Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:9][C:10]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:11][CH:12]=1)(=O)=O.[C:30]([C@:32]1([OH:40])[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1)#[CH:31].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:21]([C:8]1[C:7]([C:31]#[C:30][C@:32]2([OH:40])[CH:37]3[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]3)[CH2:33]2)=[CH:12][CH:11]=[C:10]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Oc1ccc(OCC2CCCCO2)nc1Cc1ccccc1)C(F)(F)F
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O[C@]1(C#Cc2ccc(OCC3CCCCO3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 90 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A mixture of 428 mg of 2-benzyl-6-[(tetrahydro-4H-pyran-2-yl)methyloxy]-3-pyridyl trifluoromethanesulfonate, 180 mg of (3R)-3-ethynyl-3-quinuclidinol, 57.3 mg of tetrakis(triphenylphosphine)palladium(0), 1.9 mg of cuprous iodide, 415 μl of triethylamine and 5 ml of N,N-dimethylformamide was stirred at 90° C. for 3 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 305 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[Br:16]Br>C1COCC1>[Br:16][C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:8]=1
Reactant: Clc1ccnc2ccsc12
Reactant: BrBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccnc2cc(Br)sc12
Reaction time: 0.5 h
Yield: 755.8 %

Procedure:
To a stirred solution of the chloride 2 (10.12 g, 5.59 mmol) in dry THF (200 ml) at −78° C. was added n-BuLi (24 ml, 76.7 mmol, 2.5 M solution in hexanes) and the resultant suspension was stirred for 15 minutes. Bromine (18.9 g, 120 mmol) was added slowly and the reaction mixture was stirred for additional 30 min, quenched with water and diluted with EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (9:1 EtOAc/hexane) afforded title compound 41 (10.5 g, 71% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.62 (d, J=5.09 Hz, 1H), 7.92 (s, 1H), 7.59 (d, J=5.09 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.Cl[C:39]([O:41][CH3:42])=[O:40]>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:27][CH2:28][N:29]([C:39]([O:41][CH3:42])=[O:40])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccn5)CCNCC4)c3F)s2)c1
Reactant: COC(=O)Cl
Product: COC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccccn2)CC1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-(pyridin-2-yl)piperidin-4-yl)methyl)picolinamide (compound example 47) was reacted with methyl chloroformate to give the title compound. LC/MS (M+H)+: 594. Ret. time: 1.41 min. (Condition I); analytical HPLC Ret. time: 5.73 min (Condition H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([O:16]C)=O)[CH2:3]1.[NH2:18][CH2:19][CH2:20][OH:21]>CO>[OH:21][CH2:20][CH2:19][NH:18][C:14]([CH:4]1[CH2:3][C:2](=[O:1])[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5]1)=[O:16]
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: NCCO
Solvent: CO
Product: O=C(NCCO)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
A mixture of 46.7 g (0.2 mole) of methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate (J. Org. Chem., 26, 1519 (1961)], 36.7 g (0.6 mole) 2-aminoethanol and 500 ml methanol were refluxed overnight. The reaction was cooled to room temperature and the solvent removed at reduced pressure. The residue was taken up in dichloromethane and extracted with 3×100 ml 1N sodium hydroxide. The aqueous layer was taken to pH 5 with hydrochloric acid, extracted with 3×150 ml dichloromethane, then taken to pH 8 with sodium hydroxide solution and again extracted 3×150 ml dichloromethane. The aqueous layer was concentrated at reduced pressure and the resulting slurry stirred in dichloromethane. The salts were filtered off. The combined organic layers were dried over magnesium sulfate, the solvent removed at reduced pressure to yield 47.9 g of N-(2-hydroxyethyl)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][CH2:13][CH2:12][CH2:11][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1]
Reactant: OCc1ccccc1S
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccccc1SCCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of 11.9 g of 2-(hydroxymethyl)thiophenol, 35.44 g of 1-bromo-3-chloropropane, 11.58 g of potassium carbonate and 150 ml of dimethylformamide is stirred at room temperature for 2 hours. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is distilled under reduced pressure. 16.8 g of 2-(3-chloropropylthio)benzylalcohol are obtained as colorless oil. Yield: 93%.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH:15]([CH3:17])[CH3:16])=[C:11]([Cl:18])[NH:10][C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>CN(C)C=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH:15]([CH3:16])[CH3:17])=[C:11]([Cl:18])[N:10]([CH2:27][CH2:28][CH2:29][Cl:30])[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(Cl)[nH]c(=O)n(Cc2ccccc2)c1=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(Cl)n(CCCCl)c(=O)n(Cc2ccccc2)c1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a suspension of 20.91 g (75 mmol) of 3-benzyl-6-chloro-5-isopropylpyrimidine-2,4(1H,3H)-dione and 16.58 g (120 mmol) of potassium carbonate in 120 ml of N,N-dimethylformamide, 14.8 ml (150 mmol) of 1-bromo-3-chloropropane was added at room temperature. This mixture was stirred at 90° C. for 2 hours. After cooling, the reaction mixture was concentrated to dryness; the resulting residue was dissolved in chloroform-water. After the organic layer was washed with water and dried, the solvent was distilled off to yield an oily substance, which was then purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→3/1) to yield 8.06 g (30.1%, yellow oily substance) of the desired product.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH2+:14]3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[H][H]>CO.[Pd]>[Cl-:2].[C:6]1([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH2+:14]3)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)[NH2+]CC2
Reactant: [H][H]
Agent: [Pd]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccccc3)CCC1)[NH2+]CC2

