Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[C:11]1(O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]=1.COC>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][N:10]=[C:11]2[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: OC1=NCCCCC1
Reactant: NNc1cccc(Cl)c1
Agent: COC
Agent: Cl
Solvent: CO
Product: Clc1cccc(NN=C2CCCCCN2)c1
Yield: 96 %

Procedure:
300 G of hydrogen chloride gas were introduced into a solution of 1,000g(7 moles) of 3-chlorophenylhydrazine and 980 g (7.7 moles) of caprolactim-methyl-ether in 4,000 ml of methanol at 10° to 20°C while stirring and cooling with an ice bath, and the reaction mixture was kept for a further hour at 20°C, raised to the reflux temperature and kept at 65°C for 11/2 hours. After cooling, the crystals which had separated out were filtered off and further crystal fractions were isolated by concentrating the mother liquors under reduced pressure. After recrystallization from 2 parts of methanol, 1,845 g (96% of theory) of caprolactam-(3-chlorophenylhydrazone) hydrochloride were obtained as colorless crystals of melting point 280° to 282°C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:7]([CH3:6])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCc1ccccc1)C(=O)CCl
Temperature: 25 °C
Yield: 94.5 %

Procedure:
At −75° C., chloroacetyl chloride (11.3 g, 8.1 mL, 0.1 mol) was added slowly to a suspension of methyl-phenethyl-amine (13.5 g, 0.1 mol), triethylamine (15 mL) in dichloromethane (50 mL). The suspension was warmed to 25° C. over the course of 3 hours and the salt was removed by filtration. The organic phase was washed with HCl solution (1 N, 200 mL), dried with sodium sulfate. The solvent was evaporated in vacuo to give 2-chloro-N-methyl-N-phenethyl-acetamide (20 g, 95%): 1H NMR (300 MHz, CDCl3) δ 7.2 (m, 5H), 4.03 (s, 3H), 3.6 (m, 2H), 2.99 (s, 2H), 2.8 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1)[CH:2]=C.[BH4-].[Na+].C[OH:17]>C1COCC1>[OH:17][CH2:2][CH2:1][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: CO
Reactant: C=CCc1ccc2c(c1)COC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OCc2cc(CCO)ccc21
Temperature: -78 °C

Procedure:
5-(Prop-2-en-1-yl)-2-benzofuran-1(3H)-one (1.53 g, 8.78 mmol) was dissolved in a mixture of methanol (30 mL) with just enough THF to solubilize the starting material and was cooled to −78° C. Ozone was bubbled through the solution until the reaction mixture color changed (to orange). Then nitrogen gas was bubbled through the reaction mixture for about one min. to remove the residual ozone. Sodium borohydride (0.65 g, 17 mmol) was added and the mixture was allowed to warm to room temperature. The reaction mixture was partially concentrated then was partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over MgSO4. The crude product was purified by MPLC (silica) eluting with ethyl acetate to afford pure product. LCMS: m/z 179 (M+1)+; 1H NMR (500 MHz, CD3OD) δ 7.77 (m, 1H), 7.37-7.41 (m, 2H), 5.23 (s, 2H), 192 (m, 2H), 2.99 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([CH3:24])=[CH:18][C:19]=2[CH3:23])[N:14]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([CH3:24])=[CH:18][C:19]=2[CH3:23])[N:14]=1)(=[O:10])=[O:9]
Reactant: Cc1cc(C)c2ccc(N)nc2n1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Product: Cc1cc(C)c2ccc(NS(=O)(=O)c3ccccc3Cl)nc2n1

Procedure:
At an internal temperature of 40° to 50° C., 7.5 g (35.5 mmol) of 2-chlorobenzenesulfonyl chloride was slowly dripped, while stirring, into a suspension of 4.1 g (23.6 mmol) of commercially available 2-amino-5,7-dimethyl-1,8-naphthyridine in 100 ml of anhydrous pyridine.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Product: CCS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1

