Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])=[CH:21][N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C>C(O)(C)C.C1COCC1.O>[C:42]([C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([F:46])[CH:36]=1)[C:33](=[O:47])[N:32]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:20]=[CH:21][C:22]([C:25]([CH3:27])([CH3:26])[C:28]#[N:29])=[CH:23][CH:24]=4)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:41]=[CH:40]2)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(C)(C)C#N)cn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(C)(C)C#N)cn2)c1=O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
A mixture of 156e (191 mg, 0.30 mmol) and lithium hydroxide•1 water (126 mg, 3.0 mmol) in i-propanol/THF (1:1, 8 mL) and water (2 mL) was stirred at 35° C. for 0.5 h. The mixture was evaporated under reduced pressure and diluted with water (10 mL). It was then extracted with dichloromethane (3×20 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 156 (30 mg, 17%) as a pale yellow solid. MS-ESI: [M+H]+ 594.3. 1H NMR (500 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.59 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.91 (s, 1H), 7.79-7.74 (m, 2H), 7.57-7.53 (m, 2H), 7.40 (d, J=9.0 Hz, 1H), 4.92 (bs, 1H), 4.43 (s, 2H), 3.62 (s, 3H), 1.67 (s, 6H), 1.39 (s, 9H).
Reaction SMILES: [C:1]([O:7][CH2:8]/[CH:9]=[CH:10]/[CH3:11])(=[O:6])[CH2:2]C(C)=O.C(N(CC)CC)C.C(NC1C=CC(S([N:32]=[N+:33]=[N-])(=O)=O)=CC=1)(=O)C.[OH-].[Li+]>C(#N)C.O.C(OCC)C>[N+:32](=[CH:2][C:1]([O:7][CH2:8]/[CH:9]=[CH:10]/[CH3:11])=[O:6])=[N-:33]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C/C=C/COC(=O)CC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: C/C=C/COC(=O)C=[N+]=[N-]
Reaction time: 0.29 h
Yield: 89.8 %

Procedure:
To a solution of trans-2-buten-1-yl acetoacetate (40.0 g, 256 mmol) and triethylamine (46.0 mL g, 330 mmol) in anhydrous acetonitrile (250 mL), a solution of p-acetamidobenzenesulfonyl azide (80.0 g, 333 mmol) in anhydrous acetonitrile (250 mL) was added dropwise over a period of 30 minutes. A white precipitate was observed after 15-20 minutes and additional acetonitrile (300 mL) was added to facilitate stirring. The resulting mixture was stirred at room temperature for one additional hour. Then, a solution of lithium hydroxide (35.5 g, 845 mmol) in water (300 mL) was added to the reaction mixture. After stirring for one hour, the resulting mixture was poured onto 2:1 diethylether:ethyl acetate (500 mL) and the layers were separated. The aqueous layer was extracted with 2:1 diethylether:ethyl acetate (500 mL) and the combined organic phases were washed with a saturated aqueous sodium chloride solution (200 mL). The resulting organic solution was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography using a mixture 9:1 of hexane and ethyl acetate as eluent to afford 32.2 g (90% yield) of trans-2-buten-1-yl diazoacetate as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]#[N:30])[CH:27]=3)[NH:22][CH:21]=2)[OH:19])[C:12]=1[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]#[N:30])[CH:27]=3)[NH:22][CH:21]=2)=[O:19])[C:12]=1[F:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cnc2[nH]cc(C(O)c3c(F)ccc(NC(=O)OCc4ccccc4)c3F)c2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(NC(=O)OCc4ccccc4)c3F)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
Into a round bottom flask, {3-[(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-carbamic acid benzyl ester (26, 3.79 g, 8.72 mmol), 20.00 mL of anhydrous tetrahydrofuran and Dess-Martin periodinane (4.44 g, 10.47 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, then poured into a mixture of 100 mL of 1 M potassium carbonate and 100 mL of 1 M sodium thiosulfate and extracted with 3×150 mL of ethyl acetate. The organic layers were combined and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was slurried in ether, filtered and the solids collected and dried to give the desired compound (27, 2.97 g, 79%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH2:18][OH:19])[CH:16]=2)[C@H:11]([N:22]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:10][C@@H:9]1[CH3:42])=[O:7])[CH3:4].I[CH3:44].O>CN(C)C=O>[CH2:3]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH2:18][O:19][CH3:44])[CH:16]=2)[C@H:11]([N:22]([CH2:27][C:28]2[CH:29]=[C:30]([C:38]([F:39])([F:41])[F:40])[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:10][C@@H:9]1[CH3:42])=[O:7])[CH3:4]
Reactant: CCOC(=O)N1c2cc(CO)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2cc(COC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a suspension of sodium hydride (4.2 mg, 60% dispersion in mineral oil, 0.10 mmol) in N,N-dimethylformamide (2.5 mL) was added cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-hydroxymethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic add ethyl ester (Example 85) (50 mg, 0.087 mmol). After the reaction was stirred at room temperature for 30 min, iodomethane (60 μL, 0.96 mmol) was added, and the reaction was stirred for 18 h. The reaction mixture was then poured into water and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The excess N,N-dimethylformamide was azeotroped off with heptanes. Purification by silica gel chromatography using 15-25% ethyl acetate/hexanes as eluent afforded the title product (30 mg, 59%): 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.3 (t, 3H), 3.4 (s, 3H), 3.75 (s, 3H), 3.8 (s, 3H), 6.4 (s, 1H), 7.4 (s, 1H), 7.75 (s, 2H), 7.8 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15]CC)=O.[CH3:18][O:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1.C(OCC)C>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([N:25]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:36][CH:35]=1)[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)=[O:15]
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: CCOC(=O)c1c(O)c2ccccc2[nH]c1=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2c(O)c3ccccc3[nH]c2=O)cc1
Temperature: 115 °C
Yield: 94.2 %

