Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[C:5]#[CH:6])[CH3:2].C([Li])CCC.[CH3:13][C:14]([CH3:16])=[O:15]>O1CCCC1.CCOCC.CCCCC>[CH2:1]([O:3][C:4](=[O:7])[C:5]#[C:6][C:14]([OH:15])([CH3:16])[CH3:13])[CH3:2]
Reactant: C#CC(=O)OCC
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(C)(C)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
To a stirred solution of propynoic acid ethyl ester (20 mL, 197 mmol) in a mixture of 300 mL tetrahydrofuran:ether:pentane (4:1:1 by volume) cooled in a dry ice/isopropanol bath was added n-butyllithium (79 mL, 197 mmol, 2.5 M in hexanes) dropwise. After 15 minutes, anhydrous acetone (13.1 mL, 197 mmol) was slowly added. The reaction was kept below −78° C. for 8 h and quenched with an aqueous ammonium chloride solution, and the resulting mixture was stirred for 5 min. The reaction was warmed up to room temperature and extracted repeatedly with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, and the residue was purified via silica gel column chromatography (0-15% ethyl acetate in heptane) to give the title compound (10.75 g, 68.8 mmol) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10]([NH:12][C@@H:13]([CH:21]([CH3:23])[CH3:22])[CH2:14][O:15][CH2:16][CH2:17][C:18](O)=[O:19])=[O:11])=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:28]([O:27][C:25](=[O:26])[NH:24][C@@H:9]1[CH2:8][C:5]2=[CH:4][CH:3]=[C:2]([CH:7]=[CH:6]2)[NH:1][C:18](=[O:19])[CH2:17][CH2:16][O:15][CH2:14][C@H:13]([CH:21]([CH3:23])[CH3:22])[NH:12][C:10]1=[O:11])([CH3:29])([CH3:31])[CH3:30]
Reactant: CC(C)[C@@H](COCCC(=O)O)NC(=O)[C@@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H]1COCCC(=O)Nc2ccc(cc2)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1
Reaction time: 1 h

Procedure:
The 3-{(S)-2-[(R)-3-(4-aminophenyl)-2-tert-butoxycarbonylaminopropionylamino]-3-methylbutoxy}propionic acid (˜225 mg) obtained as crude product in 7-1 D was dissolved in 225 ml of DMF. 70.0 mg (0.51 mmol) of HOAt, 0.26 ml (1.5 mmol) of N,N-diisopropylethylamine and 195.4 mg (0.51 mmol) of HATU were successively added to this solution, and the mixture was stirred at room temp. for 1 h. The reaction mixture was concentrated in vacuo. The residue obtained in this way was taken up in CH2Cl2, washed with sat. NaHCO3 solution, dried over MgSO4 and freed of solvent in vacuo. The ring-closed compound obtained in this way was employed crude in the next stage. Yield: 215.0 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:41][O:42][CH2:43][CH2:44]Cl.[I-].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][N:23]([CH2:44][CH2:43][O:42][CH3:41])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CNC1
Reactant: COCCCl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CC(C(N)=O)(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)C1
Yield: 36.1 %

Procedure:
A solution of the hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-3-carboxamide (55 mg, 0.11 mmol Example 74), diisopropylethylamine (84 μl, 0.48 mmol), 2-chloroethyl methyl ether (29 μl, 0.32 mmol) and potassium iodide (18 mg, 0.11 mmol) in acetonitrile (0.5 ml) was heated in a microwave at 145° C. for 30 minutes. Purification of the crude product on preparative HPLC (standard basic condition) gave the title product (20 mg, 36%) as a white solid; 1H NMR Spectrum: (CDCl3) 2.41 (s, 3H), 2.76 (t, 2H), 3.34 (s, 3H), 3.36 (d, 2H), 3.44 (t, 2H), 3.66 (d, 2H), 3.96 (s, 3H), 4.00 (s, 2H), 5.38 (brs, 1H), 7.16 (m, 2H), 7.24 (s, 1H), 7.21 (s, 1H), 7.42 (brs, 1H), 7.87 (brs, 1H), 8.01 (s, 1H), 8.75 (m, 1H); Mass Spectrum: (M+H)+ 503.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)[CH3:2].[Li]CCCC.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S@@:27](/[N:29]=[CH:30]/[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[CH:38][CH:37]=[CH:36]3)=[O:28])=[CH:23][CH:22]=1.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([CH:30]([NH:29][S@:27]([C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:26][CH:25]=2)=[O:28])[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[CH:38][CH:37]=[CH:36]3)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(I)cc1
Reactant: Cc1ccc([S@](=O)/N=C/c2cccc3cccnc23)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(N[S@@](=O)c2ccc(C)cc2)c2cccc3cccnc23)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 23.1 %

