Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([CH:14]=[O:15])[S:13][C:7]=2[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5]1>C(O)C>[OH:15][CH2:14][C:12]1[S:13][C:7]2[CH:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:5][N:4]([CH3:3])[CH2:10][CH2:9][C:8]=2[CH:11]=1
Reactant: CN1CCc2cc(C=O)sc2C(c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN1CCc2cc(CO)sc2C(c2ccccc2)C1

Procedure:
A solution of sodium borohydride (0.73 g) in ethanol (30 ml) was added dropwise to a stirred solution of 6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-2-carboxaldehyde (1.50 g) in ethanol (30 ml) cooled in an ice bath. After 30 minutes the solution was evaporated, the residue dissolved in water (100 ml) and extracted with dichloromethane (2×100 ml). The extracts were dried filtered and evaporated to a viscous oil. Crystallisation from cyclohexane (15 ml) gave the title product, m.p. 112°.
Reaction SMILES: Cl[C:2]1=[N:3][C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH:9]1[C:8]2[C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:22][CH:23]=3)=[N:3][C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[O:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: ClC1=Nc2ccccc2Oc2ccccc21
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 1 (229 mg, 1.00 mmol) in DME (3 mL) was added 4-methoxycarbonylphenylboronic acid (216 mg, 1.20 mmol), Pd(PPh3)4 (0.065 mg, 0.056 mmol) and 2 N Na2CO3(aq) (1.5 mL, 3.0 mmol). The reaction mixture was stirred for 2 h at 90° C. The solution was then cooled at room temperature and poured into AcOEt. The organic layer was washed with water, brine and dried (Na2SO4), filtered and concentrated to give a yellow oil. The residue was purified by silica gel column chromatography with EtOAc (15%) in Hexanes to afford 2 (327 mg, 99%) as a yellow foam. LRMS (ESI): (calc) 329.1 (found) 330.3 (MH)+.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14](/[CH:21]=[CH:22]/[CH2:23][CH3:24])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14](/[CH:21]=[CH:22]/[CH2:23][CH3:24])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:13]=1
Reactant: CC/C=C/[C@H](CC(=O)OCC)c1ccc(OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC/C=C/[C@H](CC(=O)OCC)c1ccc(O)cc1
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a stirred solution of 18.1 (180 mg, 0.57 mmol) in EtOH (5 mL) at 23 C was added PPTS (catalytic). Stirring was continued for 16 hours. The reaction was concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0 to 20% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to give a colorless oil. The residue was purified by flash chromatography (SiO2 gel 60, eluted with 0 to 20% EtOAc in hexanes). The combined fractions were concentrated under reduced pressure to afford phenol 18.2 (120 mg, 89%) as a colorless oil.
Reaction SMILES: C(O[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.[NH2:16][C:17]([CH3:23])([CH2:20][CH2:21][CH3:22])[C:18]#[N:19]>ClCCl>[C:18]([C:17]([NH:16][C:9](=[O:10])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])([CH2:20][CH2:21][CH3:22])[CH3:23])#[N:19].[CH3:5][C:4]([OH:3])([CH3:7])[CH3:6]
Reactant: CCCC(C)(N)C#N
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)O
Product: CCCC(C)(C#N)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
64.21 g (294.18 mmol) of di-tert-butyl dicarbonate were initially charged in a round-bottom flask, and 30 g (267.44 mmol) of rac-2-amino-2-methylpentanenitrile were added very gradually at RT (internal thermometer, maximum temperature 30° C.), and stirring of the mixture was continued at room temperature overnight. The reaction mixture was admixed with dichloromethane and washed twice with 1 N sodium hydroxide solution. The organic phase was dried over sodium sulphate, filtered and concentrated (at bath temperature 30° C.). 76.33 g (quantitative yield) of the target compound were obtained.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6])[CH3:2].[I-:15].[CH3:16][C:17]1[CH:22]=[CH:21][N+:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1>C(O)C>[I-:15].[CH2:1]([N:3]([C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[CH:16]/[C:17]2[CH:22]=[CH:21][N+:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6])[CH3:2]
