Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][O:8][CH2:7][CH:6]1[O:10][C:11]([CH2:13][O:14][C:15]1[C:16]([Cl:31])=[CH:17][C:18]([F:30])=[C:19]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]2)=[S:23])[CH:20]=1)=[O:12])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:38](Cl)(Cl)=[S:39]>ClCCl>[C:1]([O:4][CH:5]1[CH2:9][O:8][CH2:7][CH:6]1[O:10][C:11]([CH2:13][O:14][C:15]1[C:16]([Cl:31])=[CH:17][C:18]([F:30])=[C:19]([N:21]=[C:22]2[N:24]3[N:25]([CH2:26][CH2:27][CH2:28][CH2:29]3)[C:38](=[S:39])[S:23]2)[CH:20]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1COCC1OC(=O)COc1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1COCC1OC(=O)COc1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Yield: 72 %

Procedure:
In 15 ml of dichloromethane was dissolved 1.43 g of 1-(5-(4-acetoxytetrahydrofuran-3-yloxycarbonylmethoxy)-4-chloro-2-fluorophenylaminothiocarbonyl)hexahydropyridazine, followed by addition of 0.59 g of pyridine, which was then cooled in an ice-cold bath. Under stirring, a solution of 0.52 g of thiophosgene in dichloromethane was added dropwise, and after addition was completed, the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water, subsequently with aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After distilling off the solvent the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane=2/3), to obtain 1.12 g of a compound (No. 42) described in Table 1 (72%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][N:11]=1.C([O-])([O-])=[O:27].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:27])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][N:11]=1
Reactant: N#Cc1ccc(Cl)c(-c2ccc(CNCCC3CCCCC3)cn2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Cl)c(-c2ccc(CNCCC3CCCCC3)cn2)c1

Procedure:
To a solution of 4-chloro-3-{5-[(2-cyclohexylethylamino)methyl]pyridin-2-yl}benzonitrile (170 mg, 0.48 mmol) in DMSO (4 mL) was added K2CO3 (66 mg, 0.48 mmol) and 70% hydrogen peroxide (0.5 mL, 4.8 mmol). The mixture was stirred at rt for 5 h before water (5 mL) was added and the mixture partitioned between EtOAc (20 mL) and water (20 mL). The organic phase was washed with water (3×20 mL), brine (20 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (0.4% NH3: 4% MeOH: DCM) to give the title compound: RT=2.57 min; m/z (ES+)=372.2 [M+H]+.
Reaction SMILES: [N:1]([C:4]([CH3:13])([CH3:12])[CH2:5][C:6]([N:8]([CH2:10][CH3:11])[CH3:9])=O)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:10]([N:8]([CH3:9])[CH2:6][CH2:5][C:4]([CH3:13])([NH2:1])[CH3:12])[CH3:11]
Reactant: CCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(C)CCC(C)(C)N
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
3-Azido-N-ethyl-N,3-dimethylbutanamide (5.09 g, 27.6 mmol) was dissolved into anhydrous THF (50 mL) and added dropwise to a suspension of LAH (2.10 g, 2.0 equiv, 55.2 mmol) in anhydrous THF (100 mL) to maintain the reaction at reflux (30 min). After complete addition, the flask was fitted with a condenser and the reaction heated in a 70° C. oil bath for 8 h. The reaction mixture was cooled in an ice bath and water (2.1 mL) was added dropwise over 20 min. Then 15% NaOH solution (2.1 mL) was added dropwise over 10 min. The suspension was stirred for a further 10 min and water (2.1 mL) was added in one portion and the mixture stirred for 30 min to a give fine white suspension. The suspension was filtered through a pad of Celite® and washed with diethyl ether (2×100 mL). The combined filtrate was concentrated with a bath temperature between 10-13° C. to an orange liquid (1.87 g, 47%). LRMS (ESI+) for C8H20N2 (144.1); Found: 145 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH2:22][CH2:23][OH:24])=[CH:15]3)=[C:10]([CH2:25][CH3:26])[CH:9]=[C:8]([C:27]([O:29][CH3:30])=[O:28])[C:7]1=[O:31].CCN(CC)CC.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH2:22][CH2:23][O:24][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:15]3)=[C:10]([CH2:25][CH3:26])[CH:9]=[C:8]([C:27]([O:29][CH3:30])=[O:28])[C:7]1=[O:31]
Reactant: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCO)n2C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCOS(C)(=O)=O)n2C
Temperature: 0 °C
Yield: 98.7 %

