Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=1.[CH:40]12[N:47]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH:44]([CH2:45][CH2:46]1)[CH2:43][NH:42][CH2:41]2.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=[C:2]([N:42]2[CH2:41][CH:40]3[N:47]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH:44]([CH2:45][CH2:46]3)[CH2:43]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-3-(6-phenylpyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (226 mg, 0.39 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 1.56 mmol), NaHCO3 (196 mg, 2.33 mmol) in NMP (4 mL) was heated at 130° C. overnight. The mixture was cooled to room temperature and diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation of solvent afforded the crude displacement compound. Purification by column chromatography afforded tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: LCMS tR=3.38 Min (5 min run, UV254nm). Mass calculated for, M+H 758.4, observed m/z 758.3 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C-]#[N:13].[Na+].O>C(O)C>[C:6]1([CH2:5][CH2:4][CH2:3][C:2]#[N:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [C-]#N
Reactant: BrCCCCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCCCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 1-bromo-4-phenylbutane (58.8 g, 0.24 mole) and sodium cyanide (25 g, 0.5 mole) in ethanol (300 ml)-water (100 ml) is heated at reflux with stirring for 5 hours. The resulting reaction mixture is concentrated in vacuo and extracted with ether. The ethereal extract is filtered and evaporated at reduced pressure to afford the title compound which is purified by distillation.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:21])[CH3:20]
Reactant: Nc1ccc2ccccc2c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-naphthylamine (1.43 g, 10 mmol) and triethylamine (1.11 g, 11 mmol) in 10 mL of CH2Cl2 is cooled to 0° C. under an atmosphere of nitrogen. To this solution is added dropwise a solution of acetyl chloride (0.86 g, 11 mmol) in 10 mL of CH2Cl2. The mixture is allowed to warm to room temperature and stirred overnight. The mixture is concentrated in vacuo and then 1 N HCl is added to the residue to bring the mixture to pH 4. The mixture is extracted 3 times with 20 mL of EtOAc and the combined organic layers are washed with 20 mL each of H2O, saturated aqueous NaHCO3 and saturated brine. The organic layer is dried over MgSO4, filtered and the solvents are removed in vacuo to give 2-acetylaminonaphthalene as a solid which is used without further purification. A solution of NaClO3 in (0.33 g, 30 mmol) in 0.77 mL of H2O is added dropwise to a mixture of 1.0 g of 2-acetylaminonaphthalene in 5 mL of concentrated HCl and 6 mL of HOAc at 0° C. The mixture is allowed to warm to room temperature and stirred overnight under an atmosphere of nitrogen. The mixture is poured over 20 g of ice and is extracted three times with 20 mL of CH2Cl2. The combined organic layers are washed with 20 mL each of water, saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The mixture is filtered and the solvents are removed in vacuo to give an oil which is purified by flash chromatography on silica gel (CH2Cl2) to give 1-chloro 2-acetylaminonaphthalene as a solid. A mixture of 0.17 g (0.77 mmol) of 1-chloro 2-acetylaminonaphthalene in 3.9 mL of 6 N HCl is heated to 85° C. and is stirred for 8 hours. The mixture is cooled to 0° C. and solid Na2CO3 is carefully added to bring the mixture to pH 8. The mixture is extracted 3 times with 20 mL of CH2Cl2. The combined organic layers are washed with 15 mL of saturated brine, dried over Na2SO4 and the solvents are removed in vacuo to give 1-chloro 2-aminonaphthalene as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:6][N:5]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Br.[Cl-].[Na+]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[O:20]1[CH2:19][CH:18]1[CH2:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[O:8][C:4]([CH3:3])=[N:5][N:6]=1
Reactant: Cc1nnc(-c2ccccc2O)o1
Reactant: BrCC1CO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccccc2OCC2CO2)o1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
1.6 g of sodium hydride, in the form of a 55% strength suspension in paraffin oil (0.036 mole) are introduced into 70 ml of anhydrous tetrahydrofuran and 6.3 g (0.036 mole) of ortho-(5-methyl-1,3,4-oxadiazol-2-yl)-phenol, dissolved in 50 ml of tetrahydrofuran, are added dropwise. 5 g (0.036 mole) of epibromohydrin are then introduced dropwise, 10 ml of hexamethylphosphorotriamide are added to the reaction mixture, and the whole is stirred for 32 hours at room temperature. Thereafter, the reaction mixture is poured into 500 ml of aqueous sodium chloride solution and repeatedly extracted by shaking with diethyl ether. The combined ether extracts are dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil. This crystallizes on triturating with a toluene/hexane mixture. 5.5 g (66% of theory) of colorless crystals are obtained; melting point 38°-40° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC([OH:17])CCCCCC.CCC(O)CCCCC>>[CH3:1][CH2:2][CH2:3][CH:4]([OH:17])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)O
Reactant: CCCCCCCC
Solvent: CCCCCC(O)CC
Product: CCCCC(O)CCC

