Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[OH:30][CH2:31][CH2:32][NH:33][CH3:34]>CN(C)C(=O)C>[OH:30][CH2:31][CH2:32][N:33]([CH3:34])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1
Reactant: CNCCO
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CN(C/C=C/COC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)CCO

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with (2-hydroxy-ethyl)-methyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-(E)-but-2-enyloxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 493 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].C(C1C=COC=1)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[PH4+].[CH:35]([C:43]1[CH:47]=[CH:46][O:45][CH:44]=1)=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.CCOCC.O>[CH:35](/[C:43]1[CH:47]=[CH:46][O:45][CH:44]=1)=[CH:36]\[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C(=Cc1ccoc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=Cc1ccoc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: C(=C/c1ccoc1)\c1ccccc1
Reaction time: 1 h
Yield: 19 %

Procedure:
Potassium tert-butoxide (35.7 g) was added in one portion to a stirred suspension of benzyltriphenylphosphonium chloride (41.6 g) in ether (1 liter). After 1 hour, a solution of 3-formylfuran (17.5 g) in ether (60 ml) was added to the resulting orange mixture which was then stirred for 2 hours, poured into water, and extracted with ether. The extracts were washed with water, dried and concentrated to give a solid. Trituration of this solid with ether enabled much of the weakly-soluble triphenylphosphine oxide and excess phosphonium salt to be separated, and the ether-soluble fraction (37.06 g) was chromatographed using ether as eluent to give a mixture of (E)-- and (Z)-isomers of 3-styrylfuran (27 g) as a yellow solid. Crystallisation twice from methanol gave (E)-3-styrylfuran (5.12 g), mp 96° C., as a yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH:12]1([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]2[CH2:26][C:27](OCC)=[O:28])[CH2:14][CH2:13]1>O>[CH:12]1([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]2[CH2:26][C:27]([NH:10][C:9]([NH2:11])=[NH:8])=[O:28])[CH2:13][CH2:14]1
Reactant: CCOC(=O)CC1c2ccccc2C(=O)N1CC1CC1
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: N=C(N)NC(=O)CC1c2ccccc2C(=O)N1CC1CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 76.4 %

Procedure:
N-[(2-Cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 2.9 g of potassium tert-butoxide, 2.5 g of guanidinium chloride and 1.5 g of ethyl (2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, followed by addition of 20 cm3 of water. The aqueous phase is extracted with 3 times 100 cm3 of ethyl acetate. The organic extracts are combined and then concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 35° C. The residue is taken up in water, triturated, filtered off and then dried in a desiccator. 1.2 g of N-[(2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine are thus obtained in the form of an off-white powder melting at 229° C. Mass spectrum: DCI: m/e 287 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=5)=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N+:42]=5[O-:58])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc(C)n4)cc2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc(C)[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(6-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (340 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.15 g) at 0° C. and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added sodium thiosulfate solution and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:19) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(6-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 96) (262 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:33])([C:27]4[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=4)[C:19]4[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=4)[CH:16]=3)[N:11]([CH3:34])[C:10](=[O:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:36][O:37][CH2:38][CH2:39][NH2:40].C(O)(=O)C.[BH3-]C#N.[Na+]>C(#N)C.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:33])([C:19]4[CH:20]=[CH:21][C:22]([CH2:23][NH:40][CH2:39][CH2:38][O:37][CH3:36])=[CH:25][CH:26]=4)[C:27]4[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=4)[CH:16]=3)[N:11]([CH3:34])[C:10](=[O:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: Cn1cncc1C(O)(c1ccc(C=O)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: COCCNCc1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3C)c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.1 %

Procedure:
A mixture of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzaldehyde (described in Example B6) (0.000207 mol), 2-methoxy-ethanamine (0.000517 mol) and acetic acid (0.0000207 mol) in acetonitrile (2 ml) was stirred at room temperature for 2 hours. NaBH3CN (0.000517 mol) was added and the resulting mixture was stirred at room temperature overnight. After addition of water and extraction with EtOAc, the solvent was evaporated. The residue was purified by HPLC. The product fractions were collected and the solvent was evaporated, yielding 0.008 g (7.13%) of (±)-4-(3-chlorophenyl)-6-[hydroxy[4[[(2-methoxyethyl)amino]methyl]phenyl](1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)quinolinone, MS (ESI) m/z:543, 545 (MH+).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:37])[N:24]([CH:34]([CH3:36])[CH3:35])[CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:20]=[C:19]([Cl:38])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:38][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=1)[C:23]([N:24]([CH:34]([CH3:36])[CH3:35])[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[O:37]
Reactant: CC(C)N(CCOc1ccccn1)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCOc1ccccn1)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Yield: 18.5 %

