Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[N:5]([N:9]=[CH:10][CH:11]=2)[C:6](=O)[CH:7]=1.P(Cl)(Cl)([Cl:14])=O>C(Cl)Cl.CC(OC)(C)C>[Cl:14][C:6]1[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Nc1cc(=O)n2nccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: Nc1cc(Cl)n2nccc2n1
Temperature: 25 °C

Procedure:
A solution of 5-aminopyrazolo[1,5-a]pyrimidin-7(4H)-one (Z-2) (1.5 g, 10 mmol) in phosphoryl chloride (45 mL) is stirred at reflux overnight. The reaction mixture is allowed to cool to RT and concentrated in vacuo. The residue is then dissolved in ice-water (25 mL) and the resulting mixture is neutralized with aqueous NaOH solution (20%) to adjust the pH to 9-10. The mixture is extracted with ethyl acetate (3×50 mL) after which the combined organic layers are washed with brine (500 mL), dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the crude product which is slurried in a mixture of DCM/MTBE (3 mL/15 mL). The resulting solid is then collected by filtration to afford 7-chloropyrazolo[1,5-a]pyrimidin-5-amine (Z-3).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:20])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[NH:11][C:10](=O)[CH2:9]1>C1COCC1.C(OCC)C>[CH3:7][C:8]1([CH3:20])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[NH:11][CH2:10][CH2:9]1
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)CCNc2ccc(Br)cc21
Temperature: 25 °C

Procedure:
To 23.5 ml of 1.0M (23.5 mmol) lithium aluminum hydride in THF, heated to reflux under nitrogen, was added a solution of 4.95 g (19.48 mmol) of 4,4-dimethyl-6-bromo-2-oxo-1,2,3,4-tetrahydroquinoline in 50 ml of dry THF and 100 ml of dry diethyl ether via a double-ended needle. The mixture was heated at reflux for 2 hours and then cooled to room temperature. The reaction mixture was then quenched by the slow addition of 25 ml of water followed by 50 ml of 5% NaOH solution. The mixture was extracted with 2×25 ml of ether, the organic extracts were combined and washed successively with 25 ml each of water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 15% ethyl acetate in hexanes) to give the title compound as a brown oil.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].C([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](=O)[CH3:24])=[C:15]1Cl)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].O>CO.CCOC(C)=O>[CH2:16]([SH:1]1[C:15]2[NH:14][C:22]3[C:17]([C:16]=2[C:23]([CH3:24])=[C:2]1[C:3]([O:5][CH3:6])=[O:4])=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1c(Cl)n(Cc2ccccc2)c2ccccc12
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)c2c([nH]c3ccccc23)[SH]1Cc1ccccc1
Reaction time: 8 h

Procedure:
550 μl of methyl 2-mercaptoacetate was added to a slurry of 1.45 g of (82) and 1.6 g of K2CO3 in 15 ml of MeOH, and left with stirring overnight. 30 ml of water was added, and the product isolated as a sticky lump. This lump was dissolved in EtOAc, washed with water, dried and evaporated to give an oil, which slowly solidified. Crystallization from MeOH gave (83). Yield 330 mg. M.p. 132°-4° C.
Reaction SMILES: C(N1C=CN=C1)(N1[CH:7]=[CH:6]N=C1)=O.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][C:18]=1[NH:26][C:27](=[O:45])[CH2:28][CH:29]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]2[O:41][CH2:42][CH2:43][O:44][C:36]=12)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(C)(C)[CH3:14].[NH3:46]>C(#N)C>[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[NH2:46])=[CH:19][C:18]=1[NH:26][C:27](=[O:45])[CH2:28][CH:29]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]2[O:41][CH2:42][CH2:43][O:44][C:36]=12)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:14][CH2:6][CH3:7]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1cccc2c1OCCO2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N
Solvent: CC#N
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1CCCC)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
165 mg (1.02 mmol) of 1,1'-carbonylbis(1H-imidazole) were added to a solution of 355 mg (0.783 mmol) of N-(2-t-butyl-5-carboxyphenyl)-3-(2,3-ethylenedioxyphenyl)octanamide (prepared as described in Preparation 74C) in 7.0 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 30 minutes, after which 0.46 ml of 29% v/v aqueous ammonia was added. The reaction mixture was stirred at room temperature for 1 hour, after which the mixture was freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel using ethyl acetate as the eluent, to give 327 mg (yield 92%) of the title compound as a colorless foam-like substance.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:3]OS(C)(=O)=O.[I-:17].[Na+]>>[I:17][CH2:3][C:2]([CH3:16])([CH3:1])[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: [I-]
Reactant: CC(C)(COS(C)(=O)=O)CN1CCCCC1
Agent: [Na+]
Product: CC(C)(CI)CN1CCCCC1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
In analogy to the procedure described for example 6D, methanesulfonic acid 2,2-dimethyl-3-piperidin-1-yl-propyl ester and sodium iodide stirred at 95° C. for 3 h gave the title compound as brown oil. MS: 282.1 (MH+).
Reaction SMILES: C([O:5][NH:6][C:7](=[O:39])[C@H:8]([N:20]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:19])[CH2:15][N:16]([CH3:18])[CH3:17])(C)(C)C.C(O)C.[Cl:43]C(Cl)C>>[ClH:43].[OH:5][NH:6][C:7](=[O:39])[C@H:8]([N:20]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:19])[CH2:15][N:16]([CH3:18])[CH3:17]
Reactant: CC(Cl)Cl
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CCCCNC(=O)CN(C)C)C(=O)NOC(C)(C)C)cc1
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CCCCNC(=O)CN(C)C)C(=O)NO)cc1
Product: Cl
Temperature: -10 °C
Reaction time: 48 h