Procedure:
A further selective hydroxylation reaction was carried out with the sol-gel-embedded CYP BM-3 on the substrate n-octane. 79% of the precursor were hydroxylated. The regio isomers 2-octanol, 3-octanol and 4-octanol were obtained in a molar ratio of 1:2.1:1.6 (detected by gas chromatography).
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[CH:21]=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].Cl.[NH2:29][OH:30]>O>[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[CH:21]=[N:29][OH:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1c(OCc2ccccc2)ccc2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=Cc1c(OCc2ccccc2)ccc2ccccc12
Yield: 97.8 %

Procedure:
To 460 ml of methanol and 150 ml of water were added 120 g (0.46 mole) of 2-benzyloxy-1-naphthaldehyde, 75 g (0.92 mole) of sodium acetate and 48 g (0.69 mole) of hydroxylamine hydrochloride, and the mixture was refluxed by heating for 2 hours. After the reaction, the reaction mixture was added to 1.5 liters of water. The precipitated crystals were collected by filtration to obtain 125 g (0.45 mole) of 2-benzyloxy-1-naphthaldoxime.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH2:13][CH2:12][CH2:11]1)[C:5]#[N:6].[C:19]1(C)C=CC=CC=1>>[CH3:19][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH2:13][CH2:12][CH2:11]1)[C:5]#[N:6]
Reactant: Cc1ccccc1
Reactant: N#Cc1ccc(C2CCCc3cncn32)c(Br)c1
Product: Cc1cc(C#N)ccc1C1CCCc2cncn21

Procedure:
3-Bromo-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrile, prepared above, is converted to the corresponding toluene by the method outlined in Tet. Lett. 2000, 41, 6237. MS (ESI) m/z 238.1 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.77-1.89 (m, 2 H), 1.91-2.00 (m, 1 H), 2.29-2.39 (m, 1 H), 2.45 (s, 3 H), 2.86-2.93 (m, 2 H), 5.71 (t, J=6.1 Hz, 1 H), 6.77 (d, J=8.1 Hz, 1 H), 6.81 (s, 1 H), 7.29 (s, 1 H), 7.49 (d, J=8.1 Hz, 1 H), 7.61 (s, 1 H).
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[Si:14]([O:21][C@@H:22]1[C@@H:27]([CH3:28])[CH2:26][NH:25][CH2:24][C@H:23]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CCO>[Si:14]([O:21][C@@H:22]1[C@@H:27]([CH3:28])[CH2:26][N:25]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:24][C@H:23]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Yield: 80.1 %

Procedure:
To a mixture of 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (110.4 mg, 0.3780 mmol) and tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (from Example 28, Step 7, 100.0 mg, 0.2902 mmol) was added EtOH (2.0 mL) followed by DIPEA (163.8 mg, 1.267 mmol). The reaction mixture was heated at 100° C. for 15 h, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to afford the sub-title compound as a yellow solid (118.2 mg, 80%). LCMS calc. for C24H41N4O6Si (M+H)+: m/z=509.3. found 509.3.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][C:12]#[N:13])=[O:9])=[CH:6][CH:5]=1.BrBr.[C:18](OCC)(=[O:20])[CH3:19]>BrBr>[CH3:1][O:2][CH2:3][C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH:11]([O:20][CH2:18][CH3:19])[C:12]#[N:13])=[O:9])=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: COCc1ccc(C(=O)NCC#N)cc1
Agent: BrBr
Product: CCOC(C#N)NC(=O)c1ccc(COC)cc1
Temperature: 30 °C

Procedure:
A solution of 2-(4-methoxymethylbenzoylamino)acetonitrile (5.0 g) in dry ethyl acetate (40 ml) was treated with a couple of drops of bromine and stirred at 30° C. until initiation of the reaction occurred. The bromine was then added dropwise keeping the temperature at 25°-30° C. After completion of the addition the mixture was filtered through celite, and the filtrate treated with ethanol (5 ml), with stirring, followed by triethylamine (5.0 g), at room temperature. After completion of the addition the mixture was stirred for 5 minutes, filtered through celite, and washed with water, dried over magnesium sulphate and evaporated at less than 30° C., giving a brown oil, (5.0 g). This was purified by preparative HPLC to yield the product as white needles (1.6 g), mpt 99°-100° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=2)=[CH:2]1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1.C(N)CN.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][C:21]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=3)=[CH:2]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(-c2cc[nH]c2)cc1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Product: COC(=O)c1ccc(-c2ccn(-c3ccc(C(F)(F)F)cc3)c2)cc1
Yield: 52.6 %

