Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C:19]4([CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]4)[N:18]4[C@@H:13]([C:14](=[O:39])[O:15][C@@H:16]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C@H:17]4[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:12]3[C:40]3[CH:45]=[CH:44][N:43]=[C:42]([Cl:46])[C:41]=3[F:47])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-:49].[K+].[K+].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:12]([C:40]4[CH:45]=[CH:44][N:43]=[C:42]([Cl:46])[C:41]=4[F:47])[C@H:13]([C:14]([OH:49])=[O:39])[N:18]([C@H:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:16]([OH:15])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:19]43[CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1ccnc(Cl)c1F)[C@@]21C(=O)Nc2cc(Cl)ccc21
Reactant: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: CC#N
Product: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)O)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
The compound (630 mg, 0.94 mmol) obtained in Step 1 of Example 16 was dissolved in acetonitrile (10 ml) and water (4 ml), potassium carbonate (130 mg, 0.94 mmol) was added and the resulting mixture was heated to reflux at 85° C. for 16 hours. After cooling, anhydrous magnesium sulfate (113 mg, 0.94 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. After extraction with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (4′S,5′R)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-1′-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylic acid (650 mg, 100%) as a pale orange amorphous solid [MS (ESI) m/z: 688 (M+H)+.]. The carboxylic acid (650 mg, 0.94 mmol) obtained was dissolved in methanol (30 ml) and water (8 ml), cerium (IV) diammonium nitrate (1.55 g, 2.82 mmol) was added under ice cooling and the resulting mixture was stirred at the same temperature for 30 minutes. Potassium carbonate (780 mg, 5.64 mmol) was added under ice cooling and the resulting mixture was stirred at the same temperature for 1 hour. Insoluble matter was removed by filtration through celite, then the filtrate was concentrated under reduced pressure and water was added to the residue obtained, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=20:1→4:1 (v/v)] to give 152 mg (33%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])\[C:26]#[N:27])[CH:20]=[C:21]([F:23])[CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:19]2[CH:20]=[C:21]([F:23])[CH:22]=[C:17]([Cl:16])[CH:18]=2)[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])([C:26]#[N:27])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cc(F)cc(Cl)c1)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(F)cc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 28.7 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-5-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 83a, AgF (1.0 g, 8 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 29%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@H:20]([C:32]([OH:34])=O)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:35]([NH:42][CH2:43][CH:44]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:45]([CH3:47])[CH3:46])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(C(C)C)C(C)C)C.CCCP(=O)=O>CC(N(C)C)=O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][C@H:20]([C:32](=[O:34])[N:42]([CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:43][CH:44]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH:45]([CH3:47])[CH3:46])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(CNCc1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)C(CN(Cc1ccccc1)C(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred, ice-cooled mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (466.5 mg, 1 mmol), benzyl-(3-methyl-2-phenyl-butyl)-amine (279 mg, 1.1 mmol) and N-ethyldiisopropylamine (1.37 mL, 8 mmol) in dimethylacetamide (6 mL), propylphosphonic anhydride solution (˜50% in DMF, 0.95 mL, ˜1.5 mmol) is added. The reaction mixture is stirred for 7 h at RT and evaporated in vacuo. The residue is dissolved in ethyl acetate and washed twice with an aqueous 10% K2CO3 solution. The organic layer is dried (Na2SO4) and evaporated in vacuo and the residue is purified by flash chromatography (hexane/ethyl acetate). The combined pure fractions are evaporated to afford the title compound as a white amorphous solid. MS: 702.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, then 100% CH3CN+0.1% TFA for 2 min, flow 1.5 ml/min): 8.87 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[C:9]([CH3:17])[C:10]([Br:16])=[C:11]([CH3:15])[CH:12]=2)[C:7]1=[O:18])=[O:5])[CH3:2].[H-].[Na+].[CH3:21]I>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH3:21])[CH2:14][C:13]2[C:8](=[C:9]([CH3:17])[C:10]([Br:16])=[C:11]([CH3:15])[CH:12]=2)[C:7]1=[O:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2cc(C)c(Br)c(C)c2C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)Cc2cc(C)c(Br)c(C)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To the stirred solution of compound 4 (5.0 g, 16.1 mmol) in dry THF (50 mL), A 60% dispersion of sodium hydride (0.85 g, 35.4 mmol) in solid addition funnel was added portion wise at 0° C. The reaction mixture was warmed to room temperature and stirred for another 1 h. Then MeI (2.0 mL, 32.15 mmol) was added dropwise at 0° C. under argon atmosphere. The reaction mixture was warmed to room temperature and stirred for 5 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution at 0° C. and allowed to stir for 15 min. Then crude reaction mixture was extracted with ethyl acetate (100 mL×2 mL), washed with water (100 mL), brine (100 mL) dried (Na2SO4) and concentrated in vacuo. Purification by silica gel column chromatography (hexanes/ethyl acetate, 15:1, v/v) gave pure compound 5 (4.5 g, 86.5%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]([C:12]1[CH:13]=[C:14]([C:23](=O)[CH3:24])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:11])[CH3:10].[CH3:26][N:27]([CH3:35])[N:28]1[C:32](=[O:33])[CH2:31][S:30][C:29]1=[S:34].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:11][C:9]([C:12]1[CH:13]=[C:14]([CH2:23][CH:24]=[C:31]2[S:30][C:29](=[S:34])[N:28]([N:27]([CH3:35])[CH3:26])[C:32]2=[O:33])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:8])[CH3:10]
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CN(C)N1C(=O)CSC1=S
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CN(C)N1C(=O)C(=CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1=S

