Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][C:6]1[CH:27]=[CH:26][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:24]#[N:25])=[CH:8][CH:7]=1.[Cl:32][CH2:33][CH2:34][CH2:35]Br.[O-]CCCC.[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][C:6]1[CH:27]=[CH:26][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:35][CH2:34][CH2:33][Cl:32])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:24]#[N:25])=[CH:8][CH:7]=1
Reactant: COc1cc2c(Nc3ccc(Oc4ccccc4OC)cc3)c(C#N)cnc2cc1O
Reactant: ClCCCBr
Agent: CCCC[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Oc4ccccc4OC)cc3)c(C#N)cnc2cc1OCCCCl
Reaction time: 18 h

Procedure:
The product of step 2 (206.5 mg, 0.5 mmole) and 1-chloro-3-bromopropane (95 mg, 0.6 mmole) was dissolved in dimethylsulphoxide (5 ml) in the presence of potassium butoxide (0.55 ml, 11.0M in THF, 0.55 mmole) in and the mixture held at room temperature for 18 hours. Water was added and the mixture extracted with ethyl acetate. The combined extracts were washed with water and brine then dried (MgSO4) and evaporated to give 4-(4-(2-methoxyphenoxy)-anilino)-3-cyano-6-methoxy-7-(3-chloropropoxy)quinoline, intermediate 1, (189 mg, 77%) as a yellow gum.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=3)[CH2:15][CH:10]2[CH2:9]1)=O)(C)(C)C.[ClH:27].O1CCOCC1>CCOCC>[ClH:27].[CH2:13]1[CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[CH2:15][N:14]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=1
Reactant: CCOC(=O)c1ccc(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(N2CC3CNCC3C2)nc1
Reaction time: 2 h

Procedure:
To ethyl 2-[5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyridine-5-carboxylate (1.429 g, 3.92 mmol) was added 4M HCl in dioxane (10 ml, 40 mmol). The mixture was stirred for 2 h, then Et2O (50 ml) was added. The product was collected by filtration and washed with further Et2O (50 ml) to yield the title compound (1.19 g, quant.). 1H NMR (300 MHz, d6-DMSO) δ: 9.95 (1H, br s), 9.84 (1H, br s), 8.44 (1H, d, J=1.8 Hz), 8.20 (1H, dd, J=2.1, 9.3 Hz), 7.01 (1H, d, J=9.3 Hz), 4.31 (2H, q, J=7.2 Hz), 3.0-4.05 (10H, m), 1.31 (3H, t, J=7.2 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: COC(=O)C(C)(C)CC(CCCCN)CCCc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a solution of 0.34 g methyl 8-amino-2,2-di-methyl-4-[3-(3-pyridyl)propyl]octanoate in 5 mL dry methylene chloride is added a catalytic amount of 4-dimethylaminopyridine followed by 0.2 mL triethylamine and the mixture is cooled to 0° C.; 0.208 g (0.96 mmol) p-chlorobenzenesulfonyl chloride is added, the reaction is allowed to warm to room temperature and stirred for 48 hours. The mixture is diluted with methylene chloride and washed with saturated sodium bicarbonate, water and brine. The organic phase is dried, filtered and evaporated to yield an amber oil which is purified by flash chromatography using 1:1 ethyl acetate,hexane to yield methyl 8-(p-chlorophenylsulfonamido)-2,2-dimethyl-4-[3-(3-pyridyl)-propyl]-octanoate; IR (CH2Cl2): 3381, 1729, 1164 cm-1 ; NMR (CDCl3): delta 3.57 (s,3H), 2.9 (q,2H), 2.53 (t,2H), 1.12 (s,6H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH:14]([NH:17][C:18]([C@@H:20]1[C@H:25]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29]([NH2:34])[C:28]=2[NH2:35])[C@@H:24]2[CH2:36][C@H:21]1[CH:22]=[CH:23]2)=[O:19])([CH3:16])[CH3:15].C([O-])(=O)C.[NH4+]>>[CH:14]([NH:17][C:18]([C@@H:20]1[C@H:25]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29]3[NH:34][C:7]([C:6]4[S:5][C:4]([N:9]5[CH2:13][CH2:12][CH2:11][CH2:10]5)=[N:3][C:2]=4[Cl:1])=[N:35][C:28]=23)[C@@H:24]2[CH2:36][C@H:21]1[CH:22]=[CH:23]2)=[O:19])([CH3:16])[CH3:15]
Reactant: O=Cc1sc(N2CCCC2)nc1Cl
Reactant: CC(C)NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(C)NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CCCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 3.4 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-pyrrolidin-1-yl-thiazole-5-carbaldehyde (69.84 mg, 0.3223 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid isopropylamide (97.42 mg, 0.2901 mmol), and Ammonium acetate (44.72 mg, 0.5802 mmol) were reacted to produce 5.21 mg (3.4%) of the title compound. (300 MHz, DMSO-d6) 12.60 (s, 1H), 8.10 (d, J=8 Hz, 1H), 7.93 (s, 1H), 6.90 (s, 1H), 6.34 (m, 2H), 5.00 (t, J=17 Hz, 8.5 Hz, 1H), 3.88 (m, 1H), 3.44 (m, 4H), 2.83 (s, 1H), 2.76 (s, 1H), 2.55 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 2.01 (m, 4H), 1.37 (d, J=8 Hz, 1H), 1.07 (d, J=7 Hz, 3H), 1.00 (d, J=7 Hz, 3H). MS=531 (M+H), HPLC: 3.11 min. (G Method)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:20])[CH:11]=2)[NH:6][C:5]1=O.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:5]1[N:4]([CH2:3][CH2:2][Cl:1])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:20])[CH:11]=2)[N:6]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)N1CCCl
