Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:15])=[CH:7][C:8]=2[CH3:14])[N:3]=1.P(Br)(Br)[Br:17]>C(Cl)Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[Br:17][CH2:12][C:11]1[C:2]([CH3:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH3:14])[CH:7]=[C:6]([CH3:15])[CH:5]=2
Reactant: BrP(Br)Br
Reactant: Cc1cc(C)c2cc(CO)c(C)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C)c2cc(CBr)c(C)nc2c1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of (2,5,7-trimethylquinolin-3-yl)methanol (42.1 mg, 0.205 mmol) in DCM (1.5 ml) was added PBr3 (0.039 ml, 0.410 mmol). Reaction mixture was stirred overnight at 23° C. Reaction mixture was diluted with ethyl acetate/NaHCO3 sat. aq solution. Layers were separated and aqueous layer was extracted once more with ethyl acetate. Organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (Method G) Rt=1.409 min, MS (Method V) [M+H]+=264.2, 266.2.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24]O)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[BrH:26].C1COCC1.[OH-].[Na+]>CC(O)=O>[Br:26][CH2:24][C:20]1[CH:19]=[C:18]([C:16]2[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(c1cc(-c2cccc(CO)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(c1cc(-c2cccc(CBr)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 0 °C

Procedure:
A suspension of the {3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-methanol compound from Step 3 above (30 g, 85 mmol) in AcOH (140 mL) and HBr (48 mL, 48% aq) was stirred for 18 h at 80° C. The resulting mixture was cooled to 0° C. and poured into 2L of cold NaOH (0.3N). The pH of the resulting solution was adjusted to 5 and filtered. The resulting solid was dissolved in EtOAc, washed with saturated NaHCO3 solution, brine, dried (MgSO4), filtered and concentrated. Stirring the solid in ether/EtOAc, followed by filtration gave desired 8-(3-Bromomethyl-phenyl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline as a pale brown solid.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([N:17]([CH3:19])[CH3:18])([C:15]#N)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([Mg]Cl)[CH:25]=[CH:24]C=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([N:17]([CH3:19])[CH3:18])([C:15]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CN(C)C1(C#N)CCC(OCc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.00 g of 4-benzyloxy-1-dimethylaminocyclohexanecarbonitrile were dissolved in 50 ml of tetrahydrofuran and, while cooling with an ice bath, 19.4 ml of two molar phenylmagnesium chloride solution in tetrahydrofuran were added dropwise under a nitrogen atmosphere. After stirring overnight at room temperature, cooling was again carried out in an ice bath, and 25 ml of cold ammonium chloride solution (20 percent by weight) were added. The phases were separated and extracted twice using 80 ml of diethyl ether each time, the combined organic phases were extracted three times using 60 ml of hydrochloric acid (5 percent by weight) each time, the combined acidic extracts were rendered weakly alkaline (pH 8–9) with aqueous ammonia solution (25 percent by weight), extraction was carried out three times using 80 ml of diethyl ether each time, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. The resulting yellow oil (4.15 g) was separated on silica gel with diethyl ether/hexane (V:V=1:1). 1.83 g of the non-polar and 0.38 g of the polar diastereoisomer of (4-benzyloxy-1-phenyl-cyclohexyl)dimethylamine were obtained in the form of a yellow solid and a yellow resin, respectively. 1.48 g of the non-polar diastereoisomer were dissolved in 11.8 ml of 2-butanone; 47 μl of water and 665 μl of chlorotrimethylsilane were added, and stirred overnight. The precipitated hydrochloride was filtered off, washed with diethyl ether and dried under a high vacuum. 1.55 g of the hydrochloride of the non-polar diastereoisomer of (4-benzyloxy-1-phenyl-cyclohexyl)dimethylamine (Example 1) were obtained in the form of a white solid. In an analogous manner, 300 mg of the corresponding hydrochloride (Example 2) were obtained from 379 mg of the polar diastereoisomer.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][CH2:11][O:12][C:13]1[C:17](=O)[C:15](=[O:16])[C:14]=1[O:19]CC>C(O)C>[CH2:11]([O:12][C:13]1[C:14](=[O:19])[C:15](=[O:16])[C:17]=1[NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9])[CH3:10]
Reactant: Cc1cccc(O)c1N
