Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN1C=CN=C1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[N:30][O:31][C:32]=2[C:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=2)=[CH:24][C:23]=1[NH2:45]>C1COCC1>[C:2]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10](=[O:12])[NH:45][C:23]1[CH:24]=[C:25]([C:28]2[CH:29]=[N:30][O:31][C:32]=2[C:33]2[CH:34]=[C:35]([O:43][CH3:44])[C:36]([O:41][CH3:42])=[C:37]([O:39][CH3:40])[CH:38]=2)[CH:26]=[CH:27][C:22]=1[O:21][CH3:20])([CH3:1])([CH3:3])[CH3:4]
Reactant: COc1ccc(-c2cnoc2-c2cc(OC)c(OC)c(OC)c2)cc1N
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Agent: Cn1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cnoc2-c2cc(OC)c(OC)c(OC)c2)cc1NC(=O)CNC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of N-t-Boc-glycine (357 mg, 2 mmol) and N-methyl-imidazole (0.162 mL, 2 mmol) in THF (16 mL) cooled with ice methanesulfonyl chloride (0.158 mL, 2 mmol) was added. Ice batch was removed, compound 5 (0.4 g, 1 mmol) was added as a solid, followed by thriethylamine (0.144 mL, 2.02 mmol), and the reaction mixture was stirred at 40-50° C. overnight. A resulted solution was decanted from a solid, a flask rinsed with EtOAc, and a combined organic solution was washed with saturated ammonium chloride solution, then twice with water, brine and dried over anhydrous sodium sulfate. The solution was filtered out through a celite pad, concentrated and the residue was dissolved in 2-propanol (3 mL) with heating, and hexane (1-2 mL) was added drop-wise to start precipitation. In 1 hour a solid was filtered out, washed with 1:1 Hexane: ether mixture (10 ml×2) and vacuum-dried to give compound 6, 0.49 g (93.7%), LC purity 99 %. 1H NMR (DMSO-d6): δ 9.11 (s, 1H), 8.81 (s, 1H), 8.22 (s, 1H), 7.24 (m,1H), 7.20-7.15 (m, 2H), 6.91 (s, 2H), 3.87 (s, 3H), 3.73 (m, 2H), 3.70 (s, 3H), 3.66 (s, 6H). 1.40 (s, 9H).
Reaction SMILES: C([O-])(=O)C.[K+].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23].C(OC(=O)C)(=O)C.C(O[N:41]=O)CC(C)C>C1C=CC=CC=1>[CH2:14]([O:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[NH:6][N:41]=[C:21]2[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(C)OC(=O)c1n[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A mixture of potassium acetate (1.34 g), isopropyl 2-amino-5-benzyloxyphenylacetate (3.9 g) and acetic anhydride (4.0 g) in benzene (40 ml) was stirred at 80° C. After 30 minutes, isopentylnitrite (2.3 g) was added dropwise to the mixture over 15 minutes and then the mixture was stirred at same temperature for 4 hours. After cooling, insoluble mass was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in isopropyl alcohol (30 ml) containing conc. sulphuric acid (0.5 ml) and the mixture was stirred at 80° C. for 3 hours. After cooling to room temperatures the resulting crystals were collected by filtration and washed with isopropyl ether to give isopropyl 5-benzyloxy-1H-indazole-3-carboxylate (2.4 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Fc1ccc(CNc2nc(-c3cnccn3)nc3sc(Cl)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:6].C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([O:1][CH2:2][C:3]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:6])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CO)c(C(=O)NCc2cccnc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(C)=O)c(C(=O)NCc2cccnc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A solution of 710 mg of 2-hydroxymethyl-5-methoxy-N-(3-pyridylmethyl) benzamide and 317 mg of triethylamine in 10 ml of methylene chloride was chilled at 0° C., mixed with 320 mg of acetic anhydride and stirred at room temperature for 15 hours. The reaction mixture was washed with water and saturated brine in order. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 820 mg of the titled compound.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10](=[O:13])[S:11][CH:12]=1)=[O:7])[CH3:4]>C(Cl)(Cl)Cl>[Br:1][C:12]1[S:11][C:10](=[O:13])[NH:9][C:8]=1[C:6]([O:5][CH2:3][CH3:4])=[O:7]
Reactant: BrBr
Reactant: CCOC(=O)c1csc(=O)[nH]1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1[nH]c(=O)sc1Br
Yield: 74.7 %

Procedure:
69 g of bromine were added to a mixture of 69.2 g of 4-ethoxycarbonyl-4-thiazoline-2-one in 500 ml of chloroform and the mixture was refluxed for 20 hours. The mixture was distilled to dryness under reduced pressure and after the addition of isopropyl ether, the mixture was vacuum filtered to obtain 75.2 g of 5-bromo-4-ethoxycarbonyl-4-thiazoline-2-one melting at 121°C.
