Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[CH3:13][C:14]1([CH3:21])[NH:18][C:17](=[S:19])[NH:16][C:15]1=[S:20]>C(O)C>[N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][S:19][C:17]2[N:16]=[C:15]([S:20][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]4[C:12]=3[N:11]=[CH:10][CH:9]=[CH:8]4)[C:14]([CH3:21])([CH3:13])[N:18]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC1(C)NC(=S)NC1=S
Reactant: BrCc1cccc2cccnc12
Solvent: CCO
Product: CC1(C)N=C(SCc2cccc3cccnc23)N=C1SCc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Initially, 3 g of 8-bromomethylquinoline was added to a solution of 1 g of 5,5-dimethyl-2,4-dithiohydantoin in 50 mL of ethanol (EtOH). The reaction mixture was stirred at the room temperature for 1.5 hour, and concentrated in vacuo. To the residue, 100 mL of CHCl3 was added. The mixture was washed with an aqueous solution of K2CO3, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatograph (CHCl3). Recrystallization from diethyl ether gave the desired compound in the form of a needle-like crystal. The yield of this compound was 2.3 g with a yield ratio of 83.3%, and the melting point was 101°-104° C.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[C:6]1([C:2]2([CH2:3][C:4]#[N:5])[O:14][CH2:13][CH2:12][O:1]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCO
Reactant: N#CCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#CCC1(c2ccccc2)OCCO1
Temperature: 150 °C
Yield: 76.6 %

Procedure:
To a solution of 3-oxo-3-phenylpropanenitrile (10 g, 69 mmol) and PTSA (27 mg, 1.37 mmol) in toluene (120 mL) is added ethylene glycol (120 mL, 2057 mmol). The azeotropic mixture is heated at 150° C. for 14 h. The solvent is evaporated under reduced pressure and the residue is washed with 10% aqueous NaOH solution. The aqueous layer is extracted with diethyl ether (2×100 mL) and the combined organic layers are dried (Na2SO4) and evaporated to provide the crude compound. The crude material is purified over neutral alumina eluting with 1% of ethyl acetate/hexane to afford the title compound as an off-white solid (10 g, 77%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10].[N+:11]([O-])([OH:13])=[O:12].N>S(=O)(=O)(O)O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][N+:5]=1[O-:10]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc[n+]1[O-]
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Product: COc1cc([N+](=O)[O-])cc[n+]1[O-]
Temperature: 0 °C

Procedure:
30 ml of concentrated sulfuric acid, cooled to 0° C., are added to 15.5 g of 2-methoxypyridine N-oxide hydrochloride, after which 42 ml of fuming nitric acid and 14 ml of concentrated sulfuric acid are added dropwise at 0° C. After the temperature has been allowed to rise, the reaction mixture is heated for 3 hours at 90°-100° C. and is then cooled and poured onto 50 g of ice. It is neutralized to pH 7 by the addition of concentrated aqueous ammonia at a temperature below 10° C. The aqueous phase is extracted 6 times with methylene chloride, the organic phase is then dried over sodium sulfate and concentrated and 11 g of a yellow solid corresponding to a mixture of 2-methoxy-4-nitropyridine N-oxide and 2-methoxy-5-nitropyridine N-oxide are recovered. The 2 products are separated by chromatography on silica using a methylene chloride/methanol mixture (95/5) as the eluent. 6.3 g of 2-methoxy-4-nitropyridine N-oxide are collected.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].Cl>C(OC(C)C)(=O)C.C(O)(C)C>[CH3:11][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:1])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4]
Reactant: CC(C)(c1ccccn1)C(N)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)OC(C)C
Product: CC(C)(c1ccccn1)[C@@H](N)c1ccccc1

