Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(C1C=CC=CC=1B1OC(C)(C)C(C)(C)O1)(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(C)C)cc(Br)c3O2)cc1
Reactant: Cc1ccccc1B(O)O
Agent: CC(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(C)C)cc(-c4ccccc4)c3O2)cc1
Yield: 46 %

Procedure:
To a solution of 4-isopropylphenol (13.38 g, 98.0 mmol) with N-bromosuccinimide (17.5 g, 98 mmol) generally according to the procedure described for Example 305 afforded 13.78 g (65%) of 2-bromo-4-isopropylphenol. Treatment of 2-bromo-4-isopropylphenol (13.74 g, 41.0 mmol) with potassium carbonate (22.0 g, 160 mmol) and allyl bromide (9.23 g, 76.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-isopropylphenol. Treatment of 2-allyl-6-bromo-4-isopropylphenol (6.85 g, 27.0 mmol) with 3-chloroperoxybenzoic acid (7.72 g, 27.0 mmol, 77%) followed by potassium carbonate (9.3 g, 67.5.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.12 g, (17%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.12 g, 4.6 mmol) with p-toluenesulfonyl chloride (1.32 g, 6.9 mmol) generally according to the procedure described for Intermediate 10 gave 1.90 g (97%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.94 mmol) and 2-methylphenylboronic acid (0.38 g, 2.82 mmol) generally according to the procedure described for Intermediate 35 afforded 0.19 g, (46%) of (5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.141 g, 2.17 mmol) generally according to the procedure described for Intermediate 98 afforded 0.11 g (83%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.188 g, 0.716 mmol) according to the procedure described in Example 154 afforded 0.055 g (48%) of (±)-[(5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 221-222° C. (dec).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])=[CH:9][C:10]=2[O:12][CH:13]([CH3:15])[CH3:14])[N:5]=[CH:4][N:3]=1.[NH2:28][C:29]1[C:34]([Cl:35])=[CH:33][N:32]=[C:31]2[O:36][CH2:37][O:38][C:30]=12>>[Cl:35][C:34]1[C:29]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=4[O:26][CH3:27])=[CH:9][C:10]=3[O:12][CH:13]([CH3:15])[CH3:14])[N:5]=[CH:4][N:3]=2)=[C:30]2[O:38][CH2:37][O:36][C:31]2=[N:32][CH:33]=1
Reactant: COc1ccc(COc2cc(OC(C)C)c3c(Cl)ncnc3c2)c(OC)c1
Reactant: Nc1c(Cl)cnc2c1OCO2
Product: COc1ccc(COc2cc(OC(C)C)c3c(Nc4c(Cl)cnc5c4OCO5)ncnc3c2)c(OC)c1
Yield: 75 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-7-(2,4-dimethoxybenzyloxy)-5-isopropoxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 75% yield; NMR Spectrum: (CDCl3) 1.55 (d, 6H), 3.8 (s, 3H), 3.85 (s, 3H), 4.8 (m, 1H), 5.15 (s, 2H), 6.15 (s, 2H), 6.5 (m, 2H), 6.6 (s, 1H), 7.0 (s, 1H), 7.35 (d, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass Spectrum: M+H+ 525 and 527.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[CH:28][C:22]=1[C:23]([N:25]=[C:26]=[O:27])=O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[CH:28][C:22]=1[C:23]1[NH:25][C:26](=[O:27])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 1.00 g, 3.63 mmol) in DCM (20 mL), 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.30 g, 4.03 mmol) was added and the reaction mass was stirred at RT for 2 h. After completion of reaction, excess of solvent was removed under reduced pressure to obtain 0.700 g of the crude product. To a solution of obtained crude product in DCM (5.0 mL), TFA (5.0 mL) was added and the reaction mass was stirred at RT for 2-3 h. Excess of the solvent was removed from the reaction mass under reduced pressure and the reaction mass was quenched in ice and filtered to obtain 0.700 g of the desired title product. 1H NMR (300 MHz, DMSO d6): δ 4.45 (d, 1H), 7.50 (d, J=4.8 Hz, 1H), 7.65-7.68 (m, 2H), 8.85 (d, J=6.6 Hz, 2H), 8.18 (d, J=6.3 Hz, 2H), 10.05 (s, 1H), 12.69 (s, 1H); MS (m/z): 463.17 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-])=O.[H][H]>[Ni].C(O)C>[O:11]1[C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:12][C:8]=2[CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCO2
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2c(c1)CCO2

