Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[O:4][C:5]2[C:10]([C:11](=[O:24])[C:12]=1[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=1)=[CH:9][CH:8]=[C:7]([OH:25])[CH:6]=2.Cl>O1CCOCC1>[F:26][CH:2]([F:1])[C:3]1[O:4][C:5]2[C:10]([C:11](=[O:24])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:22][CH:23]=1)=[CH:9][CH:8]=[C:7]([OH:25])[CH:6]=2
Reactant: CCOC(=O)c1ccc(-c2c(C(F)F)oc3cc(O)ccc3c2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2c(C(F)F)oc3cc(O)ccc3c2=O)cc1
Temperature: 25 °C
Yield: 13 %

Procedure:
To a mixture of ethyl 4-(2-(difluoromethyl)-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoate (400 mg, 1.16 mmol) in 1,4-dioxane (1 mL) was added Conc. HCl (1 mL). The reaction mixture was heated to reflux overnight. The mixture was cooled to room temperature and filtered. The filtered mass was washed with water (5 mL) 2 times and ethanol (2 mL) and purified by prep-HPLC to afford a white solid (50 mg, 13%).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:15][C:14]([C:3]2[N:4]3[C:5]([S:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9][C:8]=43)=[N:1][CH:2]=2)=[O:16])[CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Product: O=C(C=Cc1cccc(Cl)c1)c1cnc2sc3c(n12)CC=CC=C3

Procedure:
1-(6,7,8,9-Tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-yl ethanone (Formula N-4), 1.87 g, and 3-chlorobenzaldehyde (0.216 g) were condensed following non-critical variations of Example 15 to provide 6,7,8,9-Tetrahydro-[2-(3-chlorophenyl)-ethenyl-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl methanone (Formula N-5, X=3-chloro), (2.72 g), m.p. 137-139°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][Si](C(C)(C)C)(C)C)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([OH:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2c(O[Si](C)(C)C(C)(C)C)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2c(O)cccc21

Procedure:
In analogy to the procedure described in example 1 c], [4-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid ethyl ester was treated with tetrabutylammonium fluoride in THF to give the title compound as colorless crystals.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:15]([F:24])[CH:14]=2)[C:8]([O:10]CC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:15]([F:24])[CH:14]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(c1ccccc1)c1ccc(NS(C)(=O)=O)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(C(=O)O)c2ccccc2)cc1F

Procedure:
Ethyl 2-phenyl-2-(3-fluoro-4-(methylsulfonamido)-phenyl)acetate (16.5 mmol, 5.8 g) was dissolved in a mixture of 32 mL of THF and 16 mL of water, 1.18 g of LiOH (49.5 mmol) were added, and the mixture was heated under reflux over a period of 15 h. To the reaction mixture there were added 15 mL of water and the phases were separated. The aqueous phase was acidified with aq. HCl and extracted with dichloromethane (3×50 mL). The combined organic phases were dried over MgSO4, concentrated, and the residue purified by means of column chromatography (silica gel: 100-200 mesh, eluent: 50% EA in cyclohexane). Yield 3.3 g (61.3%).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1.[CH2:20]1[O:30][C:23]2([CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[O:22][CH2:21]1>C1(C)C=CC=CC=1.ClCCl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:26]2([OH:29])[CH2:27][CH2:28][C:23]3([O:30][CH2:20][CH2:21][O:22]3)[CH2:24][CH2:25]2)=[N:14][CH:15]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 53.7 %

