Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5](=[C:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH:11]1[CH3:17])[C:6](OC)=[O:7])#[N:4].CC(C)=O.Cl>C(O)C>[OH:7][CH2:6][CH:5]([CH:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH:11]1[CH3:17])[C:3]#[N:4]
Reactant: COC(=O)C(C#N)=C1CC(C)(C)CC1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CC1CC(C)(C)CC1C(C#N)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.1 eq. of sodium borohydride are placed in ethanol at 10° C. under an inert atmosphere. Methyl 2-cyano-2-(2,4,4-tri-methylcyclopentylidene)acetate B is added thereto dropwise. The reaction medium is stirred at ambient temperature overnight and is then neutralized with acetone. It is subsequently poured onto a cold 10% HCl solution. The aqueous phase is extracted twice with MTBE. The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, 3-hydroxy-2-(2,4,4-tri-methylcyclopentyl)propanenitrile is obtained in the form of four diastereomers in the proportions of 11:13:23:53.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([CH2:14][O:15]C(=O)C)[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([N:19]([CH3:21])[CH3:20])[S:10]2)[C@H:6]1[O:22]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:20][N:19]([CH3:21])[C:9]1[S:10][C@H:11]2[O:12][C@H:13]([CH2:14][OH:15])[C@@H:5]([OH:4])[C@H:6]([OH:22])[C@H:7]2[N:8]=1
Reactant: CC(=O)OC[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3aR,5R,6S,7R,7aR)-5-(acetoxymethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (1.65 g, 4.41 mmol) in methanol (20 mL) was added potassium carbonate (25 mg, 0.18 mmol). The resulting mixture was stirred overnight at room temperature to yield a solid. This was collected by filtration, washed with cold methanol and dried. The product 7 was obtained as a light yellow solid (1.05 g, 94%). (ES, m/z): [M+H]+ 248.9; 1H NMR (300 MHz, CDCl3) δ 6.33-6.35 (d, J=6.3 Hz, 1H), 4.29-4.33 (t, J=6.0 Hz, 1H), 4.16 (s, 1H), 3.76-3.89 (m, 2H), 3.70 (s, 2H), 3.03 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:17])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:20]=1[C:21]([N:23]=[C:24]=[O:25])=[O:22]>>[Cl:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:20]=1[C:21]([NH:23][C:24]([NH:17][C:3]1[C:2]([Cl:1])=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:9][CH:8]=2)[O:5][N:4]=1)=[O:25])=[O:22]
Reactant: Nc1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1noc(-c2ccc(C(F)(F)F)cc2)c1Cl

Procedure:
4-Chloro-5-(4-(trifluoromethyl)phenyl)-3-aminoisoxazole was reacted with 2,6-dichlorobenzoyl isocyanate to produce the desired product according to the teaching of Example 8. The identity of the product was confirmed by NMR, m.p.=237°-238° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>>[Cl:1][C:2]1[C:3]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(F)c(F)cc2c1Cl
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1sc2cc(F)c(F)cc2c1Cl

Procedure:
Following the 8a synthetic method, using B1 (55.33 mg, 0.25 mmol) instead of A1 gave 8b as a white powder; (93.51 mg, 94.5%). [α]D25: +22.3 (c=0.43, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 7.80 (s, 1H), 7.64-7.51 (m, 3H), 7.34-7.24 (m, 5H), 5.16-5.10 (m, 1H), 3.43-3.28 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 175.44, 160.03, 153.01, 151.93, 149.64, 148.62, 135.14, 133.75, 133.28, 129.45, 128.83, 127.55, 188.89, 110.98, 110.79, 110.53, 54.04, 37.28; HRMS (ESI): calcd for: C18H12ClF2NO3S [M−H]−=394.0122, obsd [M−H]−=394.0127.
Reaction SMILES: O.[OH-].[Li+].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([O:17]C)=[O:16])[CH:11]=2)[CH:6]=[CH:5]1.Cl>CO.O1CCCC1.O>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:11]=2)[CH:6]=[CH:5]1
Reactant: COC(=O)/C=C/c1ccc2cc[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/c1ccc2cc[nH]c2c1
Yield: 97.7 %