Procedure:
Ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 67) (3.58 g, 15.4 mmol) and bis(4-methoxybenzyl)amine (4.54 g, 17.6 mmol) were suspended in toluene (36 mL) and heated at 115° C. for 5 hours, then cooled to room temperature. Diethyl ether was added (50 mL), and the resultant precipitate was collected by filtration to give crude 4-hydroxy-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (6.45 g, 95%) which was used without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH:9]([C:22]([OH:24])=O)[CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:28](OC1C=CC=CC=1)=[O:29].Cl>O1CCCC1.O>[O:29]=[C:28]1[N:8]([CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C@@H:9]2[C:22]([O:13][C:11](=[O:12])[C@@H:10]2[N:14]1[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:24]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(O)C(NCc1ccccc1)C(NCc1ccccc1)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1OC(=O)[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
220 g (0.67 mol) of meso-2,3-bis(benzylamino)succinic acid were placed under a nitrogen atmosphere in a 2 l flask fitted with two dropping funnels, a pH electrode, and a stirrer. The meso-2,3-bis(benzylamino)succinic acid was then suspended, while stirring, in 800 ml of tetrahydrofuran and 400 ml of deionized water, and brought into solution by the addition of 108 ml of a 50% potassium hydroxide solution. 200 ml of 2.4 mole eq. phenyl chloroformate were added dropwise to the solution within 3.5 hours. The pH was maintained between 9 and 11 during the addition of phenyl chloroformate by the successive addition of 50% potassium hydroxide solution and the internal temperature was maintained between 30° C. and 35° C. After the addition was completed, the mixture was stirred at about 30° C. for 2 hours and then the pH was adjusted to about 7-8 with concentrated hydrochloric acid. The aqueous solution was extracted twice with toluene and 500 ml of tetrahydrofuran were added to the combined aqueous phases. The mixture was adjusted to a pH of 1.0 with 37% hydrochloric acid, and the aqueous phase was separated off. 400 ml of toluene were added to the tetrahydrofuran phase and the tetrahydrofuran was distilled off under reduced pressure. The remaining water was removed azeotropically with toluene. After the addition of 700 ml of toluene and 130 ml of acetic anhydride, the mixture was heated to 80° C. After the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride had crystallized out, the obtained suspension was cooled to 10° C. within 2 hours in order to complete the crystallization. The crystalline 2-oxo-1,3-dibenzyl-cis4,5-imidazolidinedicarboxylic acid anhydride was filtered off and washed twice with toluene. After drying to constant weight under reduced pressure, there were obtained 173.6 g (78% yield) of 2-oxo-1,3-dibenzyl-cis4,5-imidazolidinedicarboxylic acid anhydride in the form of an analytically pure, colourless solid, with a melting point of 240.2° C. 3.0 g of 2-oxo-1,3-dibenzylamino-cis4,5-imidazolidinedicarboxylic acid anhydride were further obtained on evaporation of the main solution.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH2:10]O)=[C:8]([CH3:12])[N:7]=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:5]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[N:7][C:8]=1[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: COCc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1CO
Product: COCc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1CCl

