Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[NH:22][CH:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[NH:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:25](C(O)=O)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O1CCOCC1>[C:40]([O:39][C:37](=[O:38])[NH:24][CH:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:6](=[O:7])[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]3[NH:22][CH:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3cc[nH]c23)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc[nH]c23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
To a solution of 4-(5H-Pyrrolo[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (43 mg, 0.14 mmol) in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed and the residue was treated with TEA (2 mL), Boc-D-Phe(4-Cl)—OH (43 mg, 0.14 mmol), HOBT (30 mg, 0.222 mmol) and EDCI (41 mg, 0.214 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 12 hours. The solvent was removed and the residue was subject to chromatography on silica gel to give product {1-(4-chlorobenzyl)-2-oxo-2-[4-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester (30 mg, 44%). 1H NMR (CDCl3, 400 Hz) δ 9.85 (s, 1H), 8.48 (s, 1H), 7.37 (s, 1H), 7.25-7.23 (d, J=8.4 Hz, 2H), 7.13-7.11 (d, J=8.4 Hz, 2H), 6.60 (s, 1H), 5.39-5.37 (d, J=8.8 Hz, 1H), 4.83-4.78 (m, 1H), 3.81-3.43 (m, 7H), 3.31-3.27 (m, 1H), 3.00-2.91 (m, 2H), 1.41 (s, 9H). MS (ESI+) [M+H]+ 485.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([CH3:22])[C:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)=[O:8].B.[Na].Cl>C(O)C>[OH:8][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:20][CH:21]=1)[CH:6]([CH3:22])[CH2:5][O:4][CH2:3][CH2:2][OH:1]
Reactant: CC(COCCO)C(=O)c1ccc(Cc2cccnc2)cc1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(COCCO)C(O)c1ccc(Cc2cccnc2)cc1
Yield: 92.5 %