Procedure:
Lithium hydroxide monohydrate (4.6 g) was added to a stirred solution of methyl E-indole-6-acrylate (5.5 g) in methanol (100 ml), tetrahydrofuran (10 ml), and water (10 ml) under an atmosphere of nitrogen; and the mixture was heated at 50° for 5 hr. The cooled mixture was diluted with water (100 ml) and acidified to pH 4 with 6M hydrochloric acid. The precipitate which formed was isolated by filtration, washed twice with water, and dried to give E-indole-6-acrylic acid (5 g, 97%) as a yellow powder; mp 215°-217°; partial NMR (250 MHz, DMSO-d6): 6.42(d, J=15.9 Hz, 1H, olefinic H), 6.47(m, 1H, H3 -indole), 7.70(d, J=15.9 Hz, 1H, olefinic H), 11.35(br s, 1H, NH), 12.18(br s, 1H, COOH).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13](Cl)[C:14](=[CH2:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[CH2:15][C:14](=[CH2:13])[CH3:16]
Reactant: C=C(C)CCl
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)Cc1cc(C(=O)OCC)ccc1O
Reaction time: 40 h
Yield: 89.3 %

Procedure:
Ethyl 4-hydroxybenzoate (50.0 g), methallyl chloride (32.6 g), and potassium carbonate (45.6 g) were refluxed in acetone (150 ml) with stirring for 40 hours. The reaction mixture was filtered and the filtrate was concentrated under a vacuum. The residue, with toluene (150 ml) added thereto, was washed with 2% sodium hydroxide solution and water successively. After being dried over sodium sulfate anhydride, the solution was concentrated under a vacuum. The resulting oily material was dissolved in N,N-dimethylaniline (80 ml) and refluxed with stirring for about 10 hours. The reaction mixture was acidified with concentrated hydrochloric acid while being cooled with ice and then extracted with toluene. The extract was further extracted with 10% aqueous sodium hydroxide solution. The resulting water layer was acidified with concentrated hydrochloric acid and then extracted with toluene. The extract was washed with water, dried over sodium sulfate anhydride, and then concentrated under a vacuum, thereby yielding 59.2 g of the aimed compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1>CC(=O)CC>[O:21]=[C:2]1[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[C:36]#[N:37]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: N#Cc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a solution of 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.97 g, 3.46 mmol) in 2-butanone (25 mL) were added cesium carbonate (3.39 g, 10.39 mmol) and α-bromo-m-tolunitrile (0.85 g, 4.33 mmol). The mixture was heated to reflux for 2 h, cooled to ambient temperature, and filtered. The solid was washed with ethyl acetate. The filtrate was concentrated in vacuo, the residue was purified by column chromatography with ethyl acetate-hexanes (1:5-1:1), followed by recrystallization from ethyl acetate and diethyl ether to afford 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile (1.26 g, 92%) as a colorless solid: mp 187-193° C.; 1H NMR (300 MHz, CDCl3) δ7.61-7.58 (m, 3H), 7.47-7.44 (m, 1H), 7.25-7.19 (m, 2H), 7.07-7.03 (m, 1H), 6.73-6.71 (m, 1H), 6.43-6.41 (m, 2H), 5.11-4.70 (m, 4H), 4.53 (d, J=9.0 Hz, 2H), 3.09-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.1, 162.0, 161.4, 141.5, 137.5, 132.6, 131.9, 131.6, 130.7, 129.9, 128.9, 124.3, 123.9, 120.2, 119.9, 118.7, 118.4, 113.1, 108.8, 93.4, 80.5, 72.5, 57.7, 43.4, 29.0; MS (ES+) m/z 394.8 (M+1).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].CS([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])(=O)=O.O.C(OCC)(=O)C.CCCCCC>CS(C)=O>[CH2:25]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=[CH2:19]
Reactant: C=CCCCCCS(C)(=O)=O
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a suspension of sodium theobromine (9.05 g, 50.0 mmol) in dimethylsulfoxide (90 mL) was added 7-methanesulfonyl-1-heptene (9.30 g, 48.2 mmol). The reaction was stirred for 16 hours at 60° C. The mixture was then poured into water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic portions were combined, dried, and evaporated to give an orange solid. Chromatography (silica, ethyl acetate/hexane) yielded 6.50 g (47% yield) 1-(6-Heptenyl)-3,7-dimethylxanthine (inventive compound no. 1534) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](=O)([O-])[O-].[K+].[K+].IC.Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(Br)cccc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
