Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14]C)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17]OC)=[C:4]([CH:20](O)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=1.Cl>CO.O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([O:16][CH3:17])=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][CH:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:4]=2[CH:3]=1
Reactant: COCOc1cccc(OC)c1-c1ccc(N)cc1C(O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cccc2c1-c1ccc(N)cc1C(c1ccccc1)O2
Temperature: 85 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
The compound of Example 5E (3.449 g., 9.45 mmole) was dissolved in methanol (80 mL) containing 4N HCl in dioxane (80 mL)was stirred for 16 hours. The mixture was concentrated under reduced pressure, dissolved in chloroform washed with aqueous KHCO3, dried (Na2SO4), filtered and reduced under pressure. The residue was dissolved in toluene (450 mL), toluenesulfonic acid H2O (7.18 g.) was added and the solution was heated at 85° C. for 30 minutes. The mixture was cooled, washed with aqueous KHCO3, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on silica eluting with CH2Cl2 to provide the titled compound (2.49 g, 87%).
Reaction SMILES: OC(C(F)(F)F)=O.C([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22]2[CH:23]=[C:24]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH3:40])=[CH:34][CH:33]=3)[C:25]3[N:26]([CH:28]=[CH:29][N:30]=3)[N:27]=2)[CH2:16]1)C1C=CC=CC=1.C(N1CCCC(N)C1)C1C=CC=CC=1>C(O)(=O)C.[Pd].CO>[CH2:39]([O:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:24]2[C:25]3[N:26]([CH:28]=[CH:29][N:30]=3)[N:27]=[C:22]([NH:21][CH:17]3[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]3)[CH:23]=2)=[CH:37][CH:36]=1)[CH3:40]
Reactant: CCOc1ccc(Nc2cc(NC3CCCN(Cc4ccccc4)C3)nn3ccnc23)cc1
Agent: [Pd]
Agent: NC1CCCN(Cc2ccccc2)C1
Solvent: CO
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Nc2cc(NC3CCCNC3)nn3ccnc23)cc1
Yield: 6.8 %

Procedure:
To a mixture of a N-(1-benzylpiperidin-3-yl)-N8-(4-ethoxyphenyl)imidazo[1,2-b]pyridazine-6,8-diamine TFA salt (14 mg, 0.021 mmol), prepared by the method of example I(1) using 1-benzylpiperidin-3-amine in place of trans-1,4-diaminocyclohexane in step (1d), and MeOH (5 mL) in a 500 ml PARR bottle was added 10% Pd/C (20 mg) and 3 drops of glacial acetic acid. The PARR bottle was then charged with H2 at 55 psi and allow to shake at room temperature for hours. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC followed by neutralization with ion exchange resin to furnish 0.5 mg (7%) of the title compound 1H NMR (500 MHz, MeOH) δ ppm 7.57 (1H, s), 7.31 (1H, s), 7.24 (2H, d, J=8.7 Hz), 6.97 (2H, d, J=8.7 Hz), 5.89 (1H, s), 4.05 (2H, q, J=6.9 Hz), 3.85 (1H, m), 3.45 (1H, m), 3.10 (1H, m), 2.85 (1H, m), 2.75 (1H, m), 2.05 (1H, m), 1.90 (1H, m), 1.70 (1H, m), 1.55 (1H, m), 1.39 (3H, t, J=6.9 Hz), LC/MS, m/e 353 (M+1). HPLC Rt, 2.04 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[OH:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]2)[CH:36]=[CH:37][C:38]=1[OH:39]
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: CC(C)C(=O)c1cnc2ccc(-c3ccc(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (34 mg, 0.200 mmol) to afford the desired product (39 mg, 72%) as an off-white solid: ESI MS m/z 538 [C30H36ClN3O4+H]+.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:23][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[N:2][N:1]=3)[N:5]=2)[CH:11]=1)[C:17](=[O:20])[O:18][CH3:19]
Reactant: COC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(C)c1cccc(-c2ccc3nncn3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 2.25 g of [3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl carbamic acid, methyl ester, 0.42 g of sodium hydride (50% in oil) and 200 ml of dimethylformamide was stirred under argon, for 1 hour and then 0.55 ml of methyl iodide was added. This mixture was stirred overnight, then treated as described in Example 1, giving 1.3 g of the desired product as tan crystals, mp 195°-199° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:1]([N:10]1[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)N1CC=CCC1
Reaction time: 1.5 h

Procedure:
Benzoyl chloride (60 mmole) is added to a solution of 38 (60 mmole) in pyridine at 4 C. The mixture is allowed to stir for about 1-2 hrs and then further stirred at room temp for 12 hrs. The reaction mixture is made acidic and then extracted with methylene chloride. Following work-up and flash chromatography affords 39.
