Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([S:30]([CH2:32][CH3:33])=[O:31])[C:24](C(F)(F)F)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[ClH:34]>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([S:30]([CH2:32][CH3:33])=[O:31])[C:24]([Cl:34])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(S(=O)CC)cc3n2COCCOC)c1
Reactant: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(S(=O)CC)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfinyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.191 g, 0.420 mmol) in ethanol (2 mL) was added 4M HCl in dioxane (2 mL). The reaction mixture was stirred at 23° C. for 2 h. The resulting precipitate was collected and rinsed with diethyl ether to yield the titled compound (0.103 g, 67% yield). MS (ESI/CI): mass calcd. for C15H15ClN4O3S, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.02 (d, J=0.6 Hz, 1H), 8.40 (d, J=0.6 Hz, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 3.17 (dq, J=14.6, 7.3 Hz, 1H), 2.84 (dq, J=14.6, 7.4 Hz, 1H), 1.32 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.3 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:23])[CH2:18][CH2:17]2)[CH2:14][CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(NC(C)C)(C)C.[CH2:38]([OH:41])[C:39]#[CH:40]>C1(C)C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([O:26][C:24]([N:22]([CH3:23])[C@H:19]1[CH2:20][CH2:21][C@H:16]([N:13]([CH2:14][CH3:15])[C:4]2[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([C:40]#[C:39][CH2:38][OH:41])[CH:3]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:17][CH2:18]1)=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: C#CCO
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CCN(c1cc(C#CCO)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 5-bromo-3-(((trans)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (2 g, 4.14 mmol) in dry toluene was added CuI (0.015 g, 0.079 mmol), PPh3 (0.043 g, 0.165 mmol), PdCl2(PPh3)2 (0.058 g, 0.082 mmol), N,N-diisopropyl amine (1.08 g, 10.78 mmol) and reaction was purged with argon for 15 min. prop-2-yn-1-ol (0.46 g, 8.29 mmol) was added to it reaction was heated at 80° C. at sealed condition for 5 h. On completion, it was quenched with water and extracted with ethyl acetate. Organic layer was dried over Na2SO4. The crude compound was purified by column chromatography to afford the title compound (1.2 g, 63.2% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]3)=[O:22])[C:10]([C:30]3[C:31]([O:38][CH2:39][CH3:40])=[N:32][C:33](SC)=[N:34][CH:35]=3)=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.S(=O)(O)[O-].[Na+].[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C(Cl)Cl.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]3)=[O:22])[C:10]([C:30]3[C:31]([O:38][CH2:39][CH3:40])=[N:32][C:33]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[N:34][CH:35]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1nc(SC)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1
Reactant: C1COCCN1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1nc(N2CCOCC2)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
To a solution of rac-4-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one (160 mg, 0.261 mmol) in methylene chloride cooled to 0° C. was added 100 mg of m-chloroperoxybenzoic acid (≦77%, Aldrich). After 10 min, sodium bisulfite solution was added to quench the reaction. The product was extracted with methylene chloride. The organic layer was washed with saturated solution of sodium bicarbonate, brine, dried over Na2SO4 and concentrated to give the crude sulphoxide as light yellow foam. The crude sulphoxide/sulphone was taken in 20 mL of tetrahydrofuran, and morpholine (200 uL, 3.34 mmol, Aldrich) was added. The mixture was heated at reflux overnight. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification of the crude residue by flash column chromatography (silica gel, eluting with 50-100% ethyl acetate in hexanes, then with 0-5% methanol in ethyl acetate) gave the tittle compound (94 mg, 55%). HR-MS (ES, m/z) calculated for C32H36N7O4Cl2 [(M+H)+] 652.2201, observed 652.2202.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:23][N:24]([CH3:27])[CH:25]=O.[OH-].[Na+]>O>[CH2:7]([O:6][C:5](=[CH:23][N:24]([CH3:27])[CH3:25])[CH:4]=[O:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(COCc1ccccc1)OCC
Reactant: CN(C)C=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)C=C(C=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
[(2,2-Diethoxyethoxy)methyl]benzene (8.30 g, 37.0 mmol) stirred under ice cooling was added with phosphorus pentachloride (8.09 g, 38.8 mmol) over 15 minutes. The mixture was stirred at the same temperature for 15 minutes, and then heated and stirred on an oil bath at 75° C. for 75 minutes. The reaction mixture was cooled by stirring at room temperature for 20 minutes, and then added with anhydrous N,N-dimethylformamide (8.6 mL, 111 mmol) at the same temperature, and the mixture was stirred at room temperature for 3 days. The reaction mixture was added with 8 M aqueous sodium hydroxide on an ice bath until pH became 8 or higher, and then the mixture was diluted with water, and extracted with ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:acetone=4:1→2:1) to obtain 2-(benzyloxy)-3-(dimethylamino)acrylaldehyde (4.05 g, 53%) as a brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([F:12])[CH:4]=1.CCN(C(C)C)C(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1COCC1>[F:12][C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=1)[CH2:2][N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)cc(CBr)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2cc(F)cc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A −20° C. solution of 1-(bromomethyl)-3-fluoro-5-nitrobenzene (0.95 g, 4.06 mmol) and DIEA (1.418 ml, 8.12 mmol) in THF (20 mL) was treated drop-wise with a solution of 1-methylpiperazine (0.488 g, 4.87 mmol) in THF (10 mL) and stirred at RT overnight as the cooling bath expired. The solid was removed via filtration and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 1-(3-fluoro-5-nitrobenzyl)-4-methylpiperazine (820 mg, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.97 (dt, J=8.6, 2.3 Hz, 1H), 7.64 (dd, J=9.2, 2.2 Hz, 1H), 3.60 (s, 2H), 2.41 (s, 8H), 2.21 (s, 3H); MS (ESI) m/z: 254.1 [M+H]+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Br.Br.[NH2:12][C:13]1[C:17]([NH2:18])=[CH:16][S:15][CH:14]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[N:27]=[C:28]=[S:29]>C1COCC1>[NH2:12][C:13]1[C:17]([NH:18][C:28]([NH:27][C:21]2[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:26])=[S:29])=[CH:16][S:15][CH:14]=1
Reactant: Nc1cscc1N
Reactant: Cc1cccc(C)c1N=C=S
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(C)c1NC(=S)Nc1cscc1N