Procedure:
(S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine is prepared starting from racemic 2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine using chiral SFC chromatography. This oil is dissolved in isopropyl acetate and a solution of 5-6 N HCl in isopropyl alcohol is added. The mixture is concentrated, and triturated in ether to yield the title compound as a white solid. M.p.=188° C. 1HNMR (300 MHz, CD3OD): δ 1.59 (s, 3H), 1.76 (s, 3H), 5.09 (s, 1H), 7.25-7.28 (m, 2H), 7.38-7.40 (m, 3H), 8.00 (t, J=6.6 Hz, 1H), 8.11 (d, J=6.9 Hz, 1H), 8.56 (t, J=7.8 Hz, 1H), 8.77 (d, J=5.7 Hz, 1H). MS: m/z 227.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@@H:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].[C:40]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)(=[O:46])[CH2:41][CH2:42][C:43](O)=[O:44].Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.O1CCCC1.C(OCC)(=O)C>[C:43]([O:21][C@H:13]([CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([NH:22][C:23](=[O:39])[CH2:24][CH:25]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[O:32][C:33]3[C:38]2=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:7]=1)[CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)(=[O:44])[CH2:42][CH2:41][C:40]([O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46]
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Reactant: CC(C)(C)c1ccc(CC[C@@H](O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CC[C@H](CC2CCCCC2)OC(=O)CCC(=O)OCc2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of 249 mg (0.474 mmol) of (R)-N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 100), 218 mg (1.05 mmol) of benzyl hydrogen succinate, 76 mg (0.62 mmol) of 4-(N,N-dimethylamino)pyridine and 256 mg (1.34 mmol) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride in 5 ml of tetrahydrofuran was stirred for 17 hours at room temperature. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the diluted mixture was washed with 2N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 20 g of silica gel, using a 1:9 by volume mixture of ethyl acetate and hexane as the eluent, to give 352 mg (a quantitative yield) of the title compound as a glassy material.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Cl[CH2:7][SiH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11]>>[C:1]([O:4][CH2:7][SiH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11])(=[O:3])[CH3:2]
Reactant: COC(OC)[SiH2]CCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: COC(OC)[SiH2]COC(C)=O

Procedure:
The top, Hydroseal phase and the middle, catalyst phase from Example 5b were admixed with 180 g (2.2 mol) of sodium acetate and the suspension was dried by distilling 10 mL of Hydroseal G 400 H off through a Vigreux column (80 cm) at 1-2 mbar (head), 120-135° C. (head), 150-160° C. (pot). The suspension was cooled down to 130° C., at which point 308 g (2.00 mol) of (chloromethyl)dimethoxymethylsilane were metered in over 47 minutes. The product was distilled out through a Vigreux column (80 cm); the product (acetoxymethyl)dimethoxymethylsilane was obtained at 30 mbar (head), 71-73° C. (head) and 73-80° C. (pot) in the distillate (334 g, 1.87 mol, 94% of theory; purity 99.1% (GC area %)) as a colorless liquid. The solvent, sodium chloride, excess sodium acetate and the phase transfer catalyst in the form of the chloride, bromide and acetate salt of tetrabutylphosphonium remained in the residue.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH2:25][NH:26][CH3:27])=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:28].Br[CH2:30][CH2:31][F:32].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31][F:32])[CH3:27])=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:28]
Reactant: FCCBr
Reactant: CNCCOc1ccccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCCN(C)CCF)C3
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
A mixture of Example 144 (100 mg; 0.23 mmol; 1 eq.), 1-bromo-2-fluoro-ethane (47 mg; 0.37 mmol; 1.6 eq.) and NaHCO3 (193 mg; 2.29 mmol; 10 eq.) in DMF was stirred at 100° C. for 30 minutes. 1-Bromo-2-fluoro-ethane (47 mg; 0.37 mmol; 1.6 eq.) was added and the resulting mixture was stirred at 100° C. for 30 minutes then concentrated in vacuo. After dilution with EA, the solution was washed with sat. aq. NaHCO3 then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to 10% MeOH in EA) afforded the title compound (50 mg, 49%) as a white foam. 1H NMR (DMSO-d6) δ 7.51-7.39 (m, 1H), 7.36-7.24 (m, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.04 (t, J=7.3 Hz, 1H), 4.80 (d, J=7.3 Hz, 2H), 4.59 (d, J=19.7 Hz, 2H), 4.37 (td, J=5.0, 3.2 Hz, 1H), 4.21 (td, J=5.1, 3.3 Hz, 1H), 4.12 (t, J=5.3 Hz, 2H), 2.84 (s, 2H), 2.81 (s, 1H), 2.71 (t, J=5.2 Hz, 2H), 2.67-2.60 (m, 2H), 2.60-2.53 (m, 2H), 2.15 (s, 3H). HPLC (max plot) 97.5%, Rt 2.65 min. UPLC/MS: (MS+) 446.2 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[F:13])=[O:3].O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[F:13])=[O:3]
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1cc(N)ccc1F
Temperature: 70 °C
Yield: 48.4 %