Procedure:
In 22.5 ml of ethanol was dissolved 4.51 g of 3-[p-[3-(2-hydroxyethyl)oxy-2-methylpropionyl]benzyl]pyridine, and 286 mg of sodium boron hydride was added in small portions to the resulting solution with ice-cooling, after which the resulting mixture was subjected to reaction at the same temperature for one hour. The solvent was removed by distillation under reduced pressure, and 22.5 ml of water and 22.5 ml of ethyl acetate were added to the residue thus obtained, after which the pH thereof was adjusted to 7.0 with 2N hydrochloric acid. The organic layer was separated, washed with 10 ml of water, and 22.5 ml of water was added to the organic layer, after which the pH thereof was adjusted to 1.5 with 2N hydrochloric acid. The aqueous layer was separated, and then washed with 10 ml of ethyl acetate, after which 22.5 ml of ethyl acetate was added to the aqeous layer. The resulting mixture was neutralized with sodium hydrogencarbonate. The organic layer was separated, washed with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 4.2 g (yield 92.5%) of colorless, oily 3-[p-[1-hydroxy-3-(2-hydroxyethyl)oxy-2-methylpropyl]benzyl]pyridine.
Reaction SMILES: Cl.[C:2]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:26]=[N:27][C:28](Cl)=[N:29][CH:30]=1.CCCCCC>CCO>[Br:24][C:25]1[CH:26]=[N:27][C:28]([N:7]2[CH2:8][CH2:9][C:4]([C:2]#[N:3])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:6]2)=[N:29][CH:30]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)C1(C#N)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C1(C#N)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
To a solution of ethyl 4-cyanopiperidine-4-carboxylate hydrochloride (0.56 g, 2.6 mmol) in EtOH (10 mL) was added DIPEA (0.8 mL, 4.29 mmol) at rt and stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.33 g, 1.73 mmol). The reaction mixture was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 10% EtOAc:hexane to obtain the product as a yellow solid (0.4 g, 68% yield). 1H NMR (DMSO-d6): δ 1.20 (t, J=7.20 Hz, 3H), 2.04 (m, 2H), 2.22 (m, 2H), 3.22 (m, 2H), 4.15 (q, J=7.20 Hz, 2H), 4.32 (m, 2H) and 8.50 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][C@H:12]1[CH2:11][O:10][NH:9]2>C(O)(=O)C.[Zn]>[NH2:9][C@@:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][C@H:12]1[CH2:11][OH:10]
Reactant: COC1CC[C@]2(c3ccccc3F)NOC[C@@H]2C1
Agent: [Zn]
Solvent: CC(=O)O
Product: COC1CC[C@@](N)(c2ccccc2F)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-(3aR*,7aS*)-7a-(2-Fluorophenyl)-5-methoxyoctahydrobenz[c]isoxazole obtained in Preparation Example 59-(5) (5.60 g) was dissolved in acetic acid (128 mL). Then, zinc powder (14.1 g) was added and the mixture was stirred at room temperature for eight hours. The solid was removed by filtration through celite, and then the celite was washed with ethyl acetate. The resulting filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. Then, a saturated sodium bicarbonate solution was added, followed by vigorous stirring. The organic layer was separated and then the aqueous layer was extracted again with ethyl acetate twice. The combined organic layers were dried over anhydrous magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (5.49 g). ESI-MS; m/z 254 [M+H]
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11].[C:12]1(=[O:16])[O:15][CH2:14][CH2:13]1.Cl>O>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:14][CH2:13][C:12]([OH:16])=[O:15]
Reactant: O=C1CCO1
Reactant: Oc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.4 g (0.01 mol) of Sodium hydroxide was dissolved in 4 ml of water. To this stirred solution was added 1.63 g (0.01 mol) of 2,3-dichloro phenol was added. Once the solid had dissolved the alkaline solution was kept stirring at 100 C for 1 hour. After that β-propiolactone 0.72 g (0.628 ml, 0.01 mol) was added slowly in drops for 5 minutes. The reaction mixture was further continued heating for 12 h. The reaction mixture was cooled to room temperature and water 10 ml was added. This diluted mixture was acidified by the addition of Con. HCl. The product was extracted twice with diethyl ether (20 ml). The ether layer was then washed with 10% Sodium bicarbonate. The aqueous layer was acidified to pH=2. The precipitated solid was filtered and dried to afford the required product 3-(2,3-dichlorophenoxy)propanoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[Cl:58][C:59]1[CH:66]=[CH:65][C:62]([CH2:63][NH2:64])=[CH:61][CH:60]=1>O.ClCCl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])([C:14](=[O:15])[NH:64][CH2:63][C:62]2[CH:65]=[CH:66][C:59]([Cl:58])=[CH:60][CH:61]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)NCc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
Dry DMF (1 mL) was added to a mixture of 4-tert-butoxycarbonylamino-piperidine-1,4-dicarboxylic acid mono tert-butyl ester (151 mg, 0.44 mmol) and HATU (220 mg, 0.58 mmol) under nitrogen. N-Ethyldiisopropylamine (0.38 mL, 2.1 mmol) was added to the solution and the reaction mixture was stirred for 15 min. 4-Chlorobenzylamine (70 uL, 0.57 mmol) was added and the solution was stirred for 23 h at rt and under nitrogen. The reaction mixture was partioned between dichloromethane (10 mL) and water (10 mL). The aqueous phase was further extracted with dichloromethane (20 mL). The combined organic layers were dried (Mg2SO4), filtered and concentrated. Flash column chromatography on silica, eluting with 4% methanol in dichloromethane, gave 4-tert-butoxycarbonylamino-4-(4-chloro-benzylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (177 mg, 0.38 mmol, 86%). LC-MS (LCT2) m/z 490 [M+Na+], Rt 8.09 min.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[O:13]1[C:17]2=[N:18][CH:19]=[C:20]([CH2:22][OH:23])[CH:21]=[C:16]2[CH:15]=[CH:14]1.O.C(OCC)C>CS(C)=O>[CH:22]([C:20]1[CH:21]=[C:16]2[CH:15]=[CH:14][O:13][C:17]2=[N:18][CH:19]=1)=[O:23]
Reactant: OCc1cnc2occc2c1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: O=Cc1cnc2occc2c1
Yield: 54.6 %

