Azzindani/Open_Reaction_Data huggingface dataset:
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[Br:24])(=[O:3])[CH3:2].[NH2:25][C:26]([NH2:28])=[S:27]>CC(C)=O>[Br-:24].[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[S:27][C:26]([NH2:28])=[NH2+:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](SC(N)=[NH2+])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Product: [Br-]
Temperature: 20 °C
Yield: 90.6 %

Procedure:
2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (6; 15.00 g, 36.48 mmol) and thiourea (3.05 g, 40.07 mmol) were dissolved in acetone (75 mL). The solution was heated to reflux for 2 hours, and subsequently filtered and cooled to 20° C. Addition of pentane (75 mL) resulted in the precipitation of the product as a white, crystalline solid (16.11 g, 91%). 1H-NMR (400 MHz, [D6]DMSO,): δ=1.95 (s, 3H, CH3), 2.01 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.14 (s, 3H, CH3), 4.09 (m, 2H, H6, H6′), 4.45 (t, J=6.4 Hz, 1H, H5), 5.11 (t, J2,3=10 Hz, 1H, H2), 5.22 (dd, J2,3=9.9 Hz, J3,4=3.2 Hz, 1H, H3), 5.39 (d, J=3.2 Hz, 1H, H4), 5.71 (d, J1,2=10 Hz, 1H, H1), 9.11 (br, 2H, NH2), 9.35 (br, 2H, NH2).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][N:14](P(N(C)C)(N(C)C)=O)C.[C-]#N.[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:13]#[N:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(CC#N)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 4-methanesulfonylbenzyl chloride (10 g, 49 mmol) in DMF (100 mL) was added HMPA (9.35 mL, 54 mmol) and KCN (3.5 g, 54 mmol). The resulting reaction mixture was stirred 18 h at 80° C., then diluted with water and ethyl acetate. The organic extracts were washed (NaHCO3, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 1:1 to 25:75) provided the (4-methanesulfonyl-phenyl)-acetonitrile compound.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].[Cl:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[Cl:21].C(=O)([O-])[O-:24].[K+].[K+]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:22][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:13])=[O:24]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [K+]
Product: Cn1nc(C(F)(F)F)c(C(=O)O)c1Oc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared using 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde and 3,4-dichlorophenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2=[N:9][C:10]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:11][CH:12]=[C:7]2[N:6]=[C:5]1[NH2:22].C>CO>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2=[N:9][C:10]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[CH:11][CH:12]=[C:7]2[N:6]=[C:5]1[NH2:22]
Reactant: CC(C)(C)Cn1c(N)nc2ccc(C#Cc3ccc(F)cc3)nc21
Solvent: CO
Product: CC(C)(C)Cn1c(N)nc2ccc(CCc3ccc(F)cc3)nc21
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Add methanol (1,200 mL) to combined lots of 3-(2,2-dimethyl-propyl)-5-(4-fluoro-phenylethynyl)-3H-imidazo[4,5-b]pyridin-2-ylamine (37.30 g) and heat to reflux. Add activated charcoal (3.73 g, 10 wt %) and reflux for 1 h. Filter while slurry is hot, then add water (375 mL) to the filtrate with stirring at room temperature. Filter off solids, wash 2×100 mL water and dry under reduced pressure at 45-50° C. to provide 30.0 g (80%) of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5]Br.[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5][N:15]=[N+:16]=[N-:17]
Reactant: ClC(Cl)=C(Cl)c1cc(Br)cc(CBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(Br)cc(C(Cl)=C(Cl)Cl)c1
Yield: 55.5 %

