Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:17]=1.[CH2:18]([I:21])[CH:19]=[CH2:20]>CN(C=O)C>[I-:21].[CH2:18]([N+:13]1([CH3:16])[CH2:14][CH2:15][N:10]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=3[N:7]=2)[CH2:11][CH2:12]1)[CH:19]=[CH2:20]
Reactant: C=CCI
Reactant: CN1CCN(c2nc3cc(Cl)ccc3o2)CC1
Solvent: CN(C)C=O
Product: C=CC[N+]1(C)CCN(c2nc3cc(Cl)ccc3o2)CC1
Product: [I-]
Temperature: 25 °C

Procedure:
A 30 mg portion of 5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole was dissolved in 5 ml of DMF, and the solution which was stirred at room temperature was mixed with 100 mg of allyl iodide and then stirred for 12 hours. The solvent was evaporated under a reduced pressure, and the thus obtained mixture was purified by an LH-20 gel chromatography (chloroform:methanol=1:1) to obtain the title compound (36 mg) in light yellow color.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([CH3:30])[C:16]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[C:11]3[CH:10]=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:41]>>[ClH:41].[ClH:41].[CH3:30][C:15]1[C:16]([N:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[C:11]2[CH:10]=[N:9][NH:8][C:12]2=[N:13][CH:14]=1
Reactant: ClCCl
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc2[nH]ncc2c1N1CCNCC1
Product: Cl
Yield: 56.7 %

Procedure:
tert-Butyl 4-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (465 mg, 1.06 mmol) in 25% TFA/CH2Cl2 (25 mL) was stirred at room temperature for 2 hours. The solvent was removed, and the gum obtained was evaporated from toluene (3×20 mL; water bath 60° C.). Neat TFA was added to the residue and stirred at reflux for 3 hours. Next, TFA was removed under reduced pressure, and the resulting residue was evaporated form CH2Cl2 (2×10 mL). The residue was resuspended in CH2Cl2 (2 mL), and 2M HCl in diethyl ether (5 mL) was added. The resulting suspension was concentrated in vacuo, and the residue was crystallized from boiling EtOH to provide 5-methyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (175 mg, 0.603 mmol, 56.7% yield) as a powder after drying under high vacuum for 4 hours. LCMS (APCI+) m/z 218.1 (M+H)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=1.[H-].[Na+].C1(NS(C(F)(F)F)(=O)=O)C=CC=CC=1.[CH2:32]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)=[O:36])[CH3:33]>CN(C=O)C.CCOC(C)=O>[CH2:32]([O:34][C:35]([N:37]1[CH2:38][CH2:39][CH:40]([NH:43][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=2)[CH2:41][CH2:42]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: COc1ccc2c(c1)c(O)cc(=O)n2C
Agent: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(Nc2cc(=O)n(C)c3ccc(OC)cc23)CC1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 12 %

Procedure:
To a suspension of 4-Hydroxy-6-methoxy-1-methyl-1H-quinolin-2-one (1.8 g, 10 mmol) in DMF (30 mL) was added sodium hydride (385 mg, 10 mmol, 60% dispersion in mineral oil). After stirring for 5 minutes, N-phenyltrifluoromethanesulfonamide (3.4 g, 10 mmol) was added and the reaction was stirred and monitored by TLC to completion (20 minutes). 4-amino-piperidine-1-carboxylic acid ethyl ester was then added and the reaction mixture was heated at 60° C. over night. The reaction mixture was then diluted up with EtOAc and washed with water, NaHCO3, and brine. The organic portion was dried over MgSO4 and evaporated to afford a residue which was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95:5 v/v) to provide the title compound (445 mg, 12%). 1H NMR (300 MHz, CDCl3) δ 1.27 (2H, t, J=7.11 Hz), 1.22-1.35 (2H, m), 1.40-1.55 (2H, m), 2.10-2.20 (2H, m), 2.90-3.05 (2H, m), 3.50-3.70 (1H, m), 3.64 (3H, s), 3.87 (3H, s), 4.14 (2H, q, J=7.10), 4.50 (1H, br d, J=7.3 Hz), 5.29 (1H, s), 6.95 (1H, d; J=2.31 Hz), 7.17 (1H, dd, J=2.31, 9.03 Hz), 7.30 (1H, d, J=8.94 Hz).
Reaction SMILES: O.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1C1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2OC=C(C(O)=O)N=2)CC1)=O.Br[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:57][CH2:56][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([O:66]CC)=[O:65])=[CH:61][CH:60]=2)[CH2:54][CH2:53]1)=[O:49].FC1C(F)=CC=CC=1B(O)O>>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:53][CH2:54][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([OH:66])=[O:65])=[CH:61][CH:60]=2)[CH2:56][CH2:57]1)=[O:49]
Reactant: O=C(O)c1coc(CN2CCC(CNC(=O)c3n[nH]c4ccc(-c5cccc(F)c5F)cc34)CC2)n1
Reactant: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(Br)cc34)CC2)o1
Agent: OB(O)c1cccc(F)c1F
Solvent: O
Product: O=C(O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(-c5cccc(F)c5F)cc34)CC2)o1
Reaction time: 0.25 h

