Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=O)[CH:17]=[N:18][CH:19]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH2:48]=[C:49]([CH3:51])[CH3:50]>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:20]([C:16]1[CH:17]=[N:18][CH:19]=[C:14]([Br:13])[CH:15]=1)[CH2:48][C:49]2([CH3:51])[CH3:50])=[O:12])[CH3:2]
Reactant: C=C(C)C
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1cncc(Br)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(Br)c1)N2
Temperature: 0 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
A mixture of 4-aminobenzoic acid ethyl ester (16.5 g, 100 mmol), 5-bromo-pyridine-3-carbaldehyde (18.6 g, 100 mmol) and ytterbium(III) triflate hydrate (12.4 g, 20 mmol) in acetonitrile (350 mL) was cooled to 0° C. in a sealed reaction bottle. Then a cooled solution of isobutene (28 g, 500 mmol) was added into. The reaction mixture was heated to 90° C. and stirred for 12 h. The solvent was removed in vacuo and the residue was purified on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) to afford 2-(5-bromo-pyridin-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (16 g, 41%) as a white solid: MS (ESI) M+1=389.0.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Fc1ccc(CNc2nc(-c3cnccn3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28](=[S:29])[NH:1][C:2]2[CH:3]=[C:4]([NH:10][C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: COc1ccc(NC(=O)c2ccccc2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Product: COc1ccc(NC(=O)c2ccccc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 81.1 %

Procedure:
Prepared according to the procedure described for Example 78 using N-(3-amino-4-methoxyphenyl)-benzamide from Example 21 (0.88 g, 3.62 mmol) and 3,5-dichlorophenyl isothiocyanate (0.739 g, 3.62 mmol). Filtration without trituration afforded the product (1.31 g); m.p. 194-195° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:27][CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1CNC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC2)cn1
Yield: 28 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using azetidine instead of methylamine, to the title compound (32 mg, 28%) which was obtained as a light yellow oil. MS: m/e=350.3 [M+H]′.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26]3[C:35]([CH3:36])=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].CO.[OH-].[Na+]>C1COCC1>[CH3:6][CH:5]([CH3:7])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26]3[C:35]([CH3:36])=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:11])[C:3]([OH:37])=[O:2]
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(COc3nc4ccccc4cc3C)cc2)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2ccccc2nc1OCc1ccc(-c2ccc(S(=O)(=O)NC(C(=O)O)C(C)C)cc2)cc1
Reaction time: 72 h
Yield: 51.3 %

Procedure:
3-Methyl-2-[4′-(3-methyl-quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid methyl ester (203 mg, 0.39 mmol, 1 equiv.) was dissolved in THF (8 mL) and MeOH (4 mL) and hydrolyzed with IN NaOH (5.83 mL, 5.83 mmol, 13 equiv.). After stirring for 3 days, solvent was removed and the residue was dissolved in H2O. The mixture was then acidified to pH 3 using 1N HCl. Solid precipitated from the mixture was collected by filtration and washed with water. After drying in vacuum oven, 101 mg of 3-Methyl-2-[4′-(3-methyl-quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid was obtained in 76.3% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][S:11][CH3:12].O=P(Cl)(Cl)Cl.[CH2:18]([O:20]CC)C.[OH-].[Na+]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:10][S:11][CH3:12])[CH:18]=[O:20]
Reactant: CCOCC
Reactant: COc1ccccc1C=CSC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccccc1C(C=O)=CSC

Procedure:
A solution of 5.5 g of 1-methoxy-2-(2-methylsulphanyl-vinyl)-benzene in 15 ml of dimethylformamide is heated to 80° C. with 4.7 g of POCl3 for 2 hours with stirring. After cooling diethylether and water are carefully added and the mixture obtained is adjusted to pH 9 with aqueous NaOH solution (10%). The organic phase is separated off and after drying the solvent is eliminated in vacuo. Chromatography on silica gel (cyclohexane:ethyl acetate 70:30) yields 2.5 g of 2-(2-methoxyphenyl)-3-methylsulphanyl-propenal.
