Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[NH:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: OC1CCNCC1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Temperature: 120 °C
Yield: 64.2 %

Procedure:
A mixture of 4-fluoro-benzoic acid ethyl ester (1.68 g, 10 mmoles), piperidin-4-ol (1.12 g, 11 mmoles) and anhydrous potassium carbonate (138 g, 10 mmoles) in DMSO (10 ml) was heated at 120° C. for 6 hours. After cooling, the mixture was poured into water and ice (500 ml) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and evaporated. The residue was purified by flash chromatography on silica gel using hexane/EtOAc (10/30) as eluent to give the title compound as a white solid (1.6 g, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19](O)=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[F:37][C:38]([F:42])([F:41])[CH2:39][NH2:40]>O1CCCC1>[F:37][C:38]([F:42])([F:41])[CH2:39][NH:40][C:19]([C:10]1[C:11](=[O:18])[C:12]2[C:17](=[N:16][CH:15]=[CH:14][CH:13]=2)[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:9]=1)=[O:20]
Reactant: O=C(O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: NCC(F)(F)F
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid from Step 2 (0.1 eq) and triethylamine (3 eq) in tetrahydrofuran (0.08M) at 0° C. was added isobutyl chloroformate (1.8 eq). After stirring at 0° C. for 2 hours, 2,2,2-trifluoroethylamine (5 eq) was added and the mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then partitioned between ethyl acetate and water, the organic phase was dried and evaporated to a solid which was stirred in ether at room temperature for 3 hours and filtered to afford the N-(2,2,2-trifluoroethyl)-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a white solid.
Reaction SMILES: C([O-])=O.[NH4+].[CH2:5]([O:12][CH2:13][CH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[C@@H](C2C=CC=CC=2)CO)[CH2:17][CH2:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC[C@H]1CC[C@H]([C@H]2CCCN2)CC1)C1C=CC=CC=1.[C:56]([OH:65])(=[O:64])[C@@H:57]([C@H:59]([C:61]([OH:63])=[O:62])[OH:60])[OH:58]>CO.[Pd].CCO>[C:56]([OH:65])(=[O:64])[CH:57]([CH:59]([C:61]([OH:63])=[O:62])[OH:60])[OH:58].[CH2:5]([O:12][CH2:13][CH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C@H:21]2[CH2:25][CH2:24][CH2:23][NH:22]2)[CH2:17][CH2:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: OC[C@H](c1ccccc1)N1CCC[C@@H]1[C@H]1CC[C@H](CCOCc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Product: O=C(O)C(O)C(O)C(=O)O
Product: c1ccc(COCC[C@H]2CC[C@H]([C@H]3CCCN3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of anhydrous ammonium formate (15.8 g, 0.25 mol) and trans-(S)-2-{(R)-2-[4-(benzyloxyethyl)cyclohexyl]pyrrolidin-1-yl}-2-phenylethanol (20.5 g, 0.050 mol) in MeOH (200 mL) is added 10% palladium on carbon (1.00 g), and the resulting mixture is stirred under nitrogen atmosphere at room temperature for 2 hours and then at 35° C. for 3 hours. The reaction mixture is filtered, and the filtrate is concentrated. The crude residue is dissolved with 1N HCl and extracted with ether to remove phenethylalcohol. The water layer is neutrized by addition of 2.5 N NaOH and extracted with CH2Cl2. The combined organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated to give crude trans-(R)-2-[4-(benzyloxyethyl)cyclohexyl]pyrrolidine. To the mixture of crude trans-(R)-2-[4-(benzyloxyethyl)cyclohexyl]pyrrolidine in EtOH (65 mL), L-tartaric acid (7.60 g, 0.050 mol) is added. The resulting mixture is warmed to 60° C., then cooled slowly to room temperature. The precipitate is filtered and rinsed with additional EtOH to afford trans-(R)-2-[4-(benzyloxyethyl)cyclohexyl]pyrrolidine tartaric acid salt as off-white crystal. The tartaric acid salt is dissolved in 1N NaOH aq. and extracted with CH2Cl2, and the organic layer is dried over magnesium sulfate, filtered, and evaporated to afford pure trans-(R)-2-[4-(benzyloxyethyl)cyclohexyl]pyrrolidine.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:19][CH:18]=[CH:17][N:7]2[C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:3].[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[C:23](Br)[N:22]=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH2:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][NH:27]2)=[C:23]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[S:19][CH:18]=[CH:17][N:7]3[C:8](=[O:16])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:3])[N:22]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1ccccc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025 g, 0.092 mmol), 2-amino-6-bromopurine (0.035 g, 0.16 mmol), and N,N-diisopropylethylamine (0.029 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H17N8OS (M+H)+: m/z=405.1. Found: 405.1. 1H NMR (DMSO-d6, 400 MHz) δ 80.1 (1H, d, J=4.8 Hz), 7.65 (1H, s), 7.55 (1H, d, J=4.8 Hz), 7.47 (2H, m), 7.40 (3H, m), 6.79 (1H, br s), 5.48 (2H, br s), 5.13 (1H, m), 1.29 (3H, d, J=6.8 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH2:13])[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:51]CCl>>[ClH:51].[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(N)C1
Reactant: ClCCl
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NCc2ccccc2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of 0.120 g (0.36 mmol) of 9-amino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester in 3.6 ml of dichloromethane was added 0.041 g (0.38 mmol) of benzaldehyde, 0.192 g (0.91 mmol) of sodium triacetoxyborohydride and few drops of glacial acetic acid. The reaction mixture was stirred at room temperature for 15 hours. The residue was dissolved in dichloromethane and a saturated aqueous solution of sodium carbonate, extracted with dichloromethane and washed with saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 97/3/0.3 to give 0.145 g (95%) of pure product. The free base was transformed into its hydrochloride salt.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[NH:27]1[C:35]2[C:30](=[C:31]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1>CS(C)=O.C(OCC)(=O)C.CCCCCC>[NH:27]1[C:35]2[C:30](=[C:31]([N:36]3[CH2:41][CH2:40][N:39]([CH2:11][CH:12]4[O:25][C:16]5=[C:17]6[C:21](=[CH:22][CH:23]=[C:15]5[O:14][CH2:13]4)[NH:20][C:19](=[O:24])[CH2:18]6)[CH2:38][CH2:37]3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1Cc2c(ccc3c2OC(CN2CCN(c4cccc5[nH]ccc45)CC2)CO3)N1
Temperature: 80 °C
Yield: 73.3 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.0 g, 2.7 mmole) and 4-(1H-indol-4-yl)-piperazine (2.0 g, 10 mmole) were combined in 30 ml of dry DMSO and heated to 80° C. for 4 hours under an argon atmosphere. After cooling to room temperature, the mixture was diluted with 400 ml of 1:1 ethyl acetate/hexane and washed with 400 ml of saturated sodium bicarbonate solution, with two 250 ml portions of water and with saturated brine. The mixture was dried over sodium sulfate, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 0.5% methanol/CHCl3 as eluant. The free base of the title compound (0.80 g) thus obtained was crystallized from methanol with the addition of one equivalent of fumaric acid to give 077 g of the (S) enantiomer of the title compound as a white solid fumarate, m.p. 237°-238° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18]I)[O:15][C:14]1=[O:20])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+].C(OCC)(=O)C>CC(C)=O.O>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][N:21]=[N+:22]=[N-:23])[O:15][C:14]1=[O:20])[CH3:2]
Reactant: CCc1ccc2nc(C)[nH]c2c1N1CC(CI)OC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCc1ccc2nc(C)[nH]c2c1N1CC(CN=[N+]=[N-])OC1=O

