Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]([C:9]1[CH:23]=[C:22](I)[C:12]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[N:15][C:11]=2[CH:10]=1)#[N:8].C(N(CC)CC)C>C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][C:22]1[C:12]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[N:15][C:11]=2[CH:10]=[C:9]([C:7]#[N:8])[CH:23]=1
Reactant: C=CC(=O)OC
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cc(C#N)cc2ncn(-c3ccccc3)c12
Yield: 82.4 %

Procedure:
Methyl acrylate (0.27 ml, 3 mmol), 5-cyano-7-iodo-1-phenylbenzimidazole (346 mg, 1.0 mmol), triethylamine (0.28 ml, 2 mmol) palladium acetate (4.5 mg, 0.02 mmol), tri-o-tolylphosphine (16.1 mg, 0.05 mmol) and acetonitrile (5 ml) were combined in Reactivial™. The mixture was heated under reflux under an argon atmosphere for 17 h. The mixture was cooled, filtered through Dicalite and the filtrate was concentrated under reduced pressure. Crystals formed and were isolated by filtration and dried to give the title compound (250 mg, 83%), m/z 304.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[OH:12].[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[NH2:8][C:6]1[C:5]([F:11])=[CH:4][C:3]([OH:12])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(O)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(Cl)c(O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
Zinc dust (10 g, 160 mmol) was added portion wise to a solution of 2-chloro-5-fluoro-4-nitro-phenol (3.0 g, 16 mmol) and NH4Cl (8.4 g, 160 mmol) in THF (150 mL) and MeOH (150 mL) and the mixture was stirred at RT for 0.5 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (3×50 mL). The combined filtrate was washed with brine (3×100 mL), dried over Na2SO4 and concentrated to provide 4-amino-2-chloro-5-fluorophenol (2.5 g, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 6.76 (d, J=9.2 Hz, 1H), 6.65 (d, J=12.4 Hz, 1H), 4.70 (s, 2H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:18]3[CH2:19][CH2:20][S:21](=[O:25])(=[O:24])[CH2:22][CH:23]=3)=[C:13]([F:26])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][C:47]1NN=N[N:48]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.CO>[O:25]=[S:21]1(=[O:24])[CH2:20][CH:19]=[C:18]([C:14]2[C:15]([F:17])=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][N:1]4[N:2]=[N:3][C:47]([CH3:46])=[N:48]4)[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[F:26])[CH2:23][CH2:22]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: Cc1nnn[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnn(C[C@H]2CN(c3cc(F)c(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 56.7 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)-oxazolidin-2-one (WO 01/81350 A1) (0.50 g, 1.39 mmol), triphenylphosphine (0.55 g, 2.1 mmol), and 5-methyl-1H-tetrazole (0.18 g, 2.14 mmol) were dissolved in dry tetrahydrofuran (5 ml), and cooled on an ice-water bath. Diisopropylazodicarboxylate (0.41 ml, 2.58 mmol) was added dropwise and the mixture was stirred at 0° C. for 4 hours. Methanol (3 ml) was added, followed by evaporation of the solvent under reduced pressure and purification by flash column chromatography on silica gel with 10% acetonitrile in dichloromethane. The material obtained after chromatography was precipitated from dichloromethane with diethyl ether to give the title compound (0.335 g).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=4)[CH2:14][CH2:13]3)[N:11]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:10](=[O:34])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=4)[CH2:25][NH:26][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:14][CH2:13]3)[N:11]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:10](=[O:34])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2 mL CH2Cl2 suspension of 0.05 g (0.11 mmol) 4-(cyclohexylamino)-8-[3-(aminomethyl)benzyl]-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (Example (7-12)), 0.02 mL (0.22 mmol) methanesulfonyl chloride and excess K2CO3 was allowed to stir at rt overnight. The reaction was filtered and concentrated. The remaining oil was dissolved in 0.5 mL CH2Cl2 and purified on an Isco automated system affixed with a Biotage Flash 25(S) cartridge eluted at 20 mL/min with 0-5% MeOH in CH2Cl2 over 15 min and hold at 5% MeOH for 30 min. The product eluted second, pure by HPLC/MS and NMR. 1H NMR (400 MHz, CDCl3) δ 7.79-7.83 (m, 1H), 7.45-7.54 (m, 2H), 7.33-7.4 (m, 2H), 7.12-7.14 (m, 1H), 6.96-7.05 (m, 3H), 4.31-4.39 (m, 1H), 3.92-4.05 (m, 1H), 3.48-3.52 (m, 1H), 2.65-2.80 (m, 2H), 2.4-2.50 (m, 2H), 1.90-2.20 (m, 6H), 1.62-1.8 (m, 4H), 1.55 (s, 3H), 1.30-1.50 (m, 2H), 1.15-1.30 (m, 4H). MS 542.4
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CI.[C:14]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[Cl:1]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
2-Chloro-6-methyl-nicotinic acid (3.58 g, 20.86 mmol) was dissolved in DMF (34 mL). MeI (5.8 mL, 93.88 mmol) and K2CO3(7.78 g, 56.33 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reactant was distilled under reduced pressure to remove the solvent and extracted with EtOAc. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent EtOAc/Hex=1/2) to obtain the title compound (3.68 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8](C#N)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-:19].[K+].[K+].O>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: N#CC(c1ccc(F)cc1)c1ccc(Cl)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc(F)cc1)c1ccc(Cl)cn1
Yield: 93.2 %

