Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.[OH-].[Na+].[C:5]([C:7]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[NH:15][C:16](=[O:17])[C:11]=2[N:10]=[CH:9][CH:8]=1)#[N:6].Cl>C(O)C>[C:5]([C:7]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[NH:15][C:16](=[O:17])[C:11]=2[N:10]=[CH:9][CH:8]=1)(=[O:1])[NH2:6]
Reactant: OO
Reactant: CCOc1ccccc1-c1nc2c(C#N)ccnc2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccccc1-c1nc2c(C(N)=O)ccnc2c(=O)[nH]1
Yield: 72 %

Procedure:
30% Aqueous hydrogen peroxide solution (0.5 ml) was added to a stirred aqueous sodium hydroxide solution (1M, 40 ml), followed by 8-cyano-2-(2-ethoxyphenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 14; 0.2 g, 0.00068 mol) and ethanol (2 ml). The mixture was heated under reflux for 2 hours, allowed to cool, acidified with 1N hydrochloric acid, and then extracted with a mixture of dichloromethane and methanol (10:1, 5×50 ml). The combined organic fractions were evaporated under vacuum and the resulting residue triturated with ethanol to give the title compound as a colourless solid (0.152 g, 72%), m.p. 295°-297° C. Found: C,61.65; H,4.56; N,17.61. C16H14N4O3 requires C,61.93; H,4.55; N,18.06%.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)=[CH:9][C:8]=1[O:20][CH3:21].[CH3:22][S:23]SC.Cl>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH2:15][C:16]([CH3:18])([CH3:19])[N:17]=2)=[C:9]([S:23][CH3:22])[C:8]=1[O:20][CH3:21]
Reactant: CSSC
Reactant: COc1cc(C2=NC(C)(C)CO2)ccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(C2=NC(C)(C)CO2)c1SC
Temperature: -78 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
n-Butyllithium (2.5M in hexane, 54 ml) was added with cooling to a stirred solution of 2-(4-chloro-3-methoxyphenyl)-4,4-dimethyloxazoline (27.0 g) in tetrahydrofuran while maintaining the temperature below -40° C. The mixture was stirred at -78° C. overnight. A solution of dimethyl disulphide (26.5 g) in tetrahydrofuran was added dropwise and the mixture was stirred at -40° C. overnight. After allowing to warm to room temperature the mixture was treated with hydrochloric acid (2M). The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by dry column flash chromatography eluted with a mixture of ethyl acetate and n-hexane to give 2-[4-chloro-3-methoxy-2-(methylsulphenyl)-phenyl]-4,4-dimethyloxazoline (11.1 g) as a white solid, m.p. 50°-52° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:25]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]2[C:34]([O:36][C:37](=O)[C:27]=2[CH:26]=1)=[O:35]>>[F:22][C:21]([F:24])([F:23])[C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:34](=[O:35])[C:28]5[C:27](=[CH:26][CH:25]=[C:30]([C:31]([OH:33])=[O:32])[CH:29]=5)[C:37]4=[O:36])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])=[N:16][C:15]=2[CH:17]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(C(F)(F)F)ccc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(C(F)(F)F)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-trifluoromethylbenzoxazole (113 mg, 0.4 mmol) and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) the title compound was obtained (120 mg, 59%). 1H NMR (DMSO) δ 8.41(m, 2H), 8.30(s, 1H), 8.23(s, 1H), 8.12(d, 1H), 8.07(d, 1H), 7.97(d, 1H), 7.77(d, 1H), 7.49(dd, 1H), 7.04(d, 1H), 3.34(m, 2H) 1.75(m, 2H), 1.06(t, 3H). MS 507.7 m/z (M−H)−.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)CCCc1ccccc1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CCCc1ccccc1

