Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) (100 g, 398 mmol) and triethylamine (166 ml, 1.2 mol) are added to toluene (1 L) at room temperature. The mixture is heated to 60° C. Pivaloyl chloride (73.5 ml, 597 mmol) is added over 2 h. After a further 1 h, citric acid solution (237 g in 1 L) is added and the phases are separated. The water phase is washed with toluene (0.5 L). The organic portions are combined, washed with water (0.5 L) and then dried (MgSO4). The mixture is concentrated in vacuo. The residue is suspended in heptane (550 ml) and is heated to reflux. The mixture is then cooled to room temperature. After 1 h, the mixture is cooled to 0° C., and then filtered to give (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1, R1=pivaloyl)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:29][Si:30]([CH3:33])([CH3:32])Cl.[Na+].[I-]>C(#N)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12]([O:21][Si:30]([CH3:33])([CH3:32])[CH3:29])=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(O[Si](C)(C)C)=CC[C@@H]12
Reaction time: 1.5 h

Procedure:
20.3 g (72 mmol) of 3-methoxy-estra-1,3,5(10)-trien-17-one is suspended with exclusion of moisture in 80 ml of acetonitrile (P2O5 and molecular sieve dried) and mixed with 17.4 ml of triethylamine (125 mmol, dried on KOH) as well as with 12.24 ml of trimethylchlorosilane (96 mmol) at an inner temperature of 35° C. Then, an NaI solution, which contains 15 g of NaI (96 mmol) in 100 ml of acetonitrile (NaI dried at 140° C. in a vacuum), is instilled in this suspension, so that the reaction temperature is kept at 35° C. without external heating. The reaction performed under nitrogen is performed with vigorous stirring. It is seen that after the addition has been completed, the amount of undissolved initial product becomes smaller. Later, the crystals completely disappeared. After 1.5 hours, the silyl enol ether begins to crystallize. After 4 hours, the crystal suspension is stirred in ice water, to which some triethylamine was added. Then, it is fritted, rewashed with water, sucked dry and the substance dried on P2O5 in a vacuum. 25.4 g of silyl enol ether, which can be recrystallized from hexane or methanol, is obtained.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH2:4][C:3]21[CH2:15][CH2:14][CH2:13][CH2:12]2.C(N(CC)CC)C.[Cl:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH:30]([F:32])[F:31])[C:25]=1[C:33](Cl)=[O:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH:30]([F:31])[F:32])[C:25]=1[C:33]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][C:3]1([CH2:12][CH2:13][CH2:14][CH2:15]1)[CH:2]2[CH3:1])=[O:34]
Reactant: CC1c2cccc(N)c2CC12CCCC2
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1c2cccc(NC(=O)c3c(C(F)F)nn(C)c3Cl)c2CC12CCCC2
Reaction time: 4 h
Yield: 64 %