Procedure:
1.6M n-Hexane solution of n-butyl lithium (66 ml) was added dropwise to a solution of 2,5-dibromopyridine (23.9 g) in toluene (420 ml) at −78° C., and stirred at the same temperature for an hour. Next, a solution of 1,4-cyclohexanedione monoethyleneketal (15 g) in dichloromethane (60 ml) was added dropwise, and the reaction solution was warmed up to room temperature over 7 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate three times. The organic solution was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) and recrystallized from n-hexane/diethyl ether to give 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decan-8-ol (16.2 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>ClCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C:14]2[CH:13]=[C:12]([CH3:21])[CH:17]=[CH:16][CH:15]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1cccc(B(O)O)c1
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClCCl
Product: Cc1cccc(-n2cnc3c(Cl)nc(Cl)nc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
2,6-Dichloropurine (1.3 mmol), m-Tolyl boronic acid (4.0 mmol), anhydrous cupric acetate (1.32 mmol), 4 Å molecular sieves (1 g) [1,10]-Phenanthroline (2.64 mmol) in 25 ml of anhydrous dichloromethane were stirred at room temperature in a round bottomed flask. The reaction mixture was stirred at room temperature and monitored by TLC, LC-MS. Reaction was complete after 24 h. The molecular sieves and inorganic material were removed by filtration through a celite bed. The bed was thoroughly washed with methanol. The combined organics were purified by flash chromatography to yield 50% of the desired compound as a solid. m/z: 279.02 [MH]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([C:25]([OH:28])([CH3:27])[CH3:26])[C:17]([NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18].[CH:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]2[N:37]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:38]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[C:32]=12)=O>ClCCCl>[CH:20]1([NH:19][C:17](=[O:18])[C@H:16]([NH:15][CH2:29][C:31]2[CH:36]=[CH:35][N:34]=[C:33]3[N:37]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:38]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[C:32]=23)[C:25]([OH:28])([CH3:26])[CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)(O)[C@@H](N)C(=O)NC1CCCC1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C(C)(C)O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium triacetoxyborohydride (104 mg, 0.493 mmol) and (R)-2-amino-N-cyclopentyl-3-hydroxy-3-methylbutanamide (49.4 mg, 0.246 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. 1-tert-Butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (75 mg, 0.246 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. Following reaction, the mixture was concentrated to afford the title compound. [M+H] calc'd for C25H36N4O6, 489; found, 489.3.
Reaction SMILES: N[C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][C:5]=2[S:4][C:3]=1[CH2:17][CH3:18].FC(F)(F)C([O-])=[O:22].[K+].FC(F)(F)C(O)=O>>[CH2:17]([C:3]1[S:4][C:5]2[N:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][C:9](=[O:11])[C:10]=2[C:2]=1[OH:22])[CH3:18]
Reactant: CCOC(=O)c1nc2sc(CC)c(N)c2c(=O)[nH]1
Reactant: O=C([O-])C(F)(F)F
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2sc(CC)c(O)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The diazonium fluoborate salt is prepared as in Procedure 63 from the amino compound produced in Procedure 51 yielding 0.03 mole of the required diazonium fluoborate. The latter is added in one portion to a solution of 0.03 mole of potassium trifluoroacetate in 13 ml. of trifluoroacetic acid at 0° C. The mixture is stirred at 25° C. for one hour and then refluxed overnight. The trifluoroacetic acid is evaporated in vacuo to give a residue which is triturated with water and filtered to give the desired product.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([C:42](O)=[O:43])([CH3:41])[CH3:40])=[CH:33][CH:32]=2)=[C:28]([CH:45]([CH3:47])[CH3:46])[NH:27][N:26]=1)(=[O:3])[CH3:2].Cl.[NH2:49][C@H:50]([C:52]([NH2:54])=[O:53])[CH3:51].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([C:42](=[O:43])[NH:49][C@H:50]([C:52](=[O:53])[NH2:54])[CH3:51])([CH3:41])[CH3:40])=[CH:33][CH:32]=2)=[C:28]([CH:45]([CH3:47])[CH3:46])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[C@H](N)C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCC(C)(C)C(=O)N[C@@H](C)C(N)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxy-2-methylpropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole (0.13 g) in N,N-dimethylformamide (2 mL) were added L-alanine amide hydrochloride (46 mg), triethylamine (0.08 mL), 1-hydroxybenzotriazole (38 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloro-methane/methanol=20/1-10/1) to give the title compound (0.14 g).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]#[N:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[C:21]([C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([OH:23])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:18])=[O:19])#[N:22]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 0.1 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (4.84 g, 14.4 mol) in tetrahydrofuran (25 mL) was treated with a 0.8M aqueous lithium hydroxide solution (27 mL, 21.6 mmol). The reaction mixture was stirred at 25° C. for 2.5 h. The reaction mixture was partitioned between water and ethyl acetate and then acidified to pH=2 with a 10% aqueous hydrochloric acid solution. The layers were shaken and separated. The resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford crude 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (3.80 g, 82%) as a pale yellow oil that solidified to a pale yellow solid. An analytical sample was obtained by recrystallization from ethyl acetate to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid as a white solid: mp 180-181° C.; EI-HRMS m/e calcd for C16H19NO4S (M+) 321.1034, found 321.1039.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[N:14][C:13]([C:16]#[N:17])=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[N:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: N#Cc1cnc(N)cn1
Agent: Cl[Pd]Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cc(Cl)ncn2)cn1
Temperature: 135 °C
Yield: 19.2 %

