Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:14][CH:15](O)[CH:16]=[CH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:14]([CH:7]1[C:6]([CH3:13])([CH3:12])[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:15]=[CH:16][CH3:17]
Reactant: CC1(C)CC(=O)c2cc(F)ccc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(F)ccc2C1(C)C
Yield: 26 %

Procedure:
A solution of 10.0 g of 6-fluoro-3,3-dimethyl-1-indanone, 11.1 ml of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 200 ml of 2,2-dimethoxypropane was boiled under reflux for 96 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 8:1). In addition to 11.9 g of educt, there were obtained 3.38 g (26%) of (RS)-2-(2-buten-1-yl)-6-fluoro-3,3-dimethyl-1-indanone as a yellow oil.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[H-].[Na+].[CH2:9]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12][C:11](=[O:20])[CH2:10]1.C(O)(=O)C>O1CCCC1.CC(C)([O-])C.[K+]>[CH3:5][O:4][C:1]([CH:12]1[C:11](=[O:20])[CH2:10][CH2:9][C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:13]1)=[O:6]
Reactant: COC(=O)OC
Reactant: O=C1CCC2(CCCCC2)CC1
Agent: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CC2(CCCCC2)CCC1=O
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 106.5 %

Procedure:
To a solution of dimethyl carbonate (17.9 g) in tetrahydrofuran (130 mL) were added 60% sodium hydride (9.9 g) and potassium tert-butoxide (0.14 g). To the mixture was added a solution of spiro[5.5]undecan-3-one (20.6 g) obtained in the same manner as in Step 2 in tetrahydrofuran (120 mL) at 85° C. over 2 hours, followed by stirring the reaction mixture at 85° C. for 1.5 hours. After cooling down to room temperature and adding 15% aqueous acetic acid solution (94.2 mL), the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated to give 3-oxo-spiro[5.5]undecane-2-carboxylic acid methyl ester (29.6 g).
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>CCO>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:16])=[O:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)(C)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C(C)(C)C(=O)O)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
To a solution of 2-(3-methoxy-phenyl)-2-methyl-propionic acid ethyl ester (D98) (20.95 g, 94 mmol, 1 equiv) in EtOH (200 ml) was added 2N NaOH aqueous solution (90 ml, 180 mmol, 1.9 equiv) and the resulting mixture was stirred at 70° C. for 16 h then cooled to room temperature. Most of EtOH was removed in vacuo and the residue extracted with AcOEt then acidified to pH 1. The aqueous phase was then extracted with AcOEt and the organic phase dried over MgSO4 and concentrated in vacuo to give 2-(3-methoxy-phenyl)-2-methyl-propionic acid (D99) (15 g, 82%) as a yellow oil.
Reaction SMILES: C(O[C:4]1[C:5](=[O:14])[C:6](=[O:13])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].[K+].[Br-]>>[C:9]([NH:8][C:7]1[C:6](=[O:13])[C:5](=[O:14])[C:4]=1[NH:20][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[C:16]([F:15])([F:25])[F:26])([CH3:10])([CH3:11])[CH3:12]
Reactant: CCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: NCc1ccccc1C(F)(F)F
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)Nc1c(NCc2ccccc2C(F)(F)F)c(=O)c1=O
Yield: 73 %

