Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][C:17]=3[Br:28])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[Br:28])=[CH:29][CH:30]=2)=[O:10])=[CH:31][CH:32]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Reaction time: 3 h
Yield: 84.7 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (30 mg, 0.058 mmol) was diluted with dioxane (500 μL) followed by the addition of NaOH (0.093 ml, 0.46 mmol) and 200 μL of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetic acid (24 mg, 85% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.70 (d, 2H), 7.60 (s, 1H), 7.22-7.32 (m, 3H), 7.19 (d, 2H), 7.05 (d, 1H), 6.90 (d, 2H), 3.62 (m, 4H), 2.90 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:20][CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:21])[NH:9]2)=[CH:4][CH:3]=1.I[C:23]1[CH:24]=[C:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:20][CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:21])[N:9]2[C:23]2[CH:24]=[C:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CCC2)c2c1C(c1ccc(Cl)cc1)NC2=O
Reactant: Cc1cc(I)cn(C)c1=O
Product: Cc1nn(C2CCC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 23 using 4-(4-chlorophenyl)-1-cyclobutyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 94.1) and 5-iodo-1,3-dimethylpyridin-2(1H)-one (Step 23.2) 16 hr at 100° C. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 0.5-2%) followed by trituration in hexane/Et2O (3:1). tR: 4.74 min (HPLC 1); tR: 1.08 min (LC-MS 2); ESI-MS: 423 [M+H]+ (LC-MS 2); Rf=0.50 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.84 (m, 2H) 1.90-1.94 (m, 6H) 2.34-2.45 (m, 2H) 2.57-2.73 (m, 2H) 3.35 (s, 3H) 4.91-5.04 (m, 1H) 6.06 (s, 1H) 7.25 (d, J=8.6 Hz, 2H) 7.33-7.40 (m, 3H) 7.72 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]1[NH:28][C:27](=[O:29])[C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=1>>[CH3:31][C:25]1[N:24]=[C:23]([CH2:22][NH:21][C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[NH:28][C:27](=[O:29])[C:26]=1[CH3:30]
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Reactant: Cc1nc(CN)[nH]c(=O)c1C
Product: COc1ccc(C(=O)C2CCN(CC(=O)NCc3nc(C)c(C)c(=O)[nH]3)CC2)cc1
Yield: 49.3 %

Procedure:
The title compound (183 mg) was prepared following the general procedure of Example 1 from 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (357 mg, 0.90 mmol, 70% purity) and 2-(aminomethyl)-5,6-dimethylpyrimidin-4(3H)-one (138 mg, 0.90 mmol). 1H NMR (400 MHz, DMSO-d6) δ 12.21 (br. s., 1H), 8.20 (s, 1H), 7.96 (d, J=9.1 Hz, 2H), 7.02-7.06 (m, 2H), 4.14 (d, J=5.6 Hz, 2H), 3.84 (s, 3H), 2.86-3.08 (m, 4H), 2.25-2.39 (m, 2H), 2.22 (s, 1H), 2.16 (s, 3H), 1.88 (s, 3H), 1.63-1.82 (m, 4H). HRMS calculated for C22H28N4O4 413.2189. found (ESI, [M+H]+), 413.2195. Retention time=4.44 min.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.N1C(C)=CC=CC=1C.[Cl:20][C:21]1[CH:22]=[C:23]([C@@H:31]([CH2:35][C@H:36]2[CH2:40][CH2:39][C:38](=[O:41])[CH2:37]2)[C:32](Cl)=[O:33])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([C@@H:31]([CH2:35][C@H:36]2[CH2:40][CH2:39][C:38](=[O:41])[CH2:37]2)[C:32]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)=[O:33])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Cl)cc1Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 35 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (88 mg, 91%) as a white foam: [α]30589=−79.0° (c=0.10, methylene chloride); ES-HRMS m/e calcd for C22H28N3O5SCl (M+H)+ 482.1511, observed 482.1511; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.50 (m, 1H, CH), 1.79-2.29 (m, 8H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH22), 3.96 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=1.7 Hz, 1H, Ar), 7.51 (d, J=1.7 Hz, 1H, Ar), 7.62 (d, Jo=8.0 Hz, 1H, Ar), 7.73 (s, 1H, Ar), 8.02 (d, Jo=8.0 Hz, 1H, Ar), 10.85 (s, 1 H, NH).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:33]#[C:34][Si](C)(C)C)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[C:33]([C:4]1[CH:3]=[C:2]([F:1])[CH:32]=[CH:31][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:30])[CH3:29])=[O:9])#[CH:34]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#C[Si](C)(C)C)c(OCc1ccccc1)c2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 22 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A solution of intermediate 178, N-(4-fluoro-2-(2-(trimethylsilyl)ethynyl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.150 g, 0.28 mmol) in methanol (5 ml) was treated with potassium carbonate (0.120 g, 0.84 mmol) and the resulting mixture stirred at 22° C. for one hour. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.129 g (100% yield) of the title material as a light yellow solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.64 (6H, s, 2×CH3), 3.31 (1H, s, CH), 4.04 (4H, m, 2×CH2), 4.69 (2H, d, J=6.6 Hz, NCH2), 5.31 (2H, s, OCH2), 7.04 (1H, m, aromatic), 7.21 (1H,dd, J=2.6 Hz and J=9.1 Hz, aromatic), 7.32-7.42 (3H, m, aromatics), 7.40 (1H,dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.52-7.54 (2H, m, aromatics), 8.00 (1H, broad t, NH). HRMS (ESI+) calculated for C26H25FN3O4 [M+H]: 462.1829; found: 462.1822.
Reaction SMILES: [N:1]1([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:24][C:25](=O)[CH3:26].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[C:4]2[CH2:5][CH2:6][N:1]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:2](=[O:8])[C:3]=2[C:25]([CH3:26])=[CH:24]1
Reactant: CC(=O)CNc1ccc(Cl)cc1Cl
Reactant: O=C1CCN(N2CCCCC2)C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cn(-c2ccc(Cl)cc2Cl)c2c1C(=O)N(N1CCCCC1)CC2
Temperature: 25 °C
Yield: 25 %

