Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:6][CH2:5]2)[O:3]C1>Cl.[Pd]>[N:13]1[CH:14]=[CH:15][C:10]([CH:7]2[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: C1=C(c2ccncc2)CCC2(C1)OCCO2
Agent: [Pd]
Agent: Cl
Product: O=C1CCC(c2ccncc2)CC1
Yield: 83.7 %

Procedure:
4 g of 4-(4-pyridyl)cyclohex-3-enone ethylene acetal was dissolved in 70 ml of 0.5 N hydrochloric acid and 400 mg of 10% palladium/carbon was added thereto, to hydrogenate the starting compound at room temperature and atmospheric pressure. After the completion of the reaction, the catalyst was removed and the reaction mixture was made alkaline with an aqueous solution of sodium hydroxide and extracted with methylene chloride to thereby give 2.7 g of 4-(4-pyridyl)cyclohexanone. NMRδTMSCDCl3 : 1.7-2.3 (4H, m), 2.4-2.6 (4H, m), 2.8-3.2 (1H, M), 7.15 (2H, d) and 8.51 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH4+:11].[Cl-].[C-:13]#[N:14].[K+]>N>[NH2:11][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:9])[C:13]#[N:14]
Reactant: [NH4+]
Reactant: CC(=O)c1cccc(Br)c1
Reactant: [C-]#N
Agent: N
Agent: [Cl-]
Agent: [K+]
Product: CC(N)(C#N)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-(3-bromo-phenyl)-ethanone (10 g, 50 mmol), NH4Cl (6.4 g, 100 mmol) and KCN (6.5 g, 100 mmol) was dissolved in ammonia (200 ml). The solution was stirred at room temperature for 3 days. The mixture was extracted with diethylether (3×300 ml). The organic phase was washed with water and brine, dried with Na2SO4 and concentrated in vacuo to yield the title compound (also containing some unreacted starting material).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH:20]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1)([CH3:22])[CH3:21]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([CH2:29][N:26]4[CH2:25][CH2:24][N:23]([CH:20]([CH3:22])[CH3:21])[CH2:28][CH2:27]4)=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 537.0 [M+H]+; single peak at tR=3.08 min (System 1); Rf=0.12 (CH2Cl2/MeOH+1% NH3aq, 95:5).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])(=O)C>CO.Cl>[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:12]
Reactant: CC(=O)Nc1ccccc1C(=O)C1CCCCC1
Agent: Cl
Solvent: CO
Product: Nc1ccccc1C(=O)C1CCCCC1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of (2-acetamidophenyl) cyclohexyl methanone (0.53 g, 2.16mmol) in methanol (5 ml) and concentrated hydrochloric acid (15 ml) was heated at 80° C. for 1 hour. After this time the solution was cooled to ambient temperature and the solvents removed in vacuo. The residue was dissolved in water (10 ml) and basified with 4N sodium hydroxide solution (20 ml). The mixture was then extracted into ethyl acetate (4×20 ml) and the organic layers combined and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica in 2:1 petrol:ethyl acetate, to afford the amine (0.40 g, 91%) as a white solid. mp 73°-75° C. 1H NMR (360MHz, CDCl3) δ1.23-2.09 (10H, m), 3.27 (1H, m), 6.29 (2H, brs), 6.64 (2H, m), 7.25 (1H, dt, J=6 and 1Hz), 7.76 (1H, dd, J=7 and 1Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][CH2:18][OH:19])=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][CH:18]=[O:19])=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CCO)cc(OC)c1OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1cc(CC=O)cc(OC)c1OCc1ccccc1
Reaction time: 6 h
Yield: 57.9 %

Procedure:
To a solution of 2-(4-benzyloxy-3,5-dimethoxy-phenyl)-ethanol (1.0 g, 3.3 mmol) in dichloromethane (25 mL) was added Dess-Martin reagent (1.54 g, 3.6 mmol) and water (59 μL). After completion of addition the reaction continued to stir for 6 hours. The resulting precipitate was filtered off and the filtrate was concentrated. The crude material was purified using silica gel chromatography (gradient from 1:2 ethyl acetate:hexane to 1:1 ethyl acetate:hexane) to obtain the desired compound as a yellow oil (547 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.[C:24](=O)(O)[O-].[Na+].ClC[C:31]1[N:32]=[C:33]([C:36]2[CH:40]=[CH:39][S:38][CH:37]=2)[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23]([C:31]2[N:32]=[C:33]([C:36]3[CH:40]=[CH:39][S:38][CH:37]=3)[S:34][CH:35]=2)[CH3:24])[N:3]=1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Reactant: ClCc1csc(-c2ccsc2)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc([SH](C)c3csc(-c4ccsc4)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 96.4 mg (0.46 mmol) of 4-chloromethyl-2-(thiophen-3-yl)-1,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 141 mg (82% of theory) of product.