Procedure:
To 675 ml of toluene were added 20.9 g of 1-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]ethanone, 13.3 g of N-dimethylaminorhodanine 6.5 g of ammonium acetate and about 20 ml of acetic acid. The mixture was heated at reflux temperature and any aqueous layer generated was collected in a Dean-Stark trap. Over the following 52 hours an additional 39 g of ammonium acetate and about 100 ml of acetic acid were added in increments and a total of 89.2 ml of aqueous phase was drawn off. Following workup by conventional techniques, 17.1 g of the desired subtitled intermediate was recovered.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[N+:8]([C:11]1[N:16]=[CH:15][C:14]2[CH:17]=[CH:18][O:19][C:13]=2[C:12]=1[OH:20])([O-:10])=[O:9].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:33](=[O:45])[N:34]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:35]=[CH:36][CH:37]=2)=[O:31])=[CH:25][CH:24]=1>O>[N+:8]([C:11]1[N:16]=[CH:15][C:14]2[CH:17]=[CH:18][O:19][C:13]=2[C:12]=1[O:20][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:33](=[O:45])[N:34]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH:35]=[CH:36][CH:37]=2)=[O:31])=[CH:25][CH:24]=1)([O-:10])=[O:9]
Reactant: O=C(Nc1ccc(CBr)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: O=[N+]([O-])c1ncc2ccoc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(COc2c([N+](=O)[O-])ncc3ccoc23)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Into a DMF (1.5 ml) suspension of NaH (11.0 mg, 60% suspension in oil, 0.275 mmol), which was cooled at 0° C. under an atmosphere of nitrogen, was added the DMF (1.5 ml) solution of 6-nitrofuro[3,2-c]pyridin-7-ol (Intermediate 7) (45.1 mg, 0.248 mmol) dropwise. The mixture was stirred at 0° C. for 5 min and was then raised to rt and stirred at rt for 30 min. Then this reaction mixture was added dropwise into the DMF (4 ml) suspension of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (4-bromomethylphenyl)-amide (0.248 mmol) at rt under an atmosphere of nitrogen. The combined mixture was stirred at rt for 1 h. After that time, the reaction mixture was poured into water. The solid was filtered off and washed with water to give a beige solid. It was triturated with EtOAc (4 ml). The solid was filtered off and the mother liquor was purified by TLC eluting with 2.5% MeOH/DCM 2 times to give the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=5.58 (s, 2H), 6.59 (dd, J=6.8 & 7.2 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 7.23-7.29 (m, 2H), 7.38-7.45 (m, 4H), 7.60 (dd, J=2.0 & 4.8 Hz, 1H), 7.73 (dd, J=2.4 & 6.8 Hz, 2H), 7.88 (d, J=2.0, 1H), 8.44 (s, 1H), 8.73 (dd, J=2.4 & 6.8 Hz, 1H), 11.84 (brs, 1H). MS (ES+): m/z 500.99 [MH+]. HPLC: tR=3.58 min (polar—5 min, ZQ3).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[I:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1I
Temperature: 0 °C
Yield: 62 %