Procedure:
1-(1-(4-Chlorophenyl)cyclobutyl)-7-(2-(propylsulfonamido)ethoxy)-1,2,3,4-tetrahydroisoquinolinium chloride (187 mg, 0.374 mmol, example 4), triethylamine (91 mg, 0.897 mmol), Pd/C (11.95 mg, 0.011 mmol) were suspended in dry MeOH (5 ml) and treated with hydrogen gas at ambient pressure for 14 h. The solvent was removed and the residue was purified by column chromatography using silica gel dichloromethane/methanol (97:3->95:5) as the eluent. The product was transferred into the hydrochloride with isopropylether and HCl dissolved in isopropanol (6%). The product was obtained as a white powder (68.0 mg, 0.146 mmol, 39%.)
Reaction SMILES: [NH2:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4])[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: CC(C)[C@@H](N)C(N)=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@@H](Nc1nc(Cl)ncc1Cl)C(N)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.4 %

Procedure:
A mixture of (R)-2-amino-3-methyl-butyramide (50 mg), 2,4,5-trichloropyrimidine (67 mg) and K2CO3 (116 mg) in DMF (3 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with DCM and washed with brine three times. The organic layer was dried with sodium sulfate and concentrated. The residue was purified by silica gel chromatography to provide 60 mg of (R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-butyramide: 1H NMR (300 MHz, CDCl3) 8.2 (s, 1H), 6.2 (bs, 1H), 5.8 (bs, 1H), 5.6 (bs, 1H), 4.6 (dd, 1H), 2.4 (m, 1H), 1.2 (d, 6H). MS (m/e) 263 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]1[CH2:27][CH2:28]1
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1ccc2ncccc2c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-cyclopropylpropanamide (80 mg, 0.301 mmol), 6-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (65 mg, 0.471 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give a crude (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (130 mg). The crude (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (130 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (35 mg). MS 392.2 (M+H); UV 203.6, 266.4, 299.0, 358.5 nm; t 0.406 min.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:37]=[CH:36][C:27]([C:28]([NH:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[CH3:20][S:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:21]=[CH:22][C:2]([C:25]2[CH:26]=[C:27]([C:28](=[O:29])[NH:30][C:31]3[S:32][CH:33]=[CH:34][N:35]=3)[CH:36]=[CH:37][C:24]=2[CH3:23])=[N:3][CH:4]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.96 min, MH+522. NMR: δH [2H6]-DMSO 10.19, (2H, b), 9.35, (1H, t), 9.17, (1H, s), 8.38, (1H, dd), 8.22, (1H, s), 8.07, (1H, d), 7.84, (1H, d), 7.57, (1H, d), 7.52, (1H, d), 7.31-7.28, (2H, m), 7.22, (1H, s), 7.11, (2H, m), 4.52, (2H, d), 2.99, (3H, s), 2.45, (3H, s).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.O[C@@H]([C@H](O)C(O)=O)C(O)=O.[C:23]1([C@H:29]2[CH2:31][C@@H:30]2[NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:32]([C@H:30]1[CH2:31][C@@H:29]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:5]=[O:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@H]1C[C@@H]1c1ccccc1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C=N[C@H]1C[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triphosgene (0.33 eq.) was added to a stirred, cooled 0° C., 0.053 M mixture of (2S,3S)-2,3-dihydroxysuccinic acid and (1S,2R)-2-phenylcyclopropanamine (1:1) (prepared according to: Newman in “Optical resolution procedures for chemical compounds” Chapter 1 Amines and related com. Pages 120-122) in a 1:1 mixture of DCM and sat. aq. NaHCO3 solution, and the reaction mixture was stirred at 0° C. for 1 h. The reaction was poured into a separatory funnel and layers were separated. Aqueous layer was extracted with DCM (×3). Combined organic layers were dried and evaporated to give the title compound as colorless oil in quantitative yield. 1H NMR (300 MHz, CDCl3, 300K) δ 7.30 (2H, t, J=7.0 Hz), 7.21 (1H, t, J=7.0 Hz), 7.05 (2H, d, J=7.0 Hz), 2.92 (1H, ddd, J=7.4, 4.3, 3.3 Hz), 2.20 (1H, ddd, J=9.8, 6.8, 3.3 Hz), 1.33-1.20 (2H, m).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[H-].