Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.[OH:11]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:11])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: OO
Reactant: Clc1cnc2c(c1)CCC2
Solvent: CC(=O)O
Product: [O-][n+]1cc(Cl)cc2c1CCC2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 3-chloro-6,7-dihydro-5H-[1]pyrindine (3.03 g, 19.7 mmol) in acetic acid (19.7 ml) was treated at room temperature with hydrogen peroxide (3.45 ml, 39.5 mmol). The mixture was heated to 70° C. and stirred at this temperature overnight. After completion, the reaction mixture was allowed to cool and was concentrated at reduced pressure. Water was added and the mixture was evaporated again. This procedure was repeated another 2 times. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, then dried over sodium sulfate and evaporated at reduced pressure. The crude 3-chloro-6,7-dihydro-5H-[1]pyrindine 1-oxide was obtained as dark green crystals (2.07 g, 62% yield). MS (ISP): m/z=170 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CCCOc1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCOc1cccc(Br)c1
Temperature: 50 °C
Yield: 97.4 %

Procedure:
To a solution of ethyl 4-(3-bromophenoxy)butanoate (Preparation 55A, 3.3 g, 11.5 mmol) in THF (5 mL) was added lithium hydroxide (0.550 g, 23.0 mmol) dissolved in water (5 mL) at room temperature. The reaction mixture was heated at 50° C. for 3 h. The reaction mixture was concentrated and partitioned between ethyl acetate (50 mL) and 1N aqueous hydrochloric acid (20 mL) (pH of aqueous layer ˜3). The organic layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to yield 4-(3-bromophenoxy)butanoic acid (2.9 g, 11.2 mmol, 97% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.10-2.15 (m, 2H), 2.59 (t, J=7.26 Hz, 2H), 4.01 (t, J=6.05 Hz, 2H), 6.82 (ddd, J=8.14, 2.42, 1.10 Hz, 1H), 7.04-7.06 (m, 1H), 7.07-7.10 (m, 1H), and 7.14 (t, J=8.03 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.C(O)CCCCC.[OH-].[Na+].[C:30]([OH:39])(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]>C(OC(C)C)(=O)C>[C:30]([OH:39])(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].[CH3:13][O:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([N:1]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COc1cc(N)c2ncccc2c1
Reactant: ClCCNCCCl
Agent: O=C(O)CCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: CCCCCCO
Product: COc1cc(N2CCNCC2)c2ncccc2c1
Temperature: 145 °C
Reaction time: 21 h

