Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH3:30])[C:11]([CH2:12][OH:13])=[CH:10]2
Reactant: Cc1ccccc1B(O)O
Reactant: OCc1cc2cc(F)ccc2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-c1nc2ccc(F)cc2cc1CO
Temperature: 120 °C
Yield: 22.8 %

Procedure:
A mixture of (2-chloro-6-fluoroquinolin-3-yl)methanol (200 mg, 0.95 mmol), K2CO3 (198 mg, 1.43 mmol) and o-tolylboronic acid (143 mg, 1.05 mmol) in DME (10 mL) and water (1 mL) was degassed by bubbling N2 through it for 5 minutes. Pd(PPh3)4 (55 mg, 0.05 mmol) was added and the mixture heated in the microwave at 120° C. for 1 h. The solvent was removed in vacuo. Purification by column chromatography (SiO2, 0-50% EtOAc in heptane) then by preparative HPLC (Method 1) gave the title compound (58 mg, 23%) as a white solid. δH (CDCl3) 8.32 (s, 1H), 8.10-8.15 (m, 1H), 7.45-7.55 (m, 2H), 7.20-7.35 (m, 4H), 4.58 (s, 2H), 2.09 (s, 3H). LCMS (ES+) 268 (M+H)+, RT 2.89 minutes (Method 3).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][C:2]=1O.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1.O=P(Cl)(Cl)[Cl:25].[OH-].[Na+]>CO.C(Cl)Cl>[Cl:25][C:2]1[CH:3]=[C:4]([N:14]2[CH2:15][CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: O=P(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Clc1cc(N2CCc3ccccc3C2)c2ccccc2n1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
A mixture of 2,4-quinolinediol (1 g, 6.2 mmol) and 1,2,3,4-tetrahydroisoquinoline (1.57 ml, 12.4 mmol) was heated overnight under argon at 200° C. Reaction mixture was cooled to room temperature, diluted with MeOH, stirred for 30 min. and filtered. The solid obtained was refluxed overnight in the presence of POCl3 (3 ml). The reaction mixture was cooled to room temperature and poured into a 0° C. stirring mixture of 5N NaOH (50 ml) and CH2Cl2 (50 ml). After 15 min., aqueous phase was extracted with CH2Cl2 (2×), combined organic phases were washed with H2O, dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethyl acetate, 97:3 then 9:1) to provide 2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline (0.1 g, 5%) as a colorless oil, MS: m/e=295.3 (M+H+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:25][CH2:26][CH3:27])=[C:7]([CH:13]([NH:15][C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[CH3:11])[CH2:2]1.[CH3:28]CN(C(C)C)C(C)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C1COCC1.C(#N)C>[Cl:12][C:9]1[C:10]([CH3:11])=[C:5]([CH:3]2[CH2:4][N:1]([CH3:28])[CH2:2]2)[C:6]([O:25][CH2:26][CH3:27])=[C:7]([CH:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][NH:20]3)[CH3:14])[CH:8]=1
Reactant: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CN(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl 3-{3-chloro-6-ethoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylate (83 mg, 0.16 mmol) and 5% palladium (74 mg) was combined in methanol (5 mL), to which was added 0.25 M HCl in water (1.6 mL, 0.40 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature overnight. The suspension was filtered and concentrated to give N-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-9H-purin-6-amine. LCMS calculated for C19H24ClN6O (M+H)+: m/z=387.2. found: 387.1. The azetidine made above was combined with DIPEA (0.1 mL, 0.6 mmol) in methanol (0.5 mL)/acetonitrile (0.5 mL)/THF (0.5 mL), followed by the addition of 37% formaldehyde (0.1 mL, 2 mmol). The mixture was stirred at room temperature for 10 min before the addition of sodium triacetoxyborohydride (0.17 g, 0.80 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with MeOH and purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C20H26ClN6O (M+H)+: m/z=401.2. found: 401.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[N:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O.N>C(O)(=O)C.[Cl-].[Na+].O>[CH3:24][C:21]1[N:20]=[C:19]([C:10]2[S:9][C:8]([NH2:7])=[N:12][C:11]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:23][N:22]=1
Reactant: Cc1noc(-c2sc(NC(=O)OC(C)(C)C)nc2-c2ccccc2)n1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
[5-(3-Methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-yl]-carbamic acid tert-butyl ester was suspended in glacial acetic acid (20 mL). TFA (20 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was added to brine (100 mL) and pH was adjusted to pH 10 with ammonia. The mixture was extracted with EtOAc (2×75 mL). The combined organic phases was washed with brine (50 mL), dried with MgSO4 and solvents were removed in vacuo to give a white solid. Yield 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[CH:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>[Zn]>[OH:14][C:12]([CH3:13])([CH:11]=[CH:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)C=CCCc1ccc(Cl)cc1
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C=CCCc1ccc(Cl)cc1

