Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccccc3)sc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3ccccc3)sc2c1
Yield: 100.4 %

Procedure:
Ethyl 2-phenyl-benzothiazole-6-carboxylate 1y (220 mg, 0.78 mmol) was stirred with LiOH (74 mg, 3.1 mmol) in THF (4 mL) and H2O (4 mL) for 16 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1z (200 mg).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[C:9]1(=O)[CH:12]2[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH:11]2[CH2:10]1>CO>[C:9]1(=[N:7][OH:8])[CH:12]2[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH:11]2[CH2:10]1
Reactant: NO
Reactant: O=C1CC2c3ccccc3CC12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C1CC2c3ccccc3CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (1.45 g, 17.7 mmol) and hydroxylamine hydrochloride (0.68 g, 9.75 mmol) were added to a solution of 2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (1.4 g, 8.86 mmol) in MeOH (18 mL), and stirred overnight at room temperature. The reaction solution was concentrated via rotary evaporation. The residue was dissolved in CH2Cl2 (100 mL), washed with H2O (50 mL), dried over MgSO4, and concentrated to give the subtitle compound, which was used without further purification. MS calculated for C11H11NO+H: 174, observed: 174.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH:6]2[C:18](=[O:20])[NH2:19])[CH2:2]1.CCN(CC)CC.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>C(Cl)Cl>[C:28]([N:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH:6]2[C:18](=[O:20])[NH2:19])[CH2:2]1)(=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C2CNC2)C(C(N)=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CC(N2CCN(C(=O)OC(C)(C)C)CC2C(N)=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.6 %

Procedure:
To a solution of tert-butyl 4-(azetidin-3-yl)-3-carbamoylpiperazine-1-carboxylate (640 mg, 2.22 mmol) and Et3N (463 mg, 4.58 mmol) in DCM (10 mL) at 0° C., acryloyl chloride (248 mg, 2.74 mmol) was added dropwise and the resulting mixture was stirred at RT for 1.5 h. The mixture was partitioned between dichloromethane and saturated NaHCO3 solution. The organic layer was washed with saturated brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (350 mg, 47% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]=C)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.C[N+]1([O-])CC[O:28]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]=[O:28])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: C=Cc1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Reactant: C[N+]1([O-])CCOCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: Cn1ncc2cc(Cc3cnc4ccc(C=O)nn34)c(F)cc21
Temperature: 46 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
To a mixture of 3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)-6-vinylimidazo[1,2-b]pyridazine (50 mg, 0.163 mmol) osmium(VIII) oxide (103 mg, 8.13 μmol), was added a solution of NMO (29.5 mg, 0.252 mmol) in acetone (2 ml) and H2O (0.16 ml). The reaction mixture was heated to 46° C. After stirring for 4 h, the solvent was removed and a mixture of THF (6 ml) and H2O (1.5 ml) was added to dissolve the residue, then sodium periodate (69.6 mg, 0.325 mmol) was added and the resulting mixture was stirred at 46° C. for 12 h. The reaction mixture was then quenched with Na2SO3(aq), extracted with DCM, dried over Na2SO4, filtered through Celite and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with gradient Hex:EA to give 3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine-6-carbaldehyde (20 mg), yield 38%. 1H-NMR (400 MHz, CDCl3) δ ppm 10.09 (s, 1H), 8.07 (dd, 1H), 7.89 (d, 1H), 7.74 (s, 1H), 7.63 (m, 2H), 7.10 (d, 1H), 4.54 (s, 2H), 4.03 (s, 3H). LCMS (method A): [MH]+=310, tR=3.95 min.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][NH:19][CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:18][N:19]([CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CNCC(OC)OC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(CN(C)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])OC
Reaction time: 1 h