Procedure:
The title compound, light brown foam (77 mg, 54%), MS (ISP) m/z=421.2 [(M+H)+], was prepared in analogy to example 14 starting from trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate A) (150 mg, 0.34 mmol) and ethanesulfonyl chloride (88 mg, 0.68 mmol).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:30][CH:29]([CH2:31][NH2:32])[O:28][N:27]=2)=[CH:22][CH:21]=1>>[N:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:30][CH:29]([CH2:31][NH:32][C:17]([C:15]3[CH:16]=[C:11]([C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=4[CH3:10])[CH:12]=[N:13][CH:14]=3)=[O:19])[O:28][N:27]=2)=[CH:24][CH:25]=1
Reactant: NCC1CC(c2ccncc2)=NO1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCC3CC(c4ccncc4)=NO3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (3-pyridin-4-yl-4,5-dihydro-isoxazol-5-ylmethyl)-amine to afford the title compound. MS: m/e=418 (M+H).
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH:3]=[CH2:4].[OH-].[Na+].[C:9]([C:14]1[C:15](=[O:30])[CH2:16][CH:17]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])[CH2:18][C:19]=1[OH:20])(=O)[CH2:10][CH2:11][CH3:12].C(O)C>O>[CH2:2]([O:5][N:6]=[C:9]([C:14]1[C:19](=[O:20])[CH2:18][CH:17]([C:21]2[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])[CH2:16][C:15]=1[OH:30])[CH2:10][CH2:11][CH3:12])[CH:3]=[CH2:4]
Reactant: C=CCON
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCON=C(CCC)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Yield: 76.3 %

Procedure:
Allyloxyamine hydrochloride (0.72 g) and then a solution of sodium hydroxide (0.25 g) in water (3 ml) were added to a stirred mixture of 2-butyryl-3-hydroxy-5-mesitylcyclohex-2-en-1-one (1.78 g; 5.9 mmole) and 95% ethanol. The progress of the reaction was monitored using thin layer chromatography on silica gel (eluant dichloromethane). On completion of the reaction the ethanol was removed by evaporation using a rotary evaporator and the residue was extracted with dichloromethane. The organic extract was washed with aqueous 5% hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure using a rotary evaporator to give the product, 2-[1-(allyloxyimino)butyl]-3-hydroxy-5-mesitylcyclohex-2-en-1-one (1.6 g) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]3[C:22]([NH:23][C@@H:24]([CH2:29][OH:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[N:21][C:20]([S:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:19][C:18]=3[N:39]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>ClCCl>[C:33]1([CH2:32][S:31][C:20]2[N:21]=[C:22]([NH:23][C@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:29][OH:30])[C:17]3[S:16][C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[N:39][C:18]=3[N:19]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(NC3CCNCC3)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
The product from step (b) (40 mg, 70 μmol) was dissolved in anhydrous dichloromethane (2.5 mL) and trifluoroacetic acid (269 μL, 3.5 mmol) was added. The mixture was stirred at room temperature for two hours. 1M Aqueous potassium carbonate (3.5 mL) followed by 0.1M aqueous sodium hydroxide (1 mL) were added and the product was extracted twice with dichloromethane. The precipitate which formed was filtered off, washed with dichloromethane and dried in vacuo at 40° C. overnight resulting in 24 mg (73% yield) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:24]=[O:25])=[CH:10][C:5]=2[O:4][C:3]1=[O:11]
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(=O)oc2ccccc21
Agent: C1N2CN3CN1CN(C2)C3
Product: Cn1c(=O)oc2cc(C=O)ccc21
Reaction time: 0.5 h
Yield: 45 %

Procedure:
3-Methyl-3H-benzooxazol-2-one (2.00 g, 13.42 mmol) and hexamethylenetetramine (3.76 g, 26.84 mmol) were dissolved in trifluoroacetic acid (20 mL) and heated at reflux for 20 hours. The volatiles were removed in vacuo and the residue was treated with ice water (60 mL). The resultant mixture was stirred for 30 minutes and then made basic with sodium carbonate. The solid was isolated by filtration and washed with water then dried under vacuum. The solid was purified by column chromatography on silica gel eluting with an ethyl acetate and hexane solvent gradient. This provided the desired product as a white solid (1.07 g, 45%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)([O-:5])=[O:4].O.[ClH:15].CC[O:18][CH2:19][CH3:20]>CS(C)=O.CCOCC>[ClH:15].[Cl:15][C:8]1[CH:7]=[CH:6][N:3]=[CH:20][C:19]=1[O:18][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(COc2cnccc2Cl)cc1