Reactant: O=P(Cl)(Cl)Cl
Product: ClCCN1C(Cl)=Nc2ccc(Cl)cc2C1c1ccccc1
Temperature: 105 °C
Reaction time: 20 h

Procedure:
A mixture of 3.21 g of 3-(2-chloroethyl)-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone and 10 g of phosphorus oxychloride was heated with stirring at 105° C. for 20 hours. The resulting solution was evaporated in vacuo to dryness and the resulting residue was dissolved in chloroform. The chloroform solution was washed with an aqueous sodium bicarbonate solution and then with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2,6-dichloro-3-(2-chloroethyl)-4-phenyl-3,4-dihydroquinazoline. The crude solid was chromatographed on silica gel using chloroform as an eluting solvent. Removal of the solvent and recrystallization of the residue from a mixture of benzene and petroleum benzin gave 0.60 g of pure product, m.p. 169°-170° C. To a solution of 0.34 g of 2,6-dichloro-3-(2-chloroethyl)-4-phenyl-3,4-dihydroquinazoline in 2 ml of dimethylformamide was added 0.59 g of n-propylamine and the mixture was heated at 105° C. for 5 hours. After cooling, 10 ml of water was added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic phase was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using chloroform as an eluting solvent to give 0.24 g of 1-(n-propyl)-5-phenyl-7-chloro-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazoline hydrochloride. Recrystallization from a mixture of ethanol and diisopropyl ether gave slightly brown fine crystals, m.p. 258° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[Cl:36][C:37]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:38]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH2:46]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:46][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][C:38]2[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:37]=2[Cl:36])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (489 mg, 2.13 mmol) in dry DCM (10 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.116 g, 5.82 mmol) and triethylamine (0.3 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and 2-(2,4-dichlorophenoxy)phenylamine (AMR01026, 491 mg, 1.93 mmol) in dry DCM (5 mL) was added. After stirring at room temperature for 72 h, the mixture was diluted with DCM, washed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated to give 4-[2-(2,4-Dichlorophenoxy)phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester (754 mg, 84%) as a white solid (mp 120-121° C. from hexane), which was used in the next step without further purification. Rf: 0.31 (Hexane/EtOAc 7:3) LC/MS (APCI) tr=1.39 min, m/z 464.96 (21), 462.94 (M−−H, 32), 253.90 (66), 251.89 (100). 1H NMR (270 MHz, CDCl3) δ 1.44 (9H, s, 3CH3), 1.70 (2H, m, CH2), 1.86 (2H, br d, CH2), 2.40 (1H, tt, J=11.3, 3.7 Hz, CH), 2.77 (2H, br t, CH2), 4.14 (2H, m, CH2), 6.71 (1H, dd, J=8.2, 1.7 Hz, ArH), 6.94 (1H, d, J=8.9 Hz, ArH), 7.01 (1H, td, J=8.2, 1.5, ArH), 7.12 (1H, td, J=8.2, 1.5 Hz, ArH), 7.21 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.48 (1H, d, J=2.5 Hz, ArH), 7.76 (1H, br s, NH) and 8.40 (1H, dd, J=7.9, 1.5 Hz, ArH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.I[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1>C1COCC1.C(N(CC)CC)C.[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>[CH3:21][Si:20]([C:19]#[C:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:13][CH:14]=1)([CH3:22])[CH3:23]
Reactant: C#Cc1ccc(OC)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.5 %

Procedure:
Into a 50 ml round bottom flask was placed a mixture of 0.72 g (0.0054 mole) of p-methoxyphenylacetylene, 1.51 g (0.005 mole) of 4-iodophenyltrimethylsilylacetylene, 0.0102 g (0.0053 mmole) of CuI, 0.102 g (0.146 mmole) of bis(triphenylphosphine)palladium(II) dichloride in 10 ml of THF and 10 ml of triethylamine. The light orange brown mixture was stirred at room temperature under nitrogen for 3 days. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 10 ml of chloroform and the solution was washed two times with water (10 ml each) and then dried over anhydrous MgSO4, filtered and concentrated. 1.5 g (98.7% yield) of solid was obtained. 1HNMR: 0.28 ppm (s, 9H); 3.85 ppm (s, 3H); 6.90 ppm (d, 2H); 7.45 ppm (s, 4H); 7.48 ppm (d, 2H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([O:35]CC)=[O:34])[C:28]2[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=2[S:26][CH2:25]1)[C:18]([O:20]CC)=[O:19])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>C(O)C.[OH-].[Na+]>[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([OH:35])=[O:34])[C:28]2[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=2[S:26][CH2:25]1)[C:18]([OH:20])=[O:19])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(CCCCNC(=O)OCc2ccccc2)C(=O)OCC)CSc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1C(=O)[C@@H](NC(CCCCNC(=O)OCc2ccccc2)C(=O)O)CSc2ccccc21