Procedure:
A mixture of (±)-3-(5'-1-ethyl-2-methylbenzimidazolyl)-5-(iodomethyl)oxazolidin-2-one (XXXVIII, EXAMPLE 69, 0.531 g) and sodium azide (0.618 g) are stirred in acetone/water (2/1, 30 ml) at reflux under a nitrogen overnight. After this time the mixture is poured into ethyl acetate and the layers are separated. The aqueous layer is then extracted with ethyl acetate (2×). All organic layers are combined, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. A small amount of the crude product (oil) is purified on a silica preparative plate (20 cm×20 cm, 1000μ). The plate is eluted in methanol/ethyl acetate (10/90, 5×) to give the title compound as an oil; NMR (CDCl3, 300 MHz) 7.70, 7.53, 7.30, 4.80, 4.15, 3.89, 3.70, 3.60, 2.61 and 3.40 δ; CMR (CDCl3, 75.47 MHz) 13.62, 14.78, 38.62, 48.42, 53.05, 70.60, 109.29, 114.99, 132.1, 132.72, 142.3, 152.8 and 154.9 δ; MS (m/e) 300, 272, 227, 212, 200, 186, 172, 160, 159, 145, 131, 117, 104, 90 and 77; exact mass calcd for C14H16N6O2 =300.1335, found 300.1333.
Reaction SMILES: CC[N:3](C(C)C)[CH:4]([CH3:6])[CH3:5].[NH:10]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11]1.C(N)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:4]([NH:3][C:15]([C:12]1[CH:13]=[CH:14][NH:10][CH:11]=1)=[O:17])([CH3:6])[CH3:5]
Reactant: O=C(O)c1cc[nH]c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)c1cc[nH]c1
Reaction time: 0.33 h

