Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[I:20][CH3:21]>CCCCCC>[I-:20].[CH2:14]([P+:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCP(CCCCCC)CCCCCC
Reactant: CI
Solvent: CCCCCC
Product: CCCCCC[P+](C)(CCCCCC)CCCCCC
Product: [I-]
Yield: 85 %

Procedure:
To 143 g (0.5 mol) of a commercially available tri-n-hexylphosphine (reagent, manufactured by Tokyo Chemical Industry Co., Ltd.), 71 g (0.5 mol) of iodomethane (reagent, manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise under a nitrogen atmosphere, and the mixture was reacted at 30 to 40° C. for 5 hours. After the reaction was completed, 100 ml of hexane was added to the reaction mixture to separate layers. The resulting liquid was then washed three times with hexane and vacuum dried under a degree of vacuum of 0.5 kPa at 80° C. for 3 hours to obtain 182 g (yield 85%) of tri-n-hexylmethylphosphonium iodide. To 129 g (0.3 mol) of the resulting tri-n-hexylmethylphosphonium iodide, was added 129 g of pure water. To the mixture with stirring, was added 86 g (0.3 mol) of lithium bis(trifluoromethylsulfonyl)imide (reagent, manufactured by Kanto Chemical Co., Inc.) to allow them to react with each other, followed by stirring for 2 hours at room temperature to complete the reaction. After the completion of the stirring, the lower layer side (product) was separated from the mixture in the form of an upper and lower two-layer structure, washed four times with pure water, and then washed four times with n-hexane. After the completion of the washing, the product was vacuum dried under a degree of vacuum of 0.5 kPa at 80° C. for 3 hours. The structure of the resulting product was examined by 1H-NMR, 13C-NMR, 19F-NMR, and 31P-NMR. The product was identified as tri-n-hexylmethylphosphonium bis(trifluoromethylsulfonyl)imide (THMP-TFSI), and it had a purity of 99%. The resulting THMP-TFSI was a colorless transparent liquid at room temperature (25° C.), which had a moisture content determined by the Karl Fischer titration method of 104 ppm and a chlorine content determined by ion chromatography of 8 ppm. The amount of the product yielded was 140 g (yield 80%). The product had an electrical conductivity at 25° C. of 0.20 mS/cm.
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]1[CH2:14][C:13]2[C:8]3=[C:9]([N:15]([O:18][CH3:19])[C:16](=[O:17])[N:7]3[CH2:6]1)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH3:3].I[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C@@H:5]1[CH2:14][C:13]2[C:8]3=[C:9]([N:15]([O:18][CH3:19])[C:16](=[O:17])[N:7]3[CH2:6]1)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH3:3]
Reactant: CCCI
Reactant: CCCN[C@@H]1Cc2cccc3c2n(c(=O)n3OC)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(CCC)[C@@H]1Cc2cccc3c2n(c(=O)n3OC)C1
Yield: 80.5 %

Procedure:
Following the procedure of Example 3, a mixture of (R)-5-Propylamino-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (8b, 0.93 g,3.56 mmol), 1-iodopropane (3.05 g, 17.9 mmol), and potassium carbonate (1.97 g, 14.3 mmol) in acetonitrile (25 ml) was heated at reflux under nitrogen for 17 hours. 1-Iodopropane (3.05 g, 17.9 mmol) was again added, and the mixture was refluxed for an additional 5 hours. The solvent was removed under vacuum, and the mixture was diluted with water and extracted twice with diethylether. The organic extract was washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave an amber oil. Purification by flash chromatography (230-400 mesh silica gel; 10-25% ethyl acetate in hexane) gave the title compound (9b) as an amber oil (0.87 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[CH:25]=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[C-]#N.[Na+].C[C:35](O)=[O:36]>CO.C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[C:25]([O:36][CH3:35])=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=Cc1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a solution of the aldehyde of Step 6 (17.26 g, 41.7 mmol) in 1.5 L of MeOH:THF 2:1, NaCN (20 g, 408 mmol), AcOH (5.7 mL, 98.9 mmol) and activated MnO2 (90 g, 1.01 mol) were added and the mixture was stirred for 16 h. The inorganic solid was then removed by filtration and washed with EtOAc. To the combined organic phases, 25% aq NH4OAc (1.7 L) was added. The two phases were separated and the aqueous layer was reextracted with EtOAc. The organic phases were washed with brine and dried over Na2SO4. Flash chromatography of the residue on silica with toluene and EtOAc:toluene 2.5:97.5 afforded 15.63 g (84%) of the title ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:10]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:10]=2)[N:3]=1