Procedure:
The starting material was prepared by reaction of 4-nitro-3-hydroxy pyridine-N-oxide with acetyl chloride under reflux for 1 hour. The crude product was purified by rapid chromatography on silica gel using CH2Cl2 /MeOH 7:3 v/v as eluant to give 4-chloro-3-hydroxypyridine-N-oxide. Reduction of this compound with Raney nickel and hydrogen at ambient temperature for 2 hours in MeOH gave 4-chloro-3-hydroxypyridine. This compound was reacted with NaH in DMSO at 50°, the reaction mixture cooled and treated with 4-nitrobenzyl bromide for 1 hour. The reaction mixture was worked up with water and ether and the product treated with HCl/ether to give 4-chloro-3-(4-nitrobenzyloxy)pyridine hydrochloride. Reaction of the free base with excess methyl iodide at ambient temperature for 24 hours gave 4-chloro-1-methyl-3-(4-nitrobenzyloxy)pyridinium iodide. n.m.r. in d6DMSO: 4.35(s, 3H); 5.6(s, 2H); 7.7(d, 2H); 8.3(d, 2H); 8.4(d, 1 H); 8.7(d, 1H); 9.15(s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([CH3:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>COCCOC>[CH2:22]([NH:29][C:6]1[C:5]([CH3:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Solvent: COCCOC
Solvent: O
Product: Cc1c(NCc2ccccc2)nc(N)nc1-c1ccco1
Temperature: 80 °C
Yield: 64.9 %

Procedure:
To a stirred solution of 250 mg (0.77 mmol) trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-methyl-pyrimidin-4-yl ester in 10 ml DME in a pressure tube was added 0.63 ml (5.77 mmol) benzylamine and the mixture heated at 80° C. for 16 hours. The reaction mixture was then poured onto 80 ml water and cooled to 0° C. The resulting crystals were collected by filtration and washed sequentially with water, ether/hexane and a minimum quantity of ice-cold ether to afford 140 mg (65%) N4-benzyl-6-furan-2-yl-5-methyl-pyrimidine-2,4-diamine as a white crystalline solid. ES-MS m/e (%): 281 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([CH2:12][OH:13])=[CH:7]2>O1CCOCC1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([CH:12]=[O:13])=[CH:7]2
Reactant: Cn1c(CO)cc2cccc(F)c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cn1c(C=O)cc2cccc(F)c21
Yield: 89.5 %

Procedure:
7-Fluoro-1-methyl-1H-indole-2-methanol (2.0 g) was dissolved in 1,4-dioxan (50 ml). Manganese dioxide (2.91 g) was added and the mixture was heated at reflux for 1 h. The mixture was then filtered and the filtrate was evaporated in vacuo to give the title compound (1.77 g) as a solid, m.p. 61°-63°.
Reaction SMILES: [C:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[C:1]([N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][CH:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccc2)ccc1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(c2ccccc2)CCC1c1ccccc1
Yield: 97 %

Procedure:
To a solution of N-Boc-2,5-diphenylpyrrole (1.027 g, 3.22 mmol) in methanol (80 ml) was added palladium (5%) on activated carbon (0.250 g). The reaction mixture was hydrogenated (10 psi) for 1.5 hours. Filtration and evaporation to dryness afforded N-Boc-2,5-diphenylpyrrolidine (1.01 g, 97%). 1H-NMR (CDCl3): δ ppm 7.20-7.60 (m, ArH, 10H), 5.0 (in, ArCH, 2H), 2.45 (m, CH2, 2H), 1.17 (s, CH3, 9H)
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+].[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=O>CC1CCCO1.O>[C:2]1([C:1]2[N:8]=[C:30]([C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(Cl)c1ccco1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: c1ccc(-c2noc(-c3ccco3)n2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 64.6 %

