Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[N:23]=2)[CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:29][O:28][C:24]1[N:23]=[C:22]([CH:8]([C:4]2[N:3]=[C:2]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])[CH:7]=[CH:6][CH:5]=2)[CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cccc(C(c2cccc(Br)n2)C(c2cccnc2)c2cccnc2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cccc(C(c2cccc(NS(C)(=O)=O)n2)C(c2cccnc2)c2cccnc2)n1
Temperature: 100 °C

Procedure:
A mixture of enantiomer A of 2-bromo-6-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridine (1.00 g, 2.235 g), methanesulfonamide (0.255 g, 2.683 mmol), Cs2CO3 (1.02 g, 3.13 mmol), Pd2(dba)3 (41 mg, 0.045 mmol), and xantphos (78 mg, 0.134 mmol) in anhydrous dioxane (10 mL) under N2 was degassed (3× pump/N2) and heated to 100° C. for 16 hr. The mixture was cooled to rt and diluted with CHCl3. The mixture was filtered through a pad of celite and washed with CHCl3 and EtOAc. The filterate was concentrated and purified by silica gel chromatography (1-5% MeOH in CH2Cl2). The mixture was then purified by acidic reverse phase HPLC (95% H20:5% CH3CN to 100% CH3CN +0.1% TFA). The fractions were concentrated then quenched with saturated aqueous. sodium bicarbonate, and extracted 3× with EtOAc. The combined organic were dried (anhd. Na2SO4), filtered and concentrated to give N-{6-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridin-2-yl}methanesulfonamide. 1H NMR (500 MHz, d6 DMSO) δ 10.43 (s, 1H), 8.64 (d, 2H, J=8.3), 8.22 (t, 2H, J =5.2), 7.91 (td, 2H, J=6.2, 1.8, 7.55-7.40 (m, 2H), 7.25-7.10 (m, 3H) 7.06 (d, 1H, J=7.3), 6.55 (d, 1H, J=7.6), 6.44 (d, 1H, J=8.1), 5.43 (d, 1H, J=12.2), 5.39 (d, 1H, J=12.2), 3.82 (s, 3H), 3.45 (s, 3H), LRMS m/z (M+H) Calcd: 462.1595, found 462.1597. Enantiomer B of N-{6-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridin-2-yl}methanesulfonamide (LRMS m/z (M+H) Calcd.: 462.1595, found 462.1597) was synthesized using the method described above except with enantiomer B of 2-bromo-6-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridine.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CCOCC>[CH:1]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=1)=[O:2]
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC=O)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
Formic acid (0.35 mL, 9.1 mmol) was added to acetic anhydride (0.69 mL, 7.3 mmol) at 0° C. The mixture was warmed to 60° C. for 2 hours, then cooled to 0° C. To the anhydride mixture was added a solution of methyl 2-(4-aminophenyl)acetate (0.95 g, 5.7 mmol) in tetrahydrofuran (14 mL). The mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate and diluted with ether. The ether layer was separated, dried over sodium sulfate, and concentrated. The residue was filtered through silica (1% methanol/dichloromethane eluent) to give methyl 2-(4-formamidophenyl)acetate (0.8 g, 4.14 mmol, 56% yield). The product was dissolved in tetrahydrofuran (14 mL) and cooled to 0° C. Borane methyl sulfide complex (0.393 mL, 4.14 mmol) was added. After 15 minutes, the mixture was warmed to room temperature for 30 minutes. The mixture was cooled to 0° C. again, and 5 mL of methanol was added. The mixture was concentrated and the residue was purified by silica chromatography (10% ethyl acetate/hexane eluent) to give methyl 2-(4-(methylamino)phenyl)acetate: 1H NMR (300 MHz, CDCl3) δ ppm 2.82 (s, 3 H), 3.51 (s, 2 H), 3.67 (s, 3 H), 6.51-6.61 (m, 2 H), 6.99-7.15 (m, 2 H): MS (ESI+) m/z 179.9 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1.CN1C(=O)CCC1.Cl>O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)C1CCN(c2ccc(F)cc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture consisting of 1.62 g of 2,5-difluoronitrobenzene, 1.9 g of piperidine-4-carboxylic acid and 10 ml of NMP was heated with stirring to 80° C. for 2 hours. After it had been allowed to cool, 30 ml of water were added and the mixture was made weakly acidic using 2N hydrochloric acid and stirred at RT. The precipitated solid was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].C[N:18](C=O)C>O=S(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:5]=1[C:6]([NH2:18])=[O:7])([O-:3])=[O:2]
Reactant: CCCOc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc([N+](=O)[O-])c(C(N)=O)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A mixture of 2-nitro-5-propoxy-benzoic acid (1.97 g, 8.75 mmol) and DMF (0.1 mL) in SOCl2 (20 mL) was stirred at 65° C. for 2 h. After the reaction was completed, the mixture was cooled to room temperature. SOCl2 was removed in vacuo and the residue was dissolved in anhydrous CH2Cl2 (10 mL), which was added to NH3—H2O (28%) dropwise. After 1 h, the precipitate was collected and dried in vacuo to give 1.68 g of i-a as a yellow solid (85.2%). LCMS m/z=208.1 (M−16), 225.1 (M+1) (Method B) (retention time=1.88 min).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
64 mg (93%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (46 mg, 0.166 mmol), 1-(4-methoxyphenyl)piperazine (40 mg, 0.151 mmol), DIPEA (0.026 mL, 0.151 mmol) and NaBH(OAc)3 (96 mg, 0.453 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH:24](C(O)=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(#N)C.O.[N+]([O-])([O-])=O.[Ag+]>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH:24]([C:11]3[C:10](=[O:12])[C:9]4[C:4]([C:3](=[O:13])[C:2]=3[Cl:1])=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: O=C1C=C(Cl)C(=O)c2ccccc21
Reactant: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C1C(Cl)=C(C2CCC(c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Yield: 35 %

