Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19](=[C:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:48]([Cl:50])[Cl:49]>C(O)(=O)C>[NH3:1].[CH2:48]([Cl:50])[Cl:49].[CH:19](=[C:26]1[CH2:31][CH2:30][N:29]([CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C(=C1CCNCC1)c1ccccc1
Reactant: O=Cc1ccccc1OCCCN1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C(=C1CCN(Cc2ccccc2OCCCN2CCCCC2)CC1)c1ccccc1
Product: N
Reaction time: 16 h

Procedure:
A solution of 2-(3-piperidin-1-yl-propoxy)-benzaldehyde (212 mg), 4-benzylidene-piperidine (154 mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (290 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (6 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (148 mg). 1H NMR (400 MHz, CDCl3): 7.37 (m, 1H), 7.30 (m, 2H), 7.23-7.16 (m, 4H), 6.92 (m, 1H), 6.86 (m, 1H), 6.27 (s, 1H), 4.00 (t, J=6.3 Hz, 2H), 3.60 (s, 2H), 2.60 (m, 2H), 2.55-2.46 (m, 6H), 2.44-2.37 (m, 6H), 2.00 (m, 2H), 1.64-1.56 (m, 4H), 1.47-1.40 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:4]([C:9](=[O:11])[CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:14]Br>Br>[Br:14][CH2:10][C:9]([C:4]1[C:3]([C:2]([F:1])([F:12])[F:13])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:11].[BrH:14]
Reactant: BrBr
Reactant: CC(=O)c1ncccc1C(F)(F)F
Agent: Br
Product: O=C(CBr)c1ncccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Dissolve 1-(3-trifluoromethyl-pyridin-2-yl)-ethanone (2.10 g, 11.1 mmol) in HBr (30% by wt in AcOH) (14 mL). Cool the mixture to 0° C. and add bromine (0.62 mL) drop wise. Allow the resulting solution to warm to room temperature and stir for 3 hours. Concentrate the reaction under reduced pressure to yield the title compound as its HBr salt.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)=O.C(N(CC)CC)C.Cl.Cl.[CH2:23]([NH:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[CH2:23]([N:30]1[C:5]2[C:4](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nn(Cc2ccccc2)c2ccc([N+](=O)[O-])cc12

Procedure:
2-Fluoro-5-nitroacetophenone (H. Sato et al, Bioorganic and Medicinal Chemistry Letters, 5(3), 233–236,1995) (0.24 g) was treated with triethylamine (0.73 ml) and benzyl hydrazine dihydrochloride (0.255 g) in ethanol (20 ml) at reflux under N2 for 8 days. The mixture was cooled and the solid 1-benzyl-3-methyl-5-nitroindazole (0.16 g) was collected by filtration; m/z (M+1)+ 268.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]([OH:12])=O)[CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:40]=[C:39]([OH:41])[C:38]([C:42]([OH:44])=[O:43])=[CH:37][N:36]=2)=[CH:31][CH:30]=1>CN(C)C=O.ClCCl>[C:1]([NH:4][CH:5]([C:10]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:40]=[C:39]([OH:41])[C:38]([C:42]([OH:44])=[O:43])=[CH:37][N:36]=2)=[CH:33][CH:34]=1)=[O:12])[CH2:6][CH:7]([CH3:8])[CH3:9])(=[O:3])[CH3:2]
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reactant: CC(=O)NC(CC(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC(CC(C)C)C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
A solution of 13.0 g (75 mmol) of N-acetyl-DL-leucine, 10.5 ml (75 mmol) of triethylamine, and 150 ml of dichloromethane is stirred at -10° C. and 9.75 ml (75 mmol) of isobutyl chloroformate is added. The reaction mixture is stirred for 1/2 hour at -10° C. and a cold solution of 11.6 g (50 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid and 7.7 ml (55 mmol) of triethylamine in 200 ml of dimethylformamide is added. The mixture is stirred at 5° C. for 3 hrs and overnight at room temperature. The reaction mixture is evaporated and the residue treated with water. The pH is lowered to 2.5 with dilute hydrochloric acid and the solid filtered, washed with water, and dried to give 13.8 g of 2-[4-(N-acetyl-DL-leucylamino)-phenyl]-4-hydroxy-5-pyrimidine carboxylic acid; mp 233°-235° C. dec.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH2:31]4)[S:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:41]1[CH:46]=[N:45][CH:44]=[C:43]2[NH:47][CH:48]=[CH:49][C:42]=12>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+]>[O:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:31][CH:32]([N:34]5[CH2:35][CH2:36][O:37][CH2:38][CH2:39]5)[CH2:33]4)[S:26][C:9]=3[N:10]=[C:11]([C:41]3[CH:46]=[N:45][CH:44]=[C:43]4[NH:47][CH:48]=[CH:49][C:42]=34)[N:12]=2)[CH2:6][CH2:5]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Reactant: Brc1cncc2[nH]ccc12
Agent: [Cu+]
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: c1cc2c(-c3nc(N4CCOCC4)c4nc(CN5CC(N6CCOCC6)C5)sc4n3)cncc2[nH]1
Temperature: 25 °C
Yield: 13.5 %

