Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[N+:2]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[H-].[Na+].[CH2:33]([O:40][C:41]1[C:48]([C:49]2[C:50]([O:55][CH3:56])=[N:51][CH:52]=[CH:53][CH:54]=2)=[CH:47][C:46]([C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:45][C:42]=1[CH:43]=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([O:40][C:41]1[C:42]([CH:43]=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:30][CH:29]=2)=[CH:45][C:46]([C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:47][C:48]=1[C:49]1[C:50]([O:55][CH3:56])=[N:51][CH:52]=[CH:53][CH:54]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ncccc1-c1cc(C(C)(C)C)cc(C=O)c1OCc1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(C=Cc2ccc([N+](=O)[O-])cc2)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
step 3—To a solution of 4-nitro-benzyltriphenylphosphonium bromide (1.07 g, 2.238 mmol) in DMF (8 mL) at 0° C., was added NaH (60% in oil dispersion, 156 mg, 3.90 mmol). The reaction was stirred for 30 min at 0° C. then a solution of 50 (281 mg, 0.749 mmol) in DMF (6 mL) was added. The resulting mixture was gradually warmed to RT and stirred overnight. The reaction was quenched with 1N aqueous HCl solution (6 mL) and diluted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (5 to 10% EtOAc) to afford 311 mg (84%) of 3-{2-benzyloxy-5-tert-butyl-3-[2-(4-nitro-phenyl)-vinyl]-phenyl}-2-methoxy-pyridine (52) as a yellow oil.
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:11]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([CH:27]=[CH:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CO.O1CCCC1>[C:11]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([CH:27]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:3]([C:2]([O:9][CH3:10])=[O:8])[C:4]([O:6][CH3:7])=[O:5])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)C=Cc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(c1ccc2c(c1)CCN2C(=O)OC(C)(C)C)C(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of sodium (156 mg) in methanol (15 ml) was treated with dimethyl malonate (0.8 ml) and after stirring for 15 minutes the mixture was then treated with a solution of methyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)acrylate [1.0 g, reference Example 7(b)] in tetrahydrofuran (15 ml). The mixture was stirred at reflux for 3 hours, then cooled to room temperature, then treated with water (2 ml) and then evaporated. The residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with fresh ethyl acetate. The combined organic layer and extracts were washed with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (15:85, v/v) to give the title compound (530 mg) as a clear oil. MS (ES+) 458 (MNa+). MS (ES−) 434 (M−).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>ClCCl.C(=O)([O-])[O-].[K+].[K+]>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4.09 g of azetidine are dissolved in a two-phase solvent system of 200 ml of dichloromethane and 130 ml of an aqueous potassium carbonate solution (strength 4.0 M). Subsequently, a solution of 15.25 g of commercially available 4-bromo-benzenesulfonyl chloride in 70 ml of dichloromethane is slowly added to the reaction mixture. Thereafter, the mixture is vigorously stirred for 17 hours at room temperature. For extraction, 200 ml of dichloromethane and 100 ml of water are added. The organic layer is dried using Na2SO4, filtered with suction, and concentrated in vacuo to yield 15.22 g of the title compound as a colorless, amorphous solid of m.p. 145° C. ESI-MS: 276.1/278.0 (MH+, 100%:95%). TLC: Rf=0.59 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@:18]34[O:24][C@H:19]3[CH2:20][CH2:21][CH2:22][CH2:23]4)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[CH2:30][Mg]Cl>O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([C@@:18]3([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:30][C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([O:26][CH3:25])[CH:28]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(C[Mg]Cl)c1
Reactant: c1ccc(-c2nc([C@@]34CCCC[C@@H]3O4)oc2-c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(C[C@@H]2CCCC[C@]2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
To a solution of (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1,2-epoxycyclohexane (20 g) and CuBr (3.0 g) in tetrahydrofuran (400 ml) was dropwise added a solution of 3-methoxybenzylmagnesium chloride [prepared from 3-methoxy-benzylchloride (50 g) and Mg (9.2 g)] in tetrahydrofuran (500 ml) at −78° C. under N2. The mixture was stirred for 2 hours at the room temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2-(3-methoxybenzyl)cyclohexane (29.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH3:10][O:11][CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][O:11][CH3:12])=[C:4]([F:9])[CH:3]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Into acetone (300 ml), 4-bromo-2-fluorophenol (30 g, 157 mmol) was dissolved, to which chloromethyl methyl ether (18 ml, 237 mmol) and potassium carbonate (43 g, 235 mmol) were added, followed by stirring at room temperature for two hours. Impurities were filtered off and the filtered solution was washed with acetone. The filtrate was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-85:15, V/V) to give the desired title compound (36.5 g, yield 82%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[C:1]1([C:21]2[C:16]([C:11]3[CH:10]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Ic1ccccc1-c1ccccc1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Product: c1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 78 %

