Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[CH:48]([NH:52][C:53]1[CH:62]=[CH:61][C:60]3[C:55](=[CH:56][CH:57]=[C:58]([NH2:63])[CH:59]=3)[N:54]=1)[CH2:47][CH2:46]2>ClCCl.CN(C)C=O.O>[F:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[CH:48]([NH:52][C:53]1[CH:62]=[CH:61][C:60]3[C:55](=[CH:56][CH:57]=[C:58]([NH:63][C:8](=[O:10])[CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:59]=3)[N:54]=1)[CH2:47][CH2:46]2
Reactant: O=C(O)Cc1cccnc1
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1cccnc1)Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
3-Pyridyl-acetic acid (112 mg, 0.82 mmol), N,N-diisopropyl ethyl amine (308 mg, 2.4 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (350 mg, 1.1 mmol) were dissolved in dichloromethane (20 mL) and dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 30 minutes. rac-N2-(5-Fluoro-indan-1-yl)-quinoline-2,6-diamine (2000 mg, 0.68 mmol) was added and stirred was continued overnight. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined organic phases were dried over sodium sulfate and evaporated. The crude product was recrystallized with dichloromethane. The title compound (144 mg, 51%) was obtained as an off-white solid; MS: m/e=413.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:13]=[C:14]1[C:19]2=[CH:20][NH:21][C:22]([CH:23]=O)=[C:18]2[CH2:17][CH2:16][O:15]1>>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:23][C:22]1[NH:21][CH:20]=[C:19]2[C:14](=[O:13])[O:15][CH2:16][CH2:17][C:18]=12
Reactant: Cc1c(Br)ccc2c1CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: Cc1c(Br)ccc2c1C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2

Procedure:
5-Bromo-4-methyl-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([O:25][CH3:26])[CH:22]([NH2:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([O:25][CH3:26])[CH:22]([NH:24][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:23]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: COC(c1ccc(Cl)cc1Cl)C(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(c1ccc(Cl)cc1Cl)C(C)NC(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (195 mg, 1.0 mmol) in dichloromethane (2 ml) was added dropwise to a stirred solution of (234 mg, 1.0 mmol) 2-(2,4-dichloro-phenyl)-2-methoxy-1-methyl-ethylamine, which was prepared as described in example P2, and triethylamine (202 mg, 2.0 mmol) in dichloromethane (6 ml) at 0° C. The reaction mixture was stirred for 1 hr at ambient temperature then allowed to stand for 4 h. After removal of the solvent the residue was purified by flash chromatography over silica gel (eluant:hexane/ethyl acetate 1:1). 170 mg (43% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4-dichlorophenyl)-2-methoxy-1-methyl-ethyl]-amide was obtained in the form of a resin as a mixture of diastereomeres.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:4][CH2:3][O:2][CH3:1])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
2-Bromoethyl methyl ether (0.94 mL) was added dropwise to a suspension of piperazine-4-carboxylic acid tert-butyl ester (1.87 g) and potassium carbonate (1.38 g) in N,N-dimethylformamide (20 mL) at room temperature, and the resultant mixture was stirred at 60° C. for 24 hours. The reaction mixture was partitioned by use of ice-water and ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an oily product (1.39 g, 57%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:25]2[CH2:27][CH2:26]2)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:25]1[CH2:27][CH2:26]1)[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(C2CC2)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(C2CC2)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 6-chloro-4-(2-chloro-benzyl)-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester and 1N NaOH in ethanol. White solid. MS (ESI): 372.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH3:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:15]1([N:13]([CH3:14])[C:4]2[CH:3]=[C:2]([N:23]3[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]3)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=2[CH3:12])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1cc(Br)cc(N(C)C2CCCC2)c1C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cc(N(C)C2CCCC2)c1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
A solution of methyl 5-bromo-3-(cyclopentyl(methyl)amino)-2-methylbenzoate (1 g, 3.07 mmol), tert-butyl piperazine-1-carboxylate (0.85 g, 4.61 mmol) and Cs2CO3 (0.5 g, 1.53 mmol) in toluene (25 mL) was purged with argon for 10 min. Then, Pd2(dba)3 (0.31 g, 0.307 mmol) and BINAP (0.038 g, 0.061 mmol) was added to it and argon purged again for 10 min. The reaction mixture was stirred at 100° C. for 8 h. After completion, water was added to it and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to afford the title compound (0.44 g, 33.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([OH:32])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:25][CH3:26])[C@@H:22]([OH:24])[CH3:23])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([OH:32])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C(C)=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H]([C@H](C)O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.86 g (8.13 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-2-oxopentan-3-yl)piperidin-3-yl)acetic acid (Example 151) in THF (102 mL) was added a 1 M solution of sodium tri-sec-butylborohydride (N-Selectride®, Aldrich, St. Louis, Mo.) in THF (16.26 mL, 16.26 mmol) at −78° C. dropwise over a period of 5 min. After being stirred at −78° C. for 30 min, the reaction was allowed to warm to rt. The reaction was stirred at rt for 2 h, the reaction was quenched (sat. NH4Cl solution), extracted (3×EtOAc) and washed (3×ice-cold 1 N aq. HCl and 3×saturated aqueous sodium chloride). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by chromatography on a Biotage Isolera flash purification system (Biotage, Charlotte, N.C.) (2×1500 g columns, using a gradient from 10-30% (15% MeOH/acetone) in hexanes. The purified material was then recrystallized from 3:1 hexane/acetone (8 mL/g) to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]#[N:22])[N:5]([CH3:20])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:23][Sn](C)(C)C.O>CN(P(N(C)C)(N(C)C)=O)C>[CH3:17][C:12]1([CH3:18])[C:11]2[CH:19]=[C:7]([C:6]3[N:5]([CH3:20])[C:4]([C:21]#[N:22])=[CH:3][C:2]=3[CH3:23])[CH:8]=[CH:9][C:10]=2[NH:15][C:14](=[O:16])[O:13]1
Reactant: C[Sn](C)(C)C
Reactant: Cn1c(C#N)cc(Br)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Cc1cc(C#N)n(C)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Yield: 60.9 %