Procedure:
A mixture of 10 g. of 5-nitro-2,3-dihydrobenzofuran, 2.5 g. of Raney Nickel and 50 ml. of ethanol is hydrogenated in a Parr apparatus at a hydrogen pressure of 50 p.s.i. and room temperature until the uptake of hydrogen ceases. The resulting mixture is filtered to remove catalyst and the filtrate evaporated in vacuo to obtain an oil of 2,3-dihydro-5-benzofuranamine.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[NH2:17][C:18]1[N:23]=[N:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1.O>C(O)CCC>[CH3:14][S:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([CH2:5][C:2]3[N:23]4[N:22]=[C:21]([C:24]#[N:25])[CH:20]=[CH:19][C:18]4=[N:17][CH:3]=3)[CH:16]=[CH:15][C:9]=2[N:10]=1
Reactant: N#Cc1ccc(N)nn1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Solvent: CCCCO
Solvent: O
Product: CSc1nc2ccc(Cc3cnc4ccc(C#N)nn34)cc2s1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (1.3 g, 4.8 mmol) and 6-aminopyridazine-3-carbonitrile (0.8 g, 7.2 mmol) in 1-butanol (48 mL) was heated at reflux overnight. The mixture was cooled to rt and water (100 mL) was added. The mixture was extracted with EtOAc (3×60 mL, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile as a yellow solid (0.7 g, 44%). 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=9.0 Hz, 1H), 7.83-7.78 (m, 2H), 7.69 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.29 (d, J=9.3 Hz, 1H), 4.46 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 338 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[Cl:11].[S-2:12].[Na+].[Na+].[S]>O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([S:12][S:12][C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[Cl:11])=[C:3]([Cl:11])[CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: [S-2]
Agent: [Na+]
Agent: [S]
Solvent: O
Product: Nc1ccc(SSc2ccc(N)cc2Cl)c(Cl)c1
Temperature: 90 °C

Procedure:
76.8 g (0.4 mol) of 1,2-dichloro-4-nitrobenzene, suspended in 120 ml of water, were heated to 90° C. and treated with a solution of 62.4 g (0.8 mol) of sodium sulfide and 12.8 g (0.4 mol) of sulfur in 200 ml of water.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([CH3:20])[CH:16]=2)=[CH:5][CH:4]=1)#[N:2].N[CH2:24][CH:25]([OH:28])[CH2:26][OH:27].CC1ON=C(CCC(O)=O)C=1>>[OH:27][CH2:26][CH:25]1[O:28][C:1]([C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[O:19][N:18]=[C:17]([CH3:20])[CH:16]=3)=[CH:21][CH:22]=2)=[N:2][CH2:24]1
Reactant: Cc1cc(CCCCCCCOc2ccc(C#N)cc2)on1
Reactant: NCC(O)CO
Agent: Cc1cc(CCC(=O)O)no1
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCC(CO)O3)cc2)on1
Yield: 60 %

Procedure:
5-{7-[4(4,5-Dihydro-5-hydroxymethyl-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole [IX; R=CH3, R1, R2, R3, R4 and R5 =H, R6 =CH2OH, Y=(CH2)7, oxazole at 4-position] was prepared from the ethyl imino-ester hydrochloride of 5-[7-(4-cyanophenoxy)heptyl]-3-methylisoxazole and 3-amino-1,2-propanediol according to the procedure of Example 1, part (c), and was obtained in about 60% yield in the form of a colorless solid, m.p. 75°-76° C., when recrystallized first from isopropyl acetate and then from acetonitrile.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][NH:28][CH:27]([CH3:35])[CH2:26]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:28]1[CH:27]([CH3:35])[CH2:26][C:25]2[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH2:29]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Reactant: COc1cc2c(cc1OC)CC(C)NC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(CCCCCCCC(=O)NOCc1ccccc1)C(C)C2

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.7 g, 2.1 mmol) was reacted with 6,7-dimethoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.5 g, 2.1 mmol) in the presence of potassium carbonate (0.3 g, 2.2 mmol) and DMF as solvent to give 8-(6,7-dimethoxy-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-octanoic acid benzyloxyamide as an almost colorless wax (yield 0.35 g, 37%; purified by column chromatography using silica gel and ethyl acetate: methanol=95:5 as an eluent). MS (M+H+)=455.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].I[CH:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:23]([CH3:25])[CH3:24])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19]
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C(C)C)c3c(Cl)cccc23)c(C)c1
Yield: 61.1 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and 2-iodopropane (0.07 mL, 0.7 mmol) to give the title compound (0.100 g) as a white solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1S[C:14](=[O:25])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>C1COCC1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][C:14](=[O:25])[CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:22][CH:21]=1
Reactant: COc1ccc(CCC(=O)Sc2ccccn2)cc1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)CC(C)C)cc1
Reaction time: 1 h
Yield: 75 %

