Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:33]2([CH3:34])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:35])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:28])[CH:21]([OH:27])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[CH2:9]1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>N1C=CC=CC=1.O>[CH3:43][S:44]([O:27][CH:21]([C@H:20]([C@@H:19]1[C@:29]2([CH3:35])[C@H:16]([C:15]3[C@H:32]([CH2:31][CH2:30]2)[C@:33]2([CH3:34])[C:12]([CH2:11][C@@H:10]([O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[CH2:9][C@@H:8]2[O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:13][CH:14]=3)[CH2:17][CH2:18]1)[CH3:28])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCC(O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Solvent: c1ccncc1
Product: CC(C)CCC(OS(C)(=O)=O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
In 20 ml of pyridine was dissolved 0.58 g of the 1α,3β-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-ol obtained as above. To this solution was added 0.12 g of methanesulfonyl chloride and the mixture was stirred at 0° C. for 2 hours. Then, at room temperature, the reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. The low-boiling fraction was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The procedure yielded 0.57 g of 1α,3β-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-yl methanesulfonate (yield: 86%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.BrC[CH2:28][CH2:29][CH2:30][C:31]#[N:32]>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][CH2:28][CH2:29][CH2:30][C:31]#[N:32]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: N#CCCCCBr
Product: Cl
Product: N#CCCCCSc1c(Cl)ccc2c1CCNCC2

Procedure:
Use a method similar to the Example 387 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine with 5-bromovaleronitrile. Purify by preparative reverse phase HPLC (Column: Xterra Prep RP18 19×250 mm; Solvent A: 10 mM aqueous ammonium carbonate, Solvent B: acetonitrile; 30-100% B over 20 minutes; flow rate 25 mL/min). Use a method similar to the General Procedure 2-2 to give the title compound as an off-white solid. MS (APCI+) m/z: 295 (M+H)+.
Reaction SMILES: C(OC([NH:11][CH:12]([C:14]1[C:15]([O:35][CH3:36])=[C:16]([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13])=O)C1C=CC=CC=1.Cl.O.[H][H].N>[Pt].C(O)C>[NH2:11][CH:12]([C:14]1[C:15]([O:35][CH3:36])=[C:16]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13]
Reactant: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(C)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: COc1c(C(C)N)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 101 %

Procedure:
Platinum on carbon (10 wt. % loading (dry basis), matrix activated carbon, 200 mg) was added to a solution of tert-butyl 4-[3-(1-{[(benzyloxy)carbonyl]amino}ethyl)-5-chloro-2-methoxy-6-methylphenyl]-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.388 mmol) in ethanol (30 mL)/0.25 M HCl in water (3.9 mL, 0.97 mmol) and then the reaction was stirred at room temperature under 30 psi of hydrogen atmosphere for 3 d. The mixture was adjusted to basic pH with ammonia and then the solvent was removed. The residue was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated to give the crude desired product (0.15 g) which was used in the next step without further purification. LCMS calculated for C20H32ClN2O3 (M+H)+: m/z=383.2. found: 383.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])O[CH2:7][CH2:6]2.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=2[O:35][CH3:36])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]3=[O:13])=[CH:30][C:29]=2[O:35][CH3:36])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1cc(N)ccc1N1CCCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc2c(c1)CCOC2=O
Product: COc1ccc2c(c1)CCN(c1ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)c(OC)c1)C2=O

Procedure:
6-Methoxy-isochroman-1-one and 4-(4-amino-2-methoxyphenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester were reacted according to Method AC. In this way the product was obtained with molecular weight 481.60 (C27H35N3O5); MS (ESI): 482 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([OH:18])=[CH:13][C:12]=1[OH:19])=[O:10].[C:20](OC(=O)C)(=O)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:10])[C:11]2[C:12](=[CH:13][C:14]([OH:18])=[C:15]([Cl:17])[CH:16]=2)[O:19][C:20]=1[CH3:21]
Reactant: O=C(Cc1ccccc1Br)c1cc(Cl)c(O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccccc1Br

