Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=O)=[O:13])=[C:4]1[CH3:23])[CH3:2].[CH2:24]([N:26]([CH2:38][CH3:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>C(O)C>[CH2:34]([N:33]([CH2:36][CH3:37])[C:29]1[CH:28]=[C:27]([N:26]([CH2:24][CH3:25])[CH2:38][CH3:39])[CH:32]=[CH:31][C:30]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:18])[O:13]1)[CH3:35]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3ccccc32)c(N(CC)CC)c1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of 12.28 g (0.04 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 10.7 g (0.043 mole) of 90 percent active N,N,N',N'-tetraethyl-m-phenylenediamine and 6.0 ml of acetic anhydride was stirred at room temperature for seventeen hours. The reaction mixture was diluted with 26.0 ml of ethanol, stirred and filtered. The separated solid was washed with diethylether and dried to yield 11.8 g of 3-[2,4-bis(diethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =Y1 =H; R=R6 =CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3), a white crystalline material which melted at 139°-140° C. The infrared spectrum showed a significant band at 1760 cm-1 (C=O; s) and the nuclear magnetic resonance spectrum was in accord with the structure. A solution of this product in benzene developed a deep blue-black color when spotted on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([OH:21])=O.[CH:25]([N:28](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN.C1COCC1>CN(C=O)C.CC#N>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([NH:28][CH3:25])=[O:21]
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cccc(F)c3)n12
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2c(ccc3nnc(C)n32)n1Cc1cccc(F)c1
Reaction time: 0.01 h

Procedure:
To a solution of 6-(3-fluorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.050 g, 0.15 mmol, from Step 3) in DMF (3 mL) was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.18 g, 0.49 mmol, Aldrich). After the reaction was stirred for 30 seconds, 2.0 M Methylamine in THF (0.62 mL, 1.2 mmol, Aldrich) was added. After 1 hour, the reaction was diluted with MeCN and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (35 mg, 67%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([NH2:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].O>ClCCl>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([NH:12][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC(=O)OCc1ccccc1
Reaction time: 22 h
Yield: 51.6 %

Procedure:
In a dry flask (3R,4R)-4-aminopiperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (3.07 g, 11.3 mmol) was dissolved in dichloromethane (100 mL) and triethylamine (2.1 mL, 15.1 mmol) and benzyl chloroformate (2.0 mL, 12.6 mmol) were added. The mixture was stirred for 22 hours. Water (30 mL) was added and the layers separated. The aqueous layer was extracted with dichloromethane (30 mL). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude oil (4.91 g). Purification by flash column chromatography (40% ethyl acetate/hexanes) provided a colorless oil (2.37 g, 51%). 1H NMR (300 MHz, CDCl3), δ: 7.33 (m, 5H), 5.08 (s, 2H), 4.71 (s, 1H), 4.12 (m, 4H), 3.90 (m, 1H), 2.98 (bs, 1H), 2.85 (t, 1H, J=13), 2.37 (m, 1H), 2.06 (d, 1H, J=7), 1.45 (s, 9H), 1.37 (m, 1H), 1.20 (t, 3H, J=7).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:13]=[O:14])=[N:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Si](C)(C)C)=[CH:18][C:17]=1[F:26].[I:28]Cl>ClCCl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:13]=[O:14])=[N:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:28])=[CH:18][C:17]=1[F:26]
Reactant: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: ClI
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-6-formylaminomethyl-nicotinic acid methyl ester (2.4 g, 6.1 mmol) in dichloromethane (15 mL) at 0° C. was added ICl (2.0 g, 12.2 mmol). The mixture was stirred at 0° C. for 0.5 hour, then quenched with water, washed with a saturated solution of sodium sulphite followed by brine, dried (Na2SO4), filtered and evaporated in vacuo to afford the title compound as a brown solid (2.7 g, 98%). LCMS (method B): RT=3.81 min, [M+H]+=448.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]([C:12](=[O:35])[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:18]([O:33][CH3:34])[CH:17]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(O)CSCCSCCO>O1CCCC1.[Pd]>[C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]([C:12](=[O:35])[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23]/[CH:24]=[CH:25]\[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:18]([O:33][CH3:34])[CH:17]=1)[CH:9]([CH3:10])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(CCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc1OCC#Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: OCCSCCSCCO
Solvent: C1CCOC1
Product: COc1cc(CCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc1OC/C=C\c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To (S)-[1-(2-{4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-3-methoxy-phenyl}ethylcarbamoyl)-2-methyl-propyl]-carbamic acid-tert.-butyl ester (18 g) in tetrahyrofuran (180 ml), Lindlar-catalyst (5%-Pd on CaSO4; 7.2 g), 3,6-dithia-1,8-octandiol (45 mg) and 2,2′-(ethylenedithio)-diethanol (45 mg) are added. The resulting mixture is shaken under a hydrogen atmosphere at room temperature and at normal pressure for 5 hours. It is then filtered and evaporated. The residue is purified by flash column chromatography on silica gel (ethyl acetate/hexane 1:2) and recrystallised (ethyl acetate/hexane). Z-(S)-[1-(2-{4-[3-(4-Chloro-phenyl)-allyloxy]-3-methoxy-phenyl}-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid-tert.-butyl ester is obtained, m.p. 82-84° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[C:27]1([CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][C:38]([OH:43])=[CH:39][CH:40]=3)[O:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:43][C:38]2[CH:37]=[C:36]3[C:41]([CH2:42][CH:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][O:35]3)=[CH:40][CH:39]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Oc1ccc2c(c1)OCC(c1ccccc1)C2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)C3)nc1