Procedure:
N-(t-Butyloxy)-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-[(N,N-dimethylglycyl)amino] hexanamide (2.17 g, 3.86 mmol) is dissolved in dichloroethane (12 mL) containing ethanol (0.22 mL, 3.86 mmol), and the reaction is cooled to -10° C. Hydrochloric acid gas is bubbled through this solution for 30 minutes. The reaction is sealed, warmed to room temperature and stirred for 2 days. The solvent is reduced to 1/2 volume by evaporating solvent, and triturated with ether. The resulting solid is removed and dried in vacuo to provide N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-[(N,N-dimethylglycyl)amino] hexanamide hydrochloride, m.p. 105°-108° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[C:16](I)[C:13]([C:14]#[N:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC[N:32](C(C)C)[CH:33]([CH3:35])[CH3:34].C(N)(C)C.C(Cl)Cl>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[C:16]([NH:32][CH:33]([CH3:35])[CH3:34])[C:13]([C:14]#[N:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)c(I)c1C#N)c1ccc(F)cc1
Solvent: CC(C)N
Solvent: CCCCO
Solvent: ClCCl
Product: CC(C)Nc1c(F)c(Nc2cc(C3CC3)[nH]n2)nc(N[C@@H](C)c2ccc(F)cc2)c1C#N
Temperature: 185 °C
Yield: 50.6 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-iodonicotinonitrile (Example 134, 0.07 g, 0.14 mmol) and DIEA (0.023 g, 0.18 mol) in n-BuOH (1.5 ml) was added isopropylamine (0.16 g, 2.7 mmol). The reaction was then heated to 185° C. under microwave conditions (1 hour×4 cycles). The reaction was then cooled to room temperature, DCM (10 ml) was added, and washed with 10% aqueous Na2S2O3. The organic layer was then dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by reverse-phase column chromatography (5-50% ACN) to give the title compound (0.031 g, 51%). 1H NMR (400 MHz, CD3OD) δ 7.36-7.33 (m, 2H), 7.04-7.00 (m, 2H), 5.99-5.59 (br s, 1H), 5.14 (s, 1H), 4.29-4.23 (m, 1H), 1.87-1.83 (m, 1H), 1.52 (d, J=7.0 Hz, 3H), 1.25 (d, J=6.2 Hz, 6H), 0.95-0.94 (m, 2H), 0.65-0.63 (m, 2H). MS: Calcd.: 437. Found: [M+H]+ 438.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][N:38]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:44]([S:41]([N:38]1[CH2:37][CH2:36][CH:35]([C:26]2[C:25]3[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=[C:23]([C:10]4[CH:9]=[N:8][CH:7]=[C:6]([CH2:5][NH:4][CH2:3][CH:2]([CH3:1])[CH3:21])[CH:11]=4)[CH:24]=3)[NH:28][CH:27]=2)[CH2:40][CH2:39]1)(=[O:43])=[O:42])[CH3:45]
Reactant: CC(C)CNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC(C)C)c4)cc23)CC1
Yield: 35 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), isobutylamine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 21 mg of crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.5 mg of the title compound (35%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[F:10])[NH2:6])#[N:2].[N:11]([O-])=O.[Na+].C(O)(=O)C.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][C:29]([C:32](=O)[CH3:33])=[C:28](O)[C:27]2=[O:36])=[CH:22][CH:21]=1>Cl.O.CO>[C:1]([C:3]1[CH:4]=[C:5]([N:6]2[C:28]3[C:27](=[O:36])[N:26]([C:23]4[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=4)[CH2:31][CH2:30][C:29]=3[C:32]([CH3:33])=[N:11]2)[CH:7]=[CH:8][C:9]=1[F:10])#[N:2]
Reactant: N#Cc1cc(N)ccc1F
Reactant: O=N[O-]
Reactant: CC(=O)C1=C(O)C(=O)N(c2ccc(Br)cc2)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nn(-c2ccc(F)c(C#N)c2)c2c1CCN(c1ccc(Br)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Cyano-4-fluoroaniline (3.7 mmol, 0.5 g) in conc. HCl (4 mL) was cooled to 0° C. and NaNO2 (4.4 mmol, 0.3 g) in water (3 mL). This was stirred at 0° C. for 30 min, then acetic acid (1.3 mL) was added. SnCl2•(H2O)2 (8.5 mmol, 1.9 g) in 1:1 water: conc. HCl (3 mL) was added dropwise to the cold solution and stirred for an additional 30 min. To this mixture 1-[4-bromophenyl]-3-hydroxy-4-acetyl-5,6-dihydropyridin-2-one (3.9 mmol, 1.2 g) was slurried in MeOH (20 mL) and added with the aid of additional MeOH (6 mL). The suspension was heated at 50° C. for 3 h, then cooled at 10° C. for 18 h. The product, 1-[3-cyano-4-fluorophenyl]-3-methyl-6-[4-bromophenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]-pyridin-7-one, was isolated by filtration. There was obtained 1.34 g (3.2 mmol) of product; mp 237.6° C., LRMS (M+H)+: 425.2/427.1 m/z.
Reaction SMILES: [I-].[Na+].[Cl:3][CH:4]([CH3:19])[CH2:5][CH:6]1[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[C:9]2[CH:15]=[CH:16][CH:17]=[N:18][C:8]=2[O:7]1.[CH3:20][NH:21][CH3:22]>>[ClH:3].[CH3:20][N:21]([CH3:22])[CH:4]([CH3:19])[CH2:5][CH:6]1[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[C:9]2[CH:15]=[CH:16][CH:17]=[N:18][C:8]=2[O:7]1
Reactant: CNC
Reactant: CC(Cl)CC1CN(C)C(=O)c2cccnc2O1
Agent: [I-]
Agent: [Na+]
Product: CC(CC1CN(C)C(=O)c2cccnc2O1)N(C)C
Product: Cl
Reaction time: 168 h