Procedure:
The title compound was prepared according to the procedure for example 1-step 2 except that 3-ethoxy-4-(tert-butylamino)-cyclobut-3-ene-1,2-dione was used in place of (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione and 2-trifluoromethyl-benzylamine was used in place of 4-fluoro-benzylamine. Yield: 73%; mp: 237-239° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.37 (m, 9H), 4.81-4.88 (m 2H), 7.56-7.61 (m, 2H), 7.63-7.83 (m, 4H); IR (KBr, cm-1 ): 3299m, 3224m, 3040w, 2976w, 2940w, 1796m, 1670m, 1650m, 1576s, 1534s, 1468s, 1315s, 1216-1127brm; MS (ES) m/z (relative intensity): 349 (M+ +Na, 20), 327 (M+ +H, 100); Anal. Calcd. for C16H17F3N2O2 : C, 58.89; H, 5.25; N, 8.58. Found: C, 58.84; H, 5.28; N, 8.54.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[C:49]1([C:55]2([C:60]([OH:62])=O)[CH2:59][CH2:58][CH2:57][CH2:56]2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:49]1([C:55]2([C:60]([C:16]3[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=3)=[O:62])[CH2:56][CH2:57][CH2:58][CH2:59]2)[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)C2(c3ccccc3)CCCC2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 1-phenyl-1-cyclopentanecarboxylic acid, mp 149°-152° C.
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])[CH2:7][CH2:6][N:5]([C:8]([C@@:10]2([CH:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C@@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.Cl>CCOCC>[NH2:15][C@@H:12]1[CH2:13][CH2:14][C@@:10]([C:8]([N:5]2[CH2:6][CH2:7][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:33])[F:34])([OH:1])[CH2:3][CH2:4]2)=[O:9])([CH:23]([CH3:25])[CH3:24])[CH2:11]1
Reactant: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3C(F)(F)F)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3C(F)(F)F)CC2)CC[C@@H](N)C1
Reaction time: 3.5 h

Procedure:
To a flask containing tert-butyl {(1R,3S)-3-({4-hydroxy-4-[2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-3-isopropylcyclopentyl]carbamate (0.27 g, 0.54 mmol) was added a 2.00 M solution of HCl in ether (5 mL) and the resulting mixture stirred for 3.5 h. The solution was concentrated to give an oil which was used in the next reaction without purification. MS calculated for C21H29F3N2O2: (M+H) 399; found 399.2.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCCCCCO)cc1
Yield: 56.9 %

Procedure:
5.4 g of p-hydroxybenzoic acid was added to ethanol-dioxane mixture solvent, and an aqueous solution containing 6.6 g of potassium hydroxide was added thereto, followed by dropwise addition of 7.9 g of 6-bromohexanol and 12 hours of heat refluxing. The reaction mixture was then acidified, extracted with ethyl acetate and purified by column chromatography to obtain 5.3 g of the product (Yield: 57 %).
Reaction SMILES: N1C=CC=CC=1.N1CCCCC1.[C:13](O)(=O)[CH2:14][C:15]([OH:17])=[O:16].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[F:29])C=O>O>[F:20][C:21]1[CH:22]=[C:23](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)c(F)c1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccc(F)c(F)c1
Temperature: 90 °C
Reaction time: 0.6 h
Yield: 88.1 %

Procedure:
A stirred mixture of pyridine (15.5 kg) and piperidine (0.72 kg) were heated to 90° C. Malonic acid (17.6 kg) was added, followed by slow addition, over 50 minutes, of 3,4-difluorobenzaldehyde (12.0 kg). The reaction mixture was stirred at 90° C. for a further 4 hours and 36 minutes. Water (58.5 kg) was added and 32 litres of the pyridine/water mixture then was distilled out of the reactor under reduced pressure. The reaction mixture was acidified to pH 1 with 37% hydrochloric acid (6.4 kg) over a 40 minute period, then cooled to 25° C. with strong stirring. The solids were collected by filtration, washed twice with 1% hydrochloric acid (34.8 L per wash), once with water (61 L) and then deliquored thoroughly in the filter. The product was then dried under vacuum at 40° C. for 24 hours and 40 minutes, affording 13.7 kg of the crystalline product.
Reaction SMILES: C([O:8][C:9]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=2)[CH:13]=[CH:12][C:10]=1[NH2:11])C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[NH2:11][C:10]1[CH:12]=[CH:13][C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=2)=[CH:15][C:9]=1[OH:8]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OCc3ccccc3)c2)nc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(O)c2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.3 %

