Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[NH2:28].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH3:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[NH:28][C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1)=[O:18]
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.5 %

Procedure:
As shown in Reaction Scheme 10, 4′-nitro-1,1′-biphenyl-4-carboxylic acid (4.66 g, 19.2 mmol) was dissolved in methylene chloride (110 mL), and then oxalyl chloride (2.51 mL, 28.7 mmol) was added, followed by 3 drops of N,N-dimethylformamide. The resulting mixture was stirred at rt for 45 min, concentrated under reduced pressure, and further dried under vacuum for 30 min. The residue was dissolved in methylene chloride (75 mL) and added dropwise to an ice-cold mixture of methyl 2-methylalaninate hydrochloride (3.83 g, 24.9 mmol), methylene chloride (75 mL), and triethylamine (6.68 mL, 47.9 mmol). The resulting solution was stirred at rt for 1 h and then at 55° C. for 2 h. The mixture was allowed to cool to rt and was then washed with 1N aqueous HCl solution (5 mL) and water (2×20 mL). The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage® system, 4:1 hexanes/EtOAc) to afford methyl 2-methyl-N-[(4′-nitrobiphenyl-4-yl)carbonyl]alaninate (6.21 g, 95%). 1H NMR (400 MHz, CDCl3) δ 1.73 (s, 6H), 3.82 (s, 3H), 6.89 (broad s, 1H), 7.69 (d, 2H), 7.77 (d, 2H), 7.92 (d, 2H), 8.31 (d, 2H); LC-MS m/z 342.9 (MH+), retention time 2.98 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)Cl>[Br:29][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([F:1])=[CH:3][CH:4]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOCCn1c2ccccc2c2cc(F)ccc21
Solvent: ClC(Cl)Cl
Product: COCCOCCn1c2ccc(F)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 3-fluoro-9-(2-(2-methoxyethoxy)ethyl)-9H-carbazole (1.06 g, 3.71 mmol) in chloroform (20 ml) was added NBS (0.66 g, 3.71 mmol) batch-wise in an ice-water bath. After complete addition, the reaction mixture was allowed to warm to room temperature slowly and stirred overnight. The reaction mixture was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give compound 6 in 84% yield. 1H NMR (400 MHz, CDCl3) δ 8.09-8.06 (m, 1H), 7.63-7.60 (m, 1H), 7.52-7.50 (m, 1H), 7.36-7.26 (m, 2H), 7.21-7.16 (m, 1H), 4.40 (d, J=5.6 Hz, 2H), 3.82-3.80 (m, 2H), 3.49-3.46 (m, 2H), 3.40-3.38 (m, 2H), 3.29 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.7, 156.3, 140.1, 137.4, 128.9, 124.2, 124.2, 123.2, 122.3, 122.2, 114.4, 114.1, 111.8, 110.8, 110.0, 109.9, 106.2, 106.0. HRMS (MALDI-TOF) m/z Calcd for C17H17BrFNO2 366.0499. Found 366.0502[M]+.
Reaction SMILES: ClC1C=CC(OC)=NC=1.[Br:10][C:11]1[CH:12]=[C:13]([OH:36])[CH:14]=[CH:15][C:16]=1[N:17]1[C@@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@H:20]([CH3:31])[C:19]([C:32]([F:35])([F:34])[F:33])=[N:18]1.[Cl:37][C:38]1[C:39]([N:46]2[CH2:51][CH2:50][C@H:49](O)[C@H:48]([CH3:53])[CH2:47]2)=[CH:40][C:41]([O:44][CH3:45])=[N:42][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[N:17]1[C@@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@H:20]([CH3:31])[C:19]([C:32]([F:33])([F:34])[F:35])=[N:18]1)[O:36][C@@H:49]1[CH2:50][CH2:51][N:46]([C:39]2[C:38]([Cl:37])=[CH:43][N:42]=[C:41]([O:44][CH3:45])[CH:40]=2)[CH2:47][C@H:48]1[CH3:53]
Reactant: C[C@@H]1C(C(F)(F)F)=NN(c2ccc(O)cc2Br)[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: COc1cc(N2CC[C@H](O)[C@H](C)C2)c(Cl)cn1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: COc1ccc(Cl)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(N2CC[C@@H](Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CO[Si](C)(C)C(C)(C)C)c(Br)c3)[C@H](C)C2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 59 h
Yield: 90.1 %