[Na+].I[CH3:14]>C1COCC1.O>[CH3:14][O:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCc1cccs1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCCc1cccs1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 4-thiophen-2-yl-butan-1-ol (4.55 g, 29.09 mmol) in 20 ml of THF was carefully added to a stirred suspension of oil-free sodium hydride (1.05 g, 43.75 mmol) in 15 ml of THF. When the addition was complete, the mixture was heated to 50° C. and stirring continued for 1 hour. Iodomethane (2.7 ml, 43.75 mmol) was then added and the turbid solution was stirred at 50° C. for another 2 hours. After cooling, a few drops of water were added and the mixture was partitioned between 1N-HCl and ether. The organic layer was washed with saturated sodium bicarbonate solution and brine. Drying over sodium sulfate and careful evaporation (product is volatile) gave a pale yellow oil. Yield: 4.45 g (90%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Cl[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8](=[O:19])[C:7]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C>C(O)C>[CH2:17]([O:16][C:14]([CH2:13][N:9]1[C:10]([CH3:12])=[CH:11][C:6]([S:1][CH2:2][CH2:3][OH:4])=[C:7]([N+:20]([O-:22])=[O:21])[C:8]1=[O:19])=[O:15])[CH3:18]
Reactant: CCOC(=O)Cn1c(C)cc(Cl)c([N+](=O)[O-])c1=O
Reactant: OCCS
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)cc(SCCO)c([N+](=O)[O-])c1=O

Procedure:
2-Mercaptoethanol (0.168 mL, 2.4 mmol) was added to a stirred mixture of 4-chloro-1-ethyloxycarbonylmethyl-6-methyl-3-nitro-2-pyridinone (the product of Example 3, Step B, 549 mg, 2.0 mmol) and triethylamine (0.613 mL, 4.4 mmol) in ethanol (4 mL) and the mixture was heated to reflux for 15 min. The reaction was cooled and evaporated to a solid which was purified by flash column chromatography on silica gel (eluting with ethyl acetate), to give the title compound as a pale yellow crystalline solid:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:12][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:10])[F:11]
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1ccccc1S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1ccccc1C(F)(F)F
Reaction time: 12 h
Yield: 88.3 %

Procedure:
Dissolve 2-trifluoromethyl-benzenethiol (10 g, 56 mmol), potassium carbonate (25 g, 180 mmol), iodomethane (11 mL, 177 mmol) in DMF (100 mL). Stir for 12 hours. Filter the suspension through a pad of silica gel and elute with ethyl acetate (500 mL). Evaporate half of the solvent and wash the remaining solution with 10% aqueous LiCl (100 mL). Dry with MgSO4 and evaporate solvent. Chromatograph the residue on a SiO2 column eluting with hexane to give 9.5 g of 1-methylsulfanyl-2-trifluoromethyl-benzene (88%).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]([N+]([O-])=O)[CH3:21])=[CH:15][CH:14]=1.N1CCCCC1>C(O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][C:20]=2[CH3:21])=[CH:15][CH:14]=1
Reactant: CC(=Cc1ccc(F)cc1)[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C(C)C)oc(C)c1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl isobutyrylacetate (20.06 g, 126.8 mmol) and 1-fluoro-4-(2-nitro-1-propenyl)benzene (23.0 g, 127 mmol) in ethanol (100 ml) was added piperidine (12.5 ml, 127 mmol) at room temperature, and the mixture was stirred overnight at room temperature and at 80° C. for 1 hr. The solvent of the reaction solution was evaporated under-reduced pressure, water (50 ml) and conc. hydrochloric acid (30 ml) were added to the residue, and the mixture was stirred at room temperature for 1 hr. The reaction solution was extracted twice with ethyl acetate and the collected organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to give the objective substance.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[N:14][N:15]([C:17]3[N:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([O-])=[O:20])[CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[NH2:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:29]([OH:33])[C:30]([NH2:32])=[O:31]>CN(C)C=O>[NH2:32][C:30](=[O:31])[CH:29]([OH:33])[CH:28]([NH:27][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[N:25][C:17]=1[N:15]1[CH:16]=[C:10]2[CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12][C:11]2=[N:14]1)[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C([O-])c1cccnc1-n1cc2c(n1)CCN(Cc1ccccc1)C2
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CCN(Cc1ccccc1)C2
Yield: 129.9 %