Procedure:
To a solution of 2-(benzyloxy)-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}aniline (46 g) in a mixture of tetrahydrofuran (400 mL) and methanol (150 mL) was added palladium on carbon (7 g, 10 weight %, wet), and the mixture was stirred at room temperature for 15 h under hydrogen atmosphere. The mixture was filtered to remove the catalyst and the filtrate was concentrated. The residual solid was washed with methanol-diethyl ether to give the title compound (26.91 g, 84%) as a greenish-gray solid. MS 281 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(#N)C>[CH2:16]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCBr
Reactant: Nc1ccc(S)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCSc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
In 100 ml of acetonitrile was dissolved 5.90 g of 4-aminothiophenol. To the solution were added 6.57 ml of triethylamine and 8.44 g of n-heptylbromide, followed by stirring at room temperature for 18 hours. The precipitated crystals were collected by filtration, followed by removing the solvent. To the residue was added water and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution and dried over anhydrous potassium carbonate. After removing the solvent, the residue was purified by silica gel column chromatography using 50 g of silica gel and using chloroform as eluent to obtain 6.06 g of the titled compound.
Reaction SMILES: C(=O)([O-])O.[Na+].C([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([C:30]([O:32][CH3:33])=[O:31])[N:14]2[S:19]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)(=[O:21])=[O:20])(=O)C.Cl>CO>[Cl:29][C:24]1[CH:23]=[C:22]([S:19]([N:14]2[C:15]3[C:11](=[C:10]([OH:9])[CH:18]=[CH:17][CH:16]=3)[CH:12]=[C:13]2[C:30]([O:32][CH3:33])=[O:31])(=[O:21])=[O:20])[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: COC(=O)c1cc2c(OC(C)=O)cccc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(O)cccc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
Aqueous sodium hydrogencarbonate solution (16 ml, 50%) was added to methyl 4-acetoxy-N-(3,4-dichlorophenylsulphonyl)indole-2-carboxylate (0.63 g) in methanol (15 ml) and the reaction stirred for 48 hours at room temperature. The solution was then poured into 2M HCl and extracted with ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the desired product as a gum (0.5 g, 87%); NMR δ (CD3SOCD3) 3.83 (s, 3H), 6.71 (d, 1H), 7.31 (t, 1H), 7.42-7.5 (m, 2H), 7.92 (s, 1H), 10.31 (s, 1H); M/z (+) 402 (MH+), 400.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(-c2ncncc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cncnc1-c1ccc(CBr)cc1
Yield: 105.5 %

Procedure:
A mixture of 5-cyano-4-(p-tolyl)pyrimidine (2.5 g, 12.8 mmol), N-bromosuccinimide (2.4 g, 13.5 mmol) and benzoyl peroxide (catalytic amount) in carbon tetrachloride (100 ml) was refluxed under light radiation for 1 hour. After cooling, insoluble materials were removed and the filtrate was concentrated to dryness to afford a yellow syrup (3.7 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-c2nnn[nH]2)cc1
Solvent: CO
Product: Nc1ccc(-c2nnn[nH]2)cc1

Procedure:
Prepared by catalytic hydrogenation of 5-(4-nitro-phenyl)-1H-tetrazol in MeOH on platinum dioxide (ambient temperature, 3.5 bar, 40 minutes).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:21]3[CH:20]([N:24]([CH:26]4[CH2:28][CH2:27]4)[CH3:25])[CH2:19][CH2:18][C:17]([CH3:30])([CH3:29])[C:16]=3[CH:15]=2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[CH:26]1([N:24]([CH3:25])[CH:20]2[CH2:19][CH2:18][C:17]([CH3:29])([CH3:30])[C:16]3[CH:15]=[C:14]([NH:13][C:11](=[O:12])[NH:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=4)[CH:23]=[CH:22][C:21]2=3)[CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(NC(=O)Nc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C1CC1)C1CCC(C)(C)c2cc(NC(=O)Nc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
A solution of 4-{3-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]-ureido}-benzoic acid methyl ester (Intermediate 59, 0.045 g, 0.106 mmol) in methanol (2 mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of sodium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford a solid that was recrystallized from hot acetonitrile to afford the title product as a white solid (0.012 g, 28%).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])=[C:8]([CH3:17])[C:9]=1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:3]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:16][C:13]([O:12][C:10]([C:9]1[C:8]([CH3:17])=[C:7]([C:18]([OH:20])=[O:19])[S:6][C:5]=1[NH:4][C:2]([CH3:1])=[O:3])=[O:11])([CH3:14])[CH3:15]
Reactant: CC(=O)Nc1sc(C(=O)OCc2ccccc2)c(C)c1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1sc(C(=O)O)c(C)c1C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 95.3 %

