Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]1[CH:13](O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=2)[C:6]1=[O:19])(C)(C)C.C(O)(=O)C.O.[NH2:25]N>O>[C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:19])[NH:25][N:5]=[CH:13]2)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1ccc2c(c1)C(O)N(C(C)(C)C)C2=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2c(=O)[nH]ncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
In a 250 mL round-bottomed flask, 2,5-di-tert-butyl-3-hydroxyisoindolin-1-one (4.9 g, 18.7 mmol, Eq: 1.00) was combined with acetic acid (60 ml) to give a colorless solution. The reaction was heated to 90° C. Hydrazine monohydrate (1.61 g, 1.57 ml, 20.6 mmol, Eq: 1.1) was added dropwise. The reaction was stirred at 90° C. for 1 h. The reaction mixture was diluted with 24 mL H2O and slowly cooled to 25° C. over 3 h. The reaction mixture was concentrated but not quite to dryness. The reaction mixture was taken up in dichloromethane. The reaction mixture was poured into 75 mL sat NaHCO3 and extracted with dichloromethane (3×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. to give pure product as a white solid, which was purified by flash chromatography (silica gel, 80 g, 1% to 4% MeOH in DCM) to afford the desired product (3.7 g) as a white solid. (M+H)+=203 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.32 (s, 9 H) 6.58 (d, J=1.89 Hz, 1 H) 6.76 (dd, J=8.31, 1.89 Hz, 1 H) 7.06 (s, 1 H) 7.26 (d, J=8.31 Hz, 1 H) 9.19 (br. s., 1 H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:16]3[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=3)[CH2:21][CH2:22]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: c1cc(CN2CCNCC2)ccn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-[(4-pyridyl)-methyl]-piperazine (0.097 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as an orange solid (0.080 g). The filtrate was concentrated in vacuo, and purification of the residue on a isolute silica column using 1 to 5% methanol in ethyl acetate as eluant gave an additional 0.055 g of the product (total yield: 68%); 1H-NMR (500 MHz, DMSO-d6) 2.53 (br s, 4H, piperazine N(CH2)2), 3.08 (br s, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2), 6.97 (s, 2H, NH2), 7.34 (d, J=5.88 Hz, 2H), and 8.51 (d, J=4.48 Hz, 2H) (pyrid-4-yl protons), 8.16 (s, 1H, 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.00 min—393, 395 [(M+H)+, Br isotopic pattern].
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][C:20]=4[F:35])[C:16](O)=[O:17])[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:3][CH2:2]1.Cl.[CH3:38][N:39](C)[CH2:40]CCN=C=NCC.Cl.CNC>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:10][CH2:11][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][C:20]=4[F:35])[C:16]([N:39]([CH3:40])[CH3:38])=[O:17])[CH2:13][CH2:14]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:3][CH2:2]1
Reactant: O=C(O)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A solution of 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetic acid (0.153 mmol) in dichloromethane (1 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.230 mmol) and 4-(dimethylamino)pyridine (0.766 mmol). This mixture was stirred at room temperature for 10 min at which point dimethylamine hydrochloride (0.306 mmol) was added. The reaction vessel was sealed and the reaction was stirred at room temperature overnight. At this point an additional portion of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.230 mmol) was added. The reaction vessel was sealed and the reaction was stirred at room temperature overnight. The resulting reaction mixture was concentrated to dryness under a stream of nitrogen. Purification of the residue by reverse phase HPLC (20-65% acetonitrile/water with 0.1% NH4OH) followed by chiral HPLC (Chromegachiral CC4, methanol) and lyophilization from water (w/25% acetonitrile) afforded the title compound as a solid (25 mg, 30%). MS(ES)+ m/e 517.4 [M+H]+, >99% ee, αD=−69 deg (c=0.01, methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=[S:31]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCNC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCNC1=S
Temperature: 100 °C
Reaction time: 8 h
Yield: 127.6 %

Procedure:
To a mixture of ethyl 3-(3,4-difluorobenzyl)-2-oxopiperidine-3-carboxylate (2.8 g) in toluene (50 mL) was added Lawesson's reagent (2.67 g) at room temperature, and the mixture was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.64 g).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])C(=O)OC(C)(C)C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:20][CH2:21][CH2:22][NH:23][CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCNCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.8 %

