Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[C:15]1(=[CH:21][C:22](O)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:1]([C:5]1[C:6]([NH:14][C:22](=[O:23])[CH:21]=[C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(O)C=C1CCCCC1
Product: CC(C)(C)c1c(NC(=O)C=C2CCCCC2)nn2cccnc12

Procedure:
The product from Example 105B and 2-cyclohexylideneacetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (s, 9H), 1.50-1.63 (m, 6H), 2.15-2.18 (m, 2H), 2.80-2.82 (m, 2H), 5.80 (br s, 1H), 6.98 (dd, J=6.8, 4.1 Hz, 1H), 8.48 (dd, J=4.1, 2.0 Hz, 1H), 8.91 (dd, J=7.1, 1.7 Hz, 1H), 9.58 (br s, 1H); MS (DCI) m/z 313 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([OH:23])=O)=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1nccs1
Reactant: O=C(O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(Nc1nccs1)c1cccc2cc(-c3cccc4cnccc34)ccc12

Procedure:
6-(isoquinolin-5-yl)-1-naphthoic acid (55 mg, 0.18 mmol), 2-aminothiazole (24 mg, 0.23 mmol), DIPEA (0.048 mL, 0.27 mmol) and HATU (0.1 g, 0.27 mmol) were stirred in CHCl3 (1 mL) at room temperature overnight. The solid formed was filtered, rinsed with CHCl3, MeOH and dried under vacuum to give the titled compound as a solid. MS (ESI pos. ion) m/z: 382. (M+H). Calc'd Exact Mass for C23H15N3OS: 381.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[I:17][C:18]1[CH:19]=[N:20][N:21]([CH2:23][C:24](O)=[O:25])[CH:22]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:24](=[O:25])[CH2:23][N:21]4[CH:22]=[C:18]([I:17])[CH:19]=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1cc(I)cn1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(I)cn1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.3 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.400 g, 1.83 mmol), 2-(4-iodo-pyrazol-1-yl)acetic acid (0.554 g, 2.2 mmol) and NEt3 (0.642 mL, 4.59 mmol) in DMF (5 mL) was added HATU (0.836 g, 2.2 mmol). The mixture was stirred at rt for 40 min. It was then quenched with water. The mixture was partitioned between EtOAc (100 mL) and sat. NaHCO3 (50 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (SiO2, with a gradient elution of 0˜30% EtOAc/CH2Cl2) to yield 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-(4-iodopyrazol-1-yl)ethanone (0.82 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Clc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin (79, 1.40 g, 4.53 mmol) in tetrahydrofuran (15 mL) was added tetra-n-butylammonium fluoride (1.42 g, 5.43 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated and isolated by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound (80, 0.40 g. 58% over 2 steps). MS(ESI) [M−H+]+=153.1.
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[C:12]2[C:7](=[N:8][C:9]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][C:11]=2[OH:13])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3].C(OC([N:33]1[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]1)=O)(C)(C)C.Cl>>[ClH:1].[CH2:2]([C:4]1[C:12]2[C:7](=[N:8][C:9]([CH:14]3[CH2:15][CH2:16][N:17]([C:39]([CH:36]4[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]4)=[O:40])[CH2:18][CH2:19]3)=[N:10][C:11]=2[OH:13])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3]
Reactant: CCc1nn(-c2ccccc2)c2nc(C3CCNCC3)nc(O)c12
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Product: CCc1nn(-c2ccccc2)c2nc(C3CCN(C(=O)C4CCNCC4)CC3)nc(O)c12

Procedure:
The title compound was prepared according to the procedure as described in Example 87 reacting 3-ethyl-1-phenyl-6-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ol hydrochloride and piperidine-1,4-dicarboxylic acid mono-tert-butyl ester followed by de-protection of the adduct with HCl.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2B(O)O)[CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:35]5[CH:34]=[CH:33][CH:32]=[C:31]6[C:36]=5[N:27]=[CH:28][CH:29]=[CH:30]6)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: OB(O)c1cccc2cccnc12
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cccc6cccnc56)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and quinoline-8-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 4): tR=0.64 min; Mass spectrum (ESI+): m/z=486 [M+H]+.
Reaction SMILES: C1(C(=[N:14][CH:15]([CH2:21]CC2C=C3C(=CC=2)C2=NOC(C4C(C(F)(F)F)=C(C5C=CC=CC=5)ON=4)=C2CC3)[C:16](OCC)=[O:17])C2C=CC=CC=2)C=CC=CC=1.[C:51]1([N:57]2[C:61]([C:62]([F:65])([F:64])[F:63])=[C:60]([C:66]3[O:70][N:69]=[C:68]4[C:71]5[C:76]([CH2:77][CH2:78][C:67]=34)=[CH:75][C:74]([CH:79]=[CH2:80])=[CH:73][CH:72]=5)[CH:59]=[N:58]2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[NH2:14][C:15]([CH3:21])([CH2:80][CH2:79][C:74]1[CH:75]=[C:76]2[C:71](=[CH:72][CH:73]=1)[C:68]1=[N:69][O:70][C:66]([C:60]3[CH:59]=[N:58][N:57]([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[C:61]=3[C:62]([F:63])([F:64])[F:65])=[C:67]1[CH2:78][CH2:77]2)[CH2:16][OH:17]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Reactant: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Product: CC(N)(CO)CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F

