° C.