Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:16])[C:14]=1[F:15])[N:11]([NH:17][CH3:18])[CH:10]=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]2=[O:24].[C:25]([O:29][C:30]([C:32](=[CH2:40])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:31])([CH3:28])([CH3:27])[CH3:26].O>C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl>[F:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:16])[C:14]=1[F:15])[N:11]([N:17]([CH3:18])[CH2:40][CH:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:10]=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]2=[O:24]
Reactant: C=C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cn(NC)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(N(C)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
Methylene chloride (10 ml) solution of ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.0 g) and tert-butyl 2-tert-butoxycarbonylacrylate (1.52 g) was cooled in an ice bath in nitrogen atmosphere, and titanium tetrachloride (632.4 mg) was dropwise added thereto. After 30 minutes, this was diluted with ethyl acetate (100 ml) and then with water (100 ml). The organic layer was separated out, washed with water (2×50 ml), dried over magnesium sulfate and concentrated under reduced pressure to obtain an yellow syrup product. The syrup product was subjected to column chromatography with silica gel and eluted with a mixed solvent of methylene chloride/ethyl acetate (10/1) to obtain ethyl 6,7,8-trifluoro-1-[N-methyl-N-{2,2-bis(tert-butoxycarbonyl)ethyl}amino]-1,4-dihydro-4-oxoquinoline-3-carboxylate (988 mg), as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([Cl:62])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([Cl:62])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(Cl)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.4 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 91 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(3-chloro-phenyl)-ethyl]-amine in 1 ml DMF was added. After 2.5 h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The yellow solid foam was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 122 mg (90%) of a white semisolid. MS (EI) 444.2 (M)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH:24]([F:26])[F:25])[CH:10]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:32].[OH2:38]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH:24]([F:26])[F:25])[CH:10]=2)=[CH:7][CH:8]=1)(=[O:32])=[O:38]
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)F)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4-[5-(4-[Methylthio]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (0.5 g, 1.27 mmol) was dissolved in methylene chloride (30 mL) and cooled to 0° C. To this solution was added m-chloroperoxybenzoic acid (MCPBA) (60%, 0.77 g, 2.7 mmol) and the solution was allowed to warm to room temperature while stirring for 18 hours. A solution of Na2S2O5 (2 g) in H2O (25 mL) was added to the reaction mixture and the solution stirred vigorously for 0.5 hour. The layers were separated and the organic layer was washed with saturated NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4 and concentrated to yield 4-[5-(4-[methylsulfonyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide as a white solid, 0.22 g, 40%, mp=209°-210° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:22])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:22][C:15]1[CH:14]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:17][C:16]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(C(C)(C)C)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(C(C)(C)C)cc1CBr
Temperature: 25 °C
Yield: 42 %

Procedure:
N-bromosuccinimide (18.5 g, 0.103 mol) was added to a solution of methyl 5-tert-butyl-3-methylthiophene-2-carboxylate (109b) (20 g, 0.09 mol) and AIBN (0.774 g, 0.0047 mol) in CCl4 (200 mL). The mixture was refluxed for 2 h, cooled to room temperature and filtered. The filtrate was concentrated under vacuum and the obtained residue was purified by flash column chromatography (silica, 95:5 hexanes-/dichloromethane) to afford methyl 3-(bromomethyl)-5-tert-butylthiophene-2-carboxylate (109c) (11 g, 40%) as a pale yellow liquid.
