Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:2].[H-].[Na+].Cl[CH2:16][C:17](=[O:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C.O>[N+:10]([C:6]1[CH:5]=[C:4]([N:3]([CH2:16][C:17](=[O:19])[CH3:18])[CH:1]=[O:2])[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: O=CNc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)CN(C=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.33 h
Yield: 21 %

Procedure:
To a suspension of N-formyl-3-nitroaniline (1.0 g) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% dispersion in mineral oil, 264 mg), and the mixture was stirred for 20 minutes under nitrogen atmosphere. After a solution of 1-chloropropan-2-one (0.573 ml) in N,N-dimethylformamide (5 ml) was added dropwise to the mixture, the mixture was stirred for 2 hours and diluted with ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-(3-nitrophenyl)-N-(2-oxo-propyl)-formamide (280 mg, 21.0%).
Reaction SMILES: [Cl-].[C:2]([O:7][CH2:8][CH3:9])(=[O:6])[C:3]([O-:5])=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH:23]=[CH2:24])[NH:18]2)=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.C(Cl)(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH:23]=[CH2:24])[N:18]2[C:3](=[O:5])[C:2]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:16]=1
Reactant: C=C[C@@H]1CCC[C@H](c2ccc(F)cc2)N1
Reactant: CCOC(=O)C(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C=C[C@@H]1CCC[C@H](c2ccc(F)cc2)N1C(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl oxalate chloride (0.5 mL) was added to a solution of (2R*,6S*)-2-(4-fluorophenyl)-6-vinylpiperidine (520 mg) and DIEA (0.66 mL) in methylene chloride (10 mL), and the reaction solution was stirred at room temperature for one hour. Chloroform and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 426 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: CS(O[CH2:6][C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)(=O)=O.FC(F)(F)C1C=CC(C2(C[C:33]#[N:34])CCCC2)=CC=1>>[Cl:18][C:14]1[CH:13]=[C:12]([C:7]2([CH2:6][C:33]#[N:34])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:17]=[CH:16][CH:15]=1
Reactant: N#CCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: CS(=O)(=O)OCC1(c2cccc(Cl)c2)CCCC1
Product: N#CCC1(c2cccc(Cl)c2)CCCC1

Procedure:
2-(1-(3-Chlorophenyl)cyclopentyl)acetonitrile (498) was synthesized from (1-(3-chlorophenyl)cyclopentyl)methyl methanesulfonate (497) following the procedure described for [1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetonitrile (241).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[Na].N1C2C(=CC=CC=2)C=[CH:24]1.CI>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:24][N:3]1[C:11]2[C:6](=[C:7]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: COC(=O)c1cccc(-c2cccc3[nH]ccc23)c1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CI
Product: COC(=O)c1cccc(-c2cccc3c2ccn3C)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a suspension of sodium hydride (0.20 g) in anhydrous toluene (23 ml) was added a hot solution of methyl 3-(indol-4-yl)benzoate (1.16 g) in toluene (5.8 ml). Since a sodium salt did not form, N,N-dimethylformamide (0.5 ml) was introduced. An evolution of gas occurred with the formation of the orange sodium salt of the indole. After being stirred for 20 minutes methyl iodide was added thereto and the mixture was stirred at 60° C. for four hours. Then the sodium iodide was filtered off and washed with toluene. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and acetone (20:1) to afford methyl 3-(1-methylindol-4-yl)benzoate (0.35 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:14][C:12]1[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[CH:31][CH:30]=3)[CH:7]=2)[N:13]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.46) (0.175 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.021 g, 10%). MS (ISP) 408.3 [(M+H)+]; mp 232° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].S(=O)(=O)(O)O.[N+:21]([O-])([O-:23])=[O:22].[K+]>>[F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:21]([O-:23])=[O:22])=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[CH:3]=1
Reactant: CC(=O)Nc1ccc(C(F)(F)F)c(F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a vigorously stirred solution of N-(3-fluoro-4-trifluoromethyl-phenyl)-acetamide (0.663 g, 3.00 mmol) and sulfuric acid (3 mL) was added dropwise a solution of potassium nitrate (0.607 g, 6.00 mmol) and conc. sulfuric acid (3 mL) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then slowly pipetted into ice/water with stirring. The resulting precipitate was collected and dried in vacuo to yield the titled compound (0.648 g, 81% yield) as a single regioisomer. The compound did not yield MS data. 1H NMR (600 MHz, CDCl3): 10.67 (br s, 1H), 8.86 (d, J=12.9 Hz, 1H), 8.57 (d, J=7.2 Hz, 1H), 2.35 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25](=[O:27])(=[O:26])[NH2:24])=[CH:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(N)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(aminosulfonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.24 min; Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCNCC
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Product: CCN(CC)Cc1cc(-c2ccc(C)cc2)nn(CC(C)C)c1=O
Yield: 95 %

