Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:19]=[CH:20][C:21]=1[Cl:22].[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:25][CH2:24][N:23]([C:18]4[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=4)[CH2:28][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(3,4-dichlorophenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 87% overall yield. FDMS m/e=419 (M+ of free base). α[D]589=−7.76 (c=0.82, methanol).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]1([O:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: OCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: OCCCCCCCOc1ccccc1
Temperature: 25 °C
Yield: 101.6 %

Procedure:
Phenol (0.098 g, 1.04 mmol) and 7-bromo-1-heptanol (0.243 g, 1.246 mmol) were dissolved in acetone (25 mL) in a 50 mL round bottomed flask. Potassium carbonate (0.86 g, 6.23 mmol) was added to this solution and the flask was fitted with a condenser and refluxed using an oil bath at 70° C. for a period of 26 hours. The reaction flask was then cooled to room temperature. The contents of the flask was then filtered through a fluted filter paper and washed with acetone (10 mL). The combined filtrate was then evaporated to dryness under reduced pressure. The residue obtained was dissolved in ethyl acetate (25 mL). The ethyl acetate solution was then washed with 1N. NaOH (3×5 mL), water (2×5 mL) and brine (2×5 mL). The organic layer was dried over Na2SO4. Removal of solvent from the dried extract under reduced pressure afforded the product. The product was then purified by flash chromatography (Si gel, 12×2.5 cm) using ethyl acetate: hexane (1:1) to afford the pure 7-(phenyloxy)-1-heptanol (0.22 g, quantitative yield). The product alcohol from step A was analyzed yielding the following confirmatory data: 1H-NMR (CDCl3) δ 1.31-1.52 (m, 6H), 1.52-1.63 (m, 2H), 1.73-1.89 (m, 2H), 1.97 (bs, 1H), 3.61 (t, 2H, J=6.57 Hz), 3.93 (t, 2H, J=6.50 Hz), 6.80-6.97 (m, 3H) and 7.20-7.28 (m, 2H); 13C-NMR (CDCl3) δ 25.5, 25.8, 29.0, 29.1, 32.4, 62.5, 67.7, 114.3, 120.3, 129.2 and 158.8; IR (neat): 3348 cm−1; MS (ES+): 209 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1.[F:8][C:9]([F:29])([C:13]([F:28])([F:27])[C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:11][OH:12].[H-].[Na+]>CN(C)C=O>[F:8][C:9]([F:29])([C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:11][O:12][CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1
Reactant: CC1(CBr)COC1
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)COC1
Yield: 66 %

Procedure:
In a manner similar to that described above, 12.0 grams of 3-bromomethyl-3-methyloxetane (73 mmol) was reacted with 26.5 grams of 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol (72.7 mmol) in 300 milliliters of dimethylformamide in the presence of 3.9 grams of a 50 weight percent dispersion of sodium hydride (81 mmol) in mineral oil at 85° C. for 24 hours to give 21.5 grams (70% yield) of 3-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyloxymethyl)-3-methyloxetane, a colorless oil with a boiling point of 66-68° C./2-2.5 mm-Hg; 1H NMR (CDCl3) δ 4.50 and 4.36 (AB, J=5.5 Hz, 4 H), 3.78 (t, J=6.6 Hz, 2 H), 3.53 (s, 2 H), 2.42 (triplet of triplets, J=6.6 and 18 Hz, 2 H), and 1.31 (s, 3 H); 13C NMR (CDCl3) δ 79.89, 78.30, 63.31, 39.9, 31.64 (t), and 21.1 (signals due to carbons bearing fluorines are not included due to the complex splitting patterns and low peak intensities); 19F NMR δ −81.4 (3 F), −113.8 (2 F), −118.2 (2 F), −112.3 (2 F), −124.1 (2 F) and −126.7 (2 F). The elemental analysis was: Calculated for C13H13F13O2: C, 34.8; H, 2.9; F, 55.1. Found: C, 35.1; H, 3.0; F, 54.7.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=1[F:31].C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[F:31])[C:22]2[CH:33]=[CH:34][CH:35]=[CH:36][C:21]=2[C:20]([F:38])([F:37])[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: OC(c1ccc(Br)cc1F)c1ccccc1C(F)(F)F
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: Fc1cc(Br)ccc1C(OC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1C(F)(F)F

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (23.0 mmol) and 2-(trifluoromethyl)-2′-fluoro-4′-bromobenzhydrol (112) (34.0 mmol) using the procedure described for compound (3) (8.84 g, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:12]([CH2:15][C:16](OC)=O)(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.FC(F)COS([C:36]([F:39])([F:38])F)(=O)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([C:3]([O:2][CH3:1])=[O:4])[S:12]([CH2:15][CH2:16][CH:36]([F:38])[F:39])(=[O:13])=[O:14])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)CS(=O)(=O)Nc1nccnc1C(=O)OC
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1nccnc1N(C(=O)OC)S(=O)(=O)CCC(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 110.7 %