Procedure:
was obtained in a similar manner to the method specified in Example 6a) by reacting a mixture prepared from 0.74 g of N-ethyl-N,N-diisopropylamine in 40 ml of THF, 0.8 g of 3,4-diaminothiophene dihydrobromide and 0.47 g of 2,6-dimethylphenyl isothiocyanate.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[C:12]#[N:13])=[C:5]([CH3:22])[O:4][N:3]=1.[NH2:23][OH:24].CCOC(C)=O.O>CS(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[C:12](=[N:23][OH:24])[NH2:13])=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1C#N
Reactant: NO
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1C(N)=NO
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a solution of 4-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile in DMSO (1.5 mL) was added neutral hydroxylamine solution (2 M in water, 1.27 mL, 2.55 mmol) and stirred at 130° C. for 10 min. EtOAc and water were added and the phases were separated. The crude product was purified on preparative HPLC to give E13 4-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carboximidamide (11.3 mg, 0.035 mmol, 34%) ES/MS m/z: 328.1 (M+H), 326.5 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.29 (m, 2H), 6.78 (m, 2H), 3.95 (s, 3H), 2.10 (s, 3H) and 1.88 (s, 3H), and E14 4-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carboxamide (12.7 mg, 0.041 mmol, 40%), ES/MS m/z: 313.1 (M+H), 311.5 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.25 (m, 2H), 6.79 (m, 2H), 4.11 (s, 3II), 2.11 (s, 3H) and 1.92 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:25][CH3:26])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[CH2:17][NH:18]C(=O)C)[N:8]=1.Cl.CO>CC#N>[NH2:18][CH2:17][C:16]1[CH:15]=[C:14]([NH:13][C:9]2[N:8]=[C:7]([C:6]3[S:5][C:4]([NH:25][CH3:26])=[N:3][C:2]=3[CH3:1])[CH:12]=[CH:11][N:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CNc1nc(C)c(-c2ccnc(Nc3cccc(CNC(C)=O)c3)n2)s1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: CNc1nc(C)c(-c2ccnc(Nc3cccc(CN)c3)n2)s1

Procedure:
By treatment of N-{3-[4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-ylamino]-benzyl}-acetamide with HCl/MeOH. Yellow solid. Mp 287-289° C. Anal. RP-HPLC: tR=10.1 min (0-60% MeCN, purity 92%). 1H-NMR (DMSO-D6) δ: 2.68 (s, 3H, CH3), 3.17 (s, 3H, CH3), 4.17 (m, 2H, CH2), 7.23 (d, 1H, J=6.0 Hz, pyrimidinyl-H), 7.27 (d, 1H, J=8.0 Hz, Ph-H), 7.50 (t, 1H, J=8.0 Hz, Ph-H), 7.70 (d, 1H, J=7.5 Hz, Ph-H), 7.75 (s, 1H, Ph H), 8.44 (d, 1H, J=6.0 Hz, pyrimidinyl-H). MS (ESI+) m/z 327.37 [M+H]+ (C16H18N6S requires 326.42).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[C:4]([F:23])[CH:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:21])([F:20])[F:22])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:15])=[C:4]([F:23])[CH:3]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2F)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2F)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-2-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BT) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 98.6%, 497.0254 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]#[N:22].[Cl:23][C:24]1[CH:25]=[C:26]([NH2:38])[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.Cl.N1C=CC=CC=1>C(O)(C)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:38][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH:16]4[CH2:20][CH2:19][O:18][CH2:17]4)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:21]#[N:22])[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: N#Cc1cnc2cc(OC3CCOC3)c([N+](=O)[O-])cc2c1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: N#Cc1cnc2cc(OC3CCOC3)c([N+](=O)[O-])cc2c1Nc1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 85 °C
Yield: 73.9 %