Reactant: CS(=O)(=O)c1cccc(-c2cc(Cl)nc(Cl)n2)c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CS(=O)(=O)c1cccc(-c2cc(N3CCOCC3)nc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 38540 %

Procedure:
2,4-dichloro-6-(3-(methylsulfonyl)phenyl)pyrimidine (220 mg, 0.72 mmol, 1 eq) was dissolved in EtOH (5 mL) and DIEA was added (0.31 mL, 2.2 mmol, 3 eq). The reaction mixture was cooled to 0° C. and morpholine (94 mg, 1.1 μmol, 1.6 eq) was added. The reaction mixture was stirred at room temperature for 3 days. The ethanol was concentrated under reduced pressure and the residue was partitioned between EtOAc and sat. aq. NaHCO3. The organic layer was separated, washed with water and dried (Na2SO4). The residue was purified by column chromatography on silica gel (3% EtOAc/DCM to 40% EtOAc/DCM) to obtained the desired product (150 mg, 58%). LCMS (m/z): 302.8 (MH+), Rt: 1.51 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11])=[O:4].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.[ClH:36]>O1CCCC1.C(OCC)C>[ClH:36].[CH3:16][O:15][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[CH:14][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)CN2CCN(c3ccccc3)CC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 15.0 g (0.0522 mol) of methyl 5-(bromoacetyl)-2-methoxybenzoate in 500 ml of anhydrous tetrahydrofuran is added dropwise over 2-4 hours to a solution of 8.48 g (0.0522 mol) of 1-phenylpiperazine and 5.28 g (0.0522 mol) of triethylamine in 100 ml of tetrahydrofuran. The mixture is stirred at room temperature under exclusion of moisture overnight. The precipitated triethylamine hydrobromide is removed by filtration and the filtrate is evaporated to dryness. Addition of 2 equivalents of methanolic HCl and precipitation by addition of ethyl ether yields crude 2-methoxy-5-[2-(4-phenyl-1-piperazinyl)acetyl]benzoate hydrochloride (21.0 g) that can be used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](CO)=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OCc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccc(Cl)cc4)c(C)c3C)c2cc1OC
Yield: 67.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (4-chlorophenyl)methanol (67 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (103 mg, yield 63%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.IC.[C:13](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)nc(C)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C)cc(Br)nc1C
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A mixture of 6-bromo-2,4-dimethyl-3-hydroxypyridine (8.7 g, 43.1 mmol), iodomethane (4.0 mL, 64.6 mmol) and potassium carbonate (11.9 g, 86.1 mmol) in acetone (250 mL) was heated at reflux temperature for 3 hours. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography using 20% ethyl acetate in hexane to afford 7.9 g (85%) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[OH:10]O.O>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([OH:10])=[O:5])[CH3:2]
Reactant: OO
Reactant: CCCCC(CC)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: CCCCC(CC)C(=O)O
Temperature: 40 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 2-ethyl hexanol (8.7 mmol) in CH2Cl2 (10 ml), RuCl3H2O (0.014 mmol) and tetra butyl ammonium bromide (0.2 mmol) were added. The mixture was heated at 40° C. and 30% H2O2 (v/v) (3 ml) was added dropwise. After 1 hours the reaction was complete. Water is added, the organic phase was separated, dried over sodium sulphate and evaporated under reduced pressure to give the crude product of the title that was purified by flash chromatography (pure CH2Cl2) obtaining 0.8 g of the desired product. Yield 65%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])[N:5]=[N:4][C:3]=1[C:22]([OH:24])=O.CC1O[N:29]=[C:28](C2C=CC=CC=2)[C:27]=1[CH2:37][O:38][C:39]1N=NC(C(O)=O)=C[CH:40]=1.NC1CCOCC1>>[O:38]1[CH2:37][CH2:27][CH:28]([NH:29][C:22]([C:3]2[N:4]=[N:5][C:6]([O:8][CH2:9][C:10]3[C:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:12][O:13][C:14]=3[CH3:15])=[CH:7][C:2]=2[CH3:1])=[O:24])[CH2:40][CH2:39]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Reactant: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)O
