Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].O>[Cl-].[Zn+2].[Cl-].ClCCl>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCO2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc2c(c1)CCO2
Temperature: 100 °C
Yield: 24.1 %

Procedure:
A mixture of 44.4 g (0.37 moles) of 2,3-dihydrobenzofuran and 37.8 g (0.37 moles) of acetic anhydride were added with 5.0 g (37 mmoles) of anhydrous zinc chloride. The mixture was heated to 95-105° C. for 10 hrs; after cooling to room temperature the mixture is added with 50 ml of water and 50 ml of dichloromethane. The organic phase was separated and the aqueous phase was extracted twice with dichloromethane (2× 30 ml). The organic phases were collected together, and washed with 50 ml of a saturated aqueous solution of sodium carbonate. The organic phase was separated and evaporated u.v. (20° C./21 mbar). The residue was then distilled at 99-100° C./0.08 mbar obtaining 14.5 g (0.089 moles) of 5-acetyl-2,3-dihydrobenzofuran.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].Br[CH2:16]/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[C:3]1([CH2:2][CH2:1][NH:9][CH2:16]/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)/C=C/CBr
Reactant: NCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/CNCCc1ccccc1
Reaction time: 4 h

Procedure:
To a stirred solution of phenethylamine (20 mL, 160 mmol) in anhydrous THF (250 mL) was added NaHCO3 (7 g) followed by methyl 4-bromocrotonate (10 mL, 84 mmol). After stirring for 4 h the reaction was concentrated to approximately half the volume and filtered through a pad of silica gel and eluted with 2% MeOH/CHCl3 to wash off the product. The crude product obtained after evaporation of the filtrate was purified by flash chromatography (silica gel, 2% MeOH/CHCl3) to give the title compound as a slightly yellow liquid (16.5 g, 81%). TLC Rf 0.53 (5% MeOH/CHCl3); 1H NMR (CDCl3) δ1.2 (1H, s), 2.8 (4H, br s), 3.35 (2H, dd), 3.7 (3H, s), 5.95 (1H, dt), 7.0 (1H, dt), 7.25 (5H, br s)
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:20][S:21]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=3)[S:30][C:29]=2[CH:44]=1)(=[O:23])=[O:22].FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>CO.ClCCl>[ClH:1].[CH3:20][S:21]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[C:32]([C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)=[CH:19][CH:18]=3)=[C:31]([C:33]3[CH:34]=[CH:35][C:36]([O:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:37][CH:38]=3)[S:30][C:29]=2[CH:44]=1)(=[O:22])=[O:23]
Reactant: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Reaction time: 8 h

Procedure:
The acid chloride was formed from 2.0 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, as described in Example 1, and was combined with 2 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-benzo[b]thiophene in 50 ml. of dichloromethane. A 2.4 g. portion of trifluoromethanesulfonic acid was added, and the mixture was stirred overnight under reflux. The reaction mixture was then poured over ice and sodium bicarbonate solution, and the organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum to a yellow foam, which was treated with excess 3% hydrogen chloride in anhydrous methanol. The mixture was evaporated to dryness under vacuum to obtain a white foam which was dissolved in 18 ml. of boiling methanol. The solution was cooled to obtain 3.1 g. of the desired product, m.p. 128°-130° C., which was identified by nmr analysis.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].Br[C:9]1[CH:10]=[C:11]([CH:15]([OH:26])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=1>>[CH:3]1([C:1]#[C:2][C:9]2[CH:10]=[C:11]([CH:15]([OH:26])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C#CC1CCCC1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(C#CC2CCCC2)c1

Procedure:
Coupling of ethynylcyclopentane (40) with tert-butyl 3-(3-bromophenyl)-3-hydroxypropylcarbamate (39) following the method used in the synthesis of Example 13 gave tert-butyl 3-(3-(cyclopentylethynyl)phenyl)-3-hydroxypropylcarbamate (41) as a brown oil. Yield (0.386 g, 92%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[C:17]3[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:34])=[N:28]2>>[F:33][C:31]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27]([CH3:34])=[N:28]2)=[C:23]([O:22][CH2:21][CH2:20][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][C:8]3[C:17]4[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=4[CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:2]2)[CH:32]=1
Reactant: Cc1ccc2c(OCCBr)cc(F)cc2n1
Reactant: O=C1COc2c(CC3CCNCC3)cccc2N1
Product: Cc1ccc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5)CC3)cc(F)cc2n1