Procedure:
A mixture of 2-chloro-1,4-naphthoquinone (3.95 g, 0.02 mol), 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid (4.9 g, 0.02 mol) and powdered silver nitrate (1.05 g, 0.0062 mol) was heated to reflux with vigorous stirring in 40 ml of acetonitrile. A solution of ammonium persulphate (12.0 g, 0.0525 mol) in 50 ml of water was added dropwise over 1 hour. The mixture was refluxed for 3 hours then cooled in ice for 30 mins, after which it was filtered and the residual sticky solid extracted twice with boiling chloroform to remove inorganic material. The chloroform was removed by evaporation to leave a yellow-brown solid (ca 2.7 g). This was dissolved in 40 ml of boiling acetonitrile; a little insoluble material was removed by filtration. On cooling the title compound separated as yellow crystals, (550 mg) m.p. 172-175° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25][C@H:26]2[O:43][C@H:42]([CH2:44][O:45]C(=O)C)[C@@H:37]([O:38]C(=O)C)[C@H:32]([O:33]C(=O)C)[C@H:27]2[O:28]C(=O)C)[C@@H:18]([CH2:49][O:50]C(=O)C)[O:17][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([OH:16])=[O:15])(=O)C>C(N(CC)CC)C.CO.O>[C@H:26]1([O:25][C@@H:19]2[C@@H:18]([CH2:49][OH:50])[O:17][C@@H:6]([S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]([OH:16])=[O:15])[C@H:5]([OH:4])[C@H:20]2[OH:21])[O:43][C@H:42]([CH2:44][OH:45])[C@@H:37]([OH:38])[C@H:32]([OH:33])[C@H:27]1[OH:28]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccccc2C(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)c1ccccc1S[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Yield: 60.6 %

