Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2([OH:18])[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]2)=O)[CH:7]=1.[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].O>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][C:10]3([CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]3)[C:8](=[N:26][S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])[C:6]=2[CH:7]=1
Reactant: COC1CCC(O)(C(=O)c2cc(Br)ccc2F)CC1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 64.6 %

Procedure:
To a mixture of 5-bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one (Intermediate 12, 2.8 g, 9.00 mmol) and 2-methylpropane-2-sulfinamide (2.024 g, 16.20 mmol) in methyl THF (15 mL) was added titanium ethoxide (3.71 mL, 18.00 mmol) and the reaction was heated to reflux. After 21 h the reaction was allowed to cool to r.t. whereafter it was diluted with EtOAc (150 mL). Water (12 mL) was added dropwise over 10 min under vigorous stirring and then the mixture was left standing without stirring for 1.5 h. The solids were filtered off and the organics were evaporated. The crude product was purified by flash chromatography using a gradient of 0%-50% EtOAc in heptane, yielding 2.41 g of the title compound (65% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.33 (s, 9H), 1.81 (m, 6H), 2.12 (d, 2H), 3.33 (m, 1H), 3.42 (s, 3H), 6.94 (d, 1H), 7.59 (dd, 1H), 8.53 (m, 1H); MS (ES+) m/z 415 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]([CH2:25][CH3:26])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([O:23]C)[CH:15]=3)[CH:7]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]([CH2:25][CH3:26])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=3)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(-c2c(C#N)c3ccc(OC)cc3n2CC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc(-c2c(C#N)c3ccc(O)cc3n2CC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of [3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.65 g, 4.37 mmol) in DCM (20 mL) is added 1M BBr3 in DCM (13.12 mL) over a period of 20 min. The reaction mixture is stirred further 1 h at room temperature and then the solvents are removed under reduced pressure. The residue is dissolved in MeOH and then poured into cold water. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.5 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:15]([NH:14][CH2:12][CH3:13])=[O:16])=[O:6]
Reactant: CCN=C=O
Reactant: NNC(=O)c1cccc(F)c1
Solvent: C1CCOC1
Product: CCNC(=O)NNC(=O)c1cccc(F)c1
Reaction time: 24 h

Procedure:
To a solution of 3-fluorobenzhydrazide (5.0 g, 0.033 mol) in tetrahydrofuran (100 mL) was added ethyl isocyanate (2.6 g, 0.036 mol) at room temperature. After stirring for 24 hr, the resultant precipitate was collected by suction-filtration to give 1-(3-fluorobenzoyl)-4-ethyl semicarbazide in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]3)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cnc2ccc(Br)cc2c1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cnc2ccc(-c3ccc(Cl)cc3)cc2c1
Temperature: 150 °C

Procedure:
To a 2-5 mL microwave vial fitted with a stirbar was added methyl 6-bromoquinoline-3-carboxylate (Int-1, 0.15 g, 0.564 mmol), 4-chlorophenylboronic acid (0.114 g, 0.733 mmol), sodium carbonate (0.179 g, 1.69 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0651 g, 0.056 mmol). The vial was capped and 1,4-dioxane (1.6 mL) and water (0.47 mL) were added by syringe. The mixture was purged with argon for 5 min. The contents of the vial were heated in a microwave at 150° C. for 30 min. The reaction mixture was cooled to room temperature and the vial was opened. The mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted twice with water. The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was used as obtained in the following step. LC-MS: (FA) ES+ 298.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([O:14]C)=[O:13])[CH2:4]1.COC1C(O[N+]([O-])=O)CC(C(OC)=O)C1>>[CH3:1][O:2][CH:3]1[CH:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][CH:5]([C:12]([OH:14])=[O:13])[CH2:4]1
Reactant: COC(=O)[C@@H]1C[C@H](OC)[C@@H](O[N+](=O)[O-])C1
Agent: COC(=O)C1CC(OC)C(O[N+](=O)[O-])C1
Product: COC1CC(C(=O)O)CC1O[N+](=O)[O-]