Procedure:
5-({4-[({[5-(2,3-Difluorophenyl)-1H-indazol-3-yl]carbonyl}amino)methyl]piperidin-1-yl}methyl)furan-2-carboxylic acid 19 was prepared, according to the procedure described for compound 12, from compound 15 and (2,3-difluorophenyl)boronic acid and using the following preparative HPLC parameters for the purification: channel A=CH3CN+0.1% formic acid; channel B=H2O+0.1% formic acid: flow=40 ml/min; gradient=15%-50% of eluent A in 15 minutes. Yield: 32 mg, 11%.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl.O>[Br:23][C:6]1[C:5]([OH:11])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=[C:2]([Br:1])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc(Br)c(C(=O)O)cc1O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)c(C(=O)O)c(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
step 3—To a solution of 120 (1.0 eq, 2.27 mmol, 621 mg) in DCM (10 mL) at RT was added in three portions NBS (2.0 eq, 4.55, 809 mg). The mixture was stirred RT for 30 min. The reaction was diluted with water, the organic layer was separated, dried (MgSO4) and concentrated to afford 767 mg of 2,6-dibromo-4-tert-butyl-3-hydroxybenzoic acid (122) as a light brownish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][NH:24][CH2:25][C:26](OCC)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:31]([Si](C)(C)C)=[C:32]=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11][C@H:10]2[CH2:23][N:24]2[CH2:25][C:26](=[O:27])[NH:31][C:32]2=[O:33])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)CNC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN2CC(=O)NC2=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution (1.9 mL) of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-{[(2-ethoxy-2-oxoethyl)amino]methyl}-1,4-oxazepane-4-carboxylate (180 mg) in THF were added isocyanatotrimethylsilane (0.078 mL) and triethylamine (0.082 mL), and the mixture was stirred at room temperature for 2 hr. Then, isocyanatotrimethylsilane (0.156 ml) and triethylamine (0.164 mL) were added, and the mixture was stirred at 50° C. for 2 hr, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate). The obtained residue was diluted with methanol (1.4 mL), triethylamine (0.080 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (115 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][C:6]1[N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[S:9][CH:10]=1.[O:14]([C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=O)C1C=CC=CC=1.O>C1COCC1>[CH3:3][N:4]([C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:14])[CH2:5][C:6]1[N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[S:9][CH:10]=1
Reactant: CNCc1csc(C(C)C)n1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a stirred slurry of 95% NaH (560 mg, 23.2 mmol) at -10° C. in 20 mL of THF was slowly added N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.76 g, 22.1 mmol) keeping the temperature not more than 0° C. THF (5 mL) was added as a rinse. A solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) dissolved in 20 mL of THF was added slowly keeping the temperature not more than 0° C. THF (5 mL) was added as a rinse. After 4 hours, water (100 mL) was added, and the THF was removed under reduced pressure. The pH was adjusted to 9 with concentrated HCl, and the phenol by-product was removed with methyl tert-butyl ether washes (3×60 mL). The aqueous phase was stirred with 70 mL of toluene and adjusted to pH 3 with 4 N HCl. The aqueous phase was separated and extracted twice more with toluene (2×70 mL). The combined toluene extracts were concentrated under reduced pressure, and the residue was redissolved in toluene and heptane (50 mLs of a 1:1 v/v solution), warmed to 50° C. and allowed to cool to ambient temperature. The product was collected by filtration, washed with heptane and dried under vacuum to afford the title compound as a white powder in 83% yield.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14](O)[CH2:15][OH:16].C(OCC)(OCC)OCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH3:12])[O:16][CH2:15][CH2:14][O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCOCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(OCC)OCC
Product: CC1(CCOCc2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 80.8 %

