Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][CH:19]([CH2:24][CH3:25])[CH2:20][C:21](O)=[O:22].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:22])[CH2:20][CH:19]([CH3:18])[CH2:24][CH3:25])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: CCC(C)CC(=O)O
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: CCC(C)CC(=O)Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (40 mg, 1.1 eq, 0.18 mmol) was added to a solution 3-methylpentanoic acid (20 μl, 1.0 eq, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 1.1 eq, 0.18 mmol), 1-hydroxybenzotriazole (22 mg, 1.0 eq, 0.17 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 48 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was purified by mass directed preparative HPLC to yield the title compound as a white solid (31 mg, 0.10 mmol, 61%). LCMS: [M+H]+=325, Rt=1.64 min, 100% purity.
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:8]\[C:9]1[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[C:12]([O:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:11][CH:10]=1)/[C:5]([OH:7])=[O:6])[CH3:2]>CO.C(Cl)Cl.[Pd]>[CH2:1]([O:3][CH:4]([CH2:8][C:9]1[C:17]2[O:16][CH2:15][CH2:14][C:13]=2[C:12]([O:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:11][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccoc12)C(=O)O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2c1OCC2)C(=O)O
Yield: 55.5 %

Procedure:
A suspension of 100 mg of 2Z-ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzofuran-7-yl}-acrylic acid and 25 mg of Pd/C (10%) in 2 ml of MeOH and 2 ml of CH2Cl2 was hydrogenated at 22° C./1bar overnight. The suspension was filtered and the filtrate was again hydrogenated with 25 mg of fresh catalyst overnight. The suspension was filtered, the filtrate evaporated and the residue purified by prep. HPLC (RP-18, CH3CN/H2O, gradient) to give the title compound (56 mg, 56%) as a pale yellow solid.
Reaction SMILES: [NH2:1][OH:2].C(N(CC)CC)C.[C:10]([O:14][C:15]([O:17]C([O-])=O)=O)([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:15]([NH:1][OH:2])([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:17]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 362 %

Procedure:
To a solution of amino alcohol from Step 3 (2.60 g, 5.81 mmol) in DCM (60 mL) was added triethylamine (1.60 mL, 12.0 mmol) followed by tert-butyldicarbonate (1.50 g, 6.88 mmol) and the reaction was stirred overnight at RT. The final mixture was concentrated and purified by flash-chromatography over silica gel (eluted with Hexanes/AcOEt 80:20 to 20:80) to provide 2.80 g (88%) of Boc-amino alcohol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[C:32]([CH3:36])=[N:31]1.FC(F)(F)C(O)=O>CCCCO>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:35][C:33]2[C:32]([CH3:36])=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: Cc1nn(C)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CCC3(CCNCC3)CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (504.1 mg, 1.214 mmol) and 1,3-dimethyl-1H-pyrazol-4-amine hydrochloride (381.0 mg, 2.581 mmol) in n-BuOH (10 mL) was added trifluoroacetic acid (678.1 mg, 5.947 mmol). The mixture was stirred at 100° C. overnight, then quenched with water (30 mL), and adjusted to pH=9 with solid NaHCO3, and then extracted with DCM (200 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as brown oil (271 mg, 45.57%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18]S([O-])(=O)=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(N(CC)CC)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C=O)C.O>[F:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH2:18][C:16]3[N:17]=[C:12]([C:4]4[S:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=5[C:2](=[O:1])[N:3]=4)[CH:13]=[CH:14][CH:15]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1nc(-c2cccc(CN3CCN(c4ccc(F)cc4)CC3)n2)sc2ccccc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (0.30 g, 0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and 1-(4-fluorophenyl)piperazine (0.17 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at 70° C. for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.19 g, 50%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.[C:13]1([C@H:19]([CH2:21][OH:22])[NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(O)=O.[BH4-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([NH:20][C@H:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:21][OH:22])[CH2:3]1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC1(C)CC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C[C@H](N[C@@H](CO)c2ccccc2)c2ccccc21
Temperature: 0 °C
Yield: 91.8 %

Procedure:
To a solution of 3,3-dimethylindan-1-one (925 mg, 5.77 mmol) and (R)-(−)-2-phenylglycinol (893 mg, 6.51 mmol) in toluene (10.0 mL) was added p-toluenesulfonic acid monohydrate (62.5 mg, 0.328 mmol). The reaction was heated to reflux under an atmosphere of nitrogen for 90 min. At this point, the mixture was cooled and diluted with toluene (10.0 ml). The mixture was washed with saturated aqueous NaHCO3 solution and H2O. The organic layer was concentrated in vacuo and the residue was dissolved in THF (10.0 mL) and cooled to 0° C. AcOH (1.13 mL, 19.9 mmol) was added, followed by sodium borohydride (251 mg, 6.64 mmol) and the reaction was allowed to warm to 23° C. overnight. The mixture was partitioned between DCM and saturated aqueous NaHCO3 solution. The organic layer was concentrated and silica gel chromatography eluting with a gradient of 5 to 35% EtOAc in E)CM afforded the title compound (1.49 g, 74%). LC/MS: Rt=1.92 min, ES+ 282 (AA standard).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:4][C:3]=1[C:16]#[N:17].Br[C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:16]([C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])#[N:17]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: COc1cccc(-c2ccc(N)c(C#N)c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccc(-c3cccc(OC)c3)cc2C#N)c1
Temperature: 100 °C
Yield: 76 %

