Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.[CH2:24]([O:26][C:27](=[O:36])[CH:28](Br)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[CH2:24]([O:26][C:27](=[O:36])[CH:28]([N:12]1[C:11]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:25]
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)[nH]c2cc1F
Reactant: CCOC(=O)C(Br)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 100 °C
Yield: 75.9 %

Procedure:
To the solution of 75 g (0.28 mol) 2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole in 750 ml N,N-dimethylformamide 116 g (0.33 mol) cesium carbonate and 88 g (0.35 mol) bromo-cyclohexyl-acetic acid ethyl ester (commercially available) were added. The mixture was heated to 100° C. and after stirring for 90 min. another 116 g cesium carbonate and 88 g bromo-cyclohexyl-acetic acid ethyl ester were added. After 6 h another 116 g cesium carbonate and 88 g bromo-cyclohexyl-acetic acid ethyl ester were added. After 22 h (total reaction time) the reaction mixture was cooled to 30° C. and was poured on 1 L ice water and 2 L ethyl acetate. The phases were separated and the aqueous phase extracted with 500 mL ethyl acetate. The combined organic phases were washed three times with 500 ml ice water and once with brine, dried over magnesium sulfate and filtered. To the solution, silica gel was added and the solvent evaporated. The crude adsorbed product was purified by column chromatography over silica gel using n-heptane:ethyl acetate (9:1 v/v) as eluant. The product-containing fractions were pooled and the solvent evaporated until a suspension had formed. The suspension was cooled in an ice bath and filtered to give 92 g (75%) of the desired product as colorless solid.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].Cl[C:5]1[C:6]([C:11]#[N:12])=[N:7][CH:8]=[CH:9][CH:10]=1.CN(C=O)C.[H-].[Na+]>O>[CH2:1]([S:3][C:5]1[C:6]([C:11]#[N:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCS
Reactant: N#Cc1ncccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cccnc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.9 mL of ethanethiol was added to a mixture of 1.39 g of 3-chloropyridine-2-carbonitrile and 10 mL of DMF, 0.52 g of 60% sodium hydride (oil-based) was added to the reaction mixture under ice cooling, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 1.52 g of 3-ethylsulfanylpyridine-2-carbonitrile.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.Cl.[F:24][C:25]1([F:31])[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26]1>>[F:24][C:25]1([F:31])[CH2:29][CH2:28][CH:27]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:26]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NC1CCC(F)(F)C1
Agent: Cl
Product: Cc1nc(NCc2ccccn2)nc(NC2CCC(F)(F)C2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 3,3-difluorocyclopentylamine hydrochloride instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.73-2.27 (m, 9H), 2.36 (s, 3H), 3.30-3.34 (m, 2H), 4.30-4.40 (m, 1H), 7.73 (t, J=6.4, 1H), 7.84 (d, J=8.1, 1H), 8.28 (t, J=6.7, 1H), 8.70 (d, J=5.1, 1H); MS (ESI) m/z 334 (M+1)+.
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:57][O:58][C:59]1[N:64]=[CH:63][C:62](B(O)O)=[CH:61][CH:60]=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]4)=[CH:7][CH:8]=3)[C:3](=[O:30])[C:2]=2[C:62]2[CH:63]=[N:64][C:59]([O:58][CH3:57])=[CH:60][CH:61]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCN4CCS(=O)(=O)CC4)cc3C2=O)cn1
Yield: 68 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 of Example 92 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 6-methoxy-3-pyridinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (68%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[H-].[Li+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH2:16]([N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5][C:6]1=[O:12])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCn1c2c(ccc1=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (10.0 g), lithium hydride (0.78 g), and dimethylformamide (400 ml) was stirred for 3 hrs at 25° C., under nitrogen. 1-Bromohexane (10.6 g) was added and the mixture was stirred for an additional eighteen hrs. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel, two columns, eluted with 50% ethyl acetate/hexane). The appropriate fractions were collected and evaporated to give 4.6 (31%) of 1-hexyl-5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:27]1[S:28][CH:29]=[CH:30][N:31]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: Ic1nccs1
Product: CC(C)(C)OC(=O)N1Cc2ccc(-c3nccs3)cc2C1