Procedure:
A3E. 4-((3R,4R)-4-(3-Bromo-4(4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)phenoxy)-3-methylpiperidin-1-yl)-5-chloro-2-methoxypyridine: To a stirred solution of 3-bromo-4-((4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)phenol (10.2 mg, 0.022 mmol), (3R,4S)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol (81I, 11 mg, 0.042 mmol) and triphenylphosphine (13 mg, 0.049 mmol) in THF (0.2 mL) at rt was added di-tert-butylazodicarboxylate (11 mg, 0.047 mmol). The resulting solution was stirred at rt for 59 h and then evaporated The residue was chromatographed (SiO2, 96/4 CHCl3/Ether) to afford 4-((3R,4R)-4-(3-bromo-4-((4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)phenoxy)-3-methylpiperidin-1-yl)-5-chloro-2-methoxypyridine (14 mg, 66% yield) as a colorless oil: LC-MS [M+H] 705, 707, 709.
Reaction SMILES: [CH3:1]I.[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@@H:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C@:14]1([CH2:23][O:24][SiH:25]([CH3:27])[CH3:26])[OH:22])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].O>CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@@H:15]([C:18]([CH3:20])([CH3:21])[CH3:19])[C@:14]1([CH2:23][O:24][SiH:25]([CH3:27])[CH3:26])[O:22][CH3:1])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: C[SiH](C)OC[C@]1(O)[C@H](C(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@@]1(CO[SiH](C)C)[C@H](C(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
In DMF (10 ml), methyl iodide (0.53 ml, 8.51 mmol) was added to N-benzyloxycarbonyl-(2R)-tert-butyldimethylsilyloxymethyl-(3S)-hydroxypyrrolidine (2.60 g, 7.11 mmol) and sodium hydride (0.34 g, 14.2 mmol) under stirring at 0° C. The reaction mixture was stirred further at the same temperature for 13 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (6:1, v/v) eluate fractions, N-benzyloxycarbonyl-(2R)-tert-butyldimethylsilyloxymethyl-(3S)-methoxypyrrolidine (2.73 g, 100%) as a colorless oil.
Reaction SMILES: [F-].[Cs+].[CH3:3][C:4]1[C:5]([N:10]([C:24](=[O:40])[C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[N:6][CH:7]=[CH:8][CH:9]=1.[C:41](=[O:60])([O:45][C@H:46]([N:48]1[N:52]=[N:51][C:50]([C:53]2[N:57]([CH3:58])[N:56]=[CH:55][C:54]=2I)=[N:49]1)[CH3:47])[O:42][CH2:43][CH3:44].[Cl-].[NH4+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.CCOC(C)=O.O1CCOCC1>[CH2:43]([O:42][C:41]([O:45][C@H:46]([N:48]1[N:52]=[N:51][C:50]([C:53]2[N:57]([CH3:58])[N:56]=[CH:55][C:54]=2[C:28]2[CH:29]=[CH:30][C:25]([C:24]([N:10]([C:5]3[C:4]([CH3:3])=[CH:9][CH:8]=[CH:7][N:6]=3)[C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)=[O:40])=[CH:26][CH:27]=2)=[N:49]1)[CH3:47])=[O:60])[CH3:44]
Reactant: Cc1cccnc1N(C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)O[C@@H](C)n1nnc(-c2c(I)cnn2C)n1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)O[C@@H](C)n1nnc(-c2c(-c3ccc(C(=O)N(c4ncccc4C)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cc3)cnn2C)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A 3-neck round-bottom flask fitted with a reflux condenser was charged with dioxane (8.5 mL) and aqueous CsF (7.65 mL, 1M solution, 7.65 mmol). This was heated to 80° C. for 0.5 h under nitrogen atmosphere. After 30 min, Preparation 24, tert-butyl (3R)-3-{(3-methylpyridin-2-yl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]amino}piperidine-1-carboxylate (1.66 g, 3.19 mmol) was added followed by Preparation 23a, (S)-ethyl 1-[5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazol-2-yl]ethyl carbonate (1.00 g, 2.55 mmol), and Pd(amphos)Cl2 catalyst (90.6 mg, 0.128 mmol). The reaction was stirred at 80° C. for 5.5 h. Aqueous ammonium chloride solution (10 mL) was added followed by EtOAc (10 mL). The layers were separated, and the aqueous phase was further extracted with EtOAc (3×15 mL), dried with MgSO4, passed through a plug of silica, and concentrated. The crude material was purified via MPLC using a gradient of 20-70% EtOAc/heptane to afford tert-butyl (3R)-3-[{4-[5-(2-{(1S)-1-[(ethoxycarbonyl)oxy]ethyl}-2H-tetrazol-5-yl)-1-methyl-1H-pyrazol-4-yl]benzoyl}(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate as a colorless solid (1.05 g, 77%). 1H NMR (CDCl3) δ: 8.41 (d, 1H), 7.61 (s, 1H), 7.36-7.32 (m, 1H), 7.24-7.10 (m, 6H), 4.76-4.46 (m, 2H), 4.32 (q, 2H), 4.07 (s, 3H), 3.47-3.36 (m, 1H), 2.67-2.14 (m, 3H), 2.06-1.99 (m, 6H), 1.81-1.59 (m, 3H), 1.47 (s, 9H), 1.36 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH2:23]([O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O)[CH2:24][CH2:25][CH3:26].[O-]CC.[Na+]>C(O)C>[CH2:23]([O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1/[CH:30]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1c(C=O)cccc1OC
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)cccc1OC
Yield: 44.4 %