Procedure:
The titled compound was prepared using the experimental protocols described for Preparation 91A, and Example 93 employing 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (89A) as a starting material. The compound had an HPLC retention time=3.03 min. (condition C); LC/MS M+1=483.3; 1H NMR (400 MHz, MeOD) δ ppm 8.14 (1H, s), 7.85 (1H, d, J=7.7 Hz), 7.53-7.65 (5H, m), 7.30 (1H, s), 7.28 (1H, d, J=7.9 Hz), 3.67 (1H, d, J=11.5 Hz), 3.56 (1H, d, J=11.5 Hz), 3.03 (2H, t, J=6.9 Hz), 2.90 (2H, t, J=6.9 Hz), 2.66-2.81 (2H, m), 1.86-2.07 (2H, m), 1.37 (3H, s).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: [I-]
Reactant: COC(=O)c1cccc(OCCBr)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCCI)c1

Procedure:
A solution of methyl 3-(2-bromoethoxy)-benzoate (2.4 g, 9.26 mmol) and sodium iodide (2.78 g, 18.52 mmol) in acetone (50 mL) is refluxed for 2 hours. The resulting mixture is then filtered and concentrated. The residue is diluted with EtOAc (100 mL), washed with 5% Na2SO3 (50 mL), water (2×50 mL) and brine (50 mL), dried over MgSO4 and evaporated to yield methyl 3-(2-iodoethoxy)-benzoate, as a yellow oil, which is used directly.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:31])([F:30])[C:10]1[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1>C(Cl)Cl>[F:31][C:9]([F:8])([F:30])[C:10]1[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (26.3 mL, 342 mmol) was added to a solution of tert-butyl 4-[2-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (29.5 g, 85 mmol) in CH2Cl2 (171 mL). The mixture was stirred at room temperature for 16 h. The solvent was removed by evaporation. The residue was diluted with EtOAc (200 mL), washed with 2 N NaOH (3×100 mL), brine, dried over Na2SO4, and evaporated to give the title compound as an oil.
Reaction SMILES: O.[F:2][C:3]([F:19])([C:9](=O)[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:20]([SH:24])[CH2:21][CH2:22][SH:23]>C(Cl)Cl>[S:23]1[CH2:22][CH2:21][CH2:20][S:24][C:9]1([C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]([F:19])([F:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(F)(F)C(=O)C(F)(F)C(=O)OCC
Reactant: SCCCS
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)C1(C(F)(F)C(=O)OCC)SCCCS1
Reaction time: 18 h

Procedure:
Dissolve 12.1 mmol of the product of Example 6 in 50 mL of methylene chloride and cool in an ice/water bath under argon. Add 6 g of powdered activated 3A molecular sieves, 18.2 mmol of 1,3-propanedithiol, and then 2.4 mmol of BF3Et2O. Stir for 18 h in the cold, then filter the reaction, washing with ether. Add 100 mL of ether and wash with saturated sodium bicarbonate, water, and brine, and dry over MgSO4. Purify by silica gel chromatography using ether/hexane as eluant to yield the title compound.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21]OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:27]#[N:28].[K+].[I-].[K+].O>CN(C=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21][C:27]#[N:28])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 24 h
Yield: 96.7 %