Procedure:
In analogy to the procedure described in example 113H], [4-methoxymethyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a brown viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C(OCC)(=O)C>[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1C(=O)NCCc1ncc[nH]1)c1ccc(C(F)(F)F)cc1
Yield: 85.8 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 11 using 2.00 g (0.00869 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)-ethyl]benzamide, prepared as in Example 6A, and 3.62 g (0.01738 mol) of p-trifluoromethylbenzoyl chloride with the exception that removal of ethyl acetate provided a solid. This solid was recrystallized from ethyl acetate containing a small amount of methanol to provide 3.00 g of the desired titled compound (m.p. 207°-215° C.).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[NH:23][C:22](=[O:30])[O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:16][CH2:17][C:18]4([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[NH:23][C:22](=[O:30])[O:21]4)[CH2:19][CH2:20]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)OC(=O)Nc3ccccc34)nn2)n1

Procedure:
The object product (72 mg, 76%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (51 mg), spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one hydrochloride (89 mg) and potassium carbonate (70 mg).
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4]([C@@H:6]1[N:18](C(OC(C)(C)C)=O)[CH2:17][C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5]>C1COCC1>[ClH:1].[CH3:2][NH:3][C:4]([C@@H:6]1[NH:18][CH2:17][C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5]
Reactant: CNC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Yield: 87 %

Procedure:
Hydrochloride gas was bubbled into a solution of product (4-A) (5 g, 15 mmol) in THF (100 mL) at rt for 6 h. The solvent was evaporated to give product (5-A) (3.5 g, 87%) as a brown solid. 1H NMR (300 MHz, CD3OD): δ 7.54-7.51 (d, 1H), 7.41-7.38 (d, 1H), 7.22-7.17 (t, 1H), 7.13-7.08 (t, 1H), 4.55-4.54 (d, 2H), 4.35-4.30 (dd, 1H), 3.50-3.43 (dd, 1H), 3.18-3.08 (t, 1H), 2.91 (s, 3H). LC-MS (M+H)+=230.
Reaction SMILES: [I:1][C:2]1[C:3]([O:20][CH2:21][CH2:22][O:23][Si](C)(C)C)=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1>CC(O)=O.C1COCC1.O>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[C:5]([CH:17]([CH3:18])[CH3:19])=[CH:4][C:3]([O:20][CH2:21][CH2:22][OH:23])=[C:2]([I:1])[CH:16]=2)=[CH:13][N:12]=1
Reactant: CC(C)c1cc(OCCO[Si](C)(C)C)c(I)cc1Oc1cnc(N)nc1N
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cc(OCCO)c(I)cc1Oc1cnc(N)nc1N
Yield: 84.2 %

