Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]([CH3:25])=[CH:16][CH:17]=[CH:18][C:19]([CH3:24])=[CH:20][C:21]([OH:23])=[O:22])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:15]([CH3:25])[CH2:16]/[CH:17]=[CH:18]/[C:19](/[CH3:24])=[CH:20]/[C:21]([OH:23])=[O:22])[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C=CC=C(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1)=CC(=O)O
Solvent: CO
Product: CC(/C=C/CC(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1)=C\C(=O)O

Procedure:
Compound 14 was prepared from 13 in a similar manner as described for compound 9: TLC (10% MeOH-90% CHCl3) Rf 0.5; mp 127-128° C.; 1H-NMR (CDCl3)δ 1.28 (d, J=8 Hz, 3H, CH3), 1.32 (s, 18H, 6(CH3)), 2.23, (s, 3H, CH3), 2.46 (m, 2H, CH2), 2.86 (m, 1H, CH), 5.69 (s, 1H, =CH), 6.10 (m, 2H, =CH), 7.01 (d, J=1 Hz, 2H, Ar--H), 7.26 (t, J=1 Hz, 1H, Ar--H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH2:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH2:22][NH2:23])[CH3:16].[ClH:24]>CO>[ClH:24].[ClH:24].[CH2:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH2:22][NH:23][C:12]([C:5]1[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:14])[CH3:16]
Reactant: Nc1ccc(C(=O)O)c2c1OCCO2
Reactant: CCN1CCCC1CN
Agent: Cl
Solvent: CO
Product: CCN1CCCC1CNC(=O)c1ccc(N)c2c1OCCO2
Yield: 72.7 %

Procedure:
According to the method described in Example 2, 42 g of 8-amino-1,4-benzodioxane-5-carboxylic acid were treated with methanol and the resulting compound treated with 33 g of 1-ethyl-2-aminomethylpyrrolidine and then with a solution of 13 g of hydrochloric acid in absolute alcohol. 49 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-amino-1,4-benzodioxane-5-carboxamide dihydrochloride were obtained (M.P.: 173° C.; yield: 60%).
Reaction SMILES: Cl[C:2](OC1C=CC=CC=1)=[O:3].[NH2:11][C:12]1[C:13]([OH:29])=[C:14]([C:26](=[O:28])[CH3:27])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[C:26]([C:14]1[C:13]2[O:29][C:2](=[O:3])[NH:11][C:12]=2[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1O
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)oc12
Temperature: 92.5 °C
Reaction time: 4 h

Procedure:
41 mL phenyl chloroformate are added dropwise to a solution of 47 g (183 mmol) 1-(3-amino-4-benzyloxy-2-hydroxy-phenyl)-ethanone (known from U.S. Pat. No. 4,460,581) in 135 mL pyridine, whereupon the temperature rises to 75° C. The mixture is stirred for 4 hours at 90-95° C., poured onto ice and acidified with hydrochloric acid. The precipitated solid is suction filtered, washed with diethyl ether and heated in 500 mL 95% acetonitrile for 30 minutes at reflux temperature. After cooling the solid is filtered off and washed with acetonitrile and diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([C:28]#[N:29])=[C:25]([F:27])[CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(N(C(C)C)CC)(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>CO.Cl[Ni]Cl>[F:27][C:25]1[CH:26]=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C@H:11]3[O:10][C:9]([CH3:31])([CH3:30])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:12]3[CH2:13][F:14])=[CH:20][CH:19]=2)[CH:22]=[N:23][C:24]=1[CH2:28][NH:29][S:44]([CH3:43])(=[O:46])=[O:45]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cnc(C#N)c(F)c3)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cnc(CNS(C)(=O)=O)c(F)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4S,5R)-tert-butyl-5-(4-(6-cyano-5-fluoropyridin-3-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (1440 mg, 3.4 mmol) in methanol (25 mL) at 5° C. is treated with NiCl2 (80 mg, 0.34 mmol) and then sodium borohydride (380 mg, 10 mmol) is added in portions. The mixture is stirred for 1 hour at room temperature, concentrated to remove the methanol, quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organics are dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil is dissolved in dichloromethane (5 mL), cooled to 5° C. and treated with diisopropylethylamine (0.88 mL, 5.0 mmol) and methanesulfonyl chloride (0.30 mL, 3.7 mmol) and stirred for 2 hours at room temperature. The mixture is concentrated and chromatographed on silica eluting with ethyl acetate in heptane to give the title compound. 1H NMR (400 MHz, CDCl3) 1.53 (s, 9H), 1.63 (s, 3H), 1.75 (s, 3H), 3.80-4.00 (m, 1H), 4.40-4.50 (m, 0.5H), 4.55-4.65 (m, 2.5H), 5.22 (d, 1H, J=7.33 Hz), 5.72 (bs, 1H), 7.60-7.70 (m, 5H), 8.63 (s, 1H). m/z (CI) M+H 512.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:9](O)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][S:3]1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:9]1[C:10]2[CH:2]([CH3:1])[S:3][CH2:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1SCc2ncnc(O)c21
Product: CC1SCc2ncnc(Cl)c21
Reaction time: 1 h
Yield: 54 %