Procedure:
Using 7.17 g of 6-(p-chlorophenyl)-3-hexen-2-one, 4.2 ml of ethyl bromoacetate and 2.47 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 6.4 g of ethyl 3-hydroxy-3-methyl-7-(p-chlorophenyl)-4-heptenoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: Oc1cccnc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1cccnc1)c1ccccc1

Procedure:
The title product was prepared from 3-hydroxypyridine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (94%, colourless oil).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.C([Sn]([CH2:30][OH:31])(CCCC)CCCC)CCC>>[NH:13]1[CH2:14][CH2:15][N:16]=[C:12]1[CH:7]1[C:8]2[C:3](=[C:2]([CH2:30][OH:31])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][O:6]1
Reactant: CCCC[Sn](CO)(CCCC)CCCC
Reactant: Brc1cccc2c1CCOC2C1=NCCN1
Product: OCc1cccc2c1CCOC2C1=NCCN1

Procedure:
The title compound was prepared from 2-(5-bromoisochroman-1-yl)-4,5-dihydro-1H-imidazole (50 mg) and (tributylstannyl)methanol (86 mg) by using tetrakis(triphenyl-phosphine)palladium (10.28 mg) as catalyst, and the procedure of synthesis method C and separation methods F and G. (Yield 6.2 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)CCC>>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Product: c1ccc2sc(-c3cnc4c(c3)C[C@@]3(CN5CCC3CC5)O4)nc2c1

Procedure:
Prepared by a method analogous to that described for the preparation of Example 1 from (2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] and 2-tri-n-butylstannylbenzothiazole. The title compound was obtained as a colourless solid; m/e 350 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[C:15](Br)Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](C#CC1CCN(C(=O)OC(C)(C)C)CC1)(CCCC)CCCC
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A mixture of 23.199 g (62.85 mmole) 1-(t-butoxycarbonyl)-4-(2,2-dibromoethen-1-yl)piperidine (prepared as in Step B3 above) and 600 mL anhydrous THF was cooled with dry ice acetone bath under nitrogen. To this mixture was added 88 mL of a 1.6 M butyl lithium solution in hexanes dropwise with stirring and cooling over 50 minutes. After one hour, the flask was transferred into an ice bath. After another hour, a solution of 28.64 g (87.99 mmole) tributyltin chloride in 100 mL THF was added with stirring and cooling over 35 minutes. After three h, the mixture was concentrated under vacuum to remove some THF, and the residue was partitioned between 600 mL ice water and 800 mL ether. The organic layer was washed with 200 mL of water (1×), 2% sodium bicarbonate (1×), water (2×), and saturated brine (1×), dried over sodium sulfate and concentrated under vacuum to give 30.104 g crude product as a green-yellowish liquid. FC on 275 g silica gel using cold 2.5˜15% ethyl acetate in hexanes as quickly as possible to give 27.115 g title compound as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][CH3:10])[C:3]=1[C:13]#[N:14].[CH:15](OCC)(OCC)[O:16][CH2:17][CH3:18].C(OC(=O)C)(=O)C>O1CCOCC1>[C:13]([C:3]1[C:4]([C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][CH3:10])=[N:5][S:6][C:2]=1[N:1]=[CH:15][O:16][CH2:17][CH3:18])#[N:14]
Reactant: CCCC(C)(C)c1nsc(N)c1C#N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CCCC(C)(C)c1nsc(N=COCC)c1C#N
Yield: 100.3 %