Procedure:
The title compound was prepared from 8-piperidin-4-ylmethyl-4H-benzo[1,4]oxazin-3-one and 5-(2-bromoethoxy)-7-fluoro-2-methylquinoline in a similar manner to Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N-]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:37]([O:36][C:34]([CH:33]1[CH2:16][CH:15]1[C:13]1[CH:12]=[CH:11][C:10]([N:17]2[CH2:18][C:19](=[O:30])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[S:21]2(=[O:23])=[O:22])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1

Procedure:
To a solution of 5-(2-benzyloxy-4-vinylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (Example 81, step A) (75 mg, 0.17 mmol) in methylene chloride is added rhodium acetate dimer (cat.). Ethyl diazoacetate (0.024 mL, 0.17 mmol) in methylene chloride (0.2 mL) is added dropwise via syringe pump over 4 h. The solvent is removed under reduced pressure and the crude material purified on silica gel using a gradient of 0-40% EtOAc/hexanes to give the title compound as a mixture of isomers (cis:trans 1:2) as a colorless oil: (M+H)+=548.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)=[N:10][C:11]([C:17]([F:20])([F:19])[F:18])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)=[N:10][C:11]([C:17]([F:20])([F:19])[F:18])=[C:12]([CH:16]=2)[C:13]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[OH:33])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC2CC2)nc1C(F)(F)F
Reactant: N[C@@H]1CCCC[C@H]1O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(-c2ccc(Cl)cc2)c(OCC2CC2)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-Chloro-phenyl)-6-cyclopropylmethoxy-2-trifluoromethyl-nicotinic acid and (1R,2R)-2-amino-1-cyclohexanol as starting materials, MS (ISP) 469.3 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:3]([O:5]C(C)(C)C)=[O:4].[F:22][C:23]1([F:37])[CH2:25][CH:24]1[CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[F:22][C:23]1([F:37])[CH2:25][CH:24]1[CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:1][CH:2]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=2)[C:3]([OH:5])=[O:4])=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(OCC2CC2(F)F)cc1
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(OC(F)(F)F)cc1
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCC2CC2(F)F)cc1
Yield: 65.3 %

Procedure:
A reaction similar to that described in Example 32 (32b) was conducted using tert-butyl 2-amino-3-[4-(trifluoromethoxy)phenyl]propanoate (366 mg, 1.20 mmol) and 4-[(2,2-difluorocyclopropyl)methoxy]benzoic acid (274 mg, 1.20 mmol) prepared in Example 40 (40b) to give 360 mg of the title compound (white powder, yield: 66%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23]>ClCCl>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:22]([C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)=[O:23]
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Product: O=C(Nc1ccc2oc3c(c2c1)CCCCCC3)c1ccco1
Yield: 79.6 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.69 mmol), 2-furoyl chloride (0.075 mL, 0.76 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (12 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-2-furamide (0.17 g). MS (ESI) m/z 310 ([M+H]+).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[C:17](=[O:19])[N:16]([CH3:20])[CH2:15]2.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([Br:8])=[C:14]2[C:18]=1[C:17](=[O:19])[N:16]([CH3:20])[CH2:15]2
Reactant: CN1Cc2cccc(N)c2C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CN1Cc2c(Br)ccc(N)c2C1=O
Reaction time: 1 h
Yield: 73.6 %