Procedure:
DIPEA (284 mg, 381 uL, 2.2 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid (111 g, 1.0 mmol) and isopropylamine (118 mg, 170 uL, 2.0 mmol) in DMF (10 mL) at 0° C. Stirring for 20 min, HATU (570 g, 1.5 mmol) was added at 0° C. The reaction mixture was stirred overnight at room temperature, diluted with EtOAc (100 mL), washed with H2O (3×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc on silica gel. Yield: 80 mg (52%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.19 (d, J=6.64 Hz, 6 H), 3.95-4.31 (m, 1 H), 6.52 (dd, J=2.93, 1.56 Hz, 1 H), 6.70 (dd, J=2.93, 2.15 Hz, 1 H), 7.31 (t, J=1.76 Hz, 1 H), 7.58 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[NH2:9][C:10]([CH3:14])([CH3:13])[CH2:11]O.C1(C)C=CC=CC=1.[C:22](O)(=[O:25])[CH2:23][CH3:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][C:10]([NH:9][C:22](=[O:25])[CH2:23][CH3:24])([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CCC(=O)O
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCC(=O)NC(C)(C)CSc1ccc(Cl)cc1

Procedure:
A solution of 4-chlorothiophenol (64.8 g), 2-amino-2-methylpropanol (39.8 g) and toluene (160 ml) was treated with propionic acid (33.2 g) and the mixture boiled under reflux for 24 hours, collecting the water formed using a Dean and Stark apparatus. The mixture was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, dilute sodium hydroxide solution and then water. The organic layer was dried, filtered and evaporated to give an oil which was dried under high vacuum at 70° C. The oil, which solidified on standing, was dissolved in ether and treated with ethereal hydrogen chloride to give N-[2-(4-chlorophenylthio)-1,1-dimethylethyl]propionamide.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[OH2:15].[C:16]([OH:19])(=O)[CH3:17]>>[C:4]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:16](=[O:19])[C:17]4=[CH:5][CH:6]=[CH:1][CH:2]=[C:3]4[C:4]3=[O:15])=[CH:10][CH:9]=2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: CC(=O)O
Reactant: O
Product: O=C1c2ccccc2C(=O)N1c1ccc(Nc2ccccc2)cc1

Procedure:
In a four-necked reactor equipped with a cooler and a thermometer, 80 g (0.42 mol) of trimellitic anhydride and 76.7 g (0.42 mol) of 4-aminodiphenylamine were dissolved in a liter of acetic acid under a nitrogen gas stream. This solution was allowed to react while heated to reflux for 10 hours in an oil bath. After completion of the reaction, the reaction liquid was poured into two liters of water, and a reaction product was precipitated. Thereafter, the reaction product as a precipitated solid was suction filtered. The filter cake was washed sequentially with water and methanol, and then was dried in a vacuum dryer. Thus, 138.5 g of a purified reaction product was obtained as a yellow-green solid (yield in Step 1: 92%). In this manner, an Intermediate F formed from an N-(4-phenylaminophenyl)-phthalimide compound having a carboxyl group at the 4-position, as represented by the following formula (7):
Reaction SMILES: C(O)(C(F)(F)F)=O.C[Si](C)(C)CCOC[N:14]1[C:18]2[N:19]=[CH:20][N:21]=[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:33][CH2:32][C:31](=[CH:34][C:35]#[N:36])[CH2:30][CH2:29]4)[CH:27]=3)[C:17]=2[CH:16]=[CH:15]1.[OH-].[NH4+]>CC#N.O>[N:19]1[C:18]2[NH:14][CH:15]=[CH:16][C:17]=2[C:22]([C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:29][CH2:30][C:31](=[CH:34][C:35]#[N:36])[CH2:32][CH2:33]3)[CH:27]=2)=[N:21][CH:20]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4CCC(=CC#N)CC4)c3)ncnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: N#CC=C1CCC(n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Reaction time: 16 h

