Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2([OH:24])[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[CH3:23].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[S:35](Cl)(=[O:37])=[O:36].S(Cl)(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([S:35]([C:28]1[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=1[O:26][CH3:25])(=[O:37])=[O:36])[C:12](=[O:17])[C:11]2([OH:24])[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: Cc1ccsc1C1(O)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(=O)(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3sccc3C)c3cc(Cl)ccc32)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
Potassium tert-butoxide (1.21 g, 10.8 mmol) was added to an ice-cold solution of the intermediate from step A (3.00 g, 10.8 mmol) in DMF (30 ml), and the mixture was stirred at 0° C. for 30 min. After addition of 2,4-dimethoxy-benzenesulfonyl chloride (2.5 g, 10.8 mmol), the reaction mixture was left to stir at 0° C. for 1 hour. Further addition of 0.2 equivalent each of potassium tert-butoxide and sulfonyl chloride led to no further advance in the reaction according to thin-layer chromatography. The reaction mixture was stirred into dilute potassium carbonate solution, and the resulting precipitate was filtered off. The precipitate was taken up in ethyl acetate, and the extract was washed with saturated brine and dried over magnesium sulfate. Purification by chromatography (silica gel, gradient 30% to 50% ethyl acetate in heptane) and recrystallization from diethyl ether resulted in 0.96 g of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]4[O:29][C:28]5[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=5[O:26][CH2:25]4)=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.O[Li].O.CO.O>C(O)(=O)C>[O:29]1[C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[O:26][CH2:25][C@@H:24]1[C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:34])=[O:2])=[CH:9][CH:8]=3)[CH2:12][CH2:13]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(CC2CCN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)CC2)cc1
Agent: [Li]O
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CC2CCN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-{1-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperidin-4-ylmethyl}-benzoic acid methyl ester (prepared according to General Method C) (80 mg, 0.17 mmol), LiOH.H2O (15 mg, 0.36 mmol), MeOH (3 mL) and water (0.5 mL) is stirred at room temperature for 16 h. The reaction mixture is neutralized with acetic acid and concentrated. The residue is triturated with water to give the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[S:16](=[O:18])(=[O:17])[NH:15][C:14](=[O:19])[CH2:13]2)=[C:8]([Br:20])[CH:7]=1)(=[O:3])[CH3:2].[CH:21](N(CC)C(C)C)(C)C.[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34]CCl>C(#N)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[S:16](=[O:18])(=[O:17])[N:15]([O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30])[C:14](=[O:19])[CH:13]2[CH3:21])=[C:8]([Br:20])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)OCc1ccc(C2C(C)C(=O)N(OCC[Si](C)(C)C)S2(=O)=O)c(Br)c1
Temperature: 50 °C
Yield: 81.1 %

