Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26]([O:40][CH2:41][CH3:42])([CH3:39])[C:27](OC1C=CC([N+]([O-])=O)=CC=1)=[O:28])[CH3:24]>CN(C1C=CN=CC=1)C.C(#N)C.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH:22][C:27](=[O:28])[C:26]([O:40][CH2:41][CH3:42])([O:25][CH2:23][CH3:24])[CH3:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Reactant: CCOC(C)(OCC)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(C)(OCC)C(=O)Nc1cc(C)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 61.8 %

Procedure:
4-(2-Amino-4-methyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.31 mmol), p-nitrophenyl 2,2-diethoxyproprionate (1.00 g, 3.50 mmol), and DMAP (1.00 g, 8.2 mmol) were combined in acetonitrile (3 mL) and heated in an oil bath at 80° C. for 2 h. The mixture was cooled, diluted with diethyl ether (100 mL), washed once each with saturated aqueous NH4Cl and water, three times with 5% aqueous sodium hydroxide solution, once with brine and dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was adsorbed on a silica gel pad, and the pad was eluted with 25% ethyl acetate in hexanes to give 4-[2-(2,2-diethoxy-propionylamino)-4-methyl-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (550 mg, 0.81 mmol, 62%) of a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)[C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:49]1[CH2:54][CH2:53][O:52][CH2:51][CH:50]1[C:55]1[C:63]2[S:62][C:61]([NH2:64])=[N:60][C:59]=2[C:58]([O:65][CH3:66])=[CH:57][CH:56]=1>C1COCC1.C(Cl)(Cl)Cl>[O:49]1[CH2:54][CH2:53][O:52][CH2:51][CH:50]1[C:55]1[C:63]2[S:62][C:61]([NH:64][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][N:15]=[C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:8]=3)=[N:60][C:59]=2[C:58]([O:65][CH3:66])=[CH:57][CH:56]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: COCCOCc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOCc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccn1

Procedure:
From 2-(2-methoxy-ethoxymethyl)-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+69.2° (c=1.04, CHCl3), ES-MS m/e (%): 460 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][C:15]1=[O:21].C(N(CC)CC)C.CC(C)(O)C#N>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH:16]2[C:17](=[O:20])[CH2:18][CH2:19][NH:14][C:15]2=[O:21])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C1CCNC(=O)C1
Agent: CC(C)(O)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCNC(=O)C1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.5 %

Procedure:
A solution of 4-chloro-2-nitrobenzoyl chloride (5.8 g) in dry dichloromethane (10 ml) was added over 5 minutes to a stirred solution of piperidine-2,4-dione (3.0 g) and triethylamine (5.5 ml) in dry dichloromethane (100 ml) and the mixture was stirred at ambient temperature for 3 hours. Acetone cyanohydrin (0.5 ml) was added and the mixture was stirred at ambient temperature for 18 hours. The solution was washed successively with 2N hydrochloric acid (50 ml) and water (2×100 ml), dried over sodium sulphate and evaporated under reduced pressure to give a solid residue which was recrystallised from ethyl acetate (70 ml) to give 3-(4-chloro-2-nitrobenzoyl)piperidine-2,4-dione (1.6 g), mp 161°-164° C., as a light brown crystalline solid.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1([CH3:34])[CH2:17][O:16][C:15]([C:18]2[CH:33]=[CH:32][C:21]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=2)=[N:14]1.[Br:35]Br.Cl>O1CCCC1>[Br:35][C:33]1[CH:32]=[C:21]([CH:20]=[CH:19][C:18]=1[C:15]1[O:16][CH2:17][C:13]([CH3:34])([CH3:12])[N:14]=1)[O:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: BrBr
Reactant: CC1(C)COC(c2ccc(OCCCN3CCCCC3)cc2)=N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(OCCCN3CCCCC3)cc2Br)=N1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A 2.1 M solution of n-butyllithium in hexane (580 μl, 2 eq, 1.28 mmol) is added dropwise to a solution of 1-{3-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenoxy]propyl}piperidine 1 (200 mg, 0.64 mmol, 1 eq) in cold (0° C.) tetrahydrofuran (10 ml), and the resulting solution is stirred 4 hours at 0° C. Bromine (64 μL, 2 eq, 1.28 mmol) is then added and the mixture is left to stir at 22° C. overnight. The solution is then poured into 5 ml of 0.1 N aqueous hydrogen chloride and extracted with ether. The aqueous layer is then made basic (pH 10) with 5 N sodium hydroxide and extracted with dichloromethane. The chlorinated solution is then dried over magnesium sulfate, concentrated under reduced pressure. 1-{3-[3-bromo-4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenoxy]propyl}piperidine 17 is separated from the remaining starting material by careful chromatography over silicagel (dichloromethane/methanol, gradient).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+].O>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:10][CH3:9])=[N:3][CH:4]=1
Reactant: C[S-]
Reactant: Brc1ccc(Br)nc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 94.5 %