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2c(C)cccc2O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-amino-3-methylphenol (3.6 g, 29.2 mmol) and diethyl squarate (5 g, 29.4 mmol) in dry ethanol (80 mL) was heated to reflux for two days, then allowed to stand at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was suspended in ethyl acetate (50 mL). Hexane (50 mL) was added to produce a slurry, which was filtered, and rinsed with three portions of hexane:ethyl acetate (1:1). The resulting solid was suspended in dichloromethane (200 mL) and methanol (20 mL), stirred at room temperature for 30 minutes, and filtered. The precipitate was suspended in hot dichloromethane, filtered hot, and dried to give 3-ethoxy-4-(2-hydroxy-6-methylphenylamino)-cyclobut-3-ene-1,2-dione, 1.56 g (6.3 mmol, 22%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:16]4[CH:30]=[CH:29][C:19]([CH2:20][N:21]5[CH2:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]5=[O:28])=[C:18]([F:31])[CH:17]=4)=[C:13]([S:14][CH3:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[OH-:32].[Ca+2].[OH-:34]>C(Cl)(Cl)Cl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:16]4[CH:30]=[CH:29][C:19]([CH2:20][N:21]5[CH2:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]5=[O:28])=[C:18]([F:31])[CH:17]=4)=[C:13]([S:14]([CH3:15])(=[O:34])=[O:32])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: CSc1c(-c2ccc(CN3CC(=O)N(C)C3=O)c(F)c2)ccc2c1nnn2CC1CC1
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3S(C)(=O)=O)cc2F)C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-{4-[1-(cyclopropylmethyl)-4-(methylsulfanyl)-1H-benzotriazol-5-yl]-2-fluorobenzyl}-3-methylimidazolidine-2,4-dione (Example 15, 14 mg, 0.032 mmol) in chloroform (0.45 mL) at 0° C. was added meta-peroxychlorobenzoic acid (7.1 mg, 0.032 mmol). The mixture was stirred for 1.5 hours at 0° C. and then warmed to ambient temperature and stirred for an additional 14 hours. The mixture was cooled to 0° C. and treated with calcium hydroxide (3.3 mg, 0.045 mmol), stirred for 30 minutes and filtered. The filtrate was concentrated in vacuo and purified via preparative reversed-phase HPLC (5-95% MeCN/water+0.1% TFA) to provide the title compound: 1H NMR (400 MHz, CDCl3) 7.82 (d, 1H, J=8.0 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.39 (t, 1H, J=7.6 Hz), 7.17-7.23 (m, 2H), 4.70 (s, 2H), 4.61 (d, 2H, J=7.2 Hz), 3.89 (s, 2H), 3.67 (s, 3H), 3.06 (s, 3H), 1.41-1.47 (m, 1H), 0.71-0.76 (m, 2H), 0.54-0.58 (m, 2H) ppm. LRMS m/z (M+H) 472.2 found, 472.1 required.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClC(Cl)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH:25]([CH3:27])[CH3:26])[C:35](=[O:37])[CH3:36])[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(=O)Cl
Reactant: CC(C)Nc1ccccc1CCN1CCN(c2nsc3ccccc23)CC1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)N(c1ccccc1CCN1CCN(c2nsc3ccccc23)CC1)C(C)C
Reaction time: 72 h

Procedure:
{2-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-isopropyl-amine was diluted to 0.20 M with anhydrous dichloroethane, then delivered to an 8 mL vial via pipette (0.20 mmol). To the amine solution was added base (0.4 M triethylamine in dichloroethane, 0.40 mmol). Acetyl chloride was diluted to 0.20 M with dichloroethane, and added at rt (0.2 mmol). The reaction was shaken three days, with the temperature ramped from 50° C. to 85° C. An additional 0.20 mmol of acetyl chloride was added after the second day. Polyamine scavenging resin was added (0.5 mmol). The solution was shaken overnight at room temperature, and filtered into an 8 mL vial. The reaction was concentrated via HT-12 GeneVac, then purified by HPLC (30×100 mm ODS-A C(18) 5u column). N-{2-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-N-isopropyl-acetamide was isolated in 100% purity @ 254 nm, LCMS (APCI): 423 [M+H]+.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[S:15][CH3:16].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[C:19]=1[N+:25]([O-:27])=[O:26]>O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[C:19]=2[N+:25]([O-:27])=[O:26])=[CH:10][C:9]=1[S:15][CH3:16]
Reactant: CSc1cc(O)ccc1N
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
Method A2 Sodium hydride (148 mg) was added to dry DMSO (5.5 mL) and the mixture was stirred at RT for 20 minutes under Ar atmosphere. 4-amino-3-(methylthio)phenol (573 mg, 3.7 mmol) was added thereto, and the mixture stirred for 10 more minutes. Next, 4-Chloro-3-nitropyridin-2-amine (3.7 mmol) was added, and the mixture was heated to 100′C and stirred for 3 hours. After cooling down, water was added, and the mixture extracted three times with EtOAc. The combined organic layers were washed first with a saturated aqueous sodium hydrogen carbonate solution then water, dried over MgSO4 and evaporated to afford the title compound (657 mg, 61%) was obtained after purification by chromatography on silica gel (EtOAc-DCM, 1:1) as a red brown solid (Rf 0.56, EtOAc-DCM, 1:1).
