Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH2:21]([N:28]1[CH2:33][C:32](=O)[O:31][C:30](=[O:35])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH2:21]([N:28]1[CH2:33][C:32](=[O:31])[N:1]([C:2]2[CH:3]=[C:4]([CH2:5][C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:16])[NH:8][N:7]=3)[CH:17]=[CH:18][C:19]=2[F:20])[C:30](=[O:35])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C1CN(Cc2ccccc2)CC(=O)O1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(Cc2ccccc2)CC(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (2.51 g, 9.3 mmol; prepared in a manner similar to that described in Example 23), 4-benzylmorpholin-2,6-dione (2.3 g, 11.2 mmol) and toluene (15 ml) was heated under reflux for 20 hours, then the solvent was removed in vacuo. The residue was dissolved in dimethylacetamide (15 ml) and O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (3 g, 9.3 mmol) and diisopropylethylamine (1.63 ml, 9.3 mmol) were added sequentially. The mixture was stirred at ambient temperature for 2 hours, then it was added dropwise to stirred, ice-cold water (300 ml). The resulting solid was collected by filtration and dried in vacuo to give 4-benzyl-1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]piperazine-2,6-dione (4.01 g) as an off-white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 3.6 (s, 4H) (2×ring CH2) 3.75 (s, 2H) (NCH2Ph), 4.35 (s, 2H) (ArCH2—), 7.17–7.5 (m, 8H) (8×ArH), 7.75–8.0 (m, 3H) (3×ArH), 8.25 (d, 1H) (ArH), 12.6 (s, 1H) (CONH); m/z (M+H)+ 457, 100% purity.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].Cl.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35]>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[C:30](=[O:35])[CH2:31]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CN1CCNCC1=O
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.45 mmol) and 1-methylpiperazine-2-one hydrochloride (65 mg, 0.435 mmol) were suspended in NMP (0.483 mL). The RM was stirred at 180° C. for 5 h. The mixture was filtered and the obtained filtrate was purified by reverse phase chromatography (water+0.1% TFA/acetonitrile+0.1% TFA). The collected fractions were concentrated and the residue was dissolved in MeOH, passed through an SPE cartridge of PL-HCO3 MP. The filtrate was concentrated to afford the title compound as a brownish oil (tR 3.19 min (conditions 1), MH+=423).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH:27]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1ccnc(-n2ccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2ccnc(-n3ccnc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K48) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (32 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20]/[C:19](=[N:23]/[OH:24])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1>C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20]/[C:19](=[N:23]\[OH:24])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N\O

Procedure:
Among the reaction product from Example 1, those fractions from the fractionation by silica gel column chromatography (ethyl acetate/hexane) that are low polarity elution fractions (demonstrating high Rf value on TLC) were collected, and the title compound (29 mg) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:30]=[CH:29][C:7]2[N:8]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[CH:9]([CH2:12][C:13](O)=[O:14])[CH2:10][O:11][C:6]=2[CH:5]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[F:3][C:4]1[CH:30]=[CH:29][C:7]2[N:8]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[CH:9]([CH2:12][C:13]([NH:2][CH3:1])=[O:14])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: CN
Reactant: O=C(O)CC1COc2cc(F)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CNC(=O)CC1COc2cc(F)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Yield: 47.6 %

Procedure:
Methanamine (2 M solution in THF, 259 μL, 0.52 mmol) was added to a stirred suspension of {7-fluoro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetic acid (Intermediate 15, 40 mg, 0.10 mmol) and TEA (43 μL, 0.31 mmol) in EtOAc (2 mL) at rt. A thick white precipitate was formed. Addition of T3P (50 wt. % in EtOAc, 123 μL, 0.21 mmol) to the mixture resulted in a clear, pale yellow reaction solution. The mixture was stirred at rt over night. EtOAc (10 mL) was added and the mixture was washed with sat. aq. NaHCO3 (5 mL), HCl (1 M, 5 mL) and brine (5 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (using 5% MeOH in DCM as eluent), dissolved in ACN/water (approx. 5 mL, 1:4) and freeze-dried to give the title compound (19 mg, 46%) as a white solid.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[CH:6]1([C:9](=[O:15])[CH2:10][C:11](OC)=O)[CH2:8][CH2:7]1>C1(C)C=CC=CC=1>[CH:6]1([C:9](=[O:15])[CH2:10][C:11]2[O:5][N:4]=[C:1]([CH3:2])[N:3]=2)[CH2:8][CH2:7]1
Reactant: CC(N)=NO
Reactant: COC(=O)CC(=O)C1CC1
Solvent: Cc1ccccc1
Product: Cc1noc(CC(=O)C2CC2)n1
Temperature: 130 °C

