Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9][C:8]=2[CH:18]=1)([O-])=O.Cl[Sn]Cl>Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9][C:8]=2[CH:18]=1
Reactant: O=[N+]([O-])c1ccc2sc(-c3cccnc3)nc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1ccc2sc(-c3cccnc3)nc2c1
Yield: 80 %

Procedure:
5-Nitro-2-(3-pyridinyl)benzothiazole 11.2 g, 0.044 mole, is dissolved in 45 cc of concentrated HCl. SnCl2, 35 g, in 45 cc of concentrated HCl is added, and the resulting mixture heated for 1 hour on a steam bath. After cooling, the precipitate is filtered, washed in cold HCl and neutralized in cold NaOh solution. The amine is filtered, washed with H2O and dried to yield 8.0 g of product m.p. 189°-196°.
Reaction SMILES: F[C:2]1([Cl:11])[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]1[Cl:10].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[CH:26][S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([Cl:11])=[C:3]([Cl:10])[CH:4]=3)[C:14]3[C:27]([CH3:28])=[CH:26][S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: NCC1=CC(Cl)C(F)(Cl)C=C1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluoro-3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([F:27])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([O:25]C)=O)[CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([Mg]Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([F:27])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[OH:25])[CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COC(=O)CCN1CCC(F)(c2cccc(OCc3ccccc3)c2)CC1
Solvent: C1CCOC1
Product: OC(CCN1CCC(F)(c2cccc(OCc3ccccc3)c2)CC1)(Cc1ccccc1)Cc1ccccc1
Reaction time: 14 h
Yield: 49 %

Procedure:
A solution of methyl 3-[4-(3-benzyloxyphenyl)-4-fluoropiperidin-1-yl]propionate (100 mg, 0.27 mmol) in THF (5 mL) was cooled in an ice bath and a 2M solution of benzylmagnesium chloride in THF (0.338 mL, 0.68 mmol) added dropwise over 5 minutes. The resulting yellow solution was then stirred for 14 h during which time the reaction reached room temperature. The mixture was then quenched with 25% aqueous ammonium chloride solution (10 mL) and diluted with ethyl acetate (3×10 mL). The organic layers were then combined and dried over magnesium sulfate. Subsequent filtration, concentration and purification by silica gel chromatography (SiO2, 50% ethyl acetate/heptanes) afforded 3-[4-(3-benzyloxyphenyl)-4-fluoropiperidin-1-yl]-1,1-dibenzylpropan-1-ol as a clear viscous oil in 49% yield.
Reaction SMILES: [F:1][C:2]1[C:3]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH3:28])=[N:22][CH:21]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:18][CH:17]([OH:19])[CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C(Cl)Cl>[CH3:39][S:36]([O:19][CH:17]1[CH2:16][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:5]3[N:4]=[C:3]([C:20]4[N:24]([CH:25]([CH3:26])[CH3:27])[C:23]([CH3:28])=[N:22][CH:21]=4)[C:2]([F:1])=[CH:7][N:6]=3)=[CH:10][CH:11]=2)[CH2:18]1)(=[O:38])=[O:37]
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC(O)C4)cc3)ncc2F)n1C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC(OS(C)(=O)=O)C4)cc3)ncc2F)n1C(C)C
Temperature: 0 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
To an ice cooled solution of 1-(4-{[5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-yl]amino}phenyl)azetidin-3-ol (Example 137; 0.728 g, 1.905 mM) and triethylamine (153 μl, 2.09 mM) in dry DCM (22 ml), mesyl chloride (162 μl, 2.09 mM) was added. The reaction was stirred at 0° C. for 30 minutes and at room temperature for 20 hours. The reaction mixture was diluted with more DCM and extracted in turn with water (twice), saturated sodium chloride, dried with anhydrous sodium sulphate, filtered and evaporated to give the title compound as a brown foam (717 mg, 82%). NMR 1.37 (d, 6H), 2.48 (s, 3H+DMSO), 3.25 (s, 3H), 3.82 (m, 2H), 4.2 (m, 2H), 5.4 (m, 2H), 6.45 (d, 2H), 7.35 (m, 3H), 8.42 (d, 1H), 9.13 (s, 1H); m/z 461.