Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[CH3:15][Sn](C)(C)C>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([CH3:15])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: COC(=O)c1nc(Cl)c(I)c(N)c1Cl
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)c1nc(Cl)c(C)c(N)c1Cl
Yield: 82.4 %

Procedure:
A mixture of methyl 4-amino-3,6-dichloro-5-iodopicolinate (8.1 g, 23.4 mmol), tetramethylstannane (8.35 g, 46.7 mmol), and bis(triphenylphosphine)palladium(II) chloride (2.5 g, 3.5 mmol) in 1,2-dichloroethane (40 mL) was irradiated in a Biotage Initiator™ microwave at 120° C. for 30 min, with external IR-sensor temperature monitoring from the side. The reaction mixture was loaded directly onto a silica gel cartridge and purified by flash chromatography (silica gel, 0-50% ethyl acetate/hexanes) to provide the title compound as an orange solid (4.53 g, 19.27 mmol, 83%): mp 133-136° C.; 1H NMR (400 MHz, CDCl3) δ 4.92 (s, 2H), 3.96 (s, 3H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.34, 150.24, 148.69, 143.94, 117.01, 114.60, 53.02, 14.40; ESIMS m/z 236 ([M+H]+), 234 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[O-:26][C:27]#[N:28].[K+]>C(O)(=O)C.O>[CH2:15]([C:12]1[C:13](=[O:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:27]([NH2:28])=[O:26])[CH:3]=2)[C:9]2[N:25]=[CH:24][CH:23]=[CH:22][C:10]=2[N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
To a solution of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (200 mg) in acetic acid (2 ml) and water (2 ml) was added solution of potassium cyanate (99 mg) in water (1 ml). The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate and washed with an aqueous sodium bicarbonate solution, and brine, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (4% methanol in chloroform) to afford 2-benzyl-3-oxo-4-(3-ureidophenyl)-3,4-dihydropyrido[2,3-b]pyrazine (78 mg) as solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([NH:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:9]([NH:13][C:14]([C:16]1[C:17]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][Br:1])=[CH:24][CH:23]=2)=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1ccc(-c2ccccc2C(=O)NC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)NC(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
4.39 g of N-bromosuccinimide and 50 mg of benzoyl peroxide were added to a solution of 6.00 g of N-t-butyl-4'-methylbiphenyl-2-carboxamide [prepared as described in Preparation 38(i)] in 90 ml of carbon tetrachloride, and the mixture was heated under reflux for 4 hours. At the end of this time, the reaction mixture was cooled to room temperature, washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to give 7.04 g of the title compound as crystals, melting at 124°-126° C.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]([O:16]C)=[O:15])=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[CH:1]1([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]([OH:16])=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(=O)n(C2CCCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(=O)n(C2CCCCC2)c1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a solution of methyl 1-cyclohexyl-6-oxo-1,6-dihydropyridine-3-carboxylate (100 mg, 0.43 mmol) in 10 mL of THF:MeOH (3:1) was added 1M LiOH (1 mL, 1 mmol). The solution was stirred at room temperature until starting material was consumed as determined by LC-MS. The solution was then concentrated in vacuo, acidified with 2 N HCl to pH 2, and extracted with EtOAc (3×). The combined EtOAc layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give 60 mg (63%) of the title compound as a golden yellow solid. MS m/z: 222.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>C(O)(C)C>[OH:23][CH:20]([CH2:21][OH:22])[CH2:19][NH:18][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: NCC(O)CO
Reactant: O=[N+]([O-])c1nccnc1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1nccnc1NCC(O)CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.5 g (0.0094 mol) 3 and 1.01 g (0.01 mol) triethylamine in 25 ml isopropanol is added 0.91 g (0.01 mol) 3-amino-1,2-propanediol (10). The reaction mixture becomes reddish and is stirred at room temperature for 16 hours. The solvent is then removed on the rotary evaporator and the residue is purified by flash chromatography on silica gel to afford pure 11 as a yellow solid, m.p. 100°-102°.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].[Cl:12]C(Cl)(Cl)C(Cl)(Cl)Cl.C([Li])CCC>>[Cl:12][C:8]1[CH:9]=[CH:10][N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: CN(C)S(=O)(=O)n1cccn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Product: CN(C)S(=O)(=O)n1ccc(Cl)n1