Procedure:
A mixture of 8-amino-6-methoxyquinoline (150.0 g, 0.862 mol) and bis(2-chloroethyl)amine (219 g, 1.23 mol,) in 6 parts (volume of hexanol vs weight of 8-amino-6-methoxyquinoline) of 1-hexanol (900 mL) was heated to 145° C. and stirred for 21 hours. Upon completion, the reaction mixture is cooled 50-60° C., and 507 g of aqueous NaOH solution was added slowly. The reaction mixture was cooled to 25-30° C. and isopropyl acetate (750 mL) was added. The mixture was clarified through a celite pad. The aqueous phase was then split off. The organic solution was treated with a slurry of adipic acid (126 g, 0.862 mol) in isopropyl acetate (250 ml). The resulting mixture was stirred for 16 hours to form 6-methoxy-8-(1-piperazinyl)quinoline adipate salt. The adipate salt was filtered and washed with isopropyl acetate (2×150 ml) and dried by nitrogen flow to give adipate of 6-Methoxy-8-piperazin-1-yl-quinoline (186 g, 55% yield) with ˜97% HPLC area, 88% strength purity in 51% yield.
Reaction SMILES: Cl[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C>[Pd].C(O)C>[F:12][C:11]1[CH:2]=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[CH:5]=2
Reactant: COc1ccc2cc(F)c(Cl)nc2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2cc(F)cnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
A mixture of 2-chloro-3-fluoro-7-methoxyquinoline (310 mg, 1.47 mmol), triethylamine (310 mg, 0.4 ml, 3.07 mmol) and 10% palladium on activated charcoal (50 mg) in dry ethanol (5 ml) was stirred under hydrogen gas at ambient temperature for 24 hours. The mixture was then filtered through celite. The celite was washed with methanol and the solvent was removed by evaporation from the combined filtrates. The crude material was purified by chromatography on silica, eluting with 10% ethyl acetate in isohexane to give 3-fluoro-7-methoxyquinoline (130 mg, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:25][C@H:26]4[C@H:30]5[O:31][CH2:32][C@@H:33]([OH:34])[C@H:29]5[O:28][CH2:27]4)[N:16](COCC[Si](C)(C)C)[C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.C(O)=O.OS([O-])(=O)=O.[K+].[OH-].[Na+].Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:25][C@H:26]4[C@H:30]5[O:31][CH2:32][C@@H:33]([OH:34])[C@H:29]5[O:28][CH2:27]4)[NH:16][C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=CO
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(Br)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A flask was charged with (3R,3aR,6R,6aR)-6-[5-(4-bromophenyl)-6-chloro-1-(2-trimethylsilylethoxy-methyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (270.1 mg, 0.463 mmol), formic acid (1.5 ml, 39.1 mmol), and saturated aqueous KHSO4 (0.15 ml). The reaction mixture was stirred at room temperature for 16 h, then at 40° C. for 23 h. The reaction mixture was cooled in an ice bath. The pH of the reaction mixture was adjusted to 14 through the addition of 5 N aqueous NaOH (8.0 ml, 40 mmol). The reaction mixture was allowed to warm to room temperature. After 10 min, the pH of the reaction mixture was adjusted to 8 through the addition of 2N aqueous HCl. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a yellow solid, which was used without further purification. LC-MS: calculated for C18H15BrClN3O4 450.99, 452.99 observed m/e: 452.05, 454.02 (M+H)+ (Rt 1.15/2 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].[H-].[Na+].O>O1CCCC1.CN(C)C=O>[O:18]=[C:16]1[CH:17]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccc2)c2ccccc2[nH]1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of o-amino benzophenone (10 g) and acetic acid anhydride (10 ml) in tetrahydrofuran (150 ml) was refluxed for 8 hours. The mixture was thereafter evaporated and the residue was partitioned between sat NaHCO3, (20 ml) and diethylether (150 ml). The organic phase was dried and evaporated to give a yellow oil which was redissolved in dimethyl formamide (150 ml). To this solution was added NaH (5 g) and the mixture was stirred at 110° C. for 11/2 hour, whereafter it was cooled to room temperature, and poured into water (300 ml). This treatment afforded a precipitate of the title compound as pale crystals, which were collected by filtration. The crystals were washed with water and dried. M.p. 244°-247° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11]>ClCCl.O=[Mn]=O>[Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1ccc(CO)nc1Br
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc(C=O)nc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.5 %

Procedure:
To a solution of (6-bromo-5-methoxypyridin-2-yl)methanol (2.30 g, 10 mmol) in dichloromethane (50 mL) was added MnO2 (8.0 g) at rt. The reaction mixture was stirred at rt for 24 h. After that time the reaction was cooled to rt, filtered to remove solids and concentrated under reduced pressure to give 6-bromo-5-methoxypicolinaldehyde (1.35 g, 63%) as an off-white solid: 1H NMR (400 MHz, CDCl3): δ 9.94 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 4.03 (s, 3H).
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](OCCC)[N:3]=1.[CH3:15][C@H:16]([OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH3:15][C@H:16]([O:23][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC[C@H](C)O
Reactant: CCCOc1nc(C)ccc1C(=O)O
Product: CCCCCC[C@H](C)Oc1ccc(C(=O)O)cn1

