Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[N:21]=[CH:20][N:19]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:18]2[C:27]3[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.62 g, 18.1 mmol, 1.2 equiv) in dry DMF (20 mL) under Ar was added sodium hydride (0.99 g, 22.7 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 4,7-dichloro-quinazoline (3.0 g, 15.1 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 140° C. for 30 min. Removal of the solvent under reduced pressure and purification with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (10:1→1:1) afforded 4-(7-chloro-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (4.33 g, 79%). 1H NMR (300 MHz, CDCl3): δ 1.42-1.53 (m, 2H), 1.48 (s, 9H), 2.16-2.18 (m, 2H), 2.92-2.98 (m, 2H), 4.17-4.20 (m, 2H), 4.39-4.49 (m, 1H), 5.79 (d, J=8.0 Hz, 1H), 7.40 (dd, J=8.8 Hz, J=2.1 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.82 (d, J=2.1 Hz, 1H), 8.63 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 28.50, 32.05, 42.89, 48.38, 79.85, 113.29, 122.11, 126.75, 127.89, 138.70, 150.65, 154.78, 156.37, 158.58. MS (ISP): 363.5 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)[CH2:2]1.[NH2:20][CH:21]1[CH2:26][CH2:25][C:24]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][C@H:33]([OH:36])[C@@H:32]([CH3:37])[CH2:31]2)([OH:27])[CH2:23][CH2:22]1>>[OH:27][C:24]1([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][C@H:33]([OH:36])[C@@H:32]([CH3:37])[CH2:31]2)[CH2:25][CH2:26][CH:21]([NH:20][C:17]([C:11]2[NH:12][C:13]3[C:9]([CH:10]=2)=[C:8]([O:7][CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[CH:16]=[CH:15][CH:14]=3)=[O:19])[CH2:22][CH2:23]1
Reactant: O=C(O)c1cc2c(OCC3CCOC3)cccc2[nH]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCC5CCOC5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(tetrahydro-furan-3-ylmethoxy)-1H-indole-2-carboxylic acid 16b and amine 14.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH3:28])=[N:22][CH:21]=4)[C:17]([F:29])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3]1.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[F:29][C:17]1[C:18]([C:20]2[N:24]([CH:25]([CH3:26])[CH3:27])[C:23]([CH3:28])=[N:22][CH:21]=2)=[N:19][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:31](=[O:32])[CH2:30][OH:33])[CH2:3]3)=[CH:12][CH:11]=2)=[N:15][CH:16]=1
Reactant: O=C(O)CO
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@@H](N)C4)cc3)ncc2F)n1C(C)C
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@@H](NC(=O)CO)C4)cc3)ncc2F)n1C(C)C

Procedure:
The title compounds was prepared (38 mg, 15%), was prepared using a procedure analogous to Example 155 starting from N-{4-[(3R)-3-aminopyrrolidin-1-yl]phenyl}-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 156; 220 mg, 0.556 mmol) and glycolic acid (51 mg, 0.667 mmol). NMR: 1.39 (d, 6H), 1.92-2.04 (m, 1H), 2.14-2.26 (m, 1H), 2.44 (s, 3H), 3.04-3.13 (m, 1H), 3.18-3.49 (m, 3H), 3.80 (d, 2H), 4.46-4.51 (m, 1H), 5.34 (t, 1H), 5.42-5.51 (m, 1H), 6.49 (d, 2H), 7.31 (d, 1H), 7.35 (d, 2H), 7.82 (d, 1H), 8.41 (d, 1H), 9.06 (s, 1H); m/z 454.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[C:19]([CH3:25])=[C:18]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[BH4-].[Na+].C(O)(=O)C>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]([OH:24])[CH3:23])[C:19]([CH3:25])=[C:18]([CH2:26][O:27][CH2:28][C:29]([F:30])([F:31])[F:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)c(C)c(C(C)=O)n2)ccc1-n1cnc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Nc2nc(COCC(F)(F)F)c(C)c(C(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)ethanone (25 mg, 0.06 mmol) in dioxane (3 mL) and water (3 mL) was treated with sodium borohydride (8 mg, 0.22 mmol). The mixture was stirred at rt for 30 min. Acetic acid (0.5 mL) was added and the mixture was stirred for 25 min. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound as a dry film, 13 mg (48%).
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=O)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH4+:22].[Cl-]>CCO.[Zn]>[S:1]([N:11]1[C:19]2[C:18](=[CH:17][CH:16]=[C:15]([CH2:20][NH2:22])[CH:14]=2)[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(CN)cc32)cc1