Procedure:
A solution of 4-bromo-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (70 mg, 0.2 mmol), PhCNPdCl(PPh3)2 (cat., 7 mg) and tetramethyltin (10 eq, 0.35 g, 2 mmol) in HMPA (3 mL) was heated to 110° C. for 5 days. The solution was allowed to cool, poured into water (20 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layer was washed with brine, dried over MgSO4 and purified by flash column chromatography on silica gel eluting with 30% ethyl acetate/hexane to give 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,4-dimethyl-1H-pyrrole-2-carbonitrile (36 mg, 63%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.64 (s, 6H), 1.97 (s, 3H), 3.56 (s, 3H), 6.87 (s, 1H), 7.00 (d, 2H, J=8.1 Hz), 7.28 (dd, 1H, J=8.1, 1.6 Hz), 7.32 (s, 1H), 10.40 (s, 1H). MS (ESI (−)) 294 (M−H)−. Anal. calcd for C17H17N3O2, C, 69.1, H, 5.8, N, 14.2. Found, C, 69.1, H, 5.72, N, 14.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][N:3]=1.[Br-].[CH:18]1([CH2:24][Zn+])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[C:13]([O:12][C:10]([NH:9][CH2:8][C:5]1[C:4]([CH2:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3][CH:2]=[CH:7][CH:6]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)nc1
Reactant: [Zn+]CC1CCCCC1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccnc1CC1CCCCC1
Temperature: 60 °C
Yield: 68 %

Procedure:
Dissolve 2-bromo-5-tert-butoxycarbonylaminomethyl-pyridine (500 mg, 1.74 mmol) in anhydrous THF (5 mL) in a sealed tube. Degas the solution, purge with nitrogen and add 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (127 mg, 0.174 mmol) and 0.5M cyclohexylmethylzinc bromide in THF (10.4 mL, 5.22 mmol). Heat the mixture at 60° C. overnight. Cool to room temperature and dilute the reaction mixture with EtOAc. Add water and filter the precipitate over Celite®. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (4:1, 3:2) to give the desired intermediate as an oil (359 mg, 68%). MS (ES+) m/z: 305 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[C:15](=[O:16])[CH2:14][C:13]([CH3:18])([CH3:17])[CH2:12][C:11]2=[O:19])=[CH:2]1.[F:20][B-:21]([F:24])([F:23])[F:22].[H+].[CH2:26](OC(OCC)OCC)C>C(OCC)C>[F:20][B-:21]([F:24])([F:23])[F:22].[CH3:18][C:13]1([CH3:17])[CH2:14][C:15]2[O+:16]=[CH:26][C:2]3[NH:1][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[C:10]=2[C:11](=[O:19])[CH2:12]1
Reactant: CCOC(OCC)OCC
Reactant: CC1(C)CC(=O)C(c2c[nH]c3ccccc23)C(=O)C1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: CC1(C)CC(=O)c2c([o+]cc3[nH]c4ccccc4c23)C1
Yield: 70 %