Procedure:
In a 25 ml round bottom flask, a solution of 1′-methyl-1′,3′-dihydrospiro[cyclopentane-1,2′-inden]-4′-amine in 5 ml of DCM is cooled to 0° C. and triethylamine (0.104 ml, 0.745 mmol, 1.5 eq) is added followed by DMAP (6 mg, 0.05 mmol, 0.1 eq). A solution of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (125 mg, 0.546 mmol, 1.1 eq) in 1 ml of DCM is added dropwise. Stirring is allowed for 4 h at r.t. The reaction is quenched with 1N aq. HCl, and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc. The organics were combined, washed with NaOH 1N, dried over MgSO4 and concentrated. The crude material was purified by chromatography on silica gel to give pure material (64%)
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[C:15]1([S:21]([N:4]2[C:5]3=[N:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[C:10]3[C:2]([I:1])=[CH:3]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cnc2[nH]cc(I)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a solution of 3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine (15, 4.30 g, 15.7 mmol) in 53.6 mL of N,N-dimethylformamide under nitrogen, sodium hydride (0.690 g, 60% in mineral oil, 17.2 mmol) was added. After 10 minutes, benzenesulfonyl chloride (11, 2.20 mL, 17.2 mmol) was added and the reaction was cooled in a water bath. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate purified by silica gel column chromatography, eluting with 30-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (16, 4.60 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([NH:12][C:13]([C:15]2[O:19][N:18]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=2)=O)[CH:6]=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[N:4]=1>CC(O)=O.[Fe]>[C:20]([C:17]1[CH:16]=[C:15]([C:13]2[NH:9][C:8]3[C:3]([O:2][CH3:1])=[N:4][C:5]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])=[CH:6][C:7]=3[N:12]=2)[O:19][N:18]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1nc(-c2ccccc2C(F)(F)F)cc(NC(=O)c2cc(C(C)(C)C)no2)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1nc(-c2ccccc2C(F)(F)F)cc2nc(-c3cc(C(C)(C)C)no3)[nH]c12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid [2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide (110 mg, 0.237 mmol, prepared as described in STEP C above) in AcOH (5 mL) was treated with iron powder (66.1 mg, 1.18 mmol), and the mixture was heated to 100° C. for 3 h. The AcOH was removed in vacuo. The residue was taken up in saturated aqueous NaHCO3 (50 mL) and extracted twice with EtOAc (50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min). The chromatography was repeated as above to yield 2-(3-tert-butyl-isoxazol-5-yl)-4-methoxy-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]-pyridine as a white solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C21H19N4O2F3: 417.1 (M+H); Measured: 417.1.
Reaction SMILES: CC(C)([O-])C.[Na+].CN(C)C=O.[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.F[C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27]>O>[CH2:12]([O:19][C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Sodium t-butoxide (865 mg, 9 mmol) was added to a N,N-dimethylformamide (5 mL) solution of benzyl alcohol (0.93 mL, 9 mmol), and the mixture was stirred at room temperature for 30 minutes. Thereafter, 5-fluoro-N-methyl-2-nitroaniline (510 mg, 3 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and precipitated crystals were collected by filtration. The resulting crystals were washed with water, and dried at 50° C., thereby obtaining 710 mg of orange, powdery 5-benzyloxy-N-methyl-2-nitroaniline (yield: 92%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.CCOC(C)=O>C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)[N:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Clc1cncc(Cl)n1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Clc1cccc(Oc2cncc(Cl)n2)c1
Yield: 85 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 3-chlorophenol (193 μL, 1.86 mmol, d=1.24 g/mL), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (346 mg). Yield: 85%. 1H NMR (250 MHz, DMSO-d6) δ 7.32 (dd, 1H, Harom 4, Jo=8.2 Hz, Jm=1.9 Hz), 7.43 (d, 1H, Harom 6, J=8.0 Hz), 7.50 (d, 1H, Harom 2, Jm=1.9 Hz), 7.56 (t, 1H, Harom 5, J=8.1 Hz), 8.59 (s, 1H, HPz 5), 8.62 (s, 1H, HPz 3). m/z: 241.1 [(M+H)+, calcd for C10H6Cl2N2O 240.0].
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([S:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][C:31]=2[CH2:32][CH2:33][CH3:34])[CH:28]=[N:27][CH:26]=[CH:25]3)[CH2:17][CH2:16]1)=O)(C)(C)C.[ClH:35]>CC(O)C>[ClH:35].[NH:15]1[CH2:16][CH2:17][CH:18]([S:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][C:31]=2[CH2:32][CH2:33][CH3:34])[CH:28]=[N:27][CH:26]=[CH:25]3)[CH2:19][CH2:20]1
Reactant: CCCc1cc2cnccc2cc1SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc2cnccc2cc1SC1CCNCC1

Procedure:
85 mg (107 mmol) 4-(7-Propyl-isoquinolin-6-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester trifluoroacetate (276) were stirred in 6N HCl in iPrOH for 1 h at RT. After evaporation water was added and lyophilized. 42 mg of 6-(Piperidin-4-ylsulfanyl)-7-propyl-isoquinoline hydrochloride were obtained. Rt=0.94 min (Method B). Detected mass: 287.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=O)=O)[CH:6]=[CH:7][CH:8]=1.[NH:21]([C:25]1[NH:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1)[C:22]([NH2:24])=[NH:23].[OH-].[Na+]>CO.O>[N:29]1[C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[NH:26][C:25]=1[N:21]=[C:22]1[NH:24][C:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:24][C:22](=[N:21][C:25]3[NH:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[N:26]=3)[NH:23][C:11]2([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[NH:23]1
Reactant: COc1cccc(C(=O)C(=O)c2cccc(OC)c2)c1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2cccc(OC)c2)NC(=Nc2nc4ccccc4[nH]2)N3)c1

Procedure:
Following the procedure of Example 1, 3,3'-dimethoxybenzil (1.0 g, 3.69 mmol) and 2-guanidinobenzimidazole (540 mg, 3.08 mmol) in methanol (40 mL) was treated with a solution of sodium hydroxide (200 mg, 5 mmol) in 5 mL of water. The title compound was isolated as pale yellow crystals (655 mg, 73% yield). mp: 276-278 ° C. (dec);MS (ESI) m/z 585 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:31]3[C:32]([O:39][CH3:40])=[N:33][C:34]([S:37][CH3:38])=[N:35][CH:36]=3)=[N:28][C:29]=2[CH3:30])[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.O>[CH3:40][O:39][C:32]1[C:31]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:21]3[CH:22]=[CH:17][N:18]=[C:19]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[CH:20]=3)=[C:29]([CH3:30])[N:28]=2)=[CH:36][N:35]=[C:34]([S:37][CH3:38])[N:33]=1
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(Cl)c2)c(C)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 90 °C
Yield: 98 %