Procedure:
3-Bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)benzyl acetate (175 mg, 0.483 mmol) was dissolved in acetonitrile (1.0 mL) and N,N-diisopropylethylamine (126 μL, 0.725 mmol) was added followed by [β-(trimethylsilyl)ethoxy]methyl chloride (103 μL, 0.580 mmol), and the reaction was heated at 50° C. for 1 h. Reaction solution was cooled to room temperature and transferred to separatory funnel, partitioned between 0.1 N HCl solution and ethyl acetate, aqueous phase was washed with ethyl acetate. The combined organic phase was washed with saturated sodium chloride, dried over sodium sulfate and concentrated to give a yellow oil. This material was chromatographed (12 g column, 0–20% ethyl acetate/hexanes) to give the product as an oil (193 mg, 81%). 1H NMR (400 MHz, CDCl3): δ 7.70 (s, 1H), 7.37 (m, 2H), 5.53 (dd, J=8.0, 6.5 Hz, 1H), 5.06 (m, 4H), 3.65 (m, 2H), 3.49 (dd, J=17.4, 8.0 Hz, 1H), 3.23 (dd, J=17.4, 6.5 Hz, 1H), 2.13 (s, 3H), 0.95 (m, 2H), 0.0 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH:22]([C@:25]1([C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:40]=[N:41][CH:42]=C(C(F)(F)F)[CH:44]=3)[CH2:35][CH2:34]2)=[O:32])[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26]1)([CH3:24])[CH3:23].[CH3:49][O:50][CH:51]1[C:56](=O)[CH2:55][CH2:54][O:53][CH2:52]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:22]([C@:25]1([C:31]([N:33]2[CH2:34][CH2:35][N:36]([C:39]3[CH:40]=[N:41][CH:42]=[C:3]([C:2]([F:7])([F:6])[F:1])[CH:44]=3)[CH2:37][CH2:38]2)=[O:32])[CH2:29][CH2:28][C@@H:27]([NH:30][CH:56]2[CH2:55][CH2:54][O:53][CH2:52][CH:51]2[O:50][CH3:49])[CH2:26]1)([CH3:24])[CH3:23]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Reactant: O=C(O)C(F)(F)F
Reactant: COC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cncc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[5-(trifluoromethyl)pyridin-3-yl]piperazin-1-yl}carbonyl)cyclopentanamine tris(trifluoroacetate) (25 mg, 0.034 mmol), 3-methoxytetrahydro-4H-pyran-4-one (13 mg, 0.10 mmol) and triethylamine (0.024 mL, 0.17 mmol) in methylene chloride (5 mL) was added sodium triacetoxyborohydride (22 mg, 0.10 mmol). The mixture was stirred under N2 at room temperature overnight and diluted with EtOAc. The resulting solution was washed with saturated NaHCO3, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/MeOH/Et3N=9:1:0.5) to give 14 mg of desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give peak 1 (6.6 mg) and peak 2 (4.7 mg). LCMS calculated for C25H37F3N4O3: (M+1) 499; found 499.2 for both isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[CH3:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH2:22][CH2:21]1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]([CH3:19])[CH2:21][CH2:22]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: CN1CCNc2ccccc21
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Yield: 25.1 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (1 mL) was added 1-methyl-1,2,3,4-tetrahydro-quinoxaline (26.7 mg, 0.18 mmol, 1.2 equiv; [CAS RN 36438-97-8]), N-ethyldiisopropylamine (97 mg, 131 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (68 mg, 0.18 mmol, 1.2 equiv; [CAS RN 148893-10-1]). The reaction mixture was heated by microwave irradiation to 100° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 15.6 mg (25%) of the title compound. MS (ISP): 413.9 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[N:30]1[C:39]2[C:34](=[CH:35][C:36]([F:41])=[C:37](F)[CH:38]=2)[C:33](=[O:42])[N:32]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:31]1=[O:51]>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[N:30]1[C:39]2[C:34](=[CH:35][C:36]([F:41])=[C:37]([N:11]3[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]3)[CH:38]=2)[C:33](=[O:42])[N:32]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:31]1=[O:51]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2cc(F)c(F)cc2F)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2cc(F)c(F)cc2F)C1
Yield: 52.8 %