Procedure:
The title compound was synthesized by the condensation of Intermediate 15 (400 mg, 1.225 mmol) with 2-butoxy-3-methoxybenzaldehyde (337 mg, 1.716 mmol) in presence of sodium ethoxide (166 mg, 2.457 mmol) in ethanol (25 ml) according to the procedure described in Example 24 to give 281 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=6.9 Hz, 3H), 1.40-1.52 (m, 4H), 3.77 (s, 3H), 3.80-3.90 (m, 2H), 6.80-6.90 (m, 2H), 6.98-7.05 (m, 2H), 7.40-7.46 (m, 4H), 7.50 (d, J=4.8 Hz, 1H), 7.99 (d, J=6.0 Hz, 1H), 8.07 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 517.15 (M+H)+.
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[CH:17]([C:19]1[CH:20]=[C:21]([CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35])[O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=O>C(O)C>[O:2]=[C:3]1[NH:7][C:6](=[O:8])[C:5](=[CH:17][C:19]2[CH:20]=[C:21]([CH:31]=[CH:32][C:33]=2[N+:34]([O-:36])=[O:35])[O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:4]1
Reactant: CCOC(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCCOc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
Sodium (4.92 g, 0.21 g atom) was dissolved in absolute ethanol (600 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (50.5 g, 0.21 mole) added. After 10 minutes, a solution of ethyl 4-(3-formyl-4-nitrophenoxy)butanoate (50.0 g, 0.18 mole) in ethanol (100 mL) was added in one portion. The mixture was stirred for 2 hours, concentrated in vacuo to about 250 mL and diluted with water. After 20 minutes the precipitate was filtered off. Two further crops were subsequently collected from mother liquors. Combined solids were dried in vacuo over P2O5 to afford ethyl 4-[3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenoxy]butanoate (61.3 g, 95%) which by NMR was a 4:1 mixture of geometrical isomers. An analytical sample of the major isomer was obtained by crystallization from aqueous ethanol and had m.p. 131°-134° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=O.[CH3:17][C:18](=O)[CH2:19][C:20](=[O:22])[CH3:21]>C(O)(=O)C.S(=O)(=O)(O)O>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]1[C:19]([C:20](=[O:22])[CH3:21])=[C:18]([CH3:17])[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][C:4]=3[C:3]=12
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CCC2
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccco1)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a stirred solution of 50 mg (0.21 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-furan-2-yl-methanone in 2 ml acetic acid was added 0.016 ml (0.21 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 20 mg (31%) 1-(4-furan-2-yl-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a yellow solid. ES-MS m/e (%): 298 (M+H+, 100).
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3]C=1.FC1C=CC2NC=C3C(=O)N(C4C=CC=CN=4)N=C3C=2[N:29]=1>>[N:19]1([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][N:29]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccn1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccn1