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C([N:23]1[CH2:27][CH2:26][C:25](=O)[CH2:24]1)(OC(C)(C)C)=O.Cl.[CH2:30]1COCC1>[Zn].Cl[Ti](Cl)(Cl)Cl>[C:6]1(/[C:4](/[C:3]2[CH:2]=[C:15]([CH3:30])[CH:14]=[CH:13][CH:12]=2)=[C:25]2/[CH2:24][NH:23][CH2:27][CH2:26]/2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccccc1C(=O)c1ccccc1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [Zn]
Product: Cc1cccc(/C(=C2/CCNC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 2-methylbenzophenone (2.0 g, 10.2 mmol) and N-boc-3-pyrrolidone (1.89 g, 10.2 mmol) in THF was added zinc powder (3.3 g, 59 mmol) at 10-15° C. and stirred for 15 min. To the reaction mixture was added TiCl4 (4.76 g, 25 mmol) and the contents were brought to 60° C. and stirred for 8 h. The reaction mixture was allowed to cool to room temperature, diluted HCl was added and extracted with EtOAc. The organic layer was washed with aqueous sodium potassium tartarate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product which was washed with n-hexane to afford 1.8 g of (Z)-3-(phenyl(m-tolyl)methylene)pyrrolidine.
Reaction SMILES: ONC1C=CC=CC=1C1N=NN(C)N=1.ON[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:27]([CH3:28])[N:26]=[N:25][N:24]=1.N([O-])=O.[Na+].[S:33](=[O:35])=[O:34].[ClH:36]>O.C(O)(=O)C>[Cl:36][S:33]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:27]([CH3:28])[N:26]=[N:25][N:24]=1)(=[O:35])=[O:34]
Reactant: O=S=O
Reactant: Cl
Reactant: Cn1nnnc1-c1ccccc1NO
Agent: Cn1nnc(-c2ccccc2NO)n1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1nnnc1-c1ccccc1S(=O)(=O)Cl
Temperature: 31 °C

Procedure:
To 5 g of a mixture of 5-(2-hydroxylaminophenyl)-2-methyl-2H-tetrazole and 5-(2-hydroxyaminophenyl)-1-methyl-1H-tetrazole dissolved in 12 mL of 37% hydrochloric acid and 5 mL of acetic acid was added with stirring 2.3 g of sodium nitrite dissolved in 10 mL of water at -5° to 5° C. After one hour this solution was added, at 0°-5° C., portionwise to a mixture of 25 mL of acetic acid, 0.5 g of cupric chloride and 5 mL of liquified sulfur dioxide. After the addition was completed the cooling bath was removed and the reaction mixture was allowed to warm to 31° C. whereupon the cooling bath was reapplied and the stirring was continued until two and one half hours after completion of the addition. The mixture was then poured into ice and worked up as described in Example 1 except that the desired methylene chloride solution was concentrated in vacuo to yield an oil which solidified. This product, (3.28 g) which was a mixture of the desired sulfonylchlorides, was of sufficient purity for the preparation of the sulfonamides of Example 4.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl.CC(C)=O>[C:1]1([C:7]2[N:11]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:10]=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)=O
Product: c1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 5-phenyl-1H-tetrazole (21.9 g) and chlorotriphenylmethane (46 g) in methylene chloride (500 ml) was added triethylamine (16.7 g). The resulting mixture was stirred at room temperature for one hour. The reaction mixture was washed successively with water, 10% aqueous citric acid solution and water and was then dried over anhydrous magnesium sulfate, followed by removal through distillation. The residue so obtained was dispersed in acetone, collected by filtration and then dried, whereby 51.8 g of the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20]Cl)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+]>C(O)CCC.O>[Cl:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: O=Cc1ccc(OCCCCl)cc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: CN1CCN(CCCOc2ccc(C=O)c(Cl)c2)CC1
Yield: 63.6 %

Procedure:
N-Methylpiperazine (2.16 g, 21.5 mmol), 2-chloro-4-(3-chloro-propoxy)-benzaldehyde (3.19 g, 10.8 mmol), K2CO3 (4.46 g, 32.3 mmol), and KI (1.02 g, 5.38 mmol) were stirred in n-butanol (22 mL) at 90° C. for 18 h. The reaction mixture was diluted with water and then extracted three times with EtOAc. The combined extracts were dried (Na2SO4), filtered, and concentrated, yielding the crude product, which was purified by Method 1 to afford 2.04 g (63%) of an orange oil. 1H NMR (400 MHz, CD3OD): 10.3 (s, 1H), 7.86 (d, J=8.0, 1H), 7.08 (d, J=2.0, 1H), 7.00 (dd, J=8.0, 2.0, 1H), 4.15 (t, J=8.0, 2H), 3.00-2.30 (br s, 10H), 2.29 (s, 3H), 2.05-1.90 (m, 2H).