Procedure:
To a solution of [1,1′]bipiperidinyl-2,4-dione (520 mg, 2.65 mmol) from Example 1 step 4 in dry toluene (25 ml) at room temperature were added 1-(2,4-dichlorophenylamino)-propan-2-one (576 mg, 2.64 mmol) from Step 1 above followed by a catalytic amount of p-TSA. The reaction mixture was boiled under reflux with a Dean-Stark trap, and 10 ml toluene was collected in the trap. One molar equivalent of p-TSA (250 mg) was added and the reaction mixture was boiled under reflux for 5.5 hours. After cooling to room temperature, the reaction mixture was evaporated and purified by flash chromatography (heptane:EtOAc gradient) to give 250 mg (25%) of the title compound as a brown solid. A parallel experiment with 1.51 g 1-(2,4-dichlorophenylamino)propan-2-one afforded 0.68 g (26%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][SH:9].Cl[C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1
Reactant: SCc1ccccc1Cl
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(SCc1ccccc1Cl)nc2=O

Procedure:
The title compound or it salt was prepared by a procedure similar to that described for E62 starting from (2-chlorophenyl)methanethiol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].CON=[C:15]([CH2:21][C:22](=O)[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][C:22]([CH3:23])=[N:11]2)[CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2]
Reactant: CCOC(=O)C(CC(C)=O)=NOC
Reactant: Cc1ccc(NN)cc1C#N
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)nn1-c1ccc(C)c(C#N)c1

Procedure:
Part A: Ethyl 1-(3-cyano-4-methylphenyl)-3-methyl-5-pyrazole-carboxylate was prepared as colorless crystals following the standard condensation (3-cyano-4-methylphenyl-hydrazine and ethyl 2-(N-(methoxy)imino)-4-oxopentanoate in acetic acid) reaction protocol discussed previously. 1HNMR (CDCl3) δ: 7.68 (s, 1H), 7.57 (dd, 1H), 7.58 (d, 1H), 6.82 (s, 1H), 4.24 (q, 2H), 2.40 (s, 3H0, 2.37 (s, 3H), 1.27 (t, 3H) ppm; ESI mass spectrum analysis (270 (M+H, 100).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[CH3:25][O:26][C:27]([C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C(N(CC)CC)C>CO.COCCOC>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:32]3[CH:31]=[CH:30][C:29]([C:27]([O:26][CH3:25])=[O:28])=[N:34][CH:33]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Solvent: CO
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 120 °C
Yield: 79 %