Procedure:
5-Nitro-2-(3-phenylchroman-7-yloxy)pyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 200 mg of 3-phenylchroman-7-ol. 1H NMR (400 MHz, d6-DMSO) δ: δ: 9.05 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.34-7.38 (m, 4H), 7.27-7.30 (m, 1H), 7.22 (m, 2H), 6.70-6.74 (m, 2H), 4.31 (dd, 1H, J 10.4, 3.5 Hz), 4.12 (t, 1H, 10.4 Hz), 3.24 (m, 1H), 3.01-3.11 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=O.[OH-].[NH4+:16]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:16])=[O:12]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cc2ccccc2[nH]1
Temperature: 80 °C

Procedure:
A mixture of ethyl indole-2-carboxylate (5 g, 26.5 mmol) and ammonium hydroxide (30 mL) was heated at 80° C. in a sealed glass vessel overnight. The reaction was cooled and the title compound (3.06 g, 73%) was collected by filtration as a colorless solid: 1H NMR (400 MHz, DMSO-d6) δ 7.95 (br, 1H), 7.61 (d, 1H), 7.41 (d, 1H), 7.36 (br, 1H), 7.12, (t, 1H), 7.01 (t, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[S:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:28]3[CH:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:27]3)[S:23][CH2:22][CH2:21]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1CC2SCCC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 92.6 %

Procedure:
1.13 g of N,N'-carbonyldiimidazole are added to a solution, cooled to 0° C., of 1.16 g of 2-methoxyphenylacetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for 40 minutes at 0° C. and then a solution of 2.15 g of (4aRS,7aRS)4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride and 0.9 cm3 of triethylamine in 20 cm3 of dichloromethane is added. The reaction mixture is stirred for one hour at 0° C. and is then washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is washed with 30 cm3 of ethyl ether and 30 cm3 of diisopropyl oxide and it is then dried under reduced pressure (2.7 kPa). 2.66 g of (4aRS,7aRS)-4,4-diphenyl-6-[(2-methoxyphenyl)acetyl]perhydrothiopyrano[2,3 -c]pyrrole are obtained in the form of a white solid; melting point 172° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@@H:13]2[CH2:16][C@H:9]1[CH2:10][CH2:11][C@@H:12]2[NH:17]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:17][C@H:12]1[CH2:11][CH2:10][C@@H:9]2[CH2:16][C@H:13]1[C:14](=[O:15])[N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N

Procedure:
Examples 11p and 11q, Step 1: To a solution of the (1R,2S,5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (8 g, 21.36 mmoles) in 160 ml of methanol was added 1.6 g of 10% Pd/C (50% wet), and it was treated with H2 (52 psi)for 18 hrs. It was filtered through a plug of Celite to remove the catalyst, and the solvent was evaporated off to give (1R,2S,5R)-tert-butyl 2-amino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate as a foamy solid, which was used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=O)[O:13][C:11](=O)[C:10]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:9]23)=[CH:4][CH:3]=1.CSC1[NH:23][CH2:24][CH2:25][N:26]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9]3[C:10](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11](=[O:13])[N:23]3[CH2:24][CH2:25][N:26]=[C:14]23)=[CH:6][CH:7]=1
Reactant: O=c1oc(=O)n(-c2ccc(F)cc2)c2ccccc12
Reactant: CSC1=NCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1c2ccccc2N(c2ccc(F)cc2)C2=NCCN12
Reaction time: 4 h