Procedure:
Prepared in analogy to Example A23(b) from 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 2-Iodo-thiazole (CAS: 3034-54-6). Yellow oil. MS (m/e): 303.1 ([M+H]+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=3[N:11]([CH2:12][CH2:13][CH2:14]Cl)[C:4]=2[CH:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23].[I-].[Na+].[C:28]([OH:37])(=[O:36])[CH:29]([CH:31]([C:33]([OH:35])=[O:34])O)O.C(O)(=O)/C=C\C(O)=O>C(O)(C)C.O.C(C(C)=O)C>[C:28]([OH:37])(=[O:36])/[CH:29]=[CH:31]\[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=3[N:11]([CH2:12][CH2:13][CH2:14][NH:25][CH:22]([CH3:24])[CH3:23])[C:4]=2[CH:3]=1
Reactant: CC(C)N
Reactant: ClCCCN1c2ccccc2OCOc2ccc(Cl)cc21
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: O=C(O)/C=C\C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Solvent: CC(C)O
Product: CC(C)NCCCN1c2ccccc2OCOc2ccc(Cl)cc21
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of 32.4 g. (0.10 moles) of 2-chloro-12-(3-chloropropyl)-12H-dibenzo[d,g][1,3,6]dioxazocine prepared by the method of Example 1, 11.8 g. (0.20 moles) of isopropyl amine, 7.5 g. of sodium iodide and 200 ml. of methyl ethyl ketone is stirred under reflux for 20 hours. Thereafter the solvent is removed in vacuo, 100 ml. of benzene are added to the residue and the mixture obtained is washed with water. Thereafter 37.5 g. (0.25 moles) of tartaric acid and 150 ml. of water are added to the organic phase and the reaction mixture is stirred for 30 minutes. The aqueous phase is separated, 150 ml. of methylene chloride are added thereto and the pH is adjusted to 10 by using aqueous ammonia. The organic phase is separated and the solvent is removed. The residue is dissolved in 100 ml. of isopropanol and a solution of 9.5 g (0.82 moles) of maleic acid is added thereto. The precipitated white product is filtered off, dried and recrystallized from isopropanol. There are obtained 32.4 g. (70.0%) of the title product, melting at 126° to 129° C.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][N:16]([CH2:18][CH3:19])[CH2:15][CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1.S(Cl)([Cl:22])=O>ClCCCl>[Cl:22][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][N:16]([CH2:18][CH3:19])[CH2:15][CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1
Reactant: O=S(Cl)Cl
Reactant: CCN1CCc2sc3ncn(CCO)c(=O)c3c2C1
Solvent: ClCCCl
Product: CCN1CCc2sc3ncn(CCCl)c(=O)c3c2C1
Yield: 83 %

Procedure:
10.5 g (37.6 mM [sic]) of 3-(2-hydroxyethyl)-6-ethyl-3,4, 5,6,7,8-hexahydropyrido[3',4':4,5]thieno-[2,3-d]pyrimidin-4-one in 100 ml of 1,2-dichloroethane were heated to reflux (slow dissolution) and then 3.5 ml (48 mM [sic]) of thionyl chloride in 20 ml of 1,2-dichloroethane were added dropwise. After refluxing for 1 h, the reaction mixture was allowed to cool, and the solid was filtered off with suction and washed with 1,2-dichloroethane. The crude product was partitioned between methylene chloride and water at pH=9. The organic phase was dried and concentrated to isolate 9.3 g (83%) of product as a dark oil which slowly crystallized and is sufficiently pure for further reactions, melting point 94-96° C.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[OH:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([OH:23])=[CH:25][CH:26]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: Oc1ccc(CCBr)cc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCN(CCc2ccc(O)cc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)piperidine (0.3 g), 4-hydroxyphenethyl bromide (0.21 g), sodium bicarbonate (0.3 g) and acetonitrile (15 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography, firstly on silica eluting with dichlorometbane containing methanol (0% up to 6%), and then on alumina eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as colourless microcrystals, yield 0.042 g, m.p. 135°-140° C.
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]([CH2:35][CH2:36][O:37][C:38](=[O:51])[C@H:39]([CH:48]([CH3:50])[CH3:49])[NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:23][N:24]1[CH:32]=[N:31][C:30]2[C:29](=O)[NH:28][C:27]([NH2:34])=[N:26][C:25]1=2)(=[O:19])[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].C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:65])=O>C(#N)C.[Cl-].C[N+](C)(C)C>[NH2:34][C:27]1[N:26]=[C:25]2[C:30]([N:31]=[CH:32][N:24]2[CH2:23][C@H:22]([CH2:21][O:20][C:1](=[O:19])[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])[CH2:35][CH2:36][O:37][C:38](=[O:51])[C@H:39]([CH:48]([CH3:50])[CH3:49])[NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:29]([Cl:65])[N:28]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CCN(CC)c1ccccc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(Cl)nc(N)nc21