Procedure:
Commercially available 2,5-dibromo pyridine (6.01 g, 25.4 mmol) was dissolved in N,N-dimethylformamide (50 mL), and sodium thiomethoxide (2.20 g, 31.4 mmol) was added, followed by stirring at 0° C. for 3.5 hours under nitrogen atmosphere. The reaction solution was brought back to room temperature, water (250 mL) was added, and extraction was carried out with diethyl ether (250 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=3%-5%) to afford the desired compound (4.90 g, yield 94%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)#[CH:2].C1(C)C=CC=CC=1.S(=O)(=O)(O)[OH:18]>>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([C:1](=[O:18])[CH3:2])=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(C)nc1
Reactant: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C)nc1
Temperature: 50 °C
Yield: 2704.3 %

Procedure:
1.0 g 5-ethynyl-2-methylpyridine (8.5 mmol) was loaded into a flask provided with magnetic anchor and was dissolved in 10 mL of a 1:4 toluene/sulfuric acid mixture (0.29 mmol). The resulting solution was heated to 50° C. overnight, then after quenching to room temperature, the solution was basified by the addition of NaHCO3, then it was extracted with AcOEt (3×20 mL) and finally, anhydrified on anhydrous MgSO4. The organic phase was then concentrated under vacuum yielding 1.06 g product, equal to a molar yield of 91% as a yellow oil.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:16][C@H:15]2[N:17]([CH3:18])[C@H:12]([CH2:13][CH2:14]2)[C@H:11]1[CH:19]=[CH2:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](O[C@H]1C[C@H]2N(C)[C@H](CC2)[C@H]1/C=C/[Cl:40])(C(C)(C)C)(C)C>>[C:1]([O:9][C@H:10]1[CH2:16][C@H:15]2[N:17]([CH3:18])[C@H:12]([CH2:13][CH2:14]2)[C@H:11]1/[CH:19]=[CH:20]/[Cl:40])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1[C@H]2CC[C@@H]1[C@@H](/C=C/Cl)[C@@H](O[Si](C)(C)C(C)(C)C)C2
Reactant: C=C[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2C
Product: CN1[C@H]2CC[C@@H]1[C@@H](/C=C/Cl)[C@@H](OC(=O)c1ccccc1)C2
Yield: 22 %

Procedure:
By the same procedure used for the preparation of 2a, 180 mg (0.57 mmol) of the product of Example 5 gave 39 mg (22% yield) of compound 2b (column chromatography, hexane: ethyl acetate=2:1): [α]22D =-47.2° (c=1.925, CH2Cl2); IR (thin film) 3063, 2942, 2880, 2801, 1717, 1451, 1277, 1115, 939, 822, 712 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 7.97 (d, 2H, J=7.4 Hz), 7.55 (t, 1H, J=7.4 Hz), 7.43 (t, 1H, J=7.3 Hz), 6.42 (dd, 1H, J=13.4, 10.0 Hz), 5.93 (d, 1H, J=13.4 Hz), 5.19 (dt, 1H, J=11.4, 6.5 Hz), 3.30-3.20 (m, 1H), 3.15-3.05 (m, 1H), 2.85-2.75 (m, 1 H), 2.22 (s, 3H), 2.20-1.60 (m, 6H); 13C NMR (CDCl3, 75.46 MHz) δ166.0, 132.9, 130.4, 129.6, 128.4, 118.2, 68.6, 66.7, 61.4, 47.1, 41.3, 35.6, 26.1, 25.1; mass spectrum, m/z 307 (M+, 37Cl), 305 (M+, 35Cl), 270, 224, 184, 148, 105, 82, 77; HRMS calcd for C17H20NO235Cl (M+) 305.1178, found 305.1170.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: C[C@H](O)C(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: F[C:2]1[CH:13]=[CH:12][C:5]([C:6]([CH2:8][CH2:9][CH2:10]I)=[O:7])=[CH:4][CH:3]=1.C(CCCI)(=O)C1C=CC=CC=1.[C:26]1([C:32]2([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[ClH:44]>>[ClH:44].[C:6]([CH2:8][CH2:9][CH2:10][N:35]1[CH2:36][CH2:37][C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:33][CH2:34]1)(=[O:7])[C:5]1[CH:12]=[CH:13][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(CCCI)c1ccc(F)cc1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: O=C(CCCI)c1ccccc1
Product: O=C(CCCN1CCC(c2ccccc2)(c2ccccc2)CC1)c1ccccc1