Agent: NC1CCOCC1
Product: Cc1cc(OCc2c(-c3ccccc3)noc2C)nnc1C(=O)NC1CCOCC1
Yield: 62 %

Procedure:
As described for example 11b, 4-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.61 mmol), instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid, was converted, using 4-amino-tetrahydropyran instead of thiomorpholine 1,1-dioxide, to the title compound (SiO2, heptane:ethyl acetate=100:0 to 60:40, 156 mg, 62%) which was obtained as a white solid. MS: m/e=409.3 [M+H]−.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].C[Si]([N:20]=[N+:21]=[N-:22])(C)C.C1(C)C=CC=CC=1>O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[N:13]1[C:14](=[O:15])[NH:22][N:21]=[N:20]1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1-n1nn[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
37.1 g of 2,6-diisopropylphenyl isocyanate and 50 ml of trimethylsilyl azide are stirred for 24 hours at +140° C. The mixture is then cooled to room temperature and stirred with 250 ml of toluene and with 250 ml of water. After 1 hour, the phases are separated and the aqueous phase is extracted with toluene. The combined organic phases are extracted four times with 250 ml of 15% sodium hydroxide solution each time, and then the aqueous phases are combined and washed with ether. After acidification with semi-concentrated hydrochloric acid, crude 1-(2,6-diisopropylphenyl)-5-oxo-2-tetrazoline precipitates. This is recrystallised from a mixture of hexane and toluene in a ratio of 10:1. Melting point 177°-178.5°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=O)[CH2:9][N:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]=2[CH:20]=1)#[N:2].[CH:21]12[N:27]([C:28]3[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([C:35]#[C:36][CH2:37][N:38]([CH3:40])[CH3:39])[CH:29]=3)[CH:24]([CH2:25][CH2:26]1)[CH2:23][CH2:22]2.N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1.C(OCC)(=O)C>[CH:21]12[N:27]([C:28]3[CH:34]=[CH:33][C:31]([NH:32][C:12]([CH:10]4[O:11][C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][C:7]=5[N:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]4)=[O:14])=[C:30]([C:35]#[C:36][CH2:37][N:38]([CH3:40])[CH3:39])[CH:29]=3)[CH:24]([CH2:25][CH2:26]1)[CH2:23][CH2:22]2
Reactant: CN(C)CC#Cc1cc(N2C3CCC2CC3)ccc1N
Reactant: CCOC(=O)N1CC(C(=O)O)Oc2ccc(C#N)cc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: CCOC(=O)N1CC(C(=O)Nc2ccc(N3C4CCC3CC4)cc2C#CCN(C)C)Oc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of 6-cyano-4-ethoxycarbonyl-2,3-dihydro-1,4-benzoxazine-2-carboxylic acid (30 mg, 0.11 mmol) and 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-dimethylaminoprop-1-ynyl)aniline (29 mg, 0.11 mmol) in 2-methyltetrahydrofuran (300 μL) was added pyridine (35 μL, 0.43 mmol) followed by T3P (173 μl, of 50% w/w, 0.27 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was diluted with ethyl acetate (10 mL) and washed with aqueous 10% NaHCO3 (2×5 mL) and brine (10 mL). The organic phase was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0-20% ethyl acetate/hexanes) provided ethyl 2-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-(dimethylamino)prop-1-ynyl)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (35 mg, 61% yield). LC/MS m/z 528.5 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.16 (s, 1H), 7.56 (dd, J=2.0, 8.5 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.96-6.92 (m, 2H), 5.17 (t, J=4.5 Hz, 1H), 4.23 (s, 2H), 4.20 (q, J=7.1 Hz, 2H), 4.10 (d, J=4.4 Hz, 2H), 3.44 (d, J=2.2 Hz, 2H), 2.23 (s, 6H), 1.62 (d, J=7.0 Hz, 4H), 1.38 (d, J=6.8 Hz, 4H), 1.24 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C([Li])CCC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Cl:22])C(Cl)=O>C1COCC1.CCCCCC.Cl>[Cl:12][C:13]1[CH:14]=[C:15]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: N#CCC(=O)O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCC(=O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