Procedure:
Following General Procedure BB and using 4-phenylbutanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([CH3:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:27]4[CH:26]=[N:25][C:24]([NH2:23])=[N:29][CH:28]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-methyl-pyridine (example E.85) (0.20 g, 0.509 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.124 g, 0.56 mmol) according to the general procedure VI. Obtained as an off-white solid (0.100 g, 48%). MS (ISP) 407.2 [(M+H)+], 409.1 [(M+2+H)+] and 411 [(M+4+H)+]; mp 188° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:18][C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)([OH:20])[CH3:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (290 mg, 1.4 mmol) in DMF (6 mL) was added sodium hydride (38 mg, 1.6 mmol) and the solution was stirred at 120° C. for 1 h. The reaction mixture was cooled to 0° C. and 3-(2-methyloxiran-2-yl)pyridine (400 mg, 2.96 mmol) was added dropwise over a period of 5 min. The reaction mixture was stirred at 120° C. for 2 h, quenched with ice-water (15 mL) and extracted with EtOAc (60 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (5-15% MeOH/EtOAc) to yield 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-yl)propan-2-ol. Separation by chiral HPLC provided enantiomers 5a and 5b. 1H NMR (CDCl3, freebase) δ (ppm): 8.79 (s, 1H), 8.42 (d, 1H), 7.56 (d, 1H), 7.04 (s, 1H), 6.9 (m, 2H), 6.8 (d, 1H), 4.17 (dd, 2H), 3.42 (s, 2H), 2.8 (t, 2H), 2.62 (t, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 1.61 (s, 3H). Optical rotations: Compound No. 5a, (−) 39.27 (c 0.43, Chloroform, 99.69% HPLC purity); Compound No. 5b, (+) 58.97 (c 0.58, Chloroform, 99.49% HPLC purity).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:27][C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Oc1ccccc1
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)c(Oc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 13.6 %

Procedure:
A mixture of 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), phenol (0.16 g), 8 M potassium hydroxide solution (0.2 mL) and dimethyl sulfoxide (5 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.07 g, 13%).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[C:13]([C:20]([O:22][CH3:23])=[O:21])=[CH:12][C:11]=1[NH:24]N>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[Cl:9][C:10]1[C:11]2[NH:24][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[C:12]=2[C:13]([C:20]([O:22][CH3:23])=[O:21])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:15]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1cc(Cl)c(NN)cc1C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c2[nH]c3c(c2c1C(=O)OC)CCCC3
Yield: 31 %

Procedure:
To 10 ml of acetic acid were added 320 mg of cyclohexanone, 500 mg of zinc chloride and 800 mg of 2-chloro-4,5-bis(methoxycarbonyl)phenylhydrazine hydrochloride. The mixture was refluxed for 6 hours. Then, acetic acid was removed by distillation under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate. The solution was washed with 1 N hydrochloric acid, an aqueous saturated sodium chloride solution and an aqueous saturated sodium hydrogen-carbonate solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=1/0 to 40/1) to obtain 270 mg (yield: 31%) of dimethyl 1-chloro-5,6,7,8-tetrahydrocarbazole-3,4-dicarboxylate as colorless crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29]C3CCCCO3)=[CH:25][CH:24]=2)=O)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([C:23]2[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=2)=[C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[CH2:11][CH3:12])=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Reactant: CCC(=O)c1ccc2c(c1)CCO2
Product: CCC(=C(c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccc2c(c1)CCO2
Yield: 37 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (610 mg, 1.1 eq) was reacted with (6-chloropyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (1.0 g, 1.0 eq) to give 440 mg desired product (37%, Z/E=1/1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=[C:11]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd]>[F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1cc(C=CC(=O)OCC)cc(Oc2ccc(F)cc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)CCc1cc(CCC(=O)OCC)cc(Oc2ccc(F)cc2)c1
Yield: 70.6 %

Procedure:
Treatment of diethyl 3,3'-[5-(4-fluorophenoxy)-1,3-phenylene]bis-2-propenoate (17.0 g) with ammonium formate (27.85 g) and 10% of palladium on carbon (1.70 g) according to the method of Preparation 12 gave the title compound as an oil (12.12 g), Rf 0.30 (SS 1). Found: C,68.01; H,6.46. C22H25FO5 requires C,68.03; H,6.49%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5].[Cl-].[NH4+].O>CO.[Fe]>[NH2:10][C:8]1[CH:7]=[C:6]([Cl:13])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=1
Reactant: N#Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#Cc1c(Cl)cc(N)cc1Cl
Yield: 64.8 %