Procedure:
This compounds was synthesised in the same manner as described above. 2-(2-Bromo-phenyl)-1-(5-chloro-2,4-dihydroxy-phenyl)-ethanone (2.0 g, 5.88 mmol), acetic anhydride (2.0 ml), potassium carbonate (2.5 g 18.1 mmol). The white precipitate formed was shown to contain the required compound and was taken directly onto the next stage.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:16]=[C:15]([CH3:17])[C:14](N3C=NC=N3)=[N:13][C:12]2=[O:23])[CH2:8][C@@H:7]1[N:24]=[N+:25]=[N-:26])(=[O:3])[CH3:2].O.NN>CC#N.CCO>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:12]2=[O:23])[CH2:8][C@@H:7]1[N:24]=[N+:25]=[N-:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(-n3cncn3)nc2=O)C[C@@H]1N=[N+]=[N-]
Agent: NN
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)cnc2=O)C[C@@H]1N=[N+]=[N-]

Procedure:
1-(5-O-Acetyl-3-azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-5-methyl-4-(1,2,4-triazol-1-yl)-2-(1H)-pyrimidinone (0.5 g, 1.4 mMol) was dissolved in CH3CN (10 mL) and treated with 85% hydrazine hydrate (0.105 g, 2.1 mMol) for 30 minutes at ambient temperature, analogous to the procedure described in (1). The solvents were evaporated in vacuo and the residue chromatographed on silica gel with 9:1 CHCl3 /MeOH (v/v) as the eluting solvent. Collection and evaporation of appropriate fractions yielded a solid. The solid was dissolved in EtOH (50 mL) containing Ag2O (0.35 g, 1.5 mMol, 1.5 eq) and refluxed for 90 minutes. Filtration of the hot suspension through a bed of celite followed by removal of solvents in vacuo gave a solid. The solid was chromatographed on silica gel and eluted with 20:1 CHCl3 /MeOH (v/v). Combination and evaporation of appropriate fractions gave the title compound as a golden oil: UV (nm): at pH 1λmax =327 (ε=6900), λmin =254 (ε=700); at pH 13λmax =322 (ε=17200), λmin =247 (ε=600); 1H NMR: (DMSO-d6) δ8.46(d, J=3.13 Hz, 1H, H4), 7.92(d, J=3.90 Hz, 1H, H6), 6.03(dd, J=5.28 Hz, 6.64 Hz, 1H, H1 ') 4.46-4.03(m, 4H, H3 ', H4 'H5 '), 2.71-2.32(m, 2H, H2 '), 2.05, 2.04(2s, 6H, 5-CH3, acetyl).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:16])[C:14]=3[N:15]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[C:3]1[C:23]#[C:24][Si](C)(C)C.[CH3:29][N:30]([CH3:34])[CH2:31]C#C>>[CH3:29][N:30]([CH3:34])[CH2:31][C:24]#[C:23][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:16])[C:14]=3[N:15]=2)=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:4]=1
Reactant: Cn1c(C#C[Si](C)(C)C)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Reactant: C#CCN(C)C
Product: CN(C)CC#Cc1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 45 but using 1-dimethylamino-2-propyne in place of trimethylsilyl acetylene. Colourless solid (25 mg, 64%);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:10]#[N:11])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl.[NH2:23][NH2:24]>C(#N)C>[NH2:11][C:10]1[NH:24][N:23]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: N#CC(C(=O)c1ccc(Cl)cc1)c1ccncc1
Reactant: NN
Solvent: ClP(Cl)Cl
Solvent: CC#N
Product: Nc1[nH]nc(-c2ccc(Cl)cc2)c1-c1ccncc1
Yield: 54.3 %