Procedure:
A solution of TFA (0.5 mL, 0.006 mol) and 4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylideneacetonitrile (22.7 mg, 0.0000522 mol), was stirred for 1.5 h. The solution was then concentrated using a rotary evaporator to remove TFA. LCMS analysis showed conversion to the hydroxymethyl intermediate, M+H 335. Methanol was added; and the methanol mixture was concentrated again using a rotary evaporator. The resulting residue was dissolved in methanol (1 mL) and ammonium hydroxide (0.25 mL, 0.0064 mol) was added. The resulting solution was stirred for 16 h. LCMS analysis showed complete de-protection. The solution was then concentrated using a rotary evaporator. The product was isolated by prep HPLC using a 30 mm×100 mm C18 column; 18% CH3CN—H2O (0.1% TFA), 1 min, to 35% at 6 min; 60 mL/min; detector set at 254 nm; retention time, 4.4 min. The eluate was freeze dried. yield 7.6 mg of a white solid (TFA salt; racemic; 34.6%). 1H NMR (d6 DMSO) δ 12.9 (br s, 1H, NH); 8.9 (s, 2H); 8.5 (s, 1H); 7.8 (m, 1H); 7.3 (m, 1H); 5.6 (s, 1H, olefin); 4.6 (m, 1H, NCH); 2.8 (m, 1H); 2.6 (m, 1H); 2.5 (m, 2H); 2.3 (m, 2H) 2.0 (m, 2H). MS(ES) 305 (M+1).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=1)[C:14]#[N:15].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)#[CH:18]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])[CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cncc(C#Cc2cccc(C(F)(F)F)c2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
Add triethylamine (1.93 mL, 13.64 mmol), copper (I) iodide (37.3 mg, 0.190 mmol) and bis(triphenylphosphine)palladium (II) dichloride (120 mg, 0.170 mmol) to a solution of 5-bromonicotinonitrile (624 mg, 3.41 mmol) and 1-ethynyl-3-trifluoromethylbenzene, (prepared essentially as described in PREPARATION 13), (580 mg, 3.41 mmol) in ethyl acetate (3 mL). Stir in a sealed tube at 50° C. for 18 h, concentrate and purify by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate to give the title compound (400 mg, 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([CH2:20][C:21](OCC)=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C>C1(C)C(C)=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:21](=[O:22])[CH2:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1C
Solvent: CCO
Product: Nc1ccc(NC(=O)CC(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
15.3 gm (0.1 mol) of 1,4-diamino-2-nitrobenzene were suspended in 100 ml of xylol. This suspension was heated. After the addition thereto of 42.3 gm (0.22 mol) of ethyl benzoylacetate, this suspension was heated on an oil bath at 130°C with the simultaneous distillation of ethanol, formed in the reaction. The precipitate was separated from the cold reaction mixture and processed, as described in Example I. The product had a melting point of 182°-183°C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]2=[N:11][C:12]([Sn](C)(C)C)=[CH:13][N:14]=[C:9]2[NH:8][CH2:7][C:6]1=[O:19].Br[C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[N:31]=[CH:30][N:29](C3CCCCO3)[N:28]=2)=[CH:25][CH:26]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]2=[N:11][C:12]([C:21]3[C:22]([CH3:38])=[N:23][C:24]([C:27]4[NH:31][CH:30]=[N:29][N:28]=4)=[CH:25][CH:26]=3)=[CH:13][N:14]=[C:9]2[NH:8][CH2:7][C:6]1=[O:19]
Reactant: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Reactant: COCCN1C(=O)CNc2ncc([Sn](C)(C)C)nc21
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCN1C(=O)CNc2ncc(-c3ccc(-c4nnc[nH]4)nc3C)nc21
Temperature: 130 °C
Reaction time: 3 h
Yield: 10.1 %