Procedure:
To o-iodoxybenzoic acid (1.036g, 3.7 mmol) in dimethyl sulfoxide (7.4 mL) was added furo[2,3-b]pyridine-5-methanol (500 mg, 3.36 mmol). Stirring was continued for 2.5 h before the addition of water, filtration, and extraction of the filtrate with ethyl ether (3×30 mL). The organic phase was washed with brine (10 mL), dried with magnesium sulfate, and concentrated. Purification by flash chromatography (silica gel, 25% ethyl acetate/hexane) yielded 5-formyl-furo[2,3-b]pyridine (270 mg, 55%). This material (260 mg, 1.77 mmol) in toluene/tetra-hydrofuran (2 mL each) was added at -78° C. to a solution of methyltriphenyl-phosphorane (2.12 mmol) in toluene (15 mL). Stirring was continued at this temperature for 15 min, followed by warming to 20° C. over 1 h. Dilution with ethyl ether was followed by filtration through celite, and concentration. Purification by flash chromatography (silica gel, 25% ethyl acetate/hexane) yielded 241.5 mg (94% yield) of the title compound as a colorless oil: 1H NMR (CDCl3) ∂8.32 (d,1H, J=2 Hz), 7.97 (d, 1H, J=2 Hz), 7.68 (d,1H, J=2 Hz), 6.80 (dd, 1H, J=18+12 Hz), 6.76 (d, 1H, J=2 Hz), 5.79 (d,1H, J=18 Hz), 5.32 (d, 1H, J=12 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].O=S(Cl)Cl.Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C>ClCCl>[CH3:19][O:18][N:17]([CH3:16])[C:7](=[O:8])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=1
Reactant: Cc1cncc(C(=O)O)c1
Reactant: CNOC
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cncc(C)c1
Temperature: 75 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
A mixture of 5-methyl-nicotinic acid (1.8 g, 13.1 mmole) and SOCl2 (10 mL) was heated to 75° C. for three hours. The remaining SOCl2 was removed by vacuum distillation and the oily residue carefully redissolved in dichloromethane (16 mL). Then N,O-dimethylhydroxyl amine hydrochloride (1.4 g, 14.4 mmol) was added. The reaction mixture was purged with argon and triethylamine (5.11 mL, 36.7 mmol) was dropwise added at 0° C. It was stirred for 24 hours at room temperature. The mixture was diluted with dichloromethane, washed with NaOH 2N, brine, dried and concentrated to yield a brown oil which was purified by column chromatography (SiO2, n-Hex/EtOAc 1:1 to EtOAc) to afford the title compound (1.7 g, 71% yield) as a brownish oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](OC)=[C:7]([N+:13]([O-:15])=[O:14])[N:6]=1)=[O:4].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([N+:13]([O-:15])=[O:14])[N:6]=1)=[O:4]
Reactant: NC1CCCCC1
Reactant: COC(=O)c1ccc(OC)c([N+](=O)[O-])n1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])n1
Yield: 72.7 %

Procedure:
A solution of 5-methoxy-6-nitro-pyridine-2-carboxylic acid methyl ester (0.585 g, 2.75 mmol) and cyclohexylamine (0.636 mL, 5.51 mmol) in DMF (8 mL) was heated at 70° C. for 20 h. The mixture was poured on brine (50 mL) while mixing vigorously. The solid formed was filtered, washed with water and then dissolved in EtOAc. The solution was washed with water, saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated to give 5-cyclohexylamino-6-nitro-pyridine-2-carboxylic acid methyl ester as a brown oil (0.558 g) which was used in the subsequent step without purification.
Reaction SMILES: [CH2:1]([C:3](O)([CH:6]([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[CH2:10][CH3:11])[CH:4]=[CH2:5])[CH3:2].P(Br)(Br)[Br:16]>>[Br:16][CH2:2][CH:1]=[C:3]([CH2:4][CH3:5])[CH:6]([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[CH2:10][CH3:11]
Reactant: C=CC(O)(CC)C(C)CC=C(C)CC
Reactant: BrP(Br)Br
Product: CCC(C)=CCC(C)C(=CCBr)CC