Procedure:
A solution of 2,6-dichloro-4-nitrobenzonitrile (2.46 g, 11.3 mmol, Eq: 1.00), iron (3.17 g, 56.7 mmol, Eq: 5) and ammonium chloride (6.06 g, 113 mmol, Eq: 10) in methanol (30 mL)/water (10 mL) was heated at reflux o/n. TLC shows incomplete reaction. Continued heating at 100 deg for 6 hr, then 60 deg overnight. The reaction mixture was filtered over Celite. The filtrate was suspended in ethyl acetate to give insoluble solid. The slurry was concentrated to dryness, suspended in water, filtered, and rinsed with water. The solid was transferred to a round bottom flask, suspended in benzene, and concentrated. An additional portion of benzene was added and concentrated once more to give 1.37 g (65%) of desired product as a light brown solid.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][C:9]1([CH3:37])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:36])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:1][S:2]([NH:5][C:19]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[C:28]([NH:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:36])[C:9]([CH3:37])([CH3:8])[CH2:18]2)=[O:20])(=[O:4])=[O:3]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)Nc2ccccc2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a suspension of methanesulfonamide (237 mg, 2.5 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (100 mg, 2.48 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.5 mmol) and 1,1′-carbonyldiimidazole (162 mg, 1 mmol) in N,N-dimethylformamide (1 mL) was stirred at 70° C. for 1 h. Then the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-(6-methanesulfonylaminocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-N-phenyl-benzamide (100 mg, 18%) as a white solid: LC/MS m/e calcd for C26H27N3O4S (M+H)+: 478.59, observed: 478.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22]([OH:24])=[O:23])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:27])=[N-].C(OCC)C>C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22]([O:24][CH3:27])=[O:23])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C(=O)O)c12
Solvent: CCOCC
Product: COC(=O)c1c(F)ccc2onc(OCCNC(=O)OC(C)(C)C)c12
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carboxy-5-fluoro-1,2-benzisoxazole (0.31 g) in diethylether (20 ml) was added diazomethane/diethylether solution at 5° C. until the reaction mixture became yellow, and the mixture was then stirred for 15 minutes. The reaction mixture was evaporated under reduced pressure to give the title compound (0.32 g, 100% yield) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:29]5[CH:30]=[N:31][N:32]([CH2:34][C:35]6[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=6)[CH:33]=5)=[CH:27][N:26](C(OC(C)(C)C)=O)[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:56]>C(OCC)C>[ClH:56].[F:41][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][N:32]1[CH:33]=[C:29]([C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[C:15]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:16]=4)[CH:21]=3)[NH:26][CH:27]=2)[CH:30]=[N:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(Cc5cccc(F)c5)c3)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)ccc1N1CCNCC1
Yield: 57 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(methylsulfonamido)phenyl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (27 mg, mmol) was deprotected in methanol/HCl in diethyl ether (3/1 ml) to afford 12 mg (57% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 9.01-9.00 (d, 1H), 8.71-8.70 (d, 1H), 8.41 (s, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.87-7.86 (d, 1H), 7.66-7.63 (dd, 1H), 7.49-7.46 (d, 1H), 7.40-7.34 (m, 1H), 7.16-7.13 (m, 1H), 7.07-7.02 (m, 2H), 5.47 (s, 2H), 3.50-3.46 (m, 4H), 3.26-3.23 (m, 7H). MS: m/z=546.2 (M+1), HPLC: 98.49% in method B.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1.CCN(C(C)C)C(C)C>CCO>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH:19]=[CH:18][CH:17]=[N:16]1)([O-:14])=[O:13]
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1cccn1
Temperature: 120 °C
Yield: 80.1 %

Procedure:
1-Fluoro-2-nitro-4-trifluoromethyl-benzene (209 mg, 1 mmol) was dissolved in EtOH (4.5 mL) in a 5 mL microwave reaction vessel. 1H-pyrazole (83.5 mg, 1.2 mmol), DIPEA (329 μL, 2 mmol) and a stirrbar was added followed by sealing of the reaction vessel. The reaction mixture was then heated in the microwave for 30 min at 120° C. The reaction was concentrated in vacuo and the residue purified by flash chromatography (Silica, Hexane: EtOAc) to afford the title compound (206 mg, 81%). LC/MS>95%, m/z (ESI+)=258 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])O[C:4]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH2:14][C:3]1=2.[OH-].[NH4+:20]>>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[NH:20][C:4]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH2:14][C:3]1=2
Reactant: [NH4+]
Reactant: O=C(O)c1cc(=O)c2c(o1)-c1ccccc1SC2
Agent: [OH-]
Product: O=C(O)c1cc(=O)c2c([nH]1)-c1ccccc1SC2

