Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]1([C:11]([CH:13](Br)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[O:12])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:8]1([C:11]([CH:13]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[O:12])[CH2:10][CH2:9]1
Reactant: OC1CCNCC1
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C1CC1)C(c1ccccc1F)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
In 30 ml of dimethylformamide (DMF), 3.13 g (31 mmol) of 4-hydroxypiperidine were dissolved, followed by the addition of 7.94 g (31 mmol) of α-cyclopropylcarbonyl-2-fluorobenzylbromide and 4.7 g (34 mmol) of potassium carbonate. The resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with toluene. The resulting organic layer was dried over anhydrous sodium sulfate. The solvent was concentrated by evaporation under reduced pressure. The residue was purified by chromatography on a silica gel column (eluting solvent: chloroform/methanol=19/1), whereby 8.00 g of the title compound were obtained as a brown oil (yield: 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][N:4]=1.CC([O-])=O.[Na+].[Br:16]Br.[OH-].[Na+]>CC(O)=O.O>[Br:16][C:10]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1ccc(C=O)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ncc(C=O)cc1Br
Temperature: 90 °C
Yield: 39.2 %

Procedure:
To a mixture of 6-methoxynicotinaldehyde (3 g, 0.0219 mol) and NaOAc (3.5 g, 0.0427 mol) in HOAc (10 mL) was added a solution of bromine (1.64 mL, 0.031 mol) in HOAc (10 mL) over 30 mins via an additional funnel. The mixture was heated to 90° C. for 5 h, cooled to rt. The reaction was added iced water (100 mL), neutralized to pH=7.5 with aq. NaOH (5 N), extracted with ethyl acetate (4×50 mL), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified via flash column using dichloromethane as an eluent. The product containing fractions were collected and concentrated to give 5-bromo-6-methoxynicotinaldehyde (1.854 g, 39% yield).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13]O>>[CH2:1]([S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)CSCc1ccccc1
Product: COC(=O)CSCc1ccccc1

Procedure:
S-benzylthioglycolic acid (12.0 g) was dissolved in 250 mL of methanol and sparged with hydrogen chloride gas at room temperature for 20 minutes. The solvent was then removed under vacuum. Methyl S-benzylthioglycolate obtained was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl.[CH3:14][C:15]([CH3:24])([CH3:23])[C:16]#[C:17]/[CH:18]=[CH:19]/[CH2:20][NH:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[ClH:1].[CH3:14][C:15]([CH3:24])([CH3:23])[C:16]#[C:17]/[CH:18]=[CH:19]/[CH2:20][N:21]([CH3:22])[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CNC/C=C/C#CC(C)(C)C
Reactant: ClCc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 1.77 g (10 mmol) of 1-chloromethylnaphthalene in 10 ml of dimethyl sulfoxide were added 1.88 g (10 mmol) of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine hydrochloride and 1.66 g (12 mmol) of potassium carbonate under ice cooling. The mixture was stirred for 16 hours at room temperature, poured into 200 ml of ethyl acetate, washed with 100 ml ×2 of water, a mixture of 80 ml of water and 10 ml of 2N hydrochloric acid, and 50 ml of saturated sodium chloride aqueous solution respectively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to crystallize. The crystals were suspended in 10 ml of ethyl acetate, cooled, filtered and dried under reduced pressure to obtain 2.95 g (yield: 90%) of the above identified compound as off-white crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O=S(Cl)Cl.[BH4-].[Na+]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH2:8][OH:9])[CH:11]=1
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(CO)c1
Temperature: 30 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
To a solution of 5-methoxy-2-nitrobenzoic acid (20.0 g, 0.102 mol) in anhydrous THF (200 mL) was added SOCl2 (20 mL), the mixture was refluxed for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in anhydrous THF (100 mL). The solution was added dropwise to a suspension of NaBH4 (7.70 g, 0.202 mol) in anhydrous THF (100 mL) and DMF (140 mL) at 0° C. over a period of 30 minutes. The mixture was stirred at 30° C. for 3 hours, then quenched with ice-water (100 mL) and basified by 2M NaOH to pH 8. An EtOAc workup was followed by removal of solvent in vacuo and purification by column chromatography (PE/EtOAc=1/1) to give the product (12.0 g, yield 66%).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([F:28])[C:19]=1[CH:20]=O>O1CCCC1.C(OCC)(=O)C>[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([F:28])[C:19]=1/[CH:20]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COc1cc(F)c(C=O)c(F)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(F)cc(OC)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
A solution of ethyl diethylphosphonoacetate (2.34 g, 10.4 mmol) and 60% sodium hydride (0.38 g, 9.50 mmol) in tetrahydrofuran (40 mL) was stirred under ice-cooling for 10 min. Thereto was added 2,6-difluoro-4-methoxybenzaldehyde (1.5 g, 8.71 mmol) and the mixture was stirred for 4 hr while allowing to warm to room temperature. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (1.1 g, yield 52%) as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].FS([C:20]([F:25])([F:24])C(O)=O)(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:20]([F:25])[F:24])=[N:6][CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)Oc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
5-Bromopyridin-2(1H)-one (17.4 g, 100 mmol) was mixed with sodium sulfate (1.42 g, 10 mmol) and 2-(fluorosulfonyl)difluoroacetic acid (11.4 ml, 100 mmol) in acetonitrile, and stirred overnight at room temperature. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction solution, and the solvent was concentrated under reduced pressure. The residue was dissolved in diethyl ether, washed with saturated saline, the organic layer was dried with sodium sulfate, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (eluate: ethyl acetate/hexane=20/80 to 50/50) to obtain the entitled compound (18.75 g, 84%) as a pale yellow oily substance.
Reaction SMILES: [BrH:1].[OH:2][C:3]1[C:12]([CH2:13][CH:14]=[CH2:15])=[C:11]([NH:16][C:17]([CH3:19])=[O:18])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>[Hg].O>[OH:2][C:3]1[C:12]([CH2:13][CH2:14][CH2:15][Br:1])=[C:11]([NH:16][C:17]([CH3:19])=[O:18])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: Br
Reactant: C=CCc1c(NC(C)=O)ccc(C(=O)OC)c1O
Agent: [Hg]
Solvent: O
Product: COC(=O)c1ccc(NC(C)=O)c(CCCBr)c1O
Reaction time: 4 h