Reaction SMILES: [H-].[Na+].Br.Cl[C:5]1[C:6]2[CH2:17][CH2:16][CH2:15][C:7]=2[C:8]2[N:9]([C:11]([NH2:14])=[N:12][N:13]=2)[N:10]=1.[CH3:18][CH2:19][CH:20]([OH:23])[CH2:21][CH3:22]>CN(C=O)C>[CH2:19]([CH:20]([O:23][C:5]1[C:6]2[CH2:17][CH2:16][CH2:15][C:7]=2[C:8]2[N:9]([C:11]([NH2:14])=[N:12][N:13]=2)[N:10]=1)[CH2:21][CH3:22])[CH3:18]
Reactant: CCC(O)CC
Reactant: Nc1nnc2c3c(c(Cl)nn12)CCC3
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)Oc1nn2c(N)nnc2c2c1CCC2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-Pentanol (20 ml) was initially charged under argon, admixed with sodium hydride (991 mg) and stirred at 50° C. for 1 h. Subsequently, 6-chloro-8,9-dihydro-7H-cyclopenta[d][1,2,4]-triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.017, 2.0 g), dissolved in 3-pentanol (20 ml) and DMF (100 ml), was slowly added dropwise within 1 h. After stirring for 1 h, the mixture was concentrated, and the residue was admixed with water and extracted four times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using a 40 g silica gel cartridge (dichloromethane-methanol gradient 0-10% in 50 min). The clean product fractions were combined and dried. 1.04 g of the title compound were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[OH-:8].[Na+]>O.O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:5]1[S:1](=[O:8])[C:2](=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:3]=[CH:4]1
Reactant: O=Cc1cccs1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1C(=Cc2cccs2)C=CC1=Cc1cccs1
Reaction time: 48 h

Procedure:
About 30 mmol (3.06 g) of 2,5-dihydrothiopnene-1-oxide (MW=102) (4) and 70 mmol=(7.84 g) (6.5ml) of thiophene-2-aldehyde (MW--112, d=1.2 g/cm3) were added to a solution containing 0.9 g of NaOH in 50 ml of H2O and 12.5 ml of tetrahydrofuran. The mixture was stirred for 2 days. Purification was performed by separation by column chromatography; the reaction mixture was applied to a column of silica gel/diethyl ether. The aldehyde was eluted with ether; the product was eluted with ethyl acetate. When the solvent was stripped off in vacuo, the product precipitated. The precipitate was filtered off with suction and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[Br:8].[N:23]1[CH:28]=[CH:27][N:26]=[C:25]2[S:29][C:30]([C:32](Cl)=[O:33])=[CH:31][C:24]=12>O1CCOCC1.O>[Br:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:18])[CH3:19])[CH:12]=2)=[CH:3][C:2]=1[NH:1][C:32]([C:30]1[S:29][C:25]2=[N:26][CH:27]=[CH:28][N:23]=[C:24]2[CH:31]=1)=[O:33]
Reactant: O=C(Cl)c1cc2nccnc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c(N)c2)c1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c(NC(=O)c3cc4nccnc4s3)c2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of N-(3-amino-4-bromophenyl)-3-(2-cyanopropan-2-yl) 62 (215 mg, 0.600 mmol) and thieno[2,3-b]pyrazine-6-carbonyl chloride 63 (238 mg, 1.2 mmol) in dioxane (1 mL) was stirred for 2 h in microwave at 100° C. The reaction mixture was poured out in water, precipitate filtered off and washed with water and dried. Crystallization with acetonitrile gave crude compound 64 (340 mg, 109%). A sample of compound 64 was purified by HPLC to give the title compound N-(2-bromo-5-(3-(2-cyanopropan-2-yl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 64. NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 7.62 (t, d=7.8 Hz, 1H), 7.72-7.80 (m, 3H), 7.96 (d, J=7.8 Hz, 1H), 8.06 (m, 2H), 8.57 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.90 (d, J=2.3 Hz, 1H), 10.55 (s, 1H), 10.76 