Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH:15]=[CH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C=CC(=O)OC(C)(C)C)ccc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(CCC(=O)OC(C)(C)C)ccc2[nH]1
Yield: 100.8 %

Procedure:
A solution of 5-(2-tert-butoxycarbonyl-vinyl)-1H-indole-2-carboxylic acid ethyl ester (1.6 g, 5 mmol) in ethyl acetate (40 mL) and methanol (80 mL) was hydrogenated over 5% palladium on carbon (0.2 g) at room temperature for overnight. The catalyst was filtered off and the filtrate was concentrated to give 1.6 g (99%) of 5-(2-tert-butoxycarbonyl-ethyl)-1H-indole-2-carboxylic acid ethyl ester as a white solid. The solid was used in the next step without further purification.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:8][C:7]2[C:18]3[C:23]([CH:24]=[CH:25][C:6]=2[N:5]([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:4]1=[O:32])=[CH:22][CH:21]=[CH:20][CH:19]=3.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([O:2][C@@H:3]1[C@H:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[S:8][C:7]2[C:18]3[C:23]([CH:24]=[CH:25][C:6]=2[N:5]([CH2:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[C:4]1=[O:32])=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:35])[CH3:34]
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Yield: 84 %

Procedure:
A mixture of 2.6 g of (±)-cis-2,3-dihydro-3-hydroxy-5-[3-(dimethylamino)propyl]-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one hydrochloride and 25 mL of acetic anhydride was stirred and heated at 100° for 17 hours. The excess of reagent was removed under reduced pressure and the residue was dissolved in water. The aqueous solution was made basic with concentrated ammonium hydroxide and extracted with ethyl acetate (3×75 mL). The combined ethyl acetate solutions were washed with brine (50 mL) and dried (magnesium sulfate). Removal of the solvent gave 2.2 g (84%) (±)-cis-3-(acetyloxy)-2,3-dihydro-5-[3-(dimethylamino)propyl]-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one. A sample of this compound was crystallized from ether, mp 98°-99°.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O[N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].CC(C)N=C=NC(C)C>C1COCC1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][N:30]3[C:34](=[O:35])[CH2:33][CH2:32][C:31]3=[O:36])=[O:27])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)COCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C1CCC(=O)N1O
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(COCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reaction time: 2 h

Procedure:
2-[2-(2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethoxy)ethoxy]acetic acid (185 mg, 0.480 mmol) and N-hydroxysuccinimide (110 mg, 0.956 mmol) were dissolved in anhydrous THF (1.5 mL). DIC was added dropwise to the solution at r.t., leading to the precipitation of a white solid. After 2 h, the reaction mixture was filtrated through a PTFE membrane filter (0.2 μm), and the solvent was removed. The crude product was redissolved in Et2O. The organic phase was washed with aq. NaHCO3 and 0.5 M aq. HCl. The organic layer was dried over Na2SO4, and the solvent was removed. The crude product was dissolved in CH2Cl2, and the solution was filtrated. After removal of the solvent, the crude product 39 (210 mg) was used in the synthesis of 40 without further purification.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[S:12]([N:15]([C:24]1[C:29]([O:30][CH3:31])=[N:28][C:27](Cl)=[C:26]([Cl:33])[N:25]=1)COCC[Si](C)(C)C)(=[O:14])=[O:13]>O1CCCC1>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[S:12]([NH:15][C:24]1[C:29]([O:30][CH3:31])=[N:28][C:27]([N:2]([CH3:3])[CH3:1])=[C:26]([Cl:33])[N:25]=1)(=[O:13])=[O:14]
Reactant: CNC
Reactant: COc1nc(Cl)c(Cl)nc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Solvent: C1CCOC1
Product: COc1nc(N(C)C)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 67 using dimethylamine (5 mL of a 2M solution in tetrahydrofuran) and 2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (0.1 g). Yield 0.015g.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([Br:24])[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([Br:24])[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(Br)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(Br)nc23)C2CC2)C1
Reaction time: 3 h