Procedure:
2277 g of 66% hydrobromic acid and 308 g of methyl 2-hydroxy-3-allyl-4-acetaminobenzoate were introduced into a 3-liter round-bottomed flask equipped with a leakproof stirrer, a thermometer and a safety tube containing mercury so that a pressure of approximately 2 cm of mercury is created in the apparatus. The mixture was stirred for 4 hours and then allowed to stand overnight. 5 liters of water were then added. The precipitate formed was drained, washed with water and dried at 50° C.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[O:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[I-].ClCC[S+](C)C.O>C(O)(C)(C)C>[O:7]=[C:8]1[C:9]2([CH2:2][CH2:1]2)[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[S+](C)CCCl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)C2(CC2)C1
Reaction time: 1 h
Yield: 20.3 %

Procedure:
A solution of potassium tert-butoxide (3.26 g, 27.6 mmol) in tert-butanol (40 mL) was treated with tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol), causing the reaction to turn bright orange. The mixture was stirred for 1 h, then treated with (2-chloroethyl)dimethylsulfonium iodide (5.70 g, 22.59 mmol), added in three portions at 10 minute intervals. This addition caused the color of the reaction to gradually fade to pale yellow. The mixture was stirred for 2 hours, then diluted with tert-butanol (10 mL), treated with potassium tert-butoxide (2.96 g, 25.09 mmol), and stirred overnight at room temperature. The reaction was poured into water (100 mL) and extracted 3× with 100 mL ethyl acetate. The combined organic phases were washed with water and brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was purified over a 5×15 cm silica gel column, eluting with ethyl acetate/hexanes (10%-15%-20%-25% EtOAc, 1 L at each concentration), to yield the title compound (1.15 g, 5.10 mmol, 20.34% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:10]([O-:13])([OH:12])=[O:11].[N:14]#[C:15][NH2:16]>CCO>[N+:10]([O-:13])([OH:12])=[O:11].[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:15]([NH2:16])=[NH:14]
Reactant: Nc1ccc(F)cc1F
Reactant: N#CN
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccc(F)cc1F
Yield: 40 %

Procedure:
To a mixture of 2,4-difluoroaniline (25 mmol, 3.2 g) in EtOH (10 mL) in an ice bath was added nitric acid (69% aq soln.; 1.8 mL) dropwise. After completion of the addition cyanamide (50% aq. soln.; 4 mL) was added. The reaction mixture was refluxed under N2 for 22 h. The solvent was evaporated. The solid residue was washed with EtOH and was dried under high vacuum to afford the title compound as a purple solid (2.32 g, 40%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[OH:23][C@H:24]1[C@H:28]([OH:29])[CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>CC(O)C.CCOC(C)=O>[OH:23][C@H:24]1[C@H:28]([OH:29])[CH2:27][N:26]([C:2]2[C:11]([C:12]#[N:13])=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=3)[N:3]=2)[CH2:25]1
Reactant: COc1ccc2nc(Cl)c(C#N)c(-c3cccc(F)c3)c2c1
Reactant: O[C@@H]1CNC[C@H]1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccc2nc(N3C[C@@H](O)[C@H](O)C3)c(C#N)c(-c3cccc(F)c3)c2c1
Temperature: 150 °C
Reaction time: 72 h