Procedure:
To a solution of the compound prepared in Example 10 (1.10 g, 2.84 mmol) in EtOAc (225 ml) was added Pd(OH)2 (0.50 g, 0.47 mmol). The flask was then flushed with H2. After 1 day, the reaction was purged with N2 and filtered. The catalyst was washed with hot EtOH (2×). The combined filtrates were concentrated under reduced pressure; to yield 810 mg of a tan solid (95%). 1H-NMR (CDCl3) 1.60 (s, 9H), 2.30 (s, 3H), 2.74 (s, 3H), 5.29 (s, 2H), 7.30-7.50 (m, 5H). 1.56 (s, 9H), 2.25 (s, 3H), 2.67 (s, 3H), 5.60 (brs, 2H) 11.40 (brs, 1H).
Reaction SMILES: [CH2:1]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:18](Cl)([Cl:20])=[O:19].C(=O)=O>CC(C)=O>[Cl:20][C:18]([O:9][CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:19]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCC(CO)CCCCCC
Agent: O=C=O
Solvent: CC(C)=O
Product: CCCCCCCCC(CCCCCC)COC(=O)Cl
Reaction time: 0.5 h

Procedure:
2-Hexyldecyl chloroformate was prepared by adding 2-hexyldecanol (540 g) during 3 hours to liquid phosgene (500 g) which was refluxing below a condenser cooled with a mixture of solid carbon dioxide and acetone. After addition was complete the mixture was stirred for 30 minutes, and excess phosgene was then allowed to evaporate into a scrubbing device charged with 20% aqueous sodium hydroxide. The last traces of phsogene were removed by bubbling nitrogen through the liquid product while it was heated to 120°.
Reaction SMILES: [NH2:1][C:2]1[C:21]2[C:20](=[O:22])[C:19]([C:23]([OH:25])=[O:24])=[CH:18][N:7]3[C@@H:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:27].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][CH2:35][CH2:36][NH2:37].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:21]2[C:20](=[O:22])[C:19]([C:23]([OH:25])=[O:24])=[CH:18][N:7]3[C@@H:8]([CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:37][CH2:36][CH2:35][NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)[C:3]=1[F:27]
Reactant: NCCNc1ccccn1
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](Cc1ccccc1)CO2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](Cc1ccccc1)CO2
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
A mixture of (3S)-8-Amino-9,10-difluoro-2,3-dihydro-7-oxo-3-phenylmethyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (76.9 mg, 0.207 mmol), 2-(2-pyridylamino)ethylamine (41.8 mg, 0.303 mmol), and triethylamine (42.1 μL, 0.302 mmol) in DMSO (1.5 mL) was stirred at 100° C. for 3 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. Recrystallization of the filtered precipitates from CH2Cl2-EtOH gave (3S)-8-amino-9-fluoro-2,3-dihydro-7-oxo-3-phenylmethyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (55.4 mg, 55%) as a yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[NH:19]1[CH2:26][CH2:25]C[C@H:20]1[C:21](O)=[O:22].N1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.O.[Cu]I>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([N:19]2[CH2:20][CH2:21][O:22][CH2:25][CH2:26]2)[N:7]=3)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2nc3ccc(Cl)nc3o2)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1COCCN1
Product: COc1ccc(-c2nc3ccc(N4CCOCC4)nc3o2)cc1
Temperature: 90 °C
Yield: 13.5 %