Procedure:
25.4 g (152 mmol) of 2-fluoro-5-nitroacetophenone, 343 g (1.52 mol) of tin chloride dihydrate and 250 ml of ethyl acetate are introduced into a 1-liter three-necked flask. The reaction mixture is heated to 70° C. for 30 minutes and then poured onto 1 liter of crushed ice, 30% sodium hydroxide solution is added and the mixture is extracted with 3 times 350 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated. 11.26 g of product are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[NH:19]([C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)[C:20]([NH2:22])=[NH:21].[OH-].[Na+]>CO.O>[N:27]1[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][C:23]=1[N:19]=[C:20]1[NH:22][C:8]2([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[NH:22][C:20](=[N:19][C:23]3[NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[N:24]=3)[NH:21][C:10]2([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[NH:21]1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccc(F)cc2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1

Procedure:
Following the procedure of Example 1, 4,4'-difluorobenzil (1.0 g, 4.06 mmol) and 2-guanidinobenzimidazole (0.6 g, 3.4 mmol) in methanol (40 mL) was treated with a solution of sodium hydroxide (200 mg, 5 mmol) in 5 mL of water. The title compound was isolated as pale yellow crystals (750 mg, 79% yield). MS (ESI) m/z 561 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.22 (s, br, 1H), 7.74-6.70 (m, 12H), 5.05-4.94 (m, 1H), 3.66-3.52 (m, br, 2H), 3.02-2.83 (m, br, 2H), 2.81-2.58 (m, br, 4H), 2.58-2.36 (m, br, 2H), 2.02-1.66 (m, br, 6H), 1.66-1.46 (m, br, 1H), 1.46-1.35 (m, br, 3H), 1.26 (d, 6H, J=6.0 Hz); ESMS m/e: 535.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Cl:13][CH2:14][C:15]#[C:16][CH2:17]Cl.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Cl:13][CH2:14][C:15]#[C:16][CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: ClCC#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCc2ccc(OCC#CCCl)cc2N1
Yield: 66.1 %

Procedure:
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (930 mg, 6 mmol), 1,4-dichlorobut-2-yne (326 mg, 2 mmol) and anhydrous K2CO3 (276 mg, 2 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column to give 7-(4-chlorobut-2-ynyloxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 50) (330 mg, 66%) as a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([N:15]3[C:20](=[CH:21]2)[C:19](=[O:24])[NH:18][CH2:17][CH2:16]3)=[N:13][CH:12]=1.FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.[H-].[Na+]>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([N:15]3[C:20](=[CH:21]2)[C:19](=[O:24])[N:18]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:17][CH2:16]3)=[N:13][CH:12]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: C[C@H]1CCCN1CCCOc1cnc2c(c1)cc1n2CCNC1=O
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1CCCN1CCCOc1cnc2c(c1)cc1n2CCN(CC(F)(F)F)C1=O
Yield: 12 %

Procedure:
The title compound was synthesized in analogy to example 17, from 7-[3-((S)-2-methyl-pyrrolidin-1-yl)-propoxy]-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one (example 85), 2,2,2-trifluoroethyl trifluoromethanesulfonate and sodium hydride, to give the desired product as a colorless solid (12%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][NH:33][CH2:32][CH2:31]2.C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(#N)C>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]2[CH2:32][CH2:31][C:30]3[C:35](=[CH:36][CH:37]=[C:28]([O:27][CH3:26])[CH:29]=3)[CH2:34]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc2c(c1)CCNC2
Reactant: COc1ccc(C(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc2c(c1)CCN(CCCCCC(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1)C2
Temperature: 25 °C