Procedure:
Under oxygen atmosphere, a mixed solution of 5-chloro-2-(α-cyano-4-fluorobenzyl)pyridine (16.14 g) and potassium carbonate (10.85 g) in DMSO-water (330-66 ml) was stirred at room temperature for 3 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:4), to give 5-chloro-2-(4-fluorobenzoyl)pyridine (14.37 g) as colorless crystals.
Reaction SMILES: C([O:3][C:4]([NH:6][C:7]([CH2:27][CH3:28])=[CH:8][C:9]([NH:11][C:12]1[C:13]([F:26])=[CH:14][C:15]2[O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][C:23]#[CH:24])[C:16]=2[CH:25]=1)=[O:10])=O)C.C[O-].[Na+].Cl>CO.O>[CH2:27]([C:7]1[NH:6][C:4](=[O:3])[N:11]([C:12]2[C:13]([F:26])=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][C:23]#[CH:24])[C:16]=3[CH:25]=2)[C:9](=[O:10])[CH:8]=1)[CH3:28]
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)C=C(CC)NC(=O)OCC)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(-n3c(=O)cc(CC)[nH]c3=O)cc21
Temperature: 62 °C
Reaction time: 4 h

Procedure:
A suspension of 6.45 g of 6-[3-(ethoxycarbonylamino)-2-pentenoylamino]-3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine and 3.22 g of sodium methylate in 6.5 ml of methanol is stirred at 62° C. for 4 hours. The solution which thus results is left to stand at room temperature for 64 hours and subsequently poured into a solution of 15 ml of 2N hydrochloric acid in 400 ml of water. The resulting precipitate is filtered off under suction, washed with water and recrystallized from acetone/n-hexane. In this manner there is obtained 6-ethyl-3-[3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine-6-yl]-2,4(1H,3H)-pyrimidinedione, m.p. 240° C. (with decomposition).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Br[CH:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24].S(=O)(=O)(O)O>IC.O1CCCC1>[F:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:22]2[CH2:27][CH2:26][O:25][C:23]2=[O:24])([OH:8])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)c2ccc(F)cc2)cc1
Reactant: O=C1OCCC1Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(O)(c2ccc(F)cc2)C2CCOC2=O)cc1