Procedure:
4-Amino-3′-methoxybiphenyl-3-carbonitrile (4.23 g, 18.86 mmol), methyl 3-bromobenzoate (4.87 g, 22.63 mmol), palladium(II) acetate (0.212 g, 0.943 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.091 g, 1.886 mmol) and cesium carbonate (8.60 g, 26.4 mmol) in a pressure vessel was flushed with nitrogen and toluene (75 mL) was added. The mixture was heated at 100° C. overnight. The reaction mixture was filtered and the solid was washed with DCM (2×20 mL). The filtrate was concentrated and the product was purified by flash-chromatography eluting with hexane containing 5 to 20% ethyl acetate. This gave 5.14 g (65% yield) of methyl 3-(3-cyano-3′-methoxybiphenyl-4-ylamino)benzoate. MS (ESI) m/z 359.1 (M+H). 1H NMR (CDCl3) δ ppm 7.88 (1H, s), 7.77 (1H, d, J=7.63 Hz), 7.72 (1H, d, J=2.44 Hz), 7.61 (1H, dd, J=8.70, 2.29 Hz), 7.42 (1H, t, J=7.93 Hz), 7.30-7.39 (2H, m), 7.27 (1H, d, J=8.85 Hz), 7.08 (1H, d, J=7.93 Hz), 7.02 (1H, t, J=2.14 Hz), 6.88 (1H, dd, J=8.24, 2.44 Hz), 6.56 (1H, s), 3.91 (3H, s), 3.85 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.B(F)(F)F.[CH3:25]COCC>C1(C)C=CC=CC=1>[CH3:25][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 101 %