Procedure:
N,N-diethyl 4-iodo-benzamide (3.1 g, 10 mmol) was dissolved in dry toluene/THF (9:1, 200 mL) and cooled to −78° C. under nitrogen. n-BuLi (7.8 mL, 1.3 M in hexane, 10 mmol) was added dropwise during 5 to 10 min. After further 5 min, 3 (1.0 g, 3.4 mmol) was added dissolved in toluene (1 mL). The solution was stirred 10 min, then NH4Cl (aq.) was added. Concentration, aqueous workup and chromatography on silica gave a total of 0.70 g (44%) of a 70:30 mixture of diastereomers. The pure major isomer 5 (0.37 g) was obtained by one more chromatography. 1H NMR (CDCl3): δ1.2 (m, 6H), 2.4 (s, 3H), 3.4 (m, 4H), 6.35 (d, J=7.5 Hz, 1 H), 6.61 (d, J=7.5 Hz,1 H), 7.15-7.55 (m, 11H), 7.75 (m, 1H), 8.12 (m, 1H), 8.75 (m, 1H).
Reaction SMILES: [NH:1]([C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH3:12])[N:4]=1)[NH2:2].C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C.C(OCC)(=O)C>C(O)C>[NH2:21][C:20]1[N:1]([C:3]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH3:12])[N:4]=2)[N:2]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: CCOC=C(C#N)C#N
Reactant: Cn1nc(NN)cc1C(F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1nc(-n2ncc(C#N)c2N)cc1C(F)(F)F

Procedure:
0.85 g (4.72 mmol) 3-Hydrazino-1-methyl-5-trifluoromethylpyrazole and 0.59 g (4.72 mmol) ethoxymethylenemalononitrile in 10 ml ethanol was stirred for 10 hours at room temperature and for 2 hours at 50° C. After addition of 50 ml ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate).
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:19]3[CH:18]=[C:17]([F:20])[CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:23]>O1CCOCC1>[C:1]([C:8]1[NH:9][C:10]2[C:19]3[CH:18]=[C:17]([F:20])[CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:21]=1)(=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Se]=O
Reactant: Fc1ccc2ncc3nc(Cc4ccccc4)[nH]c3c2c1
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1nc2cnc3ccc(F)cc3c2[nH]1
Temperature: 80 °C
Yield: 94.1 %

Procedure:
To a suspension of 830 mg of 2-benzyl-8-fluoro-1H-imidazo[4,5-c]-quinoline (VII-1) in 50 ml of dioxane heated to 80° C. was added 1.07 g of selenium dioxide. The reaction mixture was refluxed for 1.5 hours. The resulting precipitate was immediately removed by filtration and concentrated under reduced pressure, and the residue obtained was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with water and saturated brine, and dried. The ethyl acetate was removed and the residue was chromatographed on a column of silica gel for purification. After elution with chloroform-methanol (30:1 v/v), 820 mg (yield 94%) of the compound (I d-1) was obtained as crystals. This was recrystallized from ethanol-chloroform to give light yellow crystals melting at 255°~256° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[CH:14]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[N:16]=[C:12]3[N:11]=[C:10]([CH3:21])[C:9]=2[C:22]#[N:23])=[C:4](C)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]1.CCN(CC)CC.C(Cl)[Cl:42]>>[C:22]([C:9]1[C:10]([CH3:21])=[N:11][C:12]2[N:13]([CH:14]=[C:15]([S:17]([N:25]3[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]3)(=[O:19])=[O:18])[N:16]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[Cl:42])#[N:23]
Reactant: CC(=O)N[C@H]1CCNC1
Reactant: Cc1cc(Cl)ccc1-c1c(C#N)c(C)nc2nc(S(=O)(=O)Cl)cn12
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CCN(S(=O)(=O)c2cn3c(-c4ccc(Cl)cc4Cl)c(C#N)c(C)nc3n2)C1
Reaction time: 14 h
Yield: 81 %