Procedure:
Under an inert atmosphere, acetamidoxime (1.56 g) is added to a solution of methyl 3-cyclopropyl-3-oxopropanoate (3.0 g) in 50 ml of toluene; the stirred mixture is heated to 130° C. while distilling off the solvent and methanol formed in the reaction.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[N:28]=[N:27][C:26]=1[O:37]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[I-].[K+]>C(#N)C>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:25]1[C:26](=[O:37])[NH:27][N:28]=[C:29]([C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)[CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nnc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCN(C)CC3)ccc2c1Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(Cc2ccc3c(Cc4ccccc4)c(-c4cc(-c5ccncc5)n[nH]c4=O)[nH]c3c2)CC1
Yield: 31.9 %

Procedure:
100 mg crude 3-benzyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-6-(4-methyl-pi-perazin-1-ylmethyl)-1H-indole are dissolved in 2.4 mL acetonitrile. 75 □L TMSCl and 99 mg potassium iodide are added. The reaction mixture is heated to reflux for 3 hours. Then again 75 □L TMSCl and 99 mg potassium iodide are added and the reaction mixture is refluxed for additional 2 hours. Purification by HPLC affords 31 mg (32%) 4-[3-benzyl-6-(4-methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-6-pyridin-4-yl-2H-pyridazin-3-one as its trifluoroacetate salt.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15]C(OCC)=O)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1.CC[O-].[Na+].[Cl:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[CH2:39]/[C:40](=[N:43]/[H])/[NH:41][OH:42]>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[O:42][N:41]=[C:40]([CH2:39][C:33]4[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=4[Cl:31])[N:43]=3)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: CCCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: [H]/N=C(/Cc1ccc(F)cc1Cl)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccc(F)cc3Cl)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C
Yield: 67.2 %

Procedure:
Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was treated with a 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and (1Z)-2-(2-chloro-4-fluorophenyl)-N-hydroxyethanimidamide (42 mg, 0.21 mmol). The reaction was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between EtOH and 2M HCl (aq). The organic layer was decanted off and concentrated. The crude product was purified on the MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (65 mg, 67%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([CH3:35])[NH:29]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:25]1[C:33]([O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([CH3:35])[NH:29]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCC1CCN(C)CC1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCC1CCN(C)CC1
Temperature: 95 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (1.22 g, 3.65 mmol), (prepared as described for the starting material in Example 241), 4-fluoro-5-hydroxy-2-methylindole (723 mg, 4.38 mmol), (prepared as described for the starting material in Example 237), in DMF (20 ml) containing potassium carbonate (756 mg, 5.48 mmol) was stirred at 95° C. for 3 hours. After cooling, the mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1) followed by methylene chloride/methanol/methanol saturated with ammonia (90/5/5). The fractions containing the expected product were combined and evvaporated. The residue was triturated with ether, filtered, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride/ethyl acetate and the minimum of methanol, filtered and the volatiles were removed under vacuum. The solid was triturated with ether, filtered, washed with ether and dried under vacuum at 50° C. to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (1.06 g, 62%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]3[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=3[CH2:21][CH2:22][CH3:23])=[O:12])[CH:10]=1)[N:7]([CH3:26])[CH:6]=[C:5]2[CH:27]([CH3:29])[CH3:28].Cl.[CH3:31][N:32]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)[CH3:33]>>[CH3:31][N:32]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]4[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=4[CH2:21][CH2:22][CH3:23])=[O:12])[CH:10]=2)[N:7]([CH3:26])[CH:6]=[C:5]3[CH:27]([CH3:28])[CH3:29])=[CH:37][CH:36]=1)[CH3:33]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c(C(C)C)cn(C)c12
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(CN(C)C)cc2)cc2c(C(C)C)cn(C)c12
Yield: 47.7 %