Procedure:
A dry 1-L, one-necked, round-bottomed flask was equipped with a Liebig condenser fitted with a rubber septum and a magnetic stirrer. The condenser was temporarily removed, and the flask was charged with 33.7 g (0.135 mol) of N-benzyloxycarbonyl-(S)-proline and 400 mL of anhydrous methanol (Mallinckrodt). The flask was flushed with nitrogen through the septum. The mixture was stirred, and 24.6 mL (28.4 g, 0.2 mol) of boron trifluoride etherate was added via cannula. The resulting mixture was stirred and refluxed for 1 hr under nitrogen. After the solvent was removed under reduced pressure, the residue was vigorously stirred with 200 mL of ice-water. The mixture was extracted with ethyl acetate (3×100 mL). The extacts were combined and successively washed with brine (2×20 mL), a 1M aqueous sodium hydrogen carbonate solution (3×20 mL), and brine (2×20 mL), and dried over anhydrous sodium sulfate. After the removal of the solvent under reduced pressure, a colorless oil was obtained. The oil was dissolved in 100 mL of dry toluene (distilled over CaH2), and the solvent was removed under reduced pressure to remove water from the oil. This treatment was repeated to give 35.9 g of N-benzyloxycarbonyl-(S)-proline methyl ester is a colorless oil (containing a small amount of toluene), [α]D21 -53.9° (methanol, c 1.0).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10](COC)[C:9]([NH:14][CH2:15][CH3:16])=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:17][C:18]1[N:27]=[C:26]([N:28]2[CH2:34][C:33]3[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:32]=3[O:31][CH2:30][CH2:29]2)[C:25]2[CH2:24][C:23]([CH3:43])([CH3:42])[CH2:22][CH2:21][C:20]=2[N:19]=1>>[CH2:15]([NH:14][C:9]1[NH:10][C:4]2[C:5]([N:8]=1)=[N:6][CH:7]=[C:2]([C:36]1[CH:37]=[CH:38][C:32]3[O:31][CH2:30][CH2:29][N:28]([C:26]4[C:25]5[CH2:24][C:23]([CH3:42])([CH3:43])[CH2:22][CH2:21][C:20]=5[N:19]=[C:18]([CH3:17])[N:27]=4)[CH2:34][C:33]=3[CH:35]=1)[CH:3]=2)[CH3:16]
Reactant: CCNc1nc2ncc(Br)cc2n1COC
Reactant: Cc1nc2c(c(N3CCOc4ccc(B(O)O)cc4C3)n1)CC(C)(C)CC2
Product: CCNc1nc2ncc(-c3ccc4c(c3)CN(c3nc(C)nc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 5 by using 6-bromo-N-ethyl-1-[(methyloxy)methyl]-1H-imidazo[4,5-b]pyridin-2-amine (reagent preparation 36) and [4-(2,6,6-trimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1 followed by MOM deprotection. 1H NMR (400 MHz, methanol-d4): 8.15 (d, 1H), 7.64 (d, 1H), 7.55 (d, 1H), 7.43 (dd, 1H), 7.06 (d, 1H), 4.71 (s, 2H), 4.31 (m, 2H), 3.99 (m, 2H), 3.46 (q, 2H), 2.75 (t, 2H), 2.47 (s, 2H), 2.41 (s, 3H), 1.66 (t, 2H), 1.30 (t, 3H), 0.91 (s, 6H); MS (EI) for C27H30N6O: 455 (MH+).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-])=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]>CO.[Pd]>[NH2:13][C:8]1[C:9]([NH:11][CH3:12])=[N:10][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:6][CH:7]=1
Reactant: CNc1nc(OC(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1nc(OC(C)C)ccc1N
Yield: 97.9 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 2.38 g of 6-isopropoxy-2-methylamino-3-nitropyridine (prepared as described in Preparation 100) were hydrogenated in 50 ml of methanol in the presence of 0.50 g of 10% w/w palladium-on-charcoal. After working up the product as described in Example 6, 2.00 g of the title compound having Rf=0.62 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent) were obtained.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[C:25]2[NH:32]N>>[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[C:25]2[N:32]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1ccnc2ccc(F)cc12
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccnc2ccc(F)cc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and (6-fluoro-quinolin-4-yl)-hydrazine according to the method described for example 1. MS: M=384.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]([NH:20][OH:21])=[NH:19])[N:9]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=O)=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([C:18]3[N:19]=[C:27]([C:26]4[CH:30]=[CH:31][C:23]([NH2:22])=[N:24][CH:25]=4)[O:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: N=C(NO)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Product: Nc1ccc(-c2nc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)no2)cn1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-N-hydroxy-6-trifluoromethyl-pyrimidine-2-carboxamidine (example C.1) (0.16 g, 0.5 mmol) and commercially available 6-amino-nicotinic acid (0.07 g, 0.5 mmol according to the general procedure VI. Obtained as an off-white solid (0.059 g, 28%). MS (ISP) 418.9 [(M+H)+]; mp 191° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([O:19]C)[CH:11]=2)=[O:8])=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl.[Cl-].[Na+].O>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([OH:19])[CH:11]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: COc1cc(NC(=O)c2ccc(-c3ccccc3)cc2)ccc1C(=O)O
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(C(=O)O)c(O)c1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A solution of 4-[(biphenyl-4-carbonyl)amino]-2-methoxy benzoic acid (2.78 g; 8 mmol) in CHCl3 (175 mL) was cooled until it became cloudy (approx. 40° C.) and BBr3 (1.5 mL; 16 mmol) was added over 2 minutes. The mixture was allowed to warm slightly with stirring for 2 hours after which time another 1.5 mL BBr3 (16 mmol) was added and the reaction mixture was left to warm to room temperature overnight. The resulting slurry was added brine (50 mL) and the organic solvent was removed in vacuo. The resulting solid was Isolated by filtration, washed with H2O, air dried, refluxed in 99% EtOH (100 mL), cooled and filtered to yield 2.2 g (82%) of a white solid. Mp. 266° C. (decomposes).
Reaction SMILES: C[O:2][C:3]1[CH:23]=[CH:22][C:6]2[C:7]([CH:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[C:11]#[N:12])=[N:8][O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:23]=[CH:22][C:6]2[C:7]([CH:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:11]#[N:12])=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(CC(C#N)c2noc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#CC(Cc1ccc(O)cc1)c1noc2cc(O)ccc12
Yield: 61.9 %