Procedure:
A solution of 1.6 g of 2-carboxyphenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside in 15 ml of a mixture of 2N triethylamine:methanol:water (3:6:2) was stirred for 16 hours, then concentrated in vacuo to a solid. This solid was dissolved in water, adjusted to pH 3.5, diluted further with water producing a slurry which was applied to 150 ml of a polystyrene resin, for example, Amberlite® XAD-2 resin (Norman Haase) and then eluted with 500 ml of water followed by one liter of 80% methanol. The methanol eluate give 0.6 g of the desired intermediate as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH3:24])[CH:11]3[C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[CH3:32])[C:5]2=[CH:4][CH:3]=1.C[O:35][CH:36]([Si](C)(C)C)[CH3:37].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:37][CH2:36][OH:35])[C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH3:24])[CH:11]3[C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[CH3:32])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(C)[Si](C)(C)C
Reactant: Cc1ccc(F)cc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)cc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)N(CCO)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.16 g, 0.26 mmol) prepared in example 56a in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated. The residue was neutralized with saturated NaHCO3 aqueous solution, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-ethanol (Yield 90 mg, 67.7%).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OP([CH2:23][C:24]#[N:25])(=O)OCC)C.CC[O-].[Na+].[H-].[Na+].[NH4+].[Cl-]>C(O)C>[C:2]1([C:1]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:23][C:24]#[N:25])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccnc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC[O-]
Agent: [Cl-]
Agent: [H-]
Solvent: CCO
Product: N#CC=C(c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
1 g (5.46 mmol, 1 eq) of 3-benzoylpyridine is dissolved in 30 ml of ethanol under Ar. 1.16 mL (7.10 mmol, 1.3 eq) of diethylcyanomethylphosphonate and 965 mg (14.1 mmol, 2.6 eq) of NaOEt are added. The mixture is stirred for 1 hour at room temperature. 108 mg (2.73 mmol, 0.5 eq) of 60% NaH in oil are added and the mixture is heated to 70-80° C. for 1 hour. A further 138 mg (3.49 mmol, 0.64 eq) of NaH are added and the mixture is heated for 40 min at 70-80° C. An NH4Cl solution is added, then the EtOH is concentrated. The basic aqueous phase is extracted with AcOEt and the organic phase is washed with brine, dried, filtered and concentrated. The oil obtained is subjected to chromatography over alumina (eluant: heptane/AcOEt: 7/1). A mixture of two stereoisomers is obtained (oil, m=1.076 g, yield=96%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([OH:11])=O)[CH:4]=1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[N:6]=4)=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCc1cc(C(=O)O)nn1C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)nn1C
Temperature: 79 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A dry flask was charged with 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid (0.159 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.248 g, 0.64 mmol, 62%).
Reaction SMILES: [CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][NH:5][C@H:4]1[CH3:8])[CH3:2].F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[C:19]([F:22])([F:21])[F:20].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][N:5]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[C:19]([F:20])([F:22])[F:21])[C@H:4]1[CH3:8])[CH3:2]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CC[C@]1(O)CCN[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)cc2C(F)(F)F)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-methylpyrrolidin-3-ol 0.5 oxalate (257 mg), 4-fluoro-3-(trifluoromethyl)benzonitrile (419 mg) and lithium carbonate (218 mg), the title compound was obtained as colorless oil (yield: 218 mg, yield: 49%).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:6]=2[S:7][CH:8]=1.O1CCCC1.C([Li])CCC.C([O-])(O)=O.[Na+]>CCCCCC>[C:3]([C:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:6]=2[S:7][CH:8]=1)#[CH:2]
Reactant: Cc1cccc2c(C=C(Br)Br)csc12
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#Cc1csc2c(C)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.6 g of 3-(dibromovinyl)-7-methylbenzo[b]thiophene are dissolved in abs. tetrahydrofuran and 3.38 ml of a 15% solution of n-butyllithium in n-hexane are added dropwise under inert gas and at -78°. Stirring is continued for one hour at -78° and the mixture subsequently warmed to room temperature, poured into saturated aq. NaHCO3 and extracted with ether. The organic phase is washed, dried, concentrated and directly further reacted.
Reaction SMILES: C([O:4][C@@H:5]([CH3:42])[C@@H:6]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([NH:23][C@@H:24]([CH2:29][OH:30])[C:25]([O:27]C)=[O:26])=[O:22])=[O:15])=[O:8])(=O)C.CO.[NH3:45]>CO>[CH2:35]([O:34][C:32](=[O:33])[NH:31][C@H:6]([C@@H:5]([OH:4])[CH3:42])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21](=[O:22])[NH:23][C@@H:24]([CH2:29][OH:30])[C:25]([O:27][NH2:45])=[O:26])=[O:15])=[O:8])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N
Reactant: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](NC(=O)OCc1ccccc1)[C@H](C)OC(C)=O
Solvent: CO
Product: C[C@H](O)[C@@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)ON
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of compound 6 (250 g, 0.42 mmol) in CH3OH (2 mL) was added MeOH—NH3 (10 mL) and was stirred at RT for 16 h. The volatiles were evaporated under reduced pressure to afford compound 7 (190 mg, 84%).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2Br)=[O:8])C.[CH2:24]([B-](F)(F)F)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.C1(P([Pd-2](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:24]([C:13]1[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]2[C:12]=1[S:11][C:10](=[O:22])[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:3])=[O:23])=[O:8])=[C:18]2[OH:19])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: F[B-](F)(F)Cc1ccccc1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(Br)c2sc1=O
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cc(Cc3ccccc3)c2sc1=O
Yield: 81.5 %