Procedure:
5-Methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-ol (10 g, 59.54 mmol) in POCl3 (100 mL) was heated to reflux for 15 minutes. After cooling, excess POCl3 was removed under vacuum. The residue was dissolved in CH2Cl2 (100 mL) and saturated NaHCO3 (400 mL) was added at 0° C. The reaction mixture was stirred for 1 hour. The aqueous phase was extracted with DCM (3×250 mL). The organic phase was combined, dried and concentrated. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (4:1) to give 4-chloro-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidine (6 g, 54%). 1H NMR (CDCl3, 400 MHz) δ 8.80 (s, 1H), 4.68 (m, 1H), 4.44 (m, 1H), 4.13 (d, J=16.8 Hz, 2H), 1.68 (d, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][C:14]=1[NH:22][CH2:23][CH:24]([CH3:26])[CH3:25]>C1COCC1>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:9](=[O:11])[CH2:8][NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:14]([NH:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH:15]=1)[CH3:21]
Reactant: O=C(O)CNc1ccccc1
Reactant: CCOc1ccc(N)c(NCC(C)C)c1
Solvent: C1CCOC1
Product: CCOc1ccc(NC(=O)CNc2ccccc2)c(NCC(C)C)c1
Temperature: 70 °C
Yield: 87.9 %