Procedure:
Benzamide oxime (2.00 g, 14.7 mmol) and a 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) were combined in 2-methyltetrahydrofuran (20 mL) and water (2 mL). The solution was warmed to 50° C. and 50% aqueous solution of sodium hydroxide (1.52 g, 19.1 mmol) and 2-furoyl chloride (2.00 g, 15.3 mmol) were added dropwise simultaneously over 10 min. The pot temperature rose to 74° C. The mixture was stirred at 60° C. for 48 hours and the solids dissolved. The mixture was cooled to room temperature and poured into water (25 mL). The 2-methyltetrahydrofuran was removed at reduced pressure and solids formed in the aqueous solution. The solids were collected by vacuum filtration. 3-phenyl-5-(2-furanyl)-1,2,4-oxadiazole (2.33 g, 9.5 mmol) was obtained as a white solid. (64% yield).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:15]=1[CH2:24]Cl>CN(C=O)C>[CH3:23][O:22][C:17]1[CH:16]=[C:15]2[C:14](=[CH:19][C:18]=1[O:20][CH3:21])[CH2:13][C:2]([C:1]([O:8][CH3:9])=[O:7])([C:3]([O:5][CH3:6])=[O:4])[CH2:24]2
Reactant: COC(=O)CC(=O)OC
Reactant: COc1cc(CCl)c(CCl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)OC)Cc2cc(OC)c(OC)cc2C1
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
To a solution of dimethyl malonate (1.7 ml, 14.9 mmol) in DMF (30 ml) at room temperature under nitrogen was added sodium hydride (1.3 g of a 60% dispersion in oil). The mixture was stirred for 20 minutes, and 1,2-bis(chloromethyl)-4,5-dimethoxybenzene (3.5 g, 14.9 mmol) was added. After 16 hours, the mixture was quenched with water and extracted three times with ether. The combined extracts were washed twice with water and dried (McSO4), filtered and evaporated. The residue was dissolved in methylene chloride and filtered through a pad of silica gel. Evaporation gave dimethyl 5,6-dimethoxyindane-2,2-dicarboxylate as a white solid (2.24 g, 55% yield).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: CCOC(=O)C[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (170 mg, 1.9 mmol) and triethyloxonium tetrafluoroborate (0.36 g, 1.9 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 1 h and then concentrated. A mixture of ethyl {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetate (150 mg, 0.45 mmol) and the above made reagent in ethanol (4.8 mL) was heated at reflux for 2 h. The mixture was concentrated and purified on silica gel column (eluting with 0-5% MeOH in methylene chloride) to give the desired product (0.15 g, 86%). LCMS calculated for C20H26N3O3S (M+H)+: m/z=388.2. Found: 388.1.
Reaction SMILES: C(O[C:9](=[O:22])[NH:10][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:12][OH:13])C1C=CC=CC=1.[Cl:23][C:24]1[CH:37]=[CH:36][C:27]([O:28][C:29]2[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=2)=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(N)CCCCC1N>[Cu]I.CN(C=O)C>[Cl:23][C:24]1[CH:37]=[CH:36][C:27]([O:28][C:29]2[CH:34]=[CH:33][C:32]([N:10]3[CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[CH2:12][O:13][C:9]3=[O:22])=[CH:31][CH:30]=2)=[CH:26][CH:25]=1
Reactant: Clc1ccc(Oc2ccc(I)cc2)cc1
Reactant: COc1cccc(C(CO)NC(=O)OCc2ccccc2)c1
Agent: [Cu]I
Agent: NC1CCCCC1N
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cccc(C2COC(=O)N2c2ccc(Oc3ccc(Cl)cc3)cc2)c1
Temperature: 110 °C
Yield: 76.8 %

Procedure:
To a dry round bottom flask is added [2-hydroxy-1-(3-methoxy-phenyl)ethyl]-carbamic acid benzyl ester (300 mg, 1 mmol), 1-(4-chlorophenoxy)-4-iodobenzene (330 mg, 1 mmol), K3PO4 (210 mg), 1,2-cyclohexanediamine (15 μL) and CuI (20 mg), and DMF (5 mL). The mixture is evacuated and back-filled with nitrogen three times. The reaction mixture is heated to 110° C. for 7 h. The reaction is then cooled to room temperature, diluted with EtOAc (50 mL), washed with 1N HCl, and brine, subsequently dried over MgSO4, filtered, and concentrated to give the crude product, which is purified by flash chromatography on silica gel (EtOAc/Hex: 1/2) to provide 3-[4-(4-chlorophenoxy)phenyl]-4-(3-methoxyphenyl)-oxazolidin-2-one (304 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:22]([OH:25])([CH3:24])[CH3:23]>>[CH:22]([O:25][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[CH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([CH3:24])[CH3:23]
Reactant: CC(C)O
Reactant: COc1cccc(O)c1Cc1cc2ccccc2nc1N
Product: COc1cccc(OC(C)C)c1Cc1cc2ccccc2nc1N