Procedure:
A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.30 g, 1.44 mmol), 5-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-4-methoxy-2-(methylthio)pyrimidine (0.49 g, 1.31 mmol), and K2CO3 (0.54 g, 3.92 mmol) in 5:1 dioxane/water (18 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.15 g, 0.13 mmol), sparged again with Ar and heated at 90° C. for 4 h. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain 4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(methylthio)pyrimidine (0.54 g, 98%). 1H NMR (400 MHz, DMSO-d6): δ 8.93 (s, 1H), 8.39 (d, J=5.7 Hz, 1H), 8.28 (s, 1H), 7.99 (d, J=0.7 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 6.66 (dd, J=5.7, 2.4 Hz, 1H), 4.06 (s, 3H), 3.85 (s, 3H), 2.58 (s, 3H), 2.42 (s, 3H); MS (ESI) m/z: 421.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([OH:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:31][C:32]1[C:37]([F:38])=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][C:33]=1[F:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([O:22][CH2:31][C:32]3[C:33]([F:41])=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[C:37]=3[F:38])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(O)cc(C)cc12)NC(=O)OC(C)(C)C
Reactant: COc1ccc(F)c(CCl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(OC)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 80 mg (0.20 mmol) of rac-(1-{[(7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl)carbonyl]amino}-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 141A and 38 mg (0.20 mmol) of 2-(chloromethyl)-1,3-difluoro-4-methoxybenzene from Example 133A in 2 ml of DMF was admixed with 129 mg (0.396 mmol) of caesium carbonate. The resulting suspension was stirred at RT for 72 h. The reaction mixture was diluted with dichloromethane (15 ml) and extracted with saturated aqueous sodium hydrogencarbonate solution (10 ml). The organic phase was concentrated under reduced pressure, which gave a crude material that contained the target compound in a multicomponent mixture (30% pure). The crude material was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].CCN(CC)CC>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:10]2[N:9]=[C:8]([C:4]3[S:3][C:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])=[N:6][C:5]=3[CH3:7])[CH:13]=[CH:12][N:11]=2)=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NS(C)(=O)=O)sc1-c1ccnc(Nc2ccc(F)cc2)n1

Procedure:
This compound was prepared from [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine by treatment with methylsulfonyl chloride and Et3N in DMF. Gray solid; 1H-NMR (DMSO-d6) δ: 3.31 (s, 3H, CH3), 3.63 (s, 3H, CH3), 7.32 (m, 1H, pyrimidinyl-H), 7.42 (m, 2H, Ph-H), 8.11 (m, 2H, Ph-H), 8.63 (d, 1H, J=5.0 Hz, pyrimidinyl-H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([F:10])[C:5]([F:11])=[C:4](F)[C:3]=1[F:13].[CH3:14][O-:15].[Na+].[Na]>CO>[CH3:14][O:15][C:4]1[C:3]([F:13])=[C:2]([F:1])[C:7]([CH2:8][OH:9])=[C:6]([F:10])[C:5]=1[F:11]
Reactant: C[O-]
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1c(F)c(F)c(CO)c(F)c1F