Procedure:
To a solution of 3-methoxycarbonylmethanesulfonylamino-pyrazine-2-carboxylic acid methyl ester (Example 9.1) (1.212 g) in acetonitrile (12 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.8 ml) at ambient temperature. The mixture was stirred at ambient temperature for 5 minutes before dropwise addition of a solution of 2,2-difluoroethyltrifluoromethanesulfonate (0.978 g) in acetonitrile (5 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate (30 ml) and aqueous sulfuric acid (2M) (30 ml). The phases were separated and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:2) to give 3-[(2,2-difluoro-ethyl)-methoxycarbonyl-methanesulfonyl-amino]-pyrazine-2-carboxylic acid methyl ester (0.819 g). 1H-NMR (400 MHz, CDCl3): 8.70 (d, 1H), 8.65 (d, 1H), 6.06-6.29 (m, 1H), 4.32-4.38 (m, 2H), 4.18 (s, 2H), 4.02 (s, 3H), 3.78 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([F:30])([F:29])[F:28])[CH:20]=2)[NH:15][CH:14]=1)[C:6]([OH:8])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:52](O)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:52]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([F:28])([F:29])[F:30])[CH:20]=3)[NH:15][CH:14]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: OCc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1Cc1c[nH]c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)OCc2ccccc2)ccc1Cc1c[nH]c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoic acid (1.54 grams, 3.43 mmol), triphenylphosphine (1.26 grams, 4.8 mmol) and benzyl alcohol (0.50 mL, 4.8 mmol) in tetrahydrofuran (50 mL), at 0° C., was added diethyl azodicarboxylate (0.65 mL, 4.1 mmol). The reaction is then warmed to room temperature and stirred 12 hours. Concentration in vacuo followed by chromatography on silica gel (1:1 hexanes:ethyl acetate) gave 3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoic acid benzylester with impurities present. The product was dissolved in cold ether, and filtered. The filtrate was concentrated, and the remaining yellow foam was chromatographed on silica gel (1:1 cyclohexane:ethyl acetate) to give 3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoic acid benzylester (1.56 grams, 87% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CS(C)=O>CN(C)C=O>[O:31]1[CH2:32][CH2:33][N:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=4)[S:11][CH:12]=3)=[CH:4][C:3]=2[N+:25]([O-:27])=[O:26])[CH2:29][CH2:30]1
Reactant: C1COCCN1
Reactant: CCOc1ccc(-c2nc(-c3ccc(Cl)c([N+](=O)[O-])c3)cs2)cc1OCC
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3ccc(N4CCOCC4)c([N+](=O)[O-])c3)cs2)cc1OCC
Yield: 91.5 %

Procedure:
A solution of 1 g of 4-(4-chloro-3-nitrophenyl)-2-(3,4-diethoxyphenyl)thiazole and 636 mg of morpholine dissolved in 20 ml of dimethylformamide and 20 ml of dimethyl sulfoxide was refluxed at 150° C. for 2-3.5 hours with heating. The reaction mixture was subjected to vacuum distillation. The residue was added to ice water, and an aqueous sodium hydrogencarbonate solution was added. The solution was extracted with dichloromethane three times. The combined extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate-n-hexane to obtain 1.03 g of 4-(4-morpholino-3-nitrophenyl)-2-(3,4-diethoxyphenyl)thiazole.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[OH:10][C@@H:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH2:13][CH2:12]1>CCO>[OH:3][NH:2][C:20]([C:15]1[C:14]2[CH2:13][CH2:12][C@H:11]([OH:10])[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[NH:21]
Reactant: NO
Reactant: N#Cc1cccc2c1CC[C@@H]2O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2c1CC[C@@H]2O
Reaction time: 16 h
Yield: 90 %

Procedure:
To hydroxylamine hydrochloride (0.87 g, 12.5 mmol) and sodium carbonate (1.32 g, 12.5 mmol) in EtOH (20 mL) was added (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile INT-2 (1.59 g, 10 mmol) in one portion and the solution was heated to reflux. After 16 h, the reaction was cooled and filtered to remove the solids. The EtOH was removed and the compound purified by chromatography (MeOH/DCM) to give 1.74 g (90%) of (S)-N,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide INT-3 as a white foam. LCMS-ESI (m/z) calculated for C10H12N2O2: 192.1. found: 193.1 [M+H]+, tR=0.56 min. 1H NMR (400 MHz, MeOD) δ 10.30 (s, 1H), 9.97 (s, 1H), 7.72-7.58 (m, 1H), 7.46-7.37 (m, 2H), 5.22 (t, J=6.5, 1H), 3.17-3.03 (m, 1H), 2.99-2.83 (m, 1H), 2.49 (dddd, J=11.4, 8.0, 7.0, 4.4, 1H), 2.02-1.88 (m, 1H). (R)-N,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide is made in an analogous fashion from (R)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[N:6][C:7]=1[Cl:8].C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:12])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(CBr)cnc1Cl
Yield: 130 %