Procedure:
6-(((2S,4R)-1-Acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 2)(3.25 g, 8.44 mmol), {6-[(methyloxy)carbonyl]-3-pyridinyl}boronic acid (1.832 g, 10.12 mmol), {6-[(methyloxy)carbonyl]-3-pyridinyl}boronic acid (1.832 g, 10.12 mmol) and triethylamine (2.352 ml, 16.87 mmol) were combined in MeOH (30 ml) and DME (5 ml). The reaction mixture was divided between 2 vials and each heated at 120° C. for 45 min. The crude reaction mixtures were combined and concentrated in vacuo to give 4.4 g of crude brown solid. This was purified by chromatography on silica (100 g), eluting with over 1500 ml of EtOAc (compound leached off slowly) to give methyl 5-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinate (2.94 g, 6.66 mmol, 79% yield) as a brown foamy solid. LCMS (Formate, 2 min), Rt=0.81 min, MH+=442.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][OH:39].C(Cl)Cl>CN(C=O)C.CCOCC>[Si:1]([O:18][CH2:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]([CH2:37][CH2:38][OH:39])[C:25](=[O:27])[O:26][C:22]=2[CH:21]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1ccc2[nH]c(=O)oc2c1)(c1ccccc1)c1ccccc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1ccc2c(c1)oc(=O)n2CCO)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 44.3 %

Procedure:
To a solution of 6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3-benzoxazol-2(3H)-one (Intermediate 78, 218 mg, 0.54 mmol) in DMF (2 mL) were added potassium carbonate (232 mg, 1.68 mmol) and 2-bromoethanol (60 μL, 0.85 mmol) and the reaction mixture was placed in a sealed vessel at 120° C. over a period of 4 hours. CH2Cl2 was added to the mixture and the solids were filtered off and washed with CH2Cl2. The resulting filtrate was washed with water and brine and the organic phase was filtered through a Phase Separator membrane to remove remaining water. The crude oil was purified by column chromatography over silica gel using Hexane:Et2O as eluent (from 0 to 100% of Et2O) to give the title compound as a white solid (107 mg, 44% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[N+:24]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Product: COc1ccc(-c2cc(Oc3cccc([N+](=O)[O-])c3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (106.9 mg, 0.327 mmol) and 3-nitrophenol were reacted as starting materials at 150° C. for 17 hours and post-treatment was then conducted, whereby the title compound was obtained as pale yellow prisms (140.4 mg, 99.9%). Melting point: 172.2-174.0° C. (ethyl acetate-diethyl ether-hexane).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:14][O:13][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N+:1]([O-:20])=[CH:2][CH:3]=[CH:4]2)=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(ccc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of methyl quinoline-6-carboxylate from above in DCM (10 mL) was added 3-chlorobenzoperoxoic acid (1.991 g, 11.54 mmol). The reaction was stirred 21 h at rt. The mixture was then diluted with saturated aqueous NaHCO3 (40 mL), and the mixture was extracted with DCM (2×30 mL). The organic layers were combined, washed with saturated aqueous NaCl (40 mL), dried (MgSO4), and concentrated. The N-oxide was isolated as an orange solid which was used without purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28]>>[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:36])([F:34])([F:35])([F:37])[F:38])[CH:32]=1)[C:27]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:28]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Product: Cc1cc(C(=O)Nc2ccc(C)c(-n3ccn4nc(-c5cccnc5)cc34)c2)cc(S(F)(F)(F)(F)F)c1

Procedure:
Analogously to the process described in Example 26, 80 mg (0.276 mmol) of the compound of Example 6A and 73 mg (0.276 mmol) of the compound of Example 34A gave 101 mg (61% of theory, 90% pure) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:20][CH3:21])=[CH:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=O)[C:11]([C:16]#[N:17])=[CH:12][NH:13]3)=[CH:8][C:7]=2[CH:19]=1.P(Cl)(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:10]1[C:9]2[C:14](=[CH:15][C:6]3[CH:5]=[C:4]([O:20][CH3:21])[C:3]([O:2][CH3:1])=[CH:19][C:7]=3[CH:8]=2)[N:13]=[CH:12][C:11]=1[C:16]#[N:17]
Reactant: COc1cc2cc3[nH]cc(C#N)c(=O)c3cc2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OC
Yield: 49.4 %

Procedure:
A mixture of 356.2 mg (1.3 mmol) of 7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile in 5 mL of phosphorus oxychloride and 4 drops of DMF is heated at 100–110° C. for 4.5 hours. After cooling, the mixture is concentrated to dryness in vacuo to give a dark residue. The residue is partitioned between methylene chloride and ice-cooled saturated aqueous sodium carbonate solution. The organic layer is washed with cooled brine and dried over sodium sulfate. The organic solvent is passed through a short column of silica gel, and the column is first eluted with additional methylene chloride, then a 99:1 methylene chloride/ethyl acetate solution. Removal of the solvent yields 187.0 mg (49.4%) of the product as a bright yellow solid, mp>265° C.
Reaction SMILES: [C:1]([C:9]1[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[C:2]1([C:1]2[C:9]3[CH:14]=[CH:13][CH:12]=[N:11][C:10]=3[C:15](=[O:17])[NH:19][N:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1cccnc1C(=O)O
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)c2cccnc12
Temperature: 25 °C
Yield: 69.7 %