Procedure:
Into a stainless steel bomb was placed 1.0 g sodium iodide, 5.0 g (0.017 mole) of 2-(2-chloropropyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one and 40 ml of dimethylamine. The bomb was sealed tightly, placed in the oven at 60° C. and rolled continuously for 7 days. The bomb was allowed to stand at room temperature for several days. The residue was combined with that of a previous run of equal size and separated via column chromatography using silica gel and eluting with ethanol and then with 3% triethylamine/ethanol. The fractions containing the desired product were combined and concentrated by rotary evaporation (80° C., 30 mm). The residue was taken up in 150 ml of chloroform and washed with 2×50 ml diluted sodium hydroxide. The chloroform was removed by rotary evaporation (70° C., 30 mm) and the residue treated with ethereal hydrogen chloride and hydrogen chloride in isopropyl alcohol. The white crystals which were collected weighed 3 g (28%), m.p. 173°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C:14]([O:16]C2C=CC=CC=2)=O)[CH:3]=1.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([S:38]([NH:41][C:14]([NH:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=3[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:16])(=[O:40])=[O:39])=[CH:36][CH:37]=2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: NS(=O)(=O)c1ccc(OCCN2CCOCC2)cc1
Product: CCOC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(OCCN2CCOCC2)cc1

Procedure:
As the starting substances, ethyl 4-chloro-2-phenoxycarbonylaminobenzoate and 4-(2-morpholinoethyloxy)benzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-[4-(2-morpholinoethyloxy)benzenesulfonyl]-N'-(2-ethyloxycarbonyl-5-chlorophenyl)urea and further to obtain from 500 mg (0.98 mmol) of N-[4-(2-morpholinoethyloxy)benzenesulfonyl)-N'-(2-carboxyl-5-chlorophenyl)urea 120 mg of the above-identified compound (yield 27.2%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):2.48 (4H,t), 2.73 (2H,t), 3.57 (4H,t), 4.22 (2H,t), 7.12 (1H,s), 7.20 (3H,t), 7.85 (1H,d), 8.09 (2H,d), 11.56 (1H,br).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>COCCOC.O.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:17]1([O:16][C:10]2[CH:15]=[CH:14][C:13]([C:2]3[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=3)=[CH:12][CH:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OB(O)c1ccc(OC2CCCCC2)cc1
Reactant: Nc1ncc(F)cc1Br
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: CCOC(C)=O
Solvent: O
Product: Nc1ncc(F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (54.5 mg) was added to a suspension of 3-bromo-5-fluoropyridin-2-amine (300 mg), 4-(cyclohexyloxy)phenylboronic acid (449 mg) and sodium carbonate (333 mg) in DME (15 mL) and water (3 mL) and the mixture was stirred at 100° C. under nitrogen for 2 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and washed with IPE to give the title compound (366 mg) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+]1C=CN([C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:12][C:11]1[C:2]([O:1][C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1nc2ccccc2nc1O
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2nc1OC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A mixture of 2-hydroxy-3-methylquinoxaline (0.48 g, 3.00 mmol) ), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours followed by heating at 50° C. for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.59 g, 67% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14](=[N:20]O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)C(C)C)(C)C.O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][C:10]1[O:11][N:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CCOC(=O)C(N)=NO
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc(Cc2cccc(OC)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
2-(3-methoxyphenyl)acetyl chloride (1.18 mL; 7.57 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.500 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (18 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.146 g (15%) of ethyl 5-(3-methoxybenzyl)-1,2,4-oxadiazole-3-carboxylate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]([NH:23][NH2:24])=O.Cl.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]2[N:4]([C:21]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][N:15]=3)=[N:23][N:24]=2)[N:3]=1
Reactant: NNC(=O)c1cnccn1
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Clc1nn2c(-c3cnccn3)nnc2cc1-c1ccccc1