Procedure:
NBS (2.3 g, 12.96) was added to a cold (−8° C. to −10° C.) solution of 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (2 g, 12.4 mmol) in DCM (40 mL) and the mixture stirred at −8° C. to −10° C. for 1 h. A solution of 10% aq. sodium thiosulfate (30 mL) was then added to the reaction mixture and stirring was continued for another 20 minutes. The layers were separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organic extracts were washed with water (3×40 mL) and brine (30 mL), and the organic layer was dried (Na2SO4) and concentrated in vacuo to yield 3.2 g of crude product. This material was triturated with ethyl acetate (10 mL) to give 2.2 g of pure 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (XXXIX, yield: 74%).
Reaction SMILES: [CH:1]1([C@H:4]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[C:20]([F:25])[CH:21]=[CH:22][CH:23]=3)[C:18](=[O:26])[N:17]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH2:33]Br)=[O:14])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH2:3][CH2:2]1.[C:35]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([CH3:38])([CH3:37])[CH3:36].C(N(CC)CC)C>C1COCC1>[CH:1]1([C@H:4]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[C:20]([F:25])[CH:21]=[CH:22][CH:23]=3)[C:18](=[O:26])[N:17]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH2:33][N:42]2[CH2:43][CH2:44][N:39]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:40][CH2:41]2)=[O:14])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=C(N[C@H](c1cccc(F)c1)C1CC1)c1c(CBr)n(-c2cccnc2)c(=O)c2c(F)cccc12
Reactant: CC(C)(C)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)N1CCN(Cc2c(C(=O)N[C@H](c3cccc(F)c3)C3CC3)c3cccc(F)c3c(=O)n2-c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromomethyl-8-fluoro-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide (118 mg, 0.225 mmol) was dissolved in THF (6 mL) mmol) and 1-tert-butyl-piperazine (64.0 mg, 0.450 mmol) and triethylamine (62 μL, 0.44 mmol) were added. The reaction mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was subjected to preperative TLC on silica gel (eluent: 80% ethyl acetate, 10% methanol, 10% triethylamine). The product-containing fraction was dissolved in methanol and the product precipitated on addition of water. After filtration and drying 3-(4-tert-butyl-piperazin-1-ylmethyl)-8-fluoro-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide was obtained.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1([OH:15])C=CC=CC=1>>[C:1]1([OH:2])[CH:8]=[CH:7][CH:6]=[CH:4][CH:3]=1.[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:9]=[O:15])[OH:2]
Reactant: Oc1cccc(O)c1
Solvent: Oc1ccccc1
Product: O=Cc1c(O)cccc1O

Procedure:
adding resorcinol in an amount between 60 and 140% of the phenol and reacting the resulting mixture for a time-temperature period effecting copolymerization producing a stable phenol-resorcinol-formaldehyde liquid resin product which will set to a hard solid upon admixture with additional formaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.CCOCC.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:6]2[CH2:17][CH2:18][CH2:19][O:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc2c(Br)cccc2[nH]1
Reactant: BrCCCOc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc2c(Br)cccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 106A (5.5 g) in N,N-dimethylformamide (60 mL) was added 1-(3-bromopropoxy)naphthalene (5.4 g) and Cs2CO3 (22 g). The mixture was stirred overnight at room temperature. The mixture was diluted with ether (300 mL) and water (200 mL). The aqueous layer was extracted with ether twice. The combined extracts were washed with water (×3), brine and dried over Na2SO4. Concentration of the mixture gave crude product, which was purified by flash chromatography (2% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24]C(=O)C)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OC(C)=O)c2)Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
The compound of step 1 (3.44 g, 8.97 mmol) was dissolved in methanol (50 ml), potassium carbonate (248 mg, 1.79 mmol) was added and the mixture was stirred for 2 h at room temperature. The mixture was evaporated to dryness, the residue partitioned between EA and 1 N hydrochloric acid and the aqueous phase extracted with EA. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to dryness to give 2.80 g of the title compound.
Reaction SMILES: OC1C=CC(CNC(=O)C2C=CC(NC3C4N(C=CN=4)C(C4C=NNC=4)=CN=3)=CC=2)=CC=1.[Br:33][C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37](Br)=[N:36][CH:35]=1.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[N:51]=[N:52][N:53]([C:55]2[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=2)[CH:54]=1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].C1(C)C=CC=CC=1>[Br:33][C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37]([NH:61][C:58]2[CH:59]=[CH:60][C:55]([N:53]3[CH:54]=[C:50]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=4)[N:51]=[N:52]3)=[CH:56][CH:57]=2)=[N:36][CH:35]=1
Reactant: Nc1ccc(-n2cc(-c3ccccn3)nn2)cc1
Reactant: Brc1ncc(Br)n2ccnc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Brc1cnc(Nc2ccc(-n3cc(-c4ccccn4)nn3)cc2)c2nccn12

Procedure:
In the same way as described for Compound 90, step 1, using 5,8-dibromoimidazo[1,2-a]pyrazine (80.5 mg, 0.291 mmol), 4-(4-pyridin-2-yl-[1,2,3]triazol-1-yl)-phenylamine (68.3 g, 0.288 mmol), NaOtBu (38.2 mg, 0.403 mmol), Pd2(dba)3 (10.5 mg, 0.0115 mmol), Xantphos (13.3 mg, 0.023mmol) and toluene (4 mL). The crude material is purified by silica gel column chromatography eluting with 98:2 DCM:MeOH followed by 97:3 DCM:MeOH affording the title compound (52.8 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[C:8](I)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O1CCCCC1[N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>>[Cl:1][C:2]1[C:9]([F:10])=[C:8]([C:20]2[NH:19][N:18]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: N#Cc1ccc(I)c(F)c1Cl
Product: N#Cc1ccc(-c2ccn[nH]2)c(F)c1Cl