Procedure:
Nickel(II) acetylacetonate has affected other cross-coupling reactions, however. Mitchell and Yan, Can. J. Chem., 58, 2584 (1980), reported yields of 35-60%, 3,3"-dichloro-2,2"-dimethyl-o-terphenyl in the cross-coupling of 3-chloro-2-methylphenylmagnesium chloride with o-dibromobenzene in tetrahydrofuran using equivalent amounts of the reactants and 6 mole percent nickel(II) acetylacetonate based on the Grignard reagent. Ibuki, et al., Bull. Chem. Soc. Japan, 53, 821 (1980), reported cross-coupling two-fold excess phenylmagnesium bromide with 2-iodobiphenyl in the presence of 1.0% nickel(II) acetylacetonate based on the limiting reagent, obtaining a 78-80% yield of o-terphenyl. Clough, et al., J. Org. Chem., 41, 2256 (1976), reported cross-coupling an eight-fold excess of phenylmagnesium iodide with 1,8-diiodonaphthalene using 0.9 mole percent nickel(II) acetylacetonate based on the limiting reagent, producing 1,8-diphenylnaphthalene in 70% yield, while Corriu and Masse, J. Chem. Soc. Chem. Comm., 144 (1972), reported yields of 40 to more than 80% in cross-coupling reactions utilizing 0.1-1 percent nickel(II) acetylacetonate with respect to Grignard reagent.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[N:5]=1)(=[O:3])[CH3:2].C(C1C2C(=CC=C(OC(F)(F)F)C=2)N(CC(O)=O)C=1)(=O)C>>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:17][C:18]([OH:20])=[O:19])[N:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C(C)=O)nn(CC(=O)OC(C)(C)C)c2c1
Agent: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: COC(=O)c1ccc2c(C(C)=O)nn(CC(=O)O)c2c1

Procedure:
The title compound was prepared from methyl 3-acetyl-1-(2-tert-butoxy-2-oxoethyl)-1H-indazole-6-carboxylate in a similar manner as described in step C of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)acetic acid. MS: 277 [M+H]+; tR (HPLC conditions k): 2.95 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][NH2:15])[CH:8]=[C:7]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])([O-:3])=[O:2].[C:23](OCC)(OCC)(OCC)[CH3:24]>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:23]([CH3:24])=[N:15][N:14]=[C:9]1[CH:8]=[C:7]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])([O-:3])=[O:2]
Reactant: NNc1cc(-c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2n1
Reactant: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3cc([N+](=O)[O-])ccc3n12

Procedure:
In the manner given in Example 2, 6-nitro-4-(o-chlorophenyl)-2-hydrazinoquinoline, and triethyl orthoacetate are refluxed in xylene to give 7-nitro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:13][CH2:14][CH3:15])[CH2:8]2.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][N:7]([CH2:13][CH2:14][CH3:15])[CH2:8]3)=[O:23])=[CH:20][CH:19]=1
Reactant: CCCN1CCc2c(N)cccc2C1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Br
Product: CCCN1CCc2c(cccc2NC(=O)c2ccc(OC)cc2)C1