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Cl:32][C:33]1[C:34]([N:62]2[CH2:67][CH2:66][N:65]([CH2:68][C:69]3[CH:70]=[N:71][CH:72]=[N:73][CH:74]=3)[CH2:64][CH2:63]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:61]=[CH:60][C:45]([CH2:46][N:47]4[CH2:52][CH2:51][N:50](C(OC(C)(C)C)=O)[CH2:49][CH2:48]4)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:32][C:33]1[C:34]([N:62]2[CH2:63][CH2:64][N:65]([CH2:68][C:69]3[CH:70]=[N:71][CH:72]=[N:73][CH:74]=3)[CH2:66][CH2:67]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:61]=[CH:60][C:45]([CH2:46][N:47]4[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]4)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cncnc6)CC5)c(Cl)cnc4[nH]3)cc2)CC1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cnc2[nH]c(-c3ccc(CN4CCNCC4)cc3)nc2c1N1CCN(Cc2cncnc2)CC1
Yield: 55.6 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl 4-(4-(6-chloro-7-(4-(pyrimidin-5-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzyl)piperazine-1-carboxylate (15 mg, 0.025 mmol), TFA (0.2 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (7 mg, 56%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 2.32 (s, br, 4H, piperazine N(CH2)2), 2.64 (s, br, 4H, piperazine N(CH2)2), 2.72 (t, J=4.6 Hz, 4H, piperazine N(CH2)2), 3.50 (s, 2H, NCH2), 3.64 (s, 2H, NCH2), 3.70 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 7.45 (d, J=8.2 Hz, 2H, phenyl H-3 & H-5), 8.11 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.12 (d, J=8.3 Hz, 2H, phenyl H-2 & H-6), 8.80 (s, 2H, pyrimidine H-4 & H-6), 9.12 (s, 1H, pyrimidine H-2);
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH2:4][C:5](=O)[CH3:6].[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][CH2:17][CH2:18][S:19][C:20]2[N:24]=[C:23]([NH2:25])[NH:22][N:21]=2)=[CH:14][CH:13]=1>C(O)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][S:19][C:20]2[N:24]=[C:23]3[N:25]=[C:5]([CH3:6])[CH:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[N:22]3[N:21]=2)=[CH:26][CH:27]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1nc(SCCOc2ccc(Cl)cc2)n[nH]1
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)n2nc(SCCOc3ccc(Cl)cc3)nc2n1
Temperature: 135 °C
Yield: 64.7 %

Procedure:
A mixture of 1,1,1-trifluoro-2,4-pentanedione (114 mg, 0.739 mmol), 3-{[2-(4-chlorophenoxy)ethyl]sulfanyl}-1H-1,2,4-triazol-5-amine (200 mg, 0.739 mmol), and glacial acetic acid (1.5 mL) was added to a 50 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser and warmed in an oil bath to a gentle reflux at 135° C. The solution was heated for 15 hours. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 and 254 nm. The starting material 3-{[2-(4-chlorophenoxy)ethyl]sulfanyl}-1H-1,2,4-triazol-5-amine elutes with retention time of 6.04 min, and the product elutes with retention time of 7.98 min. The solution was allowed to cool to room temperature and added into stirring ice/water (15 mL) to precipitate the product. Solids were isolated by filtration, rinsed with 20 mL of water, and then dried under reduced pressure. The solid was dissolved in 5 mL of ethanol with gentle warming and allowed to cool. The fine white needles that formed were isolated by filtration, washed with 3 mL of cold ethanol, and dried to afford the title compound as off-white crystals (186 mg, 65% yield). EM (calc.): 388.0; MS (ESI) m/e: 389.0 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.85 (s, 1H), 7.31 (d, 2H), 7.00 (d, 2H), 4.33 (t, 2H), 3.62 (t, 2H), 2.69 (s, 3H). 19F NMR (DMSO-d6, 376 MHz) δ ppm: −67.56 (s).
