Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(=O)NC(=O)C2=CC=CC=C12.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)COCC1(C2C=CC=CC=2)CCC(O)C1.[F:53][C:54]([F:91])([F:90])[C:55]1[CH:56]=[C:57]([CH:83]=[C:84]([C:86]([F:89])([F:88])[F:87])[CH:85]=1)[CH2:58][O:59][CH2:60][C:61]1([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH2:65][CH2:64][CH:63]([N:66]2[C:74](=[O:75])[C:73]3[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=3)[C:67]2=[O:76])[CH2:62]1>C1COCC1.C(OCC)(=O)C.O>[F:88][C:86]([F:87])([F:89])[C:84]1[CH:83]=[C:57]([CH:56]=[C:55]([C:54]([F:91])([F:90])[F:53])[CH:85]=1)[CH2:58][O:59][CH2:60][C@:61]1([C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[CH2:65][CH2:64][C@H:63]([N:66]2[C:74](=[O:75])[C:73]3[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=3)[C:67]2=[O:76])[CH2:62]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C1NC(=O)c2ccccc21
Agent: OC1CCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tripehnylphosphine (102 mg) in THF (0.20 mL) at 0° C. was added diethyl azodicarboxylate (61 μL) and the resulting solution was stirred at 0° C. for 30 min. Phthalimide (57 mg) was added followed by 3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-phenylcyclopentanol (available from Step E of Example 1) (148 mg) in THF (0.50 mL), and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with ethyl acetate and water was added. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC eluting with 20% ethyl acetate/80% hexanes to give two products as racemates: 2-((1SR,3RS)-3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-phenylcyclopentyl)isoindoline-1,3-dione (less polar fraction) and 2-((1RS,3RS)-3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-phenylcyclopentyl)isoindoline-1,3-dione (more polar fraction).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.Cl>C1COCC1>[CH3:9][C:7]1[CH:8]=[C:3]([B:11]([OH:16])[OH:12])[CH:4]=[C:5]([CH3:10])[CH:6]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(C)cc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Magnesium turnings (1.44 g, 59.43 mmol) were coverd with dry THF (18.8 mL) in a dried, nitrogen filled flask fitted with an addition funnel and reflux condenser. To this was added 5-bromo-m-xylene (10 g, 54.03 mmol) in THF (15 mL) after initiation of the Grignard reaction. The addition was carried out over several minutes and the reacton mixture was heated at reflux for 1-2 hours until most of the magnesium had reacted. The reaction mixture was then cooled and transferred to an addition funnel fitted to an nitrogen filled flask containing triisopropyl borate (24.9 mL) at −70° C. The dropwise addition was carried out over several minutes and the mixture warmed to room temperature and stirred overnight. The grey solution was poured onto 2 M HCl and immediately turned yellow. The solution was extracted with Et2O and the Et2O fractions were combined, dried over MgSO4 and the solvent was removed in vacuo to provide the desired product (2.41 g): m.p.249-251° C.; 1H NMR (CDCl3) d 2.44 (6H, s), 7.23 (1H, s), 7.84 (2H, s); 13C NMR (CD3OD) d 21.36, 133.28, 134.39, 137.48.
Reaction SMILES: [H-].[Na+].[CH2:3]([Cl:6])[CH2:4][OH:5].[CH2:7]([O:9][C:10](=[O:16])[CH2:11][C:12]([CH2:14]Br)=[O:13])[CH3:8].Cl>O1CCCC1>[CH2:7]([O:9][C:10](=[O:16])[CH2:11][C:12]([CH2:14][O:5][CH2:4][CH2:3][Cl:6])=[O:13])[CH3:8]
Reactant: CCOC(=O)CC(=O)CBr
Reactant: OCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCCl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
10.38 g (0.25 mole) of 57.8% sodium hydride are added to 110 ml of tetrahydrofurane. The mixture is cooled to a temperature between -10° C. and -20° C. whereupon at this temperature 10.08 g (0.125 mole) of ethylene chlorohydrine (III) are added under nitrogen dropwise. The mixture is stirred for 20 minutes, whereupon at the same temperature a solution of 26.18 g (0.125 mole) of ethyl-4-bromoacetoacetate (II) and 35 ml of tetrahydrofurane is added. The reaction mixture is stirred for 20 minutes, allowed to warm to room temperature, kept at this temperature for 6 hours, poured into 270 ml of 1 N hydrochloric acid under cooling and extracted with dichloro methane. The organic layer is dried and evaporated. The residual oil is made free of paraffine by treatment with a 1:1 mixture of acetonitrile and benzene. The product is distilled off in vacuo. Thus 17.47 g of the desired compound are obtained, yield 67%, bp.: 110° C./2 Hgmm.
Reaction SMILES: F[CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=4)[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[C:11]([O:38][CH3:39])[CH:10]=2)[CH2:5]1.FC(F)(F)C(O)=[O:43]>O1CCOCC1>[C:3]([N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=4)[C:19]([C:34]([F:36])([F:35])[F:37])=[CH:18][N:17]=3)=[C:11]([O:38][CH3:39])[CH:10]=2)[CH2:5]1)(=[O:43])[CH3:2]
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(NC4CN(CCF)C4)cc3OC)ncc2C(F)(F)F)c1
Reactant: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(NC4CN(C(C)=O)C4)cc3OC)ncc2C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
As shown in Scheme 2, a mixture of intermediate 1 of Scheme 2 (16 mg) and intermediate 3 of Scheme 1 (1-(3-(4-amino-3-methoxyphenylamino)azetidin-1-yl)ethanone, 20 mg) in dioxane (1.0 mL) with catalytic trifluoroacetic acid was stirred overnight at 50° C. The crude was concentrated under reduced pressure and purified using HPLC (TFA modifier) to give the title compound (12 mg) as a TFA salt. 1H-NMR (DMSO-d6, 400 MHz) δ 10.6 (s, 1H), 10.15 (s, 1H), 9.45 (s, 1H), 8.62 (br, 1H), 6.96-7.85 (m, 4H), 6.55 (dd, J=2, 10 Hz, 1H), 6.23 (d, J=10 Hz, 1H), 5.74 (d, J=10 Hz, 1H), 3.15-3.85 (m, 6H), 1.77 (s, 3H); calculated mass for C26H26F3N7O3: 541.2. found: 542.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(Br)c1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cccc(N2CCN(c3cnccc3C)C2=O)c1
Yield: 75.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84650 mmol) was reacted with 1-bromo-3-methoxy-benzene (107 mg, 0.84650 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg, 0.08465 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.2539 mmol) and potassium phosphate (538 mg, 2.539 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 180 mg of the product (75% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O>>[CH3:2][C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
nitrating acetanilide using a mixture of nitric acid and sulfuric acid to produce 4-nitroacetanilide and nitrating further using a mixture of nitric acid and sulfuric acid to produce compound VI;
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([SH:6])[CH:5]=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].NCC(O)=O>CS(C)=O.CCOC(C)=O.[Cu]I>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:6][C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[CH:10][CH:9]=1
Reactant: Brc1ccc(I)cc1
Reactant: Sc1cn[nH]n1
Agent: [Cu]I
Agent: NCC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Brc1ccc(Sc2cnn[nH]2)cc1
Temperature: 110 °C
Yield: 40.2 %