Procedure:
5-[5-Iodo-2-isopropyl-4-(2-trimethylsilanyloxy-ethoxy)-phenoxy]-pyrimidine-2,4-diamine (0.38 g, 0.69 mmol) in a solution of HOAc/THF/H2O in a ratio of 3:1:1.95 ml) was heated at 65° C. for 16 hrs. The pH of the reaction mixture was adjusted to pH=9 and extracted into methylene chloride. The combined eatracts was dried over Na2SO4, filtered and concentrated. Flash chromatography on silica (5% MeOH in methylene chloride with 0.1% NH4OH) gave 2-[4-(2,4-Diamino-pyrimidin-5-yloxy)-2-iodo-5-isopropyl-phenoxy]-ethanol (0.25 g, 86%) as a white solid. (M+H)=431
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:13][C@H:12]3[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=2[N:17]=1.S(=O)(=O)(O)[OH:19].[OH-].[NH4+]>>[CH2:14]([N:11]1[C@@H:12]2[C@H:7]([CH2:6][C:5]3[NH:17][C:2](=[O:19])[S:3][C:4]=3[CH2:13]2)[CH2:8][CH2:9][CH2:10]1)[CH2:15][CH3:16]
Reactant: CCCN1CCC[C@H]2Cc3nc(Br)sc3C[C@@H]21
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCCN1CCC[C@H]2Cc3[nH]c(=O)sc3C[C@@H]21
Temperature: 100 °C
Reaction time: 48 h

Procedure:
About 1.9 millimoles of trans-(±)-2-bromo-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline were dissolved in 10 ml. of 20% aqueous sulfuric acid. The solution was heated at about 100° C. for about five hours and then was cooled. The cooled solution was allowed to remain at ambient temperature for an additional 48 hours. The reaction mixture was then made basic with concentrated aqueous ammonium hydroxide. The aqueous mixture was extracted several times with equal volumes of chloroform. The chloroform extracts were combined, and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the chloroform in vacuo yielded trans-(±)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin-2(1H)-one which was one spot material by TLC (9:1 CHCl3 /MeOH+trace NH4OH); Rf =0.37. The compound showed a strong band at 1650 cm-1 in the infrared indicating a carbonyl.
Reaction SMILES: [Na].N.[C:3](#[N:5])[CH3:4].[C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)#[N:7]>C(OCC)C>[NH2:7][C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)=[CH:4][C:3]#[N:5]
Reactant: N#Cc1ccc2ccccc2c1
Reactant: CC#N
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: N#CC=C(N)c1ccc2ccccc2c1
Yield: 22.2 %

Procedure:
To a solution of 2.0 grams (0.087 mole) of sodium in 125 milliliters of liquid ammonia was added a solution of 3.67 grams (0.089 mole) of acetonitrile in 10 milliliters of diethyl ether over a period of about five minutes. The reaction mixture was then cooled in a dry ice-acetone bath and a solution of 10.0 grams (0.065 mole) of 2-cyanonaphthalene in a minimum of dry diethyl ether was rapidly added within about five minutes after completion of the acetonitrile addition. The reaction mixture was stirred for about one and one-half hours and the ammonia was then allowed to evaporate. Water was cautiously added to the reaction mixture under nitrogen and the resulting mixture was extracted with diethyl ether. The ether was separated and the residue recrystallized from a mixture of chloroform and hexane. There was obtained 2.8 grams (22% of theoretical) of β-amino-β-(2-naphthyl)acrylonitrile, melting point 85°-90°C. Analysis: -- Calculated for C13H10N2 (percent): C, 80.39; H, 5.19; N, 14.42. Found (percent): C, 80.08; H, 4.99; N, 14.06.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([N+:26]([O-])=O)[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:26])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(N)c(N)c2)CC1
Reaction time: 24 h
Yield: 100.4 %