Procedure:
A solution of crude 3-bromo-5-(trichlorovinyl)benzyl bromide (2.2 g) and sodium azide (760 mg) in 30 ml of ethanol was heated at reflux for 1 hour. The reaction solution was concentrated under reduced pressure and the residue triturated with 100 ml of hexane. The mixture was filtered and the filtrate chromatographed on silica (hexane) to give 1.1 g of pure azide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].BrC([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)C.[CH2:39](Cl)Cl>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([CH:17]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:39])[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: ClCCl
Reactant: CC(Br)c1ccccc1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(C)c3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
A mixture of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (500 mg, 1.48 mmol, Intermediate 1), TEA (0.41 ml, 2.96 mmol) and (±)-(1-bromoethyl)benzene (547 mg, 2.96 mmol) in DCM (25 ml) was stirred for 48 h at RT and then washed with brine. The organic phase was dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: from DCM to DCM/MeOH 96:4) to give (±)-(E)-3-{1′-(1-phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (546 mg, 90%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][C@@H:6]1[C:11]([O:13]CC)=[O:12])[CH3:4]>>[CH2:3]([C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][C@@H:6]1[C:11]([OH:13])=[O:12])[CH3:4]
Reactant: CCOC(=O)[C@H]1C[C@@H](O)C[C@H]1CC
Agent: [Na+]
Agent: [OH-]
Product: CC[C@@H]1C[C@H](O)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
NaOH (1 N aqueous, 12 mL, 12 mmol) was added to (1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (1.11 g, 5.96 mmol). The reaction mixture was stirred at ambient temperature for about 3 days and then extracted with Et2O (3×25 mL). The Et2O extracts were discarded and the aqueous portion was cooled to about 0° C. HCl (5 N aqueous) was slowly added to bring the pH to about 2. The resulting aqueous suspension was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (2×80 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give (1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g, 100%) as clear oil: 1H NMR (CDCl3) δ 4.36 (tdd, J=2.6, 4.9, 7.4, 1H), 2.95 (td, J=2.4, 7.3, 1H), 2.41 (dt, J=7.7, 14.1, 1H), 2.16-1.94 (m, 3H), 1.65-1.49 (m, 1H), 1.49-1.32 (m, 2H), 0.96 (q, J=7.4, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][C:18]3[O:19][C:20]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[CH:15][CH:14]=2)[N:10]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][C:18]3[O:19][C:20]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: COC(=O)CCc1oc(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cc2nc(-c3ccccc3)c(CCC(=O)O)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A mixture of methyl 3-[2-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-4-phenyl-5-oxazolyl]propionate (1.01 g), lithium hydroxide hydrate (255 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (6.1 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-4-phenyl-5-oxazolyl]propionic acid (881 mg, yield 92%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 74–76° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:28])[CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:14]2=3)=[CH:7][CH:6]=1)C.[OH-].[Na+]>CCO>[CH3:27][N:24]1[CH2:25][CH2:26][C:14]2[N:13]([CH2:12][CH:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[CH:6][CH:7]=3)[OH:28])[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: CCOC(=O)c1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C(=O)O)cc2)CCN(C)C1
Temperature: 65 °C
Yield: 80.7 %

Procedure:
To a solution of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzoic acid ethyl ester (800 mg, 2.04 mmol) in 5 mL EtOH was added sodium hydroxide (327 mg, 8.17 mmol, in 5 mL water) and heated to 65° C. After complete conversion of starting material (TLC and LCMS), the EtOH and water were removed under reduced pressure. The crude product was passed through HPLC to yield 600 mg of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzoic acid. 1H NMR (DMSO, freebase) δ (ppm): 7.79 (d, 2H), 7.29 (s, 1H), 7.17 (d, 2H), 7.09 (s, 1H), 6.88 (d, 1H), 5.5 b (s, 1H), 4.82 (t, 1H), 4.12 (dd, 1H), 4.06 (dd, 1H), 3.44 (s, 2H), 3.16 (s, 2H), 2.71 (d, 1H), 2.56 (m, 2H), 2.36 s (7H). Separation by chiral HPLC provides enantiomers 67a and 67b.
Reaction SMILES: [N:1]([CH:4]1[CH:10](O)[CH2:9][CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5]1)=[N+:2]=[N-:3].COCCN(S(F)(F)[F:32])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[N:1]([CH:4]1[CH:10]([F:32])[CH2:9][CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: [N-]=[N+]=NC1CCN(C(=O)OCc2ccccc2)CCC1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: [N-]=[N+]=NC1CCN(C(=O)OCc2ccccc2)CCC1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of benzyl 4-azido-5-hydroxyazepane-1-carboxylate (1.0 g, 3.45 mmol) in dry DCM (10 ml) was added deoxo-Fluor® (1.6 mL, 8.62 mmol, 50% in THF) and the mixture was stirred at room temperature for 18 hr. Saturated aqueous NaHCO3 solution was added (20 mL) and the mixture was extracted with DCM (100 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (20 mL), separated, dried over MgSO4 and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (20% EtOAc/isohexane) to give benzyl 4-azido-5-fluoroazepane-1-carboxylate as a mixture of syn and anti isomers as a pale yellow oil (0.76 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>O=S(Cl)Cl.CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:4]=3[N+:16]([O-:18])=[O:17])[N:9]=[CH:8][N:7]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3)c2c([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of 6,7-dimethoxy-5-nitro-3H-quinazolin-4-one (0.5 g, 1.99 mmol) (from Example 1, Step A, supra) in SOCl2 (20 mL) (Aldrich) and a few drops of DMF (0.05 mL) was heated with stirring at 90° C. for 3 hours. The solvents were then evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (30 mL), then 3-chloroaniline (0.25 g, 1.99 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The solvents were removed and the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:2:0.05) as eluent to give the desired (3-chloro-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine as a yellow solid. (Yield 0.4 g, 56%).
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1.[CH3:12]I>C(Cl)Cl>[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([CH2:10][O:11][CH3:12])[N:9]=1
Reactant: CI
Reactant: OCc1coc(CCl)n1
Agent: N#N
Solvent: ClCCl
Product: COCc1coc(CCl)n1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(chloromethyl)oxazol-4-yl)methanol (8.00 g, 54.22 mmol) in CH2Cl2 (32.0 mL) was treated with MeI (4.05 mL, 65.06 mmol) followed by Ag2O (18.85 g, 81.32 mmol) and the resulting mixture (protected from light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil: TLC: rf (6:4 hept-EA)=0.31. LC-MS-conditions 07: tR=0.54 min, [M+H]+=162.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@@H:13]([C:18]([OH:20])=[O:19])[CH2:14][C:15](=[O:17])[NH2:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.[Cl-].[NH4+]>[CH3:21][O:19][C:18](=[O:20])[C@@H:13]([CH2:14][C:15](=[O:17])[NH2:16])[NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(S(=O)(=O)N[C@H](CC(N)=O)C(=O)O)cc1
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H](CC(N)=O)NS(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h