Reaction SMILES: Br[C:2]1[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]2[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]=2[C:10]=1[CH3:11].[CH3:20]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:16][C:6]1[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:10]([CH3:11])=[C:2]([CH3:20])[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]=2[CH:5]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)c(Br)n2C(C)C
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: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cc2c1c(C)c(C)n2C(C)C
Temperature: 110 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a stirred solution of methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.50 g, 1.451 mmol), Trimethylboroxine (0.30 mL, 2.146 mmol) and potassium carbonate (0.31 g, 2.243 mmol) in 1,4-Dioxane (20 mL) under N2 was added palladium tetrakis (0.18 g, 0.156 mmol). The reaction was heated to 110° C. and stirred for 18 hr. After 3 hr an additional 100 uL Trimethylboroxine was added. The reaction was concentrated under vacuum, taken up in EtOAc, washed with water, dried (MgSO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-60g, 0 to 10% EtOAc in hexanes) gave the product methyl 6-chloro-1-isopropyl-2,3-dimethyl-1H-indole-4-carboxylate (0.33 g, 1.180 mmol, 81% yield) as a clear thick oil. 1H NMR (400 MHz, DMSO-d6) δ=7.80 (d, J=2.0 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 4.81 (dt, J=6.9, 13.9 Hz, 1H), 3.87 (s, 3H), 2.39 (s, 3H), 2.13 (s, 3H), 1.51 (d, J=7.1 Hz, 6H)
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1>>[Cl:30][C:31]1[N:32]=[CH:33][C:34]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])=[CH:35][CH:36]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(Cl)nc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-chloropyridine-5-boronic acid. The title compound was obtained in 36% yield as orange foam. MS (m/e): 517.3 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)[CH:3]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:20][OH:21])[CH:3]=1
Reactant: COc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(Cc2cc(Br)ccn2)=NO)cc1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
To a solution of Example 19A (13.41 g, 43.8 mmol) in methanol (231 mL) was added hydroxylamine hydrochloride (15.22 g, 219 mmol) to give a thick slurry. The mixture was treated with a solution of sodium hydroxide (8.76 g, 219 mmol) in water (58 mL), heated at reflux for two hours, cooled and concentrated to a paste. The paste was treated with 100-150 mL of water and stirred for 15 minutes to give a solid that was collected by filtration, washed with water and dried to constant mass to give the title compound as a powder (11.86 g, 84%). MS (ESI+) m/z 321/323 (M+H)+.