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=O)=O.[C-:12]#[N:13].[K+].O>CS(C)=O>[CH3:9][C:8]([CH3:10])=[CH:7][CH2:6][CH2:5][C:5]1[CH2:11][CH2:10][CH:8]([CH2:9][C:12]#[N:13])[CH2:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)=CCCC1=CCC(CC#N)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of tosylate 1H (R=4-Methyl-3-pentenyl) (20 g) in dimethylsulfoxide (178 mL) is added potassium cyanide (19.4 g). The reaction mixture is heated to 100° C., and the reaction mixture is stirred at that temperature for three hours. The reaction mixture is cooled to room temperature, added to water (300 mL), and extracted with hexane. The combined organic layers are dried over magnesium sulfate and the solution is concentrated in vacuo.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1)C1C=CC=CC=1.[Cl:17]C(OC(Cl)C)=O>ClCCCl>[ClH:17].[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1
Reactant: COC(=O)C1CCN(Cc2ccccc2)C1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: COC(=O)C1CCNC1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.52 g (2.3 mmol) of (R/S)-1-benzyl-pyrrolidin-3-yl carboxylic acid, methyl ester (from Step A) in 5 mL of 1,2-dichloroethane was treated with 0.3 mL (2.7 mmol) of 1-chloroethyl chloroformate (ACE-Cl). The resulting mixture was stirred at rt for 3 h, then at reflux for 30 min. The reaction was cooled and concentrated. The residue was warmed to reflux in 5 mL of MeOH for 1 h. The reaction was cooled and concentrated. The crude product was used in Step C without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[CH:25][C:26]([F:37])=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=3)[CH:28]=2)OC1>>[F:37][C:26]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:28][C:27]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cccc(C#N)c3)c2)OC1
Product: N#Cc1cccc(-c2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)c1
Yield: 10.4 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 5′-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-2′-fluorobiphenyl-3-carbonitrile (87 mg, 0.28 mmol) as described in Example 7 part g), affording 2′-fluoro-5′-(7-trifluoromethyl-[1,8]naphthyridin-4-yl)biphenyl-3-carbonitrile (9 mg, 11%). δH (360 MHz, CDCl3) 7.41-7.46 (1H, m), 7.51-7.63 (4H, m), 7.72 (1H, d, J 7.7), 7.79-7.87 (2H, m), 7.91 (1H, d, J 1.1), 8.52 (1H, d, J 8.8), 9.30 (1H, d, J 4.2). m/z (ES+) 394 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])=[O:4].CO.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])=[O:4]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)OC)cc23)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Reaction time: 20 h
Yield: 57.7 %

Procedure:
To a solution of methyl 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate (105.1 g) in tetrahydrofuran (1.4 L) was added methanol (450 mL) and deionized water (450 mL), followed by an equimolar amount of lithium hydroxide monohydrate (12.00 g). After the reaction mixture had stirred about 20 hours, it was acidified to pH 2 by addition of 6N hydrochloric acid (60 ml). Evaporation of the organic solvents resulted in the precipitation of a crude product (104.2 g) which was filtered and dried under vacuum before it was recrystallized by dissolving it in boiling tetrahydrofuran (600 mL), addition of toluene (about 1.2 L) and concentration to about one liter. Following cooling and stirring overnight, filtration, and drying under vacuum, a first crop is (71.1 g) was obtained. A second, similar recrystallization of this material from tetrahydrofuran (500 mL) and toluene (1 L) afforded 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoic acid (58.3 g, 57.7%) as an off-white solid; NMR (300 MHz, DMSO-d6): 3.78 (s, 3H, NCH3), 3.83 (s, 3H, CO2CH3), 3.92 (s, 3H, OCH3), 4.07 (s, ArCH2Ar'), 7.17 (d, 1H), 7.18 (s, 1H), 7.43-7.50 (m, 3H), 7.75 (dd, 1H), 8.19 (d, 1H); the same benzoic acid obtained by a similar procedure, but purified