Procedure:
To a round bottomed flask containing 3-benzoylpicolinic acid (2.00 g, 9 mmol) was added 50 mL of ethanol. Hydrazine hydrate (0.6 ml, 11 mmol) was added and the mixture was heated to reflux for 3 h. After cooling to rt, the solvent was removed in vacuo. The resulting yellow solid was recrystallized from 30 mL of boiling 1-propanol to afford 5-phenylpyrido[2,3-d]pyridazin-8(7H)-one 70 (1.4 g, 71% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 10.55 (br s, 1H), 9.16 (dd, J=8.6, 1.6 Hz, 1H), 7.73 (dd, J=8.6, 4.7 Hz, 1H), 7.56 (m, 5H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1>C(#N)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:5]=[C:3]([CH2:2][Cl:1])[N:14]=2)[CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ccc(Cl)cn1
Solvent: CC#N
Product: ClCc1cn2cc(Cl)ccc2n1
Yield: 19.2 %

Procedure:
1,3-Dichloroacetone (7.4 g, 58.3 mmol) was added to a solution of 5-chloropyridin-2-amine (5.0 g, 38.9 mmol) in acetonitrile (100 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). Upon completion of the reaction as judged by TLC, the mixture was concentrated under reduced pressure. The residue was diluted with water and the pH was adjusted to 7.5 with sodium bicarbonate solution. The mixture was extracted with EtOAc, the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (1.5 g, 30%,) as a pale yellow solid. 1H NMR: 200 MHz, CDCl3: δ 8.0 (d, 1H), 7.6 (dd, 2H), 6.8 (d, 1H), 4.75 (s, 2H). MS: [M+H]+: m/z=201.9.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:19][NH2:20])([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[CH2:4][CH2:3]1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]([CH2:19][NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([C:25]3[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=3)[CH:29]=2)([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CN1CCC(CN)(c2nc(-c3ccccc3)cs2)CC1
Product: CN1CCC(CNC(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)(c2nc(-c3ccccc3)cs2)CC1
Yield: 23 %

Procedure:
This compound was synthesized from (1-methyl-4-(4-phenylthiazol-2-yl)piperidin-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (9 mg, 23% yield): 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.21 (d, J=7.5 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.86 (d, J=6.3 Hz, 1H), 7.78 (m, 1H), 7.54 (t, J=6.2 Hz, 2H), 7.48 (s, 1H), 7.34-7.25 (m, 2H), 3.86 (s, 2H), 2.69 (m, 2H), 2.57 (m, 4H), 2.34 (s, 3H), 2.13 (m, 2H). MS (ESI) m/z: Calculated for C26H24F3N5O2S: 527.16. found: 528.1 (M+H)+.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.C([N:20]([CH2:23]C)CC)C.[CH3:25][O:26][C:27]([CH2:29][C@@:30]1([CH2:36]C(O)=O)[CH2:34][CH2:33][C@@H:32]([CH3:35])[CH2:31]1)=[O:28]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:25][O:26][C:27](=[O:28])[CH2:29][C@@:30]1([CH2:36][N:20]=[C:23]=[O:8])[CH2:34][CH2:33][C@@H:32]([CH3:35])[CH2:31]1
Reactant: COC(=O)C[C@@]1(CC(=O)O)CC[C@@H](C)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@]1(CN=C=O)CC[C@@H](C)C1
Yield: 100 %

Procedure:
Diphenylphosphoryl azide (8.07 mL, 37.4 mmol), triethylamine (5.36 mL, 39 mmol), and ((1S,3R)-1-methoxycarbonylmethyl-3-methyl-cyclopentyl)-acetic acid (7.93 g, 37 mmol) were refluxed in toluene (80 mL) for 17 hours. The mixture was allowed to cool and then taken up in ethyl acetate (250 mL), washed with saturated aqueous sodium hydrogen carbonate (250 mL), brine (100 mL), and dried (MgSO4). The solvent was removed under reduced pressure to give 7.82 g (100%) of ((1R,3R)-1-isocyanatomethyl-3-methyl-cyclopentyl)-acetic acid methyl ester which was used without further purification;