Procedure:
To solution of methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(2-(2-hydroxyethyl)-1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.142 g, 2.26 mmol) in DCM (10 mL) was added NEt3 (0.45 mL, 3.23 mmol) and mixture was cooled to 0° C. Methanesulfonyl chloride (0.22 mL, 2.84 mmol) was added dropwise and reaction mixture was stirred at 0° C. 15 min. LC/MS indicated complete consumption of the starting material. Reaction was diluted with DCM (20 mL) and washed with H2O (10 mL). Organic phase was dried over Na2SO4 and solvent was removed under reduced pressure. Methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(1-methyl-2-(2-(methylsulfonyloxy)ethyl)-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.30 g) was obtained in nearly quantitative yield as yellow solid and was pure enough to be used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:61]([NH:64][CH2:65][CH2:66][S:67]([NH2:70])(=[O:69])=[O:68])([CH3:63])[CH3:62]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:64]([CH:61]([CH3:63])[CH3:62])[CH2:65][CH2:66][S:67](=[O:69])(=[O:68])[NH2:70])[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)NCCS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
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: CC(C)N(CCS(N)(=O)=O)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.030 g) and HATU® (0.058 g) in DMF (0.4 ml) was added DIPEA (0.040 ml) followed by a solution of 2-isopropylamino-ethanesulfonic acid amide (0.058 g) in DMF (0.6 ml) after 10 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.012 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[S:17]([N:20]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][N:26]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:19])=[O:18].[H-].[Na+]>CS(C)=O>[Cl:9][C:10]1[CH:15]=[C:14]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:13]=[CH:12][C:11]=1[S:17]([N:20]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][N:26]=1)[CH2:21][CH:22]([CH3:23])[CH3:24])(=[O:19])=[O:18]
Reactant: OCC1CCOCC1
Reactant: Cc1cnc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2Cl)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cnc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2Cl)c(C)c1
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a stirred solution of 4-(hydroxylmethyl)tetrahydro-2H-pyran (2.63 mg, 0.023 mmol) and 2-chloro-N-(3,5-dimethylpyridin-2-yl)-4-fluoro-N-isobutylbenzenesulfonamide (8.4 mg, 0.023 mmol) in dimethyl sulfoxide (200 μL) at room temperature was added sodium hydride (60% wt in mineral oil) (0.906 mg, 0.023 mmol) and the reaction stirred for 2 hours. The reaction was quenched with methanol (2 mL) and water (2 mL), then the solvents evaporated in vacuo. The crude product was purified by flash silica (Si) chromatography (25% ethyl acetate-cyclohexane gradient) to give the title compound (5.2 mg). LCMS (2 min, High pH) Rt 1.48 min, m/z (ES+) 468 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([Cl:32])=[CH:25][C:26]([NH:30][NH2:31])=[N:27]4)=[CH:22][CH:21]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH:33](OCC)(OCC)OCC>CCO>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([Cl:32])=[CH:25][C:26]5[N:27]4[CH:33]=[N:31][N:30]=5)=[CH:22][CH:21]=3)[CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Cl)cc(NN)nc4c3)c2)CCOCC1
Solvent: CCO
Product: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Cl)cc5nncn5c4c3)c2)CCOCC1
Temperature: 65 °C