Procedure:
To a stirred solution of 5-(4-chloro-2-methylphenyl)-6-cyano-7-methylimidazo[1,2-a]pyrimidine-2-sulfonyl chloride (34 mg, 0.09 mmol) in CH2Cl2 (2 mL) was added (S)—N-(pyrrolidin-3-yl) acetamide (16.3 mg, 0.13 mol) and Et3N (20 mg, 0.2 mmol). After 14 h, the reaction was extracted with 1N HCl (2 mL×2) before drying over MgSO4. Filtration and concentration under reduced pressure afforded (S)—N-(1-(6-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-ylsulfonyl)pyrrolidin-3-yl)acetamide as a white solid (34 mg, 81%). This crude product was used directly for the subsequent reaction without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[C:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH:32]=2)=[CH:16][CH:15]=[CH:14]3)(=[O:10])=[O:9])=[N:3][CH:2]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[N:1]1[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=3[C:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH:32]=3)[CH:12]=2)(=[O:10])=[O:9])=[N:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3C3=CCNCC3)cccc2c1
Temperature: 25 °C
Yield: 27.5 %

Procedure:
A round bottom flask was charged with tert-butyl 4-(2-(6-(N-(pyrimidin-4-yl)sulfamoyl)naphthalen-1-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate Y) (0.031 g, 0.051 mmol) and DCM (0.508 mL) and trifluoroacetic acid (3.91 μl, 0.051 mmol) was added. The resulting solution was maintained at rt for 18 h and then concentrated. The residue was taken up in minimal MeOH/DMSO and purified by preparative HPLC (Phenomenex C18 150×30 mm, 5 μm: 25 to 85% CH3CN:H2O (1% TFA modifier) over 15 min). Fractions were combined and concentrated to afford N-(pyrimidin-4-yl)-5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide 2,2,2-trifluoroacetate (8.8 mg, 0.014 mmol) as a colorless film. 1H NMR (400 MHz, CD3OD) δ ppm 1.98-2.28 (m, 2H) 2.73-2.97 (m, 2H) 3.41-3.62 (m, 2H) 5.70 (dt, J=3.15, 1.60 Hz, 1H) 7.16 (dd, J=6.36, 1.08 Hz, 1H) 7.52 (d, J=8.02 Hz, 1H) 7.60 (dd, J=7.04, 1.17 Hz, 1H) 7.64 (d, J=9.00 Hz, 1H) 7.68-7.82 (m, 3H) 7.94 (dd, J=8.90, 1.96 Hz, 1H) 8.17 (d, J=8.31 Hz, 1H) 8.30 (d, J=6.06 Hz, 1H) 8.59 (s, 1H) 8.71 (d, J=1.86 Hz, 1H); m/z (ESI, +ve ion) 510.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:18]CN=O)[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[C:24]([NH:27]N)(=O)[CH3:25].C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]3[C:24]([CH3:25])=[N:27][N:18]=[C:7]3[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CC(=O)NN
Reactant: O=NCNC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2
Reaction time: 72 h

Procedure:
A mixture of 3.3g (0.01M) of 7-chloro-3,5-dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-one, 2g of acetylhydrazine, 5 ml of triethylamine and 50 ml of n-butanol was heated to reflux for 3 hrs. Half of the solvent was then removed by distillation and replaced by fresh n-butanol. Refluxing was continued for 3 days. The residue obtained after evaporation was chromotographed over 100 g of silical gel(Merck 70-230 mesh) using 10% (v/v) ethanol in methylene chloride for elution. Crystallization of the pure fraction from methylene chloride/ether yielded the above maned product, m.p. 298°-300°.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([C:9]([CH3:14])=[CH:10][N+:11]([O-:13])=[O:12])[CH:6]=[CH:5][C:4]=1O.[O:16]=CC1C=CC(O)=C(OC)C=1.[N+](CC)([O-])=O>>[CH3:14][C:9]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:8]=1[OH:16])=[CH:10][N+:11]([O-:13])=[O:12]
Reactant: COc1cc(C(C)=C[N+](=O)[O-])ccc1O
Reactant: COc1cc(C=O)ccc1O
Solvent: CC[N+](=O)[O-]
Product: CC(=C[N+](=O)[O-])c1ccccc1O
Yield: 80 %