Procedure:
5,6-dichloro-3-pyridinemethanol (1.0 eq.) was taken up in dichloromethane and stirred overnight with carbon tetrabromide (1.5 eq.) and 1,3-bis(diphenylphosphino)propane (0.75 eq.) Ether was added to the solution and filtration followed by concentration of the filtrate afforded the 5,6-dichloro-3-bromomethylpyridine in 130% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[NH:23]1[C:31]2[C:26](=CC=C[CH:30]=2)[C:25]2(COC3C=C4C(=[CH:42][C:32]2=3)CCO4)C1=O.Br.BrCC1C=CC=CN=1.BrCC1CCCCO1>>[N:23]1[CH:42]=[CH:32][CH:25]=[CH:26][C:31]=1[CH2:30][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Br
Agent: BrCC1CCCCO1
Agent: BrCc1ccccn1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: mp 208-209° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ8.58 (d, J=4.8 Hz, 1H), 7.65 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.28-7.15 (m, 4H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 5.21 (d, J=16.0 Hz, 1H), 4.97 (d, J=16.0 Hz, 1H), 4.96 (d, J=8.7 Hz, 1H), 4.68 (d, J=8.7 Hz, 1H), 4.22-4.17 (m, 2H), 4.15-4.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.6, 155.6, 155.3, 149.6, 144.6, 142.2, 138.3, 137.1, 132.2, 128.9, 123.8, 123.5, 122.8, 121.6, 121.1, 111.8, 109.6, 99.4, 80.2, 64.5, 63.9, 58.2, 46.1; MS (ES+) m/z 387.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[N:44]([C:47]1[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=1)=[C:45]=[O:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][N:40]([C:45]([NH:44][C:47]2[CH:48]=[CH:49][C:50]([C:53]([F:54])([F:55])[F:56])=[CH:51][CH:52]=2)=[O:46])[CH2:39][CH2:38]1
Reactant: Clc1cnc2nc1Nc1ccc(N3CCNCC3)c(c1)CCc1cccc(c1)N2
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-piperazin-1-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) and 1-isocyanato-4-(trifluoromethyl)benzene as the starting materials in 41% yield. LCMS for C30H28ClF3N7O (M+H)+: m/z=594.0. 1H NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 9.32 (br s, 1H), 9.00 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.72-7.70 (m, 2H), 7.60-7.57 (m, 2H), 7.12-7.03 (m, 3H), 6.88-6.82 (m, 2H), 3.64 (br s, 4H), 2.99 (s, 4H), 2.84 (br s, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](O)=O)=[N:4][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:12][CH:13]=2)=[CH:6][N:7]=1.[CH3:22][C:23]1[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=1.C(OP(C#N)(OCC)=O)C.C(N(CC)CC)C>COCCOC>[CH2:17]([S:14]([N:11]1[CH2:12][CH:13]=[C:8]([C:5]2[N:4]=[C:3]([C:19]3[NH:29][C:26]4[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][C:25]=4[N:30]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])[CH3:18]
Reactant: CCS(=O)(=O)N1CC=C(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: Cc1ccc(N)c(N)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nc4cc(C)ccc4[nH]3)n2)CC1
Temperature: 170 °C
Yield: 36.7 %

Procedure:
A mixture of 3-amino-6-(1-ethylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylic acid (100 mg, 0.320 mmol), 4-methylbenzene-1,2-diamine (39.12 mg, 0.320 mmol), diethoxyphosphorylformonitrile (47.83 uL, 0.320 mmol) and triethylamine (44.63 uL, 0.320 mmol) in DME (1 mL) were heated in a microwave at 170° C. for 90 min. After this time the reaction mixture was filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the title compound (46.8 mg, 21% Yield). 1H NMR (400.0 MHz, DMSO) d 8.34 (s, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.46 (s, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.78 (s, 1H), 4.00 (d, J=2.8 Hz, 2H), 3.50 (t, J=5.7 Hz, 2H), 3.16 (q, J=7.4 Hz, 2H), 2.78 (s, 2H), 2.46 (s, 3H) and 1.25 (t, J=7.4 Hz, 3H) ppm; MS (ES+) 399
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O1CCOCC1.C([O-])([O-])=O.[K+].[K+].[Br-:26].Cl[CH2:28][CH2:29][CH2:30][P+:31]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35]>C(O)C>[Br-:26].[CH2:1]([NH:13][CH:40]([P+:31]([CH2:30][CH2:29][CH3:28])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:41][CH2:42][CH3:43])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: CCCC[P+](CCCC)(CCCC)CCCCl
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCCCCCCCCCNC(CCC)[P+](CCC)(CCCC)CCCC
Temperature: 25 °C