Procedure:
5-Amino-2-n-propyl-1,2,3,4-tetrahydroisoquinoline hydrobromide was reacted with 4-methoxybenzoyl chloride according to the procedure of Example 14 to produce 5-(4-methoxybenzamido)-2-n-propyl-1,2,3,4-tetrahydroisoquinoline; m.p. 162.5°-163.5° C. after purification with ethanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: O
Product: FC(F)(F)c1ccc(N2CCNCC2)nc1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
A mixture of 2-chloro-5-trifluoromethylpyridine (Aldrich; 2.296 g), piperazine (5.45 g), and water is heated at 100° C. for 16 h. After cooling, the mixture is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel using methanol/dichloromethane (8/92) with about 0.5% ammonium hydroxide present, to give 2.20 g of 1-(5-trifluoromethylpyridin-2-yl)piperazine; mp 45-47° C.; IR (mineral oil) 1127, 1323, 1319, 1118, 1614 cm-1 ; 1H NMR (CDCl3) δ2.98, 3.62, 6.63, 7.62, 8.40.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]4[CH:19]=[C:18](I)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:21][O:22][CH2:23][CH2:24][N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]1=[O:34].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:28]5[CH:29]=[CH:30][N:25]([CH2:24][CH2:23][O:22][CH3:21])[C:26](=[O:34])[CH:27]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Ic1cc2c(Nc3ccc4[nH]ncc4c3)ncnc2[nH]1
Reactant: COCCn1ccc(B(O)O)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COCCn1ccc(-c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)cc1=O
Temperature: 100 °C

Procedure:
A mixture of (1H-indazol-5-yl)-(6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (0.076 g), 1-(2-methoxy-ethyl)-2-oxo-1,2-dihydro-pyridine-4-boronic acid (36 mg), PdCl2(PPh3)2 (7 mg) end potassium carbonate (76 mg) in dioxane/wawr (4:1) (5 mL) was heated to 100° C. for 48 h. Purification via chromatograpby afforded tJm title compound as a pale yellow solid. δH 3.30 (3H, s), 3.62 (2H, t), 4.18 (2H, t), 5.99 (1H, dd), 6.89 (1H, d), (7.27 (1H, s), 7.57 (2H, d), 7.69 (2H, m), 8.09 (1H, s), 8.16 (1H, s), 8.18 (1H, s) and 9.67 (1H, s). MH+ 402.13.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[C:10]([CH2:12][NH2:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)C(=O)O
Reactant: NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reaction time: 8 h

Procedure:
(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanamine (0.1 g) was added to a pre-stirred (15 minutes) solution of trimethylacetic acid (1.2 eq), 1-hydroxybenzotriazole (1.1 eq.), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.1 eq.), triethylamine (2 eq.) in N,N-dimethylformamide (2.77 mL). The reaction was stirred overnight then extracted with ethyl acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to give quantitative yield of N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)pivalamide.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:11]2[CH2:16][CH2:15][CH:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:21][C:22](Br)=[O:23].Cl>C(Cl)Cl>[C:17]([CH:14]1[CH2:15][CH2:16][CH:11]([C:5]2[CH:10]=[CH:9][C:8]([C:22](=[O:23])[CH3:21])=[CH:7][CH:6]=2)[CH2:12][CH2:13]1)(=[O:19])[CH3:18]
Reactant: O=C(Br)CBr
Reactant: CC(=O)C1CCC(c2ccccc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(C2CCC(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
Referring to Scheme 2-7 to a suspension of AlCl3 (1.58 g, 12 mmol) in DCM (30 mL) at −78° C. was added 1-(4-phenylcyclohexyl)ethanone (A1′) (1 g in DCM, 5.0 mmol), and bromoacetyl bromide (0.65 mL, 7.5 mmol) dropwise over 10 min. The mixture was stirred to rt for 15 min and heated at 40-50° C. for 3 h, cooled to rt and poured into a mixture of ice and HCl (1N). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were concentrated on rotovap and purified silica gel column chromatography (Hexanes/EtOAc=8/2 (v/v)) to give the desired trans-isomer A2′ (1 g, 62% yield) along with a small amount of cis-isomer.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Li]CCCC.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:22]=1)[CH:20]=[O:21]>C1COCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:20]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[OH:21])[CH:22]=1
Reactant: Brc1ccc(Br)cc1
Reactant: COc1ccc(Br)cc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1C(O)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1,4-Dibromobenzene (15.3 g; 65 mmol) in THF (350 ml) is cooled to −78° C. and treated with nBuLi (44.7 ml; 71.5 mmol of a 1.6M solution). The white precipitate is stirred for 15 minutes at −78° C. 5-Bromo-2-methoxy-benzaldehyde (6.98 g; 32.5 mmol) in THF (32 ml) is added, stirred for 5 min at −78° C. and then poured on water. The aqueous phase is extracted twice with TBME, the organic phase dried over Na2SO4, evaporated to dryness and the residue purified via SiO2 chromatography (Cyclohexane/acetone 98:2>96:4) to yield the title compound as white crystals recrystallised from ether/hexanes (9.25 g; 73.8%).
Reaction SMILES: [CH3:1][O:2][P:3]([CH3:7])(=[O:6])[O:4][CH3:5].[Li]CCCC.[C:13]([O:17][C:18]([N:20]1[C@H:24]([C:25]([O-])=[O:26])[CH2:23][O:22][C:21]1([CH3:29])[CH3:28])=[O:19])([CH3:16])([CH3:15])[CH3:14].CCOC(C)=O>C1COCC1.CCO>[C:13]([O:17][C:18]([N:20]1[C@H:24]([C:25](=[O:26])[CH2:7][P:3]([O:4][CH3:5])([O:2][CH3:1])=[O:6])[CH2:23][O:22][C:21]1([CH3:29])[CH3:28])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)[O-])COC1(C)C
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C)OC
Temperature: -75 °C
Yield: 70 %