Procedure:
4-Aminomethylindole, 5-aminomethylindole and 6-aminomethylindole are known compounds. It is sometimes convenient to protect the indole nitrogen and in those instances a tosyl group was first introduced. 1-Tosyl-1H-indole-6-carbonitrile (CASRN31274-87-1) was reduced with H2 and RaNi in 7N ammonical methanol to afford the corresponding aminomethyl derivative. 1-Tosyl-1H-indole-4-carbaldehyde was converted to the oxime and reduced with Zn and NH4Cl in EtOH to afford (1-tosyl-1H-indol-6-yl)methanamine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl.[OH-].[Na+]>[F:9][C:5]1[CH:6]=[C:7]2[C:2]([NH:1][C:16](=[O:20])[C:17](=[O:18])[NH:8]2)=[C:3]([C:10]([F:13])([F:11])[F:12])[CH:4]=1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(F)cc(C(F)(F)F)c2[nH]c1=O
Temperature: 25 °C
Yield: 58.3 %

Procedure:
A mixture of 2,3-diamino-5-fluorobenzotrifluoride (148 mg, 0.76 mmol) and oxalic acid dihydrate (96 mg, 0.76 mmol, used as received) in 4N HCl (2 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed by cold water (2×2 mL), collected by filtration, and dried at 60° C. for 2 h, affording 120 mg of crude title compound (64%) as a yellow powder. The crude product was dissolved in 1N NaOH (5 mL) and filtered. The filtrate was acidified to pH=6, affording 110 mg of pure title compound as a yellow powder. Mp: 300°-2° C. IR (KBr, cm-1): 3408, 3122, 1754, 1721, 1621, 1492. 1H NMR (DMSO-d6): δ7.178 (dd, 1H, J1 =2.7 Hz, J2 =8.7 Hz), 7.359 (dd, 1H, J1 =2.7 Hz, J2 =8.7 Hz); 11.270 (s, 1H); 12.237 (s, 1H). HRMS: calcd for C9H4N2O2 (M+) m/z: 248.0208; found: 248.0220.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27](=[O:33])[N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27](=[O:33])[N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:17]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCC(=O)N3CCCC3)ncc2[N+](=O)[O-])CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](CNc2nc(NCC(=O)N3CCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
(4-{[5-Nitro-2-(2-oxo-2-pyrrolidin-1-yl-ethylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester (19 mg, 0.04 mmol) was dissolved in CH2Cl2 (5 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The solution was treated with saturated NaHCO3 and the organic phase was separated. The aqueous phase was extracted with CH2Cl2 and the combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 10:1:0.3 CH2Cl2:MeOH:Et3N as an eluant to afford 13 mg of the title compound as a light yellow solid (83%), m/z 376.3 [M−1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[CH:3]=[C:2]([CH:27]([C:26]3[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=3)[OH:28])[CH:7]=[N:6][C:5]=2[O:8][CH3:9])[CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ncc(Br)cc1-c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ncc(C(O)c2ccc(F)cc2)cc1-c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 96 %