Procedure:
A solution of N-phenylglycine (1.51 g, 0.01 mol) and N,N′-carbonyldiimidazole (1.62 g, 0.01 mol) in THF (25 mL) was heated at 50° C. for 30 min under Ar. A solution of 55 (2.08 g, 0.01 mol) in THF (50 mL) was then added over 30 min, and the resulting mixture was heated at 70° C. overnight. The reaction mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCO3 (2×100 mL) and brine (100 mL). The organic phase was filtered through phase separation filter paper and concentrated in vacuo to give 3.0 g of a red oil which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](CO)C2)c(Br)c1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (R)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 75.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.81 min, m/z=473.1-474.1 [M+H]+, m/z=472.2-471.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.52-1.61 (m, 1H) 1.78-1.87 (m, 1H) 2.17-2.26 (m, 1H) 2.53 (s, 3H) 2.99 (dd, J=11.00, 6.85 Hz, 1H) 3.11-3.20 (m, 2H) 3.21-3.29 (m, 2H) 3.33-3.37 (m, 1H) 4.60 (t, J=5.14 Hz, 1H) 7.34 (dd, J=8.44, 3.06 Hz, 2H) 7.69 (dd, J=7.82, 2.20 Hz, 1H) 7.85 (d, J=9.05 Hz, 2H) 7.98 (d, J=2.20 Hz, 1H) 8.49 (d, J=1.96 Hz, 1H) 8.74 (d, J=2.20 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH2:11][C:10]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][OH:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH2:1]([O:8][C@H:9]1[CH2:12][CH2:11][C@H:10]1[NH:14][CH2:15][CH2:16][OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC1OCc1ccccc1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: OCCN[C@@H]1CC[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(benzyloxy)cyclobutanone (prepared according to the method of P. Bisel et al., Eur. J. Org. Chem. 1998, 4, 729-733; 2.35 g, 13.3 mmol) and 2-aminoethanol (1.63 g, 26.7 mmol) in dichloromethane (47 mL) was treated with acetic acid (0.76 mL, 13.3 mmol) and sodium triacetoxyborohydride (5.95 g, 26.7 mmol) and stirred at room temperature for 16 hours. Aqueous sodium hydroxide solution (1 N, 100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The combined organic layers were washed with aqueous sodium hydroxide solution (1 N, 100 mL), dried over magnesium sulfate and concentrated in vacuo to afford the product as a colorless oil. Yield: 2.9 g, 13 mmol, 98%. 1H NMR (400 MHz, CDCl3) δ 7.28-7.39 (m, 5H), 4.51 (AB quartet, JAB=11.7 Hz, ΔνAB=61.1 Hz, 2H), 4.13-4.18 (m, 1H), 3.54-3.58 (m, 2H), 3.32-3.39 (m, 1H), 2.72-2.78 (m, 2H), 2.5 (ν br s, 2H), 2.05-2.14 (m, 1H), 1.83-1.98 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-bromobenzoate (4.06 g, 16.6 mmol) in DCE (60 ml) under a nitrogen atmosphere was added oxan-4-one (3.07 ml, 33.3 mmol) followed by acetic acid (5.71 ml, 99.8 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (10.6 g, 49.9 mmol). The reaction was stirred for 3 h at room temperature whereupon distilled water (50 ml) was added and the solution was neutralised with solid NaHCO3. The phases were separated and then the aqueous phase was washed with EtOAc (2×100 ml), the combined organics were then dried using Na2SO4, filtered and evaporated. The residue was purified by FCC using silica and eluting with a 10% to 40% EtOAc in heptane gradient to afford the title compound as an off-white solid (3.88 g, 71%). LC-MS 100%, 2.10 min (3.5 minute LC-MS method), m/z=327.9/329.8, 1H NMR (500 MHz, Chloroform-d) δ 7.23 (d, J=1.9 Hz, 1H), 6.84 (d, J=1.7 Hz, 1H), 4.02 (dt, J=11.7, 3.5 Hz, 2H), 3.87 (s, 3H), 3.65 (d, J=7.2 Hz, 1H), 3.59-3.45 (m, 3H), 2.23 (s, 3H), 2.05 (d, J=13.8 Hz, 2H), 1.51 (ddd, J=24.1, 10.8, 4.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23][CH3:24])=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:25].[CH3:26][C:27]1[CH:39]=[CH:38][C:30]2[N:31]=[C:32](S(C)(=O)=O)[O:33][C:29]=2[CH:28]=1>ClC(Cl)C>[F:25][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23][CH3:24])=[O:22])=[O:15])=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:32]1[O:33][C:29]2[CH:28]=[C:27]([CH3:26])[CH:39]=[CH:38][C:30]=2[N:31]=1
Reactant: Cc1ccc2nc(S(C)(=O)=O)oc2c1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)c(F)c2)cc1
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(C)cc4o3)c(F)c2)cc1
Temperature: 85 °C
Yield: 42.7 %

Procedure:
To a solution of methyl (1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]-cyclopentanecarboxylate (800 mg, 2.34 mmol, 78% ee) in dichloroethane (15 mL), 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (891 mg, 4.22 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was purified by using a Biotage QuadUV flash chromatography system (eluant: 80:20 hexane/EtOAc) to give methyl (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylate (472 mg). This ester intermediate was redissolved in 1:1 dioxane/THF 20 mL), a solution of 1 N aqueous NaOH (7.02 mL, 7.02 mol) was added, and the mixture was heated at 50° C. overnight. The solvent was removed by rotary evaporation, and water (20 mL) and EtOAc (40 mL) were added to the residue. The aqueous layer was separated, acidified to pH 5 by the addition of 1 N aqueous HCl, and then extracted with EtOAc (2×60 mL). The combined organic phases were washed with saturated NaCl and dried (Na2SO4). The solvent was removed by rotary evaporation and the residue was redissolved in DMF (10 mL) and methanol (20 mL). The crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid as an off-white solid (161 mg, 15% yield, 80% ee). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (m, 1 H), 8.00–7.60 (m, 6 H), 7.30 (d, 2 H), 7.00 (d, 2 H), 4.05 (m, 1 H), 3.20 (m, 1 H), 2.40 (s, 3 H), 2.20 (m, 1 H), 1.95 (m, 1 H), 1.80–1.60 (m, 4 H); LC-MS ret. time 3.57 min, m/z 459.3 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][SH:5].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](S(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([S:5][CH2:4][C:3]([O:7][CH3:8])=[O:6])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)CS
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CSC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To sodium hydride (60% wt. suspension in mineral oil, 108 mg) in dry DMF (5 ml) was added methyl thioglycolate (160 ul) dropwise at 0° C. After 30 minutes added 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl ester (500 mg) as a solution in DMF (1.5 ml) and the reaction mixture was warmed up to room temperature over 5 hours. Aqueous work-up and purification on silica yielded 4-methoxycarbonylmethylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (414 mg).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][CH:9]=[C:8](O)[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)([Br:15])=O.CN(C=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:15][C:8]1[CH:7]=[C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=[N:10][CH:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1cnnc(N2CCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Brc1cnnc(N2CCCC2)c1
Temperature: 110 °C
Yield: 82.7 %