To a solution of 3-bromo-2-hydroxy-benzaldehyde (2.72 g, 13.53 mmol) in DMF (70 mL) were added potassium carbonate (5.61 g, 40.59 mmol) and iodomethane (1.01 mL, 16.24 mmol). The reaction mixture was stirred at RT. After 18 h, the mixture was acidified with cooling using 1 M HCl (aq), extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as an oil (2.73 g, 94%). 1H NMR (300 MHz, CDCl3): δ 10.36 (s, 1H), 7.85-7.79 (m, 2H), 7.15 (dt, J=7.7 and 0.7 Hz, 1H), 4.00 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[C:5]([C:13]([F:16])([F:15])[F:14])=[N:4]1)[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([C:13]([F:15])([F:14])[F:16])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1cc(C(=O)O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
Ethyl 1-ethyl-3-trifluoromethylpyrazole-4-carboxylate (2.17 g) was dissolved in ethanol and potassium hydroxide (1.06 g) in water was added. The reaction was stirred at room temperature overnight. Ethanol was removed under reduced pressure and the resulting residue partitioned between water and ether. The aqueous layer was separated, acidified with hydrochloric acid (2M) and extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo to give 1-ethyl-3-trifluoromethylpyrazole-4-carboxylic acid as a white solid (1.86 g). NMR (CDCl3) δ1.45(t,3H), 4.20(q,2H), 7.95(s,1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:16](=[O:26])[CH2:17][NH:18][C:19](OC(C)(C)C)=[O:20])[CH:7]2[CH2:12]C(O)=O.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:20])[CH:12]=[C:7]12
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCc2c(Br)cccc2C1CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid. To a stirred solution of methyl 2-(5-bromo-2-(2-((tert-butoxycarbonyl)amino)acetyl)-1,2,3,4-tetrahydroisoquinolin-1-ypacetate (113 g, 257 mmol) in EtOH (1000 mL), 4N aqueous NaOH (74.5 mL, 298 mmol) was added and the solution was stirred at RT for 2 h. The white precipitate was filtered off and the white solid was washed with a small amount of EtOH (1×) and diethyl ether (2×). The sodium salt was partitioned between 0.5N aqueous HCl and DCM, the organic layer was separated and washed with 0.5N aqueous HCl (1×) and brine (1×). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dried under high vacuo overnight to yield the title compound as white foam (110 g). UPLC-MS: MS 427.2/429.2 (M+H+); UPLC rt 0.98 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH:9]=O)[CH2:3][CH2:2]1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>O1CCOCC1.[Ni]>[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:11]([CH2:9][CH2:8][CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:16][CH2:17]1
Reactant: NCCCN1CCOCC1
Reactant: O=CCCN1CCOCC1
Agent: [Ni]
Solvent: C1COCCO1
Product: C(CN(CCCN1CCOCC1)CCCN1CCOCC1)CN1CCOCC1

Procedure:
143 g (1 mol) of 3-morpholinopropionaldehyde in 143 g of dioxane are pumped into 72 g (0.5 mol) of aminopropylmorpholine and 30 g of Raney nickel at 120° C. and hydrogenated at 180 bar.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH2:28][CH3:29])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Pb+3:17])=[C:21]([CH2:28][CH3:29])[CH:20]=1
Reactant: CCc1cc(Br)ccc1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1[Pb+3]
Temperature: 40 °C

Procedure:
Dry chloroform (30 ml) is added to a mixture of lead tetraacetate (8.52 g, 19.3 mmol) and mercuric diacetate (0.28 g, 0.875 mmol) under an atmosphere of nitrogen, and the reaction mixture is stirred and heated to 40° C. 4-Bromo-2-ethylphenylboronic acid (4.0 g, 17.5 mmol) is added in one portion and the mixture is stirred at 40° C. for 4 hours. The reaction mixture is cooled to 0° C., and potassium carbonate (2.66 g, 19.3 mmol) is added portionwise. The mixture is stirred for 5 minutes, then filtered through a small plug of diatomaceous earth, washing with chloroform. The filtrate concentrated under reduced pressure to give 4-bromo-2-ethylphenyllead triacetate.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:27]#[C:28]Br>C1C=CC=CC=1>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:28]#[N:27])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(NCCCCCCCCOc2cccc3ccccc23)cc1
Reactant: N#CBr
Solvent: c1ccccc1
Product: N#CN(CCCCCCCCOc1cccc2ccccc12)c1ccccc1

