Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=12.[CH2:21]([NH:25][C:26]([C:28]1[C:32]2[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:31]=2[O:30][C:29]=1[CH3:38])=[O:27])[CH:22]([CH3:24])[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:21]([NH:25][C:26]([C:28]1[C:32]2[CH:33]=[CH:34][C:35]([O:37][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH:14]5[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=34)=[CH:36][C:31]=2[O:30][C:29]=1[CH3:38])=[O:27])[CH:22]([CH3:24])[CH3:23]
Reactant: Cc1oc2cc(O)ccc2c1C(=O)NCC(C)C
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCC1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)NCC(C)C)c(C)oc4c3)c2s1

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-2-methoxymethylpyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 2a with 6-hydroxy-2-methyl-benzofuran-3-carboxylic acid isobutyl amide 84b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (CD3CN) δ8.53 (1H, d, J=5.3 Hz), 7.87 (1H, s), 7.82 (1H, d, J=8.5 Hz), 7.41 (1H, d, J=1.9 Hz), 7.20 (1H, dd, J=8.5, 1.9 Hz), 6.70 (1H, d, J=5.5 Hz), 4.38 (1H, m), 3.85 (2H, m), 3.65-3.41 (2H, m), 3.32 (3H, s), 3.23 (2H, t, J=6.4 Hz), 2.65 (3H, s), 2.15-1.94 (4H, m, partially obscured by CD3CN), 1.73 (1H, m),.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([CH:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH:25]=[CH2:26])[N:16]=3)=[C:9]([F:33])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1C[CH2:47][CH2:46][CH2:45]1.C(I)C=C>CN(C=O)C>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([CH2:23][CH2:24][CH:25]=[CH2:26])[CH2:47][CH:46]=[CH2:45])[N:16]=3)=[C:9]([F:33])[CH:8]=1
Reactant: C1CCOC1
Reactant: C=CCCC(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Agent: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCC(CC=C)(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reaction time: 0.03 h

Procedure:
Argon was bubbled through a slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylpent-4-enyl)thiazolo[5,4-b]pyridine (1.02 g, 2.21 mmol) in 20 mL DMF for 5 min. The slurry was treated with sodium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (2.66 mL, 2.66 mmol) rapidly via syringe, to give a dark blue solution. After 2 min, allyl iodide (0.306 mL, 3.32 mmol) was added via syringe, and the color gradually faded from blue to light brown. After 1 h, the reaction mixture was quenched with sat'd aq. NH4Cl and MTBE. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was dissolved in DCM, adsorbed onto 7 g silica gel, dried, and purified by silica gel chromatography ISCO, 40 g, gradient, 0-50% EA/hexanes, to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(4-phenylocta-1,7-dien-4-yl)thiazolo[5,4-b]pyridine as a light yellow foam MS (ESI) m/z: Calculated: 500.2; Observed: 501.1 (M++1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:21])([F:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH:31]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]1.CC(O)=O>CN(C=O)C>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:4]1[N:3]=[C:2]([NH:36][C:33]2[CH:34]=[CH:35][NH:31][N:32]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3ccccc3n2)nc1
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(F)(F)c2nc(Nc3cc[nH]n3)c3ccccc3n2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline (100 mg, 0.32 mmol) was added a solution of KI (20 mg, 0.12 mmol), DIEA (0.068 mL, 0.39 mmol), and 1H-pyrazol-3-amine (40 mg, 0.48 mmol) in DMF (2 mL). The mixture was stirred overnight at rt. AcOH (0.14 mL) was added and the mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=0.05% AcOH/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(1H-pyrazol-3-yl)quinazolin-4-amine (15 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 12.52 (br s, 1H), 10.82 (br s, 1H), 8.53-8.86 (m, 2H), 7.77-8.13 (m, 4H), 7.57-7.74 (m, 2H), 6.50 (br s, 1H); LC-MS (ESI) m/z 357 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[O:24])[CH:21]=3)[C:16]([S:38]([CH3:40])=[O:39])=[CH:15]2)=[N:12][CH:13]=1.CS(C1C2C(=CC(C(N3CCNCC3)=O)=CC=2)N(C2N=CC(C3C=CC=CC=3)=CN=2)C=1)=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[N:12][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:24])[CH:21]=3)[C:16]([S:38]([CH3:40])=[O:39])=[CH:15]2)=[N:10][CH:9]=1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc12
Agent: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCNCC3)ccc12
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCNCC3)ccc12