Procedure:
[(8-Bromo-6-chloro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (22(d)) (500 mg, 1.2 mmol) was dissolved in THF-water (4:1; 20 mL total volume). To the solution was added potassium benzyltrifluoroborate (285 mg, 1.2 mmol), cesium carbonate (1.2 g, 3.6 mmol), and bis(triphenylphosphino) palladium(II) dichloride (168 mg, 0.24 mmol). The mixture was heated to reflux for six hours, cooled and concentrated. The residue was triturated with hot methanol (20 mL) and filtered to provide the title compound (395 mg.) MS ESI(−) m/e: 402.355, 403.783 (M−1).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])[CH3:14]>C(O)C>[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[N:17]1[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]1=[O:11])[CH3:14]
Reactant: CCc1ccccc1N
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: CCc1ccccc1N1CCC(C(=O)O)C1=O
Yield: 95.4 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 2-ethylaniline (0.543 mL; 4.41 mmol) in ethanol (3 mL). 1-(2-ethylphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.327 g (95%) was obtained as a pale pink solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([CH:20]4[CH2:22][CH2:21]4)[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[K+].[K+]>ClC(Cl)C.O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:17]2[CH2:18][CH:19]([CH:20]3[CH2:21][CH2:22]3)[CH:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:16]2)=[CH:26][CH:25]=1
Reactant: Fc1ccc(C2CCN(CC3CNCC3C3CC3)CC2)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: O
Product: Fc1ccc(C2CCN(CC3CN(Cc4ccc(Cl)cc4)CC3C3CC3)CC2)cc1
Reaction time: 3 h

Procedure:
To a solution of 0.02 g (0.07 mmol) of 3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(cyclopropyl)pyrrolidine and 0.018 g (0.1 mmol) of 4-chlorobenzaldehyde (Aldrich) in 5 mL of dichloroethane at rt was added 0.063 g (0.3 mmol) of sodium triacetoxyborohydride and the reaction mixture was stirred for 3 h. To the reaction mixture was added a few drops of H2O and 5 mL of sat'd K2CO3 solution. The reaction mixture was extracted with ethyl acetate. The organic fractions were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, acetone: hexanes, 15%) to give the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:13]([CH2:17][N+:18]([O-])=O)[CH2:14][CH2:15]O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:13]1[CH2:14][CH2:15][NH:18][CH2:17]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@H](CCO)C[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H]1CCNC1

Procedure:
The ether compound from step 471a was treated by hydrogenation at 4 atm H2 over Pd/C in methanol to give the tile compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:19][NH2:20]>>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:19][N:20]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc([N+](=O)[O-])c(O)c1
Solvent: O
Product: O=C1CCC(c2ccc([N+](=O)[O-])c(O)c2)=NN1

Procedure:
3-(3-Hydroxy-4-nitrobenzoyl)propionic acid was cyclised with an equimolar amount of hydrazine hydrate in a similar manner to that described in Example 3(i) to give 6-(3-hydroxy-4-nitrophenyl)-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Mg].II.[CH2:4](Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].[CH2:16]1[O:18][CH2:17]1.[Cl-].[NH4+].Cl>O1CCCC1>[CH2:16]([OH:18])[CH2:17][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH2:4]
Reactant: C1CO1
Reactant: C=CCCCCCCCCCBr
Agent: Cl
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CCCCCCCCCCCCO
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
This example illustrates a synthesis of 1-(12,13-Oxidotridecyl)-3,7-dimethylxanthine (inventive compound no. 2562). To a suspension of magnesium (4.12 g, 172 mmol) and a crystal of iodine in tetrahydrofuran (40 mL) was added 10-undecenyl bromide (8.00 g, 34.3 mmol) in tetrahydrofuran (30 mL) over 30 minutes and the reaction stirred for a further 30 minutes after the addition was complete. The solution was added via a canula over 5 minutes to a solution of ethylene oxide (2.65 g, 60.0 mmol) in tetrahydrofuran (30 mL) and stirred at 25° C. for 16 hours. Saturated ammonium chloride (100 mL) and 1M hydrogen chloride (200 mL) were added and extracted with diethyl ether (2×200 mL). The combined organic extracts were dried (magnesium sulfate) and evaporated to give a residue which was distilled at 1.5 mm Hg to afford 12-tridecenyl alcohol as a clear liquid (4.11 g, 61%, b.p. 98°-101° C.).