Procedure:
A mixture of 2H-1,2,3-triazole-4-thiol (870 mg, 7.10 mmol), 1-bromo-4-iodobenzene (1.00 g, 3.50 mmol), K3PO4 (1.90 g, 8.80 mmol), CuI (67.0 mg, 0.350 mmol) and glycine (132.7 mg, 1.80 mmol) in DMSO (10 mL) was heated to 110° C. for 3 days. The reaction mixture was cooled to rt, diluted with EtOAc (500 mL) and washed with water (2×400 mL) followed by brine (400 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 360 mg of compound 63a as a white solid. Mass Spectrum LCMS, ESI (pos.) Calcd. for C8H6BrN3S: 256.1 [M+H]. found 256.1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][N:14]=1>C(O)C>[C:8]1([CH3:11])[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1ccc(N)nc1
Solvent: CCO
Product: COC(=O)c1ccc2nc(-c3ccc(C)cc3)cn2c1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
2-Bromo-4′-methylacetophenone 2 (14.5 g, 65.1 mmol) was added to a hot solution of methyl 2-aminopyridine-5-carboxylate 1 (9.0 g, 61.1 mmol) in ethanol (280 ml). The solution was then heated at reflux for 6 h, cooled to room temperature and the white solid filtered and washed with ethanol to give methyl 2-(4-tolyl)-imidazo[1,2-a]pyridine-6-carboxylate 3 (13.9 g, 80%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[O:17])[CH2:11][NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:5][C:4]=1[C:18]#[N:19]>>[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]([OH:17])[CH2:11][NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:5][C:4]=1[C:18]#[N:19]
Reactant: N#Cc1cc(C(=O)CNC2CCC2)cc(F)c1N
Agent: Cl
Product: N#Cc1cc(C(O)CNC2CCC2)cc(F)c1N