Procedure:
A solution of methanesulfonic acid 2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester (1.21 g, 3.07 mmol), potassium cyanide (0.799 g, 12.27 mmol) and potassium iodide (0.25 g) in 50 mL of DMF was heated to 95° C. under argon with stirring for 24 hours. The reaction mixture was cooled and poured into 500 mL of water. The aqueous mix was extracted three times with EtOAc, and the combined organic phases were washed with water, saturated brine, and dried (MgSO4). Evaporation of the solvent under reduced pressure gave an oil that was purified by elution on silica gel (hexanes:EtOAc 1:1). Removal of the solvent under reduced pressure yielded 0.950 g (2.97 mmol, 95.1% of 3-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionitrile as a white crystalline solid. MS: 326 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:9][CH2:8]1.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([F:49])=[C:31]([C:33]2[S:34][C:35]([NH:41]C(OC(C)(C)C)=O)=[C:36]([C:38](O)=[O:39])[N:37]=2)[CH:32]=1>>[NH2:41][C:35]1[S:34][C:33]([C:31]2[CH:32]=[C:27]([Br:26])[CH:28]=[CH:29][C:30]=2[F:49])=[N:37][C:36]=1[C:38]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9][CH2:8]1)=[O:39]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cc(Br)ccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3cc(Br)ccc3F)sc2N)c1N1CCC[C@@H](N)CC1

Procedure:
Following procedures from Examples 140, (R)-benzyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16 and the product of Example 27, 2-(5-bromo-2-fluorophenyl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid, were converted to 308. 1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 8.45 (dd, J=6.7, 2.5 Hz, 1H), 7.66-7.55 (m, 1H), 7.48 (s, 2H), 7.43 (s, 1H), 7.36 (dd, J=11.2, 8.9 Hz, 1H), 3.65 (s, 4H), 3.21-2.93 (m, 7H), 1.84 (dd, J=8.2, 3.6 Hz, 3H), 1.72-1.39 (m, 3H). MS (ESI) m/z: 508.1/510.1 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:9]([O:13][C:14](=[O:26])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[C:24]#[CH:25])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[C:9]([O:13][C:14](=[O:26])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[C:24]#[C:25][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1ccncc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccncc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 3-bromo-4-methylpyridine (Apollo; 355 mg; 2.06 mmol), tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3, 500 mg; 1.87 mmol), dichlorobis(triphenylphosphine)palladium(II) (82 mg; 0.11 mmol), copper(I) iodide (21 mg; 0.11 mmol) was degassed during two minutes under nitrogen then THF (7.5 mL) and triethylamine (520 μL; 3.75 mmol) were added and reaction mixture was stirred at 60° C. for 16 hours. The solvents were removed under vacuum affording a dark brown residue, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a dark brown sticky solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>>[CH2:13]([S:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:20])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[N:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Nn1nc(SCc2ccccc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(SCc2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 212B and (4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (s, 1H), 8.32 (dd, J=8.1, 1.3 Hz, 1H), 7.90-8.01 (m, 3H), 7.37-7.43 (m, 6H), 7.23-7.26 (m, 3H), 4.32 (s, 2H), 3.72 (s, 2H); MS (DCI+) M/Z 453 (M+NH4)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[CH2:20][C@@H:21]([OH:23])[CH3:22])[CH:13]=1.C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][C@H:21]([CH2:20]/[CH:19]=[CH:18]/[C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH3:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](O)C/C=C/c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)C/C=C/c2cccnc2)cc1
Reaction time: 18 h
Yield: 68.6 %

Procedure:
Under a nitrogen atmosphere, p-toluenesulfonyl chloride (7.01 g, 36.77 mmol) was added to a stirring solution of (2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol (3.00 g, 18.38 mmol) in dry triethylamine (20 mL) at 0° C. After stirring and warning to ambient temperature over 18 h, the mixture was stirred with cold, saturated NaHCO3 solution (50 mL) for 1 hour and extracted with chloroform (3×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation to afford a thick, dark-brown mass (˜7 g). The crude product was purified by column chromatography on silica gel, eluting with chloroform-acetone (98:2, v/v) to afford 4.00 g (68.6%) of a light-brown syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1>C1COCC1.CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]2=[O:8])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(Br)c[nH]c1=O
Reactant: Clc1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cn(Cc2ccc(Cl)cc2)c1=O
Yield: 90 %