Procedure:
A solution of 5.4 g. of N-(p-fluoro-phenyl)isatoic anhydride, 2.5 g. of 2-methylmercapto-imidazoline and one pellet (about 100 mg.) sodium hydroxide in 75 ml. of dioxane is refluxed with stirring for 4 hours. The resulting mixture is evaporated to dryness, the residue dissolved in methylene chloride, washed with water and extracted twice with 1N hydrochloric acid. The combined aqueous extracts are washed with methylene chloride and then with diethyl ether and made basic with sodium bicarbonate. The resulting precipitate is filtered off, washed thoroughly with water, dried by suction, dissolved in methylene chloride, dried with sodium sulfate, treated with charcoal and the methylene chloride exchanged for methanol to crystallize 10-(p-fluoro-phenyl)-2,3-dihydro-imidazo[2,1-b]quinazolin-5(10H)-one, m.p. 278°-280°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[N:14](C(OCC)=O)[CH:13]=[CH:12][S:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C[C:23](C)=[O:24]>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:23][OH:24])[N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)N1C=CSC1CNC(=O)OC(C)(C)C
Reactant: CC(C)=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1nc(CO)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 0.52 g of ethyl 2-(tert-butoxycarbonylamino)methylthiazole-3-carboxylate in 10 ml of ethanol was added 200 mg of lithium borohydride, and the mixture was stirred at room temperature for 30 minutes. To this reaction solution was added 2 ml of acetone. The mixture was stirred for an additional 30 minutes, and then concentrated under reduced pressure. To the residue were added 15 ml of dichloromethane and 15 ml of a saturated saline solution, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (5 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.357 g (yield 81%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:31]([F:34])([F:33])[F:32])=[CH:10]/[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH:19]([NH:23][C:24](=[O:30])[CH2:25][CH:26]([O:28][CH3:29])[CH3:27])[CH2:18][CH2:17]3)=[N:12][OH:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:37][O:38][CH2:39]Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:31]([F:34])([F:32])[F:33])=[CH:10]/[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH:19]([NH:23][C:24](=[O:30])[CH2:25][CH:26]([O:28][CH3:29])[CH3:27])[CH2:18][CH2:17]3)=[N:12][O:13][CH2:37][O:38][CH3:39])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(C)CC(=O)NC1CCc2cc(C(/C=C(/c3cc(Cl)cc(Cl)c3)C(F)(F)F)=NO)ccc21
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCON=C(/C=C(/c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc2c(c1)CCC2NC(=O)CC(C)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
0.5 g of N-[5-{(Z)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-hydroxyimino-2-butenyl}-indane-1-yl]-3-methoxybutyric acid amide was dissolved in 10 ml of tetrahydrofuran, and 0.08 g of 60% sodium hydride was added to the resulting solution under ice-cold conditions, followed by stirring for 30 minutes at room temperature. The temperature was cooled again, and 0.1 g of chloromethyl methyl ether was added to the resulting solution, followed by stirring for one night at room temperature. The reaction solution was poured into ice-water, extracted with ethyl acetate, washed with saturated brine, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=7/3 (volume ratio)) to obtain 0.3 g of the target compound. Yield was 54%.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Br:28][CH2:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: Nc1ncnc2sc(CBr)c(-c3ccc([N+](=O)[O-])cc3)c12

Procedure:
A suspension of Example 1D (500 mg, 1.75 mmol) in benzene (50 mL) was treated with NBS (340 mg, 1.91 mmol) and AIBN (50 mg), stirred at reflux for 3.5 hours, and concentrated. The concentrate was absorbed onto silica gel and purified by flash column chromatography with ethyl acetate to provide 330 mg of a 1.7:1 mixture of the desired product and recovered starting material.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17](Br)[CH:16]=[CH:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:23]([O:28][CH:29]([C:31]#[CH:32])[CH3:30])#[C:24][CH2:25][CH2:26][CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:32]#[C:31][CH:29]([O:28][C:23]#[C:24][CH2:25][CH2:26][CH3:27])[CH3:30])[CH:16]=[CH:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc2cc(Br)ccc2c1
Reactant: C#CC(C)OC#CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCC#COC(C)C#Cc1ccc2cc(OCCCCCCCCCC)ccc2c1
Yield: 82 %