Procedure:
Prepared from 13c) (170 mg, 0.30 mmol, 1.0 eq) in analogy to the procedure of 12e). White solid. Yield: 130 mg (71% of theory). Melting range: 199-203° C. HPLC (method 3): Rt=4.04 min. Mass spectroscopy: m/z: [M+H]+=464.1.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([O:29]C2CCCCO2)[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=1)[S:6]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])(=[O:8])=[O:7].Cl.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1.CO.O1CCOCC1>[Cl:1][C:2]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=1)[S:6]([C:9]1[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])(=[O:8])=[O:7]
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)cc2Cl)c2ccc(I)cc2)c(C)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)cc2Cl)c2ccc(I)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of N-[2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-N-(4-iodo-phenyl)-2,4,6-trimethyl-benzenesulfonamide (1.13 g, 1.80 mmol) in 1 mL tetrahydrofuran and 2 mL methanol was added HCl (4.5 mL of a 4.0 M solution in 1,4-dioxane, 18.05 mmol) and triethylsilane (2.88 mL, 18.05 mmol). The reaction mixture was stirred at room temperature overnight. Additional HCl (1 mL of a 4.0 M solution in 1,4-dioxane, 4 mmol) was added and the reaction mixture was stirred at room temperature for 2 days. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography of the residue (methylene chloride) afforded 0.70 g (72%) of the title compound of Step C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@H:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[Cl:29][C:30]1[CH:31]=[C:32]([C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])[CH:33]=[N:34][C:35]=1Cl>C(#N)C>[Cl:29][C:30]1[C:35]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@H:24]3[CH2:28][CH2:27][O:26][CH2:25]3)[CH:22]=2)[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)=[O:12])=[N:34][CH:33]=[C:32]([C:37]([N:39]2[CH2:40][CH2:41][O:42][CH2:43][CH2:44]2)=[O:38])[CH:31]=1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)n1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCOCC4)cc3Cl)cc(O[C@H]3CCOC3)c2)n1
Temperature: 120 °C
Yield: 76.9 %

Procedure:
Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (152 mg, 0.5 mmol) and 4-[(5,6-dichloropyridin-3-yl)carbonyl]morpholine (143 mg, 0.55 mmol) in acetonitrile (5 mL) and the mixture heated at 120° C. in a microwave reactor for 2 hours. The acetonitrile was evaporated in vacuo and the residue partitioned between water (25 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with ethyl acetate, to give the desired compound (203 mg). 1H NMR δ (CDCl3): 2.05-2.2 (m, 2H), 3.4-3.7 (m, 8H), 3.7 (s, 3H), 3.85 (m, 2H), 3.95 (d, 2H), 4.9 (m, 1H), 6.7 (d, 1H), 6.8 (d, 1H), 7.15 (d, 1H), 7.25 (d, 2H), 7.85 (d, 1H), 8.0 (d, 1H), 8.95 (s, 1H); m/z 512 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=2[C:36]([F:39])([F:38])[F:37])[CH2:24][CH2:23]1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:25]2[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]2)=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)=[O:20]
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 16.1) and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 542.9 [M+H]+; single peak at tR=3.31 min (System 1); Rf=0.16 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C)[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][OH:20])=[O:18].[N+](C1C=CC(OC(=O)CC2C=CC=CC=2NC2C(C)=CC=CC=2[Cl:46])=CC=1)([O-])=O>>[Cl:46][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][OH:20])=[O:18]
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)NO
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)NO

Procedure:
[o-(3-chloro-o-toluidino)-phenyl]-acetohydroxamic acid, M.P. 135° - 136° (from ether/petroleum ether), starting with [o-(3-chloro-o-toluidino)-phenyl]-acetic acid-p-nitrophenyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](O)=[O:25])[CH:19]=1>>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])[CH:19]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1cccnc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccnc4)cc23)CC1
Yield: 73.8 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.1 mg (0.09 mMol) pyridine-3-carboxylic acid, 7.4 mg of the title compound were recovered.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:15]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(Cl)cc1
Product: COC(=O)c1nc(C)sc1-c1ccc(Cl)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-chloro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.94 min; [M+H]+=267
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]C2C=CC=CC=2)=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][C:21](=[CH:24][C:25]2[CH:26]=[C:27]([CH:39]=[CH:40][CH:41]=2)[O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>CS(C)=O>[F:37][C:35]([F:38])([F:36])[C:32]1[CH:33]=[CH:34][C:29]([O:28][C:27]2[CH:26]=[C:25]([CH:41]=[CH:40][CH:39]=2)[CH:24]=[C:21]2[CH2:22][CH2:23][N:18]([C:9]([NH:8][C:5]3[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:10])[CH2:19][CH2:20]2)=[N:30][CH:31]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1ccc(Br)nc1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Br)nc1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of phenyl 6-bromopyridin-3-ylcarbamate (1.03 g, 3.5 mmol) in DMSO (5 mL) was added 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (1.3 g, 3.51 mmol) followed by triethylamine (0.98 mL, 7.01 mmol). The reaction was stirred at 60° C. overnight and then allowed to cool to RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4 and concentrated. Purification by silica gel column chromatography (0-5% MeOH/CH2Cl2) afforded the title compound as an oil, which foamed up on the pump (1.76 g, 94% yield). MS (APCI 10V) AP+2 535.08; 1H NMR (400 MHz, CDCl3) δ ppm 2.46 (t, 2H) 2.59 (t, 2H) 3.50 (t, 2H) 3.59 (t, 2H) 6.40 (s, 1H) 6.47 (br. s., 1H) 6.97-7.03 (m, 3H) 7.08 (d, 1H) 7.36-7.41 (m, 2H) 7.87-7.92 (m, 2H) 8.20 (d, 1H) 8.43 (d, 1H).
Reaction SMILES: [Na+].S([O-])([O-])(=O)=O.C(OCCCCCCCCCCCC)CCCCCCCCCCC.[Na+].CC[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50](OCC(O)[C@H]1OC[C@H](O)[C@H]1O)=[O:51]>>[OH:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH3:35]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Agent: *CCO*
Agent: CCCCCCCCCCCCOCCCCCCCCCCCC
Agent: O=S(=O)([O-])[O-]
Product: CCCCCCCCCCCCCCCCO