Procedure:
To a solution of 2-(6-methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxyphenyl)propanenitrile (1.5 g, 4.9 mmoles) in CH2Cl2 (100 ml) under N2, was added BBr3 1M in CH2Cl2 (4 eq, 20 ml). The mixture was refluxed for 2 h, poured into water and extracted with EtOAc, dried over Na2SO4, filtered and concentrated under vacuum to give the crude product. Purification by flash chromatography (CH2Cl2/MeOH 98/2) and crystallisation from EtOH yielded the expected crystals (850 mg, 62%). mp 214° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])=[O:5].[Br:14][CH2:15][CH2:16]Br>CCCCCC.CN(C=O)C>[Br:14][CH2:15][CH2:16][C:7]([CH3:13])([S:4]([CH3:3])(=[O:5])=[O:6])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.33 g, 58.3 mmol) was washed with hexane (2×10 mL) in a 100 mL two neck round bottom flask under nitrogen then suspended in DMF (30 mL). The suspension was treated dropwise with ethyl 2-(methylsulfonyl)propanoate (10.0 g, 55.49 mmol) in DMF (10 mL). The mixture was stirred 30 min at RT, cooled to 0° C., and treated dropwise with 1,2-dibromoethane (5.17 mL, 58.8). The mixture was allowed to warm to room temperature while stirring overnight. The mixture was quenched with saturated ammonium chloride (100 mL) and the mixture was extracted with diethyl ether (4×50 mL). Combined organics were washed with 50% saturated sodium chloride (4×50 mL), dried (MgSO4), filtered and the filtrate concentrated in vacuo. Crude material was chromatographed over silica gel (350 g, 230-400 mesh) eluting with 10-20% EtOAc/hexane to afford the title compound as a pale yellow oil (7.9 g, 50%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.05 Hz, 3 H) 1.64 (s, 3 H) 2.49-2.59 (m, 1 H) 2.78 (ddd, J=13.89, 10.16, 6.64 Hz, 1 H) 3.05 (s, 3 H) 3.33-3.41 (m, 1 H) 3.46-3.54 (m, 1 H) 4.22-4.37 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:13][C@H:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH3:15]>>[Cl:1][C:2]1[C:3]([C:4]([NH:13][C@H:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH3:15])=[O:6])=[CH:7][C:8]([F:11])=[CH:9][N:10]=1
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 45 from 2-chloro-5-fluoronicotinic acid and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.9 Hz), 8.05 (2H, d, J=8.4 Hz), 7.92 (1H, dd, J=7.8, 2.9 Hz), 7.47 (2H, d, J=8.4 Hz), 6.91 (1H, m), 5.36 (1H, m), 3.92 (3H, s), 1.64 (3H, d, J=6.9 Hz).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:25]=[C:24]2[C:14]([C:15]([OH:32])=[C:16]([C:27](OCC)=[O:28])[C:17](=[O:26])[C:18]32[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=1.Cl.[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>O1CCOCC1.CCOCC>[Cl:10][C:11]1[CH:25]=[C:24]2[C:14]([C:15]([OH:32])=[C:16]([C:27]([NH:41][CH2:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:42])=[O:28])[C:17](=[O:26])[C:18]32[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(Cl)cc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Cl)cc2C2(CCOCC2)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
DIPEA (1.47 mL, 8.42 mmol, 1.5 eq) was added to a mixture of ethyl 7-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (1.89 g, 5.61 mmol, 1.0 eq) and glycine tert-butyl ester hydrochloride (1.13 g, 6.73 mmol, 1.2 eq) in dioxane (50 mL). The reaction mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude solid was suspended in ether and filtered to give the desired ester as a white solid (2.23 g). MS (m/e)=422.2 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>O1CCCC1>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccoc1
Reactant: BrCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: BrCCCCc1ccco1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of furan (23.8 g, 0.35 mol) in dry tetrahydrofuran (150 ml) was cooled to -15° C., after which a solution of n-butyllithium in hexane (150 ml, 2.2 M, 0.33 mol) was added dropwise under nitrogen. The whole was stirred for a further 21/2 hours at 0° C. The solution thus obtained was subsequently added under nitrogen blanket during a period of about 1 hour to a solution of 1,4-dibromobutane (150 g, 0.7 mol) in dry tetrahydrofuran (225 ml), cooled to -25° C.
Reaction SMILES: CC(C1C=CC=CC=1)CN.C(Cl)(=O)C1C=CC=CC=1.CC1C2C(=CC=CC=2)CNC1.[CH3:31][CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:34][CH2:33]1.C1C2C(=CC=CC=2)C=CN=1.[OH-].[Na+].[Cl:60][CH:61]([Cl:65])[C:62](Cl)=[O:63]>O.C(Cl)Cl>[Cl:60][CH:61]([Cl:65])[C:62]([N:34]1[CH2:33][CH:32]([CH3:31])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:63]
Reactant: CC1CNC(c2ccccc2)c2ccccc21
Reactant: O=C(Cl)C(Cl)Cl
Agent: CC(CN)c1ccccc1
Agent: CC1CNCc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: c1ccc2cnccc2c1
Solvent: ClCCl
Product: CC1CN(C(=O)C(Cl)Cl)C(c2ccccc2)c2ccccc21

Procedure:
By procedures described in Example 1 (Method A), β-methyl-phenethylamine and benzoyl chloride were converted to 4-methyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged 4-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 3.0 g of this isoquinoline compound, 5 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 2 ml dichloroacetyl chloride was added dropwise to the mixture. The mixture was stirred for 5 minutes, then water was added. The organic extract was dried with magnesium sulfate, stripped of solvent and subjected to Kugelrohr distillation (160° C. @ 0.1 mm Hg) to provide 4 g of a yellow oil product having the elemental analysis reported in Table I.