Reaction SMILES: [C:1]([Br:4])(=O)[CH3:2].C[C@@H:6]1[CH2:10][O:9][C:8](=[O:11])[CH2:7]1.[CH2:12](O)C>>[CH2:10]([O:9][C:8](=[O:11])[CH2:7][C@H:2]([CH3:12])[CH2:1][Br:4])[CH3:6]
Reactant: CC(=O)Br
Reactant: C[C@@H]1COC(=O)C1
Reactant: CCO
Product: CCOC(=O)C[C@H](C)CBr
Reaction time: 2 h

Procedure:
To ethanol (55 ml) cooled to 0° C. was added acetyl bromide (41 ml, 0.6 mol) dropwise, followed by a solution of (S)-4-methyl-dihydro-furan-2-one (Tetrahedron 1983, 39, 3107; 18.6 g, 0.2 mol) in ethanol (20 ml). The ice bath was removed and the reaction allowed to reach room temperature. After 2 h of stirring the reaction was concentrated, the residue redissolved in dichloromethane, washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated affording (S)-4-bromo-3-methyl-butyric acid ethyl ester (33.6 g, quant). This was redissolved in ethanol (100 ml), cooled to 0° C. and N-benzylglycine ethyl ester (28.2 g, 0.14 mol) and triethylamine (22.4 ml, 0.16 mmol) were added. The reaction was then warmed to 75° C. for 4 d after which time the reaction was concentrated, the residue redissolved in dichloromethane, washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (ethyl acetate/heptane 5:95) afforded the titled product as a light gold oil (20.3 g, 43%). MS (ISP)=322.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH3:16])[C:4]=1[C:17](OCC)=O)#[N:2].[OH2:22].[NH2:23][NH2:24].C(O)C>O>[NH2:2][C:1]1[C:3]2[CH:7]=[CH:6][N:5]([C:8]3[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=3[CH3:16])[C:4]=2[C:17](=[O:22])[NH:23][N:24]=1
Reactant: NN
Reactant: O
Reactant: CCOC(=O)c1c(C#N)ccn1-c1c(C)cc(C)cc1C
Solvent: CCO
Product: Cc1cc(C)c(-n2ccc3c(N)n[nH]c(=O)c32)c(C)c1
Yield: 62.5 %

Procedure:
A mixture of ethyl 3-cyano-1-mesityl-1H-pyrrole-2-carboxylate (0.5 g, 1.77 mmol), hydrazine monohydrate (0.86 ml, 17.7 mmol) and ethanol (20 ml) was heated under reflux for 2 days. During the reaction, additional hydrazine monohydrate (0.86 ml×2) was added. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with dichloromethane/ethyl acetate (3:1-1:1) to give 297 mg (63%) of the title compound as crystals.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:16][C:15](=O)[CH2:14][C:13](=[O:18])[CH2:12]1.[Cl:19][C:20]1[CH:31]=[C:24]2[C:25](OC(=O)[NH:29][C:23]2=[CH:22][CH:21]=1)=[O:26].Cl>CN(C)C=O>[Cl:19][C:20]1[CH:31]=[C:24]2[C:23]([NH:29][C:15]3[CH2:16][CH:11]([C:5]4[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=4[Cl:3])[CH2:12][C:13](=[O:18])[C:14]=3[C:25]2=[O:26])=[CH:22][CH:21]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=C1CC(=O)CC(c2ccc(Cl)cc2Cl)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(c2ccc(Cl)cc2Cl)Cc2[nH]c3ccc(Cl)cc3c(=O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.96 g of 50% sodium hydride in 10 ml of N,N-dimethylformamide at -10° C. is added dropwise a solution of 5.14 g of 5-(2,4-dichlorophenyl)cyclohexan-1,3-dione in 40 ml of N,N-dimethylformamide. During the addition frothing occurs and the temperature rises to 10° C. The mixture is then stirred at room temperature for 1 hr and cooled to 5° C. A solution of 3.96 g of 5-chloroisatoic anhydride in 40 ml of N,N-dimethylformamide is added and stirring is continued at room temperature for 18 hrs and then at 85°-90° C. for 5 hr. The mixture is poured into 1300 ml of ice water containing 10 ml of concentrated hydrochloric acid. The solid is collected, washed with water, and suspended in 200 ml of methanol. The suspension is heated on a steam bath for 0.5 hr, cooled and filtered. The solid is washed with methanol and then with ether and dried in vacuo at 60° C. for 18 hrs to give 7-chloro-3-(2,4-dichlorophenyl)-3,4-dihydro-1,9(2H,10H)-acridinedione; mp 308°-310° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:19][C:20]#[C:21][CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCCCCC.CC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([O:5][C:6]([C:8]1([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC#CCC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC/C=C\CC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC

Procedure:
A 690 mg quantity of 5-tert-butoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (10)) is dissolved in a mixture of 5 ml of n-hexane and 5 ml of acetone and reduced at room temperature and atmospheric pressure with addition of 3.2 g of a Lindlar catalyst. The catalyst is filtered off from the reaction mixture, and the solvent distilled off. The residue is purified by a silica gel column and distilled in a vacuum, giving 5-tert-butoxycarbonyl-4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone (compound (2), R1 =t-Bu, R2 =CH3) in a yield of 99.8%, b.p. 81°-84° C./0.005 mm Hg.