Procedure:
A solution of 4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-2-carboxylic acid (3.0 g, 11.53 mmoles, described in Example 79 ) in concentrated ammonium hydroxide (50 ml) is heated on a steam bath for 2.5 hr., and evaporated under reduced pressure. The residue is dissolved in water (75 ml) and added to a mixture of concentrated hydrochloric acid (5 ml) and ice. The precipitate is collected, washed with 0.07 N hydrochloric acid, acetone and ether to give the title compound as light yellow crystals, m.p. 256°-257° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:7][C:8]2[O:12][C:11]([CH2:14]OS(C)(=O)=O)([CH3:13])[CH2:10][C:9]=2[C:20]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:3])[CH3:2].[I-:29].[Na+].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:6]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:7][C:8]2[O:12][C:11]([CH2:14][I:29])([CH3:13])[CH2:10][C:9]=2[C:20]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COS(C)(=O)=O)O2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CI)O2
Yield: 67.5 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 0.55 g of 5-acetoxy-4,6-di-t-butyl-2-methanesulfonyloxymethyl-2-methyl-2,3-dihydrobenzofuran and combined with 3.0 g of sodium iodide, and the mixture was heated under reflux for 24 hours. After cooling, water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 10% ethyl acetate to give 0.4 g of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran (rotamer mixture) as a colorless oil (yield 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C1(C)C=CC=CC=1>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C2CCC3(CC2)OCCO3)cc1F
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=C1CCC(c2ccc(F)c(F)c2)CC1
Reaction time: 18 h
Yield: 96 %

Procedure:
A mixture of 6.30 g of 8-(3,4-difluorophenyl)-1,4-dioxaspiro[4.5]decane, 60 ml of toluene and 40 ml of formic acid was stirred for 18 hours. The formic acid phase was separated and extracted twice with 30 ml of toluene each time. The combined toluene phase was washed neutral with water, dried over sodium sulphate and concentrated. There were obtained 5.00 g of 4-(3,4-difluorophenyl)cyclohexanone as a colourless oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH2:12][O:13][CH3:14].O>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][O:13][CH3:14])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 918.2 %

Procedure:
To a suspension of 60% NaH in mineral oil (12.7 g, 31.8 mmol) in anhydrous THF (300 mL) at 0° C. was added 4-bromophenol (50.0 g, 28.9 mmol) dissolved in THF (100 mL) dropwise over 1 h. The reaction mixture was stirred at 0° C. for 30 min, and chloromethylmethyl ether (24.8 mL, 32.6 mmol) dissolved in THF (30 mL) was added dropwise over 20 min. The reaction mixture was stirred overnight at RT. Water (250 mL) was added, and the mixture was extracted with ether (3×250 mL). The combined ethereal extracts were washed with brine, dried (MgSO4), and concentrated. The residue was distilled under vacuum to afford 57.6 g (92%) of 86 as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 3.33 (s, 3H), 5.15 (s, 2H), 6.96 (d, J=9.0 Hz, 2H), 7.43 (d, J=9.0 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:10]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1csc2c(=O)[nH]cnc12
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1csc2c(Cl)ncnc12
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 7-methyl-3H-thieno[3,2-d]pyrimid-4-one (3, 2.9 g, 18 mmol) in phosphorus oxychloride (18 mL) under N2 was heated at reflux for 1 hour. The resulting solution was allowed to cool to room temperature and then poured into a saturated aqueous solution of sodium bicarbonate to neutralize. The aqueous mixture was extracted with diethyl ether. The organic layer was washed with water followed by saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to yield 4-chloro-7-methylthieno[3,2-d]pyrimidine (3.1 g, 96% yield) as a white solid.