Procedure:
A solution of 2-chloro-4-(3-fluorophenyl)-6-methoxyquinoline-3-carbonitrile (61.0 mg, 0.20 mmol), (3R,4R)-3,4-dihydroxypyrrolidine (43 mg, 0.42 mmol) and triethylamine (0.055 mL, 0.42 mmol) in 3 mL of 2-propanol was heated in a sealed tube at 120° C. for 3 days. The temperature was raised to 150° C. After 3 days, additional portions of (3R,4R)-3,4-dihydroxypyrrolidine (40 mg) and triethylamine (0.055 mL) were added. After a total of 11 days, the solution was cooled and diluted with EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, and dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by recrystallization from EtOAc/hexane (40 mg, 54%). Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C21H19FN3O3 (M+M+): 380.1405. Found 380.1401.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:20]1[CH:32]=[CH:31][C:23]([CH2:24][CH2:25][C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:21]=[CH:22][C:23]([CH2:24][CH2:25][C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:31][CH:32]=2)=[CH:12][CH:11]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Reactant: Brc1ccc(CCc2nnn[nH]2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCc3nnn[nH]3)cc2)cc1
Temperature: 130 °C

Procedure:
A mixture of (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (50 mg, 0.185 mmol), 5-(4-bromophenethyl)-1H-tetrazole (56.3 mg, 0.223 mmol), Na2CO3 (79 mg, 0.742 mmol), and dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (1.313 mg, 1.855 μmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was heated under microwave irradiation at 130° C. for 120 min. The mixture was concentrated and the residue was purified by HPLC to give the title compound. LCMS m/z=362.5 [M+H]+; 1.22-1.31 (m, 0.4H), 1.45 (d, J=6.6 Hz, 2.6H), 1.69-1.82 (m, 1H), 2.00-2.10 (m, 2H), 2.21-2.32 (m, 1H), 3.04-3.20 (m, 6H), 3.25-3.31 (m, 2H), 3.35-3.47 (m, 1H), 3.50-3.60 (m, 1H), 3.72-3.83 (m, 1H), 7.31 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.2 Hz, 2H).
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[CH3:54][C:55]1[O:56][CH:57]=[C:58]([C:60](Cl)=[O:61])[N:59]=1>>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:53])=[O:2])=[O:22])[N:24]([C:60]([C:58]5[N:59]=[C:55]([CH3:54])[O:56][CH:57]=5)=[O:61])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:42][CH:41]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1nc(C(=O)Cl)co1
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)co1

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (30 mg) was reacted with 2-methyl-oxazole-4-carbonyl chloride (prepared above) according to General Procedure F and purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (10 mg). LCMS (m/z): 848.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.COC1C=CC(C[N:30](CC2C=CC(OC)=CC=2)[C:31]2[N:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)=CC=1>>[N:8]1([C:6]2[N:7]=[C:2]([C:34]3[CH:33]=[N:32][C:31]([NH2:30])=[N:36][CH:35]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)cn1