Procedure:
A solution of 3-(4-chlorophenyl)-3-oxo-2-(pyridin-4-yl)propanenitrile (3.50 g, 13.6 mmol) in 40 mL acetonitrile and phosphorous trichloride (14.2 ml, 163 mmol) was stirred at 100° C. for 5 hours. The reaction mixture was concentrated in vacuo, and the residue taken up in toluene and concentrated again. The residue was then taken up in ethanol (150 mL) and treated with anhydrous hydrazine (1.71 mL, 54.4 mmol). The reaction mixture was heated to reflux for 3 hours, cooled, and concentrated in vacuo. The residue was triturated with a mixture of ethanol and dichloromethane (1:4), and filtered. The solid was washed with the ethanol/dichloromethane mixture, and dried to give 5-amino-3-(4-chlorophenyl)-4-(pyridin-4-yl)-pyrazole (2.0 g, 54%): m.p.>300° C. 1H NMR (DMSO/300 MHz) δ8.40 (d, 2H), 7.40 (d, 2H), 7.29 (d, 2H), 7.11 (d, 2H), 5.05 (s, 2H). ESLRMS m/z 271 (M+H). ESHRMS m/z 271.0752 (M+H, C14H11N4Cl requires 271.0750).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.N1C2C(=CC=CC=2)C=C1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](OC)=[O:38])=[CH:29]1>>[S:15]1[CH:16]=[CH:17][N:18]=[C:14]1[NH:13][C:37]([C:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:28]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=2)[CH:29]=1)=[O:38]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: Nc1nccs1
Agent: c1ccc2[nH]ccc2c1
Product: CS(=O)(=O)c1ccc(Cn2cc(C(=O)Nc3nccs3)c3ccccc32)cc1

Procedure:
R5X=1-Bromomethyl-4-methanesulfonyl-benzene, NH2A=2-aminothiazole; Indole starting material=methyl indole 3-carboxylate
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH3:9])[CH:3]=1.[Br-].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[Zn+]>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.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: [Zn+]c1cccs1
Reactant: Cc1cc(Br)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1-c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-2-methyliodobenzene (1.0 mmol) was combined with THF solution of 2-thienylzinc bromide (2.0 mmol) in an oven-dried tube under argon. The resulting solution was degassed with a steady stream of argon for 10 min at rt. To this mixture, solid (Ph3P)4Pd (0.1 mmol) was added and the mixture was degassed with argon for 2 min after which it was stirred at rt for 8 h. The reaction mixture was combined with 1M HCl (100 mL) and ethyl acetate (200 mL). Organic layer was separated, washed sequentially with 1M hydrochloric acid (50 mL) and brine (50 mL), and dried over sodium sulfate. The desired product was isolated by flash chromatography on silica gel using hexanes as the eluant: 1H NMR (CDCl3) 7.45 (d, J=1.0, 1H), 7.39 (d, J=5.6, 1H), 7.37 (dd, J=1.0, 5.0, 1H), 7.28 (d, J=5.0, 1H), 7.13 (m, 1H), 7.08 (d, J=5.6, 1H); HPLC A 4.09 min; ESI-MS (m/z)=252, 254.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[Cl:29])/[C:22](=[N:24]/O)/[NH2:23].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.N1C=CC=CC=1.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([C:22]2[N:24]=[C:15]([C@@H:12]3[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]3)[O:17][N:23]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: N/C(=N\O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](c2nc(-c3ccc(Cl)c(Cl)c3)no2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.7 %

