Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:11]([OH:15])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH2:2][CH3:3].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].CCOCC>O>[OH:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][C@H:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:22](=[O:23])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:6]2
Reactant: CCCN[C@H]1CCc2c(O)cccc2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCCN(C(=O)OCc1ccccc1)[C@H]1CCc2c(O)cccc2C1
Yield: 81.3 %

Procedure:
A stirring suspension of (S)-6-propylamino-5,6,7,8-tetrahydro-l-naphthalenol (7.34 g, 0.0257 mol) in water (100 mL) was cooled in an ice bath and sodium bicarbonate (8.49 g, 0,101 mol) was added. This suspension was stirred for fifteen minutes then benzyl chloroformate (4.50 g, 0.0264 mol) was added dropwise. The mixture was stirred for fifteen minutes and then allowed to come to room temperature. Ether (100 mL) was added and the mixture was stirred overnight. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate, once with water, twice with dilute hydrochloric acid, once with water and once with saturated aqueous sodium chloride, dried (magnesium sulfate) and concentrated under reduced pressure to give 7.09 g (81% yield) of product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13]2[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH2:20])[CH:14]=2)=[N:10][C:9]=1[C:21]1[N:25](COCC[Si](C)(C)C)[CH:24]=[N:23][N:22]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13]2[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])[CH:14]=2)=[N:10][C:9]=1[C:21]1[NH:25][CH:24]=[N:23][N:22]=1
Reactant: Cc1cnc(N)cc1-c1nc(-c2nncn2COCC[Si](C)(C)C)c(-c2ccccc2Cl)o1
Reactant: O=C(Cl)C1CC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(NC(=O)C2CC2)cc1-c1nc(-c2nnc[nH]2)c(-c2ccccc2Cl)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23.8 %

Procedure:
A mixture of 4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)-ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-amine (0.12 g, 0.25 mmol) and TEA (0.087 mL, 0.62 mmol) in DCM (2 mL) was allowed to stir at 0° C. for 20 min. To this mixture was added cyclopropanecarbonyl chloride (0.056 mL, 0.62 mmol). The reaction mixture was allowed to stir at 0° C. for 2 h and then MeOH (20 mL) was added. The mixture was allowed to stir at rt for 20 min and was then concentrated. MeOH (25 mL) and aqueous saturated NaHCO3 (4 mL) were added to the residue and the mixture was allowed to stir at rt overnight before NaOH (1M, 3 mL) was added. The reaction mixture was allowed to stir rt for 3 h and then concentrated. EtOAc (30 mL) was added to the residue and the mixture was allowed to stir at rt for 30 min. The mixture was filtered and the filtrate was concentrated. DCM (5 mL) and TFA (2 mL) were added to the residue and the mixture was allowed to stir at rt overnight. The reaction mixture was concentrated and purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}cyclopropanecarboxamide (Compound I-77) (0.025 g, 24%). LCMS (AA): m/z=421 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:4]=2[S:5](=[O:8])(=[O:7])[CH:6]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.ClS(Cl)(=O)=O>ClCCl>[Cl:13][C:10]1[CH:11]=[CH:12][C:3]2[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:6][S:5](=[O:8])(=[O:7])[C:4]=2[CH:9]=1
Reactant: O=S1(=O)C=C(Cl)c2ccc(Cl)cc21
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: O=S1(=O)C=C(N2CCNCC2)c2ccc(Cl)cc21
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A mixture of 3,6-dichlorobenzo[b]thiophene-1,1-dioxide (16.00 g, 0.0681 mol), piperazine (20.52 g, 0.238 mol) and dichloromethane (300 ml) was heated to reflux. After 1 hour, TLC analysis showed the dichlorosulfone (Rf =0.47, 30% ethyl acetate in hexanes, silica gel) to be consumed. The cloudy mixture was washed with 0.25 N NaOH (400 ml), H2O (300 ml), brine (250 ml), dried (Na2SO4), and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 50% methanol in dichloromethane, to afford 12.90 g (66.5%) of a yellow solid. A 1.60 g sample was recrystallized from dichloromethane/ether yielding 0.480 g of light yellow crystals: m.p. 154° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:24])[CH:7]=1.[Cl:30]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>ClC(Cl)C>[Cl:30][C:7]1[C:8](=[O:24])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 50 °C