Reaction SMILES: [N+](=C)=[N-].[C:4]([CH:7]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:6])[CH3:5].[C:27](O)(=O)C>CCOCC>[C:4]([CH:7]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:27])=[O:15])(=[O:6])[CH3:5]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(C)=O
Reactant: CC(=O)O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCC(O)CCCC(CCCCCCC(=O)OC)C(C)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approx. 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 8-acetyl-12-hydroxyheptadecanoic acid (9.9 g., 0.03 mole) in ether (50 ml.). The resulting solution is allowed to stand 4 hours at room temperature. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 8-acetyl-12-hydroxyheptadecanoate, a colorless viscous oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13]OC(=O)C)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.[BrH:18]>>[BrH:18].[Br:18][CH2:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[CH:6]2
Reactant: CC(=O)OCc1ccc2c(cnn2C(C)=O)c1
Agent: Br
Product: BrCc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A suspension of 1-acetyl-5-(acetoxymethyl)indazole (12-3) (3.0 g, 13 mmol) in aqueous hydrobromic acid (15 mL, 226 mmol) was stirred at room temperature for 25 hours. The solid was collected on a Buchner funnel and dried under vacuum for 12 hours. The filtrate was stirred at room temperature for additional 24 hours and more solid was collected. After drying under vacuum, title compound was obtained as a yellow solid (12-4, 3.48 g, 92%) which was used in the next synthesis step without further purification. 1H NMR (CDCl3) δ4.88 (s, 2H), 7.43 (d, 1H, J=8.8), 7.56 (d, 1H, J=8.8 Hz), 7.87 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]2[O:9][C:10]([C:12]3[C:20]4[C:15](=[CH:16][N:17]=[CH:18][CH:19]=4)[S:14][CH:13]=3)=[CH:11][C:3]=12.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][N:32]([CH:34]3[CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]3)[CH:33]=2)O1>>[NH:36]1[CH2:37][CH:34]([N:32]2[CH:33]=[C:29]([C:2]3[CH:7]=[N:6][C:5]([NH2:8])=[C:4]4[O:9][C:10]([C:12]5[C:20]6[C:15](=[CH:16][N:17]=[CH:18][CH:19]=6)[S:14][CH:13]=5)=[CH:11][C:3]=34)[CH:30]=[N:31]2)[CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: Nc1ncc(I)c2cc(-c3csc4cnccc34)oc12
Product: Nc1ncc(-c2cnn(C3CNC3)c2)c2cc(-c3csc4cnccc34)oc12

Procedure:
The title compound was prepared from 4-iodo-2-thieno[2,3-c]pyridine-3-yl-furo[2,3-c]pyridine-7-ylamine and tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate by a procedure analogous to Example 68 followed by deprotection by a procedure analogous to Example 64, Step B. 1H NMR (400 MHz, CD3OD): δ 9.29 (s, 1 H), 8.75 (s, 1 H), 8.63 (d, J=6.1 Hz, 1 H), 8.59 (d, J=6.1 Hz, 1 H), 8.26 (s, 1 H), 8.08 (s, 1H), 7.96 (s, 1H), 7.62 (s, 1H), 5.32 (m, 1H), 4.45 (m, 4H); MS (ESI): 389.18 [M+H]+; HPLC tR=0.25 min (HPLC: Analytical—2 min).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10](OC)[CH:9]=[CH:8][C:3]=1[C:4](OC)=O.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N#N>CCN(CC)CC.CCOC(C)=O.[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>[C:3]1([C:4]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: COC(=O)c1ccc(OC)cc1Br