Procedure:
To a solution of (R)-9-(2-stearoyloxymethyl-4-(N-tert-butoxycarbonyl-L-valyloxy)butyl)guanine from step b) of Example 1 (646 mg, 0.9 mmole) in acetonitrile were added tetramethylammonium chloride (427 mg, 2.7 mmole), N,N-diethylaniline (0.716 ml, 4.5 mmole) and phosphorous oxychloride (0.417 ml, 4.5 mmole). The reaction was kept under reflux and the progression monitored by TLC. After 3 hours the reaction mixture was evaporated in vacuo and the residue was dissolved in dichloromethane, then poured into cold sodium hydrogen carbonate aqueous solution. The organic phase was evaporated and purified by silica gel column chromatography. Yield: 251 mg.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:27]([CH:28]([CH2:32]C)[CH2:29][CH2:30][CH3:31])[C:8]2[N:9]=[C:10]([N:13]=C(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Cl.CCCCCCC.CCOC(C)=O>C1COCC1>[CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:27]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[C:8]2[N:9]=[C:10]([NH2:13])[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CCCC(CC)n1c(C(=O)N(C)C)cc2cnc(N=C(c3ccccc3)c3ccccc3)nc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cnc(N)nc2n1C1CCCC1
Reaction time: 0.33 h
Yield: 76.9 %

Procedure:
To a solution of 2-(benzhydrylidene-amino)-7-(1-ethyl-butyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (3.5 g, 8.0 mmol) in 26.7 mL THF was added aqueous 2M HCl (1.32 mL) and the mixture was stirred for 20 min. To this was added 60 mL heptane:EtOAc (4:1 v/v) and 60 mL aqueous 0.5N HCl and the layers were separated. The acidic aqueous layer was basified to pH 10 with aqueous 25% NaOH solution and extracted again with EtOAc. The organic extract was then washed with brine, dried (Na2SO4), concentrated and purified via SiO2 column chromatography (0-20% MeOH in EtOAc) to give 2-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as a white solid (1.68 g, 6.15 mmol, 77% yield). MS m/z 274.4 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.Cl>O1CCOCC1.CCOC(C)=O>[Cl:27][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1
Reactant: CCN(CC)c1nc2ccc(Cl)cc2c(-c2cccc(C(C)C)c2)c1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN(CC)c1nc2ccc(Cl)cc2c(-c2cccc(C(C)C)c2)c1C(=O)O
Temperature: 25 °C
Yield: 81.5 %

Procedure:
To 6-chloro-2-diethylamino-4-(3-isopropyl-phenyl)-quinoline-3-carboxylic acid tert-butyl ester (75 mg, 0.17 mmol) was added a solution of HCl in dioxane (4N, 3 ml), and the mixture was heated to reflux for 4 h. The reaction mixture was then cooled to room temperature and then concentrated in vacuo to give a crude residue which was diluted with EtOAc (20 ml). The organic layer was washed with brine (10 ml), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 6-chloro-2-diethylamino-4-(3-isopropyl-phenyl)-quinoline-3-carboxylic acid (55 mg, 84%) as a pale yellow solid. LC-MS (ESI): 397 (M+H)+.
Reaction SMILES: C([SiH]([CH2:6][CH3:7])CC)C.C(O[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:32][CH2:31]2)=[CH:26][CH:25]=1)O)C1C=CC=CC=1.[OH2:33]>C(#N)C>[CH2:22]([O:33][C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:24]2[CH:25]=[CH:26][C:27]([CH:30]3[CH2:31][CH2:32]3)=[CH:28][CH:29]=2)[CH:6]=[CH:29][CH:24]=[CH:25][CH2:26]1)[C:17]1[CH:16]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(c1ccc(C2CC2)cc1)c1ccccc1OCc1ccccc1
Reactant: CC[SiH](CC)CC
Reactant: O
Solvent: CC#N
Product: C1=CCC(OCc2ccccc2)(c2ccccc2Cc2ccc(C3CC3)cc2)C=C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
In a nitrogen stream, triethylsilane (0.73 mL, 4.6 mmol) and a boron trifluoride-diethyl ether complex (0.5 mL, 4.0 mmol) were added to a solution of (2-benzyloxyphenyl)-(4-cyclopropylphenyl)methanol (1.3 g, 4.0 mmol) in acetonitrile (7 mL) at −40° C. and the mixture solution was stirred at the same temperature for 1.5 hours and furthermore at 0° C. for 30 minutes. Water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:7)] to obtain the title compound (1.2 g, 95%).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[F:27][C:28]([F:39])([F:38])[C:29]1([CH2:32]OS(C)(=O)=O)[CH2:31][CH2:30]1>>[CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][N:24]([CH2:32][C:29]5([C:28]([F:39])([F:38])[F:27])[CH2:31][CH2:30]5)[CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Product: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(CC4(C(F)(F)F)CC4)CC2)C3)cc1