Procedure:
The same procedure followed for the methylpropyloxynicotinic acid was used employing 1(S)-methylheptanol as the starting alcohol. A quantitative yield of 6-(1(S)methylheptyloxy)nicotinic acid (2, where R2 is 1(S)-methylheptyl was obtained as a brownish solid. The material was used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[N:5][N:6]2[C:11]([C:12]3[CH:13]=[C:14]([NH:18]C(=O)C)[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[N:8][C:7]=12)#[N:2].Cl>C(O)C>[NH2:18][C:14]1[CH:13]=[C:12]([C:11]2[N:6]3[N:5]=[C:4]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:24][CH:23]=4)[C:3]([C:1]#[N:2])=[C:7]3[N:8]=[CH:9][CH:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1cccc(-c2ccnc3c(C#N)c(-c4ccc(Oc5ccccc5)cc4)nn23)c1
Agent: Cl
Solvent: CCO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3cccc(N)c3)ccnc12
Temperature: 75 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of N-(3-(3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)acetamide (285 mg, 0.64 mmol) in ethanol (6 mL) was added HCl (3 mL). The mixture stirred at 75° C. for 3 hr. Concentrated to afford 250 mg (97%) of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J=4.4 Hz, 1H), 8.67 (br s, 2H), 8.15 (d, J=8.8 Hz, 2H), 8.06 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.57 (d, J=4.4 Hz, 1H), 7.48-7.44 (m, 3H), 7.25-7.18 (m, 3H), 7.13 (d, J=8.0 Hz, 2H). MS (ESI) m/e [M+1]+ 404.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[C:8]([CH3:13])[C:9]=1[C:10](N)=[O:11])(=O)C.[O:23]1CCOCC1>Cl>[NH2:4][C:5]1[S:6][C:7]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[C:8]([CH3:13])[C:9]=1[C:10]([OH:11])=[O:23]
Reactant: CC(=O)Nc1sc(S(=O)(=O)c2ccccc2)c(C)c1C(N)=O
Reactant: C1COCCO1
Agent: Cl
Product: Cc1c(S(=O)(=O)c2ccccc2)sc(N)c1C(=O)O
Temperature: 80 °C

Procedure:
2-Acetylamino-5-benzenesulfonyl-4-methyl-thiophene-3-carboxylic acid amide (980 mg 2.9 mmol) is dissolved in a mixture of 6 M aqueous HCl and 1,4-dioxane (1:1, 10 mL). This mixture is then heated at 80° C. for 6 h, and concentrated by evaporation to yield a residue that is as such.
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2N)[C@H:4]([O:20][C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@@H](CN)[C@@H](O)[C@H](O)[C@H]3N)[C@H]2O)[C@@H:3]([OH:41])[C@@H:2]1[NH2:42].OS(O)(=O)=O.[BrH:48]>>[CH2:1]1[C@H:2]([NH2:42])[C@@H:3]([OH:41])[C@H:4]([OH:20])[C@@H:5]([OH:8])[C@@H:6]1[NH2:7].[BrH:48]
Reactant: NC[C@@H]1O[C@H](O[C@H]2[C@@H](O)[C@H](O[C@@H]3[C@@H](O)[C@H](N)C[C@H](N)[C@H]3O[C@H]3O[C@H](CN)[C@@H](O)[C@H](O)[C@H]3N)O[C@@H]2CO)[C@H](N)[C@@H](O)[C@@H]1O
Agent: Br
Agent: O=S(=O)(O)O
Product: N[C@@H]1C[C@H](N)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 100 °C
Reaction time: 10 h
Yield: 61 %