Procedure:
A solution of {2-[3-chloro-5-(isopropyl-2-(pyridin-2-yloxy)-ethyl-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.033 g) and TFA (0.4 ml) in dichloromethane (0.4 ml) was stirred at room temp for 3 h then concentrated under vacuum. The residue was purified by flash chromatography on silica eluting with dichloromethane/methanol/ammonia (94:6:1) to give the title compound as a colourless gum (0.005 g).
Reaction SMILES: NC1C=C2C(=CC=1N)N=CC(C#N)=C2NC1C=C(OC)C=CC=1C.[NH2:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([NH:38][C:39]3[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=3[CH3:47])=[C:31]([C:36]#[N:37])[CH:32]=[N:33]2)=[CH:28][C:27]=1[NH:48][C:49]([NH:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=S.NC1C=C2C(=CC=1NC(NCCN1CCOCC1)=S)N=CC(C#N)=C2NC1C=C(OC)C=CC=1C.[S]>O1CCOCC1.C(O)C>[CH3:46][O:45][C:43]1[CH:42]=[CH:41][C:40]([CH3:47])=[C:39]([CH:44]=1)[NH:38][C:30]1[C:29]2[CH:28]=[C:27]3[N:48]=[C:49]([NH:51][CH2:52][CH2:53][N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)[N:25]=[C:26]3[CH2:35][C:34]=2[N:33]=[CH:32][C:31]=1[C:36]#[N:37]
Reactant: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N)c(NC(=S)NCCN4CCOCC4)cc23)c1
Agent: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N)c(N)cc23)c1
Agent: COc1ccc(C)c(Nc2c(C#N)cnc3cc(NC(=S)NCCN4CCOCC4)c(N)cc23)c1
Agent: [S]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(C)c(Nc2c(C#N)cnc3c2C=C2N=C(NCCN4CCOCC4)N=C2C3)c1
Temperature: 100 °C

Procedure:
A mixture of 0.1 g (0.3 mmol) of 6,7-diamino-4-(5-methoxy-2-methylanilino)-3-quinolinecarbonitrile and 0.11 g (0.62 mmol) of 2-(4-morpholino)ethylisothiocyanate in 0.3 mL of dioxane is heated at 100° C. for 2 hours under nitrogen. The mixture is cooled and solvent is evaporated to dryness to yield an oil consisting of N-[7-amino-3-cyano-4-(5-methoxy-2-methylanilino)-6-quinolinyl]-N′-[2-(4-morpholinyl)-ethyl]thiourea and N-[6-amino-3-cyano-4-(5-methoxy-2-methylanilino)-7-quinolinyl]-N′-[2-(4-morpholinyl)ethyl]thiourea. The oil is dissolved in 3.0 mL of ethanol. To this is added 0.3 g of mercuric oxide and 20 mg of sulphur powder and the resulting mixture is heated at reflux temperature for 2 hours. The product mixture is filtered hot through diatomaceous earth, washed with methanol and solvent is evaporated to yield an oil. The oil is purified by silica gel chromatography, utilizing a gradient of methylene chloride/methanol (95:5 to 85:15) to yield 0.062 g of 8-(5-methoxy-2-methylanilino)-2-{[2-(4-morpholinyl)ethyl]amino}imidazo[4,5-g]quinoline-7-carbonitrile as a pink solid, mp 148-150° C. (shrinks at 140° C. ).
Reaction SMILES: ClC1C=C2C(=CC=1)NC(C)=C2.CC([CH2:15][CH2:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=C.ClC1NC2C(C=1)=CC=CC=2.[C:36](=[O:38])=[O:37]>>[C:36]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH2:16][CH3:15])=[CH:25]2)([OH:38])=[O:37]
Reactant: O=C=O
Reactant: C=C(C)CCc1cc2ccccc2[nH]1
Agent: Cc1cc2cc(Cl)ccc2[nH]1
Agent: Clc1cc2ccccc2[nH]1
Product: CCc1cc2cc(C(=O)O)ccc2[nH]1