Procedure:
Using General Method 4, the reaction of 3-t-butoxycarbonylamino-pyrrolidine (0.231 g, 1.24 mmol), triethylamine (0.178 mL, 1.24 mmol), and 1-(2,4,5-trifluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example H-1, 0.18 g, 0.41 mmol) provided 0.13 g of the title compound as a solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:35][CH2:34][C:16]2([C:20](=[O:21])[N:19]([C:22]3[CH:33]=[CH:32][C:25]([C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:36]I>C1COCC1.Cl>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:35][CH2:34][C:16]2([C:20](=[O:21])[N:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([N:28]([CH:29]([CH3:31])[CH3:30])[CH3:36])=[O:27])=[CH:32][CH:33]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14]1)(=[O:12])=[O:11]
Reactant: CC(C)NC(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N(C)C(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To NaH (0.04 g, 55% suspension in oil, washed with pentane) was added at RT and under an argon atmosphere and at RT 4-[8-(2-chloro-benzenesulfonyl)-1-oxo-2,8-diaza-spiro[4.5]dec-2-yl]-N-isopropyl-benzamide (0.04 g), product of example 160), in THF (4 ml). The reaction mixture was stirred 1 hour at RT, then MeI (0.232 g) was added and stirring was continued overnight at RT until the conversion was complete. The reaction mixture was made acidic with 1M HCl (one drop) and stirred for one minute. The solvent was removed in vacuo, the residue adsorbed on silica gel and chromtographed over silica gel (eluent: AcoEt/CH2Cl2, gradient from 0 to 30%) to give the desired product as off-white solid. MS (ESI): 504.1 MH+).
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH:8]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)[CH:9]1[CH2:14][CH2:13][O:12][C:10]1=[O:11].[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C1C=CN=CC=1.O>[C:22]([O:7][CH:8]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH:16]1[CH:17]=[CH:18]2)[CH:9]1[CH2:14][CH2:13][O:12][C:10]1=[O:11])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1OCCC1C(O)C1CC2C=CC1C2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC(C1CCOC1=O)C1CC2C=CC1C2
Reaction time: 10 h
Yield: 98 %

Procedure:
To 127 g of pyridine were added 208 g of α-[hydroxy(5-norbornen-2-yl)methyl]-γ-butyrolactone (Monomer 1), 123 g of acetic anhydride and 6 g of 4-dimethylaminopyridine. Reaction was effected at 25° C. for 10 hours. Water, 30 g, was added to the reaction mixture to stop reaction, followed by hexane extraction. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. Purification by silica gel column chromatography yielded 245 g (yield 98%) of α-[acetoxy(5-norbornen-2-yl)methyl]-γ-butyrolactone.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:40][CH2:41][CH3:42])[C:34]=1[C:35]1[CH:36]=[N:37][O:38][CH:39]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[NH:44]1[C:48]([C:49]2[CH:50]=[C:51]3[C:61](=[CH:62][CH:63]=2)[O:60][C:54]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][C:52]3=[O:64])=[N:47][N:46]=[N:45]1>O.CN(C=O)C.CCN(CC)CC>[CH2:41]([O:40][C:33]1[CH:32]=[C:28]([C:29]([N:57]2[CH2:58][CH2:59][C:54]3([CH2:53][C:52](=[O:64])[C:51]4[C:61](=[CH:62][CH:63]=[C:49]([C:48]5[NH:47][N:46]=[N:45][N:44]=5)[CH:50]=4)[O:60]3)[CH2:55][CH2:56]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:36]=[N:37][O:38][CH:39]=1)[CH3:42]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnoc1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(OCC)c1-c1cnoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (104 μL), HOBT (57 mg) and WSC hydrochloride (71 mg) were added to a DMF (4 mL) solution of 3,5-diethoxy-4-isoxazol-4-yl-benzoic acid (86 mg) and 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (119 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, and washed with water and ether. The resulting solid was purified through high-performance preparative liquid chromatography (0.1% TFA, water/acetonitrile) to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 9.18 (1H, s), 8.96 (1H, s), 8.42 (1H, d, J=4.0 Hz), 8.21 (1H, dd, J=8.0, 4.0 Hz), 7.33 (1H, d, J=8.0 Hz), 6.74 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.64-3.20 (3H, m), 2.97 (2H, s), 2.10-1.75 (4H, m), 1.37 (6H, t, J=8.0 Hz). MS [M+H]+=545.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11](O)=[O:12])=[CH:8][C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)=[CH:16][CH:15]=3)=[N:6][C:5]=2[N:4]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[N:3]=1.[CH2:33]([N:40]1[CH2:45][C:44]([CH3:47])([CH3:46])[NH:43][CH2:42][C:41]1([CH3:49])[CH3:48])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([N:40]1[C:41]([CH3:49])([CH3:48])[CH2:42][N:43]([C:11]([C:9]2[CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)=[CH:16][CH:15]=3)[N:6]=[C:5]3[N:4]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)[N:3]=[C:2]([CH3:1])[C:10]=23)=[O:12])[C:44]([CH3:47])([CH3:46])[CH2:45]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)O)c12
Reactant: CC1(C)CN(Cc2ccccc2)C(C)(C)CN1
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)N3CC(C)(C)N(Cc4ccccc4)CC3(C)C)c12
Yield: 75.7 %