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1>>[Cl:35][C:32]1[CH:31]=[N:30][C:29]([N:23]2[CH2:22][CH2:21][C:20]3([CH2:19][C:18]4([O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=6)[CH:12]=[C:13]5[CH2:27]4)[CH2:26]3)[CH2:25][CH2:24]2)=[N:34][CH:33]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(c4ncc(Cl)cn4)CC3)C2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2,5-dichloro-pyrimidine following a procedure analogous to that described for Example 4. LC (method 1): tR=1.17 min; Mass spectrum (ESI+): m/z=502/504 (Cl) [M+H]+.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7]([C:9]1[C:10]([CH3:20])=[C:11]([CH:15]=[CH:16][C:17]=1[S:18][CH3:19])[C:12](N)=[O:13])=[O:8].S(=O)(=O)(O)[OH:22]>O.C(O)(=O)C>[CH3:5][O:6][C:7]([C:9]1[C:10]([CH3:20])=[C:11]([CH:15]=[CH:16][C:17]=1[S:18][CH3:19])[C:12]([OH:22])=[O:13])=[O:8]
Reactant: COC(=O)c1c(SC)ccc(C(N)=O)c1C
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(SC)ccc(C(=O)O)c1C

Procedure:
Sodium nitrite (2.4 g) was added dropwise to a stirred solution of 3-methoxycarbonyl-2-methyl-4-methylsulphenylbenzamide (4.2 g) in a mixture of concentrated sulphuric acid (50 ml), water (40 ml) and glacial acetic acid (70 ml) whilst maintaining the temperature below 5° C. The mixture was stirred without cooling for 0.5 hours. The brown solution was recooled to 0° C. and water (200 ml) was added. The mixture was extracted with ether (3×150 ml). The combined organic extracts were washed with water (2×150 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 3-methoxycarbonyl-2-methyl-4-methylsulphenylbenzoic acid (4.6 g) as a sticky orange solid NMR (CDCl3) 2.1(s,3H), 2.5(s,3H), 3.9(s,3H), 7.0(d, 1H), 7.85(d, 1H), 9.0(bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.[CH3:31][C:32]([NH2:36])([CH3:35])[CH2:33][NH2:34].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>C1COCC1>[NH2:36][C:32]([CH3:35])([CH3:31])[CH2:33][NH:34][C:27]([C:24]1[CH:25]=[CH:26][C:18]2[C:17]3[S:30][C:14]([C:9]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:12](=[O:13])[NH:11][N:10]=4)=[CH:15][C:16]=3[CH2:22][CH2:21][O:20][C:19]=2[CH:23]=1)=[O:29]
Reactant: CC(C)(N)CN
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(N)CNC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with 2-methylpropane-1,2-diamine, HATU and DIPEA in THF to give 332 as a colorless solid after reverse phase HPLC. MS: (ESI+) 510.0
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3([C:22](=[O:47])[NH:23][C@@H:24]([C:26]4[C:31]([F:32])=[CH:30][C:29]([C:33]5[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([F:40])[C:34]=5[C:41]5[N:45]=[C:44]([CH3:46])[O:43][N:42]=5)=[CH:28][N:27]=4)[CH3:25])[CH2:21][O:20][CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[Cl:39][C:37]1[CH:36]=[C:35]([F:40])[C:34]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[C:33]([C:29]2[CH:30]=[C:31]([F:32])[C:26]([C@H:24]([NH:23][C:22]([C:18]3([NH2:17])[CH2:21][O:20][CH2:19]3)=[O:47])[CH3:25])=[N:27][CH:28]=2)[CH:38]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc([C@@H](C)NC(=O)C3(NC(=O)OCC4c5ccccc5-c5ccccc54)COC3)c(F)c2)no1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc([C@@H](C)NC(=O)C3(N)COC3)c(F)c2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-carbamic acid 9H-fluoren-9-ylmethyl ester (71.9 mg, 0.107 mmol, step C) in DCM (5 ml) was added piperidine (0.5 ml) and the mixture was stirred at room temperature for 1 h. The colorless solution was concentrated to dryness under high vacuum. The remaining residue was purified by chromatography (silica gel; DCM/MeOH 98:2-95:5) and the title compound was obtained as colorless gum (36 mg, 75%). MS: 450.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1.[CH3:11]I>O1CCCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH3:11])=[N:8][CH:9]=1
Reactant: CI