Procedure:
A hand cream was prepared from 3.0% by weight of the polyaspartic acid derivative obtained in Preparation Example 3-2, 20.0% by weight of vaseline, 7.0% by weight of cetanol, 1.0% by weight of polyoxyethylene (20 moles added) lauryl ether sulfate sodium, 1.0% by weight of sorbitan monostearate, appropriate amounts of perfume and antiseptic, and the balance purified water.
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10]CC)=O.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C1(C)C(C)=CC=CC=1>CN(C)C=O>[OH:1][C:2]1[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:10]
Reactant: CCOC(=O)c1c(O)c2sccc2[nH]c1=O
Reactant: Nc1cccnc1
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1c(O)c2sccc2[nH]c1=O
Temperature: 140 °C
Yield: 53.2 %

Procedure:
A mixture of 2.43 g (10.2 mmols) of ethyl 4,5-dihydro-7-hydroxy-5-oxothieno[3,2-b]pyridine-6-carboxylate [J. Chem. Res. (S), 6 (1980); J. Chem. Res. (M), 113 (1980)], 1.00 g (10.6 mmols) of 3-aminopyridine, 50 ml of xylene and 10 ml of dimethylformamide was heated at 140° C. for an hour. After completion of the reaction, insoluble matters were filtered and recrystallized from dimethylformamide to give 1.56 g (yield: 54%) of Compound 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl.[CH3:24][O:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([O:36][CH2:37][C:38](O)=[O:39])=[CH:31][CH:32]=[N:33]2)=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:38](=[O:39])[CH2:37][O:36][C:30]2[C:29]3[C:34](=[CH:35][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(OCC(=O)O)ccnc2c1
Reactant: NNc1ccc(Cl)nn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(OCC(=O)NNc3ccc(Cl)nn3)ccnc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(6-chloropyridazin-3-yl)hydrazine (0.372 g, 2.57 mmol), 1-hydroxy-7-aza-benzotriazole (0.350 g, 2.57 mmol), EDC (0.641 g, 3.34 mmol), 2-(7-methoxyquinolin-4-yloxy)acetic acid (0.600 g, 2.57 mmol) and diisopropylethylamine (1.34 ml, 7.72 mmol) in DMF (20 mL) was allowed to stir at 50° C. for 2 h. Concentrated. Reconstitued in MeCN (30 mL). Concentrated with cooling. Product crashed out of solution and was isolated by filtration. Used without further purification. (ESI, pos. ion) m/z: 234.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[N:8][C:6]=2[N:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:33][CH:32]2[CH:28]([CH2:29][NH:30][CH2:31]2)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH:28]2[CH:32]([CH2:31][N:30]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[N:8]=3)[CH2:29]2)[CH2:33]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (25 mg, 0.088 mmol) in 1,2-dichloroethane (1 mL) was added hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (21 mg, 0.10 mmol). The mixture was stirred at RT for 5 min before sodium triacetoxyborohydride (28 mg, 0.130 mmol) was added. The resulting solution was stirred at RT for 1 h. The crude reaction mixture was partitioned between DCM and brine. The organic layer was isolated, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (26 mg, 61%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[N+:16]([O-:18])=[O:17].[OH-].[Na+].Cl.[Cl-].[Na+]>CO>[N+:16]([C:5]1[CH:6]=[C:7]([CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:19])=[O:2])([O-:18])=[O:17]
Reactant: COC(=O)c1ccc(CN2CCCC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(CN2CCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 2-nitro-4-pyrrolidin-1-ylmethyl-benzoic acid methyl ester (1.1 g, 4.16 mmol) in methanol (35 mL) and 2N sodium hydroxide (4.16 mL, 8.32 mmol, 2 eq.) was stirred at room temperature for 7 hours, then neutralized with 2N hydrochloric acid (4.16 mL, 8.32 mmol) and evaporated to dryness affording a mixture of the title compound and sodium chloride that was used as such for the next step.
Reaction SMILES: C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:18]([O:20][C:21](=[O:41])/[CH:22]=[C:23](\[CH3:40])/[CH2:24][CH2:25][S:26]([C:29]1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:32]=[N:31][N:30]=1)(=O)=O)C.C[C@H]([C@@H](O[Si](CC)(CC)CC)CC)C=O>C1COCC1.COCCOC>[CH3:18][O:20][C:21](=[O:41])/[CH:22]=[C:23](\[CH3:40])/[CH2:24][CH2:25][S:26][C:29]1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:32]=[N:31][N:30]=1
Reactant: CCOC(=O)/C=C(\C)CCS(=O)(=O)c1nnnn1-c1ccccc1
Agent: CC[C@H](O[Si](CC)(CC)CC)[C@@H](C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: C1CCOC1
Product: COC(=O)/C=C(\C)CCSc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114 %