Procedure:
This synthesis could start with 5-chloro-2-methylindole, which could be alkylated with methyl indole (see 28a). The product chloroindole could then be converted to its Grignard species and exposed to carbon dioxide to finish the synthesis.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][C@@H:27]([C:35]([OH:37])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C[O-].[Na+]>COCCO.C([O-])(O)=O.[Na+]>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][C@H:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]([OH:37])=[O:36])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@H](Cc2ccccc2)C(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), D-phenylalanine (296 mg, 1.8 mmol) and NaOMe (73 mg, 1.3 mmol) in 2-methoxyethanol (10 mL) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (5-60% EtOAc/hexanes+2% AcOH) to give a crude solid. The solid was dissolved in saturated NaHCO3 and washed with ether. 1 M HCl was added to the aqueous layer until pH was about 1, and the resulting precipitate was isolated by filtration to give 21 mg of the title compound as an off-white solid. MS: (+) m/z 469.02 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9](C(C)(C)C)[N:8]=[C:7]([CH2:22][CH:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)O)[N:6]=1)([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[CH:9][N:8]=[C:7]([CH:22]=[CH:23][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[N:6]=1)([CH3:1])[CH3:3]
Reactant: COCCOCOc1c(C(C)(C)C)nc(CC(O)c2cccnc2)nc1C(C)(C)C
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(C=Cc2cccnc2)ncc1O
Temperature: 190 °C
Yield: 60.7 %

Procedure:
A mixture of 4,6-bis (1,1-dimethylethyl)-5-[(2-methoxyethoxy) methoxy]-α-(3-pyridinyl)-2-pyrimidineethanol (350 mg), sodium acetate (10 g) and acetic arthydride (7 mL) in toluene (100 mL) is heated at reflux for 8 hours. The reaction mixture is cooled and the solvent is evaporated. Dichlorobenzene (30 mL) is added and the reaction mixture is heated at 190° C. for 30 minutes. The reaction mixture is cooled and partitioned between ethyl acetate and water. The aqueous layer is adjusted to pH 4 with 1 N HCl. The organic layer is collected and evaporated. Purification of the residue by flash chromatography (silica, 1:1 ethyl acetate/hexane) followed by recrystallization from hexane gives pure 4,6-bis(1,1-dimethylethyl-2-[[2-(3-pyridinyl)]ethenyl]-5-pyrimidinol (130 mg, 40%); mp 150°-151° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:6]=1)=[O:4]>CO.[OH-].[Na+]>[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=1)([OH:4])=[O:2]
Reactant: CCOC(=O)COc1cc(C(=O)OC)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cc(C(=O)O)on1

Procedure:
A solution of ethyl (5-(methoxycarbonyl)isoxazol-3-yl)oxyacetate (4 mmol, Example 73) in methanol (60 mL) and 5% aqueous NaOH is heated at reflux for 1 hour. At the end of this time, the methanol is removed, the residue diluted with additional water, and acidified to pH=4 with hydrochloric acid. The resulting precipitate is collected by filtration, washed with cold water, and dried.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[CH:18]([CH3:19])[N:17]([CH:20]([F:22])[F:21])[C:16](=[O:23])[CH2:15][NH:14]2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[F:1][C:2]1[C:12]([N:13]2[CH:18]([CH3:19])[N:17]([CH:20]([F:21])[F:22])[C:16](=[O:23])[CH2:15][NH:14]2)=[C:11]([N+:24]([O-:26])=[O:25])[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC1N(c2cc3c(cc2F)OCC(=O)N3)NCC(=O)N1C(F)F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC1N(c2c(F)cc3c(c2[N+](=O)[O-])NC(=O)CO3)NCC(=O)N1C(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[7-Fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4-difluoromethyl-3-methyl-1,4-dihydro-1,2,4-triazin-5-one (0.38 g) was dissolved in acetic acid (10 ml) and fuming nitric acid (10 ml) was added slowly at ambient temperature. The resulting mixture was stirred for 1 hour and poured into ice-water. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluted with ethyl acetate and hexanes (1:3) to give title compound (0.17 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:25].CC(O)C>>[Br:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:25])[C:6]=12
Reactant: FC(F)(F)c1nnc2n1CCN(c1nc(Br)c3c(Cl)nccn13)C2
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c(N3CCn4c(nnc4C(F)(F)F)C3)nc(Br)c12
Temperature: 120 °C