Procedure:
A degassed solution of 7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidine (120 mg, 0.18 mmol), 4-bromo-1H-pyrrolo[2,3-c]pyridine (46 mg, 0.23 mmol), PdCl2{PtBu2(Ph-p-Nme2)}2 (13 mg, 0.018 mmol) and copper(I) thiophene-2-carboxylate (7 mg, 0.036 mmol) in 1,4-dioxane (2.5 mL) was subjected to microwave irradiation at 140° C. for 20 minutes. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated to give a yellow oil. The oil was purified by chromatography (Si—PPC, DCM:MeOH, 100:0 to 98:2 to 95:5) to afford 168 as a yellow solid (12 mg, 14%). LCMS (Method E): RT=4.15 min, [M+H]− 493.2. 1H NMR (CDCl3, 400 MHz) δ 9.28 (bs, 1 H), 8.90 (s, 1 H), 7.53 (m, 2 H), 4.45 (m, 4 H), 4.02 (s, 2H), 3.90 (t, J=4.7 Hz, 4 H), 3.76-3.65 (m, 6 H), 3.19-3.09 (m, 3 H), 2.36 (d, J=4.76 Hz, 4H).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([NH:10][C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:9])=[CH:6][CH:5]=1.F[B-](F)(F)F.[H+].[H][H]>CO>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:9])=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1=C(NC(=O)c2ccc(OC(F)F)cc2)CCCC1
Reactant: [H][H]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CO
Product: CCOC(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccc(OC(F)F)cc1

Procedure:
In a 120 ml pressure resistant vessel were charged ethyl 2-{4-(difluoromethoxy)benzoyl}aminocyclohexene-1-carboxylate <5.0 g, 14.7 mmol>, diacetato{(S)-2,2′-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-1,1′-binaphthyl}ruthenium (II) (0.125 g, 0.0886 mmol), 42% tetrafluoroboric acid (14.3 ml, 0.1772 mmol) and methanol (25 ml) and the mixture was stirred. Thereafter, hydrogen (1 MPa) was filled therein, and the mixture was stirred at 45° C. for 40 hr. After confirmation of the completion of hydrogen absorption, the ordinary pressure was restored, and the mixture was concentrated into a diastereomer/enantiomer mixture to give the title compound as white crystals. yield 5.0 g. NMR data of (1S,2R) form 1H NMR (CDCl3) δ1.27 (3H, t, J=7.1 Hz), 1.4-1.9 (7H, m), 2.1-2.3 (1H, m), 2.8-2.9 (1H, m), 4.1-4.4 (3H, m), 6.56 (1H, t, J=76.6 Hz), 7.15 (2H, d, J=8.7 Hz)
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.Cl[CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21].C1(C)C=CC=CC=1.[NH2-].[Na+]>O>[C:1]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][C:4]([CH:7]([CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:8]#[N:9])=[CH:5][CH:6]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: N#CCc1ccc(-c2ccccc2)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(CCC(C#N)c1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 80 °C