Procedure:
US 20130288893(A1) describes, inter alia, certain (3-halo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amides and carbamates and their use as pesticides. The route to prepare such compounds involved the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) by the direct coupling of 3-bromopyridine with 3-chloropyrazole. The 3-chloropyrazole was prepared by a) treating 1H-pyrazole with 2-dimethylsulfamoyl chloride and sodium hydride to provide N,N-dimethyl-1H-pyrazole-1-sulfonamide, b) treating the N,N-dimethyl-1H-pyrazole-1-sulfonamide with perchloroethane and n-butyl lithium to provide 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide, and c) removing the N,N-dimethylsulfonamide from 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide with trifluoroacetic acid to give the 3-chloropyrazole.
Reaction SMILES: Cl.[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10]Cl)([CH3:4])[CH3:3].[NH2:36][CH2:37][CH2:38][SH:39]>>[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10][S:39][CH2:38][CH2:37][NH2:36])([CH3:3])[CH3:4]
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: NCCS
Agent: Cl
Product: CC(C)OCCN(C(=O)CSCCN)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 1, 1-{4-[N-(2-isopropoxyethyl)-N-chloroacetylamino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine hydrochloride is reacted with cysteamine (=2-mercaptoethylamine), yielding 1-{4-[N-(2-isopropoxyethyl)-N-(2-aminoethylmercapto-acetyl)-amino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11]C(C)C)[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=1[OH:19])([CH3:4])([CH3:3])[CH3:2].[CH:20]1(C2C=C(C)C=C(C3CCCC3)C=2O)[CH2:24]CC[CH2:21]1>>[C:15]([C:7]1[CH:8]=[C:9]([CH2:11][CH2:21][CH2:20][CH3:24])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:6]=1[OH:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: Cc1cc(C2CCCC2)c(O)c(C2CCCC2)c1
Product: CCCCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
2,6-di-tertbutyl-4-isobutylphenol; 2,6-dicyclopentyl-4-methylphenol;
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:19]([CH3:20])=NON=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CC[C@H](OC(=O)C(F)(F)F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:53][C:54]1C=CC=C[C:55]=1[S:60]([CH3:63])(=[O:62])=[O:61]>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:19]=[CH:20][CH:53]=[CH:54][C:55]=3[S:60]([CH3:63])(=[O:62])=[O:61])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Reactant: CS(=O)(=O)c1ccccc1CBr
Agent: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3ccccc3S(C)(=O)=O)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 1-(bromomethyl)-2-(methylsulfonyl)benzene and isolated as white solid. MS (m/e): 431.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([O:14]COC)=[C:6]([O:18][CH3:19])[CH:5]=1.Cl>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([OH:14])=[C:6]([O:18][CH3:19])[CH:5]=1
Reactant: COCOc1c(OC)cc(C(=O)OC)cc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To a solution of 3-methoxy-4-methoxymethoxy-5-trifluoromethylbenzoic acid methyl ester (453 mg) in THF (4 mL) was added 6N-hydrochloric acid (4 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1 to 3:1, v/v) to give the title compound (186 mg).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:4]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:4]=1)=[O:22]
Reactant: COc1ccccc1CC(=O)c1c[nH]c2ccccc12
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCn1cc(C(=O)Cc2ccccc2OC)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21.8 %