Reactant: Nc1ccc(F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1ccc(F)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 117.8 mg, 4.91 mmol) in tetrahydrofuran (25 ml) was added a solution of 5-fluoropyridin-2-amine (500 mg, 4.46 mmol) in tetrahydrofuran (25 ml) at room temperature and the reaction mixture was stirred at 40° C. for 30 min. Then to the reaction mixture was added methyl iodide (696.9 mg, 4.91 mmol) at −40° C. and the resulting mixture was stand at room temperature overnight with stirring. The reaction was quenched by the addition of water and whole mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to afford 129 mg (23%) of the title compound:
Reaction SMILES: [CH2:1]([C@@:5]1([CH2:24][CH3:25])[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]>CCCCCC.CCOC(C)=O>[CH2:1]([C@@:5]1([CH2:24][CH3:25])[NH:11][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@]1(CC)CSc2cc(OC)ccc2C(c2ccccc2)=N1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC[C@]1(CC)CSc2cc(OC)ccc2[C@@H](c2ccccc2)N1
Yield: 41.7 %

Procedure:
This compound was prepared following the procedure of Synthetic Example 1(n), using the product (54.4 g) from step (e). Chromatography on silica gel, using hexane:EtOAc (9:1) as eluant, gave the title product (22.8 g) as an orange oil. 1H NMR consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.CCN(C(C)C)C(C)C.CN([C:24]([O:28][N:29]1N=NC2C=CC=N[C:30]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]([O:28][CH3:24])[CH3:30])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Br)cc1Cl
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)c1ccc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a stirring solution of 4-bromo-2-chlorobenzoic acid (3.45 g, 15 mmol) and DIEA (7.7 ml, 44 mmol) in DMF (30 mL) was added HATU (6.1 g, 16 mmol) at 23° C. under nitrogen. Darkened suspension stirred for 1 h, then added n,o-dimethylhydroxylamine hydrochloride (2.1 g, 22 mmol). Solution stirred overnight at 23° C. Reaction then partitioned between 2.5% NaHCO3 (250 mL) and diethyl ether (100 mL). Aqueous further extracted with ether (2×50 mL). Combined ethereal extracts dried over MgSO4, then concentrated an amber oil under reduced pressure. 4-bromo-2-chloro-N-methoxy-N-methylbenzamide isolated as a light amber oil.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17][CH2:18][C:19]([C:21]1[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23]([CH3:34])[CH:22]=1)=O)([CH3:3])[CH3:2].Cl.[CH3:36][O:37][NH2:38]>>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17][CH2:18][C:19]([C:21]1[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23]([CH3:34])[CH:22]=1)=[N:38][O:37][CH3:36])([CH3:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(C(=O)CCc2sc3cc(C(F)(F)F)ccc3c2C(C)C)cc1C
Reactant: CON
Agent: Cl
Product: CCOC(=O)COc1ccc(C(CCc2sc3cc(C(F)(F)F)ccc3c2C(C)C)=NOC)cc1C

Procedure:
The titled compound was prepared from ethyl 4-[3-[3-isopropyl-6-(trifluoromethyl)benzothiophen-2-yl]propionyl]-2-methylphenoxyacetate [Example 15 (2)] (70 mg, 0.14 mmol) and methoxyamine hydrochloride (13 mg, 0.16 mmol) in a procedure similar to that of Example 13 (1) as a yellow oil (74 mg, yield>99%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:13])[O:10][C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:13])[O:10][C:11](=[O:12])[C:6]=2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc2c(=O)oc(=O)[nH]c12
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])cc2c(=O)oc(=O)[nH]c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a flask charged with 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione ((Example 295: step a) 9.27 g, 52.4 mmol) in an ice-water bath was added concentrated H2SO4 (90 mL) over 5 minutes period. After stirring for 10 minutes, fuming HNO3 (2.9 mL) was added over 15 minutes. The reaction mixture was stirred for further 30 minutes in the ice-water bath, 30 minutes at ambient temperature, then slowly poured into ice with stirring. The solid was collected, washed with H2O (3×50 mL), and dried in high vacuum to give the title compound (10.4 g, 89% yield) as a yellow solid. 1H NMR (DMSO) δ 11.65 (br s, 1H), 8.46–8.43 (m, 2H), 2.44 (s, 3H).