Procedure:
A mixture of 4,6-dichloropyrimidine (1.00 g, 6.7 mmol), 2-amino-5-cyanopyrazine (806 mg, 6.7 mmol) and bis(triphenylphosphine)palladium (II) chloride (94 mg, 0.134 mmol) in dry THF (24 mL) was degassed under a stream of nitrogen gas for 10 minutes with stirring. Lithium bis(trimethylsilyl)amide in THF (1M, 7.38 mL, 7.4 mmol) was added and the mixture was heated at 135° C. for 20 minutes using microwave irradiation. The reaction mixture was adsorbed onto silica and purified by flash column chromatography, eluting with 30% ethyl acetate in hexane, to give 5-(6-chloropyrimidin-4-ylamino)pyrazine-2-carbonitrile (300 mg, 19%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.CCCCCC.CN(C)[CH:24]=[O:25].[BH4-].[Na+]>Cl.C(O)C.O.CCOCC>[F:10][C:3]1[CH:4]=[C:5]([CH3:9])[C:6]([F:8])=[CH:7][C:2]=1[CH2:24][OH:25]
Reactant: CN(C)C=O
Reactant: Cc1cc(F)c(Br)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Cc1cc(F)c(CO)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of 1-bromo-2,5-difluoro-4-methyl-benzene (3.3 g, 16 mmol) and ether (75 mL) was cooled to −78° C., and a solution of n-butyllithium in hexane (5.4 mL, 2.5 M, 13.5 mmol) was added dropwise. After stirring for 1 hour, dimethylformamide (1.1 mL, 14 mmol) was added, and the mixture was stirred for 1 hour. The mixture was treated with 1M HCl and water, warmed to ambient temperature and was extracted 3× with ether. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was diluted with tetrahydrofuran (50 mL), and the mixture was treated with sodium borohydride (0.50 g, 13.5 mmol) and ethanol (2 mL). After stirring for 30 minutes, the mixture was diluted cautiously with 0.5M aqueous HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization of the residue from hexane afforded 1.24 g (54%) of (2,5-difluoro-4-methyl-phenyl)-methanol as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, 1H, J=6.0, 9.2 Hz), 6.84 (dd, 1H, J=6.4, 10 Hz), 4.68 (d, 2H, J=6.0 Hz), 2.23 (s, 3H), 1.76 (t, 1H, J=6.0 Hz) ppm.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.CCCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([S:8][C:9]1[CH:15]=[C:14]2[C:12](=[C:11]([F:16])[CH:10]=1)[N:13]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]2[OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(SCc2ccccc2)cc1F
Solvent: CCCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(F)cc(SCc3ccccc3)cc2c1O
Temperature: 135 °C
Reaction time: 1.5 h

Procedure:
A neat mixture of 3.58 g of compound of 4-(benzylsulfanyl)-2-fluoroaniline and 3.48 g of diethyl ethoxymethylenemalonate is heated at 135° C. under a slow argon sweep for 1 h, then diluted with 25 mL of diphenyl ether and heated to 260° C., with maintenance of the argon sweep, and kept at that temperature for 90 min. The mixture is then cooled to ca 100° C. and added to 300 mL of stirred heptane. The precipitate is filtered, washed with heptane, and dried in vacuo to provide 4.01 g of ethyl 6-(benzylsulfanyl)-8-fluoro-4-hydroxy-3-quinolinecarboxylate as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](I)=[CH:28][N:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ncc(I)cn1
Product: Nc1ncc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (337 g, 1.0 mmol) and commercially available 2-amino-5-iodopyrimidine (287 mg, 1.3 mmol) according to general procedure II. Obtained as an orange solid (52 mg, 12%). MS (ISP) 431.3 [(M+H)+]; mp 242–243° C.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].C[O:15][B:16](OC)[O:17]C.Cl>C1COCC1>[F:6][C:7]1[C:8]([F:13])=[CH:9][CH:10]=[CH:11][C:12]=1[B:16]([OH:17])[OH:15]
Reactant: COB(OC)OC
Reactant: Fc1ccccc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(F)c1F
Reaction time: 8 h