Procedure:
The title compound was prepared in the same manner as described for Example 2 using 5-bromo-1-methyl-3-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indole-7-carboxamide (300 mg, 0.65 mmol) and 4-(N,N-dimethylaminomethyl)phenylboronic acid pinacol ester hydrochloride (250 mg, 0.84 mmol). Obtained 159 mg of the title compound (47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (s, 1H), 8.48 (t, J=4.80 Hz, 1H), 7.83 (d, J=1.77 Hz, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 7.33 (d, J=1.52 Hz, 1H), 7.10 (s, 1H), 5.90 (s, 1H), 4.38 (d, J=4.80 Hz, 2H), 3.70 (s, 3H), 3.34 (br. s., 2H), 3.22 (dt, J=6.82, 13.64 Hz, 1H), 2.52-2.59 (m, 2H), 2.25 (s, 6H), 2.13 (s, 3H), 1.52-1.63 (m, 2H), 1.31 (d, J=6.82 Hz, 6H), 0.94 (t, J=7.33 Hz, 3H). MS (ES) [M+H]+ 513.3.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:18][CH2:19][CH2:20][C:21]#[N:22]>CN(C)C=O>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N#CCCCBr
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
A mixture of sodium hydride (1.5 g) and 3-(1-piperidinylmethyl)phenol (11.2 g) in dimethylformamide (60 ml) was stirred at room temperature for 5 h. 4-Bromobutannitrile (9.0 g) was added, and stirring was continued for a further 24 h. The mixture was poured onto ice and extracted with ethyl acetate which was washed with water and brine, and distilled to give the title compound as a colourless oil (14.78 g) b.p. 200°, 0.08 mm; tlc system A Rf 0.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2].[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:6]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2]
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(CBr)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(Cn3cccn3)cc2)nc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 1-[6-(4-bromomethyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 g, 0.4 mmol) in 0.8 mL of dimethylformamide was added pyrazole (0.056 g, 0.82 mmol) and potassium carbonate (0.11 g, 0.82 mmol). After stirring for 24 hours at 50° C., the mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo, affording the crude product as a colorless syrup that was used directly in the next step. MS (APCl, m/z): 479.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Cl[CH:13]([CH3:17])[C:14]([OH:16])=[O:15]>CN(C)C=O.C([O-])(O)=O.[Na+]>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][C@H:13]([CH3:17])[C:14]([O:16][CH2:10][CH2:11][CH2:4][CH2:5][CH2:6][CH3:7])=[O:15])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(Cl)C(=O)O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOC(=O)[C@@H](C)Oc1ccc(C=O)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
Sodium hydride (0.4 mole) was suspended in dimethyl formamide (20 ml). 4-Hydroxybenzaldehyde (0.2 mole) in DMF (50 ml) was added. After the effervesence had subsided, 2-chloropropanoic acid (0.22 mole) was added dropwise. During the addition the reaction temperature rose to 70° C. The mixture was stirred overnight at 110° C. Upon cooling the mixture was diluted with saturated NaHCO3 solution and extracted with ethyl acetate (3×100 ml). The aqueous phase was then acidified with concentrated HCl solution and extracted with ethyl acetate. After washing the second organic extract with water and evaporation, a brown oil was obtained. Crystallisation from hot chloroform and hexane gave a brown solid (7.6 g). The mother liquors were evaporated to dryness to yield a brown solid (17.3 g) used without further purification. (Total yield 64%). 'H-NMR spectroscopy showed these products to be greater than 90% pure (m.p. 114°-8° C.).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1([F:29])[CH2:19][CH2:18][C:17]([CH2:27][NH2:28])([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[F:29][C:14]1([F:13])[CH2:15][CH2:16][C:17]([CH2:27][NH:28][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:2]=2[F:1])([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: COc1cccc(C(=O)O)c1F
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: COc1cccc(C(=O)NCC2(c3ccc(F)nc3)CCC(F)(F)CC2)c1F