Reactant: Cc1cc[n+](CCO)cc1
Reactant: CCN(CCO)c1ccc(C=O)cc1
Agent: [I-]
Solvent: CCO
Product: CCN(CCO)c1ccc(/C=C/c2cc[n+](CCO)cc2)cc1
Yield: 67 %

Procedure:
Following the procedure of Example 6, equimolar amounts of 4-(N-ethyl-N-hydroxyethylamino)benzaldehyde, prepared according to Example 2, and 4-methyl-N-(2-hydroxyethyl)pyridinium iodide, prepared according to Example 4, were reacted in ethanol at reflux, overnight. Upon cooling, dye3 precipitated as a red solid and was collected by filtration, washed, and dried. Yield: 67%. 1H-NMR (DMSO)-d6): δ1.0 (t, 3H), 3.3 (q, 2H), 3.40 (q, 2H), 3.50 (t, 2H), 3.80 (q, 2H), 4.40 (t, 2H), 4.70 (t, 1H), 5.2 (t, 1H), 6.7 (d, 2H), 7.1 (d, 1H), 7.80 (d, 2H), 7.90 (d, 1H), 8.10 (d, 2H), 8.70 (d, 2H) ppm. The elements analy. calcd. for C19H25IN2O2 : C, 51.8; H, 5.7; N, 6.4; Found: C, 51.5; H, 5.7; N, 7.1. Td 270° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].O.[N+:20]([O-])([OH:22])=[O:21]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:14]([OH:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=1)[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(F)ccc(O)c1C(=O)Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: Cc1c(F)cc([N+](=O)[O-])c(O)c1C(=O)Oc1ccccc1
Temperature: 26 °C
Reaction time: 20 h
Yield: 109.3 %

Procedure:
A 30 L 4-neck flask equipped with mechanical stirrer, thermometer and addition funnel was charged with a solution of compound 63 (1100 g, 4.47 mol) in CH2Cl2 (8.0 L) followed by water (8.1 L) and tetrabutyl ammonium bromide (144 g, 0.45 mol). Aqueous HNO3 (591 mL, 68 w %, 8.94 mol) was added to the stirred two-phase reaction mixture at 24˜27° C. over 3 min and the mixture was stirred at 24-28° C. for 20 h. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (4×1.0 L). The organic layers were then combined and successively washed with water (3×1.0 L) and brine (2×2 L). The organic layer was dried over Na2SO4 and filtered and concentrated under reduce pressure to give 1423 g (>100%) of compound 64 as dark brown solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](O)=[O:13])=[CH:7][CH:6]=1)(O)=[O:2].CSC.B>C1COCC1>[OH:2][CH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCc1ccc(CCO)cc1
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a stirred solution of (4-carboxymethylphenyl)acetic acid (1.0 g, 5.15 mmol) in THF (100 mL) was slowly added borane dimethyl sulfide (2.3 mL, 30.9 mmol) and the resulting mixture was stirred overnight (˜18 hours). The reaction was then quenched by slowly adding 1N HCl (100 mL). The resulting mixture was then extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaCl (1×100 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to provide 750 mg of the title intermediate (87% yield), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5](=[S:9])[NH:6][C:7]=1[CH3:8].[OH-].[K+].Cl[CH2:16][C:17]#[N:18]>CN(C=O)C>[NH2:11][C:10]1[C:4]2[C:5](=[N:6][C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=2[CH3:12])[S:9][C:16]=1[C:17]#[N:18]
Reactant: N#CCCl
Reactant: Cc1[nH]c(=S)c(C#N)c(C)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc2sc(C#N)c(N)c2c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