Procedure:
To a solution of 5-chloro-2-(4-methoxy-phenyl)-oxazolo[5,4-b]pyridine (25 mg, 0.096 mmol) in DMSO (1 mL) was added L-proline (11.04 mg, 0.096 mmol), CuI (18.27 mg, 0.096 mmol), morpholine (13 μL, 0.15 mmol) and K3PO4 (40.7 mg, 0.192 mmol). The reaction vessel was sealed and heated to 90° C. overnight, at which point the reaction was diluted with water and extracted with EtOAc. The organics were concentrated leaving a residue that was purified by reverse phase chromatography to afford 2-(4-methoxy-phenyl)-5-morpholin-4-yl-oxazolo[5,4-b]pyridine (4.3 mg, 0.013 mmol, 14% yield). ES MS (M+H+)=312; 1H NMR (499 MHz, DMSO-d6): δ 8.07-8.02 (d, J=8.7 Hz, 2H); 7.98-7.94 (m, 1 H); 7.17-7.11 (d, J=8.7 Hz, 2H); 6.91 (d, J=8.8 Hz, 1H); 3.86 (s, 3H); 3.73 (t, J=4.8 Hz, 4H); 3.51 (t, J=4.8 Hz, 4H); HRMS m/z 312.1352 (C17H17N3O3+H+ requires 312.1343)
Reaction SMILES: [NH2:1][C:2]1([C:23](OC)=[O:24])[CH2:6][CH2:5][CH:4]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][C@H:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:10][C:9]=3[CH:8]=2)[CH2:3]1.[BH4-].[Na+].Cl.[OH-].[Na+]>CCO.C(Cl)Cl>[NH2:1][C:2]1([CH2:23][OH:24])[CH2:6][CH2:5][CH:4]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][C@H:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:10][C:9]=3[CH:8]=2)[CH2:3]1
Reactant: CCCCCC[C@@H]1CCc2cc(C3CCC(N)(C(=O)OC)C3)ccc2C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCCCCC[C@@H]1CCc2cc(C3CCC(N)(CO)C3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Methyl 1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentanecarboxylate (I-8F, 5.7 g, 16 mmol) was dissolved in EtOH (60 mL) and methylene chloride (15 mL). Sodium borohydride (2.5 g, 67 mmol) was added. The mixture was stirred at room temperature overnight. Hydrochloric acid (6 N aqueous, 40 mL) was added slowly at 0° C. to make pH approximately 1. After the mixture was stirred at room temperature for 60 min, sodium hydroxide (10 g in 20 mL of water) was added to make pH approximately 12. The mixture was stirred at room temperature for 40 min before being concentrated to remove organic solvents. The aqueous residue was diluted with water (20 mL) and extracted with EtOAc (100 mL, 2×50 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, decolored by charcoal, filtered through CELITE® pad, and concentrated under reduced pressure to give (1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (5.0 g, 15 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:34][CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccccn3)c2CC1)C(F)(F)F

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.17 mmol) with pyridin-2-ylmethylamine (254 mg, 2 equiv.) using palladium acetate (0.1 equiv.), BINAP (0.3 equiv.) and cesium carbonate (1.4 equiv.) in toluene (5 mL). Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1, 3:1, and 1:1) to give 7-chloro-6-(pyridin-2-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[S:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[S:21].NCCC(O)=O>>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[C:25]4[S:19][C:20](=[S:21])[NH:22][C:23]4=[O:24])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: NCCC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Yield: 66.2 %

Procedure:
A mixture of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) (4.96 g, 20 mol), rhodanine (2.66 g, 20 mmol), and β-alanine (2.0 g, 22.5 mmol) in 50 ml of acetic acid(AcOh) was refluxed for 2 hours. The solid which was formed on cooling the solution was collected to give the title compound as a red solid (4.8 g, 66%); 1H NMR (300 MHz, CDCl3) δ 1.81 (t, J=5.5 Hz, 4 H), 3.55 (t, J=5.5 Hz, 4 H), 4.00 (s, 4 H), 6.92 (d, J=8.9 Hz, 2 H), 7.58 (d, J=8.9 Hz, 2 H), 7.38 (s, 1 H); MS (ES) m/z: 362.8 (MH+); HRMS Calcd. for C17H19N2O3S2(MH+): 363.0837. Found: 363.0852. Anal. Calcd. for C17H18N2O3S2: C, 56.33; H, 5.01; N, 7.73. Found: C, 56.28; H, 4.89; N, 7.73.