Procedure:
A solution of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (0.104 g, 0.195 mmol, contains some 2-chloro impurity), 1 mL of dichloromethane and 1 mL of TFA was stirred for 3 h, then concentrated to a pale yellow oil. The oil was dissolved in 0.5 mL of dichloromethane and 0.5 mL of ethylene diamine, and the yellow solution was stirred for 1.25 h, then partitioned between 5 mL of water and 10 mL of ethyl acetate. The aqueous layer was extracted with 10 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated to give 0.087 g of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a pale yellow residue, which was used without further purification. MS: (M+Na)+=427. A major impurity is 2-chloro-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide. MS: (M+Na)+=381. Approximate 3:1 ratio of Br:Cl.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH2:38][CH2:39]O.N1C=CN=C1>ClCCl>[Br:20][CH2:39][CH2:38][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCc1ccc2ccccc2c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A solution of triphenylphosphine (0.57 g, 2.2 mmol) and N-bromosuccinimide (0.39 g, 2.2 mmol) in anhydrous dichloromethane (4 mL) was stirred for 10 minutes. 2-Naphthalenethanol (0.25 g, 1.45 mmol) was added, followed inmmediately by imidazole (0.25 g, 1.45 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between H2O and dichloromethane. The aqueous layer was extracted with diethyl ether (2×20 mL) and the combined organic extracts were dried over MgSO4 and evaporated to dryness. The crude residue was purified by column chromatography through a plug of silica gel eluting with 10% ethyl acetate in hexanes to afford a colorless solid 214 (0.29 g, 86%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:20]3[N:24](COCC[Si](C)(C)C)[C:23]4[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=4[N:21]=3)=[O:19])=[CH:14][CH:13]=2)=[N:4]1)[CH3:2].CCO.Cl.[OH-].[Na+]>O>[NH:24]1[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]=[C:20]1[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:5]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:17][CH:16]=1)=[O:19]
Reactant: CCn1nc(-c2ccc(C(=O)c3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1nc(-c2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)c2ncccc21

Procedure:
A mixture of [4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl](1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)methanone obtained, EtOH (5 mL), and 6 M HCl aqueous solution (5 mL) was refluxed for 2 h. The reaction mixture was poured into water, alkalized with 1 M NaOH aqueous solution, and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from THF to give the title compound (285 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>CN(C)C=O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: Oc1ccccc1F
Reactant: OCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCCCCCCCOc1ccccc1F
Yield: 107.1 %

Procedure:
Potassium carbonate (2.59 g, 18.7 mmol) and 9-bromo-1-nonanol (1.39 g, 6.24 mmol) were added at room temperature to a solution of 2-fluorophenol (700 mg, 6.24 mmol) in N,N-dimethylformamide (20 mL), then after 40 h insoluble material was removed by filtration. The filtrate was evaporated and the residue taken up in dichloromethane, washed with 1 M aq. sodium hydroxide solution, dried over sodium sulfate, filtered, and evaporated, to afford 9-(2-fluoro-phenoxy)-nonan-1-ol (1.7 g), which was directly used in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:42])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([NH:30][C:31](=[O:35])[NH:32][CH2:33][CH3:34])=[CH:19][C:20]=3[C:21]3[S:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)=[CH:12][N:13]=2)[C:8](=[O:36])[C:7]([C:37]([O:39]CC)=[O:38])=[CH:6]1>C(O)C>[CH3:42][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([NH:30][C:31](=[O:35])[NH:32][CH2:33][CH3:34])=[CH:19][C:20]=3[C:21]3[S:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)=[CH:12][N:13]=2)[C:8](=[O:36])[C:7]([C:37]([OH:39])=[O:38])=[CH:6]1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3CCN(C)C)cn1
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)O)cn3CCN(C)C)cn1
Temperature: 90 °C
Yield: 16.3 %