Procedure:
Butyllithium (2.5 M in hexanes, 88 ml, 0.219 mol) was added dropwise to a stirred, cooled (−78° C.) solution of difluorobenzene (25.0 g, 0.219 mol) in dry THF (400 ml) under a stream of dry nitrogen. The reaction mixture was maintained under these conditions for 2.5 h and then trimethylborate (45.5 g, 0.438 mol) was added dropwise to the reaction mixture and left overnight to reach room temperature. The reaction mixture was stirred for 1 h with 10% HCl (100 ml) at room temperature. The product was extracted into ether (2×200 ml) and the combined ethereal extracts were washed with water and dried (MgSO4), the solvent was removed under reduced pressure to give white crystals.
Reaction SMILES: [H-].C(C1[AlH2+]C=1CC(C)C)C(C)C.[F:13][C:14]1[CH:21]=[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:19]=[CH:18][C:15]=1[C:16]#N.C[OH:40]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:21]=[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:40]
Reactant: CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#N)c(F)c1
Agent: CC(C)CC1=C(CC(C)C)[AlH2+]1
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Di-isobutylaluminmum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of the 2-fluoro-4-(hexadecylamino)benzonitrile under a nitrogen atmosphere. The temperature rises to 40° C. during the addition which takes 30 minutes and the reaction is then stirred for 1 hour. A solution of methanol in toluene (50 ml., 1:1) is added during 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (500 ml., 5%). After 10 minutes, diatomaceous earth (30 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. Recrystallization from hexane affords 2-fluoro-4-(hexadecylamino)benzaldehyde as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[OH-].[Na+].I[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1>CN(C)C=O>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[O:19][CH2:18][CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: ICCOC1CCCCO1
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccccc2n1CCOC1CCCCO1
Yield: 83 %

Procedure:
The reaction was carried out in a manner similar to Reference Example 5 except for using 2.0 g (11.4 mmol) of methyl 2-indolecarboxylate, 0.55 g (13.7 mmol) of 60% sodium hydroxide, 3.63 g (13.7 mmol) of 2-(2-iodo-ethoxy)tetrahydropyran (prepared from 2-iodoethanol and 3,4-dihydro-2H-pyran) and 50 ml of dimethylformamide. Thus, 2.87 g (83.0%) of methyl 1-[2-(2-tetrahydro-pyranyl)oxyethyl]-2-indolecarboxylate was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([OH:16])[C:13]([Cl:17])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:16][C:14]2[C:13]([Cl:17])=[CH:12][C:9]3[C:10]([CH3:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][C:8]=3[CH:15]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)c1oc2cc(O)c(Cl)cc2c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cc2c1C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
The above prepared 5-chloro-6-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.900 g, 3.53 mmol) was dissolved in 15 mL of THF and treated successively at −10° C. with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.996 g, 1.4 eq.), triphenylphosphine (1.298 g, 1.4 eq.) and DIAD (0.971 mL, 1.4 eq.), and the mixture then kept at ambient temperature for another 3 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=85/15), gave 1.459 g of the title compound as colorless gum.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[CH:11]=2)(=O)=O.ClC1C=C(C=CC=1)COC1C=C2C(C=C(CO)C=[N:39]2)=CC=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O>C1COCC1>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:7]([CH2:6][NH2:39])[CH:8]=[N:9]2)=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)OCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reactant: OCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NCc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methyl methanesulfonate. To a solution of (7-((3-chlorobenzyl)oxy)quinolin-3-yl)methanol (Example 35, 55 mg, 0.18 mmol) in THF (1.8 mL) was added DIPEA (0.064 mL, 0.37 mmol), followed by methanesulfonyl chloride (0.014 mL, 0.18 mmol). The reaction was stirred at ambient temperature overnight. The crude reaction was loaded directly onto a column, purification (FCC, SiO2, 0-40%, EtOAc/hexanes) afforded the title compound as a white solid (44 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J=2.3 Hz, 1H), 8.10 (s, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.48 (d, J=9.4 Hz, 2H), 7.41-7.28 (m, 4H), 5.20 (s, 2H), 4.76 (s, 2H). [M+H]=318.2