Procedure:
A solution of 2-iodo-4-nitrobenzoic acid (9 g, 30.7 mmol), methanol (88 mL) and sulfuric acid (0.82 mL, 15.4 mmol) was heated to reflux overnight. The reaction solution was cooled down to 0° C. for 30 minutes. The solid was filtered to give the desired product (5.90 g, 62%). LCMS calculated for C8H71NO4(M+H)+: m/z=308.0.
Reaction SMILES: CN(OC)[C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=O.[H-].Cl.[OH2:21]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[O:6][C:5](/[CH:3]=[CH:3]/[C:5]([O:6][CH3:7])=[O:21])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccc(C)cc2)o1
Reactant: O
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(-c2ccc(C)cc2)o1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, to a solution of N-methyl-N-methoxy-5-(4-methylphenyl)furan-2-carboxamide (2.5 g) in tetrahydrofuran (20 ml) was added duisobutylaluminum hydride (1.01M toluene solution) (15 ml) at -78° C., and the mixture was stirred at -78° C. for 10 minutes and then at 0° C. for 15 minutes. To the reaction mixture was added 1N hydrochloric acid to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:5→1:4) to give crude product (1.49 g). A solution of the crude aldehyde (1.49 g) and methyl (triphenylphosphoranilidene)acetate (2.67 g) in toluene (30 ml) was refluxed under nitrogen atmosphere for 1 hour and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:9→1:5) to give methyl (E)-3-[5-(4-methylphenyl)furan-2-yl]acrylate (1.63 g) as pale yellow crystals.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[OH-].[Na+]>O>[N:11]1[C:1](=[O:2])[N:12]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12
Reactant: Nc1ccccc1N
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1N=c2ccccc2=N1
Yield: 94 %

Procedure:
100 g (1.01 mol) of phosgene are passed into 108 g (1 mol) of o-phenylenediamine in 800 ml of water at 80° C. over a period of 4 hours and the pH is kept constant at 6.5 by simultaneous metering in of 231 g (1.9 mol) of 50% strength aqueous sodium hydroxide solution. After filtration with suction and washing with water, 126 g of benzimidazol-2-one are obtained, which corresponds to a yield of 94% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:4]=1[CH2:5][NH:6][CH2:7][CH:8](OC)OC.[CH:19](=O)[C:20]1[CH:29]=[CH:28][C:25]([O:26][CH3:27])=[C:22]([O:23][CH3:24])[CH:21]=1.[ClH:31]>>[ClH:31].[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[C:4]2[C:13]=1[C:8]1[CH2:19][C:20]3[CH:29]=[CH:28][C:25]([O:26][CH3:27])=[C:22]([O:23][CH3:24])[C:21]=3[C:7]=1[N:6]=[CH:5]2
Reactant: COc1ccc(OC)c(CNCC(OC)OC)c1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Product: COc1ccc2c(c1OC)-c1ncc3c(OC)ccc(OC)c3c1C2
Yield: 24 %