Procedure:
A solution of 25 g of 5-amino-4-cyano-3-(1,1-dimethylbutyl)isothiazole and 35.6 g of triethyl orthoformate in 200 ml of dioxane was heated under reflux for two hours. To the solution was added 24.5 g of acetic anhydride and the mixture was heated under reflux an additional 20 hours. The mixture wss concentrated under reduced pressure and the residue was distilled in a short path still at 120° under 0.1 mm Hg to give 31.8 g of 4-cyano-3-(1,1-dimethylbutyl)-5-[N-(ethoxymethylene)amino] isothiazole which was dissolved in 125 ml of ethanol, without further purification. The ethanolic solution was placed in a flask equipped with a gas inlet tube and one outlet of which was closed by a small rubber balloon. Dimethylamine gas was passed into the solution until the balloon remained inflated; during the introduction of dimethylamine, the temperature of the mixture increased to 60°. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from a mixture of diethyl ether (90 parts) and pentane (10 parts) at low temperature to give 26.5 g of N'-[4-cyano-3-(1,1-dimethylbutyl)-5-isothiazolyl]-N,N-dimethylformamidine, m.p. 65°-67°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[N:15]=[CH:14][N:13]=[C:12](O)[C:11]=1[F:17])[CH3:9].[ClH:18]>ClCCl.P(Cl)(Cl)(Cl)=O>[Cl:18][C:12]1[C:11]([F:17])=[C:10]([CH2:8][CH3:9])[N:15]=[CH:14][N:13]=1
Reactant: CCc1ncnc(O)c1F
Reactant: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ncnc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
78.24 ml of triethylamine was added to a solution prepared by dissolving 80 g of 6-ethyl-5-fluoro-4-hydroxypyrimidine in 240 ml of dichloromethane, and 57.4 ml of phosphorus oxychloride was slowly added thereto over 30 min. The resulting solution was refluxed for 5 hours to complete the reaction, and cooled to room temperature. Then, 352 ml of 3N HCl was added thereto while maintaining the temperature at below 20° C. The resulting aqueous mixture was extracted with 100 ml of dichloromethane. The organic layer was washed with 100 ml of water, was dried over magnesium sulfate, and concentrated under a reduced pressure to obtain the title compound as an oil (85.9 g, yield: 95%).
Reaction SMILES: [CH2:1]([N:4]([CH2:29][CH2:30][CH3:31])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][CH2:22][C:23]3[NH:24][CH:25]=[CH:26][N:27]=3)[CH2:16][N:15]2[CH:28]=1)=[O:11])[CH2:2][CH3:3].[CH3:32][N:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH2:29]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]([CH2:22][C:23]3[NH:24][CH:25]=[CH:26][N:27]=3)[CH2:38][C:34]3[N:33]([CH3:32])[CH:37]=[CH:36][N:35]=3)[CH2:16][N:15]2[CH:28]=1)=[O:11])[CH2:30][CH3:31]
Reactant: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CNCc1ncc[nH]1)C2
Reactant: Cn1ccnc1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CN(Cc1ncc[nH]1)Cc1nccn1C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
The compound (19.6 mg) obtained in Example 19-4 was dissolved in methanol (2.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (6.2 mg) and sodium cyanoborohydride (5.9 mg). The solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 3 hours. The resultant was added with a saturated sodium hydrogen carbonate aqueous solution to stop the reaction and subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (22.0 mg) of the subject compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[C:36]1([CH2:42]CO)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:27][CH2:25][CH2:42][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCc4ccccc4)c(Cl)c3)c2cc1OC
Yield: 24.9 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-phenyl-1-ethanol (28 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 (18 mg, yield 22%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[C@H:17]([CH3:18])[CH2:16][N:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:14][C@@H:13]3[CH3:23])=[C:8]([CH3:24])[C:6]=2[N:7]=1.[NH2:31][C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[CH3:23][C@@H:13]1[CH2:14][N:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:16][C@H:17]([CH3:18])[N:12]1[CH2:11][C:9]1[S:10][C:5]2[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:3][C:2]([C:35]3[CH:34]=[N:33][C:32]([NH2:31])=[N:37][CH:36]=3)=[N:7][C:6]=2[C:8]=1[CH3:24]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1c(CN2[C@H](C)CN(S(C)(=O)=O)C[C@@H]2C)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2[C@H](C)CN(S(C)(=O)=O)C[C@@H]2C)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 58.6 %