Procedure:
4.5 g of 1-(1-naphthyloxy)-8-(phenylamino)octane and 1.4 g of cyanogen bromide were heated in 150 ml of benzene at 55° for 2 hours. The benzene was then evaporated from the solution, affording 1-(1-naphthyloxy)-8-(phenylcyanoamino)octane which was employed in Step B (below) without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([N:14]3[CH2:17][CH2:16][CH2:15]3)[N:11]=[C:10]([S:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25]C(=O)OC(C)(C)C)=[CH:21][CH:20]=3)[N:9]=2)[CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][C:10]2[N:9]=[C:8]([NH:7][C:4]3[NH:5][N:6]=[C:2]([CH3:1])[CH:3]=3)[CH:13]=[C:12]([N:14]3[CH2:15][CH2:16][CH2:17]3)[N:11]=2)=[CH:20][CH:21]=1
Reactant: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(NC(=O)OC(C)(C)C)cc3)n2)n[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(N)cc3)n2)[nH]n1
Reaction time: 8 h

Procedure:
tert-butyl 4-(4-(5-methyl-1H-pyrazol-3-ylamino)-6-(azetidin-1-yl)pyrimidin-2-ylthio)phenylcarbamate (prepared using method similar to that described for example 6) (2.53 g, 5.6 mmol) was dissolved in 1:1 TFA-DCM (20 mL) and the resulting solution allowed to stand overnight at room temperature. The solution was concentrated in vacuo. The residue was taken up in EtOAc and washed with saturated aqueous sodium bicarbonate solution (×2) then brine and dried over sodium sulfate. The resulting tan solid (1.8 g, 91%) [MS (ES+) 354) was used without further purification or characterization in the next step.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:32])[C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=2)[C:12]([NH:14][C:15]2[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=2)=[O:13])=[CH:6][CH:5]=1.[CH:33](OC)(OC)OC>>[CH3:28][O:27][CH2:26][C@H:25]([CH3:29])[O:24][C:22]1[CH:21]=[C:11]([CH:10]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([C:3]3[N:32]=[CH:33][O:1][N:2]=3)=[CH:31][CH:30]=2)[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13]
Reactant: COC(OC)OC
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=N)NO)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Product: COC[C@H](C)Oc1cc(Oc2ccc(-c3ncon3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 55 °C

Procedure:
3-{4-[(Hydroxyamino)(imino)methyl]phenoxy}-5-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide was taken up in trimethyl orthoformate (3 mL) and 2 drops of borontrifluoroetherate added. The resulting solution was heated to 55° C. in a CEM explorer microwave for 80 mins. The volatiles were removed under reduced pressure and the resulting oil chromatographed on silica, eluting with 0-100% ethyl acetate in iso-hexane, to give the desired compound as a white foam (295 mg)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:37])[CH2:14][C:15]2[C:16]([O:29]CC3C=CC=CC=3)=[C:17]3[C:22](=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:21]2[CH2:27][CH2:28][CH:18]3[CH2:19][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:37])[CH2:14][C:15]2[C:16]([OH:29])=[C:17]3[C:22](=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:21]2[CH2:20][CH2:19][CH:18]3[CH2:28][CH2:27]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1cc(CC(O)COS(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c2c1C1CCC2CC1
Agent: [Pd]
Product: COc1cc(CC(O)COS(=O)(=O)c2ccc(C)cc2)c(O)c2c1C1CCC2CC1
Yield: 91.6 %

