Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]([CH3:36])=[C:13]([CH2:15][N:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:22][CH:23]=4)[CH2:18][CH:17]3[CH3:35])[N:14]=2)[CH:5]=1.[Li+].[OH-].Cl>CCOCC>[CH3:36][C:12]1[O:11][C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:37])=[O:2])=[N:14][C:13]=1[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:27])([F:28])[F:29])=[CH:22][CH:23]=2)[CH2:18][CH:17]1[CH3:35]
Reactant: COC(=O)c1cccc(-c2nc(CN3c4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4CC3C)c(C)o2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1oc(-c2cccc(C(=O)O)c2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A solution of 50 mg (0.095 mmol) of 3-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-benzoic acid methyl ester (example 90) was added 1 mL of a 1M aqueous LiOH-solution and the mixture stirred at RT for 1 h. After acidification with aqueous HCl to pH of ca 3-4, Et2O was added, the phases were separated and the aqueous one extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 49 mg (quantitative) of 3-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-benzoic acid, off-white solid, MS: 513, (M−H)−.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60][CH:61]=[CH2:62].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:62][CH:61]=[CH2:60])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4 "-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg in 1.5 ml 33% methylene chlorine in cyclohexane), allyl trichloroacetimidate (53 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 3 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compounds (21 mg 4"-ether; 17 mg 3"-ether).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([O:32][CH3:33])=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[CH:18]=[C:17]2[NH:23][C:24]1[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=1[Cl:31]>>[C:1]([O:4][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([O:32][CH3:33])=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[CH:18]=[C:17]2[NH:23][C:24]1[C:25]([Cl:31])=[CH:26][N:27]=[CH:28][C:29]=1[Cl:30])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCBr
Reactant: CC(=O)[O-]
Agent: [K+]
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCOC(C)=O

Procedure:
The title compound can be prepared from potassium acetate and 8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 25) following the procedure outlined in Example 52. 1H NMR (400 MHz, CD3OD): δ 8.70 (s, 2H), 7.84 (d, 1H), 7.16 (d, 1H), 4.77 (s, 1H), 4.16 (t, 2H), 4.11 (t, 2H), 3.98 (s, 3H), 2.02 (s, 3H), 1.91 (m, 2H), 1.84 (m, 2H); MS (ESI): 466.9.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([C:38](=[O:47])/[CH:39]=[CH:40]/[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:22][C:23]([N:25]2[CH2:29][CH2:28][C@H:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26]2)=[O:24])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[NH2:30][C@H:27]1[CH2:28][CH2:29][N:25]([C:23](=[O:24])[CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([O:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:20][CH:19]=2)[C:38](=[O:47])/[CH:39]=[CH:40]/[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Oc3ccccc3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of [(S)-1-(2-{(4-phenoxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamic acid, tert-butyl ester 6 (60 mg) in dichloromethane (6 mL). The reaction mixture was stirred at room temperature for 30 min, and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1M NaOH, (×2), brine, dried (Na2SO4) and evaporated to dryness. The resultant residue was purified by column chromatography on silica gel, eluting with ethyl acetate/methanol/ammonium hydroxide (90:5:5) to give the title compound (10 mg). 1HNMR (300 MHz) (CDCl3) δ 1.6-2.3 (2H, m), 3.15-3.75 (5H, m), 4.40 (2H, m), 6.43 (1H, d, J=16 Hz), 7.02 (2H, d), 7.06 (2H, d), 7.15 (1H, t), 7.25-7.45 (9H, m) and 7.69 (1H, d J=16 Hz).
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:23])[CH2:19][CH2:20][CH:21]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([N:8]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:21][CH2:20][CH2:19][C:18]([O:17][CH3:16])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)NCc1ccccc1
Reactant: COC(=O)CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(C)N(CCCC(=O)OC)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of the product of Example 112, step a (794 mg, 3.8 mmol) in DCE (10 mL) was added methyl-4-oxobutanoate (0.891 mL, 7.7 mmol) followed by Na(OAc)3BH (1.6 g, 7.7 mmol). The mixture was stirred at room temperature overnight and then quenched by the addition of saturated aqueous NaHCO3 solution. The layers were separated and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 column eluting with EtOAc/Hex afforded the desired compound as a colorless liquid (1.11 g, 95%). MS (ESI) mass calcd. C17H25NO4, 307.2. m/z found 308.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.35-7.20 (m, 5H), 4.22-4.12 (m, 2H), 3.86-3.80 (m, 1H), 3.67-3.60 (m, 4H), 3.52-3.45 (m, 1H), 2.69-2.56 (m, 2H), 2.41-2.26 (m, 2H), 1.80-1.71 (m, 2H), 1.33-1.24 (m, 6H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[CH3:17])[N:13]=[CH:12][NH:11][C:10]2=O>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[CH3:17])[N:13]=[CH:12][N:11]=[C:10]2[Cl:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(Br)cc2c(=O)[nH]cnc2c1[N+](=O)[O-]
Product: Cc1c(Br)cc2c(Cl)ncnc2c1[N+](=O)[O-]
Temperature: 130 °C
Yield: 70 %