Procedure:
N-[4-methoxybenzenesulfonyl]-(D)-asparagine (10.1 g, 33.3 mmol) is dissolved in dimethylformamide (167.0 mL). Cesium carbonate (5.43 g, 16.66 mmol) is added, followed by the addition of methyl iodide (2.22 mL, 33.3 mmol), and the reaction is stirred overnight. The reaction is then diluted with saturated ammonium chloride (366.0 mL), and extracted well with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is recrystallized from toluene to provide N-[4-methoxybenzenesulfonyl]-(D)-asparagine methyl ester.
Reaction SMILES: O[CH:2]([CH3:8])[C:3]#[C:4][C:5](=[O:7])[CH3:6].[C:9](O)(=[S:11])[CH3:10].O>C(Cl)Cl.S(=O)(=O)(O)O>[CH3:8][C:2]1[O:7][C:5]([CH3:6])=[CH:4][C:3]=1[C:9](=[S:11])[CH3:10]
Reactant: CC(O)=S
Reactant: CC(=O)C#CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CC(=S)c1cc(C)oc1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
5.61 g of 5-hydroxyhex-3-yn-2-one [prepared according to A. F. Thomas et al., Tet. Let. 27, 505, (1986)] in 50 ml of methylene chloride are added dropwise while stirring within 15 min. to a mixture of 11.42 g of thioacetic acid in 50 ml of methylene chloride and 100 ml of 2N sulphuric acid. After leaving to stand at room temperature for 2 hours the mixture is heated to 40° C. and stirred at 40° C. for a further 4 hrs. The reaction mixture is poured into 100 ml of H2O and extracted 2× with 100 ml of methylene chloride. The organic phases, dried over MgSO4, are concentrated and fractionally distilled in a high vacuum (65° C./0.2 mbar). There are obtained 5.7 g (67% of theory) of a yellow liquid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[C:20]([N:39]1[CH:43]=[C:42]([CH:44]=[O:45])[N:41]=[CH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[F:13][C:14]1[C:19]([CH:44]([C:42]2[N:41]=[CH:40][N:39]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:43]=2)[OH:45])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Fc1ccccn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccnc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
A 2.5M n-butyl lithium in hexanes solution (6 ml, 15 mmol) was added dropwise to a solution of diisopropylamine (2.12 ml, 15 mmol) in tetrahydrofuran (30 ml), cooled to −78° C. The reaction mixture was allowed to warm up to 0° C. for 30 minutes before being cooled down to −78° C. 2-Fluoropyridine (1.36 g, 14 mmol) in tetrahydrofuran (10 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 1 hour. A solution of 1-trityl-1H-imidazole-4-carbaldehyde (4.5 g, 13.3 mmol) in tetrahydrofuran (10 ml) was added dropwise. The reaction mixture was allowed to warm up to room temperature and was stirred for 18 hours. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate and extracted into ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound (1.3 g, 22% yield).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[OH-].[Li+]>O1CCCC1.O>[C:10]([O:9][C:7]([NH:6][CH2:5][CH:4]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C:3]([OH:22])=[O:2])=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
To 3-tert-Butoxycarbonylamino-2-(3,4-dichloro-phenyl)-propionic acid methyl ester (17.11 g, 0.049 mol) in tetrahydrofuran-water (200 ml of each) was added lithium hydroxide (1.18 g, 0.049 mol). The reaction mixture was stirred at room temperature for 6 hours. THF was removed in vacuo and the pH was adjusted to pH 4 with 2M hydrochloric acid. The aqueous phase was extracted with EtOAc (3×100 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The title compound was obtained as a foam in 89% yield (14.67 g). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (9H, s), 3.22–3.35 (1H, m), 3.35–3.50 (1H, m), 3.76 (1H, t), 6.84 (1H, t), 7.24 (1H, m); 7.48 (1H, s), 7.58 (1H, d), 12.85 (1H, s); MS (ES+): m/e=334.2 (8%); MS (ES−): m/e=332.2 (100%), 334.1 (65%), 336.1 (10%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][N:15]=[CH:14]3)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:21](OCCC(C)C)=O>CN(C=O)C.CO>[Br:1][C:2]1[N:3]=[C:4]2[N:9]([CH2:10][C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]=[CH:14]4)[N:21]=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)CCON=O
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncncc2c1
Solvent: CO
Solvent: CN(C)C=O
Product: Brc1cnc2nnn(Cc3ccc4ncncc4c3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
To the solution of 5-bromo-N*3*-quinazolin-6-ylmethyl-pyrazine-2,3-diamine (1.02 g) in anhydrous DMF (12 mL) was added isoamyl nitrite (0.5 mL, 1.2 eq) at 0° C. dropwise. The ice bath was removed and the mixture was stirred for 5 minutes at room temperature, then at 70° C. for three hours. The reaction was cooled down to ambient temperature and quenched by 3 ml Sat'd Na2SO3. A precipitate was formed, and filtered. The mother liquor was extracted with ethyl acetate (2×200 ml) twice, and the combined extracts were washed twice by Sat'd NaHCO3 (2×100 ml), dried over Na2SO4, and concentrated to get the crude product which was dissolved in MeOH (10 ml), and a precipitate was formed. The solid was filtered to get 6-(6-Bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-quinazoline (0.112 g, yield 13%).
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:17][N:18]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].[Cl:30]([OH:34])(=[O:33])(=[O:32])=[O:31]>>[Cl:30]([OH:34])(=[O:33])(=[O:32])=[O:31].[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3](=[N:2][CH3:1])[C:22]2[N:18]([CH3:17])[C:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][C:21]=2[CH3:23])=[CH:5][CH:6]=1
Reactant: CN=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1cc(C)cn1C
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCOC(=O)Cc1cc(C)c(C(=NC)c2ccc(Cl)cc2)n1C