Procedure:
Amine 12d (2.82 g, 11.1 mmol) and veratraldehyde (10a, 4.00 g, 0.030 mol) were reacted in concentrated hydrochloric acid as described previously for compound 9aa. The product was isolated as a yellow-orange hygroscopic solid (1.01 g, 24%), mp 242-244° C. 1H NMR (300 MHz, TFA) δ 9.52 (s, 1H), 7.75 (s, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.38 (s, 1H), 7.08 (d, J=8.7 Hz, 1H), 4.56 (s, 2H), 4.10 (s, 3H), 4.09 (s, 3H), 4.04 (s, 6H). Anal. (C20H20NO4Cl.1.7H2O)C, H, N, Anal. Calcd for C20H20NO4Cl(H2O)1.7: C, 59.39; H, 5.83; N, 3.46. Found: C, 59.22; H, 5.53; N, 3.72.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.C([O:25][CH:26]=[C:27]([C:33](OCC)=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])C.C[O-].[Na+]>C(O)C>[CH2:31]([O:30][C:28]([C:27]1[CH:33]=[N:1][C:2]2[N:3]([N:4]=[CH:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)=[CH:9][CH:8]=2)[C:26]=1[OH:25])=[O:29])[CH3:32]
Reactant: Nc1n[nH]cc1-c1ccc(Cc2ccc3c(c2)OCO3)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(-c3ccc(Cc4ccc5c(c4)OCO5)cc3)cnn2c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-amino-4-[4-(3,4-methylenedioxyphenylmethyl)phenyl]pyrazole (1.5 g) in ethanol (10 ml) was added diethyl ethoxymethylenemalonate (2.07 ml), and the mixture was heated and refluxed for 12 hours. To the mixture was added sodium methoxide (829 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 day. The solvent was distilled away under reduced pressure, and thereto was added water (50 ml) under ice-cooling. The mixture was adjusted to acid with 10% hydrochloric acid, and the precipitate was separated by filtration, washed with water to give the title compound (2.1 g) at a quantitative yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.Cl.[NH2:13][C:14]1([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15]1>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:13][C:14]1([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15]1
Reactant: COC(=O)C1(N)CC1
Reactant: COCc1cccc(C=O)c1
Agent: Cl
Product: COCc1cccc(CNC2(C(=O)OC)CC2)c1
Yield: 82 %

Procedure:
Prepared as in Example 12-1b from 3-(methoxymethyl)benzaldehyde (Example 12-14b) and methyl 1-aminocyclopropanecarboxylate hydrochloride. Yield 82%. MS 250 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C[Li].C([Li])CCC.CN(C)[CH:33]=[O:34]>O.C1COCC1>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[O:15][C:3]1[C:2]([CH:33]=[O:34])=[CH:7][N:6]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1
Agent: [Li]C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(C=O)cn2)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
A flask was charged with 5-bromo-4-(2,6-difluorophenoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (Example 128; 1.0 g, 2.51 mmol) and THF (50 mL) and cooled to −78° C. Methyllithium (1.96 ml, 3.14 mmol) was added slowly and the reaction mixture was stirred for 5 minutes. Butyllithium (1.26 ml, 3.14 mmol) was added and the reaction mixture was stirred for 5 minutes. N,N-dimethylformamide (0.551 g, 7.53 mmol) was added and the reaction mixture was stirred for 5 minutes. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried, filtered, and concentrated. The residue was titurated with a mixture of hexanes, ether, and DCM and filtered to give the title compound (0.480 g, 51.2% yield) as yellow solid. 1H NMR (d6-DMSO) δ 11.48 (s, 1H), 10.23 (s, 1H), 8.73 (s, 1H), 7.48 (m, 3H), 6.68 (s, 1H), 6.53 (bs, 1H), 2.19 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])/[CH:18]=[CH:19]\[CH2:20][CH3:21]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:8]1[CH2:9][C@H:19]([CH2:20][CH3:21])[C@H:18]([C:17]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC/C=C\C(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CC
Reaction time: 48 h
Yield: 96.1 %

Procedure:
To a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (9.98 mL, 39.0 mmol) and (Z)-ethyl pent-2-enoate (5 g, 39.0 mmol) in DCM (50 mL) was added TFA (0.030 mL, 0.390 mmol) at rt. After about 2 days, the reaction mixture was concd in vacuo to provide crude (cis)-ethyl 1-benzyl-4-ethylpyrrolidine-3-carboxylate (9.8 g, 96%) as an oil. LC/MS (Table 1, Method a) Rt=1.62 min; MS m/z: 262 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1.C1C(=O)N([Br:23])C(=O)C1>C(#N)C>[Br:23][C:5]1[CH:6]=[C:7]2[C:12](=[N:13][C:4]=1[CH:3]([O:2][CH3:1])[O:14][CH3:15])[NH:11][CH2:10][CH2:9][CH2:8]2
Reactant: COC(OC)c1ccc2c(n1)NCCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(OC)c1nc2c(cc1Br)CCCN2
Temperature: 25 °C