Procedure:
To 5c (3.7 mmol) in EtOH (60 mL) was added triethyl orthoformate (10 mL), and the reaction was heated to 65° C. overnight. After cooling to room temperature, the mixture was concentrated, and the residue was purified by silica gel chromatography (100% EtOAc) to give the desired product, 5d.
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].O.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>[OH-].[Na+].[Rh]>[CH2:18]([O:17][C:15]([N:1]1[CH:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]1[C:7]([OH:9])=[O:8])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1cccc(C(=O)O)n1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Rh]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCC(C(=O)O)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 83.1 %

Procedure:
2,6-Pyridine dicarboxylic acid (25 g, 0.15 mol) was dissolved in 2.0M NaOH (154 mL) and H2O (30 mL) at room temperature, and placed in a 500-mL Parr bottle. Rhodium on alumina powder (5%, 1.87 g) was added and the mixture was purged with argon for 15 minutes. The reaction mixture was shaken under 55 psi of hydrogen for 48 hours. The suspension was filtered through compacted Celite, and the clear filtrate was cooled to 0° C. Benzyl chloroformate (30.62 g, 0.18 mol) was added from the top to the cooled filtrate in three portions during a period of 30 minutes, and the solution was allowed to reach room temperature and stirred for additional 5 hours. The remaining benzyl chloroformate was extracted from the mixture with diethyl ether. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate (EtOAc). The EtOAc was passed over a short plug of Na2SO4 and evaporated. The residue was triturated with EtOAc (20 mL), and the resulting white solid was collected by vacuum filtration, washed with EtOAc (3×20 mL), and air-dried to give Compound 1 (38.3 g, 83% yield). Rf=0.06 (10% MeOH/CHCl3); 1H NMR: δ 1.49-1.73 (m, 4H), 1.96-2.03 (m, 2H), 4.48-4.65 (m, 2H), 5.10 (s, 2H), 7.26-7.35 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]2[C:35]([O:37][C:38](=O)[C:28]=2[CH:27]=1)=[O:36]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:35](=[O:36])[C:29]3[C:28](=[CH:27][CH:26]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=3)[C:38]2=[O:37])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3ccc(C)cc3)ccc2o1
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc(C)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(4-methylphenyl)benzoxazole (75 mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (44 mg, 0.23 mmol) the title compound was obtained (78 mg, 67%). 1H NMR (DMSO) δ 8.43(dd, 1H), 8.33(s, 1H), 8.21(d, 1H), 8.10(d, 1H), 8.04(d, 1H), 7.85(d, 1H), 7.71(m, 2H), 7.63(d, 2H), 7.46(d, 1H), 7.30(d, 2H), 4.03(s, 3H), 2.36(s, 3H). MS 505.1 m/z (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]#[N:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1.C(N(CC)CC)C>C(O)CCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]#[N:16])[CH2:14][CH2:13][N:12]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: N#CC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: N#CC1(c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 79.7 %

Procedure:
A solution of 4-(4-chlorophenyl)piperidine-4-carbonitrile hydrochloride (0.055 g, 0.2155 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.033 g, 0.2155 mmol) and triethylamine (0.150 ml, 1.0775 mmol) in n-butanol (2.0 ml) was heated to 100° C. for 2 days. Concentration and trituration with methanol (3 ml) gave a white solid (0.058 g, 80%). LC-MS (LCT2) m/z 338 [M+H+], Rt 6.17 min.
Reaction SMILES: [Cl:1][C:2]1[C:3](=O)[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].O=P(Cl)(Cl)[Cl:12]>C1(C)C=CC=CC=1>[Cl:12][C:3]1[N:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncc(Cl)c1Cl
Solvent: Cc1ccccc1
Product: Clc1cnnc(Cl)c1Cl
Yield: 90 %