Procedure:
To a suspension of 2-(1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione of Example 1f (2.5 g, 9.8 mmol) in diethoxymethoxyethane (20 mL), tetrafluoroboric acid (54 wt % solution in diethyl ether, 2 mL, 14.5 mmol) was added in two portions under stirring. The mixture was stirred at room temperature for 2 h and diluted with diethyl ether (20 mL). The solid product was filtered off, washed with diethyl ether and air-dried at room temperature to give 2.4 g (70%) of the product as red crystals, which was used in the next step without purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=2[C:19]([F:22])([F:21])[F:20])=[CH:6][S:7][CH:8]=1>CCO>[CH3:3][C:4]1[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:19]([F:22])([F:20])[F:21])=[CH:6][S:7][CH:8]=1
Reactant: COC(=O)c1ccc(-c2cscc2C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cscc1-c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Sodium hydroxide (5M: 6 mL; 30 mmol; 3 eq.) was added to a solution of methyl 4-(4-methyl-3-thienyl)-3-(trifluoromethyl)benzoate (3 g; 10 mmol; 1 eq.) in EtOH (90 mL) and the reaction mixture was stirred at 60° C. for 2 hours. After evaporation of the solvent, the residue was taken up in water (300 mL) and the aqueous phase was washed with ethyl acetate (2×100 mL) then acidified to pH 2 with conc. HCl. The solution was concentrated to ca. 100 mL and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound (2.6 g, 91%) as a brown oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O1CCOCC1>CCOC(C)=O>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16]
Reactant: Cc1cccc2c1CCC(=O)N2CCCCl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cccc2c1ccc(=O)n2CCCCl
Yield: 66.1 %

Procedure:
A microwave vial was charged with 1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one (0.081 g, 0.34 mmol), DDQ (0.116 g, 0.51 mmol), dioxane (2 mL) and sealed. After microwave irradiation, 175° C., 10 min, the reaction was diluted with EtOAc (50 mL), washed with sat aqueous NaHCO3 (2×15 mL) and the organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and the residue was purified with prep RP-HPLC to yield the crude title compound (0.053 g), which was used without further purification. HPLC-MS (ammonium acetate) [M+H]+=236.2.
Reaction SMILES: [CH3:1][CH:2]([CH:5]=[CH2:6])[CH2:3][OH:4].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>CCOCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][CH:2]([CH2:3][O:4][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[CH:5]=[CH2:6]
Reactant: C1=COCCC1
Reactant: C=CC(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C=CC(C)COC1CCCCO1
Yield: 75.3 %

Procedure:
A solution of 2-methyl-3-buten-1-ol (54.16 g, 0.63 m), dihydropyran (52.92 g, 0.63 m), and p-toluenesulfonic acid (0.5 g) in ether (800 ml) is stirred at room temperature under a nitrogen atmosphere overnight. The reaction mixture is then diluted with ether (1 l) and washed with 5% sodium bicarbonate solution (1 l). The ether extract is dried (Na2SO4), filtered and solvent removed in vacuo to give 95.8 g of crude product. The crude product is purified by column chromatography on silica gel (500 g, hexane) to give (75%) 3-methyl-4-(tetrahydropyran-2-yloxy)-1-butene (80.62 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=1.CS(O[CH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=O)=O.Cl>CCCCCC.CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]([CH2:18][CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)OCCc1cccs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: N#CC(CCc1cccs1)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
To a flask under a nitrogen atmosphere was added, with stirring, 3.3 g. (0.0825 mole) of 60% sodium hydride, washed twice with hexane to remove the original mineral oil, in 75 ml. of a dry 2 to 1 mixture of DMF and toluene. To this slurry at room temperature was added 11.30 g. (0.075 mole) of 4-chlorobenzyl cyanide in 40 ml. of DMF. After 1.5 hours, the mixture was cooled to 10° C. and 13.7 g. (0.0782 mole) of 2-(2-thienyl)ethyl methanesulfonate in 25 ml. of DMF was added dropwise. The reaction was stirred at room temperature for 13 hours. Then aqueous 10% hydrochloric acid, 20 ml., was added followed by 150 ml. of diethyl ether which was washed three times with 50 ml. portions of water. After drying the ether and concentrating, the product was distilled at 130°-150° C. at 1-2 mm of Hg yielding 2-(4-chlorophenyl)-4-(2-thienyl)butyronitrile as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:14][CH3:15])=[N:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([CH3:25])[CH3:24].[Cl-].[NH4+]>CS(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][CH:23]([CH3:25])[CH3:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:14][CH3:15])=[N:7]2
Reactant: CNc1ccc2c(Cl)cc(Cl)c(O)c2n1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNc1ccc2c(Cl)cc(Cl)c(OC(C)C)c2n1
Yield: 78 %