Procedure:
In a similar manner as in Exampe 40 step (b) 400 mg of 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid was reacted with 212 mg 1-benzyl-2,2,5,5-tetramethyl-piperazine to obtain 450 mg (76%) of the title compound.
Reaction SMILES: C(O)=O.[C:4]([O:7][C:8](=O)[CH3:9])(=[O:6])C.[C:11]([O:15][C:16](=[O:36])[NH:17][C@@H:18]([CH2:26][NH:27]OCC1C=CC=CC=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])(O)=O.[Na+]>ClCCl>[C:11]([O:15][C:16](=[O:36])[NH:17][C@@H:18]([CH2:26][NH:27][C:4]([O:7][CH2:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:26]=1)=[O:6])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CNOCc1ccccc1)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 176.5 %

Procedure:
To a cold mixture of formic acid (2.3 g, 73.0 mmol) and acetic anhydride (0.56 mL, 6.0 mmol) was added dropwise [(R)-1-(Benzyloxyaminomethyl)-2-phenyl-ethyl)-carbamic acid tert-butyl ester (0.20 g, 0.56 mmol) in dichloromethane (2.8 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours, and then treated with saturated aq. NaHCO3 (5 mL). The aqueous layer was extracted with dichloromethane (10 mL×2). The organic extracts were washed with water and brine, and dried over MgSO4. After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (2:1) yielded 0.19 g (86%) of the title compound 1H NMR (400 MHz, CDCl3): δ 8.14 (br s, 1H), 7.32-7.07 (m, 10H), 4.90-4.67 (m, 2H), 4.15 (m, 1H), 3.74 (m, 1H), 3.36 (m, 1H), 2.78 (m, 1H), 2.68 (m, 2H), 1.32 (m, 9H). MH+385.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1.C([Mg]Br)CC=C>CN1C(=O)CCC1>[CH2:20]([C:4]1[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH2:19][CH:18]=[CH2:22]
Reactant: C1CCOC1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Agent: C=CCC[Mg]Br
Solvent: CN1CCCC1=O
Product: C=CCCc1nc(Cl)nc2c1CCC2c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
A 250 mL three-neck round bottom flask equipped with a refluxed condenser and nitrogen inlet was charged with 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2 g, 7.54 mmol), Fe(acac)2 (0.400 g, 1.131 mmol), THF (84 mL) and NMP (6.4 mL). The resulting solution was cooled to −78° C. and but-3-enyl magnesium bromide was added (20 mL) dropwise over twenty min. During the addition, the color of the reaction mixture changed from deep red to brown. After stirring for 1 h at −78° C., another 20 mL of but-3-enyl magnesium bromide was added and stirred for further 1 h. The reaction mixture was allowed to warm to 0° C. and quenched with saturated ammonium chloride solution (250 mL). It was then extracted with MTBE (2×200 mL), washed with brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to get a crude brown oil. It was purified by a Teledyne Isco instrument using a 40 g silica column and 4-7% ethyl acetate in pet ether to get 4-(but-3-enyl)-2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1.1 g, 51.2%). LC-MS (M+H)+=285.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.33-7.24 (3H, m), 7.14-7.12 (2H, m), 5.89-5.83 (1H, m), 5.09-5.00 (2H, m), 4.37 (1H, t, J=7.2 Hz), 3.04-3.01 (1H, m), 2.94-2.92 (1H, m), 2.85-2.81 (2H, m), 2.71-2.66 (1H, m), 2.55-2.51 (2H, m), 2.23-2.19 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([CH:20]=1)[CH:18]=O.[CH3:22][O-:23].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:18]/[C:17]2[CH:20]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=2[O:23][CH3:22])/[C:9]#[N:10])=[C:4]([F:11])[CH:3]=1
Reactant: C[O-]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: N#CCc1ccc(Cl)cc1F
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cl)cc1/C=C(\C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (2.8 g, 16.6 mmol) was reacted with 5-chloro-2-fluorobenzaldehyde (Alfa) (3.2 g, 19.9 mmol), methanolic solution (25 wt %) of sodium methoxide (4.17 mL, 18 mmol) in methanol (100 mL) at 50° C. for 3 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-acrylonitrile as a off white solid (3.5 g, 68.6%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[O:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([Mg]Br)[CH3:17]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([OH:15])[CH2:14][CH2:16][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCCCC[C@@H]2CO2)cc1
Reactant: CC[Mg]Br
Product: CCC[C@H](O)CCCCOCc1ccccc1