Procedure:
To a stirred solution of methyl 4-(1H-pyrrol-3-yl)-benzoate (402 mg, 1.997 mmol, 1.0 eq.) and 4-trifluoromethyl-1-iodobenzene (652 mg, 2.39 mmol, 1.2 eq.) in anhydrous 1,4-dioxane (15 mL) is added copper(I) iodide (38 mg, 0.199 mmol, 0.1 eq.), ethylenediamine (13 μL, 0.199 mmol, 0.1 eq.) and potassium triphosphate (762 mg, 1.66 mmol, 3.31 eq.). The reaction mixture is degassed, flushed with nitrogen and heated to reflux for 18 hr. The reaction mixture is cooled, filtered and washed with ethyl acetate. The filtrate is concentrated and purified by silica gel chromatography (10% ethyl acetate/hexane) to get a white powder, methyl 4-[1-(4-trifluoromethyl-phenyl)-1H-pyrrol-3-yl]-benzoate (363.2 mg, 1.05 mmol, 52.7%). MS (ES+): m/e 345.11. 1H NMR (300 MHz, CDC3): δ 8.04 (2H, d, J=8 Hz), 7.72 (2H, d, J=8 Hz), 7.63 (2H, d, J=8 Hz), 7.54 (2H, d, J=8 Hz), 7.50 (1H, m), 7.18 (1H, m), 6.75 (1H, m), 3.93 (3H, s).
Reaction SMILES: [PH2](O)=O.[CH2:4]([O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16](N)=[N:17][N:18]2[CH2:21][C@H:22]([OH:24])[CH3:23])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N(OCC(C)C)=O>CO.O>[CH2:4]([O:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH2:21][C@H:22]([OH:24])[CH3:23])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@@H](O)Cn1nc(N)c2ccc(OCc3ccccc3)cc21
Agent: CC(C)CON=O
Agent: O=[PH2]O
Solvent: O
Solvent: CO
Product: C[C@@H](O)Cn1ncc2ccc(OCc3ccccc3)cc21
Reaction time: 3 h

Procedure:
Hypophosphorous acid (3.45 L of a 50% (w/w) aqueous solution) was added to a stirred solution of 2 (1975 g, 6.65 mol) in 23.7 L of methanol under a nitrogen atmosphere. Isobutyl nitrite (1576 mL, 13.3 mol) was added in two portions, keeping the reaction temperature below 53° C. After 3 hours, a solution of Na2HPO4 (8.5 kg) in 70 L of water was added, and the mixture was extracted with ethyl acetate (30 L then 15 L). The combined organic extracts were washed with brine, dried (Na2SO4), treated with decolorizing charcoal, filtered and concentrated in vacuo. The product was purified by trituration with ethyl acetate-hexane followed by elution through silica using an acetone-hexane gradient, to give after concentration in vacuo, 1260 g (67%) of 3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH2:19])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.I.[NH2:33][C:34]1[C:35]([C:42]([NH:44][C:45](=[NH:48])SC)=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1>C(O)C>[NH2:33][C:34]1[C:35]([C:42]([N:44]=[C:45]([NH2:48])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([S:12]([NH:15][C@@H:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH2:19])=[O:18])(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[O:43])=[N:36][C:37]([Cl:41])=[C:38]([NH2:40])[N:39]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(CCCCN)cc1)C(N)=O
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1)C(N)=O
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of (2S)-[4-(4-aminobutyl)benzenesulfonylamino]-3-methylbutyramide 15 (156 mg, 0.47 mmol), diisopropylethylamine (0.60 mL, 3.0 mmol), and 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (230 mg, 0.61 mmol) in absolute ethanol (8 mL) was stirred at 70° C. for 5 h and then cooled to room temperature. The reaction mixture was concentrated by rotary evaporation. The crude residue was washed with water, filtered and the crude solid product was purified by flash silica gel column chromatography eluting with chloroform/methanol/concentrated ammonium hydroxide (5:1:0.1, v/v) to give the desired product as a yellow solid (137 mg, 54% yield). Part of the solid (86 mg) was further purified by semi-preparative HPLC (acetonitrile/water/0.1% TFA) to give the analytical pure sample which was then co-evaporated with 5% aqueous HCl to give the hydrochloride salt 16. mp 154-156° C. (decomposed). 1H NMR (300 MHz, CD3OD) δ 0.85 (d, 3H), 0.86 (d, 3H), 1.70 (m, 4H), 1.90 (m, 1H), 2.75 (m, 2H), 3.32 (m, 2H), 3.52 (d, 1H), 7.35 (d, 2H), 7.75 (d, 2H). m/z (ESI): 540 [C21H30ClN9O4S+H]+. [α]D25+5.2° (c 0.50, MeOH).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[CH2:33][O:32][CH2:31][CH2:30][NH:29]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[CH2:33][O:32][CH2:31][CH2:30][N:29]4[C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(CC3COCCN3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCOCC1Cc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-(morpholin-3-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.23 mmol), N,N-dimethylglycine (25 mg, 0.24 mmol), EDCl (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), and N,N-diisopropylethylamine (119 μL, 0.68 mmol) in DMF (1.2 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 50 mg (42%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.52-8.57 (m, 1 H), 7.88-7.96 (m, 1H), 7.76-7.84 (m, 1 H), 7.48-7.55 (m, 1 H), 7.26-7.39 (m, 5 H), 7.04-7.11 (m, 1 H), 6.58-6.63 (m, 1 H), 5.64 (s, 2 H), 4.43-4.89 (m, 1 H), 3.69-4.12 (m, 3 H), 3.24-3.57 (m, 4 H), 3.09-3.23 (m, 1 H), 2.72-2.99 (m, 1 H), 2.15-2.27 (m, 1 H), 1.88-1.99 (m, 6H); ES-MS m/z 525.15 [M+H]+, HPLC RT (min) 2.17.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:3]1.[NH2:28][OH:29].Cl.C([O-])([O-])=O.[Na+].[Na+]>CO>[OH:29][NH:28][C:11](=[NH:12])[C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([CH:6]2[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:4]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:3][C:2](=[O:1])[NH:7]2)[CH:9]=1
Reactant: N#Cc1cccc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1cccc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)c1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
A mixture of 3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile (700 mg, 2 mmol, 1 eq), NH2OH—HCl (144 mg, 2.2 mmol, 1.1 eq) and Na2CO3 (414 mg, 4.0 mmol, 2.0 eq) in methanol (5.0 mL) was heated to reflux overnight. The mixture was cooled to room temperature and filtered. The filtered mass was washed with methanol (5.0 mL) and purified by prep-HPLC to afford Compound 99 as a yellow solid (150 mg, 19.5%) and Compound 98 as a white solid (6.7%). Data for Compound 99: 1H NMR (MeOH-d4 500 MHz TMS): δ 7.69-7.72 (m, 2H), 7.58-7.61 (m, 2H), 7.26 (br, 5H), 7.04 (br, 2H), 6.88 (br, 2H), 5.51 (s 1H); MS (ESI): m/z 385.1.1 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:6][CH:5]=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:43]=1[S:49](Cl)(=[O:51])=[O:50]>>[CH:24]([N:16]1[C:17]2[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:10]([CH3:11])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:40])=[CH:9][CH:8]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:49]([C:43]1[C:44]([CH3:48])=[CH:45][CH:46]=[CH:47][C:42]=1[Cl:41])(=[O:50])=[O:51])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Product: Cc1cccc(Cl)c1S(=O)(=O)NCCc1c(CCN(C)c2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
The intermediate from Example 147 step 7 was treated with 2-chloro-6-methyl-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 96% yield.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg+].[Br-]>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH3:27])[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: C[Mg+]
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cc2c(c(C)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reaction time: 24 h
Yield: 41.3 %