The 5-chloro-4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (300 mg, 1.51 mmol) was stirred in the DMF (3.0 mL). An aqueous solution of 10% KOH (0.85 mL, 1.51 mmol) was added, followed by chloroacetonitrile (0.095 mL, 1.51 mmol). The reaction was stirred at RT for 15 minutes, LC/MS indicates initial thio-alkylation is complete. A second equivalent of 10% KOH (0.85 mL, 1.51 mmol) was added and the resulting slurry was warmed to 50° C. and stirred about 30 min. LC/MS indicates reaction is done. The slurry was cooled to RT, then poured into 50 g of crushed ice and allowed to warm until the ice melted. The cold slurry was poured through filter paper, washing the solid with cold water. The solid was collected and dried in a vacuum oven at 60° C. to give 310 mg (86%) of the pure product as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 6.56 (s, 1H), 2.80 (s, 3H), 2.62 (s, 3H). LC/MS: RT=0.73 min., m/z=238.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([O:17][CH3:18])[CH:13]=[C:12]1[CH2:19][CH2:20][CH2:21][CH2:22][C:11]=21)([O:5][CH2:6][CH3:7])=[O:4].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:23]([N:9]1[C:10]2[C:15](=[C:14]([O:17][CH3:18])[CH:13]=[C:12]3[CH2:19][CH2:20][CH2:21][CH2:22][C:11]3=2)[CH:16]=[C:8]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc2c(OC)cc3c(c2[nH]1)CCCC3
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2c(OC)cc3c(c2n1Cc1ccccc1)CCCC3
Reaction time: 18 h
Yield: 37.4 %

Procedure:
A suspension of 60% sodium hydride in mineral oil (4.08 g, 0.102 mol) was washed once with hexane and suspended in dry N,N-dimethylformamide (100 mL). 2-Carboethoxy-4-methoxy-6,7,8,9-tetrahydro-1H-benz[g]indole (25.4 g, 92.7 mmol) was added in several portions resulting in gas evolution. Benzyl bromide (12.1 mL, 102 mmol) was added in two portions over 30 min and the resulting mixture stirred for 18 h. Additional portions of 60% sodium hydride suspension (1.30 g) and benzyl bromide (2 mL) were added and the mixture stirred for 27 h. The mixture was poured into water (2 L) and the resulting solution extracted three times with ethyl acetate. The combined extracts were Washed three times with water, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel) provided 12.6 g (37%) of the title compound as a yellow solid: mp 86-88° C. 1H NMR (CDCl3) δ 7.51 (s, 1H), 7.20 (m, 3H), 6.84 (d, J=6.6 Hz, 2H), 6.24 (s, 1H), 6.12 (s, 2H), 4.23 (q, J=7.0 Hz, 2H), 3.93 (s, 3H), 2.96 (m, 2H), 2.85 (m, 2H), 1.71 (m, 4H), 1.30 (t, J=7.0 Hz, 3H); MS ES+ m/e 364 (p+1); IR (CHCl3, cm−1) 2937, 1701, 1502.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[C:14]([OH:16])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][NH2:18]>[NH4+].[Cl-].CCOC(C)=O>[C:2]1([C:1]2[C:9]3[CH:13]=[CH:12][O:11][C:10]=3[C:14]([OH:16])=[N:18][N:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccoc1C(=O)O
Reactant: NN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: Oc1nnc(-c2ccccc2)c2ccoc12

Procedure:
A brown solution of 3-benzoylfuran-2-carboxylic acid (0.770 g, 3.56 mmol) and anhydrous hydrazine (0.568 ml, 17.8 mmol) was heated to 100° C. in a sealed tube for approx. 72 h. The reaction was cooled, and diluted with sat'd aq. NH4Cl and EtOAc. The organic layer was washed with sat'd aq. NH4Cl and brine, and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-phenylfuro[3,2-d]pyridazin-7-ol which was carried on without further purification. MS m/z=213 [M+H]+. Calc'd for C12H8N2O2: 212.2.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH:14]([C:23](=[O:48])[NH:24][CH:25]([C:41](=[O:47])[NH:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)[NH:15]C(OC(C)(C)C)=O)[N:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:15][CH:14]([CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[C:23]([NH:24][CH:25]([C:41](=[O:47])[NH:42][C:43]([CH3:45])([CH3:46])[CH3:44])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:32]=1)=[O:48]