Procedure:
The resulting tert-butyl N,N-bis(2-((Z)-octadec-9-enoyloxy)ethyl)carbamate (1.22 g, 1.66 mmol) was dissolved in dichloromethane (30 mL), and stirred at room temperature for 3.5 hours after adding trifluoroacetic acid (2.56 mL, 33.2 mmol). The aqueous layer was extracted with chloroform after adding a saturated sodium bicarbonate aqueous solution to the reaction solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 96/4) to give compound 73 (998 mg, 94.6%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[C:16]([NH2:29])[N:15]=2)[CH2:12][CH2:11][CH2:10]1.O>C(Cl)(Cl)Cl>[Br:1][C:19]1[N:20]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:21]2[C:17]([N:18]=1)=[C:16]([NH2:29])[N:15]=[C:14]([O:13][CH:9]1[CH2:12][CH2:11][CH2:10]1)[N:22]=2
Reactant: Nc1nc(OC2CCC2)nc2c1ncn2C1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc(OC2CCC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 25 °C
Yield: 112.8 %

Procedure:
N-Bromosuccinimide (1.152 g, 6.47 mmol) was added to a stirred solution of 2-(cyclobutyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.248 g, 4.31 mmol) in chloroform (15 ml) at 0° C. The mixture was warmed to room temperature and left overnight when water (15 ml) was added and the phases separated. The aqueous layer was extracted with dichloromethane and the organic extracts were combined, washed with brine, dried over anhydrous magnesium sulphate and evaporated to give the title compound as an orange foam (1.79 g).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:11]=2)[CH2:6]1.O[Li].O>O1CCOCC1.O>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[NH:19][CH2:18][CH2:17][CH2:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([CH2:4][C:3]([OH:26])=[O:2])[CH2:14][CH2:13]2
Reactant: COC(=O)CC1CCc2cc(OCCCNc3ncccn3)ccc2C1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC1CCc2cc(OCCCNc3ncccn3)ccc2C1
Temperature: 100 °C
Yield: 16.2 %

Procedure:
To a solution of {6-[3-(pyrimidin-2-ylamino)-propoxy]-1,2,3,4-tetrahydro-naphthalen-2-yl}-acetic acid methyl ester (0.09 g) in 1,4-dioxane (5 mL) was added a solution of LiOH.H2O (0.04 g) in H2O (2 mL) and the reaction was heated to 100° C. for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue and the mixture was cooled in an ice bath. The mixture was brought to pH 5 by the addition of 1N HCl. The aqueous suspension was extracted with CH2Cl2 and CHCl3. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using silica gel chromatography. Elution with 10% MeOH/CH2Cl2 gave the title compound as a white solid (14 mg). NMR (300 MHz, MeOH-d4) δ8.24 (broad s, 2H), 7.32 (broad s, 1H), 6.82 (d, J=8.25 Hz, 1H), 6.68-6.63 (m, 2H), 6.52 (t, J=4.76 Hz, 1H), 4.08 (t, J=6.11 Hz, 2H), 3.63 (d, J=5.59 Hz, 2H), 2.83 (dd, J=15.90, 3.70 Hz, 1H), 2.71 (d, J=3.32 Hz, 2H), 2.42-2.34 (m, 3H), 2.11 (dd, J=11.82, 5.88 Hz, 3H), 1.90 (d, J=11.76 Hz, 1H), 1.46-1.32 (m, 1H); MS (+ESI) m/z 342 (M+H)+; Calculated for C19H23N3O3.0.5 H2O: C, 64.94; H, 6.88; N, 11.96. Found: C, 65.43; H, 6.72; N, 11.48.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:16](O)([CH3:19])([CH3:18])[CH3:17]>FC(F)(F)C(O)=O>[C:16]([C:5]1[NH:6][C:7]2[C:12](=[CH:11][C:10]([C:4]([CH3:12])([CH3:5])[CH3:3])=[CH:9][C:8]=2[C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=1[CH2:3][C@@H:2]([C:13]([OH:15])=[O:14])[NH2:1])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(C(C)(C)C)c2[nH]c(C(C)(C)C)c(C[C@H](N)C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85 %

Procedure:
Tryptophan (4.00 g, 19.59 mmol), trifluoroacetic acid 98% (60 ml) and tert-butanol (15.54 g, 209.66 mmol) were mixed. The reaction mixture was stirred at room temperature for 48 hours. The trifluoroacetic acid was evaporated. The residue was suspended in 40 ml distilled water, and the pH adjusted to neutral with addition of sodium hydrogen carbonate. The crude product was obtained by filtration. Crystallisation from 50% ethanol afforded the product as a white powder (85-90% pure).
Reaction SMILES: CO[C:3]1[N:8]=[N:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O>>[Cl:14][C:3]1[N:8]=[N:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)nn1
Reactant: O=S(Cl)Cl
Product: O=C(O)c1ccc(Cl)nn1
Temperature: 25 °C
Yield: 100 %