Reactant: Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Compound 11 (106 mg, 0.43 mmol) and copper (I) iodide (1.6 mg, 2 mol %) were added to an oven-dried reaction flask containing toluene (2 mL) and Et3N (2 mL). The reaction mixture was stirred at room temperature for 5 min with N2 (g) bubbling. Bis(triphenylphosphine)palladium(II) dichloride (3 mg, 1 mol %) and a solution of compound 8 (63 mg, 0.43 mmol) in Et3N (1 mL) were added. The reaction mixture was stirred at 100° C. for 24 h. The reaction was cooled to room temperature, then diluted with EtOAc (50 mL) and washed with brine (3×20 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (20% EtOAc in hexanes) to afford compound 12 in 62.8% (84 mg) yield as a brown solid. 1H-NMR (CDCl3, 400 MHz) δ 8.00 (1H, d, J=8.4 Hz, Ar), 7.14 (1H, s, Ar), 6.93 (1H, d, J=1.6 Hz, Ar), 6.88 (1H, dd, J=8.4 Hz, 1.6 Hz, Ar), 6.81 (1H, dd, J=8.4 Hz, 1.6 Hz, Ar), 6.68 (1H, d, J=8.4 Hz, Ar), 4.79 (2H, s, NH2), 3.89 (6H, s, 2×OCH3), 3.76 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.9, 162.3, 151.4, 144.5, 132.8, 126.6, 122.9, 118.5, 117.9, 115.8, 115.6, 114.4, 107.6, 93.9, 92.6, 56.0, 55.7, 52.2; MS (ESI) m/z Calcd for C18H17NO4 (M+): 311.1, Found: 312.0 (M+H+).
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O>>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc[n+]1[O-]
Reactant: O=Cc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1cccc(F)c1

Procedure:
Following, the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 3-fluoro-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=215 (M+).
Reaction SMILES: [C:1]([C:4](=[C:9](OC)[CH3:10])[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].Cl.[C:14]([NH2:17])(=[NH:16])[CH3:15].[CH3:18][C:19]([CH3:22])([O-:21])[CH3:20].[K+:23].Cl>C1COCC1.CO.CC(C)=O>[CH3:18][C:19]([CH3:22])([O-:21])[CH3:20].[K+:23].[CH3:15][C:14]1[N:17]=[C:1]([CH3:2])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:9]([CH3:10])[N:16]=1
Reactant: CC(=N)N
Reactant: COC(=O)C(C(C)=O)=C(C)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1c(C)nc(C)nc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-acetyl-3-methoxy-2-butenoate (34.4 g, 0.2 mole), acetamidine hydrochloride (22.7 g), acetone (136 ml) and methyl alcohol (100 ml) were charged into a 1 L 3-necked, flask (fitted with addition funnel, condenser, agitator and nitrogen inlet). The reaction was blanketed with nitrogen, the agitator started and the batch cooled to between −5 and 0° C. While the batch was cooling, a solution of potassium t-butoxide was prepared (27 g in THF, 100 ml) under nitrogen. When the batch reached the correct temperature, the potassium t-butoxide solution was slowly charged, keeping the temperature below 5° C. The batch was allowed to warm to about 25° C. The reaction was complete after about 1.5 hours. Concentrated hydrochloric acid was charged dropwise to bring the pH to 7. The batch was concentrated under vacuum until no more volatiles were collected. Methyl t-butylether (140 ml) and water (85 ml) were charged. The batch was agitated for 10 minutes and the layers were then separated. The organic layer was concentrated under vacuum to afford a solid residue of methyl 2,4,6-trimethylpyrimidine-5-carboxylate, 35.8 g. The product was purified by crystallizing from methanol. m. p. 61–62° C., 1H NMR (CDCl3): δ2.44 (6H, s, CH3), δ2.61 (3H, s, CH3), δ3.88 (3H, s, OCH3). 13H CMR (CDCl3): δ168.57, δ168.00, δ164.83, δ123.71, δ52.87, δ26.38, δ23.26. HR-MS; Calculated for C9H13N2O2, m/z=181.0977. Found 181.0972.