Procedure:
0.5M Toluene solution (64.2 ml) of potassium bis(trimethylsilyl)amide was added dropwise to a DME (280 ml) solution of ethyl-(2E)-3-methyl-5-[(1-phenyl-1-H-tetrazol-5-yl)sulfonyl]pent-2-enoate (9.0 g, 25.7 mmol) at −60° C. and the reaction solution was stirred at the same temperature for 30 minutes. Subsequently a THF (50 ml) solution of (2R,3S)-2-methyl-3-[(triethylsilyl)oxy]pentanal (12.0 g, 52.1 mmol) was added dropwise at −78° C. and the reaction solution was stirred for one hour. After the reaction solution was warmed to room temperature, distilled water was added. The reaction solution was diluted with ethyl acetate and washed with brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane: diethyl ether=100:1) to obtain the title compound (8.92 g) as a colorless oil. The title compound was determined to be a mixture of E:Z=18:1 by 1H-NMR.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[O:14][C:15]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:16]=4[N:17]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:26]([NH2:28])[CH3:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1.ClCCl>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[O:14][C:15]4[CH:21]=[CH:20][C:19]([C:22]([NH:28][CH2:26][CH3:27])=[O:23])=[CH:18][C:16]=4[N:17]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2oc(N3CCC(N4CCCCC4)CC3)nc2c1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc2oc(N3CCC(N4CCCCC4)CC3)nc2c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
2-(1,4′-Bipiperidin-1′-yl)benzo[d]oxazole-5-carboxylic acid (Example 95A, 40 mg, 0.121 mmol), ethanamine hydrochloride (15 mg, 0.182 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (55 mg, 0.146 mmol) were combined in tetrahydrofuran (3 mL). Triethylamine (51 μL, 0.364 mmol) was added and the mixture was stirred at 45° C. overnight. The reaction mixture was diluted with dichloromethane, washed with a 1 N aqueous solution of sodium hydroxide, and absorbed on silica gel. The crude mixture was purified with silica gel chromatography eluting with a gradient of methanol in dichloromethane (3-18%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.25 (t, J=7.29 Hz, 3 H) 1.39-1.51 (m, 2 H) 1.52-1.75 (m, 7 H) 1.96 (d, J=12.89 Hz, 2 H) 2.44-2.61 (m, J=4.75 Hz, 4 H) 3.01-3.15 (m, 2 H) 3.43-3.58 (m, 2 H) 4.29-4.41 (m, 2 H) 6.01 (s, 1 H) 7.21-7.28 (m, 1 H) 7.50 (dd, J=8.31, 1.86 Hz, 1 H) 7.66 (d, J=1.36 Hz, 1 H); MS (ESI+) m/z 357.0 (M+H)+.
Reaction SMILES: O=[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[O:3]1.O(Cl)[Cl:20]>N1C=CC=CC=1>[Cl:20][C:2]1[O:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: COC(=O)CCC1OC(=O)N=C1c1ccccc1
Reactant: ClOCl
Solvent: c1ccncc1
Product: COC(=O)CCc1oc(Cl)nc1-c1ccccc1
Temperature: 105 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
A mixture of methyl 3-(2-oxo-4-phenyloxazolin-5-yl)propionate (3.00 g), pyridine (0.98 ml) and phosphoric oxychloride (7.62 g) was stirred at 105° C. for 2 hrs. The reaction mixture was slowly poured into ice water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography, and methyl 3-(2-chloro-4-phenyl-5-oxazolyl)propionate (2.40 g, yield 75%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:7, volume ratio).