Procedure:
To a single-neck reaction flask (500 ml) were added 4-chloro-6-nitro-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile (5 g, 15.649 mmol), 3-chloro-4-(pyridin-2-yl-methoxy)benzenamine (4.037 g, 17.214 mmol) and pyridine hydrochloride (421 mg). To the flask was added isopropanol (150 ml). The mixture was stirred and refluxed for 2 hr at the temperature of 85° C. The reaction was stopped and cooled to the room temperature. The resultant mixture was filtered in vacuo. The filter cake was washed with mother liquor and dried in vacuo to give a yellow solid (5.988 g). Yield: 73.9%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:24][C@@H:14]4[CH2:15][N:16]([C:18](=[O:23])[C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][C@@H:13]4[C@H:12]3[CH3:25])=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH3:30][NH:31][C:32](=[O:48])[C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[OH:22][C:19]([CH3:20])([CH3:21])[C:18]([N:16]1[CH2:17][C@@H:13]2[C@@H:12]([CH3:25])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:29]=[C:2]([C:36]5[CH:35]=[N:34][C:33]([C:32](=[O:48])[NH:31][CH3:30])=[CH:38][CH:37]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:26]([NH2:28])=[O:27])[CH2:24][C@@H:14]2[CH2:15]1)=[O:23]
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@@H]1[C@H]2CN(C(=O)C(C)(C)O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2cc3c(N[C@@H]4C[C@@H]5CN(C(=O)C(C)(C)O)C[C@@H]5[C@H]4C)c(C(N)=O)cnn3c2)cn1
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 52.1 %

Procedure:
A mixture of 6-bromo-4-(((3aS,4R,5R,6aS)-2-(2-hydroxy-2-methylpropanoyl)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (32 mg, 0.055 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (29.0 mg, 0.111 mmol) and 2.0 M aqueous K3PO4 (0.111 mL, 0.221 mmol) in dimethylformamide (1 mL) was heated to 90° C. under nitrogen for 1 h. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (14.9 mg, 52% yield). 1H NMR (500 MHz, 1:1 mixture of methanol-d4/chloroform-d) d 8.93 (d, J=2.0 Hz, 1H), 8.28-8.08 (m, 3H), 8.04 (d, J=1.5 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 4.45-4.19 (m, 2H), 4.03-3.91 (m, 1H), 3.77-3.56 (m, 2H), 3.10-2.99 (m, 3H), 2.96-2.79 (m, 2H), 2.53-2.32 (m, 1H), 1.87-1.75 (m, 1H), 1.66-1.54 (m, 1H), 1.51-1.35 (m, 6H), 1.22 (d, J=6.4 Hz, 3H); MS (ES+) m/z: 520.2 (M+H); LC retention time: 1.135 min (analytical HPLC Method I).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14][CH2:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)[Cl:27]>C(O)(C(F)(F)F)=O>[ClH:27].[NH2:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([C:10]([NH:9][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:8])=[O:11])[CH2:13][CH2:14]1
Reactant: ClCCl
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](N)CC1)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl trans-4-((R)-1-phenylethylcarbamoyl)cyclohexylcarbamate (Intermediate 41, 5.2 g) was dissolved in DCM (50 mL) to which TFA was added. The resulting mixture was stirred for 45 min at room temperature. LC-MS of material showed one major peak which corresponded to desired product. The reaction mixture was then concentrated to give a clear oil. The oil was then dissolved in diethyl ether (200 mL) to which HCl (2M solution in ether) (20 mL) was added. The resulting mixture was stirred at room temperature for 2 h, resulting in a white precipitate that was collected by filtration and washed with diethyl ether (4.1 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:10]1[CH2:9][CH:8]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: Cc1ccnc2c1C(=O)CC(c1cccs1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cccs1)C2
Yield: 79.4 %

Procedure:
A mixture of 4-methyl-7-(2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (0.52 g), aminoguanidine hydrochloride (0.25 g), concentrated hydrochloric acid (0.53 ml), water (0.53 ml) and ethanol (50 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether and concentrated under reduced pressure, and the residue was recrystallized from water-ethanol to give 5-guanidinoimino-4-methyl-7-(2-thienyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 70) (0.57 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][CH3:13])[C:9]([N+:14]([O-])=O)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]>C1COCC1.CO.[Pd]>[NH2:14][C:9]1[C:10]([NH:12][CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: CNc1cc(OC)c(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(OC)c(C(=O)O)cc1N