Procedure:
Following the procedure of Example 9, 3-ethyl-4,7-dimethyl-1,6-nonadien-3-ol and phosphorus tribromide are reacted to form 1-bromo-3-ethyl-4,7-dimethyl-2,6-nonadiene.
Reaction SMILES: [C:1]([N:18](CC(C)C)[CH2:19][C:20]([OH:22])=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].S(Cl)(Cl)=O.CN(C=O)C>C(Cl)Cl>[NH:18]([C:1]([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2])[C@H:19]([C:20]([OH:22])=[O:21])[CH2:4][CH:5]([CH3:17])[CH3:6]
Reactant: CC(C)CN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 5 h

Procedure:
FMOC-Leu*-Cl was prepared by dissolving FMOC-N-isobutylglycine (150 mg, 0.42 mmol) in CH2Cl2 (2.8 mL), and adding thionyl chloride (309 μL, 4.2 mmol) and 3 μL DMF (0.04 mmol). The reaction mixture was stirred for 5 hours and concentrated in vacuo, repeatedly dissolving in CH2Cl2 (3×) to provide FMOC-Leu*-Cl as a colorless oil (146 mg, 92%): IR (cm-1) -1804, 1720, 1715. FMOC-Phe*-Cl was similarly prepared.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:10]2[CH2:9]1)C1C=CC=CC=1>CO>[C:16]1([C:17]([O:19][CH3:20])=[O:18])[N:15]=[CH:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=12
Reactant: COC(=O)c1ncn2c1CN(Cc1ccccc1)CC2
Solvent: CO
Product: COC(=O)c1ncn2c1CNCC2
Yield: 99 %

Procedure:
Methyl 7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (3.69 mmol) was dissolved in MeOH (20 ml), and the solution was flushed with nitrogen. Pd(OH)2 (250 mg) and a cat. amount of AcOH were added, and the mixture was again flushed with nitrogen for 20 min. The reaction mixture was reacted under a hydrogen atmosphere (50 psi) for 5 h on a Parr hydrogenation apparatus. Filtration over Celite was then carried out, followed by washing with methanol. The resulting crude product was purified by column chromatography (silica gel, 3-5% MeOH in DCM), and the desired product was thus obtained in the form of a yellow solid. Yield: 99%
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:17][CH3:18])[CH:8]=1)(=O)=O.[CH3:21][N:22](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:18][O:17][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[CH:16][C:7]([C:21]#[N:22])=[CH:8]2
Reactant: CN(C)C=O
Reactant: COc1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cccc2cc(C#N)ccc12
Temperature: 80 °C
Yield: 90 %