Procedure:
The title compound was prepared following the procedure described for 6a using 5b instead of 5a. 1H-NMR (CDCl3) δ (ppm): 2.97 (4H, br), 3.72 (4H, br), 6.82 (1H, d, J=9.34 Hz), 7.42 (4H, m), 7.75 (1H, m), 8.17 (2H, d, J=7.97 Hz), 8.52 (1H, s). m/z 348.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=O.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([C:6]1[S:17][C:16]([NH2:18])=[N:15][N:14]=1)[CH3:9]
Reactant: CC(Oc1ccccc1Cl)C(=O)O
Reactant: NNC(N)=S
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(Oc1ccccc1Cl)c1nnc(N)s1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A 100 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condenser was charged with 10.0 grams (0.050 mole) of 2-(2-chlorophenoxy)propanoic acid, (4.6 grams, 0.050 mole) of thiosemicarbazide and 30 milliliters of dioxane. The slurry was heated to 90° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (8.4 grams, 0.055 mole) was slowly added (for 25 minutes) while maintaining the temperature within 85°-90° C. The resulting mixture was refluxed for 75 minutes and stood at ambient temperature for 16 hours. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane) at 60° C. and then the solution was cooled. Fifty (50) milliliters of water was added and 50 percent solution of NaOH was also added until the pH of the solution was 10; a solid precipitate formed. The solid precipitate was filtered off, washed with water, then dried in a vacuum oven at 80° C. to 9.8 grams of white crystals of 5-[1-(2-chlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazole. (Melting point 160°-164° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[N:7][CH:6]=[CH:5][N:4]=1.[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nccnc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nccnc1CBr

Procedure:
2-methoxy-3-methylpyrazine (0.943 mL, 8.06 mmol), N-bromosuccinimide (1.505 g, 8.46 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.132 g, 0.806 mmol) were heated at reflux in CCl4 (65.5 mL) (oil bath=100° C.) for 2.5 h. LCMS indicated formation of the product. The crude mixture was cooled, filtered and purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted with a CH2Cl2/hexanes mixture (0% to 100%). Related fractions were pooled and co-evaporated with toluene to afford a toluene solution (30 mL) of the product. To be used as it was for next step.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[N:6]2[CH3:12].[C:20]([C:22]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23]1)#[CH:21].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]([C:21]#[C:20][C:22]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[N:6]2[CH3:12]
Reactant: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(I)nc21
Reactant: C#CC1(O)CCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(C#CC3(O)CCCC3)nc21
Reaction time: 4 h
Yield: 87.7 %

Procedure:
6-Chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine (1076 g) was dissolved in 10 liters of tetrahydrofuran and 97.2 g of bistriphenylphosphine palladium dichloride, 26.4 g of cuprous iodide and 248 g of 1-ethynylcyclopentanol were added thereto. Into this mixture were added dropwise 331 ml of triethylamine within 15 minutes keeping the bulk temperature at not higher than 26° C. in a nitrogen atmosphere. After reacting at room temperature for 4 hours, the reaction solution was diluted with 10 liters of ethyl acetate and washed with 4 liters of a saturated ammonium chloride solution and 1 liter of brine. The organic layer was dried over 2 kg of anhydrous sodium sulfate and filtered followed by concentrating to an extent of 3 liters. The resulting residue was diluted with 4 liters of hexane-ethyl acetate (1:1), filtered and washed with 1 liter of hexane to give 732 g of 1-{2-[6-chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol. The yield was 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]3[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]3[CH:21]=[C:20]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cn(-c3cc(B(O)O)ccn3)ccc2=O)cc1
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(COc2cn(-c3cc(-c4ccccc4)ccn3)ccc2=O)cc1
Temperature: 135 °C