Procedure:
The solution of 100 parts of α-(4-biphenylyl)acetonitrile and 90 parts of 2-chloro-N,N-diisopropylethylamine in 850 parts by volume of toluene is heated to about 80° C. and then 22 parts of sodium amide is added slowly over a period of 30 minutes keeping the temperature at 80°-85° C. The mixture is heated at 80° C. for another 30 minutes and then cooled to room temperature. 500 Parts by volume of water is then added to the mixture and the organic layer is separated and extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline by the addition of dilute sodium hydroxide. The alkaline mixture is extracted with ether and the ether extract is dried over calcium sulfate, filtered and stripped of solvent to afford an oil which solidifies upon standing. The crude oil is crystallized from hexane to afford α-(4-biphenylyl)-α-[2-(diisopropylamino)ethyl]acetonitrile, melting at about 54°-56° C. This compound is represented by the following structural formula ##STR21##
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.C1(B2OC(C)(C)[C:22](C)(C)[O:21]2)CC1.C([O-])([O-])=O.[K+].[K+]>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.C1(C)C=CC=CC=1.CO>[CH3:22][O:21][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Br)c(-c2ccccc2)c1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cc1-c1ccccc1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
A mixture of 2-bromo-5-nitro-3-phenylpyridine (0.72 mmol, 0.2 g), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.86 mmol, 0.16 ml), Pd(PPh3)4 (0.04 mmol, 0.05 g), K2CO3 (2 mmol, 0.28 g) in a toluene/methanol 4:1 mixture (10 ml) was heated at 100° C. for 30 minutes in a microwave, under argon atmosphere. The solvent was evaporated and the crude mixture was extracted between water and ethyl acetate. The solid residue was purified by chromatography over SiO2 eluting with hexane/ethyl acetate mixtures affording 2-methoxy-5-nitro-3-phenylpyridine (0.1 g, yield 55%) of an unexpected product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCCCCC.C(OCC)C>C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:13][C:14]3[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=3)=[C:6]([CH:12]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2)ccc1Oc1cncc(Cl)c1
Reaction time: 0.33 h

Procedure:
To a stirred solution of the aniline produced in Example 1 (168 mg, 0.574 mmol) in CH2Cl2 (3 mL) was added 4-chlorobenzenesulfonyl chloride (157 mg, 0.746 mmol, commercially available from Aldrich) at once. After 20 minutes, an additional amount (48 mg, 0.230 mmol) of 4-chlorobenzenesulfonyl chloride was added and the solution was stirred overnight. The product was isolated following column chromatography (1:1 hexane/diethyl ether). Yield: 160 mg (60%).
Reaction SMILES: [NH+]1C=CN[CH:2]=1.[N:6]1([C:11]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=3[S:13](=[O:25])(=[O:24])[N:12]=2)[CH:10]=[CH:9]N=C1.C(N)CC>>[N+:21]([C:19]1[CH:18]=[CH:17][C:15]2[NH:16][C:11]([NH:6][CH2:10][CH2:9][CH3:2])=[N:12][S:13](=[O:25])(=[O:24])[C:14]=2[CH:20]=1)([O-:23])=[O:22]
Reactant: c1c[nH+]c[nH]1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Solvent: CCCN
Product: CCCNC1=NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide imidazolium salt was treated with propylamine according to the general procedure Method A to give the title compound; m.p. 268-270° C.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C:8]1([C:12](O)=O)[CH2:11][CH2:10][CH2:9]1)=[O:6])[CH3:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[CH3:45][O:46][C:47](=[O:58])[C:48]1[CH:53]=[C:52]([NH:54][CH3:55])[C:51]([NH2:56])=[CH:50][C:49]=1[CH3:57]>C(Cl)Cl>[CH3:45][O:46][C:47]([C:48]1[C:49]([CH3:57])=[CH:50][C:51]2[N:56]=[C:12]([C:8]3([NH:7][C:5]([O:4][C:2]([CH3:15])([CH3:3])[CH3:1])=[O:6])[CH2:11][CH2:10][CH2:9]3)[N:54]([CH3:55])[C:52]=2[CH:53]=1)=[O:58]
Reactant: CNc1cc(C(=O)OC)c(C)cc1N
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc2c(cc1C)nc(C1(NC(=O)OC(C)(C)C)CCC1)n2C
Reaction time: 20 h
Yield: 58.1 %