Reaction SMILES: Br[C:2]12[CH:9]=[CH:8][CH:7]=[CH:6][CH:3]1[CH2:4][CH2:5]2.C([Li])CCC.[C:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:5]1[C:2]2[CH:9]=[CH:8][C:7]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])=[CH:6][C:3]=2[CH2:4]1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: BrC12C=CC=CC1CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1ccc2c(c1)CC2
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 42.5 %

Procedure:
3-bromobenzocylcobutene (1.5 g, 8.2 mmol) was dissolved in 50 ml of THF. The solution was cooled to −78° C. To the solution was added butyl-lithium (3.6 mL, 2.0 M in hexanes, 9.0 mmol). After 45 minutes, benzophenone (1.34 g, 7.4 mmol) was added in one portion. The reaction was allowed to warm to room temperature overnight. After normal work-up, the residue was purified by column using 1:1 dichloromethane and hexanes as solvent. 0.9 g of the desired product was obtained (42% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Br:70][C:71]1[CH:72]=[CH:73][C:74]([NH2:77])=[N:75][CH:76]=1>C(Cl)Cl>[Br:70][C:71]1[CH:72]=[CH:73][C:74]2[N:75]([C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:77]=2)[CH:76]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: Nc1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
Ethyl 3-(4-fluorophenyl)-3-oxopropanoate (2.6 g, 12 mmol) was dissolved into DCM (32 mL), cooled to 0° C. and treated with tetra-n-butylammonium tribromide (6.75 g, 14.0 mmol). The reaction mixture was stirred at 0° C. for 1 h, rt for 1 h and then washed with sat NaHCO3 (aq) (2×50 mL), dried (MgSO4), filtered and concentrated. The crude material was dissolved into EtOH (60 mL) and then 5-bromopyridin-2-amine (6.22 g, 36.0 mmol) was added and the reaction was stirred at 70° C. under nitrogen overnight (complete by LCMS). The reaction mixture was diluted with DCM (˜120 mL), washed with sat. NaHCO3 (aq) (2×100 mL) and the organic layer was dried (MgSO4), filtered and concentrated. The resulting solid was dissolved into DCM (˜30 mL), diluted with hexanes (˜70 mL) and stirred. The solids were filtered away (contained some desired product) and the mother liquor was concentrated, dissolved into DCM and purified by Biotage Horizon (40M, 10% EtOAc/hex, SiO2) (the compound crashed out in the instrument resulting in an unknown quantity being shunted to waste). The collected fractions had solid material precipitating out which was collected by filtration to yield ethyl 6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxylate (594 mg, 1.636 mmol, 13% yield) as a white fluffy solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.60 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.52 (dd, J=9.2, 1.5 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H). LCMS: m/e=743 (M+H)+, retention time=2.24 min, (Column=(2)phenomenex 4.6×50 mmC18.10 um, Solvent A=10% MeOH-90% H20-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA Start % B=0, Final % B=100, Gradient Time=2 min, Hold time=1 min, Flow Rate=5 mL/min) LC-MS retention time 2.04 min; m/z 362, 364 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.[CH2:16]([O:18][CH2:19][C:20](O)=[O:21])[CH3:17].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.O>[CH2:16]([O:18][CH2:19][C:20]([NH:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:21])[CH3:17]