Procedure:
6-(1-pyrrolidinyl)-4-pyridazinol (D47) (35 mg, 0.212 mmol) was suspended in toluene (2 mL), followed by addition of phosphorus oxybromide (121 mg, 0.424 mmol). The reaction mixture was heated to 110° C. for 2 hours. The reaction was cooled to RT followed by addition of DMF (2.0 mL). The reaction was then heated at 110° C. again for 2 hours. Reaction mixture was allowed to cool to RT, and then poured onto crush ice portionwise with stirring. The mixture was neutralized with 5M NaOH and then extracted with ethyl acetate (3×20 mL). The combined organics were dried and concentrated down to give the title compound (40 mg) which was taken on to the next step without purification. LCMS (A): m/z (M+H)+ 228/230, C8H10BrN3 requires 227/229 (acidic).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1C(O)=O.[OH:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][C:13]=1[C:21]([NH2:23])=[O:22]>>[NH:3]1[CH2:2][CH2:7][CH:6]([O:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH2:23])=[O:22])[CH2:5][CH2:4]1
Reactant: O=C(O)N1CCCCC1Cl
Reactant: NC(=O)c1oc2ccccc2c1O
Product: NC(=O)c1oc2ccccc2c1OC1CCNCC1

Procedure:
Referring to Scheme 3, methoxybenzofuran ester 1, for example, is converted to the corresponding hydroxybenzofuran carboxylic acid 2 with boron tribromide. Carboxylic acid 2 is coupled with Hca amine to yield hydroxybenzofuranamide 3. 1-Substituted 4-hydroxypiperidine 4 is coupled with amide 3 to yield (piperidin-4-yloxy)benzofuranamide 5.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][CH2:8][CH2:9][NH2:10].CS[C:13](=N)[NH:14][N+:15]([O-:17])=[O:16].C(O)C>C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH2:8][CH2:9][NH:10][C:13]1=[N:14][N+:15]([O-:17])=[O:16]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCNCC1CCCO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])N=C1NCCN1CC1CCCO1

Procedure:
Afterward, a mixture of 1.00 g Of N-[(tetrahydro-2-furanyl) methyl]ethylenediamine, 0.77/g of S-methyl-N-nitroisothiourea, 0.1 g of N,N-dimethylaminopyridine (DMAP) and 10 ml of ethanol was refluxed. After the completion of reaction, ethyl acetate was added, and insolubles were then removed by filtration. The filtrate was concentrated under a reduced pressure, and the precipitated crystals were then removed by filtration. Next, the filtrate was concentrated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (1:2 acetone/ethyl acetate) to obtain 0.25 g of 1-[(tetrahydro-2-furanyl) methyl]-2(nitroimino)imidazolidine as a pale yellow oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([C:19]([OH:22])([CH3:21])C)([CH3:18])[CH2:13]1.[CH2:23](OC(C1(CC)CCCN(CC2OC3C=CC=CC=3OC2)C1)=O)C.C[Mg]Br>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([C:19](=[O:22])[CH3:21])([CH2:18][CH3:23])[CH2:13]1
Reactant: CCOC(=O)C1(CC)CCCN(CC2COc3ccccc3O2)C1
Reactant: CC(C)(O)C1(C)CCCN(CC2COc3ccccc3O2)C1
Agent: C[Mg]Br
Product: CCC1(C(C)=O)CCCN(CC2COc3ccccc3O2)C1