Reaction time: 1 h
Yield: 85.8 %

Procedure:
In a mixture of 3 ml of ethanol and 2 ml of 1N aqueous sodium hydroxide solution is dissolved 55 mg of ethyl 3(R)-(5-benzyloxycarbonylamino-1-ethoxycarbonylpentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate.hydrochloride as obtained in Example 50, and the solution is allowed to stand at room temperature for 1 hour. Water(50 ml) is added to the reaction solution, and after the mixture is extracted with 20 ml of ethyl ether, the aqueous layer is adjusted to pH 4 with 1N hydrochloric acid. Ammonium chloride is added to the solution until it becomes saturated, and the aqueous layer is extracted ten times with 20 ml of ethyl acetate. The extract is washed with a small amount of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 40 mg of 3(R)-(5-benzyloxycarbonylamino-1-carboxypentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [CH:1](=[C:8]([C:12]([O-:14])=[O:13])C([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:15]#[N:16].[K+]>C(O)C.O>[C:15]([CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:8][C:12]([OH:14])=[O:13])#[N:16]
Reactant: [C-]#N
Reactant: O=C([O-])C(=Cc1ccccc1)C(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CC(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzalmalonate (124 g., 0.5 mole) in ethanol (560 ml.) and water (240 ml.) was heated at reflux for 60 hours with potassium cyanide (45 g., 0.7 mole). The solution was cooled, concentrated to remove ethanol, and then acidified with concentrated hydrochloric acid. The product was extracted with dichloromethane, and the extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in ethyl acetate (500 ml.) and treated with dicyclohexylamine (82 ml.) to yield 118 g. (67%) of white crystals which were collected by filtration and washed sequentially with ethyl acetate and ether and dried. A suitable cation-exchange resin in the acid form, such as Dowex® 50x8-100 ion-exchange resin, (20 g.) was washed with acetone and suspended in methanol (130 ml.) with dicyclohexylammonium salt (15 g.). After stirring at ambient temperature for 1 hour, the cation exchange resin was removed by filtration and the filtrate was concentrated to yield 3-cyano-3-phenylpropionic acid as an oil.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[C:25]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:24][CH:23]=[C:22]([F:44])[N:21]=1.C(O)C>O1CCCC1>[F:19][C:20]1[C:25]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:24][CH:23]=[C:22]([F:44])[N:21]=1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3ccc(F)nc3F)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4ccc(F)nc4F)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Lithium hydroxide (0.106 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.24 g) and diethyl [(3S,8aR)-3-(2,6-difluoropyridin-3-yl)-5-oxooctahydroindolizin-6-yl]phosphonate (1.0 g) in tetrahydrofuran (4 mL)-ethanol (16 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.42 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19](O)=[O:20])[CH2:11][CH2:10]2.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.C([O-])(=O)C.[NH4+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]([NH2:27])=[O:20])[CH2:11][CH2:10]2
Reactant: O=C(O)CN1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CN1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of [6-(3-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-acetic acid (0.245 mg, 0.744 mmol) and 1,1′-carbonyl-diimidazole (0.229 mg, 1.41 mmol) in N,N′-dimethylformamide (6 mL) was stirred at room temperature for 0.5 h. Ammonium acetate (0.917 g, 11 mol) was added and the mixture was stirred 2 h. Water was added and the mixture was extracted with ethyl acetate. Drying and evaporation of the solvent left a solid which was recrystallised with ethyl acetate and ether. MS: m/e=329.3 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:5][CH:4]([C:6]2[C:10]([CH2:11][OH:12])=[C:9]([C:13]([F:16])([F:15])[F:14])[S:8][N:7]=2)[CH2:3]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:22]=[C:23]([F:26])[C:24]=1O>>[F:17][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[C:10]([CH2:11][O:12][C:24]3[C:23]([F:26])=[CH:22][C:21]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[F:18])=[C:9]([C:13]([F:15])([F:16])[F:14])[S:8][N:7]=2)[CH2:3]1