Procedure:
The title compound was prepared by taking up methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate (1.46 g, 3.66 mmol) in dichloroethane (25 ml) and adding N-chlorosuccinimide (0.49 g, 3.66 mmol), dichloroacetic acid (catalytic), and heating to 50° C. for 6 hours. At this time, the solvent was removed in vacuo and the residue taken up in diethyl ether. The precipitate was collected on a filter pad. 1H NMR (300 MHz, CDCl3) δ 8.07 (dd, J=7.85, 1.61 Hz, 11), 7 80 (d, J=1.81 Hz, 2H), 7.62 (app q, J=846 Hz, 1H), 7.48 (d, J=7.85, 1H), 7.05-6.95 (m, 1H), 6.93-6 89 (m, 1H), 6.19 (s, 1H), 5.30 (s, 2H), 3.93 (s, 3H), 2.17 (s, 3H), 1.97 (s, 3H). ES-HRMS m/z 434.0932 (M+H calcd for C22H19ClF2NO4 requires 434.0965).
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][C:49]=1[F:57].CO.[CH2:60]([N:67]1[CH2:71][CH:70]=[C:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O>[CH2:60]([N:67]1[CH2:71][C@H:70]([C:51]2[CH:52]=[CH:53][C:48]([Cl:47])=[C:49]([F:57])[CH:50]=2)[C@@H:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Temperature: 55 °C
Yield: 33 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (31 mg, 0.05 eq.), (R)-BINAP (74 mg, 0.05 eq.) and 4-chloro-3-fluoro-phenylboronic acid (825 mg, 2.5 eq.). 30 mL of MeOH and 3 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone (480 mg). The reaction mixture was heated at 55° C. for 3 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 261 mg (33%) of the title product as a light yellow oil. ES-MS m/e: 332.1 (M+H+).
Reaction SMILES: I[CH2:2][C:3]([NH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:4].CCN(C(C)C)C(C)C.[SH:33][C:34]([CH3:52])([CH3:51])[CH2:35][N:36]([CH3:50])[CH2:37][CH2:38][O:39][C:40]1[CH:45]=[C:44]([CH2:46][OH:47])[N:43]=[C:42]([CH2:48][OH:49])[CH:41]=1>CN(C=O)C>[OH:47][CH2:46][C:44]1[CH:45]=[C:40]([O:39][CH2:38][CH2:37][N:36]([CH3:50])[CH2:35][C:34]([S:33][CH2:2][C:3]([NH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:4])([CH3:52])[CH3:51])[CH:41]=[C:42]([CH2:48][OH:49])[N:43]=1
Reactant: CN(CCOc1cc(CO)nc(CO)c1)CC(C)(C)S
Reactant: COC(=O)CCOCCOCCOCCOCCNC(=O)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCOCCOCCOCCOCCNC(=O)CSC(C)(C)CN(C)CCOc1cc(CO)nc(CO)c1
Reaction time: 24 h
Yield: 57.1 %

Procedure:
73.7 mg of methyl 3-[2-(2-{2-[2-(2-iodoacetylamino)ethoxy]ethoxy}ethoxy)ethoxy]propanoate in solution in 1 ml of DMF and 39 μl of DIPEA are added to 45 mg of 4-{2-[(2-mercapto-2-methylpropyl)(methyl)amino]ethoxy}-2,6-bis(hydroxymethyl)pyridine in solution in 1 ml of DMF. After 24 h at AT, the mixture is concentrated under RP and purified by flash chromatography on silica (Analogix Super Flash SiO2 SF25-8 g), using a gradient from 0 to 10% of methanol in DCM. 53 mg of methyl 3-{2-[2-(2-{2-[2-(2-{[2-(2,6-bis(hydroxymethyl)pyridin-4-yloxy)ethyl](methyl)amino}-1,1-dimethylethylsulphanyl)acetylamino]ethoxy}ethoxy)ethoxy]ethoxy}propanoate are thus obtained.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=O)[O:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1.Cl>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:14][CH:15]=1)[C:9](=[O:10])[NH:3][NH:2][C:12]2=[O:11]
Reactant: NN
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c(=O)c2cc(Br)ccc12
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Hydrazine monohydrate (2 ml, 33.0 mmol) was added to a suspension of 4-bromophthalic anhydride (7.5 g, 33.0 mmol) in ethanol (70 ml) and the resulting mixture was stirred at 90° C. for 24 hr. The volume of the reaction mixture was then reduced to half volume under reduced pressure and the residue was treated 0.5 N aq. HCl (20 mL). The title compound precipitated as a white solid and was collected by filtration (4.86 g, 61%); LRMS ESI+ (M+H)+ 241.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31]>CN(C=O)C.C(OCC)C>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:31])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(CO)cc2)cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCc1ccc(CN(Cc2ccccc2)c2cccc([N+](=O)[O-])c2C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product from Example 38A (0.1 g, 0.276 mmoles) in DMF (0.7 mL) was treated with sodium hydride (0.012 g, 0.3 mmoles, 60% dispersion). After 10 minutes, the reaction mixture was treated with iodomethane (0.02 mL, 0.36 mmoles) and then stirred overnight at room temperature. The mixture was diluted with diethyl ether (100 mL), washed with saturated ammonium chloride (50 mL) and water (50 mL) twice, washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:11][C:6]1[C:7]([CH2:8][CH2:9][O:10][S:13]([CH3:12])(=[O:15])=[O:14])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1c(Cl)ncnc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 2-(4,6-Dichloro-pyrimidin-5-yl)-ethanol (0.46 g, 2.4 mmol) in DCM (40 mL) and was added MsCl (0.50 g, 4.36 mmol), triethylamine (1 mL) and cat. amount of DMAP. After stirring at room temperature overnight, the solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (4:1) to afford methanesulfonic acid 2-(4,6-dichloro-pyrimidin-5-yl)-ethyl ester (0.52 g, 80%). 1H NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 4.50 (t, J=6.4 Hz, 2H), 3.42 (t, J=6.8 Hz, 2H), 3.02 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:11]([NH2:21])=[CH:10][C:9]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)[CH:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]([CH3:38])[CH:30]=3)[CH:26]=[CH:25][N:24]=2)=[CH:10][C:11]([NH:21][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17.3 %