Procedure:
A solution of neomycin sulfate (20 g, 20.8 mmol) in HBr (150 mL, 48%) was stirred under reflux at 100° C. for 40 hours. The solution was concentrated to dryness at 60° C. under reduced pressure. The residue was dissolved into water (100 mL), and activated charcoal (10 g) was added. After stirring at room temperature for 10 hours, the charcoal was removed by filtration through Celite, and the solution was concentrated to a syrup. Methanol (100 mL) was added and the mixture was stirred for 2 hours at room temperature. The solid product was filtered to give the title compound (4.1 g, 61%). Rf: 0.2 (CH3OH/NH4OH=4:1); 1H-NMR (D2O, 200 MHZ): δ 1.95 (1H, ddd), 2.5 (1H, m), 3.2-3.6 (9H, m); 13C-NMR (D2O, 200 MHZ): δ 40.0, 65.0, 87.2, 89.5. Ref. Georgiadas, M. P.; Constantinou-Kokotou, V. J. Carbohydr. Chem. 1991, 10, 739-746.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[NH:41])[NH2:40])=[CH:35][CH:34]=1.[OH-].[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:40])[NH2:41])=[CH:37][CH:38]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 3 from 1-methyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [OH:1][C:2]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1)([CH3:4])[CH3:3].[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1.CN(C=O)C>O>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:7]3[CH:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[NH:9][N:8]=3)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: CC(C)(O)c1cc(C(=O)O)n[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)O)[nH]n1
Yield: 20 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylic acid (0.646 mmol, 110 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.539 mmol, 140 mg) using DMF (2 ml) as the solvent. Water was added and the mixture was extracted three times with DCM. The combined organics were washed twice with water. The separated organic phase was evaporated and the residue was purified by flash chromatography and preparative HPLC, respectively. 44.6 mg of the title compound was obtained. 1H-NMR (400 MHz; DMSO-d6): δ 1.11 (d, 3H), 1.45 (s, 6H), 4.22-4.52 (m, 3H), 5.31 (s, 1H), 6.37 (s, 1H), 6.94 (d, 1H), 7.81 (d, 1H), 7.88-8.03 (m, 2H), 8.09 (s, 1H), 8.16 (d, 1H), 12.96 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])/[C:5](/[N+:10]#[C-:11])=[CH:6]/[N:7]([CH3:9])C)[CH3:2].[Br:13][C:14]1[CH:15]=C([CH:18]=[CH:19][CH:20]=1)N>C(O)CCC>[CH2:1]([O:3][C:4]([C:5]1[N:10]=[CH:11][N:7]([C:9]2[CH:18]=[CH:19][CH:20]=[C:14]([Br:13])[CH:15]=2)[CH:6]=1)=[O:12])[CH3:2]
Reactant: [C-]#[N+]/C(=C\N(C)C)C(=O)OCC
Reactant: Nc1cccc(Br)c1
Solvent: CCCCO
Product: CCOC(=O)c1cn(-c2cccc(Br)c2)cn1
Yield: 13 %

Procedure:
A solution of compound (Z)-3-dimethylamino-2-isocyano-acrylic acid ethyl ester (11.8 g, 79 mmol) and 3-bromo aniline (11.3 g, 65 mmol) in n-butanol (90 mL) was heated to reflux for 72 h [reaction was monitored by TLC]. Reaction mixture was concentrated under reduced pressure to remove n-butanol and the residue was passed through silica gel column, eluated with a mixture of ethyl acetate and hexane to give a mixture of ethyl and n-butyl ester compounds which was then separated by flash column chromatography over silica gel using 3:7 mixture ethyl acetate and hexane as eluant. Finally the ethyl ester was further purified by crystallization to furnish 3 (2.5 g, 13%) as a brown solid. HRMS (ESI+): m/z=295.1349 [M+H]
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][C:18]2[S:19][C:20]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[N:7]=1)C.C(O)C.[OH-].[K+]>O1CCCC1>[Cl:27][C:26]1[C:20]2[S:19][C:18]([CH2:17][N:8]3[C:9](=[O:16])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:6]([CH2:5][C:4]([OH:28])=[O:3])=[N:7]3)=[N:22][C:21]=2[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cc1nn(Cc2nc3cccc(Cl)c3s2)c(=O)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1nn(Cc2nc3cccc(Cl)c3s2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of ethyl-3-(7-chlorobenzothiazol-2-ylmethyl)-4-oxo-3-H-phthalazin-1-ylacetate (800 mg) in a 2:1 mixture of ethanol and tetrahydrofuran (30 ml) was added 5 ml of 1% aqueous potassium hydroxide solution and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated by evaporation under vacuum and the resulting residue was diluted with water (10 ml). Upon adjusting the pH of the solution to around 2 with sufficient 10% HCl, a white precipitate was obtained. The precipitate was collected by filtration, air-dried and then crystallized from methylene chloride (10 ml) to obtain the title compound (yield, 273 mg), m.p. 168° C.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([NH2:9])=[N:6][N:5]=2)[CH2:3][CH2:2]1.Br[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1>>[CH:1]1([C:4]2[S:8][C:7](=[NH:9])[N:6]([CH2:11][CH:12]3[CH2:16][CH2:15][CH2:14][O:13]3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: BrCC1CCCO1
Reactant: Nc1nnc(C2CC2)s1
Product: N=c1sc(C2CC2)nn1CC1CCCO1