Procedure:
Isobutylmagnesium bromide (0.88 mL, 1.75 mmol, 2M soln in THF) was added to a cooled −78° C. solution of 3-(4-Methoxy-phenyl)-thiopropionic acid S-pyridin-2-yl ester (0.4 g, 1.46 mmol, from Step 1) dissolved in THF (6 mL). The reaction mixture was stirred for 60 min. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to a yellow oil. The residue was purified by silica gel chromatography (5% EtOAc in hexanes) to give the title compound as a clear oil (0.24 g, 75%). 1H NMR (CDCl3): δ 0.89 (d, 6H, J=6.6 Hz), 2.12 (m, 1H), 2.26 (d, 2H, J=7.0 Hz), 2.60-2.69 (m, 2H), 2.81-2.90 (m, 2H), 3.78 (s, 3H), 6.82 (d, 2H, J=8.7 Hz), 7.09 (d, 2H, J=8.7 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:27]([CH3:29])[CH3:28])=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=1)=[CH:12][C:11]([Cl:26])=[CH:10][CH:9]=2)=[O:4].[I-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:26][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([CH:27]([CH3:28])[CH3:29])[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:24])([F:23])[F:25])[CH:16]=1
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1-c1cccc(OC(F)(F)F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)c1nc2ccc(Cl)cc2c(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Yield: 51.7 %