Procedure:
A solution of acryloyl chloride (58.4 mg, 0.64 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of 4-methoxy-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 110, 286 mg, 0.64 mmol) and DIPEA (0.134 mL, 0.77 mmol) in CH2Cl2 (20 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h at 0° C. More DIPEA was added (30 μL) then more acryloyl chloride (20 mg) was added dropwise as a solution in CH2Cl2 (1 mL). This mixture was stirred for 2 h and then diluted with CH2Cl2 (50 mL). This solution was washed with sat. NaHCO3 solution (2×25 mL) and then the combined aqueous washes were extracted with CH2Cl2 (2×25 mL). The combined organic solutions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting gum was triturated with diethyl ether to give a solid which was collected by filtration and dried in vacuo. Purification by FCC, eluting with 0-8% 7N methanolic ammonia in CH2Cl2 gave the title compound (55 mg, 17%) as a light grey solid after trituration with diethyl ether (with a few drops of CH3OH); 1H NMR: 2.27 (3H, s), 2.53-2.59 (4H, m), 2.85-2.91 (4H, m), 3.87 (3H, s), 3.91 (3H, s), 5.75 (1H, d), 6.24 (1H, d), 6.67 (1H, dd), 6.89 (1H, s), 7.15-7.28 (3H, m), 7.53 (1H, d), 7.89 (1H, s), 8.28 (1H, d), 8.32 (1H, d), 8.58 (1H, s), 8.81 (1H, s), 9.07 (1H, s); m/z: ES+ MH+ 498.58.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([CH2:44][N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][C@@H:46]2[CH3:55])=[CH:14][N:13]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[N:19]=3)=[CH:16][C:15]([CH2:44][N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:52])=[O:53])[CH2:47][C@@H:46]3[CH3:55])=[CH:14][N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
A mixture of 5-fluoro-6-methoxypyridin-3-amine (3.34 g, 23.53 mmol) and (S)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (13.6 g crude from previous step) in THF (150 mL) at −10° C. was treated dropwise with LiHMDS (1.0 M in THF, Aldrich; 64.2 mL, 64.2 mmol) and the mixture was stirred for 30 min. The reaction was quenched with water and saturated NH4Cl(aq) (100 mL each) and diluted with EtOAc (50 mL). The organic layer was separated, and precipitated solids were collected by filtration. The filtered organic layer was then concentrated to minimal volume, and the precipitated brownish-yellow solid was collected by filtration and washed with a minimal amount of EtOAc. All collected solids were then combined, slurried in isopropanol, collected by filtration, and dried in vacuo to give (S)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (9.678 g, 81% over 2 steps) as a yellow solid. m/z (ESI, +ve ion) 758 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH:15]3[CH:10]([CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14]3)[CH2:9]2)=[O:7])=[C:4]([N:25]2[CH:29]=[CH:28][N:27]=[N:26]2)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:15]12[N:8]([C:6]([C:5]3[C:4]([N:25]4[CH:29]=[CH:28][N:27]=[N:26]4)=[N:3][C:2]([CH3:1])=[CH:24][CH:23]=3)=[O:7])[CH2:9][C@H:10]1[CH2:11][CH2:12][NH:13][CH2:14]2
Reactant: Cc1ccc(C(=O)N2CC3CCN(C(=O)OC(C)(C)C)CC32)c(-n2ccnn2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2C[C@H]3CCNC[C@H]32)c(-n2ccnn2)n1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To 1S,6R)-tert-butyl 8-(6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinoyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.05 g, 2.64 mmol) in DCM (15 mL) was added TFA (3 mL). The resulting mixture was allowed to stir at ambient temperature. After 16 h the mixture was concentrated under reduced pressure and the crude residue was purified by FCC (SiO2, gradient DCM to 15% MeOH/10% NH3/DCM) to yield the title compound (790 mg, 71%). MS (ESI) mass calcd. for C15H18N6O, 298.2; m/z found, 299.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1.Cl.[OH-].[Na+]>O.C(O)C>[CH2:19]([O:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[NH:27][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)[CH3:18]
Reactant: CCOc1cccc(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Yield: 63.6 %