Procedure:
The title compound was prepared by following step D for example 1, except that the reagent (+)-methyl (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate was replaced by methyl (1RS,3RS,4RS)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate. 1H NMR (500 MHz, CDCl3) δ 2.10-2.19 (m, 3H), 2.57-2.65 (m, 1H), 3.14 (m, 1H), 3.41 (s, 3H), 3.90 (m, 1H), 5.23-5.27 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34].O>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:34])[O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:25][CH:24]=1)#[N:18]
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)cc3)c2cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
The 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (3.354 g, 10.0 mmol) obtained in Production Example 10 was dissolved in dimethylformamide (35 ml) under a nitrogen atmosphere, and then the solution was cooled in an ice water bath, pyridine (2.43 ml, 30.0 mmol) and phenyl chloroformate (1.38 ml, 11.0 mmol) were added in that order, and the mixture was stirred at room temperature for 3 hours. Water (40 ml) was added to the reaction solution and the precipitated crystals were filtered out. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the crystals obtained by concentration under reduced pressure were combined with the previous crystals, suspended in hexane-ethyl acetate (5:1) and stirred overnight, after which the crystals were filtered out and dried under reduced pressure to obtain the title compound (4.334 g, 9.52 mmol, 95.2%) as light brown crystals.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.S(=O)(=O)(O)[OH:19]>O>[OH:19][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(C2CCOCC2)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(C2CCOCC2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.2 g of sodium nitrite in 10 ml of water was added to a mixture of 13 g of 4-(p-aminophenyl)-tetrahydropyran and 100 ml of concentrated sulfuric acid cooled to 5° C and the mixture was stirred at 5° C for 30 minutes. The mixture was poured into a solution of 100 ml of water and 10 ml of concentrated sulfuric acid heated to 75°-80° C and the mixture was held at 75°-80° C for 15 minutes and was then cooled to 4° C. The mixture was filtered and the recovered crystals were washed with water and dried to obtain 12.7 g of 4-(p-hydroxyphenyl)-tetrahydropyran melting at 164° C.
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][CH:11]([CH3:13])[O:10][C:9]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>[Pd].C(O)C>[CH2:1]([CH:8]1[CH2:12][CH:11]([CH3:13])[O:10][C:9]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC=C1CC(C)OC1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCC1CC(C)OC1=O
Yield: 98.4 %

Procedure:
Using the same general hydrogenation procedure described in Example I, 3-heptylidene-5-methyldihydro-2(3H)-furanone (10 g; 0.051 mole) was combined with 0.5 g 5% palladium on carbon catalyst and 10 ml ethanol. Hydrogen gas was bubbled into the mixture over a 12 hour period with stirring. After removal of the catalyst and evaporation of the solvent, 9.95 g (96% assay by GLC; 95% yield) 3-heptyl-5-methyldihydro-2(3H)-furanone was recovered. The proton nuclear resonance spectrum for the product was as follows:
Reaction SMILES: C(OC(N1C[CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:39]=CC(N)=C[CH:34]=1>>[CH3:31][O:32][C:33]1[CH:39]=[CH:9][C:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:11][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 4-methoxyaniline instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 365 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.14 (1H, s) 9.73 (1H, s) 8.00 (1H, d, J=5.42 Hz) 7.85 (1H, d, J=5.42 Hz) 7.44-7.55 (3H, m) 7.29 (1H, dd, J=3.20, 2.71 Hz) 6.89 (2H, d, J=8.98 Hz) 6.80 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.47, 1.90 Hz) 3.72 (3H, s)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:13])[C:3]=1[OH:14].[C:15]1([N:25]=[C:26]=S)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>CO>[C:15]1([NH:25][C:26]2[O:14][C:3]3[C:4]([F:13])=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=3[N:1]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: S=C=Nc1cccc2ccccc12
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Solvent: CO
Product: COC(=O)Cc1ccc2nc(Nc3cccc4ccccc34)oc2c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.5 %

Procedure:
Methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (996 mg, 5.00 mmol) was dissolved in methanol (50 ml). To the resulting solution was added 1-naphthyl isothiocyanate (926 mg, 5.00 mmol). After the resulting mixture was stirred at room temperature for 2 days, mercuric oxide (yellow) (1.08 g, 5.00 mmol) was added thereto. The mixture was stirred at 70° C. for 3.5 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The crude crystals thus obtained were recrystallized from chloroform/n-hexane to give methyl (2-(1-naphthylamino)-7-fluoro-6-benzoxazolyl)acetate (1.41 g, 81%) as a pale gray crystalline powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[CH:11][CH:10]=1)([O:8][CH3:9])=[O:7]
Reactant: ClCCc1c[nH]cn1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(OCCc2c[nH]cn2)cc1