Procedure:
Following the procedure of Example 9 (4), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and diethylamine were reacted to yield the title compound as a pale yellow oil (yield: 95.0%).
Reaction SMILES: O.[OH-].[Li+:3].[B:4]([OH:7])([OH:6])[OH:5].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[OH:17])[C:12]#[N:13]>O>[B:4]([O-:7])([O-:6])[O-:5].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[OH:17])[C:12]#[N:13].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[OH:17])[C:12]#[N:13].[Li+:3].[Li+:3].[Li+:3]
Reactant: OB(O)O
Agent: N#Cc1ccc(O)c(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: [O-]B([O-])[O-]
Temperature: 25 °C

Procedure:
Lithium hydroxide monohydrate (0.839 g, 0.02 mmol), boric acid (1.236 g, 0.02 mmol), and 2 equivalents of 3,4-dihydroxybenzonitrile (5.4 g, 0.04 mmol) were mixed in 4 ml water. The mixture was heated to near boiling for few minutes till a clear pink colored solution was obtained. Upon cooling to room temperature a white solid was formed. The supernatant solution was decanted and the solid was recrystallized from small quantity of hot water. After drying in an oven, lithium bis(3,4-dihydroxybenzonitrile) borate was isolated as a white powder. Yield=5.3 g (93%), mp>300° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH:3]1[CH2:8][CH2:7][N:6]([CH:9]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=3[F:21])[CH2:10]2)[CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:1][N:2]([CH3:22])[CH:3]1[CH2:4][CH2:5][N:6]([CH:9]2[CH2:10][N:11]([C:13]3[N:18]=[C:17]([CH:19]=[O:20])[CH:16]=[CH:15][C:14]=3[F:21])[CH2:12]2)[CH2:7][CH2:8]1
Reactant: CN(C)C1CCN(C2CN(c3nc(CO)ccc3F)C2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CN(C)C1CCN(C2CN(c3nc(C=O)ccc3F)C2)CC1
Yield: 134.1 %

Procedure:
To a mixed solution of (6-(3-(4-(dimethylamino)piperidin-1-yl)azetidin-1-yl)-5-fluoropyridin-2-yl)methanol (240 mg, 0.779 mmol) described in Production Example 25-3 and dichloromethane (6.00 mL) was added Dess-Martin periodinane (400 mg) at 0° C. The resultant mixture was stirred for 1.5 hours. Quenched with an aqueous sodium hydrogen carbonate solution and sodium thiosulfate, and the reaction solution was extracted with chloroform. An organic layer was dried over sodium sulfate and then filtrated, and the solvent was then evaporated under a reduced pressure to give the title compound (320 mg). The product was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[CH2:12][CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(OCCCCl)cc1OC
Reactant: COc1ccc(C(c2ccc(OC)cc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: COc1ccc(C(c2ccc(OC)cc2)C2CCN(CCCOc3ccc(OC)c(OC)c3)CC2)cc1

Procedure:
A mixture of 5.58 g (0.02 mole) of 4-[bis(4-methoxyphenyl)methyl]piperidine, 4.83 g (0.021 mole) of 4-(3-chloropropoxy)-1,2-dimethoxybenzene, and potassium carbonate, 5.52 g (0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g). The reaction mixture was stripped to dryness, and the residue partitioned between chloroform-5% sodium hydroxide and chloroform-water. Removal of chloroform gave a dark brown oil. The oil was subjected to column chromatography on a silica gel column with elution via ethyl acetate-dimethoxy ethane. This produced 4.72 g (46.7%) of dark brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1ccc(OC)cc1
Product: COC(=O)C(=CN(C)C)c1ccc(OC)cc1
Yield: 6.9 %

Procedure:
Combined methyl 2-(4-methoxyphenyl)acetate (3.58 mL, 22.20 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (11.89 mL, 89 mmol) and heated to 100° C. for 14 h. The reaction was concentrated in vacuo to afford a light yellow oil which was purified by flash chromatography (100 g basic silica using a 5% to 50% EtOAc in heptanes gradient to give the title compound (361 mg, 6.91%) as a colorless oil. MS m/z [M+H]+ 236.1.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([C:5]1[O:6][C:7]([C:10](=[O:12])[CH3:11])=[CH:8][CH:9]=1)=[O:4].[Br:14]Br>C(O)(=O)C>[CH3:13][N:2]([CH3:1])[C:3]([C:5]1[O:6][C:7]([C:10](=[O:12])[CH2:11][Br:14])=[CH:8][CH:9]=1)=[O:4]
Reactant: CC(=O)c1ccc(C(=O)N(C)C)o1
Reactant: BrBr
Solvent: CC(=O)O
Product: CN(C)C(=O)c1ccc(C(=O)CBr)o1

