Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)[C:3]=12.[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2scc(-c3cccc(C)c3)c2c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc2sc(Br)c(-c3cccc(C)c3)c2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a stirred solution of ethyl 4-amino-6-methyl-3-(3-methylphenyl)thieno[2,3-b]pyridine-5-carboxylate (Description 57) (880 mg, 2.70 mmol) in DCM (10 mL) at RT was added dropwise N-bromosuccinimide (528 mg, 2.97 mmol) pre-dissolved in DCM (15 mL). The reaction mixture stirred at RT under nitrogen atmosphere for ca. 1 h. The reaction mixture was then quenched with saturated NaHCO3 aqueous solution and the aqueous layer separated and re-extracted with DCM (ca. 30 mL). The combined organic layer was then passed through a phase separator and the solvent removed in vacuo. Purification by chromatography on silica, eluting with a gradient of 0-40% ethyl acetate in cyclohexane afforded the title compound (900 mg). LCMS (A) m/z: 405/407 [M+1]+, Rt 1.55 min (acidic).
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:6]([CH2:20][CH2:21][OH:22])[S:7]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][C:11]=2[CH3:19])(=[O:9])=[O:8])[CH2:5][CH2:4]1.[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:3]1([N:6]([CH2:20][CH2:21][O:22][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])[S:7]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][C:11]=2[CH3:19])(=[O:9])=[O:8])[CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc(C)c(S(=O)(=O)N(CCO)C2CC2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)OC(C)(C)C)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
tetra-n-Butylammonium chloride (0.33 eq) and 35% sodium hydroxide solution (18 ml) were added to a solution of N-cyclopropyl-N-(2-hydroxyethyl)-4-methoxy-2,6-dimethylphenylsulfonamide (3.3 mmol) in toluene (18 ml), cooled to 0° C. tert-Butylbromoacetate (1.5 eq) was added slowly to this mixture at 0° C. On completion of the addition the mixture was stirred for 90 min at 25° C. until the reaction was complete. The organic phase was separated off, washed with water until a neutral pH was measured, dried over MgSO4, filtered and concentrated completely to obtain the desired product. Yield: 90%
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH:7]2[N:9]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]4[NH:22][C:23]5[C:28]([CH:29]=4)=[C:27](Br)[CH:26]=[CH:25][CH:24]=5)=[O:20])[CH2:14][CH2:13]3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[OH:1][CH:2]1[CH2:8][CH:7]2[N:9]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]4[NH:22][C:23]5[C:28]([CH:29]=4)=[C:27]([C:36]4[CH:37]=[N:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)[CH:26]=[CH:25][CH:24]=5)=[O:20])[CH2:14][CH2:13]3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1
Reactant: O=C(NC1CCN(CCN2C3CCC2CC(O)C3)CC1)c1cc2c(Br)cccc2[nH]1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCN5C6CCC5CC(O)C6)CC4)cc23)cn1

Procedure:
This compound is synthesized from compound 197 (see example 175) and (6-methoxy-pyridin-3-yl)-boronic acid analogously to the method described in Example 156.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:23])[CH2:21]Cl)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(=O)=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]2[CH2:21][O:23]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2c(C(O)CCl)ccc(OCc3ccccc3)c2[nH]1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1ccc2c(C3CO3)ccc(OCc3ccccc3)c2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 20 g (61 mmol) 8-benzyloxy-5-(2-chloro-1-hydroxy-ethyl)-1H-quinolin-2-one in 160 mL DMF is added dropwise at 0° C. to 35 mL of a 4 molar sodium hydroxide solution and then stirred for 2 hours at this temperature. The reaction mixture is combined with 1.5 L ice water, buffered by the addition of dry ice and extracted with ethyl acetate. The organic phases are dried with sodium sulphate, the solvent is distilled off and the residue is chromatographed over aluminium oxide (dichloromethane/ethyl acetate gradient). The fractions containing the product are evaporated down to 60 mL and then combined with petroleum ether, during which time a solid is precipitated, which is suction filtered and dried.