Procedure:
To a solution of 4.23 g of 4-[6-bromo-1-[(4-methylphenyl)thio]hexyl]-1,2-dimethoxybenzene in 40 mL of acetonitrile is added 3.88 g of 6-methoxy-1,2,3,4-tetrahydroisoquinoline, 1.74 mL of diisopropylethylamine and 0.01 g of sodium iodide. The solution is heated to reflux for 43 hours and cooled to room temperature. The reaction mixture is partitioned between chloroform and aqueous potassium carbonate and the organic layer is dried over magnesium sulfate. The volatiles are removed at reduced pressure and the residue chromatographed on silica gel using a gradient elution of hexane to chloroform to methyl alcohol. The residue from the chromatography is dissolved in diethyl ether and passed through diatomaceous earth. This affords 4.4 g of the desired product as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:7][C:6]2=1)#[N:2]>[Pt].CO>[NH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:12]1[C:11]2[CH2:10][CH2:9][CH:8]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([C:1]#[N:2])[CH:4]=2
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc([N+](=O)[O-])c2)C1
Agent: [Pt]
Solvent: CO
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(N)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add sulfided platinum (5 wt % on carbon) (120 mg) to a solution of N-[6-cyano-9-(3-nitro-benzyl)2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 88) (470 mg, 1.1 mmol) and methanol (50 mL). Purge and fill the reaction vessel with nitrogen (3×), then with hydrogen (3×, 55 psi). Seal the reaction vessel at about 55 psi, and stir the mixture at room temperature overnight. Filter the reaction mixture through a Celite® pad, and wash the filter cake with methanol. Concentrate under reduced pressure and purify the crude residue by flash chromatography (2.5% methanol/methylene chloride) to give the title compound. LCMS (Method D): m/z 387.1 (M+1, APCI); 1H NMR (DMSO-d6): δ 7.97 (d, 1H), 7.88 (d, 1H), 7.57 (d, 1H), 7.42 (dd, 1H), 6.94 (t, 1H), 6.24 (d, 1H), 6.20 (m, 1H), 5.26 (s, 2H), 5.07 (s, 2H), 4.03-4.06 (m, 1H), 3.01 (dd, 1H), 2.72-2.86 (m, 2H), 2.55 (dd, 1H), 2.38-2.46 (m, 1H), 1.98-2.02 (m, 2H), 1.79-1.87 (m, 1H), 1.04 (d, 3H), 1.02 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH2:18][OH:19])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH2:6][N:7]([CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH2:18][OH:19])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:5])[CH3:2]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CNc1cc(CO)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1cc(CO)cc(C(=O)OC)c1)C(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
A mixture of the product from step (iv) (3 g), potassium carbonate (15.48 g) and bromodiphenylmethane (2.77 g) in dimethylformamide (100 ml) was heated at 50° C. for 24 hours. The mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.51 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[N:19]=[C:20]([NH:23][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[S:21][CH:22]=1
Reactant: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(F)c2)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of 4-(2-fluoro-4-(4-methoxyphenoxy)-6-methylphenyl)thiazol-2-ylamine (30-7, 0.10 g, 0.30 mmol) in CH2Cl2 (10 mL) was added DMAP (73 mg, 0.60 mmol) followed by isonicotinoyl chloride hydrochloride (69 mg, 0.39 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was collected and recrystallized in toluene to give N-{4-(2-dluoro-4-(4-methoxyphenoxy)-6-methylphenyl)thiazol-2-yl}isonicotinamide (30, 42 mg, 0.10 mmol) as white solids in 32% yield: 1H NMR (500 MHz, CDCl3) δ 8.86 (d, J=5.8 Hz, 2 H), 8.04 (d, J=5.6 Hz, 2H), 6.99 (d, J=7.2 Hz, 3 H), 6.92 (d, J=9.0 Hz, 2 H), 6.61 (s, 1 H), 6.50 (m, 1 H), 3.82 (s, 3 H), 2.26 (s, 3 H). ESI-MS: m/z 436.1 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][OH:9])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>ClCCl>[OH:9][CH2:8][CH:3]([NH:2][C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=1)=[O:24])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(N)CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-amino-3-hydroxypropanoate hydrochloride (L-serine methyl ester hydrochloride, 1.71 g, 11 mmol) was stirred in dichloromethane (20 ml) at 0° C., and triethylamine (2.79 ml, 20 mmol) added, followed by dropwise addition of 4-trifluoromethylbenzoyl chloride (1.486 ml, 11 mmol). The mixture was stirred at 0° C. for 30 minutes, then partitioned between dichloromethane and water, dried over magnesium sulfate, and filtered. Solvent was removed from the filtrate under reduced pressure, and the residue was purified by column chromatography, to yield methyl 3-hydroxy-2-{[4-(trifluoromethyl)phenyl]carbonylamino}propanoate, a compound of formula (13). B. Preparation of a Compound of Formula (14)
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:33][C:34](=[O:41])[C@@H:35](O)[CH2:36][CH:37]([CH3:39])[CH3:38]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][C@H:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:34]([OH:41])=[O:33])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O)CC(C)C
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Product: CC(C)C[C@@H](Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and (S)-(−)-hydroxyisocaproic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 81-83° C.; MS m/e 645 (M−H)+;