Procedure:
In the same manner as Step D in Example 1-B-01, from 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (119 mg, 0.374 mmol) and bis-(4-methoxybenzyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]amine, the desired compound was obtained as a colorless solid (16.6 mg, yield 12%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][CH:24]([C:29](OC)=[O:30])[C:25](OC)=[O:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][CH:24]([CH2:29][OH:30])[CH2:25][OH:26])=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(Oc1ccc(OCc2ccccc2)cc1)C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCC(CO)Oc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Diisobutylaluminum hydride (7.08 ml) was slowly added dropwise to dimethyl 2-(4-benzyloxyphenoxy)malonate (477 mg, 1.44 mmol) in 16 ml of toluene under argon at 0° C. The reaction mixture was stirred at 0° C. for 2 h and, after addition of 1M hydrochloric acid solution, extracted with ethyl acetate. The organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 98.6 mg (25%), M+H+: 275.20.
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:16][C:17]([Cl:23])([S:21]Cl)[CH:18]([Cl:20])[Cl:19]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH:3]1([N:9]([S:21][C:17]([Cl:23])([Cl:16])[CH:18]([Cl:20])[Cl:19])[S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Reactant: CC(C)S(=O)(=O)NC1CCCCC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N(SC(Cl)(Cl)C(Cl)Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
A 2.4 g (0.29 mol) sample of 50% weight aqueous sodium hydroxide solution was added dropwise to a cooled (12° C.) solution of 5.6 g (0.027 mol) N-cyclohexyl-isopropanesulfonamide, 7 g (0.029 mol) 1,1,2,2-tetrachloroethylsulfenyl chloride and 0.5 g benzyl triethylammonium chloride in 150 ml methylene chloride. A precipitate formed in the reaction mixture during the first 10 minutes of the addition. After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for one hour. The reaction mixture was then washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give the reaction product. The reaction product was chromatographed through 250 g silica gel with 50% chloroform/50% hexane elution to give 4 g (37%) of N-cyclohexyl-N-(1,1,2,2-tetrachloroethylthio)-isopropanesulfonamide, m.p. 122°-123° C. This reaction is tabulated in Table II as Run No. 1.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:26]([CH3:28])[CH3:27].C(Cl)(Cl)Cl>CN(C=O)C.CO>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:26]([CH3:28])[CH3:27])=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Fc1nc(NCc2ccncc2)c2nc[nH]c2n1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(NCc3ccncc3)nc(F)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (2-Fluoro-9H-purin-6-yl)-pyridin-4-ylmethyl-amine (0.6 g, 2.46 mmol) in DMF (10 mL) under an argon atmosphere, at RT, was added K2CO3 (powdered, anhydrous, 1.7 g, 5 eq, 12.3 mmol) followed by 2-bromopropane (2.3 ml, 10 eq, 24.6 mmol). The reaction mixture was stirred at RT for 24 h, when TLC (CHCl3:MeOH; 90:10) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between water (200 ml) and EtOAc (50 ml). The aqueous phase was separated and extracted with more EtOAc (2×50 mL). The bulked organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo, and the residue was purified by gradient column chromatography on silica gel, eluted with chloroform:methanol (100:0→95:5), to provide the product as a white solid; Yield: 0.40 g (57%). mp 170-173° C. 1H-NMR (d6-DMSO, 250 MHz): δ 1.49 (6 H, d, J 7.5, —CH(CH3)2), 4.63 (3 H, m, —CH(CH3)2+—HNCH2-Pyr), 7.30, 8.47 (4 H, 2×m, Pyr-H), 8.28 (s, 1 H, —N═CH—N—), 8.97 (1 H, s, br, —HNCH2-Pyr). m/z: 287 ([M+H].
Reaction SMILES: [O-2].[Pr+3:2].[O-2].[O-2].[Pr+3].[N+:6]([O-:9])([OH:8])=[O:7]>>[N+:6]([O-:9])([O-:8])=[O:7].[Pr+3:2].[N+:6]([O-:9])([O-:8])=[O:7].[N+:6]([O-:9])([O-:8])=[O:7]
Reactant: O=[N+]([O-])O
Agent: [O-2]
Agent: [Pr+3]
Product: O=[N+]([O-])[O-]
Temperature: 100 °C

Procedure:
Praseodymium oxide, Pr6O11 (1.55 g) was weighed into a silica crucible, concentrated nitric acid (2.5 ml) added and heated on a hot plate until the oxide had dissolved and the acid evaporated (~2 hr). The crucible and contents were heated overnight in an oven at 100° C. The praseodymium nitrate was dissolved in water, transferred to a volumetric flask (25 ml) and made up to volume.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:5]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:6][C:7]2[C:12]([C:13]=1[CH:14]([CH3:16])[CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.[Li]CCCC>C1COCC1>[C:3]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:6][C:7]2[C:12]([C:13]=1[CH:14]([CH3:16])[CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)#[CH:2]
Reactant: CC(C)c1c(C=C(Br)Br)c(-c2ccc(F)cc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1c(-c2ccc(F)cc2)nc2ccccc2c1C(C)C
Temperature: -78 °C
Reaction time: 1.25 h
Yield: 72.9 %

Procedure:
A solution of 3-(2,2-dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline (2.563 gm, 5.71 mmol) in dry THF (30 ml) was cooled to -78° C. and treated with n-BuLi (1.5M in hexane, 8.0 ml, 12 mmol) over a 5 minute period. After stirring at -78° C. for 1.25 hours, the brown solution was quenched with saturated NH4Cl, warmed to room temperature, diluted with H2O, and extracted 2× with Et2O. The combined Et2O extracts were washed with brine, dried (Na2SO4), filtered and stripped to give a yellow solid. The solid was recrystallized from hot hexane to afford analytically pure 3-ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline as off-white crystals (1.205 gm, 73%).