Procedure:
Dimethylmethylphosphonate (2.3 ml, 21 mmol, 210 mol-%) was dissolved in 10 ml of THF and cooled to -85° C. (internal temp. -75° C.). To this solution was added 14 ml (1.6M, 21 mmol, 210 mol-%) of n-BuLi in hexanes. The reaction mixture was allowed to warm to -25° C. for 1 hour and then cooled back to -85° C. (internal temp. <-75° C.) after which 2.6 g (10 mmol, 100 ml-%) of methyl ((S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4oxazolidine carboxylate was dissolved in 5 ml of THF and cooled to -85° C. (internal temperature <-75° C.). This solution was cannulated onto the anion at such a speed that the internal temperature stayed <-75° C. at all times. After the addition the reaction mixture was allowed to warm to 0° C. very slowly and then it was quenched with 5 w-% citric acid. The pH was adjusted to 3 with sat. citric acid and the reaction mixture was extracted several times with ethyl acetate (EtOAc). Organic phases were washed with brine, combined, dried over Na2SO4 and the solvents were removed in vacuo. The product can be crystallized if necessary from iso-octane. An analytical sample was purified by flash chromatography using 20% EtOAc in hexanes to remove the traces of starting material and then as a stepgradient with 100% EtOAc to remove the excess of dimethylmethylphosphonate to yield 70% of pure 3. Rf, 100% EtOAc: 0.28. mp. 86°-7° C. 1H NMR (250 MHz, CDCl3) δ:1.30 (s, 3 H, major rotamer) , 1.36 (s, 3 H, minor rotamer) , 1.40 (s, 3 H both rotamers), 1.51 (s, 3 H, major rotamer), 1.55 (s, 3 H minor rotamer), 3.06 (d, 2 H, major rotamer, 2J(HP)=20 Hz), 3.10 (d, H, minor rotamer, 2H(HP)=20 Hz), 3.68 (d, 6 H, 3J(HP)=11,2 Hz), 3.91 (dd, 1 H, minor rotamer, J=3.6 Hz, <0.5 Hz), 3.93 (dd, 1 H, major rotamer, J=3.6 Hz, <0.5 Hz), 4.05 (m, 1 H, both rotamers) , 4.38 (m, 1 H, major rotamer) , 4.48 (m, 1 H, minor rotamer). Rotameric ratio is 2:1 at 20° C. 13C NMR (50 MHz, CDCl3) δ:23.7 (CH3), 25.0 (CH3), 28.0 (CH3), 52.7 (CH3), 65.0 (c), 65.1 (CH2), 89.8 (c), 94.4 (CH2), 95.(C), 150.9 (C=O), 199.0 (C=O) . Anal. Calcd. C 47.86: H 7.46; N 3.99; Found C 48.11; H 7.70; N 4.26. α20 =-40.1(c=14.0, EtOH).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([S:25][CH3:26])[N:20]=2)=[CH:10][CH:9]=1)(C)(C)C.Cl>O1CCOCC1>[CH3:26][S:25][C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH2:7])=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CSc1nccc(Oc2ccc(NC(=O)OC(C)(C)C)c3ccccc23)n1
Agent: Cl
Solvent: C1COCCO1
Product: CSc1nccc(Oc2ccc(N)c3ccccc23)n1
Yield: 151.7 %