Procedure:
To a stirred suspension of ethyl 1-[2-(dimethylamino)ethyl]-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Example 15, 100 mg, 0.16 mmol) in ethanol (10 mL) 10% potassium hydroxide (0.3 mL) was added. The reaction mixture was heated to 90° C. for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature then concentrated under reduced pressure to a residue. The residue was diluted with water and acidified with 2N HCl to pH 2-3 to obtain a solid which was filtered, washed with water and dried to afford 50 mg of crude product. This was purified by preparative HPLC to give 15 mg (15%) of 1-[2-(dimethylamino)ethyl]-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])=[CH:8][CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:6]1C(OC(C)(C)C)=O)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]1[CH:5]([CH2:4][NH2:1])[NH:6][CH:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C(CN=[N+]=[N-])C(c2cc(F)ccc2F)=CC1c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCC1NC(c2ccccc2)C=C1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-1a (0.21 g, 0.51 mmol) and triphenylphosphine (0.133 g, 0.51 mmol) in THF (10mL) was allowed to stir at rt overnight. The reaction was quenched with water (10 mL) and heated at 60° C. for 1 h. The product was extracted with EtOAc (2×30 mL) and washed with brine (30 mL), dried over MgSO4, filtered and concentrated. The remaining oil was dissolved in CH2CL2 (5 mL)I TFA (2 mL) and allowed to stir at rt overnight. The solvent was removed in vacuo. The remaining oil was dissolved in CH3CN (3 mL) and purified on a Gilson automated system affixed with a YMC J'sphere H80 30×100 mm column (eluting with 5-95% CH3CN +0.1% TFA in water +0.1% TFA over 20 min) to afford pure 2-3a.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: O=C(O)c1cc(F)ccc1Br
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a suspension of 2-bromo-5-fluorobenzoic acid (2.0 g, 9.13 mmol) in DCM (90 mL) at room temperature was added N,O-dimethylhydroxylamine hydrochloride (1.069 g, 10.96 mmol), N-(3-dimethylaminopropyl)-K-ethylcarbodiimide hydrochloride (2.276 g, 11.87 mmol), hydroxybenzotriazole (1.818 g, 11.87 mmol) and triethylamine (2.55 mL, 18.26 mmol). The resulting mixture was stirred at room temperature for 5.5 h after which time the reaction was quenched by addition of sat. aq. NaHCO3 solution and the layers separated. The organic layer was then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-40% EtOAc/Hexanes) to afford 2-bromo-5-fluoro-N-methoxy-N-methylbenzamide as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.54 (dd, J=8.8, 4.9 Hz, 1H), 7.05 (dd, J=8.2, 3.0 Hz, 1H), 7.00 (td, J=8.4, 3.0 Hz, 1H), 3.50 (s, 2H), 3.38 (s, 3H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Br[C:19]1[C:20]([C:27]#[N:28])=[N:21][C:22]([Cl:26])=[CH:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[Cl:26][C:22]1[CH:23]=[C:24]([CH3:25])[C:19]2[C:20](=[C:27]([NH2:28])[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=2)[N:21]=1
Reactant: Cc1cc(Cl)nc(C#N)c1Br
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: Cc1cc(Cl)nc2c(N)nc3ccccc3c12
Temperature: 25 °C

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-bromo-6-chloro-4-methylpicolinonitrile (from step 2) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 3-chloro-1-methylbenzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (dmso-d6): δ 8.44 (d, 1H), 7.83 (s, 1H), 7.50-7.58 (m, 2H), 7.02 (bs, 2H), 2.98 (s, 3H).
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23](O)[C:24]2[C:32]3[C:27](=[N:28][CH:29]=[CH:30][N:31]=3)[NH:26][CH:25]=2)=[CH:19][N:18]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][NH:7][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]3[C:32]4[C:27](=[N:28][CH:29]=[CH:30][N:31]=4)[NH:26][CH:25]=3)=[CH:19][N:18]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3c[nH]c4nccnc34)cn2)cn1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc(CNc2ccc(Cc3c[nH]c4nccnc34)cn2)cn1
Temperature: 80 °C
Yield: 38.1 %