Procedure:
To a 20 mL microwave vial (Biotage) was added {3-[(4-methoxybenzyl)oxy]-4-oxo-4H-1,2′-bipyridin-4′-yl}boronic acid (300 mg, 0.85 mmol), iodobenzene (348 mg, 1.70 mmol), cesium carbonate (6 mL of a 1.0 M aq solution, 6.0 mmol), and 69.6 mg (0.085 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex. The vial was sealed and the reaction mixture was heated at 135° C. under microwave irradiation for 15 minutes, then cooled. The organic layer was separated, washed with 5 mL water, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-10% MeOH in EtOAc gradient) afforded 3-[(4-methoxybenzyl)oxy]-4′-phenyl-4H-1,2′-bipyridin-4-one. LCMS (M+H)+=385.4.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:14]=[C:13]([O:15][CH2:16]/[CH:17]=[C:18](/[C:34]2[CH:39]=[CH:38][C:37]([S:40][CH3:41])=[CH:36][CH:35]=2)\[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]>C(O)(=O)C.O>[CH3:3][C:4]1[CH:14]=[C:13]([O:15][CH2:16]/[CH:17]=[C:18](/[C:34]2[CH:35]=[CH:36][C:37]([S:40]([CH3:41])=[O:1])=[CH:38][CH:39]=2)\[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: OO
Reactant: CSc1ccc(/C(=C/COc2ccc(OCC(=O)O)c(C)c2)c2ccc(C#CCN3CCOCC3)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(S(C)=O)cc2)ccc1OCC(=O)O

Procedure:
30% Aqueous hydrogen peroxide (0.0613 mL, 0.6 mmol) was added to a solution of (E)-[2-methyl-4-[3-(4-methylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-allyloxy]-phenoxy]acetic acid (272 mg, 0.5 mmol; example 40) in glacial acetic acid (7 mL) at 5° C. under stirring. The mixture was left to stand over night at ambient temperature, diluted with water and extracted with ethyl acetate (2×30 mL). The collected extracts were alkalized with 15% solution of ammonium hydroxide; the solution was decanted from the separated oil and the oil was and dissolved in chloroform (45 mL). The solution was washed with water (2×10 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was triturated with hexanes (3×15 mL) to yield the title compound as pale solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([O:19]CC3C=CC=CC=3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(Cc1c[nH]c2c(OCc3ccccc3)cccc12)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(Cc1c[nH]c2c(O)cccc12)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 96.2 %

Procedure:
A mixture of [2-(7-benzyloxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (20.75 g, 52.6 mmol), 5% Pd/C (1.00 g, 5 wt %), and 3A ethanol (200 mL) is pressurized to 55 psig with H2, and is heated to 50° C. After 40 minutes, the slurry is filtered, and the filtrate is concentrated to give 15.41 g of [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (96%). FDMS m/e=305 (M++1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[C:36]([NH:44][NH2:45])(=O)[C:37]1[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=1>CC1C=CC(C)=CC=1>[C:29]1([C:19]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)=[N:28][C:22]3[O:23][CH2:24][C:25]4[N:26]([C:36]([C:37]5[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=5)=[N:44][N:45]=4)[C:21]=3[CH:20]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NNC(=O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: Cc1ccc(C)cc1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3cccnc3)CO4)cc2)CCC1
Temperature: 150 °C
Yield: 34.1 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (100 mg, 0.205 mmol) and nicotinic acid hydrazide (84 mg, 0.308 mmol) in p-xylene (2 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in cyclohexane) to give the title compound (33 mg, 25%). LCMS (Method D): RT=1.364 min, M+1=573. 1H NMR (500 MHz, CDCl3): 9.00 (1H, d), 8.87 (1H, dd), 8.10 (1H, dt), 7.56 (1H, dd), 7.36-7.27 (5H, m), 7.24-7.17 (3H, m), 6.99-6.93 (2H, m), 5.67 (2H, s), 2.56-2.39 (4H, m), 2.13-2.01 (1H, m), 1.88-1.75 (1H, m), 1.49-1.26 (9H, bs).