Reaction SMILES: Cl[C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[N:16][N:17]([CH3:28])[C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.[CH3:29][O-:30].[Na+]>C1COCC1.O>[CH3:29][O:30][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[N:16][N:17]([CH3:28])[C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1
Reactant: CN(N=Cc1ccccc1-n1c(Cl)nn(C)c1=O)c1ncccc1C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nn(C)c(=O)n1-c1ccccc1C=NN(C)c1ncccc1C(F)(F)F
Temperature: 25 °C

Procedure:
The title compound of Step B (0.38 g, 0.93 mmol) was dissolved in THF (10 mL) and then sodium methoxide (25% in methanol, 0.56 mL) was added dropwise. The mixture was heated at reflux for 1 h, cooled to room temperature and then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to an oil which was purified by flash column chromatography on silica gel to afford 0.27 g of the title compound of Step C, a compound of the invention, as a pale yellow solid melting at 185-187° C. 1H NMR (300 MHz, CDCl3): δ 8.41 (dd,1H, J=5, 1.5 Hz), 8.12 (dd,1H, J=8, 1.5 Hz), 8.01 (dd,1H, J=8, 1.5Hz), 7.42 (m,3H), 7.23 (d,1H J=8 Hz), 15 7.02 (dd,1H, J=8, 5Hz), 3.93 (s,3H), 3.56 (s,3H), 3.48 (s,3H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([NH:17][OH:18])=[NH:16])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]1([C:22]([Cl:24])=O)[CH2:21][CH2:20]1>>[ClH:24].[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([CH2:12][CH2:13][CH2:14][C:15]3[N:16]=[C:22]([CH:19]4[CH2:21][CH2:20]4)[O:18][N:17]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N=C(CCCC1CCN(C2CCCC2)CC1)NO
Reactant: O=C(Cl)C1CC1
Product: C(Cc1noc(C2CC2)n1)CC1CCN(C2CCCC2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 3, starting from 4-(1-cyclopentylpiperidin-4-yl)-N-hydroxybutyramidine and cyclopropylcarbonyl chloride.
Reaction SMILES: [CH:1]1([C:6]2[NH:7][C:8]3[CH2:9][C:10]([CH3:38])([CH3:37])[CH2:11][C:12](=[O:36])[C:13]=3[CH:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:15]=2[C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([C:6]2[C:15]([C:16](=[O:27])[C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]3[C:12](=[O:36])[CH2:11][C:10]([CH3:38])([CH3:37])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)C2=C(C1)NC(C1CCCC1)=C(C(=O)c1ccc(C(F)(F)F)cc1)C2c1ccc(F)c(F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(=O)c2c(nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)c(F)c2)C1

Procedure:
0.9 g (1.7 mmol) of 2-cyclopentyl-4-(3,4-difluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-4,6,7,8-tetrahydro-1H-quinolin-5-one were oxidized at room temperature within one hour to give the pyridine, using 4.5 g of manganese dioxide (activated) in 25 ml of methylene chloride. The manganese dioxide was separated off and the methylene chloride was distilled off, and the mixture was then filtered off with suction using petroleum ether. This gave 0.8 g of crystals of melting, point: 210-212° C.