Procedure:
m.p. of the hydrochloride: 222°-224° C. (decomp.), was prepared from 4'-amino-3'-cyano-2-cyclobutylamino-5'-fluoroacetophenone analogous to Example 49.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[CH:3]1[CH:12]1[CH2:16][N:15]([CH2:17][C:18]([NH2:20])=[O:19])[C:14](=[O:21])[CH2:13]1.CN(C)CCO>>[OH:1][C:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:10])=[O:9])[C:4](=[O:11])[C:3]=1[C:12]1[CH2:16][N:15]([CH2:17][C:18]([NH2:20])=[O:19])[C:14](=[O:21])[CH:13]=1
Reactant: NC(=O)CN1CC(C2C(=O)N(CC(N)=O)CC2O)CC1=O
Agent: CN(C)CCO
Product: NC(=O)CN1CC(C2=C(O)CN(CC(N)=O)C2=O)=CC1=O

Procedure:
In a manner analogous to that described in Example 13, from 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-3H-pyrrole]-1,1'-diacetic acid diamide and 5 ml of 2-dimethylaminoethanol there is obtained the N,N-dimethyl-N-ethanolammonium salt of 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid diamide in the form of a white powder; melting point 170° (decomposition).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=O.[O-:19][C:20]#[N:21].[K+]>S1(CCCC1)(=O)=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([C:7](=[O:9])[NH:21][C:20](=[O:19])[N:12]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=1
Reactant: N#C[O-]
Reactant: CCOC(=O)CNc1cc(Cl)ccc1C(=O)O
Agent: Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Yield: 86.6 %

Procedure:
Hydrogen chloride is passed into 1 g of 4-chloro-N-(ethoxycarbonylmethyl)anthranilic acid and 1.6 g of potassium cyanate in 20 ml of sulfolane at 50° C. until analysis by HPLC indicates complete conversion. The product is precipitated by addition of water, filtered off, washed with water and dried. 0.95 g (87%) of ethyl 1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate is obtained.
Reaction SMILES: BrC1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11](OCC)=O.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:8][C:5]1[CH:6]=[CH:7][C:11]([CH2:10][C:9]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(Br)cc1
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Product: CCOC(=O)Cc1ccc(C)cc1
Temperature: 160 °C
Reaction time: 10 h
Yield: 76 %

Procedure:
A dry Schlenk vessel was initially charged with 171 mg [1 mmol] of 4-bromotoluene, 1056 mg [6.6 mmol] of diethyl malonate, 2.88 mg [0.005 mmol] of Pd(dba)2, 2.22 mg [0.011 mmol] of P(tert-Bu)3, 594 mg [2.8 mmol] of dried K3PO4 and 132 mg [0.5 mmol] of 18-crown-6. The reaction vessel was three times evacuated and filled with nitrogen. This was followed by stirring at 160° C. until completion of conversion (8 to 12 hours). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The resulting solution was washed successively with 20 ml each of water, saturated aq. NaHCO3 solution and saturated aq. NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatographic purification using silica gel (hexane/ethyl acetate) gave ethyl 4-methylphenylacetate in a yield of 76% of theory.
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([C:18]2[N:22]3[N:23]=[C:24](Cl)[CH:25]=[C:26]([NH:27][CH:28]4[CH2:30][CH2:29]4)[C:21]3=[N:20][CH:19]=2)=[O:17])[CH:10]=1)C1C=CC=CC=1.[C@H:32]1([NH2:39])[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1>CO>[NH2:38][C@H:35]1[CH2:36][CH2:37][C@H:32]([NH:39][C:24]2[CH:25]=[C:26]([NH:27][CH:28]3[CH2:29][CH2:30]3)[C:21]3[N:22]([C:18]([C:16]([NH:15][C:11]4[CH:10]=[C:9]([OH:8])[N:14]=[CH:13][N:12]=4)=[O:17])=[CH:19][N:20]=3)[N:23]=2)[CH2:33][CH2:34]1
Reactant: O=C(Nc1cc(OCc2ccccc2)ncn1)c1cnc2c(NC3CC3)cc(Cl)nn12
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4cc(O)ncn4)n3n2)CC1
Temperature: 160 °C

Procedure:
A mixture of N-(6-(benzyloxy)pyrimidin-4-yl)-6-chloro-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (70 mg, 0.161 mmol, 15C) and (trans)-cyclohexane-1,4-diamine (367 mg, 3.21 mmol) was heated at 160° C. for 2 hrs. The reaction mixture was diluted with methanol and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 10% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropylamino)-N-(6-hydroxypyrimidin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (13 mg, 19.12% yield) as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.280 minutes. [M+H]=424.15. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35-12.78 (1H, m), 11.67 (1H, s), 8.29 (1H, s), 7.96 (1H, s), 7.69-7.94 (2H, m), 7.63 (1H, d, J=1.76 Hz), 7.05 (2H, s), 5.96 (1H, s), 3.62-3.85 (1H, m), 2.93-3.17 (1H, m), 2.05-2.24 (2H,
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:12]O)=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CO)c(O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.2 %