Procedure:
To the stirred solution of 6-chloro-2-isopropyl-4-(3-trifluoromethoxy-phenyl)-quinoline-3-carboxylic acid methyl ester (50 mg, 0.118 mmol) in 3 ml of pyridine under nitrogen was added lithium iodide (158 mg, 1.18 mmol) at RT. Then the reaction mixture was refluxed for 16 h. Volatiles were removed under vacuo to afford a crude residue which was diluted with water and ethyl acetate. The organic phase was discarded and the aqueous layer was made acidic to pH 3 with 10% aqueous citric acid under cooling. The aqueous phase was then extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by prep TLC (mobile phase: 5% MeOH in DCM) to afford 6-chloro-2-isopropyl-4-(3-trifluoromethoxy-phenyl)-quinoline-3-carboxylic acid (25 mg, 52%) as an off white solid. LC-MS: 410 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:27])[CH2:20]2.[OH-].[Na+]>O.C(OCC)C>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:21]1([OH:27])[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]1)[CH:16]=[CH:15]2
Reactant: O=C1CN2CCC1CC2
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2cc(C3(O)CN4CCC3CC4)ccc2c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (2.5 M, 1.86 ml, 4.64 mmol) was added to a mixture of 2-bromo-6-methoxynaphthalene (1.0 g, 4.22 mmol) and diethyl ether (10 ml) at 20° C. The temperature was kept below 35° C. for 30 min. The mixture was cooled to −70° C. and 3-quinuclidinone (0.53 g, 4.22 mmol) was added at −70° C. The mixture was stirred at −70° C. for 1 h. The mixture was allowed to reach room temperature. Water (1 ml) was added followed by aqueous sodium hydroxide (1 M, 10 ml). The crystalline product was filtered and was washed with cold diethyl ether (2 ml). Yield 0.49 g (41%). Mp >330° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]=O)=[N:4][CH:5]=[C:6]([N:8]([CH:10]2[CH2:13][CH2:12][CH2:11]2)[CH3:9])[N:7]=1.[CH2:16]([NH:23][CH2:24][C@@H:25]([OH:29])[CH2:26][O:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:16]([N:23]([CH2:14][C:3]1[C:2]([Cl:1])=[N:7][C:6]([N:8]([CH:10]2[CH2:11][CH2:12][CH2:13]2)[CH3:9])=[CH:5][N:4]=1)[CH2:24][C@@H:25]([OH:29])[CH2:26][O:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC[C@H](O)CNCc1ccccc1
Reactant: CN(c1cnc(C=O)c(Cl)n1)C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC[C@H](O)CN(Cc1ccccc1)Cc1ncc(N(C)C2CCC2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 3-chloro-5-[cyclobutyl(methyl)amino]pyrazine-2-carbaldehyde (451 mg), (2R)-1-(benzylamino)-3-methoxypropan-2-ol (469 mg) and acetic acid (343 μL) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (636 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise a saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (674 mg, 83%).
Reaction SMILES: [F:1][C:2]1[C:3](B(O)O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)C.C([O-])([O-])=O.[K+].[K+].Br[C:21]1[S:22][C:23]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][N:25]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([C:21]2[S:22][C:23]([N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:24][N:25]=2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(Br)s1
Reactant: OB(O)c1ncccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(-c2cncc(F)c2)s1
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
To a 3-neck round bottom flask was added fluoropyridine boronic acid (4.55 g, 32.3 mmol), ethanol (54 mL), and aqueous K2CO3 solution (27 mL, 2.0 M, 53.8 mmol), followed by 50 mL toluene. To this mixture was added di(tert-butyl) 2-bromo-1,3-thiazol-5-ylimidodicarbonate (10.2 g, 26.9 mmol). Next, tetrakis(triphenylphosphine)palladium(0) (6.2 g, 5.4 mmol) was added in one portion. The flask was fitted with a reflux condenser and was heated to reflux. After 45 minutes, the reaction was cooled in an ice bath and partitioned between aqueous saturated NaHCO3 and ethyl acetate. The layers were separated and the aqueous layer was extracted once with ethyl acetate. The combined organics were washed once with brine, dried over MgSO4, filtered, and then concentrated. This solid was triturated with 20% ethyl acetate/hexanes. The solids were filtered off and the filtrate evaporated to provide a residue which was purified via silica gel column chromatography (0 to 100% ethyl acetate/hexanes) to afford the desired product as an off-white solid (7.74 g, 73% yield): mp 94-96° C.; 1H NMR (300 MHz, CDCl3) δ 8.91 (app t, J=1.3 Hz, 1H), 8.52 (d, J=3.0 Hz, 1H), 7.96 (ddd, J=9.2, 3.0, 1.8 Hz, 1H), 7.66 (s, 1H), 1.48 (s, 18H); ESIMS m/z 396 (M+1).
Reaction SMILES: [ClH:1].[C:2]1([C:8](=O)[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19]>CO>[ClH:1].[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:22][S:18](=[O:20])(=[O:19])[N:21]=2)[CH:12]=1
Reactant: O=C(C(=O)c1cccnc1)c1ccccc1
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: CO
Product: O=S1(=O)N=C(c2ccccc2)C(c2cccnc2)=N1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Hydrogen chloride gas is bubbled into a solution of 1-phenyl-2-(pyridin-3-yl)ethan-1,2-dione (1.63 g, 7.7 mmol, J. Org. Chem., 1999, 64, 6102) and sulfamide (750 mg, 7.7 mmol) in methanol (10 mL) until the solution begins to reflux. The gas flow is turned off, and the solution stirred at 65° C. for 3 h then cooled to rt. The solid that formed is filtered and dried to give 2.06 g of the product 497. MS: m/z 272 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:19][CH2:18][C:17]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccccc1
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C(CC(=O)OC)c1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 356 g of 4-nitro-3-phenylbutanoic acid methyl ester, 138 g of methyl acrylate, and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-phenylheptanedioic acid dimethyl ester.
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl[CH2:20][C:21]#[C:22][CH2:23][S:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].O>CO>[C:26]([O:28][CH3:29])(=[O:27])[CH2:25][S:24][CH2:23][C:22]#[C:21][CH2:20][S:18][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCS
Reactant: COC(=O)CSCC#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCSCC#CCSCC(=O)OC
Reaction time: 0.5 h

Procedure:
460 μl of a 30% solution of sodium methoxide in methanol were added to a solution of 665 μl of tetradecanethiol in a 5 ml methanol/2 ml THF mixture, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then 0.47 g of methyl 7-chloro-3-thia-5-heptynoate in 5 ml of methanol was added, under an inert atmosphere. The mixture was maintained under stirring for 8 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The wax thus obtained was chromatographed on a silica gel column (CH2Cl2) providing 1.05 g of methyl 3,8-dithia-5-docosynoate in the form of an oil. (Quantitative yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[C:5]2=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:5]2[C:6](=[N:7][C:2]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:3][CH:4]=2)[NH:8][N:9]=1
Reactant: Nc1ccccc1
Reactant: COc1ccccc1-c1n[nH]c2nc(Cl)ncc12
Product: COc1ccccc1-c1n[nH]c2nc(Nc3ccccc3)ncc12
Yield: 69 %

Procedure:
The compound was prepared from 6-chloro-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 6) and aniline (Aldrich) in an analogous manner as described in Example 32 (175° C.) and the title compound was obtained in 69% yield. MS (M+H)+, 318.2.