Procedure:
4-[2-(3,4-Dinitro-phenoxy)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.3 mmol) was dissolved in DMF (3 ml) under an atmosphere of nitrogen. Pd/C (10%, 0.012 g) was added and the reaction mixture was shaken under a hydrogen atmosphere for 24 h. The reaction mixture was diluted with methanol (20 ml) and insoluble material was removed by filtration. The filtrate was reduced in vacuo to give 4-[2-(3,4-diamino-phenoxy)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester as a brown oil (0.101 g, 100%). (LC/MS: Rt 2.21, [M+H]+ 336.16).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[N:3]1.[C:11]([CH2:13][C:14]1([N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[N:27][N:26]4[C:29]([C:32]5[CH:33]=[C:34]([NH:38][C:39]([NH:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[O:40])[CH:35]=[CH:36][CH:37]=5)=[CH:30][N:31]=[C:25]4[CH:24]=3)[CH:20]=[N:19]2)[CH2:17][NH:16][CH2:15]1)#[N:12].C(N(CC)CC)C>C(#N)C.CO>[C:11]([CH2:13][C:14]1([N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[N:27][N:26]4[C:29]([C:32]5[CH:33]=[C:34]([NH:38][C:39]([NH:41][CH2:42][C:43]([F:45])([F:46])[F:44])=[O:40])[CH:35]=[CH:36][CH:37]=5)=[CH:30][N:31]=[C:25]4[CH:24]=3)[CH:20]=[N:19]2)[CH2:15][N:16]([S:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)(=[O:9])=[O:8])[CH2:17]1)#[N:12]
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: Cn1ccc(S(=O)(=O)N2CC(CC#N)(n3cc(-c4cnn5c(-c6cccc(NC(=O)NCC(F)(F)F)c6)cnc5c4)cn3)C2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Methyl-1H-pyrazole-3-sulfonyl chloride (5.5 mg, 0.030 mmol) (Maybridge and Cat. No. CC 48303) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (10.0 mg, 0.0202 mmol) and triethylamine (8.4 μL, 0.060 mmol) in acetonitrile (1.0 mL) and MeOH (0.2 mL). The reaction mixture was stirred at r.t. for 30 min. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=640.2.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[N:5][N:6]=1.[C:11]([O:14][CH2:15][C:16](=O)[CH2:17][C:18](OCC)=[O:19])(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:15][C:16]1[NH:1][C:2]2[N:6]([N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=2)[C:18](=[O:19])[CH:17]=1)(=[O:13])[CH3:12]
Reactant: COC(=O)c1nnc(N)[nH]1
Reactant: CCOC(=O)CC(=O)COC(C)=O
Product: COC(=O)c1nc2[nH]c(COC(C)=O)cc(=O)n2n1
Reaction time: 0.67 h
Yield: 82.6 %

Procedure:
A mixture of 71 mg (0.5 mmol) of methyl 5-amino-4H-s-triazole-3-carboxylate and 188 mg of ethyl 4-acetoxy-3-oxo-butyrate is held at about 160° C. for 40 minutes. After cooling the product is crystallized and recrystallized from methanol. There are obtained 110 mg of methyl 5-(acetoxymethyl)-4,7-dihydro-7-oxo-s-triazolo[1,5-a]pyrimidine-2-carboxylate as beige crystals of melting point 223° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:9][O:10][C:11]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[C:52]([O:58][CH3:59])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:45]([O:46][CH3:47])=[CH:44][C:43]([O:48][CH3:49])=[CH:42][C:41]=1[O:50][CH3:51])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH2:37])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH2:24])[CH:17]=1>>[CH3:59][O:58][C:52]1[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=[C:11]([O:10][CH3:9])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:41]([O:50][CH3:51])=[CH:42][C:43]([O:48][CH3:49])=[CH:44][C:45]=1[O:46][CH3:47])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH:37][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH:24][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])[CH:17]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NS(=O)(=O)C(F)(F)F)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NS(=O)(=O)C(F)(F)F)c2)c(OC)c1
Yield: 59.9 %

Procedure:
A solution of trifluoromethanesulfonyl chloride (10 mmol) and (E)-2,4,6-trimethoxy styryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method A. The product obtained was purified by column chromatography to give the desired product in 59.9% yield. (m.p. 144-46° C.)