Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:16][O:17][C:18]([C:20]1[N:21](C)[N:22]=[C:23](O)[CH:24]=1)=[O:19]>>[CH3:16][O:17][C:18]([C:20]1[NH:21][N:22]=[C:23]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:15])[CH:24]=1)=[O:19]
Reactant: Cc1onc(-c2ccc(F)cn2)c1CO
Reactant: COC(=O)c1cc(O)nn1C
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Yield: 47 %

Procedure:
As described for example 17d, [3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol (1.03 g, 4.95 mmol), using 5-hydroxy-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester instead of 5-hydroxy-2H-pyrazole-3-carboxylic acid methyl ester, was converted to the title compound (770 mg, 47%) which was obtained as a white solid. MS: m/e=333.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=O.C(=O)(O)[O-].[Na+]>C(O)CC>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[N:1]=[C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]3[CH:13]=2)=[CH:17][CH:18]=1
Reactant: Nc1ccc2ccccc2n1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: Clc1ccc(-c2cn3c(ccc4ccccc43)n2)cc1

Procedure:
17.7 g (0.123 mole) of 2-aminoquinoline, 28.7 g (1 equivalent of α-bromo-p-chloroacetophenone and 20.6 g (2 equivalents) of sodium bicarbonate are mixed in 180 ml of n-propanol and heated under reflux for 20 hours. The precipitate obtained is filtered off, washed with ethanol and water and dried. A white solid is obtained which is recrystallized from nitromethane.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([I:10])=[C:8]([F:11])[CH:7]=[CH:6][C:5]=1[CH2:12]Br.[OH-].[NH4+:16]>C1COCC1>[F:11][C:8]1[C:9]([I:10])=[C:4]2[C:5]([CH2:12][NH:16][C:3]2=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(CBr)ccc(F)c1I
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1NCc2ccc(F)c(I)c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.3 %

Procedure:
A solution of 2-bromomethyl-5-fluoro-6-iodo-benzoic acid methyl ester (0.373 g, 1.0 mmol), in THF (4 mL) was treated with 30% aq. Ammonium hydroxide (0.256 mL, 2.2 mmol) and heated with stirring at 100° C. for 2 h. After this time, the resulting mixture was concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 6-fluoro-7-iodo-2,3-dihydro-isoindol-1-one (0.070 g, 25%). GC-MS: m/z 277 (M)+, 249 (M−28)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][N:13]=2)[CH2:8]1.[CH2:24]([Sn](CCCC)(CCCC)C=C)[CH2:25]CC>CN(C=O)C.C(N(CC)CC)C.Cl.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]>[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:24]=[CH2:25])=[CH:14][N:13]=2)[CH2:8]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc(CN[C@H]2CCN(c3ccc(I)cn3)C2)c(Cl)c1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 65 °C