Procedure:
A solution of 5-tert-butyl-2-hydroxymethyl-phenol (Intermediate 106, 0.215 g, 1.19 mmol) in ethyl acetate was treated with 5% palladium on carbon (0.04 g) and the resulting reaction mixture was stirred under an atmosphere of hydrogen at ambient temperature for 2.5 h. The reaction mixture was then filtered over a bed of celite and the filtrate was evaporated in vacuo to afford the title compound as a white solid (0.19 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[S:14])[NH:12][N:13]=1.Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[C:11]([S:14][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:10]=1
Reactant: Cc1ccc(-c2n[nH]c(=S)[nH]2)c(C)c1
Reactant: BrCc1ccccn1
Agent: Br
Product: Cc1ccc(-c2nc(SCc3ccccn3)n[nH]2)c(C)c1
Yield: 64 %

Procedure:
Prepared in a similar manner to example 1 using 5-(2,4 dimethylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 3a) and 2-(bromomethyl)pyridine hydrobromide. Yield 64%. 1H NMR (500 MHz, CDCl3): δ 2.34 (s, 3H), 2.57 (s, 3H), 4.37 (s, 2H), 4.51 (s, 2H), 7.04-7.08 (m, 2H), 7.28-7.31 (m, 1H), 7.41-7.43 (d, 1H), 7.74-7.77 (m, 2H), 8.63-8.64 (d, 1H). MS (M+H, 297); mp=112-114° C.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.C[Si](C=[N+]=[N-])(C)C.C([N-]C(C)C)(C)C.[Li+].[C:28]1(=O)[CH2:39][CH2:38][CH2:37][CH:36]=[CH:35][CH2:34][CH2:33][CH:32]=[CH:31][CH2:30][CH2:29]1.[O:41]1CCC[CH2:42]1>>[CH:28]1([CH:42]=[O:41])[CH2:39][CH2:38][CH2:37][CH:36]=[CH:35][CH2:34][CH2:33][CH:32]=[CH:31][CH2:30][CH2:29]1
Reactant: O=C1CCC=CCCC=CCCC1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li+]
Solvent: CC(C)NC(C)C
Product: O=CC1CCC=CCCC=CCCC1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
i-Pr2NH [80 g; 0.79 mol] was added to tetrahydrofuran (THF) (100 ml), cooled to −30° C., and n-BuLi [40 ml of 2.5 M, 0.1 mol] added dropwise by syringe, under N2. (Trimethylsilyl)diazomethane (TMSCHN2) [50 ml; 1.9 M in hexane; 0.095 mol] was added dropwise to this lithium diisopropylamide (LDA) solution at −70° C. After complete addition, a solution of 4,8-cyclododecadien-1-one [14.2 g; 0.08 mol] in anhydrous THF (50 ml) was added, and the reaction mixture allowed to stir for 1 hour at −70° C., then allowed to reach ambient temperature. It was, subsequently, refluxed for 3 hours. Most of the THF was removed in vacuo, Et2O (300 ml) was added, and the reaction mixture poured into ice-water. After extraction into Et2O, the solvent was removed, the residue redissolved in ethyl acetate (300 ml), and silica gel (100 g) added, together with H2O (1 ml). The mixture was stirred overnight under N2, the mixture concentrated in vacuo, then loaded onto a short silica column. Flash chromatography using a mixture of hexane (90%) and Et2O (10%) as eluent, gave 4,8-cyclododecadiene carboxaldehyde (QRM 2815) as a colourless oil (14.0 g).
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]=2[C:28]2[O:29][CH:30]=[CH:31][N:32]=2)=[O:7])=[CH:4][N:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CN1C(=O)CCC1>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:33]=[CH:34][C:2]([N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[N:3][CH:4]=3)=[O:7])=[C:11]([C:28]3[O:29][CH:30]=[CH:31][N:32]=3)[N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCCCC2)nc1
Temperature: 120 °C