Procedure:
Potassium dichromate (3.3 g, 11.2 mmol) was added in portions to a solution of 3-Chloro-6-methyl-pyridazine (1.2 g, 9.3 mmol) in H2SO4 (10 ml). After addition the mixture is stirred at 50° C. on. The reaction was pored on ice and the mixture was extracted three times with diethyl ether. The combined organic phases were dried and concentrated to give the title compound (840 mg, 57%). LC-MS (M++1): 159 and 161 (3:1). Step 2: 6-Chloro-pyridazine-3-carboxylic acid methyl ester: A solution of 6-chloro-pyridazine-3-carboxylic acid (700 mg, 4.53 mmol) in thionyl chloride (15 ml) was refluxed for 3 h. The reaction was cooled to ambient temperature and evaporated to dryness. Sodium methoxide (244 mg, 4.53 mmol) in MeOH (20 ml) was added to the residue and the solution was stirred on at room temperature (rt). H2O was added and the mixture was extracted three times with DCM. The combined organic phases were dried and concentrated. Flashchromatography (SiO2, Heptane/EtOAc 1:1) afforded 560 mg (72%) of the title compound. 1H NMR (CDCl3), δ (ppm): 4.09 (s, 3 H), 7.69 (d, 1 H), 8.18 (d, 1 H).LC-MS (M++1): 173 and 175 (3:1). Step 3: 6-Methoxy-pyridazine-3-carboxylic acid methyl ester: A solution of 6-chloro-pyridazine-3-carboxylic acid methyl ester in NaOMe in MeOH (1M, 10 ml) was refluxed on. H2O was added and the mixture was extracted three times with DCM to give organic phase I. The combined organic phases I were dried and concentrated to give the title compound (40 mg, 10%). The water phase was acidified with concentrated hydrochloric acid and extracted three times with DCM to give organic phase II. The combined organic phases II were dried and concentrated to give 6-methoxy-pyridazine-3-carboxylic acid (LC-MS (M++1): 155) (230 mg, 65%). A solution of 6-methoxy-pyridazine-3-carboxylic acid in thionyl chloride (6 ml) was refluxed for 3 h. The reaction was cooled to ambient temperature and evaporated to dryness. MeOH (10 ml) was added to the residue and the solution was stirred on at rt. Saturated NaHCO3 (aq) was added and the mixture was extracted three times with DCM. The combined organic phases were dried and concentrated to give the title compound (253 mg, 100%).LC-MS (M++1): 169. Step 4: 4-Ethyl-5-(6-methoxy-pyridazin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione: NaOMe (86 mg, 1.6 mmol) was added to a solution of 6-methoxy-pyridazine-3-carboxylic acid methyl ester (210 mg, 1.25 mmol) and 4-ethyl-3-thiosemicarbazide (190 mg, 1.6 mmol) in MeOH (6 ml) and the mixture was heated to 70° C. at 72 h. The reaction was cooled to ambient temperature and evaporated to dryness. H2O (10 ml) was added to the residue and the mixture was acidified with concentrated hydrochloric acid and the title compound 35 mg (12%) was collected by filtration. LC-MS (M++1): 238.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[C:7](=[CH:19][NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1F)=[O:9])[CH3:4]>O1CCOCC1>[CH2:3]([O:5][C:6]([C:7]1[C:8](=[O:9])[C:10]2[C:11](=[CH:12][C:13]([F:17])=[C:14]([F:16])[CH:15]=2)[N:20]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:19]=1)=[O:25])[CH3:4]
Reactant: CCOC(=O)C(=CNC(C)(C)C)C(=O)c1cc(F)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C(C)(C)C)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
There was added 1.1 g (27 mmoles) of 60% sodium hydride portionwise, at a temperature between 18° C. to 22° C., to a suspension of 7.22 g (21.9 mmoles) of 3-(2,4,5-trifluorophenyl)-3-oxo-2-(((1,1-dimethylethyl)amino)methylene)propanoic acid ethyl ester in 73 mL of anhydrous dioxane. An exothermic reaction occured. After stirring at room temperature during 1 hour, the resulting mixture was evaporated to dryness, and taken up with CH2Cl2 (150 mL) and H2O (200 mL). After decantation the organic layer was dried over MgSO4. Evaporation of dichloromethane gave 6.41 g of an amorphous solid which was washed twice with water to yield 6.08 g of titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl.O>C(O)C>[ClH:27].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=3[C:10](=[N:26][NH:25][C:22]([NH2:24])=[NH:23])[CH2:9]2)[CH:7]=1
Reactant: Cc1cc(C)c2c(n1)CC(c1cc(F)ccc1C)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(n1)CC(c1cc(F)ccc1C)CC2=NNC(=N)N
Yield: 85.7 %