Procedure:
A solution of 5-methoxy-2-naphthyl trifluoromethanesulfonate (1.04 g, 3.4 mmol) in DMF (5 mL) is degassed by repeatedly evacuating the flask then flushing with N2. Zinc cyanide (234 mg, 2.0 mmol) is added followed by Pd(PPh3)4 (196 mg, 0.17 mmol). The resulting mixture is again degassed and heated to 80° C. for 3 hours. The reaction is allowed to cool, poured into water and washed twice with toluene and once with CH2Cl2. The combined organic extracts are dried (Na2SO4), filtered and concentrated. The resulting material is purified by column chromatography (step gradient, 25–50% CH2Cl2 in hexanes) to give 5-methoxy-2-naphthonitrile as a white solid (560 mg, 90%). HRMS (EI) calculated for C12H9NO 183.0684, found 183.0684.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]3[C:18]4[CH:19]=[CH:20][S:21][C:17]=4[C:16]4=[N:22][NH:23][C:24](=[O:25])[C:15]4=[N:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.I[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33].CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O.[Cu]I>[CH3:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:23]1[C:24](=[O:25])[C:15]2=[N:14][N:13]([CH2:12][C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:11][CH:10]=3)[C:18]3[CH:19]=[CH:20][S:21][C:17]=3[C:16]2=[N:22]1
Reactant: O=c1[nH]nc2c3sccc3n(Cc3ccc(-n4cccn4)cc3)nc1-2
Reactant: Cc1ccccc1I
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1nc2c3sccc3n(Cc3ccc(-n4cccn4)cc3)nc-2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-{[4-(1H-Pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazol[4,3-c]thieno[2,3-e]pyridazin-3-one (20 mg, 0.058 mmol), 2-iodotoluene (38 mg, 0.17 mmol, 3 equiv), copper(I) iodide (11 mg, 0.058 mmol, 1 equiv), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (24 mg, 0.17 mmol, 3 equiv) and potassium phosphate (86 mg, 0.41 mmol, 7 equiv) were combined in degassed N,N-dimethylformamide (3 mL) and placed into an oil bath preheated to 110° C. for 2 hours. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (25 mL, aqueous saturated) and extracted with ethyl acetate (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound as a deep red solid: 1H-NMR (400 MHz, CDCl3) δ 7.91 (1H, d, J=2.5 Hz), 7.73-7.71 (3H, m), 7.66 (1H, d, J=5.6 Hz), 7.46-7.43 (3H, m), 7.36-7.27 (4H, m), 6.47 (1H, dd, J=2.4, 1.9 Hz), 5.83 (2H, s), 2.35 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 439.1336 [(M+H)+; calculated for C24H19N6OS: 439.1336].
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12]C)=[C:10]2[C:5]([C:6](=[O:21])[C:7]([I:20])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([I:20])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: COc1c(N)ccc2c(=O)c(I)c(-c3ccccc3)oc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 7-amino-3-iodo-8-methoxy-2-phenyl-chromen-4-one (494 mg, 1.26 mmol) in DCM (25 mL) under a nitrogen atmosphere at −78° C. was added a solution of BBr3 (1 M in DCM, 8 mL, 8 mmol) dropwise over 15 mins. The mixture was stirred at −78° C. for 1 hour before allowing to warm to RT and stirred for a further 18 hours. The reaction mixture was quenched with the slow addition of saturated aqueous NaHCO3. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM (2×50 mL) and the combined organic phase was washed with brine, dried (NaSO4), filtered, and the solvent removed to give the title compound as a brown solid (405 mg, 85%). LCMS (Method G): RT=3.04 min, [M+H]+=380.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:11]3[CH:12]=[C:13]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([OH:29])=O)[C:14]([N:16]([CH2:21][CH2:22][OH:23])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1([NH2:49])[CH2:48][CH2:47]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:11]3[CH:12]=[C:13]([C:24]4[CH:32]=[CH:31][CH:30]=[C:26]([C:27](=[O:29])[NH:49][C:46]5([C:41]6[CH:42]=[CH:43][CH:44]=[CH:45][N:40]=6)[CH2:48][CH2:47]5)[CH:25]=4)[C:14]([N:16]([CH2:21][CH2:22][OH:23])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CCO)S(C)(=O)=O)c(-c3cccc(C(=O)O)c3)cc12
Reactant: NC1(c2ccccn2)CC1
Agent: Cl
Product: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CCO)S(C)(=O)=O)c(-c3cccc(C(=O)NC4(c5ccccn5)CC4)c3)cc12

Procedure:
Methyl 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-5-(3-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxylate was prepared from 3-(2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-3-(methoxycarbonyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid (0.05 g, 0.10 mmol) and 1-(pyridin-2-yl)cyclopropanamine dihydrochloride (0.03 g, 0.15 mmol). LCMS: retention time: 1.473 mM. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 254 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 mM, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 644 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[C:8](=[O:13])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[OH:12][C:10]1[CH:11]=[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:3]=[C:4]2[C:9]=1[C:8](=[O:13])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCC(=O)c2c(O)cc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC1(C)CCC(=O)c2c(O)cc(C#C[Si](C)(C)C)cc21
Yield: 100.5 %

Procedure:
Following General Procedure D and using 6-bromo-8-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 65, 1.56 g, 5.8 mmol), triethyl amine (20 mL), copper(I)iodide (0.088 g, 0.46 mmol), trimethylsilyl acetylene (3 mL, 21.22 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.325 g, 0.46 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane to 2-5% ethyl acetate in hexane as the eluent, the title compound (1.67 g, 100%) was obtained as an orange solid.