Procedure:
The product from Example 1 step b) (1 g, 4.46 mmol) was suspended in xylene (25 ml) with pyrazine-2-hydrazide (0.74 g, 5.35 mmol) and triethylamine hydrochloride (0.61 g, 4.46 mmol) and the reaction mixture was heated at reflux for 2 days. The solvent was removed under high vacuum, and the residue was dissolved in dichloromethane, basified with sodium bicarbonate and the aqueous extracted with dichloromethane (2×150 ml). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by silica gel chromatography using 0-40% ethyl acetate in dichloromethane as eluent to give the required product (0.249 g). 1H NMR (250 MHz, DMSO) δ 7.56 (5H, m), 8.43 (1H, s), 8.87 (1H, d, J=2.5 Hz), 8.96 (1H, d, J=2.5 Hz), 9.49 (1H, d, J=2.5 Hz); MS (ES+) m/e 309 [MH+].
Reaction SMILES: CC([N:5]([C@@H:9]([CH3:13])[CH2:10][C:11]#[N:12])[C:6](=[O:8])[O-:7])(C)C.CS(OC[C@@H](NC(O[C:26]([CH3:29])([CH3:28])[CH3:27])=O)C)(=O)=O.[C-]#N.[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.O>[C:11]([CH2:10][C@@H:9]([NH:5][C:6](=[O:8])[O:7][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:13])#[N:12]
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: C[C@@H](CC#N)N(C(=O)[O-])C(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H](CC#N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88 %

Procedure:
1,1-Dimethylethyl[(1S)-2-cyano-1-methylethyl]carbamate. The nitrile was prepared in two steps using a modified procedure as described in example Z-29. To a stirred solution of (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl methanesulfonate (8.40 g, 33.2 mmol) in DMSO (50 mL) and KCN (6.51 g, 100.0 mmol) cooled to 0° C. was added 18-crown-6 (9.05 g, 34.3 mmol). The solution was allowed to warm to room temperature and then heated to 70° C. for 1 hour. After cooling at room temperature, water was added and the mixture was extracted with Et2O. The ethereal layers were washed with a brine solution, dried over Na2SO4, filtered and concentrated to give 1,1-dimethylethyl [(1S)-2-cyano-1-methylethyl]carbamate (5.37 g, 88%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.32 (d, J=6.8 Hz, 3H), 1.44 (s, 9H), 2.52 (dd, J=4.0, 16.4 Hz, 1H), 2.74 (m, 1H), 3.95 (m, 1H), 4.65 (br s, 1H). b) [(3S)-3-Aminobutyl](2-methylpropyl)amine dihydrochloride was prepared in a similar manner as described in example Z-29. 1H NMR (400 MHz, CDCl3/CD3OD) δ 0.99 (m, 6H), 1.34 (m, 3H), 2.13-2.27 (m, 3H), 2.76 (m, 2H), 3.07 (m, 2H), 3.47 (m, 1H), 8.22 (m, 1H), 8:83 (m, <1H). c) (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2. 16a (80 mg, 0.17 mmol) and free based [(3S)-3-aminobutyl](2-methylpropyl)amine (107 mg, 0.74 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (76 mg, 76%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (39 mg, 80%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 0.76 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 1.32 (d, J=7.2 Hz, 3H), 1.45-1.50 (m, 1H), 1.60-1.69 (m, 1H), 2.03-2.12 (m, 2H), 2.21-2.27 (m, 1H), 2.73-2.79 (m, 1H), 2.87-2.93 (m, 1H), 4.16-4.25 (m, 2H), 4.45 (s, 1H), 4.57-4.68 (m, 2H), 4.96-5.01 (m, 1H), 6.75-6.82 (m, 2H), 7.32-7.38 (m, 1H), 8.26 (s, 1H), 10.45 (s, 1H), 12.56 (s, 1H); ES+ MS: 475 (M+1).