Procedure:
Magnesium turnings (3.5 g) are covered with anhydrous tetrahydrofuran, and a few drops of iodomethane are added. As soon as the reaction has started, a mixture of 24.6 g of 4-fluoro-4'-methanesulfonylbenzophenone and 8.1 ml of α-bromo-γ-butyrolactone in 250 ml of anhydrous tetrahydrofuran is run in dropwise so as to maintain a gentle reflux. When the addition is complete, the reaction medium is cooled and then run into a mixture of ice and 10% dilute sulfuric acid. The organic phase is extracted with tetrahydrofuran, washed with saturated sodium bicarbonate solution and then dried over magnesium sulfate. After evaporation of the solvent, the residue obtained is chromatographed on silica gel with a 9/1 dichloromethane/acetone mixture to give 7 g of 3-[1-(4-fluorophenyl)-1-hydroxy-1-(4-methanesulfonylphenyl)methyl]dihydrofuran-2-one in the form of an amorphous beige powder, which is used as such in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Cl:9])[CH:3]=1.[Mg].[C:11]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:20]2([OH:23])[CH2:21][CH2:22][N:18]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:19]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Fc1ccc(Br)cc1Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(Cl)c2)C1

Procedure:
Preparation according to Preparation 5: 4-bromo-2-chloro-1-fluorobenzene (4.0 g, 19.1 mmol), dry tetrahydrofuran (50 mL), magnesium turnings (0.5 g, 21.0 mmol) and 1-N-boc-3-pyrrolidinone (3.89 g, 21.0 mmol). Yield: 1.65 g. MS m/z (rel. intensity, 70 eV) 315 (M+, 1), 259 (50), 214 (63), 157 (44), 57 (bp).
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][N:5]=1.[CH3:10][NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+].O>CN(C=O)C>[CH3:2][O:3][C:4]1[N:5]=[CH:6][N:7]=[C:8]([N:11]([CH3:10])[CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: CNCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: ClCOc1ccncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N(C)CCOc2ccc(CC3SC(=O)NC3=O)cc2)ncn1
Temperature: 100 °C

Procedure:
A starting mixture consisting of 2.9 g (0.02 mol) 4-chloromethoxypyrimidine and 5.6 g (0.02 mol) 5-[4-(2-methylaminoethoxy)-benzyl]-thiazolidine-2,4-dione in 60 ml DMF and in the presence of 17 g NaHCO3 is heated at 100° C. for 24 h. Once the reaction completed, the mixture is poured onto 600 ml water and it is extracted with 4×200 ml AcOEt.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:9][C:10]1[CH:15]=[C:14](Br)[CH:13]=[C:12]([CH3:17])[C:11]=1[CH2:18][C:19]([O:21]C)=[O:20]>CN(C=O)C.[Cu]I>[CH3:17][C:12]1[CH:13]=[C:14]([O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[CH:15]=[C:10]([CH3:9])[C:11]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: COC(=O)Cc1c(C)cc(Br)cc1C
Reactant: OCC(F)(F)F
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(F)(F)F)cc(C)c1CC(=O)O

Procedure:
18.05 g (451 mmol) of sodium hydride are initially charged in 500 ml of DMF. 41.05 g (410 mmol) of trifluoroethanol are added dropwise, after the evolution of gas has ended 15.63 g (82 mmol) of copper(I) iodide are added, a solution of 21.10 g (82 mmol) of methyl 2,6-dimethyl-4-bromophenylacetate in 100 ml of DMF is slowly added dropwise and the mixture is boiled at reflux for 2.5 h.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:3]1.C([Li])CCC.[Si:18]([O:25][C:26]1[C:27]([F:36])=[C:28]([CH:31]=[C:32]([CH2:34][CH3:35])[CH:33]=1)[CH:29]=[O:30])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[Si:18]([O:25][C:26]1[C:27]([F:36])=[C:28]([CH:29]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)[OH:30])[CH:31]=[C:32]([CH2:34][CH3:35])[CH:33]=1)([C:21]([CH3:22])([CH3:24])[CH3:23])([CH3:20])[CH3:19]
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: Cn1cnc(-c2ccccc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3)nn2C)c1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
To a solution of 1-methyl-3-phenyl-1H-1,2,4-triazole (310 mg, 1.95 mmol, see J. Chem. Soc., 1954, 3319-3322) in THF (25 mL) cooled to −78° C. was added 1.6 M n-butyl lithium (1.33 mL, 2.12 mmol) dropwise and stirred for 15 min. Next a solution of Intermediate 368.2 (500 mg, 1.77 mmol) in THF (5 mL) was added dropwise and stirred for 5 min before allowing the mixture to warm to 23° C. The mixture was quenched with aqueous NH4Cl and extracted with EtOAc (3×50 mL). The organic layer was washed with H2O, brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 440 mg of Example 368.3. HPLC (2 min gradient) RT=2.42 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[O:15]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16]1.C(=O)(O)[O-].[Na+]>O.C(COC)OC.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>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:17]2[CH:18]=[CH:19][O:15][CH:16]=2)=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1ccc(-c2ccoc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 63 %