Procedure:
To {5-[hydroxy-(5H-pyrrolo[2,3-b]pyrazin-7-yl)-methyl]-pyridin-2-yl}-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (7, 0.220 g, 0.48 mmol) in 10.4 mL of acetonitrile, triethylsilane (2.1 mL 0.013 mol) and trifluoroacetic acid (1.0 mL 0.014 mol) were added. The reaction was heated to 80° C. for 4 hours, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography eluting with methanol:dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a white solid (P-0001, 63.4 mg, 38.5%). MS (ES1): [M+H+]+=347.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:16][O:17][C:18](=[O:26])[CH2:19][O:20][C:21]([CH3:25])([CH3:24])[C:22]#[CH:23]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:16][O:17][C:18](=[O:26])[CH2:19][O:20][C:21]([CH3:24])([CH3:25])[C:22]#[C:23][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: C#CC(C)(C)OCC(=O)OC
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)COC(C)(C)C#Cc1cc(-c2ccc(Cl)cc2)ccc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 3-bromo-4′-chloro-4-methylbiphenyl (12.6 g, 44.7 mmol) and (1,1-dimethylprop-2-ynyloxy)acetic acid methyl ester (prepared according to WO2001/066544) (8.4 g, 53.8 mmol) in triethylamine (70 ml) is added bis(triphenylphosphine)palladium(II) dichloride (0.63 g, 0.9 mmol) and copper(I) iodide (0.34 g, 1.8 mmol). The reaction mixture is degassed and flushed with nitrogen (×3), then stirred under nitrogen at 80° C. for one hour. The cooled mixture is filtered through diatomaceous earth to remove the catalyst, and the filtrate evaporated in vacuo. The residue is resubjected to the same reaction conditions (8.4 g 1,1-dimethylprop-2-ynyloxy)acetic acid methyl ester, 0.63 g bis(triphenylphosphine)-palladium(II) dichloride, 0.34 g copper(I) iodide in 70 ml triethylamine under nitrogen) and stirred at 80° C. for one hour. The cooled mixture is filtered through diatomaceous earth, then concentrated in vacuo and purified by flash chromatography (hexane/ethyl acetate 3:1) to afford [3-(4′-chloro-4-methylbiphenyl-3-yl)-1,1-dimethylprop-2-ynyloxy]acetic acid methyl ester (6.70 g,) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.O.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: NCC/C=C\c1cccc(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Solvent: O
Product: NCCCCc1cccc(Cl)c1
Yield: 74.2 %

Procedure:
A solution of cis-4-(3-chlorophenyl)-but-3-enylamine (1.2 g) in 20 mL methanol was added to platinum(IV) oxide monohydrate (0.12 g). The mixture was stirred under 1 atm of hydrogen for 16 h. The mixture was filtered through celite, and the methanol was removed in vacuo to yield 0.9 g of 4-(3-chlorophenyl)-butylamine.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[CH3:30][CH:31]([O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:32].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([C:37]3[CH:38]=[CH:39][C:34]([O:33][CH:31]([CH3:32])[CH3:30])=[CH:35][CH:36]=3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)C)cc2)c2nc(C)nn12
Reaction time: 48 h
Yield: 40.7 %

Procedure:
To a suspension (40 mL) of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1 g), [4-(1-methylethoxy)phenyl]boronic acid (0.9 g), triethylamine (1 mL), pyridine (2 mL) and molecular sieves 4A (2 g) in dichloromethane was added copper(II) acetate (0.91 g), and the mixture was stirred for 48 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 43%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:79][C:80]([CH3:92])([CH3:91])[C:81]([O:83][CH2:84][C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)=[O:82]>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:32]=[CH:33][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40](=[O:41])[NH:79][C:80]([C:81]([O:83][CH2:84][C:85]3[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=3)=[O:82])([CH3:92])[CH3:91])=[CH:35][CH:36]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)(N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)NC(C)(C)C(=O)OCc3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (0.4 g) in N,N-dimethylformamide (2 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.18 g), 1-hydroxybenzotriazole (0.13 g), benzyl 2-amino-2-methylpropionate p-toluenesulfonic acid salt (1.16 g) and triethylamine (0.64 g) at room temperature, and the mixture was stirred overnight. To the reaction mixture was added water, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-ethyl acetate) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{(1E)-3-[1-benzyloxycarbonyl-1-(methyl)-ethylcarbamoyl]prop-1-enyl}phenyl)methyl]-5-isopropyl-1H-pyrazole (0.18 g). This material was dissolved in methanol (2 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.15 g).