To a solution of cyanoacetic acid (4.07 g, 47.8 mmol) in THF (240 mL) cooled to −78° C. under an atmosphere of argon was added 1.6 M n-butyllithium in hexane (59.8 mL). The reaction mixture was stirred for 10 min at −78° C. and was then allowed to warm to 0° C. The reaction mixture was recooled to −78° C. To the mixture was added dropwise 3,4-dichlorobenzoyl chloride (5.01 g, 23.9 mmol) in THF (30 mL). The reaction mixture was allowed to warm to rt. The reaction mixture was diluted with 1N HCl and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography to give 3-(3,4-dichlorophenyl)-3-oxopropanenitrile (3.9 g, 76%). LCMS: (FA) ES− 212.0. 1H NMR (400 MHz, CDCl3) δ: 8.01 (d, 1H), 7.75 (dd, 1H), 7.63 (d, 1H) and 4.05 (s, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:7][C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[C:4]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](=O)([O:22]CC)[NH2:21]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:7][C:6]3[CH2:8][CH2:9][CH2:10][CH2:11][C:5]=3[C:4]=2[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:21][C:20]1=[O:22]
Reactant: CCOC(N)=O
Reactant: CNc1sc2c(c1C(=O)c1ccccc1)CCCC2
Agent: [Cl-]
Agent: [Zn+2]
Product: Cn1c(=O)nc(-c2ccccc2)c2c3c(sc21)CCCC3
Temperature: 200 °C

Procedure:
A mixture of 1.5 g of 2-methylamino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b]thiophene, 1.5 g of ethyl carbamate and 0.11 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The chloroform extracts are combined, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure and residue is recrystallized from ethanol to give 1-methyl-4-phenyl-1,2,5,6,7,8-hexahydrobenzothieno[ 2,3-d]pyrimidin-2-one as crystals having a melting point of 215° - 216°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]([CH3:43])[C:39]([SH:42])=[N:40][N:41]=2)=[CH:33][CH:32]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]5[N:38]([CH3:43])[C:39]([SH:42])=[N:40][N:41]=5)=[CH:35][CH:36]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cn1c(S)nnc1-c1ccc(N)cc1
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(-c5nnc(S)n5C)cc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (50 mg, 0.12 mmol) and 5-(4-aminophenyl)-4-methyl-4H-1,2,4-triazole-3-thiol (25 mg, 0.12 mmol) in pyridine (10 mL) was added POCl3 (0.3 mL, 3.29 mmol) at 0° C., the reaction mixture was stirred at room temperature for 8 hours, a sat. NaHCO3 solution (15 mL) was added slowly, the solvent was removed in vacuo, dichloromethane (40 mL) was added and filtrated, the filtrate was collected, concentrated and purified by a silica column chromatography (silica gel 200-300 mesh, eluting with dichloromethane:methanol=50:1) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)piperidine-3-carboxamide (24.0 mg, 33.1%) as a white solid. 1H NMR (300 MHz, DMSO): δ 13.88 (s, 1H), 10.34 (s, 1H), 9.68 (s, 1H), 8.87 (s, 1H), 7.82-7.66 (m, 5H), 7.38-7.35 (m, 1H), 6.83 (brs, 1H), 4.83 (d, 1H, J=12.0 Hz), 4.68 (d, 1H, J=11.7 Hz), 3.71 (s, 3H), 3.63 (s, 3H), 3.58 (s, 3H), 3.15-3.07 (m, 1H), 3.00-2.93 (m, 1H), 2.62-2.58 (m, 1H), 2.07-2.03 (m, 1H), 1.83-1.71 (m, 2H), 1.51-1.47 (m, 1H). LC-MS: 604 [M+H]+, tR=1.50 min. HPLC: 99.39% at 214 nm, 99.39% at 254 nm, tR=5.36 min.
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]([OH:28])=O)=[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([O:49]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N1C[CH2:76][CH2:75][N:74]([CH:78]2[CH2:83][CH2:82][CH:81]([NH2:84])[CH2:80][CH2:79]2)[CH2:73][CH2:72]1)C1C=CC=CC=1>CN(C=O)C>[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]([NH:84][C@H:81]5[CH2:82][CH2:83][C@H:78]([N:74]6[CH2:75][CH2:76][O:49][CH2:72][CH2:73]6)[CH2:79][CH2:80]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: NC1CCC(N2CCCN(Cc3ccccc3)CC2)CC1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCOCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

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) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1.5 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-morpholinocyclohexanamine (Intermediate 16) (33 mg, 0.18 mmol, 1.2 eq). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2) 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-((trans)-4-morpholinocyclohexyl)benzamide (off-white solid, 13 mg, 14%).