Procedure:
4-Chloro-3,5-dinitrobenzotrifluoride (5.4 grams; 0.02 mole) dissolved in benzene was charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. N-Methyl-N-2,2-dimethoxyethylamine (2,4 grams; 0.02 mole) and triethylamine (2.02 grams; 0.02 mole) both dissolved in benzene (50 ml) were then added dropwise with stirring. After the addition was completed stirring was continued for a period of 1 hour resulting in the formation of a precipitate. The reaction mixture was filtered to remove the acid acceptor salt and was chromatographed. The solution was then evaporated to yield a solid product. This solid was recrystallized from hexane to yield the desired product N-methyl-N-(2,2-dimethoxyethyl)-2,6-dinitro-4-trifluoroemethylaniline melting at 48° to 50° C.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2]1.[O-:14][C:15]#[N:16].[K+].CN(C=O)C>[Br-].C([N+](CC)(CC)CC)C.O>[CH2:4]([CH:3]1[O:1][C:15](=[O:14])[NH:16][CH2:2]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCC1CO1
Reactant: N#C[O-]
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCC1CNC(=O)O1
Yield: 65.2 %

Procedure:
4.6 g of 1,2-epoxydodecane, 12.2 g of potassium cyanate, 25 ml of DMF, 0.2 g of tetraethylammonium bromide and 1.8 ml of water were stirred and heated at 120°-130° C. for 5 hours. The disappearance of the epoxide was followed by thin layer chromatography (tlc). The cooled reaction mixtre was poured into 200 ml of water and this was extracted with ethyl acetate. The combined organic extracts were washed with water, followed by brine, dried and concentrated to give a solid. Recrystallization from methylene chloride/hexane gave 3.7 g (65.2%) of product, m.p. 86°-87° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:30][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=4)=[O:23])=[CH:25][CH:26]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: NCCc1cc[nH]c(=O)c1
Reactant: COc1ccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cc(-c3ccc(C(=O)NCCc4cc[nH]c(=O)c4)cc3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
A mixture of 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (76 mg, 0.195 mmol), 4-(2-aminoethyl)pyridin-2(1H)-one (64 mg, 0.215 mmol), 1-methyl-1H-imidazole (96 mg, 1.17 mmol) and EDCI (223 mg, 1.17 mmol) in dichloromethane (10 mL) and DMF (0.5 mL) was stirred at room temperature for 16 h then dichloromethane (20 mL) was added. The mixture was washed with water (2×2 mL) and brine (2×2 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, MeOH:dichloromethane=1:10) to afford 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide (44 mg, 44%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 11.35 (s, 1H), 9.94 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.19 (s, 1H), 8.02-7.93 (m, 4 h), 7.66 (s, 1H), 7.40 (d, 1H, J=8.4 Hz), 7.26 (d, 1H, J=6.6 Hz), 7.10 (d, 1H, J=8.1 Hz), 6.16 (s, 1H), 6.08 (d, 1H, J=6.3 Hz), 4.00 (s, 3H), 3.76 (s, 3H), 3.50-3.40 (m, 2H), 2.69-2.67 (m, 2H). LC-MS: [M+H]+, 512, tR=1.412 min, HPLC: 98.19% at 214 nm, 97.49% at 254 nm, tR=7.244 min.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[CH:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:13][S:14]2)=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)([CH2:3][CH:2]=[CH2:1])[CH2:13][S:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Reactant: C=CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCC1(c2ccc(OC)cc2)CSc2cc(OC)ccc2C1=O
Temperature: 10 °C
Reaction time: 15 h
Yield: 78.7 %