Procedure:
Pentafluorobenzyl alcohol (1.98 g) was added to a stirred solution of sodium methoxide (obtained by dissolving sodium (0.4 g) in methyl alcohol (10 ml) at the ambient temperature, and the mixture heated at the reflux temperature for 3.5 hours. After cooling the mixture, the solvent was removed by evaporation under reduced pressure and the residue partitioned between water and diethyl ether. After separating the ethereal layer and washing with water, it was dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure to yield 4-methoxy-2,3,5,6-tetrafluorobenzyl alcohol (1.8 g), identical with the product of Example 5.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[CH2:6]1.[N+]([O-])(O)=O.C(Cl)Cl.[NH4+].[OH-]>C(Cl)Cl>[N+:1]([C:11]1[CH:10]=[C:9]([CH:7]2[CH2:8][O:5][CH2:6]2)[CH:14]=[CH:13][C:12]=1[NH:15][C:16](=[O:18])[CH3:17])([O-:4])=[O:2]
Reactant: CC(=O)Nc1ccc(C2COC2)cc1
Reactant: O=[N+]([O-])O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C2COC2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
The organic phase (upper phase) was isolated and the process was repeated with an additional 20 ml CH2Cl2. The organic extracts were combined, it was assumed the organic phase contained about 5 g (−80 mmol) of anhydrous HNO3. Using a 50 fold excess, this required about 25 ml of solution. The nitric acid solution was cooled in a ice bath. The N-(4-oxetan-3-ylphenyl)acetamide (21.0 mg, 0.70 mmol) was treated with 25 ml of the chilled HNO3/CH2Cl2 solution and was allowed to stir about 30 minutes. The reaction mixture was carefully poured into 45 ml 10% NH4OH solution and carefully shaken. The phases were separated and the aqueous phase was washed with 20 ml CH2Cl2. The combined organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:31]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][C:18]=1[F:30])(C(C)(C)C)(C)C.C1COCC1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[F:30][C:18]1[CH:19]=[C:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:14]1[CH:31]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[C:12]([O:11][CH2:10][CH2:9][OH:8])[CH:13]=1
Reactant: CCOC(=O)CCc1ccc(OCc2cc(OCCO[Si](C)(C)C(C)(C)C)cc(Oc3ccccc3)c2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2cc(OCCO)cc(Oc3ccccc3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
Ethyl 3-(4-{[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-5-phenoxybenzyl]oxy}-3-fluorophenyl)propanoate (0.43 g, 0.75 mmol) was dissolved in a solution of tetrabutylammonium fluoride in THF (3 mL, 3.00 mmol), and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=5:5) to give the title compound (0.25 g, yield 74%) as an oily matter.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.[F:16][C:17]([F:36])([F:35])[C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([CH2:33]Cl)[N:29]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>>[F:36][C:17]([F:16])([F:35])[C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([CH2:33][N:6]3[C:7]4[C:3](=[C:2]([Cl:1])[C:10]([C:11]#[N:12])=[CH:9][CH:8]=4)[CH:4]=[C:5]3[CH2:13][CH2:14][CH3:15])[N:29]=2)[CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 2H), 8.50 (s, 1H), 7.96 (s, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 5.87 (s, 2H), 2.97-2.82 (m, 2H), 1.70-1.56 (m, 2H), 0.97-0.89 (m, 3H); MS (ES) m/z 513 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=3)[CH2:8][CH2:9][O:10][C:11]=2[N:12]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30]>>[CH:21]([N:20]1[C:16]([C:14]2[N:15]=[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([N:27]5[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]5)=[N:12][C:11]=4[O:10][CH2:9][CH2:8][N:7]3[CH:13]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Cl)nc1OCC2
Reactant: O=C1CNCCN1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCNC(=O)C3)nc1OCC2

Procedure:
Following the procedures in Example 323, 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine and piperazin-2-one were reacted to give 324. MS: (ESI+)=395.1. 1H NMR (400 MHz, DMSO) δ 8.55 (d, J=8.7 Hz, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 6.70 (d, J=8.8 Hz, 1H), 5.88 (dt, J=13.2, 6.6 Hz, 1H), 4.60-4.40 (m, 4H), 4.06 (s, J=8.0 Hz, 2H), 3.84-3.68 (m, 2H), 1.47 (d, J=6.6 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].F[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].[OH-].[Li+]>CS(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]#[N:12])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: N#Cc1c(N)sc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1c(Nc2ccc(F)cc2[N+](=O)[O-])sc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.2 %

Procedure:
Combine 2-amino-benzo[b]thiophene-3-carbonitrile (3.75 g, 21.5 mmol), 1,4-Difluoro-2-nitro-benzene (2.33 mL, 21.5 mmol), and lithium hydroxide (1.03 g, 43.0 mmol) in anhydrous dimethylsulfoxide (50 mL), and heat at 55° C. for about 5 hours. Cool to ambient temperature, pour into a beaker filled with ice/deionized water (200 mL), and stir for 30 minutes. Isolate the precipitated material by suction filtration, wash the solid with dichloromethane, and dry it under reduced pressure to give the title compound (0.618 g). Add deionized water and ethyl acetate to the filtrate, and then separate the organic layer. Extract the aqueous layer with ethyl acetate many times, and then with dichloromethane many times. Then wash the organics with deionized water (3×). Combine the washes and back extract them with ethyl acetate. Wash the organics with a saturated solution of sodium chloride, and then dry (sodium sulfate), filter, and concentrate the organics under reduced pressure to a dark solid. After triturating with methanol, isolate the resulting solid by suction filtration, wash with methanol, and dry at ambient temperature under reduced pressure to give the title compound (4.422 g). Total solid: 5.04 g (74.8%): Mass spectrum (ES+, m/e): 314 (M+1); NMR (1H, 300 MHz, CDCl3), δ (ppm): 9.96 (s, 1H), 8.06-7.98 (m, 1H), 7.85-7.77 (m, 1H), 7.77-7.69 (m, 1H), 7.68-7.59 (m, 1H), 7.56-7.47 (m, 1H), 7.45-7.34 (m, 2H).