Procedure:
Coupling of sodium 2-(5-benzyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)nicotinate (106 mg, 0.297 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (80 mg, 0.412 mmol) in N,N-dimethylformamide (10 mL) according to example 1.3 and work-up gave 197 mg of the title compound a amorphous solid; ESI-MS [M+H]+: 511.2.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[S:18](Cl)(=[O:20])=[O:19]>>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[S:18]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:20]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Cc1noc(N)c1Br
Product: Cc1cc(C)c(S(=O)(=O)Nc2onc(C)c2Br)c(C)c1
Yield: 64 %

Procedure:
2,4,6-Trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,4,6-trimethylbenzenesulfonyl chloride according to the procedures described in Example 1 b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a pink solid, m.p. 92°-95° C., yield 64%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:12]([N:16]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19](Cl)[CH:18]=[N:17]1)([CH3:15])([CH3:14])[CH3:13].O>CN(C)C=O>[C:12]([N:16]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=[N:17]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: OCc1ccc(F)cc1
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(F)cc2)cnn(C(C)(C)C)c1=O
Yield: 62.2 %

Procedure:
To a solution of 0.63 g (0.005 mol) of p-fluorobenzyl alcohol dissolved in 20 ml of N,N-dimethylformamide was added 0.24 g of 55% sodium hydride at room temperature under stirring. After addition, the resulting mixture was further stirred at room temperature for fifteen minutes. The reaction liquid was added dropwise with 1.0 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone, and was stirred at room temperature for eight hours. The reaction mixture was poured into 200 ml of water and then extracted with 50 ml of benzene. The resulting benzene layer was washed successively with 50 ml of 10% sodium hydroxide, 50 ml of 1N-hydrochloric acid, and 100 ml of water, dried over anhydrous sodium sulfate, and freed of solvent by distillation to give 1.5 g of crude product. The crude product was recrystallized from 20 ml of hexane to obtain 0.9 g of 2-t-butyl-5-(p-fluorobenzyloxy)-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[CH2:8][C:9]#[N:10].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)=O>C(O)C>[C:14]1(=[C:8]([C:7]2[CH:6]=[C:5]([CH3:4])[CH:13]=[CH:12][CH:11]=2)[C:9]#[N:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cccc(CC#N)c1
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Product: Cc1cccc(C(C#N)=C2CCCCC2)c1
Temperature: 85 °C
Yield: 57.7 %

Procedure:
Sodium methylate (5.40 g, 0.10 mol) is dissolved in ethanol (70 ml) and 3-methyl benzylcyanide (1310 g, 0.10 mol) is added over 2 min. Cyclohexanone (9.80 g, 0.10 mol) is added to the white suspension. The resulting mixture is heated to 85° C. (bath) for 4.5 h. Under icecooling, formic acid (5.0 ml) is added dropwise, upon which the mixture turns colourless. Standard aqueous workup as described in example 1, followed by a short path distillation at 0.05 mbar/157-165° C. yields 12.2 g of product (58% yield), which is further purified by a fine distillation at 0.05 mbar/183° C. to yield 3.95 g (19%) of product as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[F:55]C1C=C(C=CC=1)C[Zn+]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([F:55])[CH:29]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Reactant: Fc1cccc(C[Zn+])c1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Cl-]
Product: Fc1cccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Yield: 32 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and (3-fluorobenzyl)zinc(II) chloride in 32% yield.