Reactant: CC(C)(C)NC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(N)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A solution of [S—(R*,R*)]-4-{2-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylcarbamoyl]-2-tert-butoxycarbonylamino-ethyl}-imidazole-1-carboxylic acid tert-butyl ester (1.92 g, 2.87 mmol) in 70 mL dichloromethane was cooled to 3° C., then TFA (14 mL) was added. The resulting solution was warmed to 25° C. and stirred 2 hours. The mixture was concentrated at reduced pressure to a viscous amber oil which was dissolved in 100 mL ethyl acetate and washed twice with 100 mL saturated aqueous sodium bicarbonate solution and twice with 100 mL brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure affording 1.18 g (85%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH:29]1[CH:30]=[CH:31]C2N(O)N=[N:35][C:33]=2[CH:34]=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:52][C:53]([F:69])([F:68])[C:54]1[CH:67]=[CH:66][CH:65]=[CH:64][C:55]=1[O:56]NC1CCNCC1>CN(C=O)C.O>[O:18]=[C:16]([N:35]1[CH2:31][CH2:30][CH:29]([O:56][C:55]2[CH:64]=[CH:65][CH:66]=[CH:67][C:54]=2[C:53]([F:52])([F:68])[F:69])[CH2:34][CH2:33]1)[CH2:15][C:14]([NH:13][C:10]1[CH:11]=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=1)=[O:19]
Reactant: On1nnc2ccccc21
Reactant: FC(F)(F)c1ccccc1ONC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1)Nc1ccc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a stirred solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid (0.07 g, 0.00024 mole) in DMF (1 mL) was added DIPEA (0.153 g, 0.00120 mole), HOBt (0.039 g, 0.00029 mole) and EDCI.HCl (0.055 g, 0.00029 mole). After 2 minutes (2-trifluoromethyl-phenoxy)-piperidin-4-yl-amine hydrochloride (0.080 g, 0.00029 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 57.5 mg (50%) of 3-oxo-N-(6-phenyl-pyridin-3-yl)-3-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-propionamide. LC-MS purity: 484.18 (M+1)+, 98.83%, 1H NMR (DMSO-d6): δ 10.5 (s, 1H), 8.8 (d, 1H), 8.2 (d, 1H), 8.1 (d, 2H), 8.0 (d, 1H), 7.7-7.6 (m, 2H), 7.5-7.3 (m, 4H), 7.1 (t, 1H), 4.9 (m, 1H), 3.7-3.5 (m, 6H), 2.0-1.6 (m, 4H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[O:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5])C.[OH-].[Na+].Cl>O.CCO>[NH2:17][C:13]1[N:12]=[C:11]([C:9]2[O:8][C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)oc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nccc(-c2cc(C(=O)O)c(-c3ccccc3)o2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of ester 59 (221 mg, 0.71 mmol) in 1:1 H2O/EtOH (9 mL), 4M aq NaOH (10 eq) was added and the reaction mixture was stirred at 100° C. for 1 h. After cooling to rt, the solution was acidified with 2M HCl yielding 5-(2-amino-pyrimidin-4-yl)-2-phenyl-furan-3-carboxylic acid as a white solid which was filtered, washed with water and dried under reduced pressure (quant.).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[F:16])[N:3]=1.Cl.[CH3:18][N:19]([C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]2[O:36][CH2:35][CH2:34][NH:33][CH2:32]2)=[CH:27][CH:26]=1)[C@@H:20]1[CH2:24][CH2:23][O:22][CH2:21]1.C(N(CC)CC)C>O1CCCC1>[F:16][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]([N:33]2[CH2:34][CH2:35][O:36][C@@H:31]([C:28]3[CH:27]=[CH:26][C:25]([N:19]([CH3:18])[C@@H:20]4[CH2:24][CH2:23][O:22][CH2:21]4)=[CH:30][CH:29]=3)[CH2:32]2)[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=1
Reactant: CN(c1ccc([C@H]2CNCCO2)cc1)[C@@H]1CCOC1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1ccc([C@H]2CN(c3nc(-c4ccncc4F)cc(=O)n3C)CCO2)cc1)[C@@H]1CCOC1
Yield: 39 %

Procedure:
2-Chloro-3-methyl-6-(3-fluoropyridin-4-yl)-3H-pyrimidin-4-one (0.26 g, 1.09 mmol) was added to a solution of (2S)-2-(4-(N-methyl-N-((3R)-tetrahydrofuran-3yl)amino)phenyl)morpholine hydrochloride obtained in Reference Example 6 (0.4 g, 1.19 mmol) and triethylamine (0.6 g, 5.93 mmol) in tetrahydrofuran (20 ml) at room temperature for 15 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-fluoropyridin-4-yl)-2-((2S)-2-(4-(N-methyl-N-((3R)-tetrahydrofuran-3-yl)amino)-phenyl)morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.20 g, 39%) as white crystals.