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:27](Br)[CH:28]=[CH2:29]>C1COCC1>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH2:15][CH2:29][CH:28]=[CH2:27])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCBr
Reactant: CC(=O)c1ccc(Sc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCC(=O)c1ccc(Sc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
20 mmol of 1-(4-(phenyl thio)phenyl)ethanone was dissolved in 100 mL of THF, and cooled at −78° C. To this, 22 mmol of lithium hexamethyldisilazide was added dropwise and stirred for 1 hour. Further, 20 mL of THF solution of 20 mmol of allyl bromide was added dropwise over 10 minutes and a solution temperature was slowly set back to room temperature, and further stirred for 1 hour. Then quenching was carried out with 100 mL of water. An organic layer was extracted with ethylacetate, and washed with an aqueous sodium chloride. Thereafter, the organic layer was concentrated. The thus-obtained mixture was purified by column chromatography (hexane/ethyl acetate=10/1). Thereby, 1-(4-(phenyl thio)phenyl)pent-4-en-1-one having the following structure was obtained with a yield of 52%.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].Cl.Cl.[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][O:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][C:37]3=[O:41])=[CH:13][C:12]=2[N:11]=1.C(N(CC)CC)C>ClCCl>[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][O:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][C:37]3=[O:41])=[CH:13][C:12]=2[N:11]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCN4CCCC4=O)ccc3c2n1CCCCN
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(OCCCN4CCCC4=O)ccc3c2n1CCCCNC(=O)NC(C)C
Reaction time: 1.5 h
Yield: 71.2 %

Procedure:
Isopropyl isocyanate (0.187 mL, 1.90 mmol) was added dropwise to a stirred solution of 1-(3-{[4-amino-1-(4-aminobutyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)pyrrolidin-2-one dihydrochloride (prepared as described in Example 398, 1.0 g, 1.90 mmol) and triethylamine (0.530 mL, 3.80 mmol) in dichloromethane (20 mL) at room temperature. After 1.5 hours, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, gradient elution with 2-12% CMA in chloroform) followed by recrystallization from acetonitrile to yield 0.730 g of N-(4-{4-amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butyl)-N′-isopropylurea as an opaque solid, mp 98-101° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([CH3:12])[C:3]=1[C:13]([F:16])([F:15])[F:14].C(O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:12])[C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: CC(=O)Nc1ccc(Br)c(C(F)(F)F)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(N)ccc(Br)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
To a mixture of N-[4-bromo-2-methyl-3-(trifluoromethyl)phenyl]acetamide (9.0 g) and ethanol (40 mL) was added concentrated hydrochloric acid (40 mL) at room temperature. The reaction mixture was stirred at 100° C. for 4 hours. The reaction mixture was left to be cooled to room temperature, and ethyl acetate and water were added thereto, followed by alkalification with potassium carbonate. Then, a liquid-separation operation was carried out, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate 90:10-60:40) to obtain 4-bromo-2-methyl-3-(trifluoromethyl) aniline (6.9 g).