Reaction SMILES: O=C1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=CN1.[C:11](=O)([O-])[O-].[K+].[K+].IC.[CH3:19][N:20]([CH:22]=[O:23])[CH3:21]>O>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:19][N:20]([CH3:21])[C:22](=[O:23])[CH:7]=1)=[O:9]
Reactant: O=C(O)c1cc[nH]c(=O)c1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1ccn(C)c(=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
2-Oxo-1,2-dihydropyridine-4-carboxylic acid (5.0 g, 36 mmol) and potassium carbonate (24.8 g, 179 mmol) were stirred in DMF (75 mL) at room temperature. Iodomethane (6.72 mL, 108 mmol) was added slowly via a syringe and the reaction mixture was stirred for 3 days at room temperature. The reaction mixture was then diluted with water and extracted with dichloromethane until the product was removed from the aqueous phase. The combined organics were dried over magnesium sulfate, filtered and concentrated, then chromatographed in ethyl acetate on silica gel to yield the title compound (4 g, 66%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:19][S:20](O)(=[O:22])=[O:21].[OH-].[K+:25]>>[CH2:7]([C:1]1[CH:6]=[CH:5][C:4]([S:20]([O-:22])(=[O:21])=[O:19])=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[K+:25]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCCCCCCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)[O-])cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 1-phenyldodecane (7.5 g, 30.5 mmol) and concentrated H2SO4 (8.4 mL) was stirred vigorously at 90° C. for 1 h, cooled to room temperature, and then gradually poured with stirring into 10% aqueous KOH solution (175 mL). The resulting white precipitate was collected by filtration, washed with cold water (40 mL) and dried to give potassium 4-dodecylbenzene sulfonate (10.6 g, 29.1 mmol, 84%). This salt (10.0 g, 27.5 mmol) and POCl3 (4.2 g, 27.4 mmol) were stirred at room temperature and gradually heated to 170° C. The hot reaction mixture was poured into cold water and extracted with CHCl2. The organic layer was washed with water, dried over anhydrous Na2SO4, and filtered. Evaporation of the volatiles yielded p-dodecylbenzenesulfonyl chloride as a pale yellow liquid (9.2 g, 97%) which eventually became crystalline, mp 33° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=6.5), 1.20-1.38 (m, 18H), 1.60-1.68 (m, 2H), 2.72 (t, 2H, J=7.5 Hz), 7.40 (d, 2H, J=8.4 Hz), 7.79 (d, 2H, J=8.4 Hz); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.6, 29.1, 29.3, 29.3, 29.5, 29.6, 30.9, 31.9, 36.0, 127.0, 129.6, 141.7, 151.6.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1.C[O:22][B:23](OC)[O:24]C>C1COCC1>[CH3:20][S:19][C:16]1[CH:17]=[CH:18][C:13]([B:23]([OH:24])[OH:22])=[CH:14][CH:15]=1
Reactant: CSc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
n-BuLi in hexane (2.5M, 625 mmol, 250 ml) is added slowly to a mechanically stirred solution of 4-bromothioanisole (100 g, 492 mmol) in THF (1 ) below −55° C. (internal temp.). After aging at −72° C. for 1 h trimethylborate (73 ml, 1.3 eq.) is added at such a rate to keep the internal temperature below −55° C. After 0.25 h at −78° C. the solution was allowed to warm to 0° C. for 10 min. 2N HCL (500 ml) is added and the solvent is evaporated. Water (500 ml) is added and the product is extracted with EtOAc (1.5 ). The organic layer is dried over Na2SO4, concentrated and the solid is stirred in hexane (500 ml) for 2 h. Filtartion gave 61.9 g (75%) of the desired product. 1H NMR (acetone-d6, 400 MHz) δ7.80 (d, 2H), 7.22 (d, 2H), 7.15 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[O:32])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1OC
Yield: 36 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml), and p-fluorophenyl isocyanate (23 μl) was then added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 26 mg (yield 36%) of the title compound.