Procedure:
A microwave vial was charged with cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (0.24 g, 0.98 mmol), DMAP (0.12 g, 0.98 mmol) and Intermediate 33A (0.20 g, 0.98 mmol). The reactants were dissolved in DMF (1 mL) and DIC (0.15 mL, 0.98 mmol) was added. The reaction mixture was stirred at rt for 14 h. The reaction mixture was diluted in 3 mL of pyridine. The vial was capped and the reaction mixture was heated in the microwave at 145° C. for 20 minutes, allowed to cool to rt, diluted with EtOAc and washed with water and brine. The solution were concentrated under reduced pressure and purified by flash chromatography with EtOAc/hexanes to give Intermediate 33B (233 mg, 0.565 mmol, 57.9% yield) as a white solid. LCMS=434.1 [M+1], RT=2.43 min (Method B); 1H NMR (500 MHz, chloroform-d) δ ppm 8.19 (1H, d, J=1.93 Hz), 7.92 (1H, dd, J=8.53, 1.93 Hz), 7.56 (1H, d, J=8.25 Hz), 4.59 (1H, br. s.), 3.71 (1H, d, J=9.63 Hz), 3.14-3.22 (1H, m), 2.07-2.17 (2H, m), 1.92-2.02 (2H, m), 1.84 (2H, td, J=8.67, 4.13 Hz), 1.62-1.73 (2H, m), 1.44 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN([CH:24]=[O:25])C>O1CCCC1>[CH:24]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[C:8]([CH3:14])[CH:9]=1)=[O:25]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)OC(C)(C)C
Temperature: -100 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester (500 g, 1.8 mol) in tetrahydrofuran (5 L) was added n-butyl lithium (1.6 M solution, 1.4 L, 2.2 mol) at such a rate that the reaction temperature is between −95° C. to −100° C. After completion of the addition, the reaction mixture was stirred for 30 min at −100° C. and monitored by quenching the reaction mixture with water and following the product by TLC. After complete conversion, DMF (170 ml, 2.2 mol) was added to the reaction mixture and after 15 min the reaction mixture was quenched with ammonium chloride (sat. solution, 5 L). The organic layers were separated at room temperature and the aqueous layer was extracted with ethyl acetate (3×2 L). The combined organic layer was washed with water (3×5 L), dried over sodium sulphate and concentrated to yield tert-butyl 4-formyl-2-methyl-benzoate (390 g, 96% isolated yield, 75-78% HPLC purity). The crude product was used as such without any further purification for the next step. 1H-NMR (CDCl3, 400 MHz): δ in ppm=1.59 (s, 9 H), 2.61 (s, 3 H), 7.71 (d, 2 H), 7.92 (d, 1 H), 10.01 (s, 1 H).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[C:3]([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[O:9][C@@H:8]([N:18]2[C:22]3[N:23]=[C:24]([NH:29][CH:30]=[O:31])[N:25]=[C:26]([O:27][CH3:28])[C:21]=3[CH:20]=[CH:19]2)[CH2:7]1)=[O:4].[Br:33]N1C(=O)CCC1=O.C(Cl)Cl.O>CN(C)C=O.C([O-])(O)=O.[Na+]>[Br:33][C:20]1[C:21]2[C:26]([O:27][CH3:28])=[N:25][C:24]([NH:29][CH:30]=[O:31])=[N:23][C:22]=2[N:18]([C@@H:8]2[O:9][C@H:10]([CH2:11][O:12][C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])[C@@H:6]([O:5][C:3](=[O:4])[CH:2]([CH3:32])[CH3:1])[CH2:7]2)[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc(NC=O)nc2c1ccn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1nc(NC=O)nc2c1c(Br)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Yield: 75 %

Procedure:
A solution of compound 18 (10.1 mmol) in dimethylformamide was stirred, at room temperature for 1 hour, together with N-bromosuccinimide (10.1 mmol). A few drops of 5% aqueous NaHCO3 are added to the solution, in order to buffer it, and methylene chloride is then added. The organic phase is shaken with water, separated, dried over sodium sulfate and evaporated. Chromatography of the residue on a silica gel column in the eluent dichloromethane/acetone (95:5) results in two zones. The evaporation residue from the slowly migrating main zone yields colorless (19) (75%) as a solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([Sn](CCCC)(CCCC)CCCC)[CH:6]=[CH:5][N:4]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=1>C1(C)C(C)=CC=CC=1.Cl[Pd]Cl>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)=[CH:25][CH:24]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Agent: Cl[Pd]Cl
Solvent: Cc1ccccc1C
Product: CSc1nccc(-c2ccc(Br)cc2)n1

Procedure:
2-Methylthio-4-tributylstannylpyrimidine (3.5 g, 7.5 mmol), PdCl2 (525 mg, 0.75 mmol) and 1,4-dibromobenzene (5.3 g, 22.5 mmol) were refluxed in xylene (75 ml) for 30 minutes, filtered and poured directly on a column of silicagel. Chromatography (acetone/hexanes:3/97 to 5/95) gave the title compound as white solid, which was crystallized from hexanes. Yield: 1.1 g (52%).
Reaction SMILES: ClC1C=C(S)C=CC=1.Cl[C:10]1[CH:11]=[C:12]([S:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[CH2:24][CH2:23][CH2:22]3)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>>[C:12]1([S:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[CH2:24][CH2:23][CH2:22]3)(=[O:18])=[O:17])[CH:11]=[CH:10][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCc2cc(S(=O)(=O)c3cccc(Cl)c3)ccc21
Agent: Sc1cccc(Cl)c1
Product: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21