Procedure:
A mixture of 1d from Example 18 (8.5 g, 32.8 mmol), 3-furanylboronic acid (3.67 g, 32.8 mmol), sodium bicarbonate (13.8 g, 0.16 mol) and tetrakis(triphenylphosphine)palladium(0) (0.5 g) in a mixture of water (40 ml) and dimethoxyethane (80 ml) is heated to 80° C. under a stream of nitrogen over night. After cooling the mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated under reduced pressure.(*). The residue is dissolved in 40 ml dimethoxyethane. Aqueous sodium hydroxide (78 ml, 1 M) is added and the mixture is stirred at ambient temperature over night. The mixture is poured into water and rendered acidic with diluted hydrochloric acid. The precipitate is filtered off, washed with water and dried to yield 1e (5.09 g, 76%). Mp 152-154° C.
Reaction SMILES: Cl[C:2]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:13][CH2:12][CH:11]([S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].[CH3:33][S-:34].[Na+].O>CC(O)C>[CH:18]1([CH2:17][S:14]([CH:11]2[CH2:12][CH2:13][C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]3[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:2]=3[S:34][CH3:33])([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:9][CH2:10]2)(=[O:16])=[O:15])[CH2:20][CH2:19]1
Reactant: C[S-]
Reactant: O=C(NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1)c1ccc(C(F)(F)F)nc1Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CSc1nc(C(F)(F)F)ccc1C(=O)NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Yield: 97.8 %