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.Cl.[CH2:16]([O:23][NH2:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.FC(F)(F)C(O)=O>N1C=CC=CC=1.C(Cl)Cl>[CH2:16]([O:23][N:24]=[C:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CON=C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 4-oxopiperidine-1-carboxylate (524 mg, 2.63 mmol) and O-benzylhydroxylamine hydrochloride (504 mg, 3.16 mmol) in pyridine (5 mL) was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ether and H2O. The separated organic phase was washed with 1 N aqueous HCl and brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 816 mg of crude N-tert-butoxycarbonyl intermediate. This material was taken up in CH2Cl2 (5 mL), followed by addition of trifluoroacetic acid (5.0 mL, 65.0 mmol) via syringe. After stirring for 30 minutes at ambient temperature, the reaction was cooled to 0° C. and quenched by slow addition of 2 N aqueous NaOH solution (35 mL). The mixture was diluted with 75 mL CH2Cl2 and the phases were separated. The organic layer was washed with 1 N aqueous NaOH solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.27 (m, 5H), 5.07 (s, 2H), 3.02-2.94 (m, 2H), 2.94-2.86 (m, 2H), 2.63-2.54 (m, 2H), 2.33-2.23 (m, 2H), 1.58 (bs, 1H); MS (DCI+) m/z 205 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[C:14]1[N:15]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([CH3:29])[CH:24]=[CH:23]3)[C:16]([NH2:19])=[N:17][N:18]=1.Br[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[CH:34]2.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O1CCOCC1>[CH:11]([C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:14]2[N:15]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([CH3:29])[CH:24]=[CH:23]4)[C:16]([NH:19][C:31]3[CH:32]=[C:33]4[C:38](=[CH:39][CH:40]=3)[N:37]=[CH:36][CH:35]=[CH:34]4)=[N:17][N:18]=2)[CH:5]=1)([CH3:13])[CH3:12]
Reactant: COc1cc(OC)c(C(C)C)cc1-c1nnc(N)n1-c1ccc2c(ccn2C)c1
Reactant: Brc1ccc2ncccc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(OC)c(C(C)C)cc1-c1nnc(Nc2ccc3ncccc3c2)n1-c1ccc2c(ccn2C)c1
Temperature: 95 °C
Yield: 87.9 %

Procedure:
A tube was charged with 5-(2,4-bismethoxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-amine (0.25 mmol, 100 mg.), 6-bromoquinoline (0.5 mmol, 100 mg.), tris(dibenzylideneacetone) dipalladium(O), (10 mol %), cesium carbonate (1 mmol, 326 mg.), Xantphos (20 mol %), and dioxane (2 mL). The reaction is place under an atmosphere of nitrogen, and heated to 95° C. for 16 hours. The crude mixture is run directly down a silica gel column for purification, giving N-(5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)quinolin-6-amine (114 mg.)
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[CH3:2].[CH3:15][O:16][C:17]([C:19]1[CH:36]=[CH:35][CH:34]=[CH:33][C:20]=1[CH2:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1)=[O:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=1)[C:30](=[O:31])[CH2:29][C:26]1[CH:25]=[CH:24][C:23]([S:22][CH2:21][C:20]2[CH:33]=[CH:34][CH:35]=[CH:36][C:19]=2[C:17]([O:16][CH3:15])=[O:18])=[CH:28][CH:27]=1)[CH3:2]
Reactant: CCNCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccccc1CSc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)Cc1ccc(SCc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Ethyl[4-(trifluoromethyl)benzyl]amine (284 mg, 1.40 mmol) and (4-{[2-(methoxycarbonyl)benzyl]thio}phenyl)acetic acid (443 mg, 1.40 mmol, See Example 2 b) were mixed in DMF (15 ml). TBTU (472 mg, 1.47 mmol) was added and then DIPEA (190 mg, 1.47 mmol) was added. The mixture was stirred at room temperature for 1 hour. EtOAc (20 ml) was added. The mixture was then washed with sodium hydrogencarbonate aqueous solution (sat.), 1% HCl, water (×2) and brine, dried with magnesium sulphate and evaporated. The title compound (663 mg) was left, yield 94%.