Procedure:
Synthesis was performed according to EXAMPLE 3 from 2-[(2-aminoquinolin-3-yl)methyl]-3-methoxyphenol and isopropanol.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[NH:3]1.[H-].[Na+].[CH2:17]([N:24]([CH2:26][CH2:27][CH2:28]Cl)[CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN1CCCN(C)C1=O.C(O)(C)C.COC(C)(C)C.CC(C)=O>[CH2:17]([N:24]([CH2:26][CH2:27][CH2:28][O:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[CH:5]=1)[CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1NC(c2ccccc2F)CC1=O
Reactant: CN(CCCCl)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: CN(CCCOc1cc(-c2ccccc2F)nn1C)Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
3.3 g of 2-methyl-5-(2-fluorophenyl)-pyrazolin-3-one were dissolved in 50 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone. 0.55 g of sodium hydride (as an 80 % strength solution in paraffin) was added to this solution and the reaction mixture was stirred at 80° C. for 30 minutes. 3.3 g of 3-(N-benzyl-N-methylamino)-propyl chloride were added to the reaction mixture which was stirred at 80° C. for a further 2 hours. After the reaction mixture had cooled, 10 ml of a 2N solution of hydrochloric acid in isopropanol were added to it, and the mixture was then added dropwise to 2 liters of a 1:3 mixture of acetone and tert-butyl methyl ether. The resulting precipitate was filtered out and dissolved in a mixture of saturated aqueous sodium carbonate solution and ethyl acetate. The organic phase was separated and the aqueous phase was subsequently extracted repeatedly with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulfate and evaporated. The crude base obtained was purified by chromatography on silica gel. 4.4 g of 3-[3-(N-benzyl-N-methylamino)-propyloxy]-2-methyl-5-(2-fluorophenyl)-pyrazole were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[CH:3]=1
Reactant: Oc1cccc(F)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(F)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 22.4 g (200 mmole) of 3-fluorophenol in 400 mL of CH2Cl2 under N2 was prepared and cooled to 5° C. The stirred mixture was treated with 23.1 g (267 mmole) of chloromethyl methyl ether. The reactor was equipped with a thermocouple and an addition funnel. To the stirred mixture was added dropwise 34.8 mL of DIEA (25.8 g, 200 mmole) such that the temperature did not exceed 10° C. After 30 min, an additional 18 mL of DIEA was added dropwise. After a total of 1 h, an additional 18 mL of DIEA was added. The mixture was allowed to stand overnight. The solution was washed with 500 mL of 1N HCl and the aqueous layer extracted two times with CH2Cl2. Combined extracts were dried with Mg2SO4, carefully concd and distilled in vacuo 61-68° C. @ 15 torr to afford 28.7 g (75.3%) of a clear, colorless liquid: (lit. bp 25-26° C. @ 0.6 torr); 1H NMR (CDCl3/400 MHz) 3.46 (s, 3H), 5.14 (s, 2H), 6.70 (tdd, 1H, J=8.3 Hz, J=2.4 Hz, 0.8 Hz), 6.75-6.82 (m, 2H), 7.21 (q, 1H, J=7.7 Hz); 19F NMR (CDCl3/400 MHz) −112.0 (m, 1F); 113C NMR (CDCl3/100 MHz) 56.1, 94.5, 104.1 (d, J=25.0 Hz), 108.6 (d, J=21.3 Hz), 111.9 (d, J=2.9 Hz), 130.2 (d, J=9.9 Hz), 158.6 (d, J=11.0 Hz), 163.5 (d, J=245.3 Hz).