Reactant: OCc1c(C2CC(F)(F)C2)nsc1C(F)(F)F
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: O=C(O)CCc1cc(F)c(OCc2c(C3CC(F)(F)C3)nsc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(3,3-difluorocyclobutyl)-5-(trifluoromethyl)isothiazol-4-yl)methanol and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 6.96 (d, J=7.2 Hz, 2H), 5.19 (s, 2H), 3.80-3.93 (m, 1H), 2.99-3.16 (m, 4H), 2.89 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.2 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C18H14F7NO3S, 456.1 (M−H). found 456.1.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[O:9][C:8]([NH2:10])=[N:7][CH:6]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[O:9][C:8]([NH:10][C:27]([C:24]2([C:22]3[CH:21]=[CH:20][C:19]4[O:15][CH2:16][O:17][C:18]=4[CH:23]=3)[CH2:26][CH2:25]2)=[O:28])=[N:7][CH:6]=1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1ncc(Cc2ccccc2Cl)o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ncc(Cc2ccccc2Cl)o1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 37 %

Procedure:
5-(2-Chloro-benzyl)-oxazol-2-ylamine (21 mg, 0.10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (22 mg, 0.10 mmol) were dissolved in acetonitrile (1.5 mL) containing triethylamine (42 L, 0.30 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 49 mg, 0.11 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product (15 mg, 0.037 mmol, 37%). ESI-MS m/z calc. 396.1. found; 396.6 (M+1)+ Retention time 3.17 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2OCC)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:37][C@H:38]1[O:42][C@@H:41]([C@H:43]([NH2:46])[CH2:44][CH3:45])[CH2:40][CH2:39]1>CC#N.CCO>[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:9])=[O:10])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[NH:46][C@@H:43]([C@H:41]2[CH2:40][CH2:39][C@@H:38]([CH3:37])[O:42]2)[CH2:44][CH3:45])=[CH:4][CH:3]=1
Reactant: CC[C@@H](N)[C@H]1CC[C@@H](C)O1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CC#N
Product: CC[C@@H](Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O)[C@H]1CC[C@@H](C)O1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a stirred suspension of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (7 g, 17.91 mmol) in MeCN (2 ml) and EtOH (1 ml) under N2 at RT was added ((R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylamine para-toluenesulfonate salt (Intermediate E) (5.67 g, 17.91 mmol) and TEA (0.999 ml, 7.16 mmol) and the reaction mixture was heated at 50° C. for 16 hours. Further TEA was added (2.48 ml, 17.91 mmol) and the reaction was heated at 50° C. for 1 hour then 60° C. for 20 hours. Further TEA (2.48 ml, 17.91 mmol) and Intermediate E (1.13 g, 3.58 mmol) was added and the reaction was heated at 60° C. for 17.5 hours. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and 1M HCl (aq). The aqueous layer was adjusted to pH 5 using 2M NaOH (aq) and extracted using EtOAc. The EtOAc layers were combined and washed with saturated sodium bicarbonate (aq), water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting residue was recrystallised from toluene to give a light brown solid; [M+H]+ 488.2. 1H NMR (DMSO) 0.9 (3H, t, CH3), 1.2 (3H, d, CH3), 1.3 (1H, m) 1.6 (3H, m) 1.9 (2H, m) 3.6 (3H, s, CH3), 3.6 (3H, s, CH3), 3.9 (2H, m) 4.0 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.2 (1H, d), 9.5 (1H, s), 10.1 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>C(Cl)(Cl)Cl>[CH2:28]([NH:32][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH2:30][CH3:31]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCCCN
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -15° C. during 15 minutes. After stirring for 5 minutes, 6.43 g (0.088 mol) of butylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -10° C. and -15° C. during 50 minutes. The reaction mixture is stirred for 1 hour at the same temperature and then let to stand under cooling by ice. For working up, the mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate and evaporated to give 14.9 g (71.8%) of the named product as yellow crystals, m.p.: 127°-130° C.