Procedure:
A mixture of 4-benzyloxy-2-butanone (10 g, 56.1 mmol), ethylene glycol (40 ml, 718 mmol), triethyl orthoformate (9.3 ml, 55.9 mmol) and p-toluenesulfonic acid monohydrate (290 mg, 1.52 mmol) was stirred at room temperature for 13.5 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (40 ml) was added and the mixture was extracted three times with chloroform (50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=1/0 to 4/1 gradient). Desired fractions were concentrated to obtain the title compound (10.08 g, 80.8% yield) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[CH3:10][S:11]SC.Cl.CCOCC>CN(C=O)C.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:11][CH3:10])=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(I)ccc1Br
Reactant: CSSC
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSc1ccc(Br)c(F)c1
Yield: 490.5 %

Procedure:
A stirred suspension of 1-bromo-2-fluoro-4-iodobenzene (100 g, 332 mmol), NiBr2 (7.26 g, 33.2 mmol), 2,2-dipyridyl (5.19 g, 33.2 mmol) and zinc dust (27.2 g, 415 mmol) in DMF (600 mL) was treated with MeS—SMe (15.65 g, 166 mmol), and the mixture was heated in a sand bath set for 80° C. After 10 min (color changes to black and reaction was complete according to HPLC analysis), the mixture was poured onto water. 1N HCl (100 mL) was added along with Et2O (300 mL), and the suspension was filtered through a glass fritted funnel. The zinc plug was further washed with Et2O and the Et2O layer was separated and the aqueous layer was extracted with Et2O (3×). The organic extracts were then dried over Na2SO4 and the solvent evaporated (note that the product is very volatile) to afford 1-bromo-2-fluoro-4-(methylthio)benzene (180 g), which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 7.43-7.38 (m, 1H), 6.97 (dd, 1H, Ja=9.1 Hz, Jb=2.0 Hz), 6.90-6.86 (m, 1H), 2.46 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F-].[K+]>C1COCC1>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2)cc1
Yield: 96 %

Procedure:
Chlorobenzene (56 mg, 0.50 mmol) reacted with phenylboronic acid (92 mg, 0.75 mmol) using 0.5/1.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in THF solvent at 45° C. to give the title compound (74 mg, 96%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](O)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(C)C=CC=CC=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1ccc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a mechanically stirred solution of 1H-Indole-5-carboxylic acid (1-1, 20.01 g, 124 mmol) in THF (500 mL) was added at ambient temperature slowly a solution of 1M-LAH in toluene (186 mL, 186 mmol, 1.5 equiv). The reaction mixture was heated at reflux for 1 hour, quenched with ice, partitioned between ethylacetate and saturated aqueous NaHCO3. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. The crude product solidified upon standing under the reduced pressure. The crude solid was suspended in hexanes (200 mL) and ethyl acetate (10 mL), stirred overnight, collected by filtration and air-dried to afford the desired product as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.24 (br s, 1H), 7.62 (s, 1H), 7.36 (d, 1H, J=8.4 Hz), 7.23 (d, 1H, J=8.4 Hz), 7.20 (s, 1H), 6.54 (s, 1H), 4.75 (s, 2H), 1.68 (s, 1H).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[CH3:16].CN(C)[CH:19]=[O:20]>CCCCC.C1COCC1>[CH3:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH:19]=[O:20])[CH:8]=2)[NH:12][N:11]=1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1n[nH]c2ccc(C=O)cc12
Reaction time: 0.25 h

Procedure:
Tetrahydrofuran (600 ml) was cooled down to −78° C. under argon atmosphere. At this temperature, a 1.7 M solution of tert-butyllithium in n-pentane (200 ml) was added dropwise. After 15 minutes at −78° C., a solution of 22.4 g (106.1 mmol) 5-bromo-3-methyl-1H-indazole in THF (300 ml) was added dropwise at such a rate that the temperature of the solution did not exceed −70° C. The mixture was stirred for 30 minutes before N,N-dimethylformamide (24.5 ml) was added dropwise. After 20 min, the cooling bath was removed, and stirring was continued for 1 h before water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 18.5 g of crude 3-methyl-1H-indazole-5-carbaldehyde, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1.C(O[C:17](=O)[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](=[O:30])N(OC)C)[CH2:21][CH2:20]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C=O)[CH:41]=[CH:42][C:36]=2[O:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[C:8]([C:25]([C@H:22]3[CH2:21][CH2:20][C@H:19]([NH:18][CH2:17][C:40]4[CH:41]=[CH:42][C:36]5[O:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=5[CH:39]=4)[CH2:24][CH2:23]3)=[O:30])[S:9][C:5]=2[CH:4]=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: COc1ccc2ncsc2c1
Product: COc1ccc2nc(C(=O)[C@H]3CC[C@H](NCc4ccc5c(c4)NC(=O)CO5)CC3)sc2c1