Reaction SMILES: [OH-].[K+:2].[CH2:3]([C:7]1[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]([NH:35][C:36]([NH:38][CH2:39][CH2:40][CH3:41])=[O:37])(=[O:34])=[O:33])=[CH:22][CH:21]=2)[C:9]([C:14]([O:16]CC)=[O:15])=[C:10]([S:12][CH3:13])[N:11]=1)[CH2:4][CH2:5][CH3:6]>C(O)C>[K+:2].[K+:2].[CH2:3]([C:7]1[N:8]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]([NH:35][C:36]([NH:38][CH2:39][CH2:40][CH3:41])=[O:37])(=[O:34])=[O:33])=[CH:24][CH:25]=2)[C:9]([C:14]([O-:16])=[O:15])=[C:10]([S:12][CH3:13])[N:11]=1)[CH2:4][CH2:5][CH3:6].[CH2:3]([C:7]1[N:8]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]([NH:35][C:36]([NH:38][CH2:39][CH2:40][CH3:41])=[O:37])(=[O:34])=[O:33])=[CH:24][CH:25]=2)[C:9]([C:14]([O-:16])=[O:15])=[C:10]([S:12][CH3:13])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(SC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(SC)c(C(=O)[O-])n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1

Procedure:
2.3 ml of a 6N solution of potassium hydroxide were added at 0° C. to a solution of 2 g of the product of Stage H in 40 ml of ethanol and the reaction medium was allowed to return to ambient temperature. After. 72 hours, the precipitate was separated and washed with 4 ml of ethanol, then with 4 ml of ethyl acetate to obtain after drying, 2.04 g of the desired product melting at >260° C.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9](O)[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3].N12CCCN=C1CCCCC2.[F:32]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>C1(C)C=CC=CC=1>[N:1]([CH2:4][C@@H:5]1[C@H:9]([F:32])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Reaction time: 1 h

Procedure:
Process B: (3R,4R)-3-Azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine (1.79 g) was dissolved in toluene (56 mL). While this solution was chilled in an ice water bath, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.03 mL) was added, followed by dropwise addition of perfluoro-1-octanesulfonyl fluoride (2.80 mL) and stirring for 1 hour. The insoluble material in the reaction mixture was filtered and washed with toluene. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3R,4S)-3-azidomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a pale brown syrup (1.58 g). This compound was identical to the compound obtained by Process A.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Reactant: C1CCNC1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN2CCCC2)cc1)c1ccc2oc(Cl)cc2c1
Yield: 68 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with pyrrolidine (1 mL) in MeOH (3 mL) under reflux to give the desired product (51 mg, 68%, Z/E=1/2.6) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.20 (d, J=9.2 Hz, 1H), 7.09 & 7.06 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.8 Hz, 1H), 6.78 & 6.72 (d, J=8.2 Hz, 2H), 6.68 (d, J=8.6 Hz, 2H), 6.46 & 6.45 (s, 1H), 6.41 & 6.27 (d, J=8.4 Hz, 2H), 4.10 & 3.89 (t, J=5.8 Hz, 2H), 2.94 & 2.83 (t, J=6.2 Hz, 2H), 2.68 & 2.61 (m, 4H), 2.49 (q, J=7.4 Hz, 2H), 1.84 & 1.81 (m, 4H), 0.91 (t, J=7.4 Hz, 3H); m/z=488[M+1]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH:15](O)[CH3:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]([F:45])([F:44])[C:22]1[CH:31]=[C:30]2[C:25]([C:26]([NH:32][C:33]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:34]=3[C:35]([O:37]C)=[O:36])=[CH:27][CH:28]=[N:29]2)=[CH:24][CH:23]=1>>[F:45][C:21]([F:20])([F:44])[C:22]1[CH:31]=[C:30]2[C:25]([C:26]([NH:32][C:33]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:34]=3[C:35]([O:37][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=4)[CH2:10][CH2:11]3)=[O:36])=[CH:27][CH:28]=[N:29]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Reactant: CC(O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: O=C(OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1)c1cc(F)ccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Yield: 76.8 %

Procedure:
Using the procedure of Step B of Example 7, 6.57 g of 4-(3-trifluoromethylphenyl)-piperazin-1-yl-ethanol and 9.19 g of methyl 2-(7-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate were reacted to obtain 12.72 g of raw product which was chromatographed over silica gel. Elution with 95-5 methylene chloride-methanol mixture yielded 11.16 g of 2-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-ethyl 2-(7-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate. The said product was dissolved in 25 ml of hot absolute ethanol and then 5.6 ml of an ethanol solution of 6.6 N hydrochloric acid was added thereto at 50° C. The mixture was stirred and 60 ml of anhydrous ether were added thereto in small amounts. The mixture was stirred overnight at room temperature and after the addition of 0.5 ml of the ethanolic hydrochloric acid solution, the mixture was stirred for one hour and was vacuum filtered. The recovered crystals were washed with a 1-3 anhydrous ethanol-ether mixture and then with ether to obtain 11.7 g of the dihydrochloride of 2-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-ethyl 2-(7-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate melting at 200° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][C:7]([O:9][CH3:10])=[O:8].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.CCOCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C/C=C\CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C/C=C\CCOC1CCCCO1
Yield: 98.4 %

Procedure:
A solution of methyl 6-hydroxy-(Z)-3-hexenoate (0.7684 g, 5.3 mmol), 3,4-dihydropyran (0.72 mL, 7.9 mmol, 1.5 eq) and pyridinium p-toluenesulfonate (PPTS, 125 mg, 0.5 mmol) in methylene chloride (25 mL) is stirred for 4 hours at room temperature. The solution is then diluted with ether (150 mL), and the ether layer is washed with half-saturated brine (50 mL) to remove the catalyst, and dried over magnesium sulfate. Purification by flash chromatography using hexane/ethyl acetate (90:10, v/v) affords methyl 6-tetrahydropyranyloxy-(Z)-3-hexenoate (1.19 g, 99%) as a clear colorless oil: Rf=0.38, hexane/ethyl acetate (7:3, v/v), IR (film) ν2850-3000 (C=CH, alkane CH), 1740 (C=O) and H NMR (CDCl3) δ1.45-1.65 (m, 6H), 2.35 (m, 2H), 3.10 (d, J=6 Hz, 2H), 3.30-3.70 (m, 4H), 3.58 (sS, 3H), 4.55 (br s, 1H), 5.65 (br t, J=6 Hz, 2H).
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[OH:16][C:15](=[C:4]([C:3]#[N:7])[C:5]#[N:6])[CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CCC#N
Reactant: O=C(Cl)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C#N)=C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To 60% NaH/mineral oil dispersion (3.2 g, 79.5 mmol) in THF (100 ml) at room temperature under argon was added dropwise malononitrile (5.0 ml, 79.5 mmol) in THF (20 ml) over 30 minutes. The reaction mixture was stirred at room temperature for 30 minutes, then phenylacetyl chloride (10.5 ml, 79.5 mmol) in THF (10 ml) was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 1.5 hours, the solvent was removed in vacuo, and the residue was partitioned between ether and 2N H2SO4. The ether layer was separated, washed with water, dried over anhydrous MgSO4, filtered through a silica gel plug and the solvent was removed in vacuo to afford 13.8 g (94%) of (1-hydroxy-2-phenylethylidene)malononitrile as an amber oil.
Reaction SMILES: [CH3:1][CH:2]([CH:7]([CH3:9])[CH3:8])[CH2:3][CH:4]([OH:6])[CH3:5].[C:10](O)(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:5][CH:4]([O:6][C:10](=[O:14])[CH:11]=[CH:12][CH3:13])[CH2:3][CH:2]([CH3:1])[CH:7]([CH3:9])[CH3:8]
Reactant: CC(O)CC(C)C(C)C
Reactant: C/C=C/C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OC(C)CC(C)C(C)C
Temperature: 125 °C
Yield: 53.5 %

Procedure:
The obtained 4,5-dimethyl-hexan-2-ol (296 g), crotonic acid (391 g,), PTSA (3 g), and toluene (300 mL) were charged into a 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a Dean-Stark trap, and a condenser. The reaction mixture was heated to reflux at about 120-130° C. Water was removed azeotropically. The reaction was aged at reflux for about 4-5 hours until no more water evolved. The reaction was cooled to room temperature and quenched with water (400 mL). The organic layer was separated and subsequently washed with sodium carbonate (5%, 300 mL), and further fractional distilled to provide but-2-enoic acid 1,3,4-trimethyl-pentyl ester (241 g) with a boiling point of 108° C. at 13 mmHg.