Procedure:
A mixture of phosphorous oxychloride (5 mL) and 6-bromo-7-methyl-8-nitroquinazolin-4(3H)-one (800 mg, 2.82 mmol) was refluxed at 130° C. for 4 h. On cooling, POCl3 was removed under reduced pressure. The resulting crude product residue was diluted with ice-water and extracted out of the aqueous layer with DCM (3×20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give 6-bromo-4-chloro-7-methyl-8-nitroquinazoline (595 mg, 70% yield) as an amorphous light yellow solid. MS (ESI, pos. ion) m/z: 302 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=1/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:12]([CH2:15][Br:16])=[CH:11][C:4]=1/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)/C=C\c1cc(C)ccc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C/c1cc(CBr)ccc1OC

Procedure:
As described in step b. of Example 16 methyl cis-2-methoxy-5-methylcinnamate was treated with N-bromosuccinimide in carbon tetrachloride to provide the oily title compound which was purified by chromatography on silica gel with ether/hexane: NMR in CDCl3 (δ units) 3.76 and 3.83 (singlet, 3); 4.43 (singlet, 2); 6.47 and 7.92 (doublet, J=16 Hz, 1); 6.83 (doublet, J=9 Hz, 1); 7.65 (multiplet, 2).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:24]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: c1ccc(COC2CCCNC2)cc1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Product: O=C(O)c1cc(S(=O)(=O)N2CCCC(OCc3ccccc3)C2)ccc1Cl

Procedure:
2-Chloro-5-chlorosulfonylbenzoic acid is reacted with 3-benzyloxypiperidine by the method of Example 1. Recrystallization from ether-hexane yields the product, m.p. 173°-174° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[OH:30]>>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[OH:30])=[O:9]
Reactant: O=C(O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F
Reactant: N[C@@H]1CCCC[C@H]1O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(pyridin-2-ylmethoxy)-2-trifluoromethyl-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials, MS (ISP) 476.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.O.[NH2:16][NH2:17]>N1C=CC=CC=1>[NH:16]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[NH2:17]
Reactant: NN
Reactant: Fc1ccc(-c2cnc(Cl)nn2)cc1
Solvent: O
Solvent: c1ccncc1
Product: NNc1ncc(-c2ccc(F)cc2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 9.8 g. of 3-chloro-6-(p-fluorophenyl)-1,2,4-triazine in 125 ml. of pyridine is cooled to 0° C. and 15 ml. of hydrazine hydrate is added. The mixture is stirred at room temperature for one hour and then poured into icewater. The solid is recovered by filtration and washed with ethanol, giving 3-hydrazino-6-(p-fluorophenyl)-1,2,4-triazine as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])(=O)C.[Na+]>C(O)C.C(OCC)C>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CNc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aniline (0.096 mole), ethyl bromoacetate (0.096 mole) and sodium acetate (0.096 mole) in ethanol (150 ml) were refluxed for four hours and stirred at room temperature for 18 hours. The ethanol was removed by a rotary evaporator to give an oil. The oil was dissolved in ethyl ether (200 ml), filtered and the solvent removed by a rotary evaporator. The dark oily residue crystallized from cold hexane. Structural assignment was supported by NMR and the compound is used as is to prepare title compound of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][C:21](=[O:23])[C:20]4[N:24]([CH3:27])[CH:25]=[CH:26][C:19]=4[S:18]3(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH:21]([OH:23])[C:20]4[N:24]([CH3:27])[CH:25]=[CH:26][C:19]=4[S:18]3(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1ccc2c1C(=O)CN(CCCN1CCN(c3ccc(F)cc3)CC1)S2(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1ccc2c1C(O)CN(CCCN1CCN(c3ccc(F)cc3)CC1)S2(=O)=O
Yield: 85.2 %