Procedure:
The title compound was prepared according to the same protocol as that described for example 1, steps 1.a to 1.c, using 6-methoxy-benzothiazole (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.3 mmol). A yellowish solid (43 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Nc2ccc(F)cc2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4)C3)CC2)cc1
Yield: 40 %

Procedure:
The title compound (D167) (43 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-((4-fluorophenyl)amino)azetidin-1-yl)nicotinic acid (D117) (70 mg, 0.217 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (50 mg, 0.217 mmol).
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[N:10][C:9]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[N:13]=3)=[N:8][C:7]=2O)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH3:35]>C(#N)C>[CH:1]1([C:6]2[N:11]=[N:10][C:9]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[N:13]=3)=[N:8][C:7]=2[NH2:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C1CCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
730 mg (1.870 mmol) of 6-cyclopentyl-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazin-5-ol were admixed with 9 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 50 ml of dry acetonitrile and, with ice-cooling, stirred into 130 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 48 h at RT and for 24 h at 50° C. After cooling, the acetonitrile was removed on a rotary evaporator, the precipitate was filtered off with suction and the filtercake was washed with a little water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 508 mg (70% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[O:19]=[C:20]1[N:24]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])=[CH:27][CH:26]=2)[CH:23]=[CH:22][N:21]1[C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH:49]=[N:48][NH:47][C:46]2=[O:50])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:47]1[C:46](=[O:50])[N:45]([C:42]2[CH:41]=[CH:40][C:39]([N:21]3[CH:22]=[CH:23][N:24]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])=[CH:29][CH:30]=4)[C:20]3=[O:19])=[CH:44][CH:43]=2)[CH:49]=[N:48]1)[CH3:12]
Reactant: O=c1[nH]ncn1-c1ccc(-n2ccn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ncn(-c2ccc(-n3ccn(-c4ccc(OCC(F)(F)C(F)F)cc4)c3=O)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 90 °C
Reaction time: 42 h
Yield: 7.8 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (1.2 g), 4-[4-[2-oxo-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1H,3H-imidazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (2.2 g) and potassium carbonate (powder: 3.5 g) were added to N,N-dimethylformamide (50 ml), and the mixture was heated with stirring at 90° C. for 42 hours. After cooling, the resultant was diluted with ethyl acetate (150 ml) and tetrahydrofuran (50 ml). Ice water (150 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), 1N-hydrochloric acid (100 ml) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (elute:ethyl acetate/acetone=10/1) and crystallized from tetrahydrofuran-diisopropyl ether to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-[2-oxo-3-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-1H,3H-imidazol-1-yl]phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 2; 0.26 g) as a colorless crystalline powder.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH:25]C(C)(C)C)(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.B(Cl)(Cl)Cl.O>C(Cl)Cl>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (0.097 mmol, 42.0 mg, see step (b) above) in CH2Cl2 (10 mL) was added BCl3 (0.5 mL, 1M, 0.5 mmol) under N2 (g). The mixture was stirred for 0.5 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine and dried over MgSO4 and the solvent was removed in vacuo. The crude product was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:14][C:15]1([CH2:19][OH:20])[CH2:18][O:17][CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:14][C:15]1([CH2:19][OH:20])[CH2:18][O:17][CH2:16]1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: OCC1(COc2ccc(C(F)(F)F)cc2Cl)COC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
600 mg of 3-chloro-4-hydroxybenzotrifluoride and 829 mg of 3-bromomethyl-3-oxetanemethanol were dissolved in 20 ml of acetonitrile, and 1.49 g of cesium carbonate were added. The reaction mixture was heated to 110° C. and stirred at this temperature for three hours. 50 ml of water and 50 ml of ethyl acetate were added to the cooled reaction mixture. The organic phase was removed, dried over MgSO4 and then concentrated under reduced pressure. The residue was purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100% n-heptane=>100% ethyl acetate. This gave 990 mg of [3-(2-chloro-4-trifluoromethylphenoxymethyl)oxetan-3-yl]methanol.