Procedure:
Dissolve (S)-(2,4-dichlorobenzyl)-[1-(5-iodopyridin-2-yl)-pyrrolidin-3-yl]-amine hydrochloride (200 mg, 0.41 mmol) in DMF (7 mL) and triethylamine (60 μL). Add tetrakis(triphenylphosphine)palladium (0) (24 mg, 0.021 mmol) and tributyl(vinyl)tin (150 μL, 0.49 mmol). Heat the mixture at 65° C. overnight. Cool to room temperature, dilute with 1 N HCl (15 mL). Wash the mixture with dichloromethane (3×). Basify the aqueous solution to about pH=9 by adding solid potassium carbonate. Extract with dichloromethane (3×), dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with 10:90 to 1:1 ethyl acetate:hexanes, to give the title compound as a residue. Dissolve the residue in methanol, add 1 N HCl in methanol (1 mL). Concentrate and dry in a vacuum oven at 60° C. to give the title compound as its hydrochloride salt (97 mg, 56%): 1H NMR (400 MHz, MeOH-d4) 8.30 (dd, 1H, J=8.8, 2.0 Hz), 7.97 (d, 1H, J=2.4 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.68 (d, 1H, J=1.6 Hz), 7.50 (dd, 1H, J=8.0, 2.2 Hz), 7.16 (d, 1H, J=9.2 Hz), 6.70 (dd, 1H, J=17.6, 11.2 Hz), 5.87 (d, 1H, J=17.6 Hz), 5.40 (d, 1H, J=11.2 Hz), 4.55-4.47 (m, 2H), 4.34-4.28 (m, 1H), 4.18-4.13 (m, 1H), 3.97-3.91 (m, 2H), 3.80-3.74 (m, 1H), 2.77-2.68 (m, 1H), 2.55-2.46 (m, 1H), MS (ES): m/z 348 [M+H].
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH2:13][CH3:14])[CH2:11][OH:12])=[CH:6][CH:5]=1.[Br:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH2:25]Br)=[CH:19][CH:18]=1.O>CN(C=O)C.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH2:13][CH3:14])([CH3:15])[CH2:11][O:12][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:21][C:20]3[CH:30]=[CH:31][C:17]([Br:16])=[CH:18][CH:19]=3)[CH:23]=2)=[CH:8][CH:9]=1
Reactant: CCC(C)(CO)c1ccc(F)cc1
Reactant: BrCc1cccc(Oc2ccc(Br)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)(COCc1cccc(Oc2ccc(Br)cc2)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To 20 ml of toluene was added 0.60 g of sodium hydride (60% in oil) and the mixture was refluxed, and a solution of 2.0 g of 2-(4-fluorophenyl)-2-methylbutyl alcohol in 10 ml of 40% DMF/toluene was added dropwise to the mixture over a period of 20 minutes. The mixture was stirred for 10 minutes and a solution of 4.0 g of 3-(4-bromophenoxy)benzyl bromide in 10 ml of toluene was added dropwise to the mixture over a period of 10 minutes. The mixture was further heated and refluxed for 1 hour and cooled to room temperature, and poured into water. The toluene layer was separated, washed with water, dried over Na2SO4, and evaporated under reduced pressure and the obtained crude ether was purified by column chromatography on 100 g of silica gel (1:1 mixed solvent of toluene and hexane was used as eluent) to give 3.7 g of the desired ether (the yield was 76% of the theoretical yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]([C:20](O)=[O:21])=[C:17]([CH3:19])[N:18]=2)=[C:10]([O:23][CH3:24])[CH:9]=1.C(OCC)(=O)C>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]([CH2:20][OH:21])=[C:17]([CH3:19])[N:18]=2)=[C:10]([O:23][CH3:24])[CH:9]=1
Reactant: COc1cc(Cl)ccc1-c1nc(C)c(C(=O)O)s1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1-c1nc(C)c(CO)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
Lithium aluminum hydride (380 mg, 10.0 mmol) was suspended in tetrahydrofuran (10 ml), and a suspension (10 ml) of 2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid (1.42 g, 5.00 mmol) prepared in Example 7-1 in tetrahydrofuran was added thereto at a room temperature. The mixture was stirred for 3 hours at a room temperature. Under an ice cooling, 5 drops of a saturated sodium bicarbonate solution were slowly added to the mixture. Ethyl acetate was added to the mixture, and another 5 drops of a saturated sodium bicarbonate solution were added thereto. The precipitate was removed by filtration, and the removed solid was washed with chloroform. The washings and the filtrate were concentrated together. The concentrate was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the title compound (580 mg, 43%) as a light-brown powder.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([NH:36]C(OC(C)(C)C)=O)[C:6]([NH:8][CH:9]([C:32]([O:34][CH3:35])=[O:33])[CH2:10][C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[CH:29]=[CH:28][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=[O:7].[ClH:44]>ClCCl>[ClH:44].[CH3:1][S:2][CH2:3][CH2:4][CH:5]([NH2:36])[C:6]([NH:8][CH:9]([C:32]([O:34][CH3:35])=[O:33])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:29]=[CH:28][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:18][CH:17]=2)=[CH:30][CH:31]=1)=[O:7]
Reactant: COC(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)C(CCSC)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)C(N)CCSC
Yield: 89.2 %