Reaction SMILES: [CH3:1][C@@:2]([OH:34])([C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:3]1[C@:8]2([O:28][CH3:29])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.[C:35](O)(=[O:43])[CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].O.[ClH:46]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][C@@:2]([OH:34])([C:30]([CH3:33])([CH3:32])[CH3:31])[C@@H:3]1[C@@:8]2([O:28][CH3:29])[C@@H:9]3[O:23][C:18]4=[C:19]([O:22][C:35]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:43])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.[ClH:46]
Reactant: CO[C@@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Reactant: O=C(O)CCCCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CO[C@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(OC(=O)CCCCC(=O)O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Reaction time: 0.33 h
Yield: 69.2 %

Procedure:
Alternate Method: To a stirred solution of 4-dimethylaminopyridine (1.232 g, 0.010 mol, acylation catalyst) in tetrahydrofuran (1.5 L, THE) was added buprenorphine free base (93.534 g, 0.20 mol) followed by adipic acid (239.952 g, 1.64 mol). The suspension was stirred for 20 minutes and dicyclohexylcarbondiimide (45.409 g, 0.22 mol) was added over approx 30 minutes whilst maintaining the internal temperature between 16-21° C. with cold water cooling. Stirring was continued overnight. The insoluble precipitate (mostly dicyclohexylurea) was removed by filtration under vacuum and washed with more THF. Solvent was removed under vacuum from the filtrate (960 ml recovered). The precipitate (mainly adipic acid) was removed by filtration and washed with a little more THF and dried in air. The combined filtrates were stirred at room temperature and treated with concentrated hydrochloric acid (20.606 g, 0.20 mol). The resulting precipitate was removed by filtration, washed with THF and dried in air. This crude product was crystallized from ethanol/dichloromethane with a hot filtration and removal of solvents under vacuum to concentrate the suspension. The solid was removed by filtration, washed with ethanol and dried to give buprenorphine hemiadipate hydrochloride (87.525 g). The identity of the material was confirmed by full assignment of the 1H and 13C NMR spectrum and by comparison of these spectra with the NMR spectra of buprenorphine hydrochloride.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:35]=[CH:34][C:19]([CH2:20][O:21][C:22]([C:30]([F:33])([F:32])[F:31])([C:26]([F:29])([F:28])[F:27])[C:23](Cl)=[O:24])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>N1C=CC=CC=1>[ClH:9].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([CH2:20][O:21][C:22]([C:26]([F:27])([F:28])[F:29])([C:30]([F:31])([F:32])[F:33])[C:23]([O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:24])=[CH:34][CH:35]=2)=[CH:12][CH:11]=1
Reactant: CCN(CC)CCO
Reactant: O=C(Cl)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCN(CC)CCOC(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Product: Cl
Reaction time: 48 h
Yield: 112.7 %

Procedure:
A mixture of 2-diethylaminoethanol (814 mg.) and pyridine (10 ml.) is added at 0° C. to 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionyl chloride (3.07 g.). The mixture is stirred at room temperature until the acid chloride dissolves, and the solution is stored at 0° C. for 2 days. The mixture is filtered and the filtrate evaporated. The residue is triturated with ether and combined with the solid previously filtered off. The combined solids are crystallised from dioxan-ether to give 2-diethylaminoethyl 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate hydrochloride (2.2 g.), m.p. 139°-140° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Cl.[N:13]1([CH:28]2[CH2:34][CH:33]3[N:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:30]([CH2:31][CH2:32]3)[CH2:29]2)[CH2:18][CH2:17][C:16]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][NH:20][CH2:19]2)[CH2:15][CH2:14]1>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:20]2[CH2:19][C:16]3([CH2:17][CH2:18][N:13]([CH:28]4[CH2:29][CH:30]5[N:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:33]([CH2:32][CH2:31]5)[CH2:34]4)[CH2:14][CH2:15]3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CNCc1ccccc13)C2
Reactant: COc1cccc(B(O)O)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CN(c1cccc(OC)c1)Cc1ccccc13)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of 3-methoxyphenylboronic acid (30 mg, 0.2 mmol), Cu(OAc)2H2O (2 mg, 5 mol %), 3 Å molecular sieves (75 mg) in 1 mL of CH2Cl2 were stirred at room temperature for 5 min. Ethyl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate hydrochloride 5c (42 mg, 0.1 mmol) was added to the reaction and mixture was stirred at room temperature for 24 h. The reaction was diluted with methanol, filtered and subjected to reverse-phase HPLC purification (2-50% CH3CN—H2O gradient, with 0.05% TFA, 15 min) to give pure ethyl 3-(2-(3-methoxyphenyl)-2,3-dihydro -1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. LC-MS: m/z [M+H]+ 490.0, retention time 2.61 min (10-90% CH3CN—H2O gradient, with 0.05% TFA, 5 min).