Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:23]([O:24][C:25]3[CH:26]=[N:27][C:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])=[CH:29][CH:30]=3)=[CH:22][C:12]3[NH:13][C:14]([C:16]4[CH:21]=[CH:20]C=CN=4)=[N:15][C:11]=3[CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:36][N:37]1C=CC(C(O)=O)=[N:38]1>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[C:23]([O:24][C:25]3[CH:26]=[N:27][C:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])=[CH:29][CH:30]=3)=[CH:22][C:12]3[NH:13][C:14]([C:16]4[CH:21]=[CH:20][N:37]([CH3:36])[N:38]=4)=[N:15][C:11]=3[CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2Cl)cn1
Reactant: Cn1ccc(C(=O)O)n1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccn(C)n4)nc3cc2Oc2cccnc2Cl)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 203 or in accordance with the method or by combining it with an ordinary method but using 4-(2-chloropyridin-3-yloxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 242 and 1-methyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([CH3:28])[C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:3]4=[O:29])=[CH:8][CH:9]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(N3CCCC3)C2=O)cc1

Procedure:
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with pyrrolidine by method L. This resulted in the product with the molecular weight of 445.61 (C28H35N3O2); MS (ESI): 446 (M+H+).
Reaction SMILES: [Si]([CH:5]=[N+:6]=[N-:7])(C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[CH:16][C:17]2[N:21]=[C:20]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]5[C:42]([C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=5)=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)[NH:19][C:18]=2[CH:49]=1>C1COCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[N:21]=[C:20]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]5[C:42]([C:43]6[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=6)=[CH:41][C:38]([C:39]6[N:40]=[N:7][NH:6][CH:5]=6)=[CH:37][N:36]=5)=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)[NH:19][C:18]=2[CH:49]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#Cc1cnc(-c2ccc(CN3CCC(c4nc5ccc(F)cc5[nH]4)CC3)cc2)c(-c2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc2nc(C3CCN(Cc4ccc(-c5ncc(-c6c[nH]nn6)cc5-c5ccccc5)cc4)CC3)[nH]c2c1
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
To a solution of TMS diazomethane (2 M in hexanes, 0.205 mL, 0.410 mmol) in anhydrous THF (1 mL) was added n-butyl lithium (2.5 M in hexanes, 0.164 mL, 0.410 mmol) dropwise@−5° C. The mixture was stirred to 20 min@−5° C. when this solution was added dropwise to a mixture of 6-(4-{[4-(6-fluoro-1H-benzimidazol-2-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (4-1, 0.050 g, 0.103 mmol) in THF (1 mL)@−5° C. The reaction was allowed to stir@−5° C. for 3 hr when it was quenched with saturated aqueous Na2HCO3 and extracted with CH2Cl2 (3×15 mL). The combined organics were dried (anhydrous Na2SO4), filtered, and concentrated. The residue was taken up in THF (2 mL) and TBAF (1 M in THF, 0.205 mL) was added. The reaction was heated to 60° C. for 2 hr, at which time it was cooled and concentrated. The resulting residue was taken up in DMF and purified by reverse phase HPLC (8-1; 5% CH3CN: 95% H2O+0.01% TFA to 95% CH3CN: 5% H2O+0.01% TFA). 1H-NMR (500 MHz, d6 DMSO) δ 9.74 (bs, 1H), 9.20 (d, J=2.20, 1H), 8.65 (bs, 1H), 8.29 (d, J=2.21, 1H), 7.60-7.70 (m, 1H), 7.25-7.55 (m, 12H), 7.18 (t, J=7.08, 1H), 4.35 (s, 2H), 3.50 (d, J=12.06, 2H), 3.25-3.39 (m, 1H), 3.09-3.20 (m, 2H), 2.29-2.39 (m, 2H), 1.97-2.10 (m, 2H). HRMS m/z (M+H) Calcd: 530.2463, found: 530.2454.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[C:14]([C:13]1[CH:12]=[C:11]([C:10]2[N:9]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:8]=[C:7]3[C:6]=2[C:5](=[O:19])[N:4]([CH3:20])[C:3](=[O:21])[N:2]3[CH3:1])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: CCOC(=O)CCCCBr
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Product: CCOC(=O)CCCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared from 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9, step 4) and ethyl 5-bromopentanoate (0.712 mL, 4.50 mmol) by an analogous method to Example 9 step 5;
Reaction SMILES: [N:1]1([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>O1CCCC1>[CH3:23][N:24]([CH3:28])[C:25]([O:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[N:8]=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:26]
Reactant: CN(C)C(=O)Cl
Reactant: Oc1cnccc1N=CN1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1cnccc1N=CN1CCCCC1