Procedure:
4,5-dichloropyridazin-3(2H)-one (10.0 g, 60.6 mmole) in POCl3 (60 mL, 642 mmole) was stirred at 110° C. for 18 hours. Toluene was added and the solvents removed under reduced pressure. EtOAc (200 mL) and water were added to the resulting residue and the organic layer washed with water and brine and then dried over MgSO4. Concentration under reduced pressure provided the desired product as an off white solid in 90% yield, 10 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[H-].[Na+].[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH3:1][C:2]1([CH3:9])[N:6]([S:22]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:24])=[O:23])[C:5](=[O:7])[N:4]([S:22]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:24])=[O:23])[C:3]1=[O:8]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC1(C)NC(=O)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(S(=O)(=O)c2cccc3ccccc23)C(=O)N1S(=O)(=O)c1cccc2ccccc12
Reaction time: 0.5 h
Yield: 6 %

Procedure:
5,5-Dimethylimidazolidine-2,4-dione (1.28 g) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (60%, in oil) (0.25 g) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 1-naphthalenesulfonyl chloride (2.38 g) was added at 0° C., and the mixture was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate (150 mL) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. After drying over anhydrous magnesium sulfate, the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded 160 mg of white crystals.
Reaction SMILES: [CH3:1][CH:2]([O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:3]#[CH:4].C[OH:12]>C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH3:1][CH:2]([O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:3](=[O:12])[CH3:4]
Reactant: CO
Reactant: C#CC(C)OCC(=O)OC
Agent: CC(=O)[O-]
Agent: [Hg+2]
Product: COC(=O)COC(C)C(C)=O

Procedure:
The product from Example 84A (20 g, 0.14 mol) in methanol (700 mL) was treated with mercury(II) acetate (4.6 g, 0.014 mol), heated to reflux for 1 hour, concentrated to approximately 100 mL total volume, treated with 1M HCl (100 mL) and extracted with dichloromethane (3×, 100 mL). The extractions were combined, dried (MgSO4), filtered and concentrated to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([O:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@H:10]([CH3:22])[CH:11]=[CH:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([O:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@H:10]([CH3:22])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[CH:21]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCC(=O)OC(NC(=O)OC(C)(C)C)[C@H](C)C=Cc1ccc2ccsc2c1
Agent: [Pd]
Solvent: CO
Product: CCCCCC(=O)OC(NC(=O)OC(C)(C)C)[C@H](C)CCc1ccc2ccsc2c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 86.4 %

Procedure:
(2R)-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4-(benzo[b]thiophen-6-yl)-3-butene (28.0 g, 64.9 mmol) obtained in Example 68(a) was dissolved in methanol (700 ml), and 10% palladium-charcoal (14.0 g) was added thereto followed by stirring for 6 days at room temperature under a hydrogen atmosphere. After the palladium-charcoal in the reaction solution was filtered out through Celite, the filtrate was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=15:1-10:1) to give the title compound (24.30 g, 87% yield) as a colorless oil.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:23]([Sn](CCCC)(CCCC)CCCC)=[CH2:24]>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([CH:23]=[CH2:24])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Temperature: 90 °C
Yield: 85 %