Procedure:
2-Chloro-6-((2S,6R)-4-methanesulfonyl-2,6-dimethyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (135 mg, 0.29 mmol) was reacted with 2-amino-pyrimidine-5-boronic acid pinacol ester (88 mg, 0.4 mmol) in General Procedure A. After extraction into 2M HCl, the mixture was washed with ethyl acetate then made basic and the precipitate collected by filtration. Purification using a thiourea SPE cartridge gave 420 as a cream solid (90 mg, 0.17 mmol) NMR (CDCl3, 400 MHz), 9.25 (s, 2H); 5.12 (s, 2H); 3.95 (t, 4H, J=4.6 Hz); 3.95 (s, 2H); 3.82 (t, 4H, J=4.8 Hz); 3.51 (d, 2H, J=11.3 Hz); 2.82 (m, 2H); 2.74 (s, 3H); 2.55 (t, 2H, J=10.8 Hz); 2.33 (s, 3H); 1.06 (d, 6H, J=6.3 Hz) MS: (ESI+): MH+=533.30
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23]OS(C)(=O)=O)=[CH:16][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH3:6]>CO.C1(C)C=CC=CC=1>[CH2:3]([CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][NH:2][CH3:1])=[CH:16][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(Cc1ccc(OCCCOS(C)(=O)=O)cc1)C(=O)OCC
Reactant: CN
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCC(Cc1ccc(OCCCNC)cc1)C(=O)OCC
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A solution of methylamine in methanol (40%, 5.0 ml) was added to a solution of ethyl 2-butyl-3-[4-(3-methansulfonyloxypropoxy)phenyl]propionate (500 mg), which is the product of Reference example 21 (c) in toluene (10 ml). The mixture was stirred at 90° C. for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using dichloromethane/methanol=5/1 as the eluant to afford the title compound (389 mg) as a pale yellow oil.
Reaction SMILES: [C:1](#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][OH:11].O>CCO>[OH:11][N:10]=[C:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC#N
Reactant: NO
Solvent: CCO
Solvent: O
Product: CCCCCCCC(N)=NO
Yield: 74.3 %

Procedure:
Octanonitrile (1 g, 7.99 mmol) and hydroxylamine (50% in water, 0.74 cm3, 0.79 g, 12 mmol, 1.5 eq) in EtOH (1 cm3) were stirred at room temperature for 7 days. Water (10 cm3) was then added. This caused crystals to precipitate, these were collected by filtration and dried in high vacuum line to give the product N′-hydroxyoctanimidamide (0.94 g, 74.6%) as a white solid, mp 73-75° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]([CH2:11][C:12]([OH:14])=O)[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1>O>[CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:8]([OH:10])=[O:9])[CH2:11][C:12](=[O:14])[C:4]=2[CH:3]=1
Reactant: Cc1ccc(C(CC(=O)O)C(=O)O)s1
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1cc2c(s1)C(C(=O)O)CC2=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 26.5 %

Procedure:
23.5 g of (5-methyl-2-thienyl) succinic acid was added to a mixture of 1.2 kg of polyphosphoric acid and 200 cc of xylene, previously heated to 100° C., and stirred for 3 hours at this temperature. After cooling to 80° C. the reaction mixture was poured in 4 liters of water and extracted with ethyl acetate. The organic phase was washed with water, dried on sodium sulfate then concentrated under reduced pressure. The residue was chromatographed on a silica column (successive eluants: 1/1 hexane-ethyl acetate, then 9/0.9/0.1 methylene chloride-ethanol-acetic acid). 5.7 g (yield: 26%) of 2-methyl-4oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylic acid was obtained which was purified by recrystallization in a hexane-ethyl acetate mixture. Mp=140°-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)=[CH:12][CH:11]=1)[C:6]([OH:8])=O)=[O:4].S(Cl)(Cl)=O.[NH3:34]>C1C=CC=CC=1.C(OCC)(=O)C>[C:6]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])(=[O:8])[NH2:34]
Reactant: N
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(N)=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
To a solution of 2-(methoxycarbonyl)-3-[4-[2-(6-quinolinoxy)ethoxy]phenyl]propionic acid (2.11 g, 5.29 mmol) in benzene (20 ml) at room temperature is added thionyl chloride (0.76 g, 6.34 mmol). Then the mixture was heated at 80° C. for 90 min. After cooled to room temperature, the solvent is removed under a vacuum. To the residue is added 28% ammonia solution (5.49 ml, 79.30 mmol) at room temperature. The mixture is stirred for 30 min, dissolved in ethyl acetate (20 ml), washed with brine (3×15 ml), dried over sodium sulfate, and concentrated. The crude product is crystallized from ethanol to give title compound (1.20 g, 57%). HRMS calcd for C22H26N2O5: 398.4558. Found: 398.4554. MA calcd for C22H26N2O5: C, 66.32%; H, 6.58%; N, 7.03%. Found: C, 66.44%; H, 6.54%; N, 7.05%