Reaction SMILES: O.[OH:2][CH2:3][C:4]12[O:11][CH:7]([CH2:8][CH:9]1[CH3:10])[CH2:6][C:5]2([CH3:13])[CH3:12]>C(O)C>[CH:3]([C:4]12[O:11][C@H:7]([CH2:8][C@H:9]1[CH3:10])[CH2:6][C:5]2([CH3:12])[CH3:13])=[O:2]
Reactant: CC1CC2CC(C)(C)C1(CO)O2
Solvent: CCO
Solvent: O
Product: C[C@@H]1C[C@@H]2CC(C)(C)C1(C=O)O2
Yield: 85 %

Procedure:
Workup: The reaction mixture obtained as in Example 1a was mixed with 200 ml of water at RT, the upper phase was separated off, and the aqueous phase was extracted three times with 150 ml of hexane each time. The organic phases were combined, washed twice with 150 ml of water and evaporated (rotary evaporator). The residue of 25.5 g was distilled to result in 22.1 g of 1-formyl-2,2,6-trimethyl-7-oxabicyclo[2.2.1]heptane with a boiling point of 54-61° C. under 1.5 mbar, which is 90% pure according to gas chromatography (GC), (equivalent to a yield of 85% of theory). A byproduct was ascertained to be 1-hydroxymethyl-2,2,6-trimethyl-7-oxabicyclo[2.2.1]heptane (about 4% of theory). The structure of the product was evident for example from the 1H-NMR spectrum: 250 MHz, (C6D6), δ=1.09 (d, J=8 Hz, 3 H), 4.16 (t, J=6 Hz, 1 H), 9.94 (s, 1 H); [α]D25 =-20.7 (c=1, ethanol).
Reaction SMILES: [Li]C(C)(C)C.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10](I)=[CH:9][N:8]=1.Cl([O-])(=O)(=O)=O.[CH2:20]1[C:27]2[CH2:26][CH2:25][CH2:24][N+:23]=2[CH2:22][CH2:21]1.Cl>CCCCC.CCOCC>[Cl:13][C:12]1[CH:11]=[C:10]([C:27]23[CH2:26][CH2:25][CH2:24][N:23]2[CH2:22][CH2:21][CH2:20]3)[CH:9]=[N:8][C:7]=1[Cl:6]
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Clc1cc(I)cnc1Cl
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CCCCC
Product: Clc1cc(C23CCCN2CCC3)cnc1Cl
Temperature: -20 °C
Reaction time: 0.03 h
Yield: 54.3 %

Procedure:
A solution of 1.7M tBuLi (4.7 mL, 8.0 mmol) in pentane was added to 2,3-dichloro-5-iodopyridine (from step 8a, 1.0 g, 3.65 mmol) in Et2O (15 mL) precooled to -100° C. After stirring for 2 minutes, 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (1.5 g, 7.3 mmol) was added, and the reaction mixture was allowed to stir for 20 minutes at -100° C. then gradually warm to -20° C. A solution of 2N HCl was added, and the cold bath was removed. After warming to ambient temperature, the reaction mixture was poured over EtOAc and the phases were separated. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 phases were combined, dried (MgSO4), concentrated and the residue was chromatographed (silica gel; CHCl3 /MeOH, 99.5:0.5) to afford a light yellow oil (510 mg, 54%). MS (CI/NH3) m/e: 257 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.59-1.71 (m, 2H), 1.80-2.08 (m, 6H), 2.64-2.72 (m, 2H), 3.11-3.20 (m, 2H), 7.99 (d, J=2.2 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[N:14]1([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]3)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:17]1[CH2:18][CH2:19][N:14]([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]3)=[O:21])[CH2:15][CH2:16]1)=[O:8]
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: COc1ccc(C(=O)O)cc1OC
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC

Procedure:
1.8 Grams of 3,4-dimethoxybenzoic acid and 2.75 g of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril were added to a mixed solvent of 20 ml of dioxane with 20 ml of methylene chloride. Under the condition that the outside of reaction vessel was ince-cooled with stirring, a solution of 2.1 g of N,N-dicyclohexylcarbodiimide being dissolved in 5 ml of methylene chloride by keeping its temperature to 10°-20° C. was added dropwise thereto and stirred at the same temperature for 3.5 hours. The crystals formed in the reaction mixture were removed by filtration, and the mother liquor was concentrated under a reduced pressure. The residue thus obtained was dissolved in 100 ml of methylene chloride and the organic layer was washed with 