Procedure:
When proceeding as described in Example 28, but replacing 3-(p-fluorobenzoyl)propyl iodide (used as the one reactant in said example) by 3-benzoylpropyl iodide and reacting 27.4 g. of said 3-benzoylpropyl iodide with 24.4 g. of 4,4-diphenylpiperidine, on addition of hydrochloric acid to the etheric solution of the diphenylpiperidine base 19.5 g. of 1-(3-benzoylpropyl)-4,4-diphenylpiperidine hydrochloride are obtained. On recrystallization from ethanol, the hydrochloride melts at 200° C.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:16][C:17]1[N:18]=[C:19]([CH:22](O)[CH2:23][CH2:24][N:25]2[C:33]([C:34]3[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=3)[C:37]#[N:38])=[C:32]3[C:27]([N:28]([CH3:45])[C:29](=[O:44])[N:30]([CH3:43])[C:31]3=[O:42])=[CH:26]2)[S:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:16][C:17]1[N:18]=[C:19]([CH:22]2[C:26]3[N:25]([C:33]([C:34]4[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=4)[C:37]#[N:38])=[C:32]4[C:31](=[O:42])[N:30]([CH3:43])[C:29](=[O:44])[N:28]([CH3:45])[C:27]4=3)[CH2:24][CH2:23]2)[S:20][CH:21]=1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCC(O)c3nc(Cl)cs3)cc2n(C)c1=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)CC3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trifluoromethanesulfonic anhydride (0.445 mL, 2.63 mmol) was added to a solution of 3-(6-(3-(4-chlorothiazol-2-yl)-3-hydroxypropyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (600 mg, 1.316 mmol) and triethylamine (0.550 mL, 3.95 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 90 mins. Further portions of triethylamine (0.550 mL, 3.95 mmol) and trifluoromethanesulfonic anhydride (0.445 mL, 2.63 mmol) were added to allow the reaction to run to completion. The reaction mixture was quenched with saturated NaHCO3(aq) and extracted with DCM (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-80% EtOAc/hexane gave a crude material which was triturated with DCM/diethyl ether/hexane to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[I:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:31])[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[CH3:16]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([N:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([NH:17][C:12]3[CH:13]=[CH:14][C:15]([CH3:16])=[C:10]([I:9])[CH:11]=3)=[O:31])=[CH:20][N:21]=2)[CH2:26][CH2:27]1)=[O:5]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)CC(C)(C)C)CC3)nc2)cc1I
Temperature: 25 °C