Procedure:
The procedure described for 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]propan-2-ol was repeated except that 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine-3-carboxylic acid ethyl ester was used as starting material and only one instead of three equivalents of methyl magnesium bromide was used.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:2]1=[O:15].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])[CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:25]1([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:12]3[CH2:11][CH2:10][C:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:1][C:2]4=[O:15])[CH2:14][CH2:13]3)[CH:18]=2)=[O:24])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1
Reactant: O=C1Nc2ncccc2C12CCNCC2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC3(CC2)C(=O)Nc2ncccc23)ncn1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
43 mg (0.21 mmol) spiro[piperidine-4,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one were added to 50 mg (0.19 mmol) (6-chloro-pyrimidin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 52 μL (0.58 mmol) DIPEA in 5 mL DMF. The reaction mixture was stirred for 2 h at RT. The reaction mixture was evaporated down using the rotary evaporator and the residue was mixed with 20 mL water and stirred for 30 min at RT. The product precipitated was suction filtered, stirred with diisopropylether and isopropanol, suction filtered and dried.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([N:1]2[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]2)=[N:15][CH:14]=1)#[N:17]
Reactant: O=C(O)c1c[nH]cn1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2cnc(C(=O)O)c2)nc1
Temperature: 120 °C

Procedure:
A mixture of 1H-imidazole-4-carboxylic acid (500 mg), 6-chloropyridine-3-carbonitrile (0.93 g), and N,N-diisopropyl-ethyl-amine (3.6 mL) in N,N-dimethylformamide (6 mL) is heated to 120° C. overnight. The crude product is purified by HPLC. LC (method 20): tR=1.73 min; Mass spectrum (APCI): m/z=215 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH:4]([OH:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:3].CCOCC.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:12][C:2]([CH3:3])([C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:1]
Reactant: CCCCCCC(O)C(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCC(=O)C(C)(C)C
Yield: 67 %

Procedure:
2,2-dimethyl-nonan-3-ol, available as a concentrated solution in ether (ca. 0.23 moles, cf. previous procedure), was dissolved in ca. 350 mL CH2Cl2 in a 500 mL round bottom flask. With vigorous stirring and external cooling, pyridinium chlorochromate (PCC, 76.6 g, 0.355 mol) was added slowly. The reaction mixture turned black and began to warm. The reaction was stirred overnight at mom temperature, and the supernatant was decanted from a black sludge which had formed. The sludge was extracted with ca. 40 mL of hexane, which was combined with the CH2Cl2 solution. This mixture was applied directly to a 100 g silica gel column, and eluted first with CH2Cl2/hexane and then with 10% ethyl acetate in hexane to yield 35.8 g crude, green-colored product. This material was rechromatographed; elution with hexane and careful evaporation at 25° C. on a rotary evaporator yielded 26.1 g 2,2-dimethyl-nonan-3-one (67% yield). 1H NMR (500 MHz, CDCl3), δ (ppm): 2.47 (t, 2H), 1.28 (br, 8H), 0.89 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH2:10][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][CH:3]=1
Reactant: CC1=CCC(C(C)CC=O)CC1
Reactant: C1CCNCC1
Product: CC1=CCC(C(C)CCN2CCCCC2)CC1

Procedure:
The procedure of Example 1 was followed using 50g (0.3 mole) of 3-(4-methyl-3-cyclohexenyl)butyraldehyde and 28g (0.33 mole) of piperdine. Obtained following distillation was 31g of a mixture of N-[3 . . . butyl] piperdine and N-[3-(4-methylcyclohexyl)butyl]piperdine; bp 89- 91° (0.1mm); ir (τ max. film) 3.5 (s), 3.7 (s), 6.9 (s), 7.3 (s), 8.7 (s), 9.0 (s), 9.7 (s), 11.6 (m), 12.6 (w) microns; nmr (δ, CDCl3) 5.37 (m, 1H), 2.95 to 2.55 (m, 6H), 2.0 to 0.8 (m, 22H) ppm; ms (molecular ion) 236 and 238. ##STR2##