Procedure:
Allyl bromide (5.7 ml, 66.56 mmol) was added dropwise to a solution of 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (2 g, 6.64 mmol) in dimethyl sulfoxide (34 ml). To this mixture, a solution of potassium tert-butoxide (5.22 g, 46.55 mmol) in dimethyl sulfoxide (70 ml) was slowly added dropwise at 10° C., followed by stirring for 2 hours at 10° C. and for 15 hours at room temperature. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/9) to give 7-methoxy-3-(4-methoxyphenyl)-3-(2-propenyl)thiochroman-4-one (1.78 g, Yield 79%) as a colorless oil.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:3]1=[O:12].[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2([C:36]([F:39])([F:38])[F:37])[O:25][N:24]=[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([CH3:35])[CH:27]=3)[CH2:22]2)[CH:17]=[C:18]([Cl:20])[CH:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2([C:36]([F:38])([F:37])[F:39])[O:25][N:24]=[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:1][N:2]4[CH2:6][CH2:5][N:4]([CH2:7][C:8]([F:9])([F:11])[F:10])[C:3]4=[O:12])=[O:31])=[C:28]([CH3:35])[CH:27]=3)[CH2:22]2)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: NN1CCN(CC(F)(F)F)C1=O
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NN1CCN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Into a 25-mL round-bottom flask, was placed 1-amino-3-(2,2,2-trifluoroethyl)imidazolidin-2-one (90 mg, 0.49 mmol, 1.00 equiv), 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (200 mg, 0.48 mmol, 0.97 equiv), EDCI (192 mg, 1.00 mmol, 2.04 equiv), HOBT (135 mg, 1.00 mmol, 2.03 equiv), triethylamine (303 mg, 2.99 mmol, 6.09 equiv), dichloromethane (10 mL). The resulting solution was stirred for 30 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 39 mg (13%) of 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methyl-N-[2-oxo-3-(2,2,2-trifluoroethyl)imidazolidin-1-yl]benzamide as a white solid. (ES, m/z): 583 [M−H]−; 1H NMR (300 MHz, CDCl3) δ 7.89 (s, 1H), 7.43-7.62 (m, 6H), 4.06-4.12 (m, 1H), 3.54-3.89 (m, 7H), 2.47 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:38])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28]5[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=5)=[CH:27][C:22]4=[N:21][CH:20]=3)=[CH:15][C:14]=2[F:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:26]3[CH:25]=[CH:24][N:23]4[C:19]([C:16]5[CH:17]=[CH:18][C:13]([NH:12][C:11]([NH:10][C:7]6[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[O:9][N:8]=6)=[O:38])=[C:14]([F:37])[CH:15]=5)=[CH:20][N:21]=[C:22]4[CH:27]=3)=[CH:29][CH:30]=2)[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cnc4cc(-c5ccc(C(=O)O)cc5)ccn34)cc2F)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(NC(=O)Nc6cc(C(C)(C)C)on6)c(F)c5)cnc4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Combine 4-(3-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-3-fluoro-phenyl}-imidazo[1,2-a]pyridin-7-yl)-benzoic acid (2.00 g, 3.89 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.09 g, 5.84 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.821 g, 4.28 mmol), triethylamine (1.63 mL, 11.68 mmol), and 1-hydroxybenzotriazole (0.579 g, 4.28 mmol) in DMF (50 mL). Stir at room temperature for 14 hours. Partition between ethyl acetate and 1 N NaOH, wash with aqueous saturated sodium chloride, dry over magnesium sulfate, filter, and concentrate. Triturate the resulting solid from CH2Cl2/hexanes, filter, and dry to give off-white solid as product (1.53 g, 58%). MS (ES), m/z 683 (M+1).
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([CH3:36])[C@@H:32]([C:37](O)=[O:38])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([CH3:36])[C@@H:32]([C:37](=[O:38])[NH:22][CH2:21][C:19]2[N:20]=[C:15]3[CH:14]=[CH:13][N:12]([S:2]([C:5]4[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=4)(=[O:3])=[O:4])[C:16]3=[N:17][CH:18]=2)[CH2:31]1)=[O:29])([CH3:25])([CH3:26])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)[C@H]4CN(C(=O)OC(C)(C)C)CC[C@H]4C)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.4 %

Procedure:
To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (34.0 g, 100 mmol, Example #5, Step C), (3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (24.43 g, 100 mmol) and HATU (38.2 g, 100 mmol) in DCM (700 mL) was added DIEA (52.6 mL, 301 mmol). The reaction was stirred at ambient temperature for about 45 min. The reaction was washed with saturated aqueous NaHCO3 (300 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered then concd in vacuo. The resulting residue was purified by chromatography on silica gel (330 g) using 33-100% EtOAc in heptane to give (3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (53 g, 96%) as a pale-yellow foam: LC/MS (Table 1, Method b) Rt=2.40 min; MS m/z: 528 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[CH:12][CH:11]=2)=[N:4][S:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:27]([O-])=O.[Na+]>Cl.CN1CCCC1=O.O>[CH2:20]([O:19][C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([C:3]2[C:2]3[N:1]=[N:27][NH:9][C:7](=[O:8])[C:6]=3[S:5][N:4]=2)=[CH:15][CH:14]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1snc(-c2ccc(NC(=O)OCc3ccccc3)cc2)c1N
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1ccc(-c2nsc3c(=O)[nH]nnc23)cc1)OCc1ccccc1
Yield: 71.6 %