Procedure:
To a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) in THF (3 mL) was added Ni(dppp)Cl2 (24 mg, 0.044 mmol) at room temperature. After stirring for a few minutes MeMgBr (3M, 0.59 mL, 1.76 mmol) was added and the mixture was allowed to stir for 24 h. The mixture was quenched with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided 2-anilino-5,7-dimethyl-1-phenyl-1,6-naphthyridin-4(1H)-one (31 mg, 40%): LCMS RT: 1.51 min, MH+: 342.4.
Reaction SMILES: [CH:1]1([CH:4]([NH2:8])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl.O.O>[CH:1]1([CH:4]([NH:8][C:15](=[O:16])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COCC(N)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCC(NC(=O)OCc1ccccc1)C1CC1
Temperature: 17.5 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Crude 1-cyclopropyl-2-methoxyethanamine from the previous step was dissolved in CH2Cl2/H2O (300 mL/300 mL) and Na2CO3 (111.9 g, 1.06 mol) was added. The reaction mixture was placed in an ice bath and CbzCl (16.46 g, 96.78 mmol) was added via syringe. During the addition, the internal reaction mixture temperature was maintained at 15-20° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The mixture was poured into a separatory funnel, diluted with H2O, (300 mL), and extracted with CH2Cl2 (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate in hexanes) to furnish benzyl 1-cyclopropyl-2-methoxyethylcarbamate (17.2 g, 78% yield for 2 steps) as an oil which crystallized upon standing: mp 190.5-192° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.29 (m, 5H), 7.17 (d, J=8.5 Hz, 1H), 5.00 (s, 2H), 3.36-3.34 (m, 2H), 3.23 (s, 3H), 3.19-3.14 (m, 1H), 0.85-0.79 (m, 1H), 0.43-0.37 (m, 1H), 0.35-0.22 (m, 2H), 0.20-0.16 (m, 1H), LRMS (ESI) m/e 250.3 [(M+H)+, calcd for C14H20NO3 250.1].