Procedure:
From 2-fluoro-3-methoxybenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=397.2, tR (minutes, Method D)=0.69
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C@@H:9]2[C@@H:10]3[O:12][C@H:11]3[C@H:5]1[CH2:6][C@@H:7]([O:13]C([C@@H](C1C=CC=CC=1)CO)=O)[CH2:8]2.Cl>C(O)C.C(OCC)C>[CH3:3][N:4]1[CH:9]2[CH2:8][CH:7]([OH:13])[CH2:6][CH:5]1[CH:11]1[CH:10]2[O:12]1
Reactant: CN1[C@@H]2C[C@@H](OC(=O)[C@H](CO)c3ccccc3)C[C@H]1[C@@H]1O[C@H]12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CN1C2CC(O)CC1C1OC12
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
Sodium borohydride (39.0 g, 1.03 mol) was added portionwise to a stirred suspension of scopolamine (75 g, 171 mmol) in ethanol (743 mL), at 0° C. under a nitrogen atmosphere and the reaction mixture was stirred at ambient temperature for 24 h. The mixture was then acidified with 2M hydrochloric acid in diethyl ether (600 mL) and stirred for another 24 h at ambient temperature. The reaction mixture was filtered and the resulting solid was washed with diethyl ether. The dried solid was dissolved in the minimum amount of 10% aqueous potassium carbonate solution and extracted with trichloromethane (6×150 mL). The combined organic extracts were dried (magnesium sulfate), filtered and the solvent was removed under reduced pressure to give the title compound as crystals (13.2 g, 85.5 mmol, 50%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([N:21]([CH2:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([OH:38])=[O:37])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.NN.Cl>C(O)C>[NH2:3][CH2:12][CH:13]([N:21]([CH2:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([OH:38])=[O:37])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32])(=[O:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccccc1S(=O)(=O)N(Cc1ccccc1C(=O)O)C(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccccc1S(=O)(=O)N(Cc1ccccc1C(=O)O)C(CN)Cc1ccccc1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
The mixture of compound 2e (100 mg, 0.17 mmol) and hydrazine monohydrate 98% (85 mg, 1.7 mmol) in ethanol (5 mL) was heated to reflux for 2 hr. The reaction mixture was cooled down to rt and acidified to pH=3 with 1N aqueous HCl. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to give compound 2f as a white solid (30 mg, 39% yield).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH2:8][C:7]2[C:9]([CH3:16])=[C:10]([NH2:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.C(=O)([O-])[O-].[Na+].[Na+].[C:36](Cl)(=[O:38])[CH3:37]>O1CCCC1.O>[CH3:3][C:4]1([CH2:17][N:18]2[CH2:19][CH2:20][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)[CH2:8][C:7]2[C:9]([CH3:16])=[C:10]([NH:15][C:36](=[O:38])[CH3:37])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1
Reactant: CC(=O)Cl
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(c3ccccc3)CC1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CN1CCC(c3ccccc3)CC1)O2
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a suspension of 2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranamine dihydrochloride (1.3 g) in tetrahydrofuran (10 mL) was added a solution of sodium carbonate (0.95 g) in water (5 mL) with ice-cooling and the mixture was stirred for 5 minutes. Then, 0.26 mL of acetyl chloride was added dropwise and the mixture was stirred at room temperature for 15 minutes. This reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/diisopropyl ether to provide 1.1 g of the title compound. Yield 90%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[C:4]([F:13])[CH:3]=1.[BH4-].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:12])[CH2:9][OH:10])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)(C=O)c1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(CO)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution of 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionaldehyde (1.37 g, 5.58 mmol) in MeOH (18 ml) at 0° C. was added NaBH4 (0.21 g, 5.58 mmol). After being stirred for 2 hours at 0° C., the mixture was allowed to warm to room temperature. The reaction mixture was diluted with water (20 ml) and extracted with ether (3×75 ml). The combined organic layers were dried over MgSO4. The solvent was removed, and the residue was purified by flash column chromatography (15–35% EtOAc in Hexane) to give the product (1.10 g, 80.0% yield). 1H NMR (CDCl3) δ: 1.23 (s, 1 H) 1.35 (s, 3 H) 1.35 (s, 3 H) 3.75 (d, J=1.26 Hz, 2 H) 7.17 (d, J=2.27 Hz, 1 H) 7.20 (d, J=3.03 Hz, 1 H) 7.22 (m, 1 H).