Procedure:
Into a 3 l 4-necked round-bottom flask was placed 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 4, 114.6 g, 550.3 mmol) in acetonitrile (2 l). This was followed by the addition of NBS (103 g, 578 mol) in portions with stirring at 25° C. The resulting solution was stirred for 30 min at 25° C. The resulting mixture was concentrated under vacuum and the residue was diluted with 1000 ml of diethylether. The mixture was washed with 3×100 ml of ice/water. The aqueous phase was extracted with 2×100 ml of diethylether and the organic layers were combined. The resulting mixture was washed with 1×100 ml of brine, dried over sodium sulfate and concentrated under vacuum to give the title compound as a light yellow solid. LC-MS: (ES, m/z):
Reaction SMILES: C=O.[CH:3](O)=O.[OH:6][CH2:7][CH:8]1[CH:13]([OH:14])[CH:12]([OH:15])[CH:11]([OH:16])[CH2:10][NH:9]1>O>[OH:6][CH2:7][CH:8]1[CH:13]([OH:14])[CH:12]([OH:15])[CH:11]([OH:16])[CH2:10][N:9]1[CH3:3]
Reactant: OCC1NCC(O)C(O)C1O
Reactant: O=CO
Agent: C=O
Solvent: O
Product: CN1CC(O)C(O)C(O)C1CO

Procedure:
A mixture of 7 ml of aqueous formalin, 15 ml of formic acid, 1.5 g of 2-hydroxymethyl-3,4,5-trihydroxypiperidine, m.p. 204°-205°, [α]D25 +45° (H2O), is heated under reflux for 20 hours. The reaction mixture is then concentrated to dryness under reduced pressure, the residue is dissolved in water and the insolubles are removed by filtration. The filtrate is passed over ion exchange resin column (Dowex 50 W×4). The column is rinsed with water and the absorved material is eluted with 0.28% aqueous ammonia. The eluate is concentrated to dryness under reduced pressure and the crystalline residue is recrystallized from ethanol to yield 2-hydroxymethyl-3,4,5-trihydroxy-N-methylpiperidine, m.p. 142°-143°, [α]D24 +15.5° (H2O), yield 1.2 g. Treatment with an equimolar amount of p-toluenesulfonic acid gives the corresponding p-toluenesulfonate which, in turn, is recrystallized from methanol. m.p. 198°-199°, [α]D24 +12.2° (methanol).
Reaction SMILES: CO[CH:3](OC)[CH2:4]Br.Br.O.[NH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1>CN(C)C=O>[N:12]1[CH:13]=[CH:14][N:10]2[CH:4]=[CH:3][N:15]=[CH:16][C:11]=12
Reactant: COC(CBr)OC
Reactant: Nc1cnccn1
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Product: c1cn2ccnc2cn1
Reaction time: 12 h

Procedure:
A mixture of 34 g (0.2 mol) of bromoacetaldehyde dimethyl acetal, 6,6 ml of concentrated aqueous HBr solution and 28 ml of distilled water is brought to reflux for one hour. After reaction, the mixture is alkalinized and extracted with ether. This organic phase is added to a solution of 19 g (0.2 mol) of aminopyrazine in 50 ml of dimethylformamide (DMF). The ether is removed by distillation and the mixture is maintained with stirring and under a stream of nitrogen for 12 hours. After reaction, the DMF is distilled off; the reaction medium is dissolved in 150 ml of anhydrous ethanol, and then brought to reflux for one hour. The alcohol is then removed by distillation; the residue is dissolved in water, alkalinized with Na2CO3 and extracted using dichloromethane. After chromatography on a neutral alumina column (eluant =anhydrous ether), 10.7 g (Yld=45%) of imidazo[1,2-a]pyrazine (m.p. 84° C.). are obtained.