Procedure:
The title compound was prepared from 2-chloro-3-fluoro-4-iodobenzonitrile (0.242 g, 0.86 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (0.239 g, 0.86 mmol) using the method of Example 34 (a) and (b). Yield 0.075 g. 1H NMR (400 MHz; MeOD): δ 6.84 (dd, 1H), 7.59 (m, 2H), 7.79 (s, 1H), 8.08 (bs, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:10]1([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc(O)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-hydroxylbenzaldehyde (10 g, 81.9 mmol) in anhydrous CH2Cl2 (500 mL) at RT, under N2, pyrrolidine (10.2 mL, 122.9 mmol) was added, followed by NaBH(OAc)3 (34.6 g, 163.9 mmol) and AcOH (19.7 g, 327.8 mmol). After the mixture was stirred at RT for 24 h, a saturated solution of NaHCO3(aq) (150 mL) was added. The mixture was vigorously stirred for an additional 1 h and then extracted with CH2Cl2 (3×200 mL). The combined organic layer was washed with brine (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as amber oil. This was used crude in the next step. MS m/z: 178 (M+1). Calc'd for C11H15NO-177.2.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].Br[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>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.C1(C)C=CC=CC=1>[S:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:13]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:1]=[O:2])=[CH:14]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Brc1csc2ccccc12
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2csc3ccccc23)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
(3-Formylphenyl)boronic acid (1.7 g, 11.3 mmol), 3-bromo-1-benzothiophene (2.0 g, 9.39 mmol) and cesium carbonate (4.6 g, 14.1 mmol) were added to a mixed solvent of ethanol (10 mL) and toluene (50 mL). After argon substitution, tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 70° C. for 18 hr. The reaction mixture was cooled, and the insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (2.1 g, yield 94%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9](C(C1C=CC=CC=1)C1C=CC=CC=1)[C:8](=[O:24])[CH:7]2[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:24])[C:7]12[CH2:35][O:34][C:26]2[CH:27]=[C:28]3[C:29](=[CH:33][C:25]1=2)[CH2:30][CH2:31][O:32]3
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cccc(F)c2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 7-fluoro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (97%) as a colorless solid: mp>250° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ11.01 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.1 Hz, 1H), 7.00-6.94 (m, 1H), 6.56 (s, 1H), 6.40 (s, 1H), 4.80 (d, J=9.4 Hz, 1H), 4.68 (d, J=9.4 Hz, 1H), 4.49 (m, 2H), 2.95 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ178.5, 161.0, 160.5, 139.4, 134.7, 128.4, 123.4, 122.3, 120.1, 119.8, 118.9, 113.8, 92.3, 79.8, 72.0, 58.0, 28.2; MS (ES+) m/z 298.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[N:27]=1>C(O)(C)C>[Br:28][C:26]1[N:27]=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c1=O
Temperature: 85 °C
Yield: 76 %

Procedure:
A mixture of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (2.5 g, 9.06 mmol) and 3,5-dibromo-1-methylpyrazin-2(1H)-one (2.2 g, 8.23 mmol) in isopropanol (30 mL) was heated at 85° C. for 15 h. After the reaction was finished, it was filtered and the solid was washed with isopropanol to afford 282a as a white solid (2.9 g, 80%).LCMS: (M+H)+ 463
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2=[N:7][C:8]3[NH:9][CH:10]=[C:11]([C:16]#[N:17])[C:12](=O)[C:13]=3[CH:14]=[C:5]2[CH:4]=1.P(Cl)(Cl)([Cl:24])=O>CCCCCC>[Cl:24][C:12]1[C:13]2[CH:14]=[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:19]([O:20][CH3:21])=[CH:18][C:6]3=[N:7][C:8]=2[N:9]=[CH:10][C:11]=1[C:16]#[N:17]
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3nc2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: COc1cc2cc3c(Cl)c(C#N)cnc3nc2cc1OC
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of 7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carbonitrile (500 mg, 1.78 mmol) and 5 mL of phosphorous oxychloride is heated at reflux for one hour then cooled to room temperature. Hexane (20 mL) is added and the resultant solids are collected by filtration washing with hexane, water, methanol and ethyl acetate to provide 258 mg (49%) of 4-chloro-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile as a brown solid, mp>300° C.