Procedure:
228 mg (1.5 mmol) of methyl 4-hydroxybenzoate, 251 mg (1.5 mmol) of 4-[2-chloroethyl]-1H-imidazole hydrochloride, 500 mg (3.6 mmol) of potassium carbonate and sodium iodide (catalyst) are stirred at 80° C. for 3 days in 5 ml of dimethylformamide. The reaction mixture is cooled and filtered and the filtrate is evaporated under reduced pressure to give an oily residue which is subjected to column chromatography (using, as first eluent, chloroform and, as second eluent, a 95/5 chloroform/methanol mixture). The product is purified by preparative high performance liquid chromatography and crystallized from water; M.p.: 116°-118° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14]CC)=O)=[C:7]2[OH:17].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:12]([C:8]2[CH:9]=[N:10][C:11]3[C:6]([C:7]=2[OH:17])=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])=[O:14])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2c(F)cccc2c1O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cccc2c1O
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 0.50 g of ethyl 8-fluoro-4-hydroxy-3-quinolinecarboxylate (J. Med. Chem., 22, 816 (1979)) and 3.0 mL of 4-chlorobenzylamine is stirred 1 hour at 200° C. The mixture is cooled to 25° C. and it is diluted with 25 mL of hexanes. After stirring for an additional 1 h the solid precipitate is collected by filtration and washed with 10 mL of hexanes. It is dried in a stream of air and then it is suspended in 20 mL of glacial acetic acid. The mixture is heated until the solid is completely dissolved and the resulting solution is diluted with 200 mL of distilled water. The mixture is allowed to cool to 25° C. and the solid is collected by filtration. It is washed with a small volume of 10% aqueous acetic acid and then it is dried at torr and 45° C. for 18 h. The yield is 0.52 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (193 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (320 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:23]=[C:11]3[N:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[N:14]=[C:15]([NH2:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][C:25]1[C:29]([CH:30]=O)=[C:28]([CH3:32])[O:27][N:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:24][C:25]1[C:29]([CH2:30][N:20]2[CH2:19][CH2:18][N:17]([C:13]3[N:14]=[C:15]([NH2:16])[N:10]4[N:9]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)[N:23]=[C:11]4[N:12]=3)[CH2:22][CH2:21]2)=[C:28]([CH3:32])[O:27][N:26]=1
Reactant: Cc1noc(C)c1C=O
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3cccc(F)c3)nn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1noc(C)c1CN1CCN(c2nc(N)n3nc(-c4cccc(F)c4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(3Fluoro-phenyl)-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of 3,5-dimethyl-isoxazole-4-carbaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 6.9-7.25 (m, 3 H), 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 1.6 (br s, 6H). MS: m/z: 424 [M+H]+.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.F[B-](F)(F)F.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[N+]#N.N1C(C)=CC=CC=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O.C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[CH:3]1[CH:4]=[CH:5][N:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Reactant: N#[N+]c1cc(F)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1C=CC(c2cc(F)ccc2Cl)C1
Temperature: 23 °C

Procedure:
Palladium(II) acetate (24 mg, 0.11 mmol, 0.020 equiv) was added to a vigourously stirred, deoxygenated mixture of tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (900 mg, 5.32 mmol) and 2-chloro-5-fluorobenzenediazonium tetrafluoroborate (1-1, 1.30 g, 5.32 mmol) in water and carbon tetrachloride (1:1, 50 mL) at 23° C., and the resulting mixture was stirred for 20 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was dissolved in toluene (100 mL), and the resulting solution concentrated in vacuo to facilitate azeotropic removal of residual water. 2,6-Lutidine (1.24 mL, 10.6 mmol, 2.00 equiv) and trifluoroacetic anhydride (0.558 mL, 2.66 mmol, 0.500 equiv) were then sequentially added to a solution of the residue in toluene (100 mL) at 0° C. The resulting mixture was stirred at 0° C. for 8 hours, then warmed to 23° C. and stirred an additional 8 hours. The reaction mixture was heated at reflux for 1 hour, then cooled to 23° C. and concentrated. The residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 60% EtOAc in hexanes) to give tert-butyl 3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (1-2) as an orange oil. LRMS m/z (M+H—CH3) 283.0 found, 283.1 required.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:16]C)[C:6](=[O:18])[C:5]=2[CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[OH:16])[C:6](=[O:18])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)c1cccc(OC)c1-2
Agent: Br
Solvent: CC(=O)O
Product: O=C1c2cc(O)ccc2-c2c(O)cccc21
Temperature: 80 °C