Procedure:
A mixture prepared from 4-[[(1-piperidinyl)methylene]amino]-3-pyridinol (3.5 g), triethylamine (3.69 mL), dimethylcarbamyl chloride (2.3 mL) and tetrahydrofuran (130 mL) was refluxed for 2 hours, filtered, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate to yield 4.49 g of product. Recrystallization from ethyl acetate and drying under high vacuum yielded 3.94 g of crystals, m.p. 88°-89° C.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH:2]=1.Br>C(O)(=O)C>[C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: COc1ccc(Oc2cccc(C)c2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cccc(Oc2ccc(O)cc2)c1
Temperature: 0 °C

Procedure:
77 g of p-(m-tolyloxy)anisole are dissolved in 360 ml of acetic acid and treated with 300 ml of 48% hydrobromic acid. Then, the mixture is allowed to react at reflux temperature for 5 hours. The cooled solution is poured into 1.5 l of ice-water and extracted three times with 150 ml of methylene chloride each time. The organic solution is washed three times with 150 ml of water each time and with 150 ml of saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated. Distillation of the crude product yields pure p-(m-tolyloxy)phenol; b.p. 88°-89° C./0.04 Torr.
Reaction SMILES: I[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=[CH2:31].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:24][C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH2:9][N:6]3[C:5]4[CH:27]=[CH:28][C:2](/[CH:31]=[CH:30]/[C:29]([O:33][CH2:34][CH3:35])=[O:32])=[CH:3][C:4]=4[N:8]=[CH:7]3)[CH:26]=[CH:25][C:13]=2[N:14]=1
Reactant: C=CC(=O)OCC
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 120 °C
Yield: 130.8 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (150 mg, 0.30 mmol) from Step 5 of Example 183 in DMF (2 mL) were added ethyl acrylate (0.036 mL, 0.33 mmol), palladium (II) acetate (7 mg 0.03 mmol), and triethylamine (0.088 mL, 0.63 mmol). The mixture was flushed with argon and heated in a sealed vessel at 120° C. for 3 h. The mixture was cooled to rt and partitioned between EtOAc and water. The separated aqueous layer was extracted twice with EtOAc and the combined organic phases were washed three times with a 1:1 mixture of water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford (E)-ethyl 3-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)acrylate (187 mg) as a solid. The product was used directly in the next step. LCMS (ESI) m/z 477 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:16]=1)=[O:10].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[O:10])(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(N2CCOCC2)nc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(N3CCOCC3)nc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 158 mg of (2-Amino-5-chloro-phenyl)-(6-morpholin-4-yl-pyridin-3-yl)-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.22 (s, 3H), 3.76 (t, 4H, J=4.6 Hz), 3.857 (t, 4H, J=4.6H), 8.78 (d, 1H, J=9.2 Hz), 7.30 (m, 2H), 7.34 (m, 1H), 7.46 (m, 1H), 7.54-7.56 (m, 3H), 7.99 (d, 1H, J=9.2 Hz), 8.16 (v, 1H), 9.29 (s, 1H). MS: m/z 515.1 (M++1).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[O:4]=[V+3:5].[CH2:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8].Cl>C1(C)C=CC=CC=1>[Cl-:1].[CH2:6]([O:11][V+:5]([O:11][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)CO
Reactant: O=[V+3]
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)(C)CO[V+](=O)OCC(C)(C)C

Procedure:
Added to a glass bottle with a capacity of 200 ml sealed with a rubber stopper after drying and nitrogen substitution were 0.05 mol of VOCl3 (oxovanadium trichloride), 0.10 mol of neopentyl alcohol, and toluene. Then, hydrochloric acid generated while bubbling with nitrogen was removed through a needle to obtain a toluene solution of dineopentoxy oxovanadium chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])=[O:26])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[BH4-].[Na+].O.C(OCC)(=[O:41])C>C1COCC1.[Cu]Cl>[CH3:1][O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]2[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=2[Cl:33])=[O:26])=[CH:22][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][OH:41])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: C=CCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)OC)CCCC1
Reactant: CCOC(C)=O
Agent: Cl[Cu]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCCCO)CCCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 62 %