Procedure:
1-((1,1-Dimethylethoxycarbonyl)amino)cyclobutanecarboxylic acid (1.40 g, 6.5 mmol) was dissolved in CH2Cl2 (45 mL) and reacted with TBTU in the presence of Et3N for a period of 30 min to pre-activate the acid. A solution of 4-amino-2-methyl-5-(methylamino)benzoic acid methyl ester 6-8 from Example 6 (1.33 g, 6.85 mmol) in CH2Cl2 (10 mL) was added slowly over a period of 30 min and stirring of the reaction mixture was continued for 20 h. The reaction mixture was concentrated to dryness, and the residue was re-dissolved in AcOH (10.0 mL) and stirred at 70° C. for 2 h to achieve cyclization of the benzimidazole ring. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (˜250 mL), extracted with aqueous saturated NaHCO3 (2×100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography (using a solvent gradient from 40% to 50% EtOAc in hexane) to obtain the pure 2-(1-tert-butoxycarbonylaminocyclobutyl)-3,6-dimethyl-3H-benzoimidazole-5-carboxylic acid methyl ester 7-1 as a beige solid (1.41 g, 55% yield) and recover some of the unreacted diamino starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:35][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[F:31])=[O:29]
Reactant: NCc1ccccc1F
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2F)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-fluorobenzylamine
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[O:9][C:8](=[O:17])[CH:7]=1)=[CH2:5])C.[Br:18]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>C1COCC1.O>[Br:18][CH2:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[O:9][C:8](=[O:17])[CH:7]=1)=[O:5]
Reactant: C=C(OCC)c1cc(=O)oc2cc(C)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(C(=O)CBr)cc(=O)oc2c1
Temperature: 25 °C

Procedure:
To a solution of 4-(1-ethoxyvinyl)-7-methyl-2H-chromen-2-one (1.56 g, 6.77 mmol) in THF-water (27.5 mL, 10/1 mixture), N-bromosuccinimide (1.33 g, 7.45 mmol) was added. The reaction was then stirred at room temperature. After 3 hours stirring, toluene was added and the crude mixture was evaporated under reduced pressure. The crude residue obtained was purified by column chromatography (EtOAc/hexanes, 30:70) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.71 (d, 1H), 7.24 (s, 1H), 7.22 (d, 1H), 6.94 (s, 1H), 4.90 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3Cl)=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:24]=[C:25](B(O)O)[S:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:25]2[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=2)[C:14]=1[C:10]1[NH:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Reactant: Cc1csc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1csc(-c2ccc(-n3nc(-c4c(F)cccc4-c4cc(C)cs4)[nH]c3=O)cc2)c1
Yield: 22 %

Procedure:
The title compound was prepared according to the procedure described in Example-2 using 2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-1, 0.100 g, 0.271 mmol), (4-methylthiophen-2-yl)boronic acid (0.059 g, 0.407 mmol), K2CO3 (0.112 g, 0.81 mmol), tetrakistriphenyl phosphine palladium (0) (0.062 g, 0.054 mmol) and DMSO (3.0 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 6.86 (s, 1H), 6.91 (s, 2H), 7.13 (s, 1H), 7.21 (d, J=9.3 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.48-7.55 (m, 1H), 7.61 (d, J=8.1 Hz, 211), 7.92 (d, J=9.0 Hz, 2H), 9.27 (br s, 1H). MS (m/z): 384.88 (M−H)−.
Reaction SMILES: [C:1]([O:7][C@@H:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])C)(=[O:6])[CH2:2]C(C)=O.[CH2:17](N(CC)CC)C.S([N:34]=[N+:35]=[N-])(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>C(#N)C>[N+:34](=[CH:2][C:1]([O:7][C@@H:8]([C:13]([Cl:14])([Cl:15])[Cl:16])[C:9]([CH3:17])=[CH:10][CH3:12])=[O:6])=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)O[C@H](C=C(C)C)C(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC=C(C)[C@@H](OC(=O)C=[N+]=[N-])C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
To a solution of (1R)-3-methyl-1-trichloromethyl-2-butenyl acetoacetate (1.63 g, 5.68 mmole) from Example IA.2.(a) and triethylamine (0.57 g, 5.68 mmole) in 10 ml of acetonitrile was added dropwise in small portions at 7-10 minute intervals over a total period of 30 minutes a solution of tosyl azide (1.12 g, 5.68 mmole) in 2 ml of acetonitrile. After stirring at room temperature for 21/4 hours, the mixture was poured into 17 ml of aqueous 1 NaOH. After stirring an additional 45 minutes, the mixture was extracted three times with ether, and the combined ethereal extracts were dried over MgSO4. The dried solution was concentrated to give an orange oil. The oil was chromatographed on 8 (20×20 cm) preparative tlc plates (silica gel) with CH2Cl2 as eluent to afford (1R)-2-methyl-1-trichloromethyl-2-butenyl diazoacetate (0.96 g, 62% isolated yield) as a yellow oil; [α]D31 =+59° (hexane).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[N:5]=1.C(=O)([O-])[O-].[Na+].[Na+].CO.O>C(=O)(O)[O-].[Na+]>[Br:1][C:7]1[C:6]([Cl:11])=[N:5][C:4]([NH2:3])=[N:9][C:8]=1[Cl:10]
Reactant: BrBr
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1nc(Cl)c(Br)c(Cl)n1
Temperature: 25 °C
Reaction time: 42 h
Yield: 83.7 %