Procedure:
A solution of 5,7-dichloro-2-methylamino-8-hydroxyquinoline (1.02 g, 4.21 mmol), anhydrous potassium carbonate (2.4 g) and 2-bromopropane (0.6 mL) in dimethyl sulphoxide (10 mL) was stirred at RT for 2 days. Saturated ammonium chloride solution was added and the mixture was extracted with dichloromethane (30 mL×3). The extracts were combined, dried, and concentrated. The residue, after column chromatography (silica gel, dichloromethane), gave 5,7-dichloro-2-methylamino-8-isopropoxy-quinoline 11 as an off-white solid (938 mg, 78%). 1H NMR (CDCl3): δ 8.13 (d, J=9.0, 1H), 7.28 (s, 1H), 6.69 (d, J=9.0, 1H), 5.10 (m, 1H), 4.90 (br, 1H), 3.11 (d, J=5.0, 3 H), 1.43 (s, 3H), 1.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:15]=[C:14]([CH2:16][N:17]3[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]3)[CH:13]=[CH:12][N:11]=2)=[CH:4][C:3]=1[O:24][CH3:25].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH:26]([CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([C:5]3[CH:4]=[C:3]([O:24][CH3:25])[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=3)[CH:15]=2)[CH2:18][CH2:19]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccccc1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1Cl
Product: COc1cc(-c2cc(CN3CCC(Nc4ccccc4)CC3)ccn2)cc(OC)c1Cl

Procedure:
1-[[2-(4-Chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (600 mg) and aniline (0.18 mL) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[S:13][C:14]1[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23].[CH3:25][NH2:26]>C1(C)C=CC=CC=1.O1CCOCC1>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[S:13][C:14]1[S:18][C:17]([C:19]([NH:26][CH3:25])=[O:20])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2cccc(Cl)c2Cl)s1
Reactant: CN
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc([N+](=O)[O-])c(Sc2cccc(Cl)c2Cl)s1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
Thionyl chloride (0.102 g, 0.86 mmol) was added to a suspension of 5-(2,3-dichlorophenylsulfanyl)-4-nitrothiophene-2-carboxylic acid (0.15 g, 0.43 mmol) in toluene (5 mL) and the stirred mixture was heated at 80° C. for 1 hour. TLC analysis showed no acid remaining so the mixture was allowed to cool to ambient temperature and then concentrated in vacuo to give the dark brown viscous oil. The oil was dissolved in 1,4-dioxane (1 mL) and added at 5° C. to stirred 40% aqueous methylamine solution (5 mL). The mixture was stirred for 15 minutes then the resulting solid was collected by filtration, washed with water (3×1 mL) and dried in vacuo at 40° C. overnight to afford the title product as a beige solid (55 mg, 35% yield). 1H NMR (CDCl3) δ: 7.84 (1H, s) 7.70 (2H, m), 7.36 (1H, m), 6.01 (1H, broad s), 2.95 (3H, d, J=4.9 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C:6]([CH2:15][CH:16]=O)([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:18])[CH2:7][C:6]([CH2:15][CH2:16][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([CH3:19])[CH:21]=2)([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1
Reactant: Cc1cccc(CN)c1
Reactant: Cc1ccc(C2(CC=O)CCOC(C)(C)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(C2(CCNCc3cccc(C)c3)CCOC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]acetaldehyde (61.6 mg, 0.25 mmol), 3-methylbenzylamine (63 μl, 0.5 mmol) and acetic acid (50 μl, 8.6 mmol) in CH2Cl2 (3 ml) was stirred at rt for 1 h before it adding sodium triacetoxyborohydride (106 mg, 0.50 mmol). The resulting mixture was stirred at rt for 18 h. The mix was concentrated and dissolved in MeOH and purified by HPLC to give {2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(3-methylphenyl)methyl]amine as a white solid (35 mg, 40%, m/z: 352.3 [M+H]+ observed).
Reaction SMILES: C(OC(COC1C=CC(F)=CC=1)CCC1N(CCCCCCC(OCC2C=CC=CC=2)=O)C(=O)CS1(=O)=O)C1C=CC=CC=1.[C:45]([O:48][C:49]1([C:55]#[C:56][CH2:57][O:58]CC2C=CC=CC=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)(=[O:47])[CH3:46]>>[C:45]([O:48][C:49]1([CH2:55][CH2:56][CH2:57][OH:58])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]1)(=[O:47])[CH3:46]
Reactant: CC(=O)OC1(C#CCOCc2ccccc2)CCCCC1
Agent: O=C(CCCCCCN1C(=O)CS(=O)(=O)C1CCC(COc1ccc(F)cc1)OCc1ccccc1)OCc1ccccc1
Product: CC(=O)OC1(CCCO)CCCCC1

Procedure:
This compound is prepared essentially by the method as described in Example 4, Step E, except that the benzyl 7-{2-(3-benzyloxy-4-[4-fluorophenoxy]butyl)-1,1,4-trioxo-3thiazolidinyl}heptanoate is replaced by 1-(1-Acetyloxycyclohexyl)-3-benzyloxy-1-propyne and no chromatographic purification is needed. The title compound is obtained as an essentially colorless, mobile liquid which is used immediately in Step A-3 below.