Procedure:
2-methoxy-4-(α-methyl-β-nitroethenyl)-phenol was also prepared by a variation of the above procedure in which vanillin was treated with nitroethane instead of nitromethane. The conditions employed for the reaction, however, were essentially the same as those described above for nitromethylation. The α-methyl-β-nitroethenyl phenol product was obtained in 80% yield with m.p. 110°-112° and had λ max (ethanol) of 368 and λ max (TRIS 8.8) of 475 with ε of 13,100.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24](=[O:27])[CH2:25]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:25][C:24]([O:23][CH3:22])=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)C1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
To a solution of 3-(4-Chloro-benzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.3 g, 10.7 mmol) in DMF (40 mL) was added Bromo-acetic acid methyl ester (1.01 mL, 10.7 mmol) and K2CO3 (1.48 g, 10.7 mmol). The resultant suspension was stirred at 70° C. overnight. The reaction mixture was diluted with water and ethyl ether. The organic extract was dried over MgSO4, filtered and concentrated to provide the desired product as an oil. The crude product was purified on SiO2 and concentrated to provide the desired product as an oil (3.5 g, 87%). LCMS (retention time=2.96, ES+383)
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+:13]([CH:16](C(OC)=O)[C:17]([O:19][CH3:20])=[O:18])([O-])=[O:14]>C1(C)C=C(C)C=C(C)C=1>[C:2]([C:3]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[N:13][O:14][C:4]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:12])([CH3:11])[CH3:1]
Reactant: CC(C)(C)C#Cc1ccccc1
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Solvent: Cc1cc(C)cc(C)c1
Product: COC(=O)c1noc(-c2ccccc2)c1C(C)(C)C
Yield: 15.4 %

Procedure:
A solution of (3,3-Dimethylbut-1-ynyl)benzene (400 mg, 2.53 mmol) and dimethyl nitromalonate (0.853 mL, 6.32 mmol) in mesitylene (5 mL) was heated at 150° C. for 48 h. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to yield methyl 4-tert-butyl-5-phenylisoxazole-3-carboxylate (101 mg). The compound had an HPLC ret. time=3.39 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=260+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([F:14])=[CH:16][CH:17]=2)=[CH:8][N:7]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)COc1ccc(N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)COc1ccc(NC(=O)c2ccc(F)cc2)cn1
Yield: 67.2 %

Procedure:
To a solution of (5-aminopyridin-2-yloxy)acetic acid methyl ester (0.16 g, 0.88 mmol) in dichloromethane (5 mL) was added 4-fluorobenzoyl chloride (0.11 mL, 0.97 mmol) and N,N-diisopropylethylamine (0.33 mL, 1.9 mmol). After 24 h the reaction was poured into ethyl acetate, washed with water, and dried over sodium sulfate. Removal of the solvent gave a white solid that was purified by trituation using ethyl acetate/hexanes to give the titled product 0.18 g (67%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H); 8.40 (m, 1H); 8.03 (m, 3H); 7.35 (m, 2H); 6.92 (m, 1H); 4.87 (m, 2H); 3.64 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N:12]=[C:13]=[S:14])[C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:16]([NH2:19])[CH2:17][NH2:18]>C1(C)C=CC=CC=1>[NH2:18][CH2:17][CH2:16][NH:19][C:13](=[S:14])[NH:12][C:10]1[C:9]([CH3:15])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([F:1])[CH:11]=1
Reactant: Cc1c(N=C=S)cc(F)c2cccnc12
Reactant: NCCN
Solvent: Cc1ccccc1
Product: Cc1c(NC(=S)NCCN)cc(F)c2cccnc12
Reaction time: 0.17 h

Procedure:
A solution of 5-fluoro-7-isothiocyanato-8-methylquinoline (0.38 g) in toluene (40 mL) is added dropwise to a solution of ethylenediamine (0.78 g) in toluene (40 mL). A white precipitate is observed after the reaction stirs for 10 minutes at room temperature. The precipitate is filtered and dried in vacuo to afford 7-[N'-(2-aminoethyl)thioureido]-5-fluoro-8-methylquinoline as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]([CH3:55])([CH3:54])[C:20]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]3[C:34]([O:41][C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)=[N:35][NH:36][C:37]=3[CH:38]([CH3:40])[CH3:39])=[C:28]([CH3:53])[CH:27]=2)=[O:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]([CH3:55])([CH3:54])[C:20]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]3[C:34](=[O:41])[NH:35][NH:36][C:37]=3[CH:38]([CH3:39])[CH3:40])=[C:28]([CH3:53])[CH:27]=2)=[O:21])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Temperature: 50 °C
Reaction time: 48 h
Yield: 99.2 %