Procedure:
1-(2-Methoxyethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.5 g, 1.348 mmol), 3-bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (0.436 g, 1.348 mmol), tris(dibenzylidineacetone)dipalladium(0) (0.123 g, 0.135 mmol), tri-o-tolylphosphine (0.082 g, 0.270 mmol), triethylamine (0.584 mL, 4.04 mmol) and N,N-dimethylformamide (10 mL) were combined in a 75 mL sealable flask, the atmosphere in the flask was removed and replaced with nitrogen. The mixture was stirred at 130° C. for 3 h. The resulting mixture was cooled to room temperature and filtered. The organic layer was concentrated under reduced pressure. The resulting residue was diluted with methanol and dimethylsulfoxide, filtered and purified using reverse-phase preparatory HPLC (10-30% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing clean product were passed through a Phenomenex Strata-X—C solid phase extraction column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol eluent and was concentrated under reduced pressure. The residue was triturated with ethyl ether in hexane to make a fine powder and dried under vacuum at 50° C. to give the desired product (0.05 g, 0.136 mmol, 10% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.10 (br. s., 1H), 7.98 (br. s., 1H), 7.94 (s, 1H), 7.73 (br. s., 1H), 4.13-4.28 (m, 4H), 3.55 (t, J=6.25 Hz, 2H), 3.24 (s, 3H), 2.70 (br. s., 3H); MS (ESI) m/z 367.2[M+1]+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH:3]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[O:4][C:5]1[N:10]=[C:9]2[CH:11]=[N:12][CH:13]=[CH:14][C:8]2=[N:7][C:6]=1[NH2:15].[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26].[H-].[Na+].O>C1COCC1.C(OCC)(=O)C>[F:23][C:2]([F:1])([F:22])[CH:3]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[O:4][C:5]1[N:10]=[C:9]2[CH:11]=[N:12][CH:13]=[CH:14][C:8]2=[N:7][C:6]=1[NH:15][S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1nc2ccncc2nc1OC(c1cccnc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCS(=O)(=O)Nc1nc2ccncc2nc1OC(c1cccnc1)C(F)(F)F
Temperature: 80 °C
Yield: 30.2 %

Procedure:
3-[2,2,2-Trifluoro-1-(pyridin-3-yl)ethoxy]-pyrido[3,4-b]pyrazin-2-amine (100 mg, 0.310 mmol) obtained in Step 2 was dissolved in THF (2.50 mL). To this, propane-1-sulfonyl chloride (0.094 mL, 0.840 mmol) and 60% sodium hydride (in oil) (23.0 mg, 0.560 mmol) were added, and the mixture was stirred with heat at 80° C. for 4 hours. The reaction was stopped by addition of water to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=1/0 to 16/1) was performed to give Compound 361 (40.0 mg, yield: 30%).
Reaction SMILES: [Cl:1]C1C=CC(OC)=C([C@@]2(F)C3C(=CC(C(F)(F)F)=CC=3)N(C([NH:23][C@@H:24]([CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=O)C2=O)C=1.C(N(CC)CC)C>>[ClH:1].[C:28]([O:27][C:25](=[O:26])[C@H:24]([CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH2:23])([CH3:30])([CH3:31])[CH3:29]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Product: Cl
Yield: 50 %

Procedure:
(S)-di-tert-butyl 2-((S)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indoline-1-carboxamido)succinate (XVIII2): Following general procedure (F), after forming the intermediate, (L)-Aspartic acid di-t-butyl ester hydrochloride (0.391 g, 1.39 mmol) and triethylamine (0.39 mL, 2.78 mmol) were added. After work-up and purification, 0.44 g of the title compound as white foam solid was obtained (50% yield). mp: 63–66° C. MS: 631 (MH+). Anal. Calcd. for C29H31ClF4N2O7: C, 55.20; H, 4.95; N, 4.44. Found: C, 55.07; H, 4.63; N, 4.27. 1H NMR (CDCl3): δ 1.44 (s, 9H), 1.51 (s, 9H), 2.87 (dd, J-16.8 Hz, 4.8 Hz, 1H), 3.01 (dd, J=16.8 Hz, 4.8 Hz, 1H), 3.52 (s, 3H), 4.78 (dt, J=7.8 Hz, 4.7 Hz, 1H), 6.75 (dd, J=8.8 Hz, 1.2 Hz, 1H), 7.25 (m, 1H), 7.35 (dd, J=8.7 Hz, 2.6 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.80 (dd, J=2.6 Hz, 0.9 Hz, 1H), 8.6 (s, 1H), 9.02 (d, J=7.7 Hz, 1H). IR (KBr, cm−1): 3338, 2982, 2942, 1766, 1733, 1520, 1491, 1440, 1319, 1262, 1170, 1132.