Procedure:
A mixture of 1.81 g. (0.01 mole) of N,N-dimethyl-5-acetylfuran-2-carboxamide, 1.59 g. (0.01 mole) of bromine and 40 ml. of glacial acetic acid was stirred at room temperature for 18 hours, and then the acetic acid was removed by evaporation in vacuo. The residue was partitioned between water and ethyl acetate and the layers were separated. The aqueous layer was further extracted with ethyl acetate, and the combined ethyl acetate solutions were washed with sodium bicarbonate solution followed by water, dried (Na2SO4) and evaporated in vacuo. This afforded 2.6 g. of the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[N:4]([CH2:15][CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[C:3]1=[O:21].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]#[CH:31])[CH2:25][CH2:24]1.C(O)(=O)/C=C/C(O)=O>>[OH:20][C:18]([CH3:19])([C:31]#[C:30][CH2:29][N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[CH2:17][CH2:16][CH2:15][N:4]1[C:5](=[O:14])[C:6]2[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:21]
Reactant: CCCn1cnc2c1c(=O)n(CCCC(C)=O)c(=O)n2C
Reactant: C#CCN1CCN(C)CC1
Agent: O=C(O)/C=C/C(=O)O
Product: CCCn1cnc2c1c(=O)n(CCCC(C)(O)C#CCN1CCN(C)CC1)c(=O)n2C
Yield: 82 %

Procedure:
1-(4-Hydroxy-4-methyl-7-[4-methylpiperazino]-5-heptynyl)-3-methyl-7-propylxanthine was prepared as oily substance in 82% yield using 3-methyl-1-(4-oxopentyl)-7-propylxanthine and 4-methyl-1-(2-propynyl)-piperazine from stage C1) as in Example 6C1). Salt formation with fumaric acid took place as in Example 7F2) in 55% yield.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([N:11]2[CH2:15][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:13]([CH2:22][N:23]([C@@H:31]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)[CH3:32])C(=O)OC(C)(C)C)[CH2:12]2)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.O1CCOCC1>O1CCOCC1>[C:33]1([C@H:31]([NH:23][CH2:22][C@@H:13]2[C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:15][N:11]([C:9]([C:8]3[CH:43]=[CH:44][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[O:10])[CH2:12]2)[CH3:32])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(S(N)(=O)=O)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NC[C@H]1CN(C(=O)c2ccc(S(N)(=O)=O)cc2)C[C@@H]1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Yield: 70.6 %

Procedure:
A 1.6 ml 1,4-dioxane solution of 110 mg of tert-butyl ({(3R,4S)-1-[4-(aminosulfonyl)benzoyl]-4-phenylpyrrolidin-3-yl}methyl)[(1R)-1-(1-naphthyl)ethyl]carbamate was mixed with 1.5 ml of 4 M hydrogen chloride/1,4-dioxane and stirred at room temperature for 60Hours. The reaction solution was concentrated under a reduced pressure, mixed with water and neutralized with saturated sodium bicarbonate solution. The organic layer extracted with chloroform was dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. By crystallizing the thus obtained residue from ethyl acetate, 65 mg of 4-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}benzene sulfonamide was obtained as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:35](=[O:37])[CH3:36])=[CH:10][N:11]2[CH2:14][C:15]([N:17]2[CH2:21][C@H:20]([F:22])[CH2:19][C@H:18]2[C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[F:33])=[O:16])=[CH:7][CH:6]=1.[OH-].[Na+]>C1COCC1.O>[C:35]([C:9]1[C:8]2[C:12](=[CH:13][C:5]([CH2:4][C:3]([OH:38])=[O:2])=[CH:6][CH:7]=2)[N:11]([CH2:14][C:15]([N:17]2[CH2:21][C@H:20]([F:22])[CH2:19][C@H:18]2[C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[F:33])=[O:16])[CH:10]=1)(=[O:37])[CH3:36]
Reactant: COC(=O)Cc1ccc2c(C(C)=O)cn(CC(=O)N3C[C@H](F)C[C@H]3C(=O)NCc3cccc(Cl)c3F)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(CC(=O)O)ccc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of (3-acetyl-1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indol-6-yl)-acetic acid methyl ester Example 549 (200 mg, 0.366 mmol) in THF (5 mL) and water (0.5 mL) was added 1N NaOH (1.46 mL, 1.46 mmol) and the reaction was stirred at RT for 60 h. The mixture was partitioned between diethylether and water. The layers were separated and the aqueous phase was adjusted to pH=2 by addition of a 1N HCl solution to form a precipitate. The solid was filtered off, washed with water diethylether and dried in vacuo to afford the title compound as a solid. MS (LC/MS): 532 [M+H]+; tR (HPLC conditions k): 3.19 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([CH:8]([C:10]2[C:11]([CH3:17])=[N:12][CH:13]=[CH:14][C:15]=2[CH3:16])[OH:9])=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([C:8]([C:10]2[C:11]([CH3:17])=[N:12][CH:13]=[CH:14][C:15]=2[CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1ccnc(C)c1C(O)c1ncc(Cl)cc1[N+](=O)[O-]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
A mixture of (5-chloro-3-nitro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanol (1.46 g) and Dess-Martin periodinane (2.52 g, 5.91 mmol) in CH2Cl2 (15 mL) at room temperature was stirred for 5 h. A mixture of 10% aqueous Na2S2O3 (10 mL) and saturated aqueous NaHCO3 (10 mL) was then added and the biphasic mixture vigorously stirred for 30 min. The phases were then separated and the aqueous portion extracted with CH2Cl2. The combined organic extracts were washed with saturated aqueous NaHCO3, then brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue purified by flash column chromatography over silica gel to provide (5-chloro-3-nitro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanone. Mass spectrum m/z: 292.3 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21][CH:22]=C(C)CCC(O)=O.CCCCCC.C(OCC)(=[O:38])C>>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21][CH:22]=[O:38]
Reactant: CCOC(C)=O
Reactant: COCCOCOc1c(CC=C(C)CCC(=O)O)c(OC)c(C)c2c1C(=O)OC2
Solvent: CCCCCC
Product: COCCOCOc1c(CC=O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
By following the procedure of part A and substituting methyl (E) 6(4-t-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with (E) 6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, there was obtained 2-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-acetaldehyde, m.p. 61°-63° C. (hexane-ethyl acetate).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:37])[CH2:17][CH2:18][CH2:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[C:27]([O:29]CC1C=CC=CC=1)=[O:28])=[O:21])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:27]([C@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:37])([OH:29])=[O:28]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)CCCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 45.8 %