Procedure:
To a 75 ml sealed vessel was charged with 7-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (595 mg, 1.408 mmol) along with ammonia in IPA (2N, 0.704 ml, 1.408 mmol). The vessel was sealed with screw cap and heated in an oil bath of 120° C. for 18 hrs overnight. LC-MS showed complete conversion of starting material to product. The mixture was then cooled to room temperature, solid (gel) precipitated and was filtered, washed with IPA and dried to afford 1-bromo-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)imidazo[1,5-a]pyrazin-8-amine (250 mg). The filtrate was concentrated and the residue was purified by MPLC (12 g silica gel, 0 to 10% methanol in methylenechloride, 28 CV) to afford another batch of product. Totally 1-bromo-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)imidazo[1,5-a]pyrazin-8-amine (386 mg, 0.957 mmol, 68.0% yield) was obtained. LC-MS: C12H10BrF3N8,402. found 403.08 [M+H]+, RT=1.09 min.
Reaction SMILES: Cl[C:2]1C=C(OCCN(CC)CC)C=CC=1C(=O)C(=C)CC.[Cl:22][C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]([CH3:36])[CH2:32][N:33]([CH3:35])[CH3:34])[CH:26]=[CH:25][C:24]=1[C:37](=[O:41])[CH2:38][CH2:39][CH3:40]>>[Cl:22][C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]([CH3:36])[CH2:32][N:33]([CH3:34])[CH3:35])[CH:26]=[CH:25][C:24]=1[C:37](=[O:41])[C:38](=[CH2:2])[CH2:39][CH3:40]
Reactant: CCCC(=O)c1ccc(OCC(C)CN(C)C)cc1Cl
Reactant: C=C(CC)C(=O)c1ccc(OCCN(CC)CC)cc1Cl
Product: C=C(CC)C(=O)c1ccc(OCC(C)CN(C)C)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step B except that the 2-chloro-4-(2-diethylaminoethoxy)butyrophenone of Example 1 Step B is replaced by an equimolecular quantity of 1-[2-chloro-4-(3-dimethylamino-2-methylpropoxy)phenyl]-1-butanone. The product is obtained as a yellow oil upon distillation in vacuo (0.3 mm.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17](=[O:18])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:4][C:3]=2[F:15])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1

Procedure:
50.3 Using general method G, 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to WO 2003045912) was activated with 4-nitrophenyl chloroformate to give [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester. Pale pink solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[CH:42][C:43]([Cl:55])=[C:44]([CH:54]=2)[O:45][CH2:46][CH2:47][CH2:48]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[CH:42][C:43]([Cl:55])=[C:44]([O:45][CH2:46][CH2:47][CH2:48][N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)[CH:54]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCCOS(C)(=O)=O)c2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OCCCN3CCOCC3)c2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 34.1 %

Procedure:
A solution of Intermediate 76a (214 mg, 0.27 mmol) and DIPEA (95 μL, 0.54 mmol) in THF (5 mL) was treated with morpholine (47 μL, 0.54 mmol). The mixture was stirred at 50° C. for 18 h in a sealed vial. The volatiles were concentrated in vacuo and the product was purified by MDAP purification (Method 7) to give the title compound (72 mg, 34%). LCMS (Method 5): Rt 3.60 min, m/z 782.6 [MH+].+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.57-1.65 (2H, m), 1.68-1.77 (4H, m), 1.80-1.94 (4H, m), 1.99-2.17 (2H, m), 2.24-2.32 (3H, bs), 2.36-2.42 (2H, t, J=6.9), 3.11-3.17 (4H, m), 3.48-3.52 (4H, m), 4.09-4-15 (2H, t, J=6.52 Hz), 4.76-4.84 (1H, m), 5.54 (1H, t, J=4.3 Hz), 6.34 (1H, s), 7.03-7.11 (2H, m), 7.16 (1H, dd, J=2.0, 9.9 Hz), 7.21-7.41 (5H, m), 7.54 (1H, d, J=8.5 Hz), 7.59-7.65 (2H, m), 8.14 (1H, br s).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][C:7]2=[O:18])(=[O:3])[CH3:2].[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.[Cl-].[NH4+]>[CH2:14]([C:9]1[NH:10][C:11]2[C:6]([C:7](=[O:18])[N:8]=1)=[CH:5][C:4]([C:1]([OH:3])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:2])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH3:17]
Reactant: Br[Mg]c1ccccc1
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(C)(O)c3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.08 g of 6-acetyl-2-butyl-4(1H)-quinazolinone in 80 ml of tetrahydrofuran is added dropwise at room temperature 14.2 ml of 3.0M phenylmagnesium bromide. The reaction mixture is stirred at room temperature overnight then diluted with aqueous ammonium chloride and extracted with chloroform. The organic layer is dried and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate-hexanes to give 0.535 g of the desired product as a solid. CI mass spec (MH+) 323.