Procedure:
A solution of 7-(5-fluoro-2-methylphenyl)-2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) and aminoguanidine hydrochloride (0.52 g) in ethanol (30 ml) was combined with concentrated hydrochloric acid (1.0 ml) and water (1.0 ml), and the mixture was heated under reflux for 12 hours. The mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to obtain 7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-2,4-dimethyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound L) (1.25 g) as a colorless crystal.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[C:20]([C@H:23]1[C@@H:28]([NH2:29])[CH2:27][CH:26]=[CH:25][CH2:24]1)(=[O:22])[NH2:21]>>[C:20]([C@H:23]1[C@@H:28]([NH:29][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH2:27][CH:26]=[CH:25][CH2:24]1)(=[O:22])[NH2:21]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NC(=O)[C@@H]1CC=CC[C@@H]1N
Product: CCc1cc(-c2cncc(C(=O)N[C@H]3CC=CC[C@H]3C(N)=O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and ((1S,6R)-6-carbamoyl-cyclohex-3-enyl)-amine to afford the title compound. MS: m/e=381 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:23][CH:22]5[N:24]([CH3:25])[CH:19]([CH2:20][CH2:21]5)[CH2:18]4)[C:8]=23)=[C:4]([F:37])[CH:3]=1.[F:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH:50]=[CH:49][N:48]=[C:47]([C:51]([OH:53])=O)[C:46]2=[O:54])=[CH:41][CH:40]=1>>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:51]([C:47]2[C:46](=[O:54])[N:45]([C:42]3[CH:41]=[CH:40][C:39]([F:38])=[CH:44][CH:43]=3)[CH:50]=[CH:49][N:48]=2)=[O:53])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([NH:16][CH:17]3[CH2:23][CH:22]4[N:24]([CH3:25])[CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[C:8]=12
Reactant: O=C(O)c1nccn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(NC3CC4CCC(C3)N4C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: CN1C2CCC1CC(Nc1n[nH]c3nccc(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)c13)C2
Yield: 18 %

Procedure:
Prepared by a 2-step process from 4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (prepared as described in Example 101, Step A except using 8-methyl-8-azabicyclo[3.2.1]octan-3-amine) and 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (Example 125, Step E) according to the procedure of Example 101, Step B. The crude was rinsed with Et2O to afford 7 mg (18%) of the desired product. The desired product was treated with 2N HCl (Et2O solution) in a solution of MeOH and EtOAc to afford HCl salt compound. LRMS (ESIpos) m/e 599.2 (M+1). 1H-NMR (400 MHz, CD3OD) δ 8.36 (m, 1H), 8.14 (d, 1H), 7.94 (m, 1H), 7.80 (m, 1H), 7.60 (m, 4H), 7.35 (t, 2H), 6.54 (d, 1H), 4.07 (m, 1H), 3.93 (m, 2H), 2.81 (s, 3H), 2.35-2.58 (m, 8H); 19F NMR (376 MHz, CD3OD) δ −113.5, −129.6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([NH:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH:9]([OH:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([NH:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(O)Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 3-allyloxycarbonylamino-4-hydroxy-5-phenyl-pentanoic acid tert-butyl ester, 107, (0.8 g, 2.23 mmol) in CH2Cl2 (10 mL) is added to a solution of Dess-Martin reagent (1.05 g, 2.47 mmol) in CH2Cl2 (10 mL). After 1 hour the reaction solution is diluted with ether (50 mL) and the solution poured into a 1.3 M solution of NaOH (20 mL). Stir for 1 hour and decant the organic layer. Dry the organic layer over Na2SO4, concentrate in vacuo to afford a crude residue that is purified over silica to afford the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:13]=[C:12]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:11]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:10]2[N:15]=[C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:13]=[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:11]=2)[CH:6]=1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnn(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a cooled (0° C.) solution of 4-bromopyrazole (0.29 g, 2.0 mmol) in anhydrous DMF (4 ml) was added NaH (60% dispersion in mineral oil, 0.088 g, 2.2 mmol) in a portionwise fashion over 10 minutes. The mixture allowed to warm to room temperature where it was stirred for 30 minutes before the adition of 2-Chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (3b)(0.571 g, 2.00 mmol). The mixture was then heated under the influence of microwave radiation (120° C., 14 minutes). Upon cooling the reaction was diluted with water (10 ml) and filtered. The filtercake was washed with more cold water (10 ml), collected and dried to give the title compound (92.4%, 0.73 g) in suitably pure form to be used without any further purification. m/z (LC-MS, ESP): 396 [M+H]+, R/T=3.56 mins.