Reaction SMILES: C([N:4]1[CH2:16][C:14]2=[C:15]3[C:10](=[CH:11][CH:12]=[CH:13]2)[C@@H:9]2[CH2:17][CH2:18][CH2:19][C@@H:8]2[N:7]3[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>CO>[CH2:6]1[N:7]2[C:15]3[C:10]([C@@H:9]4[CH2:17][CH2:18][CH2:19][C@@H:8]42)=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:16][NH:4][CH2:5]1
Reactant: CC(=O)N1CCN2c3c(cccc3[C@@H]3CCC[C@@H]32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1cc2c3c(c1)[C@@H]1CCC[C@@H]1N3CCNC2

Procedure:
(7bS, 10aS)-3-Acetyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]-diazepino[6,7,1-hi]indole was treated with solid NaOH in MeOH under reflux to give (7bS, 10aS)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino-[6,7,1-hi]indole (WAY-163907) mp: 54-56° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C1CCN2C(=NCCC2)CC1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[O:30][CH3:31].O>CC#N.CN(C=O)C>[CH3:31][O:30][C:22]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Nc1cc(O)ccn1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
To a suspension of 2-aminopyridin-4-ol (0.251 g, 2.28 mmol) in MeCN (4.0 mL) at RT was added DBU (423 μl, 2.80 mmol) and after 30 min a solution of 1-fluoro-2-methoxy-4-nitrobenzene (300 mg, 1.75 mmol) in DMF (2.0 mL) was added dropwise. The reaction mixture was maintained at RT for 1 hr and was then heated to 80° C. for 16 hr. After cooling to RT water (2.0 mL) was added and the mixture was evaporated in vacuo. The residue was partitioned between DCM (30 mL) and brine (20 mL) and the organic layer was separated and dried (MgSO4) and was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 20-100%, gradient elution) to afford 4-(2-methoxy-4-nitrophenoxy)pyridin-2-amine as a bright yellow solid (234 mg, 50%); Rt 1.25 min (Method 2); m/z 262 (M+H)+ (ES+).
Reaction SMILES: [H-].[Na+].[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[Br:15][C:16]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>CN(C)C=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:20]1[CH:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]([Br:15])[CH:21]=1)[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: COC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Br)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 163.6 %

Procedure:
Sodium hydride (60%, mineral oil; 0.985 g) was suspended in dimethylformamide (20 mL), and a solution of tert-butyl methyl malonate (4.29 g) in dimethylformamide (5 mL) was added dropwise thereto under ice-cooling. After foam generation is stopped, a solution of 2-bromo-4-fluoro-1-nitrobenzene (2.71 g) in dimethylformamide (5 mL) was added dropwise thereto at the same temperature, and the mixture was further stirred at 60° C. for 3 hours, and then concentrated. The residue was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel with ethyl acetate:hexane=1:4 to 1:5 to give the title compound (7.54 g) as an oil.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:23][C:24]#[N:25])[CH:14]=[C:15]([S:21][CH3:22])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:23]([C:24]#[N:25])[C:1]([O:5][CH2:6][CH3:7])=[O:8])[CH:14]=[C:15]([S:21][CH3:22])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)OCC
Reactant: CCCOc1c(OC)cc(CC#N)cc1SC
Solvent: Cc1ccccc1
Product: CCCOc1c(OC)cc(C(C#N)C(=O)OCC)cc1SC
Yield: 92 %

Procedure:
1.4 g of sodium was dissolved in absolute EtOH with warming to 70° C., then EtOH was removed under vacuum to give a white solid residue of NaOEt. A mixture of 35 ml of diethyl carbonate, 43 ml of toluene, 13.46 g of 3-methoxy-5-methylthio-4-propoxyphenyl acetonitrile was added slowly. The mixture was refluxed for 3 hours. EtOH was removed under vacuum. The solid was filtered and washed with toluene (3×) and ether (3×). The solid was suspended in 200 ml of H2O and acidified with 6N HCl. The solid dissolved and a brown oil formed. The oil was extracted with ether (3×), the combined ether extracts were washed with H2O (2×), saturated NaCl (2×) and finally dried over MgSO4. The ether was removed under vacuum to give 16 g (92% yield) of ethyl 3-methoxy-5-methylthio-4-propoxy-α-cyanobenzeneacetate.