Procedure:
In a 20 mL flask, 6-chloro-N-((7-chloro-2-(oxazol-2-yl)-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)nicotinamide (Example I-6) (6 mg, 0.012 mmol) and piperidine (10.4 mg, 0.012 mL, 0.122 mmol) were combined with NMP (0.500 mL) to give a light yellow solution. The reaction mixture was heated at 120° C. for 1.5 hr. After this time, LC/MS showed that the reaction was complete. The reaction mixture was cooled to room temperature, and the solvent was evaporated. The crude product was purified using preparatory reverse-phase HPLC. The product 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (d, J=2.30 Hz, 1H) 8.31 (d, J=8.59 Hz, 1H) 8.08 (br. s, 1H) 7.96 (d, J=0.80 Hz, 1H) 7.78-7.83 (m, 1H) 7.45-7.54 (m, 4H) 7.38 (d, J=8.20 Hz, 2H) 7.15 (d, J=0.80 Hz, 1H) 6.78-6.85 (m, 1H) 6.71 (d, J=1.95 Hz, 1H) 4.21 (d, J=4.69 Hz, 2H) 3.54-3.61 (m, 4H) 1.45-1.63 (m, 6H). MS calcd. for C30H26ClN5O3 [(M+H)+] 540.2, obsd. 540.1
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.C(O)(=O)C.[N:15]([O-])=[O:16].[Na+]>O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[C:4]=1[N:15]=[O:16]
Reactant: CSc1cc(N)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSc1nc(N)nc(N)c1N=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 6-Methylthio-pyrimidine-2,4-diamine (50.0 g; 321 mmol) in water (1000 mL) was added 500 mL of 2N acetic acid. The mixture was warmed to 50° C. and NaNO2 solution was added (24.0 g; 353 mmol in 200 mL H2O) rapidly. After 1 hr at 50° C., the deep Blue/purple mixture was allowed to cool to room temperature and filtered. The blue/purple solid was washed several times with water and finally washed with ether. The solid was allowed to air dry to give 51.0 g of 6-Methylthio-5-nitroso-pyrimidine-2,4-diamine 2 as blue/purple solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:5]([CH3:7])=O.[C:19]1(=[O:40])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:34])/[CH:30]=[C:31](\[NH2:33])/[CH3:32])[C:22](=[O:35])[C:21]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:20]12>C(O)C>[CH3:7][C:5]1[NH:33][C:31]([CH3:32])=[C:30]([C:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[C:19](=[O:40])[C:20]3=[CH:39][CH:38]=[CH:37][CH:36]=[C:21]3[C:22]2=[O:35])=[O:34])[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: C/C(N)=C/C(=O)OCCCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCN2C(=O)c3ccccc3C2=O)C1c1ccccc1[N+](=O)[O-]

Procedure:
13.7 g (55 mmol) of 2-(2-nitrobenzylidene)-acetoacetic acid methyl ester and 16.6 g (55 mmol) of 3-aminocrotonic acid-(4-phthalimido-butyl)ester are boiled in 150 ml of ethanol for 18 hours. The orange yellow oil (28.7 g-98%) obtained after removal of the solvent by evaporation under vacuum is used for further reactions without further purification.
Reaction SMILES: C([O:5][CH2:6][CH:7]([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][CH3:11])(=O)C=C.C(=O)([O-])[O-:15].[Cs+].[Cs+]>C(#N)C>[CH3:11][CH2:10][CH2:9][CH2:8][CH:7]([C:6]([OH:5])=[O:15])[CH2:12][CH3:13]
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCCC(CC)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 399.2 %

Procedure:
A mixture of TMIT (1.0 g, 6.33 mmol), 2-ethylhexyl acrylate (1.16 g, 6.33 mmol) and cesium carbonate (1.0 g, 3.3 mmol) in acetonitrile (15 mL) was stirred at room temperature for 24 h. The reaction mixture was filtered to separate solid cesium carbonate and solvent was evaporated from the filtrate to obtain the product as a colorless oil (1.9 g, 88%). IR: 3325, 2961, 1732, 1595, 1480 cm−1; 1H NMR (CDCl3, 500 MHz): δ 3.96 (overlapping d, 2 H), 3.83 (t, 1.72 H), 3.22 (t, 0.28 H), 2.82 (t, 1.72 H), 2.71 (t, 0.28 H), 1.91 (bs, 1H), 1.42 (s, 6 H), 1.40 (s, 6H), 1.35-1.20 (m, 8 H), 0.85 (overlapping t, 6 H) ppm; 13C NMR (CDCl3, 125 MHz): δ 205.8, 173.6, 171.9, 171.3, 130.2, 128.5, 88.7, 82.9, 70.35, 69.6, 67.2, 66.9, 66.8, 40.6, 38.6, 33.9, 31.4, 30.26, 30.21, 28.79, 28.71, 28.23, 25.8, 23.64, 22.83, 13.9, 10.9 ppm.