Procedure:
Prepared analogously to example 1b by hydrogenation of 2-methoxy-4-methylamino-5-nitro-benzoic acid using palladium/charcoal 10% in THF and methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].O.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][N:12]([C:24](=[O:27])[CH:25]=[CH2:26])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a mixture of 2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (9.62 g), sodium hydrogen carbonate (6.0 g), methylene chloride (100 ml) and water (50 ml) is added dropwise with stirring a solution of acryloyl chloride (5.0 g) in methylene chloride (20 ml) under ice cooling over a period of about 30 minutes. The mixture is stirred at room temperature for 3 hours, and the organic layer is washed and dried. After the solvent is distilled off, the resulting crystals are washed with n-hexane to give 2-(4-chlorophenyl)-4-acryloyl-3,4-dihyro-2H-1,4-benzothiazine (10.76 g, yield 93%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]2[S:11][CH2:12][C:13](=[O:15])[N:14]=2)=[N:6][CH:7]=1.[N:16]1[C:25]2[C:20](=[N:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]2[S:11][C:12](=[CH:26][C:22]3[CH:23]=[CH:24][C:25]4[C:20](=[CH:19][CH:18]=[CH:17][N:16]=4)[N:21]=3)[C:13](=[O:15])[N:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(CNC2=NC(=O)CS2)cn1
Reactant: O=Cc1ccc2ncccc2n1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1cnc(CNC2=NC(=O)C(=Cc3ccc4ncccc4n3)S2)cn1
Temperature: 130 °C
Yield: 18.3 %

Procedure:
To a suspension of 2-[(5-methyl-pyrazin-2-ylmethyl)-amino]-thiazol-4-one (35.6 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 10 min., then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 2-[(5-methyl-pyrazin-2-ylmethyl)-amino]-5-[1,5] naphthyridin-2-ylmethylene-thiazol-4-one as a brown solid (10.6 mg, 18.3%). HR-ES (+) m/e calcd. for C18H14N6OS: (M+H)+ 363.1023. Found: 363.1022.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)NC1C=C(C(O)=O)C(NC2C=CC=C(Cl)C=2)=CC=1C(O)=O>>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=C(O)c1cc(Nc2cccc(Cl)c2)c(C(=O)O)cc1Nc1cccc(Cl)c1
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 125 °C

Procedure:
450 parts of polyphosphoric acid containing 85.0% P2O5 are metered into a stirred vessel. Then 127.5 parts of 2,5-dianilinoterephthalic acid and 22.5 parts of 2,5-di(3-chloroanilino) terephthalic acid are introduced at 125° C. with stirring and the mixture is heated at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction mixture is subsequently metered with stirring over 2 minutes (CG: 50%/min) into 860.8 parts of 85% strength phosphoric acid at 140° C., during which it is hydrolyzed. During this hydrolysis the temperature rises to 160° C. The phosphoric acid concentration after the hydrolysis is 95%. Then 294.5 parts of 40% strength phosphoric acid are added dropwise and the suspension is cooled to 150° C. The phosphoric acid concentration thereafter is 85%. The mixture is stirred at 150° C. for 3 hours. The mixture is then cooled to 140° C. and the mixed crystal pigment is filtered off with suction, washed with 85% strength phosphoric acid until the runoff is colorless, washed to neutrality with water. and dried at 80° C. This gives 126.4 parts of mixed crystal pigment (Pigment Violet 19, γIV phase). At twice the Bragg angle, 2θ, X-ray spectrum shows three strong lines at 6.4°, 13.5° and 26.5°, seven moderate lines at 5.4°, 13.0°, 16.6°, 20.7°, 24.0°, 25.5° and 28.4°, and one weak line at 30.4°.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N+]([C:13]1[CH:18]=CC=C[CH:14]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([F:9])[CH:3]=1)[N:6]=[CH:18][CH:13]=[CH:14]2
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Nc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: Fc1cc(Br)cc2cccnc12
Reaction time: 7 h

Procedure:
A mixture of 4-bromo-2-fluoroaniline (12.825 g, 67.5 mmol), 4.275 g of ferrous sulfate, 25.46 g (20.2 ml) of glycerol, 5.067 g (4.2 ml) of nitrobenzene and 11.79 ml of concentrated sulfuric acid was heated gently. After the first vigorous reaction, the mixture was boiled for 7 hours. The nitrobenzene was removed in vacuo. Water was added. The aqueous solution was acidified with glacial acetic acid, and the dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate=12/1) to return the title compound as white solid (9.72 g, 63.7%).