Procedure:
A mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol), m-phenetidine (19 μl, 0.144 mmol), and 2N HCl (75 μl) in water:ethanol (2:1, 5 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was filtered, washed with water, water:ethanol (2:1) and dried to give a yellow solid (22 mg, 63%). 1H NMR (CDCl3): 8.88–8.85 (m, 1H), 8.58 (d, J=8.1 Hz, 1H), 7.93–7.88 (m, 1H), 7.61 (s, 1H), 7.48–7.44 (m, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.05 (s, 1H), 6.89–6.81 (m, 3H), 4.07 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:31])([F:30])[CH2:25][S:26](Cl)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH2:21][NH:22][S:26]([CH2:25][C:24]([F:31])([F:30])[F:23])(=[O:28])=[O:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cnccc1-c1cccc(OCc2ccccc2)c1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=S(=O)(CC(F)(F)F)NCc1cnccc1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-(3-benzyloxyphenyl)pyridin-3-ylmethylamine (1.0 equiv.) in 2:1 DCE/Pyridine (0.15 M) was cooled to 0° C. and treated with 2,2,2-trifluoroethanesulfonyl chloride (1.8 equiv.). The mixture was allowed to warm to ambient temperature and stir overnight. The reaction was treated with anhydrous potassium carbonate, stirred for 40 min, and filtered. The filtrate was purified via preparative HPLC eluting with 70:30 to 60:40 DCM/ethyl acetate, evaporated, and then triturated with diethyl ether to give the title compound. Anal Calcd for C21H19F3N2O3S: C, 57.79; H, 4.39; N, 6.42. Found: C, 57.60; H, 4.47; N, 6.41. 1H NMR (400 MHz) 3.77 (2H, q, J=9.0 Hz), 4.86 (2H, d), 4.99 (2H, d), 6.82 (2H, m), 6.95 (1H, m), 7.25 (2H, m), 7.34-7.40 (5H, m), 7.67 (1H, td, J=2.0, 8.0 Hz), 8.32 (1H, bs), 8.50 (1H, d, J=4.0 Hz). MS found 437.1 [M+H]+
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:44]([Si:48]([CH3:51])([CH3:50])Cl)([CH3:47])([CH3:46])[CH3:45].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:48]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:51])[CH3:50])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.85 g (6.48 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-[p-(2-methoxyethoxy)-phenyl]-2(R)-[(p-benzyloxyphenyl)methyl]hexanoic acid in 11 ml of DMF are silylated, at RT for 16 h and under a protective gas, with 4.49 g (29.8 mmol) of tert-butyldimethylchlorosilane and 3.6 g (53.1 mmol) of imidazole. The reaction mixture is poured onto ice-water and the whole is extracted 3 times with ethyl acetate. The organic phases are washed with 10% citric acid solution, 2 times with water and with saline, dried with Na2SO4 and evaporated. The residue is dissolved in 79 ml of methanol and 30 ml of THF, and this solution is treated with 5.37 g of potassium carbonate and 30 ml of water and stirred at RT for 3 h. The reaction mixture is subsequently poured onto an ice-cold 10% citric acid solution, and this mixture is extracted 3 times with ethyl acetate. The organic phases are washed with 2 portions of H2O and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 1:1) affords the title compound: TLC Rf (C)=0.28; tRet (II)=20.9 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][O-:11].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5](=[NH:6])[O:11][CH3:10]
Reactant: N#Cc1cccc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 471.7 %

Procedure:
To a solution of 3-chlorobenzonitrile (4.0 g, 29.1 mmol) in methanol (30 mL) was added sodium methoxide (0.16 g, 2.9 mmol). The mixture stirred at rt for 2 d, diluted with water, and extracted with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (2.32 g, 47%) as a clear oil. MW=169.61. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.46-7.42 (m, 1H), 7.35 (t, J=7.9 Hz, 1H), 3.94 (s, 3H); APCI MS m/z 170 [M+H]+.