Procedure:
A mixture of 4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (0.23 g), p-toluenesulfonic acid monohydrate (0.41 g) and 2-propanol (10 mL) was stirred at 50° C. for 2 days. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, 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: dichloromethane/methanol=10/1) to give the title compound (0.18 g).
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[CH:27]1[C:36]2[C:31](=[C:32]([NH:37][C@@H:38]3[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]3)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1.C(OC(C)C)(=O)C.[OH-].[Na+]>>[NH:40]1[CH2:41][CH2:42][C@@H:38]([NH:37][C:32]2[C:31]3[CH:30]=[CH:29][N:28]=[CH:27][C:36]=3[CH:35]=[CH:34][CH:33]=2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2cccc3cnccc23)C1
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Product: c1cc(N[C@@H]2CCNC2)c2ccncc2c1

Procedure:
To a 5 L flask equipped with a mechanical stirrer and an internal temperature probe were added (R)-tert-butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylate dibenzoyl-D-tartaric acid salt (150 g, 0.22 mol, from Example 2) and 2.25 L of isopropyl acetate. The suspension was stirred while 0.525 L of 1N sodium hydroxide was added maintaining an internal reaction temperature below 30° C. Stirring was continued until a biphasic solution was obtained. The aqueous layer was removed and the remaining organic layer was washed with 1N sodium hydroxide (300 mL) and water (300 mL). Five normal HCl (180 mL) was added and the reaction was stirred until all (R)-tert-butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylate was consumed. The two layers were separated. The pH of the aqueous layer was adjusted to >12 with 225 mL of 5N sodium hydroxide. The cloudy mixture was extracted with two portions of dichloromethane (2.25 L and 1.13 L). The solution was aged for 3 days for crystallization. (R)-N-(pyrrolidin-3-yl)isoquinolin-5-amine was isolated by filtration as a off-white crystalline solid (700 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][C:7]([O:9][CH3:10])=[O:8].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.CCOCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C/C=C\CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C/C=C\CCOC1CCCCO1
Yield: 98.4 %

Procedure:
A solution of methyl 6-hydroxy-(Z)-3-hexenoate (0.7684 g, 5.3 mmol), 3,4-dihydropyran (0.72 mL, 7.9 mmol, 1.5 eq) and pyridinium p-toluenesulfonate (PPTS, 125 mg, 0.5 mmol) in methylene chloride (25 mL) is stirred for 4 hours at room temperature. The solution is then diluted with ether (150 mL), and the ether layer is washed with half-saturated brine (50 mL) to remove the catalyst, and dried over magnesium sulfate. Purification by flash chromatography using hexane/ethyl acetate (90:10, v/v) affords methyl 6-tetrahydropyranyloxy-(Z)-3-hexenoate (1.19 g, 99%) as a clear colorless oil: Rf=0.38, hexane/ethyl acetate (7:3, v/v), IR (film) ν2850-3000 (C=CH, alkane CH), 1740 (C=O) and H NMR (CDCl3) δ1.45-1.65 (m, 6H), 2.35 (m, 2H), 3.10 (d, J=6 Hz, 2H), 3.30-3.70 (m, 4H), 3.58 (sS, 3H), 4.55 (br s, 1H), 5.65 (br t, J=6 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].[F:10][C:11]([F:18])([F:17])[CH2:12][CH2:13][C:14](O)=[O:15]>>[CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]([F:18])([F:17])[F:10])[CH3:3]
Reactant: O=C(O)CCC(F)(F)F
Reactant: CC(C)[C@H]1COC(=O)N1
Product: CC(C)[C@H]1COC(=O)N1C(=O)CCC(F)(F)F
Yield: 40.7 %

Procedure:
Preparation 3A was prepared from (4S)-4-(propan-2-yl)-1,3-oxazolidin-2-one (4.66 g, 36.1 mmol) and 4,4,4-trifluorobutanoic acid (5.02 g, 35.3 mmol) by the general methods shown for Preparation 1B. Preparation 3A was obtained as a colorless oil (3.64 g, 40%). 1H NMR (400 MHz, CDCl3) δ ppm 4.44 (1H, ddd, J=8.41, 3.51, 3.39 Hz), 4.31 (1H, t, J=8.66 Hz), 4.25 (1H, dd, J=9.03, 3.26 Hz), 3.13-3.32 (2H, m), 2.47-2.59 (2H, m), 2.38 (1H, dddd, J=13.96, 7.01, 3.89 Hz), 0.93 (3H, d, J=7.28 Hz), 0.88 (3H, d, J=6.78 Hz).