Procedure:
To a suspension of 4-[[(2,6-dichlorophenyl)carbonyl]arnino]-N-[[1-(3-butenyl)cyclopentyl]-carbonyl]-L-phenylalanine methyl ester (3.13 mmol, 1.62 g) and anhydrous copper (I) chloride (5.0 mmol, 500 mg) in THF (30 mL) was added solid sodium borohydride (5.0 mmol, 200 mg) at −5° C. over 5 min. After the addition, the reaction mixture was allowed to warm to room temperature and the brown reaction mixture was stirred for 36 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the excess hydride was quenched by the addition of water (5 mL) and the reaction mixture was cooled to 0° C. To this, a solution of sodium acetate (20 mL, 3.0N) was added dropwise maintaining the temperature below 10° C. this was followed by H2O2 (25 mL, 30%). After addition of hydrogen peroxide, the reaction mixture was allowed to warm to room temperature and was stirred for 3 h and followed by 1 h at 40-45° C. to complete the hydrolysis. Then, it was poured into a mixture of water (50 mL) and ethyl acetate (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The comined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent gave a crude product which was purified by silica gel column chromatography to afford 1.04 g (62%) of a white amorphous solid. HR MS (C27H32Cl2N2O5): Obs. mass, 535.1758. Calcd. mass, 535.1766, M+H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])(=O)C.[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.[OH-].[K+]>C(O)C>[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH2:4]
Reactant: BrCc1ccccc1Br
Reactant: CC(=O)Nc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccccc1OCc1ccccc1Br

Procedure:
To a 500 mL, 3-neck round-bottomed flask equipped with a mechanical stiffer, a condenser and a thermometer was charged 23.6 grains (0.156 mol) of 2-Acetamidophenol in 300 mL of ethanol (200 proof). 41.02 grams (0.164 mol) of 2-Bromobenzyl bromide was added, followed by the addition of 21.24 grains (1.09 molar equivalents) of potassium hydroxide (“KOH”) in a 45% aqueous solution which formed a clear reaction solution. The reaction solution was heated to reflux for several hours until the starting materials were consumed. Additional KOH (6.0 molar equivalents) was then added and the reaction mixture was further heated for several hours to form 2-(o-Bromobenzyloxy) aniline. The reaction mixture was cooled and about 3/4 of the ethanol was removed under vacuum at 30-40° C. Methyl-tert-butyl ether (“MTBE”) (200 mL) and water (300 mL) was added, the resulting layers were mixed and the lower aqueous layer was separated from the product-rich MTBE layer. The water layer was washed with MTBE (100 mL) and the MTBE layers were combined. The combined MTBE layers were washed with water (150 mL). Then, to the MTBE layers was added slowly 17.4 grams of HCl (1.0 molar equivalent) in a 37% aqueous solution to crystallize the product. The resulting crystal slurry was cooled to 0° C. and stirred for 1 hour. The crystals were filtered and washed with 30 mL of ice-cold ethanol and twice with 30 mL portions of ice-cold MTBE. The crystals were dried under nitrogen and vacuum to yield 41.5 grams (84% yield by weight) of 2-(o-Bromobenzyloxy) aniline HCl salt in 99.02% purity.
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([Li])[CH2:14][CH2:15][CH3:16]>O1CCCC1>[CH2:16]([C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH2:9][CH2:10][CH2:11][S:12]1)[CH2:15][C:14]#[CH:13]
Reactant: [Li]CCCC
Reactant: c1ccc(C2SCCCS2)cc1
Solvent: C1CCOC1
Product: C#CCCC1(c2ccccc2)SCCCS1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-phenyl-1,3-dithiane (6.4 g, 32.7 mmol) in tetrahydrofuran (100 mL) at -40° C. under argon atmosphere was added 2.5M n-butyllithium (13.1 mL, 37.7 mmol). After 30 minutes the temperature was adjusted to -20° C. and maintained for 1.5 hour. The temperature of the dark brown solution was lowered to -78° C. and but-4-yne (1.5 g, 14.9 mmol) was added neat. After 1 hour, the temperature was raised to -60° C. for 1.5 hour and the solution was then stored at -20° C. overnight. The reaction mixture was poured onto water, the layers separated, and the aqueous layer was back-extracted with methylene chloride (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and the solvents evaporated at reduced pressure to give the product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>O>[C:19]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)Oc1cccc(Br)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
To a stirred solution of 3-bromophenol (25 g, 145 mmol) in acetic anhydride (14 ml) was added a few drop of sulfuric acid, and the mixture was stirred for 2 hours. The mixture was poured into a solution of NaHCO3 (1.3 g, 15.5 mmol) in water (160 ml). The whole was extracted with diethylether. The organic layer was washed with saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without purification. (31 g, 99% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:20]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2].[CH3:41]I>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:20]([CH:25]([C:26]2[CH:27]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=2)[CH3:41])[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: CI
Solvent: C1CCOC1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N(C(=O)OC)C(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a pre-dried flask under nitrogen atmosphere was added cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (0.200 g, 0.346 mmol) and tetrahydrofuran (2 mL). The solution was cooled to -78° C. and a 1.83 M solution of n-butyl lithiumin hexanes (0.23 g, 0.41 mmol) was added. The reaction was stirred at -78° C. for 45 min, then methyl iodide (0.026 mL, 0.41 mmol) was added and the reaction was warmed to 0° C. and stirred for 90 min. The reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give crude product. Purification by silica gel chromatography using 20% ethyl acetate/hexanes, followed by 70% ether/hexanes as eluent afforded the desired methylated product. MS m/z 593 (M+ +H); 1H NMR (CDCl3) δ 7.85 (bs, 1H), 7.8 (bs, 2H), 7.05 (bs, 1H), 6.5 (bs, 1H), 3.9 (s, 3H), 3.85 (s, 3H), 1.65 (d, 1.5H, J=7 Hz), 1.05 (d, 1.5H, J=7.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]I)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(CCI)cc1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCNC2
Product: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCN(CCc1ccc([N+](=O)[O-])cc1)C2
Yield: 72 %