Reactant: CCOCC(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: CCOCC(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.5 g, 2.46 mmole) in 25 mL of dichloromethane was cooled to 0° C. and was successively treated with ethoxyacetic acid (0.26 mL, 1.1 eq.), dimethylaminopyridine (30 mg, 0.1 eq.) and dicyclohexylcarbodiimide (560 mg, 1.1 eq.). The reaction mixture was stirred at 0° C. for two hours then at room temperature for two hours, diluted with 25 mL water and extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting solid/oil was triturated in ether, the solid removed and the volatiles removed in vacuo, to give 674 mg (95%) of 2-ethoxy-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (35) as a pale yellow solid, which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[S:5][CH:6]=1.[H-].[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)=[CH:18][CH:17]=1>CN(C)C=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:9]2[CH2:10][CH2:11][N:7]([C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)[C:8]2=[O:12])=[CH:18][CH:17]=1
Reactant: BrCCCCCCOc1ccc(Br)cc1
Reactant: Cc1csc(N2CCNC2=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1csc(N2CCN(CCCCCCOc3ccc(Br)cc3)C2=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(4-methyl-1,3-thiazol-2-yl)-2-imidazolidinone (0.11 g, 0.61 mmol) dissolved in 10 mL of dimethylformamide at 0° C. was added NaH (60% dispersion in mineral oil, 36.6 mg, 0.92 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled in ice bath. 1-Bromo-4-[(6-bromohexyl)oxy] benzene (0.21 g, 0.61 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with methanol, and the solvents were removed under reduced pressure. A saturated aqueous NH4Cl solution and dichloromethane were successively added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 10) as a yellow viscous oil (0.19 g, 74%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:12]([O:13][C:14]2[C:15]([C:27]#[N:28])=[N:16][CH:17]=[C:18]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:19]=2)=[C:11]([CH3:29])[CH:10]=[CH:9][N:8]=1.[OH-:30].[Na+]>>[CH3:6][C:7]1[C:12]([O:13][C:14]2[C:15]([C:27]([NH2:28])=[O:30])=[N:16][CH:17]=[C:18]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:19]=2)=[C:11]([CH3:29])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Concentrated sulfuric acid (8 mL) was added to 3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (2.03 g, 6.07 mmol). The reaction was stirred overnight, then poured onto ice (100 g), cooled in an ice bath and made basic to pH 10 with 50% NaOH. The reaction was extracted with ethyl acetate, washed with brine, dried (MgSO4), and concentrated to afford 3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (2.02 g, 5.73 mmol, 94.4% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].O=[C:16]([CH:20]=[N:21][OH:22])[CH:17]=[N:18][OH:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:16]([CH:20]=[N:21][OH:22])[CH:17]=[N:18][OH:19]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C(C=NO)C=NO
Solvent: CCO
Product: ON=CC(C=NO)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A mixture of 2,6-dichloro-4-trifluoromethylphenylhydrazine (34 g), 2-oxopropanedial 1,3-dioxime (17 g) and ethanol (300 ml) was heated under reflux for 31/2 hours. The solvent was evaporated under reduced pressure and the residue triturated with light petroleum (bp 40°-60°) and filtered to give 2-oxopropanedial 2-(2,6-dichloro-4-trifluoromethylphenylhydrazone) 1,3-dioxime. This product (36 g) was stirred in acetic anhydride (350 ml) and acetic acid (220 ml) at room temperature for 45 mins. The mixture was poured into water and filtered and the residue dried in vacuo at 40° to give 2-oxopropanedial 1-acetyloxime 2-(2,6-dichloro-4-trifluoromethylphenylhydrazone) 3-oxime.