Procedure:
440 mg (0.87 mmol) (R)-1-[5-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylic acid benzyl ester in 100 ml ethanol were hydrogenated in the presence of 40 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded 130 mg (46%) (R)-1-(5-[(R)-2-carboxy-pyrrolidin-1-yl]-5-oxo-pentanoyl]-pyrrolidine-2-carboxylic acid as colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH3:30])[CH:28]=2)[C:23]([CH:31]=O)=[CH:22]1.CO>COCCOC>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH3:30])[CH:28]=2)[C:23]([CH2:31][C:17]#[N:18])=[CH:22]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc2c(C=O)cn(C)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: Cc1ccc2c(CC#N)cn(C)c2c1
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
A suspension of potassium tert-butoxide (KOtBu) (2.21 g, 19.7 mm) in DME (30 mL) was cooled to -30° C., and treated with a solution of TosMIC (1.97 g 10.1 mm). After addition was complete, the mixture was further cooled to -60° C., treated with 1,6-dimethyl-1H-indole-3-carboxaldehyde (5.8 mm) in DME(20 mL), and stirred at that temperature for 1.5 hours. Addition of methanol (15 mL) to the cooled solution, was followed by heating to reflux temperature for 15 minutes, and evaporation of the solvent. The residue was treated with H2O (20 mL) containing acetic acid (HOAc) (0.75 mL), then extracted with CH2Cl2 (50 mL×3). The combined organic fractions were extracted with saturated NaHCO3 solution, dried over MgSO4, filtered and evaporated. Purification by flash column chromatography afforded (1,6-dimethyl-1H-indol-3-yl)-acetonitrile (0.86 g, 81%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:3]=1.[Cl:19][C:20]1[C:21](B(O)O)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[Cl:19][C:20]1[C:21]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[N:3]=2)=[CH:22][C:23]([F:26])=[N:24][CH:25]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: N#Cc1ccc(Cl)nc1NCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ccc(-c2cc(F)ncc2Cl)nc1NCc1cccc(F)c1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
6-chloro-2-(3-fluorobenzylamino)nicotinonitrile (0.602 g, 2.30 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (1.21 g, 6.91 mmol), and sodium carbonate (2.99 mL, 5.99 mmol, 2M in H2O) were dissolved in DME (10.5 mL). The resulting solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf)CH2Cl2 adduct (0.376 g, 0.460 mmol). The resulting reaction mixture was heated in the microwave at 120° C. for 10 min. It was then filtered through a pad of Celite. The filtrate was concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 5 EtOAc/95 hexanes to 50 EtOAc/50 hexanes yielded 0.2689 g (33%) of 5′-chloro-2′-fluoro-6-(3-fluorobenzylamino)-2,4′-bipyridine-5-carbonitrile. LCMS (m/z): 357.2 (MH+), retention time=1.02 min.