Procedure:
A solution of 5-[4-(4-(2-(4-methylthio-2-t-butoxycarbonylaminobutyramido)-2-methoxycarbonylethyl)phenoxy)benzyl]thiazolidin-2,4-dione (1 g, 1.58 mmol) in dichloromethane (30 ml) was bubbled with HCl gas at 20° C. for 30 minutes. The excess HCl gas was removed by N2 bubbling and the solvent was removed by distillation to furnish the title compound (0.8 g, yield 89.2%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([C:12](OCC)=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1ccc2nc(SC)sc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: CSc1nc2ccc(CO)cc2s1
Temperature: -78 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a stirred mixture of ethyl 2-(methylthio)benzo[d]thiazole-6-carboxylate (1.7 g, 6.6 mmol) from Step 2 of this Example in CH2Cl2 (50 mL) at −78° C. under argon was added 1 M diisobutyl aluminum hydride in CH2Cl2 (13.8 mL, 13.8 mmol) dropwise. After the mixture was stirred at −78° C. under argon for 3 h, it was allowed to warm slowly to 0° C. To the stirring mixture was added a saturated aq potassium sodium tartrate (50 mL) and the mixture was allowed to slowly warm to rt. After the mixture was stirred for 12 h, the organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford (2-(methylthio)benzo[d]thiazol-6-yl)methanol (1.05 g, 76%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.93 (m, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.40 (dd, J=1.3, 8.3 Hz, 1H), 5.32 (t, J=5.7 Hz, 1H), 4.60 (d, J=5.8 Hz, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 212 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[C:10]([F:31])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH:32]([N:35]=[C:36]=[O:37])([CH3:34])[CH3:33]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][N:21]([C:36]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:37])[CH2:20][C:18]=4[N:19]=3)=[C:10]([F:31])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)N=C=O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CCNC2
Solvent: CN(C)C=O
Product: CC(C)NC(=O)N1CCc2c(nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc2N2CCOC[C@@H]2C)C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a stirred solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (Example 163) (100 mg, 0.23 mmol) in DMF (2 ml) was added isopropyl isocyanate (35 μl, 0.35 mmol). Reaction mixture was stirred at 20° C. for 2 hours. The crude reaction mixture was then partitioned between water (10 ml) and DCM (10 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. Residue was then purified by prep. HPLC at high pH to afford the title compound as a white solid (61 mg, 0.12 mmol, 52%)
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][CH:21]=2)=[CH:11][CH:10]=1)(=O)=O.[NH:30]1[CH:34]=[N:33][N:32]=[N:31]1>>[C:24]1(/[CH:23]=[CH:22]/[C:19]2[O:20][CH:21]=[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:31]4[N:32]=[N:33][CH:34]=[N:30]4)=[CH:10][CH:11]=3)[N:18]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1nnn[nH]1
Product: C(=C/c1nc(COc2ccc(CCCn3ncnn3)cc2)co1)\c1ccccc1
Yield: 41 %