Procedure:
Bromine (0.85 mL, 0.0166 mole) was added dropwise over 20 minutes to a stirred suspension of 2-amino-4,6-dichloropyrimidine (CAS#56-05-3, 1.70 g, 0.01037 mole) and sodium carbonate (1.00 g, 0.01244 mole) in 1:1 methanol/water (30 mL) at ambient temperature. Ten minutes after the addition was complete, more sodium carbonate (0.78 g, 0.0093 mole) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 42 hours, then it was diluted with aqueous sodium bicarbonate to provide 5-bromo-4,6-dichloropyrimidin-2-amine as a precipitate that was collected by filtration and rinsed with water. The vacuum-dried solid weighed 2.11 g (83.7% yield). 1H NMR (300 MHz, d6-DMSO) δ ppm 7.67 (s, 1H), 7.70 (s, 1H). MS (DCl—NH3) m/z=241 (M+H)+, m/z=258 (M+NH4)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[CH2:9][C:10]1[N:15]=[C:14]2[S:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2=[C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:11]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C)C=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:12]2[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:10]([CH2:9][N:3]3[CH:7]=[N:6][CH:5]=[N:4]3)[N:15]=[C:14]3[S:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=23)=[CH:22][CH:23]=1
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cn2cncn2)nc2sc(C)c(C)c2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
Sodium hydride (60% in oil, 0.158 g) was added to a solution of 1H-1,2,4-triazole (0.252 g) in N,N-dimethylformamide (DMF) (15 ml). The mixture was stirred for 15 minutes at room temperature, to which was added ethyl 6-chloromethyl-4-(4-chlorophenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (1.2 g). The mixture was stirred for 35 minutes at 80° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was subjected to column chromatography on silica gel. From the fraction eluted with dichloromethane-ethyl acetate (20:1, v/v), was obtained ethyl 4-(4-chlorophenyl)-2,3-dimethyl-6-(1,2,4-triazol-1-ylmethyl)thieno[2,3-b]pyridine-5-carboxylate (0.655 g, 50%). Recrystallization from ethanol gave colorless prisms, m.p.144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:12][CH:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10]1)=[O:8].[S:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[N:29]=[CH:28]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[C:3]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:12][CH:11]([N:13]2[CH2:18][CH2:17][N:16]([C:32]([C:30]3[N:29]=[CH:28][S:27][CH:31]=3)=[O:33])[CH2:15][CH2:14]2)[CH2:10]1)=[O:8]
Reactant: O=C(c1sc2cc(C(F)(F)F)ccc2c1Cl)N1CC(N2CCNCC2)C1
Reactant: O=C(O)c1cscn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1cscn1)N1CCN(C2CN(C(=O)c3sc4cc(C(F)(F)F)ccc4c3Cl)C2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of compound 1d (0.15 mmol), thiazole-4-carboxylic acid 1e (23 mg, 0.18 mmol), and Et3N (0.09 mL, 0.65 mmol) in CH2Cl2 (3 mL) at room temperature was added HATU (68 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 18 h. It was diluted with diethyl ether, washed with aq. NaHCO3 and aq. NaCl, dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave compound 1. 1H NMR (400 MHz, CD3OD): δ 8.80 (d, J=2 Hz, 1H), 8.13 (t, J=0.8 Hz, 1H), 8.03 (d, J=2 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.73 (dd, J=1.2 Hz, 8.6 Hz, 1H), 4.31 (m, 2H), 4.21 (m, 1H), 4.15 (m, 1H), 4.01 (m, 1H), 3.93 (m, 2H), 3.81 (m, 1H), 3.33 (m, 1H), 2.55-2.40 (m, 4H); MS m/z (M+H+) 515.