by flash chromatography, eluting with (methylene chloride:tetrahydrofuran:acetic acid (sequentially, 1:0:0, 1:9:0, and 0:400:1) followed by isolation and drying under vacuum of crystals formed on standing in methylene chloride:tetrahydrofuran fractions, had mp 228.0°-229.5° C. An additional amount of the benzoic acid (23.6 g, 23.3%), as well as recovered diester (11.5 g, 10.7%), was obtained by concentration and flash chromatography of the mother liquors, eluting with methylene chloride:tetrahydrofuran (sequentially, 1:0, 3:1, 2:1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].[CH2:14]([C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]2[C:26](=O)[CH2:27][CH2:28][CH2:29][CH:30]=2)[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].Cl.C([O:35]CC)C>>[CH2:14]([C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]2[CH2:26][CH2:27][C:28]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:12])([F:11])[F:1])=[CH:5][CH:6]=3)([OH:35])[CH2:29][CH:30]=2)[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOCC
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CCCCC[C@H]1CC[C@H](C2=CCCCC2=O)CC1
Agent: Cl
Agent: [Mg]
Product: CCCCC[C@H]1CC[C@H](C2=CCC(O)(c3ccc(OC(F)(F)F)cc3)CC2)CC1

Procedure:
A solution of 7.7 g of 4-trifluoromethoxybromobenzene in 30 ml of anhydrous diethyl ether was added dropwise under stirring at 10°-15° C. to 0.66 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of trans-4-pentylcyclohexylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 1-(trans-4-pentylcyclohexyl)-4-(4-trifluoromethoxyphenyl)-4-hydroxycyclohexene was obtained as a crude reaction product.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=C12.O.[NH2:13]N>CO.ClCCl>[NH2:13][CH2:10][CH2:9][C:8]1[C:1](=[O:11])[NH:5][CH:4]=[CH:3][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: NCCc1ccc[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a suspension of 1.2 g (2.5 mmol) of phthalimide 4 in 100 ml of methanol was added 6 ml of hydrazine monohydrate. This was stirred at room temperature overnight upon which the suspension turned into a clear yellow solution. The mixture was concentrated and residue was diluted with water and extracted with chloroform. The organic solution was washed with brine and dried (MgSO4), and the residue was purified by column chromatography with silica eluting with 10% methanol in dichloromethane affording 0.48 g of the aminoethyl-pyridone 5 (55% yield).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6]1)C.Cl.[NH2:14][C:15](=[NH:29])[N:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.C[O-].[Na+]>CO>[C:24]([O:23][C:22](=[O:28])[NH:21][C@@H:18]1[CH2:19][CH2:20][N:16]([C:15]2[N:14]=[CH:4][C:5]3[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][C:10]=3[N:29]=2)[CH2:17]1)([CH3:26])([CH3:25])[CH3:27]
Reactant: CN(C)C=C1CN(C)CCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=N)N)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCc2nc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ncc2C1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
3-[(Dimethylamino)methylene]-1-methylpiperidin-4-one (9.04 g, 53.7 mmol) and tert-butyl {(3R)-1-[amino(imino)methyl]pyrrolidin-3-yl}carbamate hydrochloride (14.2 g, 53.7 mmol) were dissolved in methanol (100 mL) and to this was added dropwise sodium methoxide (9.66 g of a 30% solution in methanol). The reaction mixture was refluxed for 3 hours and then cooled to room temperature. The reaction mixture was then evaporated to dryness, and the residue was treated with water (50 mL). The precipitate was separated by filtration, washed with water (25 mL) and diethyl ether (50 mL) and dried to give the title compound 10.43 g (yield 58%). LCMS (ES+) M+H 334. 1H NMR (DMSO-d6) 1.39 (s, 9H) 1.85 (m, 1H) 2.13 (m, 1H) 2.33 (s, 3H) 2.60 (m, 2H) 2.67 (m, 2H) 3.23-3.26 (m, 1H) 3.31-3.37 (m, 3H) 3.40-3.536 (m, 1H) 3.63 (m, 1H) 4.04 (br s, 1H) 7.20 (br s, 1H) 8.04 (s, 1H).