Procedure:
60% Sodium hydride in mineral oil (480 mg, 12 mmol) was suspended in dimethylformamide (50 ml) and 1-(1H-indol-3-yl)-2-(2-methoxyphenyl)ethanone 3 (2.66 g, 10 mmol) was added portionwise at room temperature, allowing to stir further 45 min at room temperature after the addition was finished. Ethyl 5-bromovalerate (2.37 ml, 15 mmol) was added dropwise at room temperature and the reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the residue was taken into water (30 ml) and extracted three times with ethyl acetate (3×50 ml). The organic fractions were combined and dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) to give 856 mg (22%) of ethyl 5-(3-(2-(2-methoxyphenyl)acetyl)-1H-indol-1-yl)pentanoate (Ethyl N-(carboxybutyrate) JWH-250) 7 as a semi solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41][S:54]([CH3:53])(=[O:56])=[O:55])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (0.1 g) and triethylamine (0.026 mL) in dichloromethane (3 mL) was added methanesulfonyl chloride (0.013 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (0.11 g). This material was dissolved in a solution of acetonitrile (2 mL) and methanol (2 mL). To the solution were added 3-benzylaminopropionamide (46 mg) and sodium iodide (24 mg), and the mixture was stirred at 60° C. for 3 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give the title compound (78 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:19])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:20]1([C:26]2([C:29](O)=[O:30])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:29]([C:26]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:28][CH2:27]3)=[O:30])[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1
Reactant: Cn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)C1(c2ccccc2)CC1
Product: Cn1cc(C(=O)c2cncc(NC(=O)C3(c4ccccc4)CC3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Library protocol 1 starting from (5-amino-pyridin-3-yl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 110) and 1-phenylcyclopropanecarboxylic acid to afford the title compound. LCMS: Rt=2.61 min; m/z 398 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10](O)=[O:11])[S:9][C:5]=2[CH:4]=1.CN([C:20]([O:24][N:25]1N=NC2C=CC=N[C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:20][O:24][N:25]([CH3:26])[C:10]([C:8]1[S:9][C:5]2[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:14]=[CH:13][C:6]=2[CH:7]=1)=[O:11]
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)cc2s1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc2ccc(C(F)(F)F)cc2s1
Reaction time: 0.03 h

Procedure:
To 6-(Trifluoromethyl)-1-benzothiophene-2-carboxylic acid dissolved in DMF (0.5 M) was added HATU (1.2 equiv) at 0° C. and the reaction was stirred for 2 min followed by addition of N,O-dimethylhydroxylamine hydrochloride (1.5 equiv). The reaction was stirred for 2 min prior to the addition of iPr2NEt (5 equiv). The reaction was stirred for an additional 20 min at 0° C. The reaction was quenched with equivalent amounts of half-saturated aqueous NaHCO3 and H2O. The title compound was obtained as a solid and filtered on a Büchner funnel before being and air-dried.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH2:8][C:9]=1[C:10]#[N:11].[CH2:12](I)[CH3:13]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:12]([N:6]1[CH2:7][CH2:8][C:9]([C:10]#[N:11])=[C:3]([Cl:2])[CH2:4][CH2:5]1)[CH3:13]
Reactant: CCI
Reactant: N#CC1=C(Cl)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CCC(Cl)=C(C#N)CC1
Reaction time: 8 h

Procedure:
7.1 gm (0.037 mol) of 4-chloro-5-cyano-2,3,6,7-tetrahydro-1H-azepine hydrochloride were dissolved in 170 ml of chloroform by addition of 28.5 ml of triethylamine. Then, 8.6 gm (0.055 mol)=4.9 ml of ethyl iodide were added dropwise at the boiling point, while stirring, and the mixture was refluxed for 4 hours. To complete the reaction, another 10 ml of triethylamine and 2.5 ml of ethyl iodide were added, and the mixture was boiled further. After a total of 10 hours the reaction was finished. After standing overnight, the mixture was concentrated by evaporation in vacuo. The residue was chromatographed on a silica-gel column (chloroform/methyl alcohol/ammonia=9:1:0.1). After the corresponding fractions had been concentrated by evaporation, the mixture was evaporated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:20].[Na+].II>CN.C(O)C.O>[OH:19][C:16]1[C:17]([I:20])=[CH:18][C:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Reactant: [I-]
Agent: CN
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2cc(O)c(I)cc2CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 7-hydroxy-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (5.2 g, 20 mmol) in 33% methylamine in ethanol (30 ml) was stirred at 0° C. A solution of sodium iodide (4.6 g, 30 mmol) and iodine (5.2 g, 20 mmol) in water (30 ml) was added below the surface of the reaction mixture. After stirring at 0° C. for 1 hour the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was separated, washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound (D41); (7.0 g, 90%), 1H NMR (d6-DMSO) 10.0 (1H, br s), 7.41 (1H, s), 6.65 (1H, s), 3.40 (4H, m), 2.70 (4H, m), 1.40 (9H, s).
Reaction SMILES: [F:1][C:2](=[CH:5][CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:3]=[O:4].[Na].C1(S)C=CC=CC=1.O>CCCCCC>[F:1]/[C:2](=[CH:5]\[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11])/[CH:3]=[O:4]
Reactant: CC(C)(C)[Si](C)(C)OCCC=C(F)C=O
Agent: Sc1ccccc1
Agent: [Na]
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC/C=C(\F)C=O