5%-hydrochloric acid aqueous solution, 5%-sodium hydrogen-carbonate aqueous solution and water in this order, then the organic layer was dried with anhydrous sodium sulfate. The solvent was removed by distillation under a reduced pressure and the residue thus obtained was recrystallized from chloroform-ethanol to obtain 0.9 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([NH:25][C:26](N)=[O:27])([O-])=O.CN(C)C=O>O>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([N:16]3[CH2:21][CH2:20][N:19]([C:26]([NH2:25])=[O:27])[CH2:18][CH2:17]3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)N1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Yield: 54.8 %

Procedure:
A mixture of 4.9 g of 1-phenyl-3-(1-piperazinyl)-1H-indazole, 5.1 g of nitrourea, and 80 ml of dimethylformamide was heated on a steam bath for 15 minutes. The reaction mixture was then poured into water and the resulting precipitate was recrystallized from ethyl acetate (2×) to yield 3.1 g (57%) of 4-(1-phenyl-1H-indazol-3-yl)-1-piperazine carboxamide, m.p. 151°-153°.
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:36])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[S:48](Cl)([CH3:51])(=[O:50])=[O:49].[OH-].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:36])=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][O:35][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:31][CH:32]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCO)cc2)n1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCOS(C)(=O)=O)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one (2) (1.2 g; 2.35 mmol) in CH2Cl2 (30 mL) was cooled to 0° C. and 1.5 mL of diisopropylethyl amine was added. A second solution containing 0.75 mL mesyl chloride in 3 mL CH2Cl2 was added dropwise to the stirring reaction solution under N2 and the reaction allowed to warm to rt for 1 hr. 0.1N Sodium hydroxide was then added carefully to the reaction, and the layers separated. The CH2Cl2 layer was washed with brine and dried over solid sodium sulfate, then filtered and evaporated to a light red-brown oil (1.5 g). The crude methanesulfonic acid 2-(4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-ethyl ester (3) was used directly in subsequent reactions.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH:20][C:21]1[N:22]=[N:23][C:24]([C:40]([NH2:42])=[O:41])=[C:25](NC2C=CC=C(C3N=CC=CN=3)C=2)[N:26]=1>>[NH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH:20][C:21]1[N:22]=[N:23][C:24]([C:40]([NH2:42])=[O:41])=[C:25]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:7][CH:8]=2)[N:26]=1
Reactant: Nc1ccc(-c2ncco2)cc1
Reactant: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Product: NC(=O)c1nnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ncco2)cc1

Procedure:
The title compound was prepared with 4-(oxazol-2-yl)aniline using the similar procedure described in Example 3-((1R,2S)-2-aminocyclohexylamino)-5-(3-(pyrimidin-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide. MS found for C19H22N8O2 as (M+H)+ 395.6. UV: λ=240, 297 nm. Proton NMR: (CD3OD) δ 8.13 (2H, m), 8.03 (1H, s), 7.90 (2H, m), 7.34 (1H, s), 4.45 (1H, m), 3.72 (1H, m), 1.90-1.63 (8H, m) ppm.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[C:8]([F:15])[CH:7]=1.[Cl:16][CH2:17][CH2:18]Cl>>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](=[O:11])[CH2:18][CH2:17][Cl:16])=[C:8]([F:15])[CH:7]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: ClCCCl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCl)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a stirred suspension of aluminum trichloride (153 g, 1.15 mol) in DCE (1000 mL) was added a solution of 144b (271 g, 1.14 mol) in DCE (1000 mL) at 0° C. See FIG. 3. Ethylene gas was bubbled through the dark suspension for 3 h until the acid chloride was consumed. The reaction mixture was then stirred at RT overnight, cooled to 0° C., and quenched with 4M HCl (500 mL). The organic phase was separated and washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by column chromatography (PE/EA=30 to 10:1) to give 1-(4-bromo-2-fluorophenyl)-3-chloropropan-1-one 144c (210 g, 68%).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:7]=[N:6][CH:5]=[N:4]1.[OH-].[Na+].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCCCCCn1cncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCCCn1cncn1)c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