Procedure:
In substantially the same manner as in Working Example 33, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate was allowed to react with tetrazole, and the reaction mixture was subjected to extraction. The extract was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:1, v/v), 2-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2H-tetrazole was obtained. The yield was 41%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 97-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH:12]([CH2:17][NH:18][C:19]([N:21]=[N+]=[N-])=[O:20])[N:11]3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1.[OH-:25].[Na+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH:12]([CH2:17][NH:18][C:19]([NH:21][CH2:17][CH:12]4[N:11]5[CH:24]=[C:8]([C:4]6[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=6)[CH:9]=[C:10]5[C:15](=[O:25])[NH:14][CH2:13]4)=[O:20])[N:11]3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: [N-]=[N+]=NC(=O)NCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21)NCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Step b 71 mg (0.206 mmol) of {[7-(3-chlorophenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]methyl}carbamic azide were dissolved in 10 ml of dry THF, NaOH 1N (2 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction was diluted with EtOAc and extracted with water, the organic layer was mixed with HCl 2N (5 ml) for 10 minutes, and then discarded; the aqueous solution was brought to pH 10 with NaOH 23% (10 ml) and portioned between EtOAc (10 ml) and THF (10 ml). The organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give the title compound 50 mg (89%) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[C:21]([CH3:22])=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=2[CH3:23])=[O:9])[C:5]([CH3:24])=[CH:4][CH:3]=1.[CH3:25][C:26]1([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:32][C:26]1([CH3:25])[CH2:31][CH2:30][N:29]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[C:21]([CH3:22])=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=3[CH3:23])=[O:9])[C:5]([CH3:24])=[CH:4][CH:3]=2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Reactant: CC1(O)CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(C)(O)CC3)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of ethyl 4-[(6-chloro-3-methyl-pyridine-2-carbonyl)amino]-3,5-dimethyl-benzoate (275 mg, 792.93 μmoles), 4-methylpiperidin-4-ol (120 mg, 1.04 mmol) and Cs2CO3 (0.8 g, 2.46 mmol) in 1,4-dioxane (6 ml) is added Pd(OAc)2 (27 mg, 120.26 μmoles) followed by racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (54 mg, 86.72 μmoles). The reaction mixture is purged with nitrogen for 5 minutes and then heated to reflux. After 2 hours, the reaction is cooled to ambient temperature and diluted with ammonium chloride and extracted twice with EtOAc. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 0-70% ethyl acetate in hexane to afford the title compound as a yellow oil (0.27 g, 80%). Mass spectrum (m/z): 426.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[C:10]([N:13]1[CH2:17][C:16](=O)[N:15]=[CH:14]1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[CH2:17][CH2:16][N:15]=[C:14]1[NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: CCc1cc(N)n(C)n1
Product: CCc1cc(NC2=NCCN2C(C)=O)n(C)n1

Procedure:
5-Amino-3-ethyl-1-methyl pyrazole (British Pat. No. 863,060) (35.2 g.) and 1-acetyl-2-imidazolinone (43.2 g.) were reacted as described in Example I to give 1-acetyl -2-(3-ethyl-1-methyl-5-pyrazolyl) amino-2-imidazoline which was de-acetylated without purification by the method of Example II giving 39.3 g. product. mp 160°-162°
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4.C(N(CC)CC)C.Br.[Br:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.Br>C1COCC1>[BrH:29].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:20]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4
Reactant: BrCc1cccnc1
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(Cc1cccnc1)CC3

Procedure:
Similarly to the preparation of Example 4, the title compound was prepared from the reaction of (+)-3-methoxy-morphinan hydrochloride (1 g, 3.4 mmol) in THF (20 ml), triethylamine (1.43 ml, 10.3 mmol), and 3-(bromomethyl)pyridine hydrobromide (0.95 g, 3.75 mmol) gave a solid which was treated with 45% HBr to afford 1 g of a tan solid (68% yield); ms(ESI+): m/z 349 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][N:16]3[CH:11]([C:4]4[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]3=[O:17])=[CH:21][CH:22]=2)[CH:30]=[CH:29][CH:28]=[N:27]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: BrCc1ccc(-n2cccn2)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(-n2cccn2)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(4-(bromomethyl)phenyl)-1H-pyrazole. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.73 min.; [M+H]+: 392.16 g/mol.
Reaction SMILES: CC1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@@H:21]([NH2:26])[CH2:20]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>CCOC(C)=O.O>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@@H:21]([NH:26][C:34](=[O:35])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:20]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)OCc1ccccc1
Reaction time: 8 h
Yield: 89.5 %