Procedure:
(R)-6-Benzyloxyhex-1-ene oxide was prepared by copper catalyzed addition of 3-benzyloxypropyl-1-magnesium bromide to R-epichlorohydrin to form R-1-chloro-6-benzyloxyhexan-2-ol, which was then ring closed under basic conditions to (R)-6-benzyloxyhex-1-ene oxide. This epoxide was then treated with ethyl magnesium bromide (1.5 M in diethyl ether) in the presence of dilithiotetrachlorocuprate (0.02 molar equivalents, 0.1 M in tetrahydrofuran) to yield (S)-1-benzyloxy-5-hydroxyoctane.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH2:23]=O>C(O)=O>[CH3:23][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: C=O
Reactant: CCCn1nc(C(=O)NC2CCNCC2)c2ccccc21
Agent: Cl
Solvent: O=CO
Product: CCCn1nc(C(=O)NC2CCN(C)CC2)c2ccccc21
Yield: 18 %

Procedure:
To N-(4-piperidyl)-1-n-propylindazole-3-carboxamide hydrochloride (0.32 g) obtained in Example 20 were added formic acid (0.7 ml) and a 36% aqueous solution of formaldehyde (0.3 ml), and the mixture was stirred at room temperature for 5 hours. Then formic acid (4 ml) and a 36% aqueous solution of formaldehyde (1.6 ml) were further added, and the mixture was heated under reflux for 2.5 hours. The reaction solution was distilled off under reduced pressure, and to the residue were added chloroform and aqueous ammonia. After extraction with chloroform, the chloroform layer was washed with saturated aqueous sodium chloride, dried over anhydrous potassium carbonate, and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform methanol:aqueous ammonia 90:10:2) to give the title compound (0.06 g). Yield 18%.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)=[C:5]([O:18][CH2:19][C:20]#[CH:21])[CH:4]=1.C([O-])(=O)/C=C/[C:25]([O-])=[O:26]>>[CH3:25][O:26][C:8]1[CH:7]=[C:6]([C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([O:18][CH2:19][C:20]#[CH:21])=[CH:4][CH:3]=1
Reactant: C#CCOc1cc(OC)ccc1-c1nc2cnccc2[nH]1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: C#CCOc1ccc(OC)cc1-c1nc2cnccc2[nH]1

Procedure:
2-(4-Methoxy-2-propargyloxyphenyl)imidazo(4,5-c)-pyridine, fumarate, m.p. 210°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][C:14]([C:17]([NH:19][C@@H:20]4[CH:25]5[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]5)[CH2:21]4)=[O:18])=[CH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([Cl:35])=[O:34]>>[ClH:35].[N:22]12[CH2:23][CH2:24][CH:25]([CH2:26][CH2:27]1)[C@@H:20]([NH:19][C:17]([C:14]1[O:15][C:16]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:33]([C:29]5[O:28][CH:32]=[CH:31][CH:30]=5)=[O:34])[CH:3]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=1)=[O:18])[CH2:21]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: O=C(Cl)c1ccco1
Product: Cl
Product: O=C(Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1)c1ccco1

Procedure:
50 mg (0.14 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114) and 36.1 mg (0.28 mmol) of furan-2-carbonyl chloride are reacted together by general method F. 7.4 mg (10.6% of theory) of the title compound are obtained.