Procedure:
To a stirred solution of [4-(2-methylsulfanylpyrimidin-4-yloxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester (1.375 g, 3.6 mmol) in anhydrous dioxane (10 ml) at room temperature is added 4M HCl in dioxane (12 ml, 48 mmol). After 1 day the mixture is evaporated to dryness to give 4-(2-methylsulfanylpyrimidin-4-yloxy)-naphthalen-1-ylamine as a light purple powder (1.547 g).
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[CH2:26]([OH:31])[CH:27]=[CH:28][C:29]#[CH:30]>C(#N)C.C(N(CC)CC)C.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.[Cu]I>[NH2:25][C:4]1[C:3]([C:30]#[C:29]/[CH:28]=[CH:27]/[CH2:26][OH:31])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: C#CC=CCO
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#C/C=C/CO)c3N)cc2C)cn1
Yield: 106.6 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydriodide (507 mg) was dissolved in a mixed solvent of acetonitrile (19.4 mL)/triethylamine (14.5 mL), 2-penten-4-yn-1-ol (106 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (38.8 mg) and copper(I) iodide (13.4 mg) were sequentially added. The title compound (373 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: Cl.O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14].[BrH:15]>C(O)(=O)C>[BrH:15].[BrH:15].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: Cc1[nH]cnc1CO
Reactant: NCCS
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc[nH]c1CSCCN

Procedure:
A mixture of 4-hydroxymethyl-5-methylimidazole hydrochloride (15.0 g.), cysteamine hydrochloride (11.5 g.) and a solution of hydrogen bromide in acetic acid (48%, 225 ml.) was heated under reflux for 7 hours. Cooling afforded 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide (21.6 g.), m.p. 208°-211°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[S:23][C:24]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH2:18][N:17]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:16][CH:15]2[CH2:14]1)=[O:12]
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Reactant: Cc1ccc2nc(Cl)sc2c1
Product: COc1ccc(C(=O)N2CC3CN(c4nc5ccc(C)cc5s4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-6-methyl-benzothiazole. MS (ESI) mass calcd. for C23H25N3O3S, 423.54; m/z found, 424.2 [M+H]+.
Reaction SMILES: [CH:1]([C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O:8][CH3:9])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:23](Br)[C:24]#[CH:25]>CN(C)C=O>[CH:1]([C:4]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([O:8][CH3:9])[C:5]([O:7][CH2:25][C:24]#[CH:23])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(C(=O)O)(c1ccccc1)C(C)C
Reactant: C#CCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCOC(=O)C(OC)(c1ccccc1)C(C)C

Procedure:
A solution of 4.2 g of α-(iso-propyl)-α-methoxyphenyl acetic acid, 3.0 g of triethylamine and 2.6 of propargyl bromide in 20 cc of dimethylformamide was stirred for 2 hours, whereby white precipitates were deposited. The reaction mixture was poured in water, and the resultant was subjected to extraction with ether. The extract was washed with an aqueous solution saturated with sodium chloride and dried over anhydrous sodium sulfate, and thereafter evaporation of ether gave 4.5 g of oily propargyl α-(iso-propyl)-α-methoxyphenylacetate, nD25 1.5071.