Procedure:
Similarly prepared using the above procedure with 3-chlorobenzenethiol in step 4, was 6-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-naphthalen-1-one. MS: 287 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:6]=1[CH3:21])=[O:4].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[C:6]=1[CH2:21][Br:22])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(=O)n([C@@H](C)c2ccccc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n([C@@H](C)c2ccccc2)c1CBr
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture of (S)-5-bromo-2-methyl-6-oxo-1-(1-phenyl-ethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.34 g, 6.69 mmol), N-bromosuccinimide (1.31 g, 7.35 mmol), and benzoyl peroxide (0.16 g, 0.669 mmol) in CCl4 (70 mL) was refluxed for 16 h. After cooling the mixture to r.t., the precipitate was removed by filtration. The filtrate was evaporated in vacuo, and the residue was chromatographed (0-25% EtOAc/hexanes) to give 2.67 g of the title compound as a white solid. MS: (+) m/z 452.06 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([OH:27])=[O:26].[CH3:28]S(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CI>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([O:27][CH3:28])=[O:26]
Reactant: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1Br
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a 2 L flask was added 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (82.5 g, 187 mmol), DMSO (1249 mL), cesium carbonate (67.2 g, 206 mmol) and methyl iodide (23.44 ml, 375 mmol). The mixture was stirred at room temperature for 2 h. To the resulting slurry was added water (500 mL). The mixture became warm and was cooled with an ice/water bath. Stirring was continued an additional 30 min, then filtered and washed with H2O (2 L). The resulting solid was dried under reduced pressure then azeotroped with toluene two times to afford methyl 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (72.3 g, 85% yield) as a tan solid. MS (m/z) 456 (M+H+).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CC(N(C)C)=O.Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[N:27][CH:28]=1>C1COCC1.[Zn]>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][C:23]2[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[N:27][CH:28]=2)[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: COC(=O)c1ccc(Br)cn1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
Rieke Zinc (slightly excess by estimation) was stirred in 10 mL of THF under argon. tert-Butyl 4-(bromomethyl)piperidine-1-carboxylate (1.0 g, 3.6 mmol) in 5 mL of THF was added. The resulting mixture was stirred at rt for 3 h. The solution was then allowed to settle and the supernatant was transferred via a syringe to a stirred 5 mL of DMA solution. Methyl 5-bromopicolinate (0.78 g, 3.6 mmol) and Cl2Ni(Ph2PCH2CH2PPh2) were added sequentially, and the resulting mixture was stirred at rt for 60 h. LC-MS indicated a partial conversion. The reaction mixture was quenched with 15 mL of sat. NH4Cl, and extracted with 50 mL of EtOAc. The organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give an oil which was purified by silica gel flash chromatography, eluting with 10-80% EtOAc in hexanes, to give methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)picolinate as a white solid (200 mg, 17%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Br:17])=[C:4]2[N:11]([OH:12])[C:10]([C:13]([F:16])([F:15])[F:14])=[N:9][C:5]2=[N:6][C:7]=1[Br:8].[CH3:18][N:19]=[C:20]=[O:21].C(N(CC)CC)C>C(OCC)C>[CH3:18][NH:19][C:20]([O:12][N:11]1[C:4]2[C:5](=[N:6][C:7]([Br:8])=[C:2]([Cl:1])[C:3]=2[Br:17])[N:9]=[C:10]1[C:13]([F:14])([F:16])[F:15])=[O:21]
Reactant: CN=C=O
Reactant: On1c(C(F)(F)F)nc2nc(Br)c(Cl)c(Br)c21
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CNC(=O)On1c(C(F)(F)F)nc2nc(Br)c(Cl)c(Br)c21
Reaction time: 0.25 h

Procedure:
6-Chloro-5,7-dibromo-1-hydroxy-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (0.9 gram) was mixed with ether (15 milliliters) and methyl isocyanate (2 milliliters) and stirred for 15 minutes. Triethylamine (0.01 milliliter) was added, and the solution became homogenous. It was permitted to stand for 16 hours, diluted with 50 milliliters diethyl ether; washed with 0.5N HCl, water, and saturated NaCl; then dried over magnesium sulfate, and evaporated. The resulting 1-(methylcarbamoyloxy)-6-chloro-5,7-dibromo-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product was recrystallized from chloroform, m.p., 216°C.