Procedure:
6-[4-(3,3-Dimethyl-butyryl)-piperazin-1-yl]-N-(3-iodo-4-methyl-phenyl)-nicotinamide was synthesized by the addition 3,3-dimethyl-butyryl chloride (0.055 mmol) to N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide (0.05 mmol) partially dissolved in DCM followed by the addition of TEA and stirred at room temperature over night. The reaction was diluted with ethyl acetate washed with water and brine, dried over sodium sulfate, concentrated and the residue was trirturated with ether and hexanes to afford the product, 6-[4-(3,3-dimethyl-butyryl)-piperazin-1-yl]-N-(3-iodo-4-methyl-phenyl)-nicotinamide. LCMS calcd for C23H29IN4O2 (m/e) 520, obsd 521 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]([CH3:36])=[C:13]([CH2:15][N:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:22][CH:23]=4)[CH2:18][CH:17]3[CH3:35])[N:14]=2)[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:32][C:30]([F:31])([F:33])[C:25]([C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:16]([CH2:15][C:13]1[N:14]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=3)[O:11][C:12]=1[CH3:36])[CH:17]([CH3:35])[CH2:18]2)([OH:34])[C:26]([F:29])([F:28])[F:27]
Reactant: COC(=O)c1cccc(-c2nc(CN3c4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4CC3C)c(C)o2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1oc(-c2cccc(CO)c2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
A solution of 1.25 g (2.37 mmol) of 3-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-benzoic acid methyl ester (example 90) in 15 ml of THF was treated at 0° C. with 180 mg (4.73 mmol) of lithium aluminium hydride and allowed to reach RT within 3 hrs. Distribution of the crude between a saturated aqueous solution of NH4Cl and EtOAc, drying of the combined organic phases over Na2SO4 and evaporation of the solvent gave 1.1 g (93%) of 1,1,1,3,3,3-hexafluoro-2-{1-[2-(3-hydroxymethyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-2,3-dihydro-1H-indol-5-yl}-propan-2-ol, off-white foam, MS : 499 (M−H)−.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1>CN(C=O)C.O>[CH3:18][S:17][C:13]1[N:14]=[C:15]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:16]=[CH:11][N:12]=1
Reactant: Oc1ccccc1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(Oc2ccccc2)n1

Procedure:
To a suspension of sodium hydride (0.3 g,6.85 mmol, 50% dispersion in oil pre-washed with n-hexane) in dry DMF (4 ml) was added dropwise a solution of phenol (0.59 g, 6.23 mmol) in dry DMF (1 ml). The resulting mixture was stirred under an atmosphere of nitrogen until effervescence had ceased. The resulting mixture was diluted with dry DMF (3 ml) and then added dropwise to a stirred solution of 4-chloro-2-methylthiopyrimidine (1.00 g, 6.23 mmol) in dry DMF (3 ml) at 0° C. An exothermic reaction took place and the temperature of the reaction mixture rose to 5° C. After stirring under nitrogen for 30 minutes at 10° C., GC analysis indicated the formation of a single product (98.8%). The reaction mixture was diluted with water (15 ml) and extracted with ether (2×20 ml). The combined ether extracts were washed with 5% sodium hydroxide solution (2×15 ml) and brine (15 ml) and then dried. Evaporation of the solvent gave 2-methylthio-4-phenoxypyrimidine as a pale yellow oil (1.40 g, 94% pure by GC) which was used directly in the next stage. 1H NMR delta: 2.37(3H, s)ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29].Cl>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=2[N+:28]([O-:30])=[O:29])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 95.8 %

Procedure:
A solution of 4-Benzyloxy-phenol (2.00 g, 0.01 mol) and potassium hydroxide (1.12 g, 0.02 mol) in anhydrous dimethylsulfoxide (20 mL) was stirred at room temperature for 10 minutes under a nitrogen atmosphere. A solution of 4-chloro-3-nitrobenzoic acid (2.01 g, 0.01 mol) in dimethylsulfoxide (5 mL) was added and the mixture heated to 120° for 1 hour. The reaction was then cooled in an ice bath and poured into 100 mL of ice-water. The mixture was acidified with concentrated HCl to pH 3 then the resultant solid was colleted by vacuum filtration, washed with water and dried in a vacuum oven to provide the title product (3.5 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[O:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1oc(C)nc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc(C)nc1CBr
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
10 mmol of ethyl 2,4-dimethyl-1,3-oxazole-5-carboxylate was dissolved in 30 ml of carbon tetrachloride, then 11 mmol of N-bromosuccinimide was gradually added with keeping the temperature at 20 to 30° C. After the end of the adding, 0.5 mmol of azobisiso butyronitrile was gradually added. Then stirring was continued for 30 minutes at a room temperature. The temperature was heated up to 80° C. to carry out the reaction for 3 hours. The reacted liquid was cooled down to a room temperature. A precipitated solid matter was eliminated by filtration. The filtrate was washed with 30 ml of water and the organic phase was separated and extracted and dried under sodium sulfate. Then the solvent was evaporated out, obtaining ethyl 4-(bromo methyl)-2-methyl-1,3-oxazole-5-carboxylate.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:38]C)=[CH:6][C:7]([O:36]C)=[C:8]([C:10]2[N:11]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH3:35])[CH:30]=[CH:29]4)[C:12]([NH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].N1C=CC=CC=1>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[C:8]([C:10]2[N:11]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH3:35])[CH:30]=[CH:29]4)[C:12]([NH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)=[N:13][N:14]=2)[C:7]([OH:36])=[CH:6][C:5]=1[OH:38])([CH3:3])[CH3:2]
Reactant: COc1cc(OC)c(C(C)C)cc1-c1nnc(Nc2ccc3ncccc3c2)n1-c1ccc2c(ccn2C)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)c1cc(-c2nnc(Nc3ccc4ncccc4c3)n2-c2ccc3c(ccn3C)c2)c(O)cc1O
Temperature: 210 °C
Yield: 38.9 %