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12]2[CH:13]=[CH:14][O:15][C:11]=2[CH:10]=[C:9]([CH:16]([NH:18][CH:19]2[CH2:21][CH2:20]2)[CH3:17])[CH:8]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][O:32][C@@H:31]([C:35](O)=[O:36])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:19]1([N:18]([CH:16]([C:9]2[CH:8]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]3[CH:13]=[CH:14][O:15][C:11]=3[CH:10]=2)[CH3:17])[C:35]([C@@H:31]2[O:32][CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:30]2)=[O:36])[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: COCCCOc1cc(C(C)NC2CC2)cc2occc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COCCCOc1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cc2occc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a solution of N-{1-[4-(3-methoxypropoxy)-1-benzofuran-6-yl]ethyl}-cyclopropanamine (200 mg) and (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (240 mg) in N,N-dimethylformamide (7 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (212 mg) and 1-hydroxybenzotriazole (140 mg) under ice-cooling, and then stirred at room temperature for 18 hours. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water, 10% aqueous citric acid solution and saturated saline, and then concentrated under reduced pressure to give tert-butyl (2R)-2-[(cyclopropyl{1-[4-(3-methoxypropoxy)-1-benzofuran-6-yl]ethyl}amino)carbonyl]morpholine-4-carboxylate [Ex(161-1)] (306 mg) as a yellow oil.
Reaction SMILES: C(=O)(O)O.C(OC(C1CC[N:13](C(N)=O)[CH2:12]C1)=O)C.N([C:23]1[CH:49]=[CH:48][C:26]([C:27]([NH:29][CH:30]([C:45]([OH:47])=[O:46])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]=2)=[O:28])=[CH:25][CH:24]=1)C(N)=N.C1CCCCC=1>CO.[Pd]>[NH2:13][CH2:12][C@H:23]1[CH2:24][CH2:25][C@H:26]([C:27]([NH:29][CH:30]([C:45]([OH:47])=[O:46])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]=2)=[O:28])[CH2:48][CH2:49]1
Reactant: CCOC(=O)C1CCN(C(N)=O)CC1
Reactant: N=C(N)Nc1ccc(C(=O)NC(Cc2cccc(Oc3ccccc3)c2)C(=O)O)cc1
Agent: [Pd]
Agent: O=C(O)O
Solvent: CO
Solvent: C1=CCCCC1
Product: NC[C@H]1CC[C@H](C(=O)NC(Cc2cccc(Oc3ccccc3)c2)C(=O)O)CC1

Procedure:
A solution of the compound (III) (0.62 g), a palladium black (0.15 g), and cyclohexene (2 ml) in methanol (30 ml) was allowed to react under reflux of methanol for 1.5 hours. The reaction mixture was suction filtered while hot to remove the solid materials, followed by concentrating in vacuo. N-(trans-4-aminomethylcyclohexylcarbonyl)-3-phenoxy-DL-phenylalanine (0.30 g) was obtained in the form of a white powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.[C:26]([O:30][C:31]([N:33]1[CH2:36][CH:35]([N:37]2[CH:41]=[C:40](I)[CH:39]=[N:38]2)[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:26]([O:30][C:31]([N:33]1[CH2:36][CH:35]([N:37]2[CH:41]=[C:40]([C:14]3[CH:13]=[N:12][C:11]([NH2:25])=[C:10]([C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[CH:15]=3)[CH:39]=[N:38]2)[CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(I)cn2)C1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)C1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylamine (BB8) (30 mg, 0.080 mmol), 3-(4-iodopyrazol-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (59 mg, 0.17 mmol), potassium carbonate (40 mg, 0.20 mmol), and Pd(dppf)Cl2 (3 mg, 0.01 mmol) in 1,4-dioxane (1.5 mL) and H2O (0.5 mL) was left to stir at 100° C. for 30 min in the microwave reactor. The mixture was passed through PL-Thiol MP SPE and the residue was concentrated in vacuo. The resulting oil was partitioned between EtOAc and water (3×). The combined organic extracts were treated with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep TLC (EtOAc:hexane (3:2)), giving 3-[4-(6-Amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-azetidine-1-carboxylic acid tert-butyl ester, MS (ES+): m/z=449 [MH+]. This material was left to stir at rt in a (1:1) DCM:TFA mixture for 15 min. The solid that formed was filtered off and dried in vacuo, affording