Procedure:
A solution of 2-chloro-N-(4-cyclopropylmethanesulfonyl-1-cyclopropylmethylcyclohexylmethyl)-6-trifluoromethylnicotinamide (75 mg, 0.15 mmol) in propan-2-ol (5 ml) was treated with sodium thiomethoxide (21 mg, 0.30 mmol) and the mixture was heated under reflux for 4 hours. Water (1 ml) was added and the solvent was evaporated. The residue was partitioned between dichloromethane (5 ml) and water (5 ml) and the layers were separated using a 5 micron PTFE frit and the filtrate was evaporated. The residue was purified by preparative plate chromatography eluting with 10% ethyl acetate in dichloromethane. Collecting the appropriate band followed by trituration of the silica with ethyl acetate, filtration and evaporation gave a pale yellow foam (74 mg, 97%). 1H NMR δ (ppm) (CDCl3): 8.00 (1H, d, J=7.8 Hz), 7.41 (1H, d, J=7.8 Hz), 6.40 (1H, s), 3.64 (2H, d, J=6.3 Hz), 2.98-2.89 (3H, m), 2.63 (3H, s), 2.09-1.90 (6H, m), 1.46-1.16 (5H, m), 0.79-0.69 (3H, m), 0.55-0.51 (2H, m), 0.45-0.40 (2H, m), 0.09-0.06 (2H, m). MS (m/e)=505.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>>[C:25]([O:24][C:22]([N:16]1[CH2:21][CH2:20][N:19]([S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:18][CH2:17]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2Cl)CC1
Yield: 85.8 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (500 mg, 1.72 mmol), tert-butyl 1-piperazinecarboxylate (320 mg, 1.72 mmol) and triethylamine (479 ,μL, 3.44 mmol) were reacted to form the desired product (650 mg, 84%). LC-MS (m/z) 440.2 (M+).
Reaction SMILES: C(O[C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)C.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C1COCC1>[C:11]1([C:4]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC1=CC(=O)CCC1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1C=C(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., 3-ethoxycyclohex-2-enone (2 g, 14.3 mmol) in THF (2 mL) was added phenylmagnesium bromide (1.0 M solution in THF, 15.0 mL) slowly. After the addition, the reaction mixture was warmed up to room temperature and stirred for 1 hr. Then 1N HCl solution (15.16 mL) was added to quench the reaction and the organic layer was separated. The aqueous layer was extracted with dichloromethane 3 times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the title compound as yellow solid (quantitative yield). 1H NMR (400 MHz, CDCl3) δ 2.16 (2H, dt, J=4, 12 Hz), 2.48 (2H, t, J=8 Hz), 2.77 (2H, dt, J=2, 6 Hz), 6.41 (1H, t, J=2 Hz), 7.39-7.41 (3H, m), 7.52-7.54 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][C:22]([OH:24])=O)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=O.CNC.C1COCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][C:22](=[O:24])[N:27]([CH3:28])[CH3:25])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccccc23)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
The 2-t-butoxycarbonyl-9-carboxymethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.65 g, 5.0 mmol) obtained in the above step (1) was dissolved in methylene chloride (30 ml), and the solution was mixed with carbonyldiimidazole (0.81 g, 5.0 mmol), stirred at room temperature for 30 minutes, mixed with 2 M dimethylamine-THF solution (3 ml, 6.0 mmol) and further subjected to 1 hour of the reaction. The reaction solution was concentrated, the resulting residue was dissolved in ethyl acetate (50 ml), washed with water and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure. By adding diisopropyl ether (30 ml) to the resulting residue, 1.71 g of the thus precipitated title compound (4.8 mmol, 96% in yield) was obtained as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)=[O:4].[NH2:14][CH2:15][CH2:16][OH:17]>C(Cl)Cl>[OH:17][CH2:16][CH2:15][NH:14][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: NCCO
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
Into an ice-cooled and stirred solution of 4-methoxycarbonylbenzoyl chloride 1 (53.6 g, 0.270 mol) in methylene chloride was dropwisely added a solution of 2-aminoethanol (36.3 g, 0.594 mol) in methylene chloride (40 ml) under nitrogen during 1 hr, and the mixture was stirred for 3 hr at room temperature. The resulting precipitate was collected by vacuum filtration, washed thoroughly with water and dried in vacuo at 50° C. to give N-(2-hydroxyethyl)-4-methoxycarbonylbenzamide 2 (53.3 g, 88% yield) as white powder: 1H NMR (CD3SOCD3)δ3.45 (t of t, 2H, J=5.4 and 5.9 Hz, CH2N), 3.64 (t, 2H, J=5.9 Hz, CH2O), 3.90 (s, 3H, CH3O), 4.87 (brs, 1H, OH), 8.02 (d, 2H, J=9.3 Hz, 2,6-Ar-H), 8.05 (d, 2H, J=9.3 Hz, 3,5-Ar-H), 8.65 (t, 1H, J=5.4 Hz, NH).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[NH2:39][C@@H:40]([CH3:43])[CH2:41][OH:42].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[C:20]([N:19]1[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:39][C@@H:40]([CH3:43])[CH2:41][OH:42])=[CH:8][CH:7]=2)=[N:16][N:17]=[N:18]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO)NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(4′-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole made as described in Preparation 1 (9.7 g, 17.4 mmol), (2S)-2-aminopropan-1-ol (3.9 g, 52.3 mmol), and potassium carbonate (2.4 g, 17.4 mmol), in THF (170 mL) was stirred at room temperature overnight. Water (100 mL) was added, and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography gave intermediate (5a).