Reaction SMILES: O[C:2]1[N:3]=C[C:5](C(O)=O)=[N:6][CH:7]=1.S(Cl)([Cl:13])=O.CN(C=O)C.N1C=CC=CC=1.[C:26]([O:29][CH2:30]C)(=[O:28])[CH3:27].CCCCCC>>[CH3:30][O:29][C:26]([C:27]1[CH:5]=[N:6][C:7]([Cl:13])=[CH:2][N:3]=1)=[O:28]
Reactant: O=S(Cl)Cl
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cnc(O)cn1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
Reflux a mixture of 5-Hydroxy-pyrazine-2-carboxylic acid (6.568 g, 46.88 mmol), thionyl chloride (51 mL, 703.2 mmol), and DMF (0.50 mL) for 4 h. Cool the mixture to room temperature, concentrate in vacuo, and pump on high vacuum for 3 h. Dilute the mixture with MeOH (25 mL) and add pyridine (4.5 mL, 55.7 mmol). Stir the mixture overnight at room temperature. Adsorb the reaction mixture onto silica gel and subject the mixture to flash column chromatography (330 g column, 25%-60% ethyl acetate/n-hexane) to yield the desired product (7.380 g, 91%). mass spectrum (m/e): 173.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([Si](C)(C)C)[N:17]=[N:16]3)[O:11][C:10]2=[O:24])[CH:5]=[CH:6][C:7]=1[I:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:24])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: C[Si](C)(C)c1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
A solution of the crude (5R)-3-(3-fluoro-4-iodo-phenyl)-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-one (1024, 14.72 g, 32.0 mmol) in an 1 M solution of tetrabutylammonium fluoride in THF (TBAF, 128 mL, 128 mmol, 4.0 equiv) was treated with acetic acid (HOAc, 5 mL) at room temperature, and the resulting reaction mixture was stirred at room temperature for 24 h. When TLC and HPLC/MS showed that the reaction was complete, the solvents were removed in vacuo. The residue was treated with H2O (300 mL) at room temperature and the resulting mixture was stirred at room temperature for 1 h. The solids were collected by filtration, washed with H2O (2×100 mL) and 20% EtOAc/hexane (2×100 mL), dried in vacuo. The crude, (5R)-3-(3-fluoro-4-iodo-phenyl)-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one (1025, 11.65 g, 12.416 g theoretical, 93.8%) was obtained as off-white powders, which by HPLC/MS and 1H NMR was found to be essentially pure and was directly used in the subsequent reactions without further purification. For 1025: 1H NMR (300 MHz, DMSO-d6) 3.89 (dd, 1H, J=6.4, 9.2 Hz), 4.23 (t, 1H, J=5.4 Hz), 4.84 (d, 211, J=4.9 Hz), 5.12-5.18 (m, 1H), 7.14 (dd, 1H, J=2.4, 8.7 Hz), 7.49 (dd, 1H, J=2.4, 8.7 Hz), 7.76 (d, 1H, J=1.0 Hz, triazole-H), 7.82 (dd, 1H, J=7.5, 8.7 Hz), 8.17 (d, 1H, J=1.0 Hz, triazole-H); C12H10FIN4O2, LCMS (EI) m/e 389 (M++H).