Procedure:
5.50 Grams of 2-fluoro-5-(tert-butyldimethylsilyloxy)-2-pentenal (E form:Z form=11:1) was dissolved in 50 ml of dry hexane, and after adding 20 mg of the sodium salt of thiophenol, the resulting solution was heated under reflux for 20 hours with stirring. Thereafter, 10 ml of water was added to the reaction solution, and the toluene layer was separated. The aqueous layer was extracted twice with ether, and the ether extracts were combined with the above toluene layer. This mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 5.50 g of (Z)-2-fluoro-5-(tert-butyldimethylsilyloxy)-2-pentenal.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CC#N>[N+:18]([C:14]1[CH:13]=[C:12]([C:10]2[S:11][C:4]3=[N:3][C:2]([N:24]4[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]4)=[CH:7][C:6](=[O:8])[N:5]3[N:9]=2)[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=c1cc(Cl)nc2sc(-c3cccc([N+](=O)[O-])c3)nn12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc([N+](=O)[O-])c4)sc3n2)CC1
Temperature: 150 °C
Yield: 96.9 %

Procedure:
To 7-chloro-2-(3-nitrophenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (1.0 g, 3.24 mmol) in MeCN (30 ml) in a microwave vial is added tert-butyl 1-piperazinecarboxylate (0.724 g, 3.89 mmol) followed by DIPEA (1.697 ml, 9.72 mmol). The mixture is heated in the microwave to 150° C. for 25 min., cooled and concentrated in vacuo and purified via column chromatography on a 50 g snap column with 0-10% MeOH/DCM gradient elution to give tert-butyl 4-(2-(3-nitrophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (1.44 g, 3.14 mmol, 97% yield) as a tan solid.
Reaction SMILES: CC(C)([O-])C.[K+].COP([CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC)=O.[CH3:24][NH:25][C:26](=[O:46])[C@H:27]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[NH:28][C:29](=[O:36])[C:30](=O)[CH2:31][CH:32]([CH3:34])[CH3:33].O>CN(C)C=O>[CH3:24][NH:25][C:26](=[O:46])[C@H:27]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[NH:28][C:29](=[O:36])[C:30]([CH2:31][CH:32]([CH3:33])[CH3:34])=[CH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: COP(=O)(CC(=O)OCc1ccccc1)OC
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(=O)CC(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(=CC(=O)OCc1ccccc1)CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tertiary butoxide (2.1 g., 0.0188 mol.) was suspended in dry dimethylformamide (50 mls.). To the suspension was added benzyl dimethylphosphonoethanoate (4.6 g., 0.0187 mol.) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hours. N-(4-Methyl-2-oxopentanoyl)-O-methyl-L-tyrosine N-Methylamide (3.0 g., 0.00913 mol) was added portionwise to the reaction mixture over a period of 10 minutes to yield a red solution. The red solution was stirred at room temperature for 4 hours, and then poured into water (500 mls.). The resulting mixture obtained was extracted with ethyl acetate (2×100 mls.) and the ethyl acetate extract was washed with water (2×25 mls.), brine (25 mls.) and dried over anhydrous magnesium sulfate. The ethyl acetate was removed by evaporation in vacuo to yield a crude solid product (4.2 g.). The crude product was purified by recrystallization from a mixture of ethyl acetate and hexane to yield E and Z N-[3-(benzyloxycarbonyl)-2-(2-methylpropyl)propenoyl]-O-methyl-L-tyrosine N-methylamide as a light brown crystalline solid. (m.p. 167°-9° C. Found: C, 68.3; H, 7.1; N, 6.3 %. C25H30N2O5 requires C, 68.5; H, 6.9; N, 6.4%).