Procedure:
To a suspension of 42 mg (0.1 mmol) of Compound 21 in 5 ml of ethanol, 38 mg (1 mmol) of sodium borohydride were added gradually under ice-cooled stirring. The resulting mixture was stirred under ice cooling for 1 hour and further at room temperature for 13 hours. Water (5 ml) was added to the reaction mixture. The thus-obtained mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. Post treatment and purification were conducted as in Example 15, whereby 36 mg of the title compound were obtained (yield: 85%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:28])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:29]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH2:30][CH2:31][CH3:32]>>[CH2:29]([N:33]1[CH2:38][CH2:37][N:36]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:28])[NH:11][C:12]3[CH:13]=[CH:14][C:15]([S:18]([N:21]([CH2:22][CH2:23][OH:24])[CH2:25][CH2:26][OH:27])(=[O:19])=[O:20])=[CH:16][CH:17]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:35][CH2:34]1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)N(CCO)CCO)cc2)c1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)N(CCO)CCO)cc3)c2)CC1
Yield: 18 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N,N-bis(2-hydroxyethyl)benzenesulfonamide following procedure C and using 2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li][CH2:17][CH2:18][CH2:19][CH3:20].C(C(C)=O)C.OS(O)(=O)=O>C1COCC1>[CH2:18]([C:19]1([CH3:20])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH3:11])[C:3]2[C:2]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:17]
Reactant: [Li]CCCC
Reactant: CN(c1ccccc1)c1ccccc1Br
Agent: O=S(=O)(O)O
Solvent: CCC(C)=O
Solvent: C1CCOC1
Product: CCC1(C)c2ccccc2N(C)c2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A flame-dried two-necked flask was charged with 2-bromo-N-methyl-N-phenylaniline (1.0 g, 3.8 mmol) and 100 mL dry THF under argon and cooled to −78° C. in a dry ice-acetone bath. 2.6 mL of a 1.6 M solution of n-BuLi in hexanes (4.16 mmol) was added dropwise over 5 minutes and the reaction stirred at −78° C. under argon for 1 h. Methyl ethyl ketone (0.302 g, 4.2 mmol) was added in one portion to the reaction mixture at −78° C., the reaction allowed to warm to room temperature and stirred overnight under argon. After quenching with saturated ammonium chloride, the reaction was extracted with Et2O, the organic layers combined, washed with brine and water and dried over anhydrous MgSO4 and the solvent evaporated under reduced pressure. To the neat residue thus obtained was added 2 mL of concentrated H2SO4 under argon and the mixture stirred at room temperature for 1 h under argon. After dilution with 30 mL DI H2O, the reaction was extracted with Et2O (5×50 mL), the organic layers were combined, washed with brine and water and dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using hexanes as the eluent to yield 0.57 g (57%) of the desired compound as a clear oil. 1H NMR (400 MHz, CHCl3) δ 1.66 (dd, J=6.8 Hz, J=0.8 Hz, 3H), 1.78 (t, J=1.2 Hz, 3H), 3.10 (s, 3H), 5.49 (m, 1H), 6.66 (m, 3H), 7.18 (m, 6H). 13C NMR (100 MHz, CHCl3) δ 14.2, 15.2, 16.5, 24.2, 39.2, 39.6, 113.8, 114.1, 117.1, 117.4, 122.4, 124.4, 125.7025.9, 128.0, 128.2, 128.5, 128.8, 128.9, 130.6, 131.5, 136.4, 140.4, 144.3, 145.8, 146.9, 149.2, 149.4. HRMS (ESI) calc for C17H19N [M+H]+ 238.1590, found 238.1587. IR (KBr plate) 692 (m), 747 (m), 1345 (m), 1444 (m), 1499 (s), 1592 (s), 1602 (s), 2918 (m), 3024 (m) cm−1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C@:8]2([C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[O:13][C@H:12]([C:21]([NH2:23])=[O:22])[CH2:11]2)[NH:7][C:6]1=[O:24].[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C@:8]3([C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[O:13][C@H:12]([C:21]([NH2:23])=[O:22])[CH2:11]3)[NH:7][C:6]2=[O:24])[CH2:28][CH2:27]1
Reactant: OC1CCNCC1
Reactant: NC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCCl)C2=O)c2cc(F)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCN3CCC(O)CC3)C2=O)c2cc(F)ccc2O1
Temperature: 80 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
A mixture of (2S,4S)-1'-(3-chloropropyl)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (Reference Example 2, 15.0 g, 42.2 mmol), 4-hydroxypiperidine (8.52 g, 84.4 mmol), K2CO3 (7.00 g, 50.7 mmol) and N,N-dimethylformamide (100 ml, 1.29 mol) was stirred for 5 hours at 80° C. After distilling off the solvent, the residue was chromatographed on silica gel, eluted with CH2Cl2 /MeOH/NEt2 (5/1/1), and recrystallized from AcOEt/MeOH to give prism crystals of the desired compound (16.2 g, 91.5%).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]#[CH:6].O1CCCC1.C([Li])CCC.[CH2:28]([C:30]([CH2:32][CH3:33])=[O:31])[CH3:29]>CCCCCC>[CH3:1][N:2]([CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]#[C:6][C:30]([CH2:32][CH3:33])([OH:31])[CH2:28][CH3:29]
Reactant: C#CCCN(C)Cc1cccc2ccccc12
Reactant: CCC(=O)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)(C#CCCN(C)Cc1cccc2ccccc12)CC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2 g N-methyl-N-(1-naphthylmethyl)-3-butyn-amine in abs. tetrahydrofurane (THF) are added dropwise, at -70°, 5.6 ml of a 15% by weight solution of n-butyllithium in hexane and half an hour later, at -70°, 0.95 ml diethylketone. The mixture is stirred for 3 hours at room temperature, poured onto ice and extracted with ether. The organic phase is washed, dried and evaporated in vacuum. The title compound (Compound 25) is obtained as an oil by chromatography over silica gel (with toluene/ethylacetate 3/1).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:11]=[C:12]([S:21](Cl)(=[O:23])=[O:22])[CH:13]=[C:14]([CH:17]([CH2:19][CH3:20])[CH3:18])[C:15]=2[OH:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Br.[Br:26][CH2:27][CH2:28][NH2:29].C(N(CC)CC)C>C(#N)C>[N:1]1[N:2]([C:10]2[CH:11]=[C:12]([S:21]([NH:29][CH2:28][CH2:27][Br:26])(=[O:23])=[O:22])[CH:13]=[C:14]([CH:17]([CH2:19][CH3:20])[CH3:18])[C:15]=2[OH:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCC(C)c1cc(S(=O)(=O)Cl)cc(-n2nc3ccccc3n2)c1O
Reactant: NCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(C)c1cc(S(=O)(=O)NCCBr)cc(-n2nc3ccccc3n2)c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.9 %