Procedure:
To a cooled solution, −78° C., of 5-bromo-3-(3-chlorophenyl)-2-methoxypyridine (Intermediate 7, 1.5 g, 5 mmol) in THF (25 mL), under nitrogen, was added nBuLi (4.8 mL, 5.5 mmol) drop-wise over 2 minutes. The reaction mixture was stirred at −78° C. for 40 min. A solution of 4-fluorobenzaldehyde (744 mg, 6 mmol) in THF (2 mL) was added, and the reaction mixture was stirred an additional 30 min at −78° C. The reaction was quenched with saturated sodium sulfate, filtered, and concentrated under reduced pressure. Purification (FCC, SiO2, 0-25% EtOAc/hexanes) afforded the title compound as a colorless solid (1.65 g, 96%). 1H NMR (400 MHz, CD3OD) δ 8.11 (d, J=2.3 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.51 (s, 1H), 7.47-7.29 (m, 5H), 7.07 (t, J=8.6 Hz, 2H), 5.84 (s, 1H), 3.93 (s, 3H). [M+H]=344.18.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26].O>C(OCC)(=O)C>[C:25]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:27])[CH3:26]
Reactant: CCOC(=O)Cn1c(C)cc2c(N)cccc21
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)Cn1c(C)cc2c(NC(C)=O)cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The (4-amino-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester prepared above (8.59 g) was dissolved in ethyl acetate (175 ml) then triethylamine (5.2 ml, 37 mmol) added followed by acetyl chloride (2.6 ml, 37 mmol). An exotherm to 35° C. was observed and a thick suspension resulted. After stirring for 4 hours during which the mixture was allowed to cool back to ambient temperature, water (85 ml) was added and the ethyl acetate removed by evaporation under vacuum. The solid was collected by filtration, washed with water (25 ml) followed by 50% v/v aqueous acetonitrile (50 ml) then dried in a vacuum oven at 50° C. overnight to provide (4-acetylamino-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester, as an off-white solid, 7.26 g (77% from (4-nitro-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[CH3:16][O-:17].[Na+]>CO>[CH3:16][O:17][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(OC)nc1C(F)(F)F
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Methyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (1128 mg) was dissolved in MeOH (23 ml) before addition of sodium methoxide (380 mg), the reaction mixture was stirred for 2 hours in a sealed tube at 110° C. The solvent was evaporated, the product dissolved in ethyl acetate and washed with water, the organics were dried over Na2SO4, and concentrated in vacuo to afford title compound as a colourless oil. MS (ISP) 237.0 ([M+H]+)
Reaction SMILES: C([NH:5][S:6]([C:9]1([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7])(C)(C)C.CC1(S(N)(=O)=O)CC1>>[C:12]([C:9]1([S:6]([NH2:5])(=[O:8])=[O:7])[CH2:10][CH2:11]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)NS(=O)(=O)C1(C(=O)c2ccccc2)CC1
Agent: CC1(S(N)(=O)=O)CC1
Product: NS(=O)(=O)C1(C(=O)c2ccccc2)CC1
Yield: 87 %

Procedure:
This compound, Example 6,1-benzoylcyclopropyl-sulfonamide, was obtained in 87% yield from N-tert-butyl(1-benzoyl)cyclopropylsul-fonamide using the procedure described for the synthesis of 1-Methylcyclopropylsulfonamide, followed by recrystallization from the minimum amount of EtOAc in hexane: 1H NMR (DMSO-d6) δ 1.39 (m, 2H), 1.61 (m, 2H), 7.22 (s, 2H), 7.53 (t, J=7.6 Hz, 2H), 7.65 (t, J=7.6 Hz, 1H), 8.06 (d, J=8.2 Hz, 2H); 13C NMR (DMSO d6) δ 12.3, 48.4, 128.1, 130.0, 133.4, 135.3, 192.0.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:34])=[N:29]2.C(O)(=O)C.O>C1(C)C=CC=CC=1.CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@@:11]([C:14]([F:16])([F:15])[F:17])([OH:18])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:34])=[N:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(F)c1OC
Reactant: Cc1ncc2c(N)cccc2n1
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F)c1ccc(F)c(F)c1OC
Temperature: 100 °C
Yield: 81.2 %