Reaction SMILES: [H-].[Li+].[CH3:3][C:4]([C:11]1[CH2:16][CH2:15][C:14]([CH3:17])=[CH:13][CH:12]=1)([CH3:10])[CH2:5][CH2:6]C(O)=O.[CH:18]([Li])=C.C1COCC1.[CH2:26]([CH2:29][O:30]C)OC>>[CH3:18][C:14]12[CH2:13][CH2:12][C:11]3([CH:16]=[CH:15]1)[CH:26]([C:29](=[O:30])[CH2:6][CH2:5][C:4]3([CH3:3])[CH3:10])[CH2:17]2
Reactant: CC1=CC=C(C(C)(C)CCC(=O)O)CC1
Reactant: [Li]C=C
Reactant: COCCOC
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC12C=CC3(CC1)C(C2)C(=O)CCC3(C)C
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
A mixture of freshly distilled dimethoxyethane (250 ml), lithium hydride (880 mg, 110 mmol) and 4-methyl-4(4-methyl-1,3-cyclohexadien-1-yl)pentanoic acid was refluxed under Argon for 2.5 hours. The mixture was then cooled to 5° C and vinyl lithium in THF (111 g, 130 ml, 208 mmol) was added over a ten minute period. After stirring for an additional 5 minutes, the mixture was quenched by siphoning into a vigorously stirring solution of 28 ml of conc. HCl in 400 ml ice water. The aqueous layer was saturated with sodium chloride, and extracted with methylene chloride. The methylene chloride solution was washed (5% NaOH, 10% NaCl) and then concentrated. The product was crystallized from hexane to yield 7.5 g (40%) of the 1,7,7-trimethyltricyclo[6.2.2.03,8 ]dodec-9-en-4-one (8). Analysis by gas liquid chromatography and thin layer chromatography showed this to be a mixture of two isomers.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH2:17])[CH3:16].FC1C=C(F)C=CC=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32](=[O:34])C.C([O-])(=[O:37])C.[NH4+].C([BH3-])#N.[Na+]>CO>[F:8][C:6]1[CH:7]=[CH:2][C:3]2[C:9]3[C:10]([CH:15]([CH3:16])[N:17]([C:32]([C:27]4[CH:28]=[C:29]([OH:37])[CH:30]=[CH:31][CH:26]=4)=[O:34])[C:4]=2[CH:5]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: CC(=O)[O-]
Reactant: CC(=O)c1ccccc1-c1ccc(F)cc1F
Reactant: CC(N)c1ccccc1-c1ccc(F)cc1F
Agent: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1cccc(O)c1

Procedure:
1-(-2′,4′-difluoro-biphenyl-2-yl)-ethylamine—The title compound was prepared from 1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethanone (3.67 g, 15.8 mmol), anhydrous methanol (200 mL), ammonium acetate (12.2 g, 158 mmol), and sodium cyanoborohydride (1.99 g, 31.6 mmol) according to the procedure and in the same manner as described in Example 24, step b resulting in the isolation of a clear oil that was used without further purification. MS [(ES+), m/z]: 217 [M-16]+, benzylic cation as a result of the loss of NH2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(C(=O)O)c(OC)c1
Product: COc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 10 °C
Reaction time: 8 h

Procedure:
1,800 ml of chlorosulphonic acid is placed in a 4 liter flask fitted with an agitator and a thermometer, and is cooled to 10° C. 328 g of finely powdered 2,4-dimethoxy benzoic acid is added in stages in the course of 45 minutes, between 10° and 15° C. The acid dissolves gradually as it is introduced. When all the acid has been added the solution is gradually heated to 55° C. and that temperature is maintained for 5 hours. The solution is left to stand overnight, then poured very slowly into 17 kg of ice, with agitation and with external cooling. The acid which is precipitated is drained, washed with water and dried in air.