Procedure:
To a stirred suspension of 3-benzotriazol-2-yl-5-sec-butyl-4-hydroxybenzenesulfonyl chloride (14.19 g, 0.0388 mol) and 2-bromoethylamine hydrobromide (8.44 g, 0.0412 mol) in acetonitrile (100 g) at 0-5° C. under nitrogen was added dropwise a solution of triethylamine (8.05 g, 0.0796 mol) in acetonitrile (60 g). When the addition was complete, the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was suction filtered and the filter cake was washed with acetonitrile (20 g). The filtrate was spin-evaporated and the residue was suspended in water (130 g). The suspension was suction filtered and the filter cake was dried to give 10 g of 3-benzotriazol-2-yl-N-(2-bromoethyl)-5-sec-butyl-4-hydroxy-benzenesulfonamide as a white powder.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCCCCC>[CH2:14]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C=CCOc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-trifluoromethyl phenol (4.05 g, 0.025 mol) and allyl bromide in acetone (50 mL) was added K2CO3 (3.5 g, 0.025 mol). The mixture was stirred overnight at 60° C. and was diluted with n-hexane. The solution was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to 1-alkyloxy-3-trifluoromethyl-benzene (4.0 mg, 79%).
Reaction SMILES: O[N:2]1[C:11]([CH3:12])=[C:10]([CH2:13][C:14]([OH:16])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].P(Cl)(Cl)Cl>C(OCC)(=O)C>[CH3:12][C:11]1[NH:2][C:3](=[O:17])[C:4]2[C:9]([C:10]=1[CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1c(CC(=O)O)c2ccccc2c(=O)n1O
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1[nH]c(=O)c2ccccc2c1CC(=O)O
Temperature: 0 °C

Procedure:
1,2-Dihydro-2-hydroxy-3-methyl-1-oxo-4-isoquinoline acetic acid (4.0 g., 17.2 mmol) dissolved in 30 ml. ethyl acetate at 0° was reacted with phosphorous trichloride (1.50 ml., 17.2 mmol). The mixture was heated at 80° for 1.5 hr then poured onto 100 g. of ice water, stirred for 16 hr and filtered yielding a light yellow crude product; 3.307 mg (89%) mp 280°-295° d. Recrystallization from acetic acid afforded analytically pure material of mp 295°-300° d.
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[CH2:21]([SH:24])[CH2:22][SH:23]>>[SH:23][CH2:22][CH2:21][S:24][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Reactant: SCCS
Product: CC1(c2ccccc2)OC(CC(SCCS)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 1,2-ethanedithiol to provide 5-[2-[(2-mercaptoethyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (CDCl3) δ1.63 (m, 1H) and overlapping 1.65 and 1.68 (singlets, 3H), 2.47-2.80 (m, 4H), 3.07-3.25 (m, 2H), 4.47 (m, 1H), 5.37 and 5.39 (singlets, 1H), 7.05-7.18 (m, 2H), 7.25-7.45 (m, 6H); MS (HR-EI) m/z 376.0605 (M+ calcd. for C19H20O2S3 376.0626).