Procedure:
18.2 g (0.05 mol ) of 6-decyloxy-2-bromonaphthalene (VI-60), 15.4 g (0.1 mol ) of (+)-2-pentynyloxy-3-butyne (VII*-60), 0.5 g of copper iodide, 0.8 g of triphenylphosphine, 0.4 g of bis(triphenylphosphine)-palladium chloride and 100 ml of triethylamine were stirred under reflux for 7 hours in an atmosphere of nitrogen gas. After completion of the reaction, the reaction mixture was poured into ice-aqueous hydrochloric acid and extracted with 200 ml of ethyl acetate. The organic layer was further washed with water and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene-ethyl acetate as eluent to obtain 17.9 g (yield 82%) of optically active (+)-6-decyloxy-2-(3-pentynyloxy-1-butynyl)naphthalene (I'-60), [α]D20 =+93 (c=1, chloroform).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1)C.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([CH:21]([NH2:23])[CH3:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:13][C:11]1[CH:10]=[C:9]([NH:23][CH:21]([CH3:22])[C:20]2[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:8]=[C:7]([S:6][CH2:5][C:4]([OH:3])=[O:15])[N:12]=1
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(Nc1cc(Cl)nc(SCC(=O)O)n1)c1ccc(Cl)cc1

Procedure:
A stirred mixture of 2.7 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 1.6 g of p-chloro-α-methylbenzylamine and 1.1 g of sodium carbonate in 120 ml. ethanol was heated under reflux for 2 hr. The reaction mixture was filtered and the filtrate taken to dryness in a rotary evaporator in vacuo. The residual oil was treated with 100 ml. of 30% sodium hydroxide solution containing a few ml. of ethanol. After a few minutes the clear solution was acidified with concentrated hydrochloric acid and the mixture thus formed was extracted with ether (3 × 50 ml.). The ether solution was dried over magnesium sulfate, filtered and the filtrate evaporated to dryness. The residue was dissolved in 50 ml. of benzene and petroleum ether was added until the solution became cloudy. On cooling in ice a precipitate was deposited. Recrystallization of this material from 50% aqueous ethanol afforded the product, mp. 155°-160°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([C:12](O)=[O:13])[C:8]=2[CH:15]=1)([O-:3])=[O:2].S(Cl)([Cl:18])=O>C(Cl)CCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([C:12]([Cl:18])=[O:13])[C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1nsc2ccc([N+](=O)[O-])cc12
Solvent: ClCCCl
Product: O=C(Cl)c1nsc2ccc([N+](=O)[O-])cc12
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 5-nitro-1,2-benzisothiazole-3-carboxylic acid (5.5 g, 0.0246 mole) and ethylene dichloride (55 ml) is added thionyl chloride (2.92 g, 1.63 ml, 1.0 eq.), and the reaction mixture heated to 70° C. An additional portion of thionyl chloride (1.46 g, 0.82 ml, 0.5 eq) is added and heating at 70° C. continued for 2.5 hours. The cooled solution is concentrated in vacuo to afford the title compound which is identified by NMR and IR analysis, and used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[O:19][C:20]1[CH:21]=[C:22]([C@@H:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:28][C@H:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:14]2[N:13]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:21]=1)[CH3:27])=[O:8]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: C[C@H](N)c1cccc(Oc2ncccn2)c1
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(Oc2ncccn2)c1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid following the general procedures as described for Example 1 with the exception that (S)-1-[3-(pyrimidin-2-yloxy)-phenyl]-ethylamine was used.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[C:25]([C:32]5[CH:37]=[CH:36][C:35]([S:38][CH3:39])=[CH:34][CH:33]=5)=[CH:26][C:27]([CH:30]=[O:31])=[CH:28][CH:29]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].[BH4-].[Na+]>CCO.C1COCC1>[CH3:3][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[C:25]([C:32]5[CH:33]=[CH:34][C:35]([S:38][CH3:39])=[CH:36][CH:37]=5)=[CH:26][C:27]([CH2:30][OH:31])=[CH:28][CH:29]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:1]
Reactant: CSc1ccc(-c2cc(C=O)ccc2-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1ccc(-c2cc(CO)ccc2-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of aldehyde from step 2 in EtOH: THF (4:1, 0.05M) at 0° C. was added NaBH4 (1 eq). The reaction mixture was stirred 1 h at 0° C., quenched with a solution of NH4Cl and diluted with ether. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (hexane:EtOAc, 1:1 to 1:9) to afforded the title compound.