Procedure:
22.5 g of 4-amino-3-(4-benzyloxyformamidophenyl)-5-isothiazolecarboxamide in 25 ml of concentrated hydrochloric acid and 150 ml of N-methylpyrrolidone were cooled in an ice-bath and stirred during the addition of 4.89 g of sodium nitrite dissolved in 20 ml of water. After 0.5 hour 150 ml of water were added and the resulting precipitate was filtered off, washed with water, dried in vacuo and recrystallized from ethyl acetate to yield 16.6 g of 7-(4-benzyloxyformamidophenyl)isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one of melting point 190°-191° C. (dec.).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=3)[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=3)[CH:24]=2)[NH:19][N:18]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc3[nH]nc(-c4nc5ccccc5[nH]4)c3c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.7 %

Procedure:
TFA (0.5 mL, 6.490 mmol) was added to a solution 3-(1H-benzo[d]imidazol-2-yl)-5-(3-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (7 mg, 0.015 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (4 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.84 (s, 1H), 8.39 (m, 1H), 7.17 (m, 1H), 7.95 (m, 1H), 7.85 (m, 2H), 7.78-7.73 (m, 3H), 7.28 (m, 2H); ESI-MS [M+H]+: 389.3.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20](B1OC(C)(C)C(C)(C)O1)=[CH2:21].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH:20]([C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH2:21]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
A mixture of tert-Butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (852 mg, 2.60 mmol), vinylboronic acid pinacol ester (400 mg, 2.60 mmol), saturated aqueous sodium carbonate solution (12 ml), and tetrakis(triphenylphosphine)palladium(0) (84.8 mg, 0.0734 mmol) in dimethoxyethane (15 ml) was stirred under a nitrogen atmosphere at 85° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product (250 mg, 34.9%) as an oil.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C@H:9]1[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1.Br[CH2:32][C:33]#[N:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:24]=1)[CH2:6][O:7][CH2:8][C@H:9]1[C@H:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([CH2:32][C:33]#[N:34])[CH2:10]1
Reactant: Fc1ccc([C@@H]2CCNC[C@H]2COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CC[C@@H](c2ccc(F)cc2)[C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of (−)-(3S,4R)-3-(3,5-bis-trifluoromethyl-benzyloxymethyl)-4-(4-fluoro-phenyl)-piperidine (150 mg, 0.345 mmol), bromoacetonitrile (45 mg, 0.37 mmol) and potassium carbonate (95 mg, 0.69 mmol) in 4 ml of acetonitrile was stirred at room temperature over night. Quenching with water was followed by extraction with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 163 mg (99.7%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17]O)=[N:9]2)=[CH:4][CH:3]=1.CO.C(Cl)(Cl)[Cl:25]>O=S(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17][Cl:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: OCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 813 mg (2.75 mmol) of trans-3-[2-(7-chloroquinolin-2-yl)ethenyl]benzyl alcohol in 40 ml of CHCl3, 1.0 ml of SOCl2 was added, followed by stirring at room temperature for 24 hours. A small amount of MeOH was added to the reaction mixture and the solvent was distilled off under reduced pressure, whereby trans-3-[2-(7-chloroquinolin-2-yl)ethenyl]benzyl chloride was obtained as pale yellow powder.
Reaction SMILES: C([S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)(=O)C.[N:13]([CH2:16][C@@H:17]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:18]O)=[N+:14]=[N-:15]>>[N:13]([CH2:16][C@@H:17]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:18][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)=[N+:14]=[N-:15]
Reactant: CC[Si](CC)(CC)O[C@@H](CO)CN=[N+]=[N-]
Reactant: CC(=O)Sc1ncn2ccsc12
Product: CC[Si](CC)(CC)O[C@H](CN=[N+]=[N-])CSc1ncn2ccsc12
Yield: 85.2 %

Procedure:
The procedure of Synthesis Example 11b) was repeated, except that 907 mg of 7-acetylthioimidazo[5,1-b]thiazole and 1.27 g of (2R)-3-azido-2-triethylsilyloxy-1-propanol was used as the starting compound. Thus, 1.44 g of 7-((2R)-3-azido-2-triethylsilyloxypropyl)thioimidazo[5,1-b]thiazole was prepared.