Procedure:
According to Scheme 1 Step 2: The title compound was prepared from methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (1 eq, 10.0 mmol, 3.00 g) and 1-(bromomethyl)-4-chlorobenzene (1.5 eq, 20.0 mmol, 4.00 g) according to the procedure described for Example 1 Step 2. Reaction conditions: 3 hours at 50° C. in THF/DMF (2:1, 300 mL). The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked 130 g column SiO2) using CH2Cl2/AcOEt 85/15 as the eluent and recrystallized from Et2O to afford the title compound (9.00 mmol, 4.17 g, 90%) as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][C@@:23]1([CH2:37][CH2:38]O)[CH2:32][CH2:31][C:30]2[C:25](=[C:26]([CH3:36])[C:27]([CH3:35])=[C:28]([OH:34])[C:29]=2[CH3:33])[O:24]1>C(Cl)Cl>[CH3:22][C@@:23]1([CH2:37][CH2:38][Br:20])[CH2:32][CH2:31][C:30]2[C:25](=[C:26]([CH3:36])[C:27]([CH3:35])=[C:28]([OH:34])[C:29]=2[CH3:33])[O:24]1
Reactant: BrBr
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCO)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCBr)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
5.5 g of triphenylphosphine were dissolved in 100 ml of anhydrous methylene chloride, 3.4 g of bromine were added dropwise, the reaction mixture was stirred for 30 minutes at room temperature, 5 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman were added, and the mixture was refluxed for one hour and then poured onto sodium carbonate solution. The aqueous phase was extracted with methylene chloride, the combined organic phases were washed with sodium chloride solution, dried and evaporated down, and the residue was recrystallized from methanol. 5.3 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-bromoethyl)-chroman were obtained. [α]D20 =-15 (c=2, MeOH), mp.=120° C.
Reaction SMILES: [P:1](=[O:9])([N:6]=[C:7]=[O:8])([S:4][CH3:5])[O:2][CH3:3].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CCOCC>[N:10]1([C:7]([NH:6][P:1](=[O:9])([S:4][CH3:5])[O:2][CH3:3])=[O:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: COP(=O)(N=C=O)SC
Solvent: CCOCC
Product: COP(=O)(NC(=O)N1CCCCC1)SC

Procedure:
A solution of 6.0 grams (g) of O,S-dimethyl phosphoroisocyanatidothioate in 100 milliliters (ml) of ether was cooled to 0° C. and to this was added dropwise with stirring 3.1 g of piperidine. A precipitate began to form almost immediately and after 1 hour this precipitate was collected by filtration and extracted with ether. It was then recrystallized from toluene-hexane to obtain the title compound as white crystals melting at 96° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=1)=[O:11].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[Na].CN(C)C(=O)C>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:14][CH:13]=1)=[O:11]
Reactant: c1nc[nH]n1
Reactant: O=C(Cc1ccc(F)cc1F)c1ccc(F)cc1
Agent: [Na]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1C
Product: O=C(Cc1ccc(F)cc1F)c1ccc(-n2cncn2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 17.5 %

Procedure:
A mixture of 2-(2,4-difluorophenyl)-1-(4-fluorophenyl)-1-ethanone (5.0 g, 20 mmol-see EP-A-0069442), sodium 1,2,4-triazole (2.18 g, 24 mmol) and N,N-dimethylacetamide (100 ml) was stirred at 100° C. for 18 hours. The mixture was diluted with xylene (300 ml) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 ml) and washed with water (3×50 ml). The organic solution was dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (eluting with ethyl acetate:dichloromethane 1:1) gave a white solid (1.05 g, 18%), which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[C:13]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C(O)(C(F)(F)F)=O.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CNc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
4-Formylbenzoic acid methyl ester (10.6 g, 64 mmol) was dissolved in methanol (200 mL). 4-tert-Butylaniline (9.61 g, 64 mmol) was added and the resulting suspension was refluxed for 15 min. After cooling to room temperature, TFA (5.18 mL, 68 mmol) was added followed by portion wise addition of sodium cyanoborohydride (3.26 g, 52 mmol). The resulting mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was partitioned between ethyl acetate (200 mL) and 1 N aqueous sodium hydroxide (150 and 100 mL). The organic phase was dried (magnesium sulphate) and evaporated in vacuo to afford 19.0 g (99%) of 4-[(4-tert-butylphenylamino)methyl]benzoic acid methyl ester as a solid.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14]C(=O)OC(C)(C)C)[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1>CO>[NH2:14][C@@H:4]([CH2:5][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([F:12])[CH:11]=1)[C@H:3]([OH:22])[CH2:2][Cl:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl
Solvent: CO
Product: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl

Procedure:
tert-butyl (1S,2S)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (IV, EXAMPLE 3, 1.0 gm, 2.98 mmol) and Dowex50WX2-400 resin (4.6 gm, 23.8 mmol) and methanol (25 mL) are mixed. The mixture is then placed over a J-Kim shaker with heating at 50° for 2 hr. ESMS analysis indicates no starting material left in the mixture. The reaction contents are filtered through a sintered funnel and the resin washed with methanol (25 mL) and methanol/methylene chloride (1/1, 25 mL). The resulting mixture is eluted with ammonia in methanol (2N, 2×25 mL) The eluate is concentrated under reduced pressure to give the title compound, ESMS=236.1.