Procedure:
The same procedure as in Example 17 was used except an equivalent amount of 2-amino-3-(4-chloro-benzoyl) 4,5,6,7-tetrahydrothieno[2,3-c]pyridine was used in place of 2-Amino-3-benzoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2 mmol), and an equivalent amount of p-nitrophenylethyl iodide was used in place of methyl iodide (3 mmol). (m.p. 150-152° C.; 72% yield).
Reaction SMILES: [C:1]1(=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[K+]>CS(C)=O>[N+:13]([CH2:16][C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:15])=[O:14]
Reactant: CCOC(=O)C=C1CCCCC1
Reactant: C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCCCC1
Yield: 89.4 %

Procedure:
16.8 g (0.1 mole) Ethyl cyclohexylideneacetate, 9.2 g, (0.15 mole) nitromethane and 0.64 g (0.01 mole) potassium hydroxide (content 88%) in 40 mL dimethyl sulphoxide are stirred for 2 hours at 100° C. The reaction mixture is worked up analogously to Example 2 to give 20.5 g ethyl 1-nitromethyl-1-cyclohexaneacetate (89.4% of theory). According to GC., the content is 82.8% and 10.2% of starting compound and 4.1% of by-product are obtained (see Example 3).
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=3[Cl:21])[N:10]=[C:6]2[C:5]([F:22])=[CH:4][N:3]=1.[Br:23][Si](C)(C)C>C(#N)CC>[Br:23][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=3[Cl:21])[N:10]=[C:6]2[C:5]([F:22])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(-n2cc3c(Cl)ncc(F)c3n2)c(Cl)c1
Reactant: C[Si](C)(C)Br
Solvent: CCC#N
Product: O=[N+]([O-])c1cc(Cl)c(-n2cc3c(Br)ncc(F)c3n2)c(Cl)c1
Temperature: 105 °C
Yield: 102.9 %

Procedure:
4-Chloro-2-(2,6-dichloro-4-nitrophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (1.78 g, 4.93 mmol) was suspended in propionitrile (30 mL), under an atmosphere of nitrogen and bromo trimethylsilane (5.1 mL, 38.3 mmol) was added. The reaction mixture was heated at 105° C. overnight. The resultant mixture was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was further extracted with ethyl acetate (×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with pentane and the solid obtained was dried under reduced pressure to afford the title compound as a pale yellow solid (2.06 g, quantitative yield). 1H NMR (300 MHz, CDCl3): δ 8.44 (s, 2H), 8.33 (d, J=2.2 Hz, 1H), 8.05 (d, J=3.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)[C:9]2=O)=[CH:4][CH:3]=1.[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].CCOC(C)=O>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)[C:9]2=[N:26][S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])=[CH:4][CH:3]=1
Reactant: COC1CCC2(CCc3ccc(Br)cc3C2=O)CC1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC1CCC2(CCc3ccc(Br)cc3C2=NS(=O)C(C)(C)C)CC1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
7′-Bromo-4-methoxy-3′,4′-dihydro-1′H-spiro[cyclohexane-1,2′-naphthalen]-1′-one (Intermediate 9, 2.26 g, 6.99 mmol), 2-methylpropane-2-sulfinamide (1.27 g, 10.5 mmol) and titanium ethoxide (2.88 mL, 14.0 mmol) were dissolved in 2-Me THF (15 mL) and heated to reflux over the weekend. The reaction was stopped and cooled to r.t. EtOAc (30 mL) and water (15 mL) were added under stirring. The mixture was then let to stand without stirring for 1 h. The organic phase was collected by filtration, dried using a phase separator and concentrated in vacuo. The product was purified by flash column chromatography using a gradient of 0-100% EtOAc in heptane to give the title compound (0.61 g, 20% yield): MS (ES+) m/z 426.11 [M+H]+.