Procedure:
300 mg (0.92 mmol) of (2R,4R)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 146 mg (0.92 mmol) of 5-amino-2-methylquinazoline are dissolved in 20 ml of toluene, and the solution is admixed with 0.29 ml (0.92 mmol) of titanium tert-butoxide and 0.1 ml of acetic acid. The reaction mixture is heated at 100° C. for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 349 mg of (2R,4R)-4-(3,4-difluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol as a crude product. The crude imine is dissolved in 35 ml of CH2Cl2 and the solution is cooled to −30° C. 6 ml (6 mmol) of a 1 M BBr3 solution in dichloromethane are added slowly dropwise over 5 minutes and the reaction solution is allowed to warm to room temperature over 16 hours. It is poured onto a mixture of saturated NaHCO3 solution and ice. Extraction is carried out repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/isopropanol 0-10%) and subsequent HPLC separation on a chiral stationary phase afford 70 mg of product (analytical HPLC: Rt=8.36 min (Chiralcel OD 5μ, 250×4.6 mm, hexane/ethanol 5%, 1 ml/min flow rate) as the (−)-enantiomer.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][NH:3]1.Br[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>C(#N)C.CCCCC.CCOCC>[CH2:16]([N:3]1[CH:4]=[CH:5][C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[C:7]([C:8]#[N:9])[C:2]1=[O:1])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: N#Cc1c(-c2cccs2)cc[nH]c1=O
Reactant: CC(C)CCBr
Solvent: CCOCC
Solvent: CC#N
Solvent: CCCCC
Product: CC(C)CCn1ccc(-c2cccs2)c(C#N)c1=O
Yield: 60 %

Procedure:
According to Scheme 21: The title compound was prepared according to Example 1 Step 2 from 1,2-dihydro-2-oxo-4-(thiophen-2-yl)pyridine-3-carbonitrile (1 eq, 0.50 mmol, 0.10 g) and 1-bromo-3-methylbutane (1.5 eq, 0.70 mmol, 0.10 g). Reaction conditions: 17 hours at 60° C. in acetonitrile (10 mL). The crude product was purified by chromatography over silicagel (AIT Flashsmart prepacked column SiO2, cyclohexane/AcOEt 80/20) and recrystallized in pentane/Et2O yielding the title compound (88 mg, 0.30 mmol, 65%) as a yellow solid. M.p.: 123° C.; LC (XTerra RP18, 3.5 μm, 3.0×50 mm Column): RT=4.29 min; MS m/z (CI) [MH]+=273; 1H NMR (300 MHz, DMSO-d6) δ 0.92 (d, J=5.6 Hz, 6H), 1.48-1.63 (m, 3H), 3.90-4.02 (m, 2H), 6.72 (d, J=7.2 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.96-8.04 (m, 2H), 8.08 (d, J=7.2 Hz, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=[O:8])[CH2:6][C@:5]2([CH:9]([CH3:11])[CH3:10])[C@H:3]1[CH2:4]2.[N:12]1[C:25]2[C:16](=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH:15]=[CH:14][CH:13]=1>>[OH:8][C@@:7]1([C:22]2[CH:21]=[CH:20][C:19]3[C:24](=[C:25]4[C:16](=[CH:17][CH:18]=3)[CH:15]=[CH:14][CH:13]=[N:12]4)[N:23]=2)[C@@H:2]([CH3:1])[C@@H:3]2[C@@:5]([CH:9]([CH3:11])[CH3:10])([CH2:4]2)[CH2:6]1
Reactant: CC(C)[C@@]12CC(=O)[C@@H](C)[C@@H]1C2
Reactant: c1cnc2c(c1)ccc1cccnc12
Product: CC(C)[C@@]12C[C@@H]1[C@H](C)[C@@](O)(c1ccc3ccc4cccnc4c3n1)C2
Yield: 45 %