Reaction SMILES: [O:1]=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C@H:10](C(O)=O)[CH2:11][C:12](=[O:14])[NH2:13].C>O1CCOCC1>[N-:13]=[C:12]=[O:14].[CH3:4][O:3][C:2](=[O:1])[C@H:10]([CH2:11][C:12](=[O:14])[NH2:13])[NH2:9]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)C[C@H](N)C(=O)O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CC(N)=O
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of the methyl ester of asparagine and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the filtrate is fractionally distilled to give asparagine methyl ester isocyanate.
Reaction SMILES: N1([C:6]([N:8]2[CH2:12][CH:11]=[N:10]C2)=[S:7])CC=NC1.N1C=CN=C1.[Cl:18][C:19]1[C:24]([S:25][CH3:26])=[C:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:22]=[C:21]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[N:20]=1.[C:40]1(N)[C:41](N)=CC=[CH:44][CH:45]=1>CC#N>[NH2:10][C:11]1[CH:44]=[CH:45][CH:40]=[CH:41][C:12]=1[NH:8][C:6]([NH:39][C:36]1[CH:37]=[CH:38][C:33]([C:21]2[N:20]=[C:19]([Cl:18])[C:24]([S:25][CH3:26])=[C:23]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:22]=2)=[CH:34][CH:35]=1)=[S:7]
Reactant: CSc1c(Cl)nc(-c2ccc(N)cc2)nc1N1CCOCC1
Reactant: Nc1ccccc1N
Reactant: S=C(N1CC=NC1)N1CC=NC1
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CSc1c(Cl)nc(-c2ccc(NC(=S)Nc3ccccc3N)cc2)nc1N1CCOCC1
Temperature: 0 °C
Yield: 93.2 %

Procedure:
A mixture of bis-(2,5-dihydro-imidazol-1-yl)-methanethione (29.2 mg, 0.164 mmol), imidazole (3.7 mg, 0.05 mmol, 0.5 eq) in CH3CN (5 ml) was stirred at 0° C., then added dropwise to a slurry of 4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (50 mg, 0.109 mmol.). The resulting mixture was reacted 3.0 hrs at r.t. and then benzene-1,2-diamine (23.6 mg, 0.218 mmol, 2.0 eq) was added thereinto. The reaction resulted in a white solid, which was filtered, collected and evaporated in vacuo to give 49.5 mg of a white compound (68.5%).
Reaction SMILES: Cl.C(O[C:7](=[O:28])[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:21]3[N:22]=[C:23]([NH2:25])[S:24][C:20]=3[CH2:19]2)[CH2:11][CH2:10]1)(C)(C)C.C(O)(=O)[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=N[CH2:45][CH2:46][CH2:47]N(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>O1CCOCC1.C1COCC1>[NH2:25][C:23]1[S:24][C:20]2[CH2:19][C@@H:18]([N:17]([CH2:45][CH2:46][CH3:47])[CH2:16][CH2:15][C@H:12]3[CH2:11][CH2:10][C@H:9]([NH:8][C:7](=[O:28])[CH:30]=[CH:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:14][CH2:13]3)[CH2:27][CH2:26][C:21]=2[N:22]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN[C@H]2CCc3nc(N)sc3C2)CC1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C=Cc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCN(CC[C@H]1CC[C@H](NC(=O)C=Cc2ccccc2)CC1)[C@H]1CCc2nc(N)sc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.0 M HCl solution in dioxane (1.0 mL, 4.0 mmol) was added to a solution of compound 20 (87 mg, 0.2 mmol) in dioxane (10 mL) and the reaction mixture was stirred at room temperature for 2 hours. Solvent was evaporated in vacuo and the residue was used directly for the next step without further purification. To a solution of the residue in THF (20 mL) were added cinnamic acid (29 mg, 0.2 mmol), EDCI (38 mg, 0.2 mmol), HOBT (27 mg, 0.2 mmol), and DIPEA (103 mg, 0.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. Solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, and dried over anhydrous Na2SO4. Flash column chromatography (MeOH/EtOAc, 1:6) gave compound 12 as a colorless oil (75 mg, 80%). 1H NMR (CDCl3, 300 MHz) δ 7.63 (d, J=15.6 Hz, 1H, 7.52-7.35 (m, 5H), 6.39 (d, J=15.6 Hz, 1H), 5.60 (s, broad, 1H), 4.90 (s, 2H), 3.95-3.80 (m, 1H), 3.30-2.30 (m, 8H), 2.20-1.95 (m, 3H), 1.93-1.02 (m, 13H), 0.92 (t, J=6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 165.87, 165.05, 144.85, 140.66, 134.92, 129.54, 128.77, 127.73, 121.10, 69.73, 57.86, 52.54, 48.71, 35.18, 33.06, 31.80, 30.84, 26.34, 25.36, 24.76, 18.88, 11.79; HRMS-Electrospray (m/z): [M+H]+ calcd 467.2845. found 467.2830; purity HPLC 95.4%, tR=29.227 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:43])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([C:27]5[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:43])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(-c5ccncc5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(-c4ccncc4)cc3)cc12