Procedure:
Prepare a solution of 2,5-dimethoxy-fluoren-9-one (0.031 mmol) in glacial acetic acid (50 mL) and warm to 80° C. Add hydrogen bromide (150 mL, 48% solution) and prepare according to the procedure set forth in Example 1D to obtain 2,5-dihydroxy-fluoren-9-one.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([CH:15]([NH:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25])[CH3:16])([O:13][CH3:14])=[O:12]>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:25])[C:18]=1[N:17]([CH:15]([C:11]([O:13][CH3:14])=[O:12])[CH3:16])[C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)Nc1c(C)cccc1C
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)N(C(=O)Cc1ccccc1)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
17 g (0.11 mol) of phenylacetylchloride were added dropwise in 30 minutes and at room temperature, to a solution of N-(1-carbomethoxy-ethyl)-2,6-dimethyl-aniline(21.2 g at a purity of 95%, 0.1 mol) in toluene (150 ml) and dimethylformamide (1 ml.). The reaction mixture was stirred 1 hour at room temperature and 3 hours at reflux temperature, then it was cooled down to room temperature and washed with an aqueous solution of NaHCO3 at 5% and successively with water. The organic phase was separated and anhydrified with anhydrous Na2SO4. The solvent was evaporated and the rough product obtained was recrystallized from ligroin (75°-120° C.), so obtaining 26 g. of the desired product (white solid, m.p. 78°-80° C.).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][NH:7][CH2:6][C:5]2[S:9][CH:10]=[CH:11][C:4]1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)(Cl)Cl>[OH:2][CH:3]1[CH2:8][N:7]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:6][C:5]2[S:9][CH:10]=[CH:11][C:4]1=2
Reactant: OC1CNCc2sccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1Cc2sccc2C(O)C1
Reaction time: 2 h
Yield: 76 %

Procedure:
To a mixture of 4-hydroxy-4,5,6,7-tetrahydro-thieno-[2,3-c]pyridine hydrochloride (50 g; 0.26 mole), chloroform (200 ml) and saturated aqueous potassium carbonate solution (100 ml) is added dropwise a solution of methanesulfonyl chloride (30 g; 0.26 mole) in chloroform (50 ml), at room temperature and with vigorous mechanical stirring. Stirring is continued a further 2 hours at room temperature. After decantation, the chloroform phase is washed with dilute hydrochloric acid, then with water, and is dried over anhydrous sodium sulfate. Evaporation of the solvent, in vacuo, leaves crystals which are recrystallized from methanol. Light brown crystals; M.p.=140° C. (methanol); Yield: 76%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[CH:17]=1)[CH3:12]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(Br)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)c2)c1

Procedure:
3-Bromo-benzoic acid (112 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:17])[C:4]1[C:5](=[C:9]([Cl:16])[C:10](Cl)=[C:11]([Cl:14])[C:12]=1[Cl:13])[C:6]([OH:8])=[O:7].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][N:2]=[C:3]([OH:17])[C:4]1[C:5](=[C:9]([Cl:16])[C:10]([S:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[C:11]([Cl:14])[C:12]=1[Cl:13])[C:6]([OH:8])=[O:7]
Reactant: CN=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN=C(O)c1c(Cl)c(Cl)c(Sc2ccc(OC)cc2)c(Cl)c1C(=O)O

Procedure:
41.41 g (138 millimols) of tetrachlorophthalic acid N-methylimide, 19.42 g (138 millimols) of p-methoxythiophenol, 57.43 g of potassium carbonate and 410 ml of tetrahydrofuran are stirred at 25° C. for 24 hours. After evaporation, the residue is acidified and extracted with methylene chloride. After drying and evaporation, the residue is recrystallised from toluene. This yields 35.38 g (64% of theory) of the title imide; melting point 182°-6° C.