Procedure:
Treatment of (±)-3-[5-(benzyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-ethanonaphthalen-6-yl]-2-hydroxypropyl 4-methylbenzenesulfonate (20.00 g, 38.3 mmol) with palladium on carbon (10 wt. %, 2.0 g) generally according to the procedure described for Intermediate 4 provided 15.18 g (92%) of (±)-2-hydroxy-3-(5-hydroxy-8-methoxy-1,2,3,4-tetrahydro-1,4-ethanonaphthalen-6-yl)propyl 4-methylbenzenesulfonate as a brown oil. Anal. calcd. for C23H28O6S: C, 63.34; H, 6.56. Found: C, 62.98; H, 6.66.
Reaction SMILES: CC1C=CC(C(O)=O)=C([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)N=1.Cl[C:17]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=1.ClC1N=C(C)C=CC=1C(O)=O>>[N:12]1([C:17]2[C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:13]=[CH:14][N:15]=[N:11]1
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Reactant: O=C(O)c1cnccc1Cl
Agent: Cc1ccc(C(=O)O)c(Cl)n1
Product: O=C(O)c1cnccc1-n1ccnn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 70 substituting 4-chloronicotinic acid for 2-chloro-6-methylnicotinic acid. MS (ESI): mass calculated for C11H10N4O3, 246.22; m/z found 247.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.09 (t, J=2.8 Hz, 1H), 7.92-7.86 (m, 3H), 7.66 (dd, J=8.7, 3.3 Hz, 1H), 2.17 (dd, J=2.5, 1.3 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH2:19][C@@H:20]1[CH2:22][C@@H:21]1[NH2:23]>N1C=CC=CC=1>[NH2:19][C@H:20]1[CH2:22][C@H:21]1[NH:23][C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: N[C@@H]1C[C@@H]1N
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N[C@@H]3C[C@@H]3N)cc21

Procedure:
A mixture of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and cis 1,2-diamino cyclopropane [Synthetic Communications, 11(6), 493-495 (1981)] in pyridine is reacted as described in Example 1 giving the desired product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:24](OC)[O:25]C)=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH3:1][C:2]1[NH:3][C:4]([CH:24]=[O:25])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1ccccc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1C#N
Yield: 98.2 %

Procedure:
To a solution of dimethyl 2-methyl-4-(2-cyanophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (6.0 g) in acetone (60 mg) was added 6N hydrochloric acid (6 ml), and the resultant mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with water (30 ml), and adjusted to pH 7.5 with an aqueous sodium bicarbonate solution, and acetone was distilled off under reduced pressure. The resultant crystalline mass was crushed as finely as possible with a glass rod, washed with an additional water (100 ml), collected by filtration, further washed thoroughly with water, and air-dried to give crystalline powder of dimethyl 2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (5.19 g).
Reaction SMILES: [CH2:1]([CH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=2)[NH:21][CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1(C)C=C(C)C=C(C)C=1.[Pd]>[CH2:1]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=2)[NH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCC1CNc2ccc(C(=O)O)cc21
Agent: [Pd]
Solvent: Cc1cc(C)cc(C)c1
Product: CCCCCCCCCCCCCCCCCCc1c[nH]c2ccc(C(=O)O)cc12
Yield: 55.3 %

Procedure:
(RS)-3-(n-Octadecyl)indoline-5-carboxylic acid (2.0 g) in mesitylene (20 ml) was treated with palladium on charcoal (5% w/w, 0.15 g) and the mixture was refluxed for 2 hours. The catalyst was removed by hot filtration and the solvent was evaporated in vacuo to give a solid. The solid was recrystallised from methanol to give 3-(n-octadecyl)indole-5-carboxylic acid (1.10 g) in the form of a buff solid (m.p. 110°-112° C.).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[CH3:9][NH:10][NH2:11]>CC(O)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([NH2:7])[N:10]([CH3:9])[N:11]=2)[CH2:3][CH2:2]1
Reactant: CNN
Reactant: N#CCC(=O)C1CC1
Solvent: CC(=O)O
Product: Cn1nc(C2CC2)cc1N
Temperature: 100 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a solution of 3-cyclopropyl-3-oxo-propanenitrile (2.22 g, 20.3 mmol) in HOAc (40 mL) was added methylhydrazine (40% [w/w] in water, 2.81 g, 24.4 mmol). The reaction mixture was stirred at 100° C. overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM) to give the title compound as yellow oil (2.80 g, 100%).