Procedure:
5-cyclopropyl-1,3,4-thiadiazol-2-amine (ASD) and 2-(bromomethyl)tetrahydrofuran (Acros) were processed using the method described in Example 1C to afford the title compound.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:28]([O:32][CH3:33])([O:30][CH3:31])=[O:29])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].O.CO.O[Li].O>C1COCC1>[CH3:31][O:30][P:28]([CH2:27][CH:26]=[CH:25][CH2:24][CH:4]([CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21])[C:3]([OH:34])=[O:2])([O:32][CH3:33])=[O:29]
Reactant: COC(=O)C(CC=CCP(=O)(OC)OC)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1c(C)c2c(c(O)c1CC=C(C)CC(CC=CCP(=O)(OC)OC)C(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester (460 mg, 0.927 mmol) in a solution of 1:1:2 of H2O, MeOH, THF (8 mL) was stirred with LiOH.H2O (78 mg, 1.86 mmol) at ambient temperature for 12 hours. A second batch of LiOH.H2O (40 mg, 0.952 mmol) was added. The reaction mixture was stirred at room temperature for another 16 hours, after which no further progress was observed. The reaction was quenched by addition of a saturated aqueous solution of NH4Cl. The organic layer was removed in vacuo and the product was extracted with EtOAc from the aqueous layer, which had been acidified by addition of 5 drops of 2 N HCl. The product was further purified by chromatography to provide the desired product. 1H NMR (300 MHz, CDCl3) δ 1.79 (s, 3H), 2.08-2.38 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J=22 Hz), 2.60 (d, 1H, J=22 Hz), 2.57-2.64 (m, 1H), 3.38 (d, 2H, J=7 Hz), 3.72 (d, 6H, J=11 Hz) 3.76 (s, 3H), 5.20 (s, 2H), 5.27 (t, 1H, J=6 Hz), 5.36-5.63 (m, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 30.5 ppm; MS (m/z) 481.2 [M−H]−.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[N:8][C:7]2=[O:16].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19](B(O)O)[CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[NH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[N:8][C:7]3=[O:16])[CH:18]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: O=c1nc(C(F)(F)F)[nH]c2c(Cl)cccc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Product: O=c1nc(C(F)(F)F)[nH]c2c(-c3cnc4ccccc4c3)cccc12
Temperature: 100 °C
Reaction time: 15 h
Yield: 62.6 %

Procedure:
A suspension of compound (114a) (0.57 g), 3-quinolineboronic acid (0.45 g), Pd2dba3 (0.031 g), X-Phos (0.064 g), and potassium phosphate (1.4 g) in butanol was stirred at 100° C. for 15 hours in a nitrogen atmosphere. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was then purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 8-(quinolin-3-yl)-2-(trifluoromethyl)quinazolin-4(1H)-one (0.49 g) as a white solid. Phosphorus oxychloride (5 ml) was added to the obtained 8-(quinolin-3-yl)-2-(trifluoromethyl)quinazolin-4(1H)-one (0.49 g), and the mixture was heated to reflux for 13 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The reaction solution was neutralized with an aqueous sodium bicarbonate solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 4-chloro-8-(quinolin-3-yl)-2-(trifluoromethyl)quinazoline (0.43 g) as a white solid. Compound (114) was obtained as a yellow solid (yield based on 4 steps: 25%) according to Example 1(5) using the obtained 4-chloro-8-(quinolin-3-yl)-2-(trifluoromethyl)quinazoline instead of compound (1d) and 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.