Procedure:
(R)-5-bromo-2,3-dihydro-1H-inden-2-amine((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (12.56 mmol, 5.58 g) was dissolved in EtOAc (30 mL)/water (30 mL) and potassium carbonate (37.7 mmol, 5.21 g) added. The mixture was cooled in an ice bath and benzyl chloroformate (13.81 mmol, 1.964 mL, 2.356 g) added dropwise. Stirring was continued overnight during which time the reaction came to room temperature. The crude reaction mixture was diluted with water and ethylacetate and the phases mixed and separated. The aqueous layer was further extracted with EtOAc (×2). Combined organics were dried and concentrated before crystallisation of the product from ethylacetate/heptane mixture to give (R)-benzyl 5-bromo-2,3-dihydro-1H-inden-2-ylcarbamate as colourless needles (3.89 g, 89%). 1H NMR (400 MHz, CDCl3) δ 2.79 (m, 2H) 3.26 (m, 2H) 4.53 (bm, 1H) 4.93 (bm, 1H) 5.10 (bs, 2H) 7.07 (m, 1H) 7.26-7.37 (m, 7H)
Reaction SMILES: C([O:4][C@@H:5]([C:12](=[O:59])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]4[N:33]=[CH:32][N:31](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:30]=4)[CH:27]=3)[N:22](C3CCCCO3)[N:21]=2)[CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.C([O-])(O)=O.[Na+]>Cl.O1CCOCC1>[NH:31]1[CH:32]=[N:33][C:29]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[C:20]3[C:16]2[CH:15]=[C:14]([NH:13][C:12](=[O:59])[C@H:5]([OH:4])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:19]=[CH:18][CH:17]=2)=[N:30]1
Reactant: CC(=O)O[C@@H](C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
(1R)[N-(3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carbamoyl]phenylmethyl acetate was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. Monitoring of the reaction showed that the alcohol functionality had been partially deprotected under these conditions. After neutralization with aqueous NaHCO3 after 48 hours, the crude product was extracted in ethyl acetate. The residue was then dissolved in 2 mL of MeOH and the solution was treated with 0.5 mL of aqueous saturated K2CO3 solution. After 2 hours at room temperature, deprotection was complete. The reaction mixture was neutralized and the crude product extracted with ethyl acetate and purified by preparative HPLC (0.036 g, 35% yield over 3 steps): 1H NMR (CD3OD) δ 8.74, 8.55 (s, 1H), 8.22 (br s, 1H), 8.10 (br s, 2H), 7.78 (dt, 2H), 7.68 (br s, 1H), 7.58 (d, 2H), 7.51 (t, 1H), 7.382–7.30 (m, 3H), 5.21 (s, 1H); ES-MS (m/z) 411 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].[NH2:19][C:20]1[CH:48]=[CH:47][C:23]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]3[CH:31]=[C:32]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]4)[S:33][C:26]=23)=[C:22]([F:49])[CH:21]=1.C1(C)C=CC=CC=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCO>[C:43]([O:42][C:40]([N:37]1[CH2:38][CH2:39][CH:34]([C:32]2[S:33][C:26]3[C:27](=[N:28][CH:29]=[CH:30][C:25]=3[O:24][C:23]3[CH:47]=[CH:48][C:20]([NH:19][C:2]4[N:12]=[CH:11][CH:10]=[CH:9][C:3]=4[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:21][C:22]=3[F:49])[CH:31]=2)[CH2:35][CH2:36]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cccnc1Nc1ccc(Oc2ccnc3cc(C4CCN(C(=O)OC(C)(C)C)CC4)sc23)c(F)c1
Temperature: 110 °C
Yield: 65.5 %

Procedure:
A microwave vial was charged with ethyl 2-chloronicotinate (0.209 g, 1.13 mmol), Cs2CO3 (0.331 g, 1.01 mmol), tert-butyl 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)piperidine-1-carboxylate (Example 154, Step A, 0.200 g, 0.451 mmol), Palladium acetate (0.0101 g, 0.0451 mmol), PdCl2(dppf)-dcm (0.0185 g, 0.0225 mmol), toluene (2 mL) and EtOH (1 mL). The mixture was heated to 110° C. for 3 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organics were isolated and dried (MgSO4). After filtration and concentration, the crude product was purified by preparative TLC (2.0 mm thickness, eluting with EtOAc. The product (175 mg, 59%) was isolated as a yellow solid. LRMS (esi+)593 m/z (M+1) detected.