Procedure:
3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromo-6-chloro-pyridine from Example 69a (0.95 g, 2.4 mmol) and tetrakis(triphenylphophino) palladium (0.14 g, 0.12 mmol) were dissolved in toluene (50 mL) and degassed with nitrogen gas for 5 min. Vinyl tributyltin (0.78 mL, 2.67 mmol) was added and the mixture was heated to 90° C. for 1 day. The reaction solvent was evaporated and the crude residue was chromatographed (silica gel; hexanes/EtOAc, 4:1) to provide the title compound (0.69 g, 2.04 mmol, 85%). TLC Rf 0.3 (4:1 hexanes/EtOAc). MS (CI/NH3) m/z 339 (M+H)+. Continued elution provided a minor amount of 5, 6-diethenylpyridine (0.044 g, 0.13 mmol, 5.5%): TLC Rf 0.25 (4:1 hexanes/EtOAc); MS (CI/NH3) m/e 331 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.CO.O1C[CH2:17][CH2:16][CH2:15]1>[Ni]>[CH2:16]([C:17]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][C:6]([CH3:11])=[C:7]2[N:8]=1)[CH3:15]
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Ni]
Solvent: CO
Product: CCc1nc2c(C)ccnc2[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
10 g (65.3 mmol) of 2-amino-4-methyl-3-nitropyridine are hydrogenated in 40 ml of tetrahydrofuran and 40 ml of methanol in the presence of Raney nickel. The catalyst is filtered off, the solvent is removed, the residue is treated with ethanolic HCl solution and the precipitated 2,3-diamino-4-methylpyridine hydrochloride is filtered off with suction. 7 g of this hydrochloride are dissolved in 57 g of polyphosphoric acid (from 28.5 g of P2O5 and 28.5 g of H3PO4 (85% strength)) and treated with 1.26 ml of propionic acid, and the solution is stirred at 100° C. for 2 h. After cooling, it is poured into ice-water, rendered alkaline by addition of Na2CO3 and extracted several times with EA. The combined EA phases are washed with saturated NaCl solution, dried over Na2SO4 and concentrated and the residue is chromatographed on SiO2 (EA/MeOH 5:1). 4.2 g of the title compound result.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[CH2:14]([NH2:19])[C:15]([CH3:18])([CH3:17])[CH3:16].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:19][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(C)CN
Reactant: CCOC(=O)C(Br)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NCC(C)(C)C)c1cccnc1
Yield: 39.2 %

Procedure:
Bromopyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol), prepared in a manner similar to preparation 340, was reacted in refluxing CH2Cl2, overnight with neopentylamine (4.83 mL; 41.0 mmol; 4 equiv) and Et3N (5.8 mL; 41.0 mmol; 4 equiv). The reaction solution was evaporated to dryness, dissolved in CH2Cl2, washed five times with saturated NaHCO3(aq), washed once with saturated NaCl (aq), dried with Na2SO4, filtered, and concentrated in vacuo. The resulting brown oil was purified with silica gel chromatography in a 3×25 cm glass column using a 0.5% methanol/chloroform (v/v) mobile phase. A second column purification with 100% chloroform followed by 1% methanol/chloroform (v/v) produced pure product as a yellow oil (1.0 g; 40% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)[OH:6].[CH:13]([O-])=[O:14].[Na+]>C(O)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH:13]=[O:14])[C:5]=1[OH:6]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)c1cccc(NC=O)c1O

Procedure:
To a solution of methyl-3-aminosalicylate (3.34 grams, 20 mmol) in concentrated formic acid (20 mL) was added solid sodium formate (1.36 grams, 20 mmol, 1 eq.) and the resulting suspension stirred under reflux for 2 hours. The precipitate was filtered at room temperature and washed with water until neutral. After drying on air, 3.595 grams (92%) light brown crystals were collected. M+196, M−194.
Reaction SMILES: [Br:1]Br.[F:3][CH:4]([F:11])[C:5]1[CH:9]=[CH:8][N:7]([CH3:10])[N:6]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:9]1[C:5]([CH:4]([F:11])[F:3])=[N:6][N:7]([CH3:10])[CH:8]=1
Reactant: BrBr
Reactant: Cn1ccc(C(F)F)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(Br)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
At 25° C., bromine (Br2, 3 g) was added dropwise to a solution of 3-difluoromethyl-N-methylpyrazole (2.0 g) in methylene chloride (80 ml). The reaction mixture was stirred for a total of 22 h at 25° C., and aqueous sodium thiosulfate solution (0.1 M, 210 ml) was then added. After phase separation, the organic phase was freed from the solvent under reduced pressure (40° C./5 mbar). Part of the residue obtained (2.4 g of 2.8 g) was separated by column chromatography (SiO2, ethyl acetate/cyclohexane 1:6). 4-bromo-3-difluoromethyl-1-methylpyrazole was isolated in an amount of 1.4 g.