Yield: 24.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4-(pyridin-4-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (120 mg, 0.19 mmol) was hydrolyzed by lithium hydroxide (36.7 mg, 0.27 mmol), in THF/Methanol/water (2/2/1 ml) to afford 22 mg 24.3% yield of pure compound after purification by preparative TLC (SiO2) using 5% methanol in chloroform as eluent. 1H NMR (DMSO-d6, 300 MHz): δ 8.44-8.3 (b, 1H), 7.899-7.877 (d, 1H), 7.767-7.743 (s, 1H), 7.44 (m, 1H), 7.34-7.30 (m, 1H), 7.02-6.99 (m, 1H), 6.87-6.84 (m, 1H), 5.32 (s, 1H), 2.16 (s, 6H). MS: 453.2 m/z=(M+1), HPLC: 93.5% in method A.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[OH:22][C:23]1[C:24]([CH3:38])=[C:25]([CH3:37])[C:26]2[O:30][CH:29]([CH2:31][CH2:32][CH2:33]O)[S:28][C:27]=2[C:35]=1[CH3:36].CN(C)[CH:41]=[O:42]>>[Br:20][CH2:33][CH2:32][CH2:31][CH:29]1[S:28][C:27]2[C:35]([CH3:36])=[C:23]([O:22][CH:41]=[O:42])[C:24]([CH3:38])=[C:25]([CH3:37])[C:26]=2[O:30]1
Reactant: BrBr
Reactant: CN(C)C=O
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(C)c2c(c(C)c1OC=O)SC(CCCBr)O2

Procedure:
1.5 g of triphenylphosphine was dissolved in 3 ml of dimethylformamide, and then a solution of 0.9 of bromine in 2 ml of dimethylformamide was added dropwise. The mixture was allowed to react for 30 minutes at room temperature, after which 0.5 g of 3-(5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 71) was added. The reaction mixture was allowed to react for a further 20 hours at room temperature. The same treatment and separation procedures as described in Example 75 were carried out. From the fraction eluted first was obtained 2-(3-bromopropyl)-5-formyloxy-4,6,7-trimethyl-1,3-benzoxathiole.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: CN1CCN(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (22 mg, 0.05 mmol, 1 eq), DIPEA (17 μl, 0.10 mmol, 2 eq) and TBTU (18 mg, 0.055 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 30 min before the addition of 1-amino-4-methylpiperazine (12 μl, 0.1 mmol, 2 eq). The RM was then stirred at rt for 4 hours before purifying by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide (white solid, 8 mg, 30%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][CH2:19][C:18]=1[CH3:25])(=[O:3])[CH3:2].O.C([O:31]O)(C)(C)C>C1CCCCC1.O.[Ru](Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][C:19](=[O:31])[C:18]=1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CC(=O)OCCCCCCCCCCCCC1=C(C)CCCC1(C)C
Agent: Cl[Ru](Cl)Cl
Solvent: C1CCCCC1
Solvent: O
Product: CC(=O)OCCCCCCCCCCCCC1=C(C)C(=O)CCC1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(12-acetoxydodecyl)-2,6,6-trimethyl-1-cyclohexene (321 mg) in cyclohexane (6 ml) was added water (0.8 ml), ruthenium trichloride hydrate (1.3 mg) and 70% t-BuOOH (1.26 ml). The solution was stirred at room temperature for 6 hours, filtered through a pad of celite and poured into a solution of 10% Na2SO4. The solution was extracted with ethanol, washed with brine, dried with MgSO4 and distilled off under reduced pressure. The residue was purified by chromatography over silica gel to give 3-(12-acetoxydodecyl)-2,4,4-trimethyl-2-cyclohexen-1-one as a colorless oil (227 mg). TLC: (hexane-AcOEt: 3-7) Rf=0.68
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13]C(N)=O>P(O)(O)O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=O
Agent: OP(O)O
Product: NC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 94.3 %

Procedure:
334 g (2.0 mol) of 4-nitrobenzoic acid, 120 g (2.0 mol) of urea and 2.0 g of phosphorous acid are heated in 1000 ml of the organic mother liquor from the preceding experiment, with stirring, at from 158° to 163° C. The mixture is worked up as described above. 313.4 g of 4-nitrobenzamide are obtained having a melting point of from 192° to 195° C. This corresponds to a yield of 94.4% of theory. By acidification of the aqueous mother liquor to pH 2, 8.8 g of 4-nitrobenzoic acid (2.6% of theory) are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.[C:45](=O)([O:56][CH:57]1[CH2:61][CH2:60][O:59][CH2:58]1)[O:46]C1C=CC([N+]([O-])=O)=CC=1>C(Cl)Cl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][C:45](=[O:46])[O:56][CH:57]3[CH2:61][CH2:60][O:59][CH2:58]3)[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CNC(=O)OC2CCOC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (18 mg, 0.032 mmol) and triethylamine (22 μL, 0.16 mmol) in methylene chloride (1 mL) was added 4-nitrophenyl tetrahydrofuran-3-yl carbonate (9.8 mg, 0.039 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.8 mg, 12%). LCMS calculated for C22H29N4O4S (M+H)+: m/z=445.2. Found: 445.0.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19][CH2:20]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,3dibromopropane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,3-dibromopropane, the crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 792 mg (52%). 1H-NMR (400 MHz, d6-DMSO) δ=2.01 (tt, J=7.0, 6.6 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H), 3.95 (t, J=7.0 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 7.74 (d, J=9.0 Hz, 2H), 9.02 (s, 2H). 13C-NMR (100 MHz, d6-DMSO) δ=30.38, 32.13, 52.72, 103.17, 113.83, 119.74, 134.63, 144.14, 151.65. LRMS (FAB+): 306.0 (100, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[O:12][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: ClCCN1CCOCC1
Reactant: CC(=O)Nc1ccc(Cl)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)Nc1ccc(Cl)c(OCCN2CCOCC2)c1
Yield: 69 %

Procedure:
The compound 23a was prepared by using the general procedure H, as given in Example 9, in 69% yield starting from 17a, with 2.5 eq of cesium carbonate and 1.1 eq of 4-(2-chloroethyl) morpholine hydrochloride.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]2[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=2[C:19]([N:27]=[C:28]=[O:29])=[CH:18][CH:17]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI>>[Cl:15][C:16]1[C:21]2[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=2[C:19]([N:27]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[N:3]([CH3:30])[C:28]2=[O:29])=[CH:18][CH:17]=1
Reactant: CC1(C)Cc2c(Cl)ccc(N=C=O)c2O1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3c2OC(C)(C)C3)c1=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 0.40 g (0.01 0 mole) of sodium hydride and 1.83 g (0.10 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate was cooled to -20° C. To this mixture was slowly added 2.23 g (0.01 mole) of 4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-yl isocyanate. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature at which it was stirred for one hour. At the conclusion of this period the reaction mixture was heated to 85° C. at which it was stirred for approximately 16 hours. Then 1.38 g (0.01 mole) of potassium carbonate and 2.80 g (0.020 mole) of methyl iodide were added to the reaction mixture, and it was heated at 75° C. for seven hours. At the conclusion of this period the mixture was filtered, and the filtrate diluted with 200 mL of water. This mixture was extracted with diethyl ether. The extracts were dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated from the filtrate under reduced pressure, leaving a yellow oil as residue. This oil was passed through a column of silica gel, eluting with methylene chloride:heptane (70:30). Product-containing fractions were combined, and the solvent was evaporated under reduced pressure, leaving a solid residue. This residue was washed with petroleum ether, yielding 1.50 g of 3-(4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil (Compound 3), m.p. 152°-153° C. The NMR spectrum was consistent with the proposed structure.