Procedure:
The title compound was prepared as in Example X from N-methyl 4-chlorobenzimidoyl chloride (7.52 g, 40 mmole), chlorosulfonic acid (0.47 g, 4 mmole), ethyl 1,4-dimethyl-1H-pyrrole-2-acetate (7.25 g, 40 mmole), and 70% perchloric acid (7.0 g, 48 mmole) to yield 6.6 g (38%) of a green solid, m.p. 126°-130° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[CH3:7].I.[PH2](O)=O.[CH3:12][CH:13]1OC(C)OC(C)O1.[C:21](O)(=O)[CH3:22]>>[CH3:1][C:2]1[NH:3][C:4]([CH2:21][CH3:22])=[C:5]([CH2:12][CH3:13])[C:6]=1[CH3:7]
Reactant: CC(=O)O
Reactant: CC1OC(C)OC(C)O1
Reactant: Cc1cc[nH]c1C
Agent: I
Agent: O=[PH2]O
Product: CCc1[nH]c(C)c(C)c1CC

Procedure:
As in Example 58, using 2,3-dimethyl-pyrrole (1.6 g), acetic acid (40 ml), hydriodic acid (40 ml), hypophosphorous acid (8 ml) and paraldehyde (1.4 ml). The product (48%) was an oil, b.p. 45°-47° (0.05 mm). Anal. Calc. for C10H17N: C, 79.40; H, 11.34; N, 9.26. Found: C, 79.09; H, 11.27; N, 9.37.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C:9](=[O:11])[CH2:8][CH2:7][C@@H:6]1[C:12]([OH:14])=O)=[O:4].CN(C)C=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[C:53]1([N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(N(CC)C(C)C)(C)C>>[O:11]=[C:9]1[CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([C:12]([N:62]2[CH2:63][CH2:64][N:59]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:60][CH2:61]2)=[O:14])[CH2:7][CH2:8]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)[C@H]1CC(=O)CC[C@@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC(=O)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.5 %

Procedure:
To a stirred solution of (1S,2S)-2-(methoxycarbonyl)-4-oxocyclohexanecarboxylic acid (1.014 g, 0.005065 mol) in anhydrous N,N-dimethylformamide (20.0 mL, 0.258 mol) at rt was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.989 g, 0.005572 mol), 1-phenylpiperazine (1.17 mL, 0.00760 mol), followed by N,N-diisopropylethylamine (2.66 mL, 0.0152 mol). The reaction mixture was stirred at rt for 15 h. The reaction was quenched with water (40 mL), extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by Combiflash with 40-70% EtOAc/Hex. to give the product as a colorless solid (1.299 g, 74% in yield). MS (ESI): (M+H)+=345.1.