the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=4.53 (d, J=8.1 Hz, 1H), 4.58 (d, J=7.3 Hz, 4H), 5.49 (quint, J=7.4 Hz, 1H), 7.49-7.56 (m, 1H), 7.60 (dd, J=15.4, 1.3 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 8.16 (s, 1H), 8.21 (s, 1H), 8.33 (d, J=2.3 Hz, 1H), 8.57 (d, J=2.0 Hz, 1H). MS (ES+): m/z=349.16 (100) [MH+]. HPLC: tR=1.99 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]([CH:4]([CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:5]([NH:7][CH:8]([C:11]1[C:12](=[O:29])[NH:13][C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)=[N:15][N:16]=1)[CH2:9]C)=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:4]([C:5]1[N:16]2[C:11]([C:12](=[O:29])[NH:13][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)=[N:15]2)=[C:8]([CH3:9])[N:7]=1)[CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:3])[CH3:2]
Reactant: CCOc1cc(Cc2nnc(C(CC)NC(=O)C(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)ccc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc(Cc2nn3c(C(CCCc4ccccc4)C(C)=O)nc(C)c3c(=O)[nH]2)ccc1OC

Procedure:
Analogously to Example 1, 123 mg (0.24 mmol) of 2-acetyl-N-{1-[3-(3-ethoxy-4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-5-phenylpentanamide and 41.0 mg (0.27 mmol) of phosphorus oxychloride are reacted to give 7-(1-acetyl-4-phenylbutyl)-2-(3-ethoxy-4-methoxybenzyl)-5-methylimidazo[5,1-f][1 ,2,4]triazin-4(3H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH2:7]2.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=3)[N:23]=2)=[CH:15][CH:14]=1.C[O-].[Na+]>CN1C(=O)CCC1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=3)[O:32][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([CH3:7])[C:11]=3[C:9]([OH:10])=[O:8])[N:23]=2)=[CH:17][CH:18]=1
Reactant: Oc1cccc(OCc2coc(-c3ccc(F)cc3)n2)c1
Reactant: Cc1cccc2c1C(=O)OC2
Agent: C[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(COc2cccc(OCc3coc(-c4ccc(F)cc4)n3)c2)c1C(=O)O
Temperature: 130 °C

Procedure:
1 g (6.8 mmol) of 7-methylphthalide and 2 g (7.0 mmol) of 3-[2-(4-fluorophenyl)oxazol-4 -ylmethoxy]phenol are dissolved in NMP. 3.9 ml of methanolic sodium methoxide (30% strength) are added, the methanol is distilled off, and the mixture is heated to 130° C. No formation of 2-{3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]phenoxymethyl}-6-methylbenzoic acid is observed. The 3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]phenol decomposes.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[N:10]=[C:11]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:12]2[CH:17]=[C:16]([CH:18]=O)[S:15][C:13]=2[N:14]=1>>[Cl:8][C:9]1[N:10]=[C:11]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:12]2[CH:17]=[C:16]([CH2:18][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[S:15][C:13]=2[N:14]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
N-Methylpiperazine was reacted with 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde via General Procedure B-3. Purification on silica yielded 2-chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine.
Reaction SMILES: C(OC([N:11]1[CH2:26][CH2:25][C:14]2([CH:16]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:21]([O:20][C:18]([NH:17][CH:16]1[C:14]2([CH2:13][CH2:12][NH:11][CH2:26][CH2:25]2)[CH2:15]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CC12CCN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CC12CCNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the title compound of step 5 (2.2 g, 6.10 mmol) in ethanol (60 ml) was added ammonium formate (1.15 g, 18.3 mmol) followed by palladium on activated carbon (10% palladium content, 1.94 g, 1.83 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to afford the title compound as a white foam (1.4 g, 6.1 mmol, yield 100%).