Procedure:
By using the general procedure above, (−)-thujone (0.186 g, 1.22 mmol) was reacted with 1,10-phenanthroline to provide 0.083 g (45% yield) of the title compound as a colorless oil: 1H NMR (300 MHz, CDCl3) δ9.16 (dd, J=4.50, 1.80 Hz, Hp9), 8.27 (d, J=8.40 Hz, Hp4), 8.24 (dd, J=8.10, 1.80 Hz, Hp7) 7.82 and 7.76 (two d, J=8.80 Hz, Hp5 and Hp6), 7.72 (d, J=8.40 Hz, Hp3), 7.62 (dd, J=8.10, 4.50 Hz, Hp8), 6.38 (br s, OH), 2.75 (dq, J=6.6, 4.5 Hz, CHCH3), 2.50 (dd, J=13.5, 1.2 Hz, C(OH)CHH), 2.21 (d, J=13.5 Hz, C(OH)CHH), 1.53 (sep, 6.9 Hz, CH(CH3)2), 1.37 (t, J=3.9 Hz, cyclopropyl H), 1.31 (dd, J=4.2, 8.4 Hz, cyclopropyl H), 1.07 (d, J=6.9 Hz, CH3), 0.95 (d, J=6.9 Hz, CH3), 0.89 (d, J=6.9 Hz, CH3), 0.37 (dd, J=4.5, 9.0 Hz, cyclopropyl H); 13C NMR (75 MHz) δ165.09, 150.16, 145.56, 142.86, 137.10, 136.05, 128.98, 127.17, 126.29, 126.05, 122.87, 119.72, 81.85, 48.66, 46.71, 33.01, 32.70, 29.53, 20.10, 19.94, 13.12, 11.60; IR (CHCl3) 3381 (OH), 2957 (C—H Ar), 2928 (CH), 850 (C—H Ar) cm−1; HRMS m/e Calcd for C22H25N2O (MH+): 333.1967, found: 333.1943.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[Cl:16].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1OB(O)O.[F-].[Cs+].O1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[Cl:16][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[C:21]1[CH:20]=[CH:19][C:18]([F:17])=[CH:23][C:22]=1[F:24])=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2ncc(Cl)c(Br)c2c1
Reactant: OB(O)Oc1ccc(F)cc1F
Agent: [Fe+2]
Agent: [Pd]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2ncc(Cl)c(-c3ccc(F)cc3F)c2c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 69.3 %

Procedure:
Under argon gas atmosphere, a mixture of methyl 4-bromo-3-chloroquinoline-6-carboxylate (130 mg), 2,4-difluorophenylboric acid (137 mg), a 1,1′-bis(diphenylphosphino)ferrocene palladium (H) dichloride/dichloromethane complex (177 mg), cesium fluoride (197 mg), 1,4-dioxane (8 mL), and water (2 mL) was heated under stirring in an oil bath at 100° C. for one day. The reaction mixture was returned to room temperature, and water was added, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 3-chloro-4-(2,4-difluorophenyl)quinoline-6-carboxylate (100 mg).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.[N:10](N)([CH3:12])[CH3:11].Cl.[OH-].[Na+]>CCOCC>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:10]([CH3:12])[CH3:11]
Reactant: CN(C)N
Reactant: C=CCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: C=CCCCCCCN(C)C

Procedure:
HOSiPcOSi(CH3)2(CH2)8N(CH3)2 Compound XXII A solution of CH2═CH(CH2)6Br, (CH3)2NNH2 and ether was stirred, the reaction mixture was worked up with HCl, NaNO3, and NaOH, and the resulting CH2═CH(CH2)6N(CH3)2 was isolated and distilled. A solution of this compound, (CH3)2SiHCl, CHCl3, H2PtCl6xH2O and isopropanol was warmed and the CH3OSi(CH3)2(CH2)8N(CH3)2—HCl formed was isolated. Next, a suspension of this intermediate, CH3SiPcOH and pyridine was partially distilled, and the CH3SiPcOSi(CH3)2(CH2)8N(CH3)2 obtained was isolated and recrystallized. Finally, a solution of this compound and CH2Cl2 was irradiated with light and the product was isolated, chromatographed, and recrystallized: MS-HRFAB exact mass, m/z: calculated for C44H45N9O2Si2 (M+H)+, 788.3313; found, 788.3300, 788.3290.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:15])[CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH2:15])[CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: C=C(CCC(=O)OC)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=C(CCCO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
A solution of methyl 4-(4-chlorophenyl)pent-4-enoate (5.5 g) in dry diethyl ether (20 ml) was added dropwise over 10 minutes to a stirred suspension of lithium aluminium hydride (1.9 g) in dry diethyl ether (130 ml), cooled in an ice-water bath and under an atmosphere of nitrogen. Following the addition, the cooling bath was removed and the reaction mixture was stirred for 1 hour at room temperature and then diluted with aqueous ammonium chloride. The mixture was extracted with diethyl ether, and the extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(4-chlorophenyl)pent-4-en-1-ol (4.5 g, 93%) as a pale yellow oil, IR (film): 3400 cm-1.