Procedure:
In a 100 ml of reaction flask, 9.30g of n-dodecylamine (about 0.05 mol) (Tianjin Kelong Chemical Agent Factory, CP Grade) was added, and dissolved by adding 25 ml of dioxane under stirring, then 25 ml of anhydrous ethanol and 7.0 g anhydrous K2CO3 (ground) were added, heated to reflux, and 30 ml of an ethanol solution of 13 g (about 0.035 mol) of γ-chloropropyl tributyl phosphonium bromide (13 g of γ-chloropropyl tributyl phosphonium bromide was dissolved previously in 30 ml ethanol) was then added dropwise within 6 hrs under stirring and reflux, then again reacted for 2hrs under stirring and reflux, when the reaction was ended, the inorganic salt was filtered out while the solution was hot, and the solvent was distilled off from the filtrate, then the residue was cooled to room temperature, then 100 ml of diethyl ether was added to separate a large quantity of white solid, and filtered, the crude product was then obtained. The crude product was recrystallized from the mixed solvent of tetrahydrofuran and diethyl ether (volume ratio 1:1) for purification, the γ n-dodecylamino-propyl tributyl phosphonium bromide having the structural formula was then obtained: n-C12H25NH(CH2)3P+(C4H9)3 Br−.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:40]1([SH:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[F:30][C:28]([F:31])([F:29])[C:27]([C:24]1[CH:23]=[CH:22][C:21]([N:8]2[CH2:9][CH2:10][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:12][C@@H:7]2[CH2:6][S:46][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:26][CH:25]=1)([OH:33])[CH3:32]
Reactant: Sc1ccccc1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CSc2ccccc2)cc1)C(F)(F)F
Temperature: 140 °C
Yield: 78 %

Procedure:
To a 5-mL microwave vial was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (0.200 g, 0.378 mmol, Intermediate B), potassium carbonate (0.105 g, 0.757 mmol), thiophenol (0.076 mL, 0.76 mmol, Aldrich, St. Louis, Mo.), and acetonitrile (3.0 mL). The vial was sealed and heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 40 min. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (40 g of silica, 10 to 40% acetone in hexanes) to afford 1,1,1-trifluoro-2-(4-((2R)-2-((phenylsulfanyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.160 g) as a mixture of two isomers:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[C:10]([N+:17]([O-:19])=[O:18])[C:9]2=[O:20])=[CH:5][CH:4]=1.C1(S(Cl)(=O)=O)C=CC=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[C:10]([N+:17]([O-:19])=[O:18])[C:9]2=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2ccc(CCO)c([N+](=O)[O-])c2=O)cc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=Cc1ccn(Cc2ccc(OC)cc2)c(=O)c1[N+](=O)[O-]
Reaction time: 96 h
Yield: 83.3 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-4-hydroxyethyl-3-nitro-2-pyridone (0.35 g, 1.2 mmol) in pyridine (4 mL) was added benzenesulfonyl chloride (0.2 mL). After 4 days, the mixture was diluted with ethyl acetate, and washed with dilute hydrochloric acid. The aqueous phase was basified to pH 13 with aqueous KOH, and after 30 minutes was extracted with ethyl acetate. The organic phase was dried, filtered and evaporated to give 1-(4-methoxybenzyl)-4-vinyl-3-nitro-2-pyridone (0.29 g, 1.0 mmol, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(CCOc2ccc([N+](=O)[O-])cn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CCOc2ccc(N)cn2)cc1
Yield: 94.8 %

Procedure:
2-(4-Methylphenethyloxy)-5-nitropyridine (3.7 g) and 1.7 g of 5% palladium charcoal were suspended in 37 ml of ethanol, and catalytic reduction was carried out until 1.1 liters of hydrogen were absorbed. After removal of the catalyst by filtration, the solvent was distilled out under reduced pressure. The crystals were collected on a glass filter and washed with ether to give 3.1 g of 2-(4-methylphenethyloxy)-5-aminopyridine as yellow crystals. Yield, 84.9%. M.P., 64.5°-65° C.