A mixture of about 2.30 g of 1H-1,2,4-triazole-1-pentanamine dihydrochloride, about 75 ml of methylene chloride, about 30 ml of approximately 1N sodium hydroxide and about 1.2 ml of 4-chloro benzoyl chloride was stirred for about 18 hours, then about 5 ml of approximately 1N sodium hydroxide and about 50 ml of methylene chloride were added and the layers were separated. The organic layer was washed with water dried and concentrated, giving the desired product, mp 68°-70° C.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH:4]1([C:10]2[S:14][C:13]([N:15]=[C:16]=[O:17])=[N:12][N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.NN>C(Cl)Cl>[CH3:1][N:2]([C:16]([NH:15][C:13]1[S:14][C:10]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[N:11][N:12]=1)=[O:17])[NH2:3]
Reactant: CNN
Reactant: O=C=Nc1nnc(C2CCCCC2)s1
Agent: NN
Solvent: ClCCl
Product: CN(N)C(=O)Nc1nnc(C2CCCCC2)s1
Temperature: 25 °C

Procedure:
A solution of methylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-methyl-4-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][O:11][CH3:12])=[C:8]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=3)[N:14]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1>>[CH2:1]([N:5]1[C:9]([CH2:10][O:11][CH3:12])=[C:8]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:25]=[CH:24][C:21]([CH2:22][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)=[CH:20][CH:19]=3)[N:14]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)C1CNC1
Reactant: COCc1c(-c2nc(-c3ccc(C=O)cc3)no2)cnn1CC(C)C
Product: COCc1c(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)cc3)no2)cnn1CC(C)C

Procedure:
The title compound was prepared following the procedure described for Example 64 (step 2), but starting from 4-{5-[1-isobutyl-5-(methoxymethyl)-1H-pyrazol-4-yl]-1,2,4-oxadiazol-3-yl}benzaldehyde, obtained from step 1, (170.2 mg; 0.50 mmol) and using 3-azetidine carboxylic acid (101.1 mg; 1.0 mmol) to give Example 76 as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.14-8.11 (3 H, m), 7.56 (2 H, d, J=8.0 Hz), 4.99 (2 H, s), 4.17 (2 H, s), 4.13-4.09 (2 H, m), 4.05 (2 H, d, J=7.6 Hz), 3.97 (2 H, t, J=9.3 Hz), 3.43-3.38 (4 H, m), 2.41-2.32 (1 H, m), 0.95 (6 H, d, J=6.7 Hz). LC/MS: 426 (M+H)+. HPLC (Method A) Rt=2.32 min (Purity: 99.3%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)(=O)C.[NH2:19][C@@H:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([CH3:24])([OH:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:23][C:21]([CH3:24])([CH3:22])[C@@H:20]([NH:19][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(O)[C@@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N[C@@H](c2ccccc2)C(C)(C)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask charged with boc-4-piperidone (2.412 g, 12.10 mmol, Alfa-Aesar) was added DCM (60.5 mL), acetic acid (0.901 mL, 15.74 mmol), (S)-1-amino-2-methyl-1-phenylpropan-2-ol (2 g, 12.10 mmol, BOC Scientific) and sodium triacetoxyborohydride (3.59 g, 16.95 mmol) respectively. The resulting orange suspension was stirred at room temperature for 3 h. LCMS indicated good conversion to desired product. To the mixture was added saturated NaHCO3 and K2CO3 pellets. The mixture was transferred to a separatory funnel and extracted with DCM (2×). The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The material thus obtained was used without further purification.