Procedure:
The title compound is prepared from 5-(4-methanesulfonylmethyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 2. LC (method 1): tR=0.95 min; Mass spectrum (ESI+): m/z=495 [M+H]+.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1I.Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C(NCC)C>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6]
Reactant: Brc1ccccc1I
Reactant: C#CCCC(=O)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCNCC
Product: O=C(O)CCC#Cc1ccccc1Br
Reaction time: 2 h

Procedure:
To 10 ml of diethylamine was added with stirring 0.5 g (5.1 mmol) of 4-pentynoic acid, 1.4 g (5 mmol) of 1-bromo-2-iodobenzene, and 60 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium(0) The slurry was degassed with argon and 0.19 g (1.0 mmol) of CuI was added. The reaction mixture was stirred for 2 hr. at room temperature and then poured into approximately 100 ml of a 10% HCl solution. The resulting precipitate was filtered, washed with water and dried. The solid was taken up in hot CHCl3 and filtered to remove insoluble salts. After evaporation of the solvent, the resulting orange solid was recrystallized from a a chloroform-hexane mixture to produce a tan solid, m.p. 87°-91° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[CH2:10]1[O:18][C:17]2[C:12](=[C:13]([S:19]([NH:22]C(OC(C)(C)C)=O)(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=2)[O:11]1.FC(F)(F)C(O)=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[CH2:10]1[O:18][C:17]2[C:12](=[C:13]([S:19]([NH2:22])(=[O:20])=[O:21])[CH:14]=[CH:15][CH:16]=2)[O:11]1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)c1cccc2c1OCO2
Agent: COCCNCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 199.4 %

Procedure:
Boc methylenedioxybenzenesulfonamide bis-methoxyethylamine tethered product (18) (0.023 g, 0.033 mmol) was dissolved in DCM (1 mL). Trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo, and the resultant orange oil was dissolved in DCM (1 mL) and the solution cooled to 0° C. using an ice bath. Diisopropylethylamine (0.173 mL, 0.99 mmol) was added dropwise with stirring, followed by (3R,3aS,6aR) hexahydrofuro[2,3-b]furan-2-yl 4-nitrophenyl carbonate (0.012 g, 0.040 mmol) in one portion as a solid. After 5 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature with stirring overnight. The solvent was removed in vacuo, and the resultant yellow oil was purified by flash column:chromatography (4:1 ethyl acetate/hexane to ethyl acetate to 9:1 DCM/methanol) to give bis-THE methylenedioxybenzenesulfonamide bis-methoxyethylamine tethered product (51) (0.022 g, 89%) as a yellow foam: Rf=0.50 (9:1 DCM/methanol); 1H NMR (CDCl3): 7.33 (1H, dd, J=8.2, 1.8 Hz), 7.17 (1H, d, J=1.8 Hz), 7.13 (2H, d, J=8.6 Hz) 6.89 (1H, d, J=8.2 Hz), 6.80 (2H, d, J=8.6 Hz), 6.09 (2H, s), 5.65 (1H, 8, J=5.2 Hz), 5.08-4.98 (2H, m), 4.35-4.24 (2H, m), 4.00-3.90 (1H, m), 3.90-3.63 (6H, m), 3.61-3.49 (2H, m), 3.42-3.31 (2H, m), 3.35 (6H, s), 3.16-3.07 (2H, m), 3.05-2.88 (4H, m), 2.88-2.74 (2H, m), 1.83 (1H; septet, J=6.6 Hz), 1.74-1.54 (1H, m), 1.48-1.35 (5H, m); 0.92 (3H, d, J=6.6 Hz), 0.88 (3H, d, J=6.6 Hz), OH signal not observed; coupled LCMS showed the product as a single major peak with m/z 752 [M+H]+; HPLC (205 nm) showed the material as a single major peak at RT of 1.92 min. (purity=91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Cl)ccc1C(=O)O
Product: COc1cc(Cl)ccc1C(=O)Cl

Procedure:
A solution of 2.0 g of 4-chloro-o-anisic acid in 22 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.0 g of the desired product as a residue.