Procedure:
A tube was charged with N-(5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)quinolin-6-amine (114 mg) and pyridine*HCl (4 g.), and placed under a nitrogen atmosphere. It was heated to 210° C. for 50 minutes, and then cooled. The solid was dissolved in ethyl acetate (20 mL) and washed with a saturated solution of ammonium chloride (3×20 mL). The organic layer was dried and evaporated to give 4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(quinolin-6-ylamino)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol (42 mg). In some cases column chromatography was necessary for purification. 1H-NMR (CDCl3): 8.69 (dd, 1H); 8.50 (d, 1H), 8.22 (d, 1H), 7.98 (d, 1H), 7.75 (d, 1H), 7.63 (d, 1H), 7.45-7.36 (m, 2H), 7.33 (d, 1H), 7.27 (dd, 1H), 6.64 (d, 1H), 6.42 (s, 1H), 6.30 (s, 1H), 3.98 (s, 3H); 2.83 (q, 1H); 0.50 (m, 6H). MS: expected ion=491.4; observed ion=491.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:27])[C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([Cl:28])[C:3]=1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:51]>ClCCl>[Cl:1][C:2]1[C:7]([N:8]([CH3:27])[C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([Cl:28])[C:3]=1[CH2:29][Br:51]
Reactant: BrC(Br)(Br)Br
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CO)c2Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CBr)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
To a mixture of 2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzene (8.10 g) in dichloromethane (81 ml) was added triphenylphosphine (5.66 g) and carbon tetrabromide (8.95 g) at 0° C. After 15 minutes the reaction mixture was stirred at ambient temperature for 3 hours. To the mixture was added triphenylphosphine (1.42 g) and carbon tetrabromide (2.39 g) and stirred for another 2 hours. The reaction mixture was washed with saturated sodium hydrogen carbonate, water and brine. After dried over anhydrous magnesium sulfate, the mixture was filtered and evaporated in vacuo. The residue was purified by flash column chromatography eluting with dichloromethane:ethyl acetate (1:1, V/V) and dichloromethane:methanol (20:1, V/V) followed by crystallizing from ethyl acetate to give 2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyl bromide (6.40 g) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:37]=[CH:36][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][Si](C(C)(C)C)(C)C)[C:22]=4[Cl:35])[CH3:20])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](B(O)O)[CH:39]=1>>[Cl:35][C:22]1[C:23]([OH:27])=[CH:24][CH:25]=[CH:26][C:21]=1[C@H:19]([O:18][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:36]=[CH:37][C:2]([C:40]4[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[S:13][C:12]=1[C:14]([O:16][CH3:17])=[O:15])[CH3:20]
Reactant: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O[C@H](C)c1cccc(O[Si](C)(C)C(C)(C)C)c1Cl
Reactant: OB(O)c1cccnc1
Product: COC(=O)c1sc(-n2cnc3cc(-c4cccnc4)ccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Yield: 52.6 %

Procedure:
Methyl 5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate (Intermediate 8, 500 mg, 0.80 mmol) and pyridine-3-boronic acid (120 mg, 0.96 mmol) were coupled using a procedure analogous to Intermediate 9 to give 213 mg of the title compound (53%). MS m/z=506 [M+H]+.