Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:46])=[C:4]([C:28]2[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)[CH:32]=2)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3C2CCCCO2)[CH3:9])[CH:7]=1.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[Cl:1][C:2]1[C:3]([CH3:46])=[C:4]([C:28]2[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[CH:32]=2)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1-c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1cnn(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-{4-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]-1H-pyrazol-1-yl}piperidine-1-carboxylate (0.040 g) was dissolved in CH2Cl2 (0.4 mL) and then TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour. After evaporated to dryness, the residue was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C23H28ClN8O (M+H)+: m/z=467.2. found: 467.2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]1([NH:17][CH:18]=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:3]1([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:17]=[CH:18]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=CNc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1I
Product: c1ccc(-n2cnc3ccccc32)cc1
Yield: 72.1 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-Iodo-2-nitrobenzene (124 mg, 0.5 mmol) and N-Phenyl-formamide (73 mg, 0.6 mmol) as starting materials to yield the title compound as a yellow solid (70 mg, 72%). 1H NMR (DMSO) δ 7.28-7.33 (m, 2 H), 7.49 (d, J=7.3 Hz, 1 H), 7.59-7.68 (m, 5 H), 7.79 (d, J=6.9 Hz, 1 H), 8.56 (br s, 1 H); 13C NMR δ 110.6, 119.9, 122.4, 123.6, 123.9, 127.6, 130.0, 133.1, 135.9, 143.8.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][CH:3]=1.Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:20]3[CH:30]=[C:24]4[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]4[C:22](=[O:31])[N:21]=3)=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)cc3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(4-fluorophenoxy)-5-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20]>CN(C)C=O>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CBr)cc1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 82.8 %

Procedure:
Using 0.21 g of 4-isopropylbenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.24 g of 2-(4-isopropylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (35)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[N:22][N:23]3[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[CH:19][CH:18]=2)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[N:22][N:23]3[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(N)nc3)ccc12
Yield: 0.1 %

Procedure:
0.45 g of 2-amino-5-bromopyridine is added to 1.0 g of N-[6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared in Example 56, in 50 cm3 of dioxane, 142 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium, dichloromethane and 646 mg of sodium carbonate in 10 cm3 of water are added to the pale yellow solution, and the mixture is refluxed for 2 hours. The reaction medium is diluted with 50 cm3 of ethyl acetate and 50 cm3 of water, and then filtered through a sinter funnel packed with Celite. The filtrate is separated by settling and the aqueous phase is washed with 2×50 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate gradient mixture (70/30 to 50/50 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) to give 0.53 mg of N-[6-(6-amino-pyrid-3-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of a solid melting at 138° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:16][CH2:17][CH2:18][CH2:19][O:20]N)(=[O:11])=[O:10])#[N:2].[ClH:26].N1C=CC(C(N)=N)=N1>CN(C)C=O>[ClH:26].[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10])#[N:2]
Reactant: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2C#N)c1
Agent: Cl
Agent: N=C(N)c1cc[nH]n1
Solvent: CN(C)C=O
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.6 %

Procedure:
3-[13-(2-Cyanophenylsulfonyloxy)-5-methylphenoxy]propoxy guanidine hydrochloride: To a solution of 3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy] propoxyamine (362 mg, 1.0 mmol), as prepared in the preceding step, in N,N-dimethylformamide (10 mL) was added 1H-pyrazole-carboxamidine hydrochloride (590 mg, 4.0 mmol). The reaction mixture was stirred at ambient temperature for two days. N,N-Dimethylformamide was removed under high vacuum. Acetonitrile (10 mL) was added, the solid was removed by filtration, the filtrate was concentrated in vacuo, and the residue was dried under high vacuum. The residue was partitioned between water (30 mL plus 2 mL brine) and diethyl ether (20 mL). The water solution was extracted with diethyl ether (20 mL), and the combined diethyl ether extracts were extracted with acidic water (pH 5). The combined water solutions were adjusted to pH 8-9 by using 2N NaOH and extracted with ethyl acetate (3×50 mL). The ethyl acetate solution was washed with pH 7 buffer solution (2×30 mL) and brine (30 mL) and dried over Na2SO4. After removing the solvent. 0.6 N HCl methanol (10 mL) was added, and the solution was concentrated to give the title compound as a colorless oil (340 mg, 77%). 1H-NMR (300 MHz, DMSO-d6) δ 8.30 (d, J=7.5 Hz, 1H), 8.09 (t, J=7.5 Hz, 1H), 8.04 (m, 2H), 7.72 (br s, 5H), 6.79 (s, 1H), 6.49 (s, 1H), 6.47 (s, 1H), 3.99 (t, J=6.2 Hz, 2H), 3.90 (t, J=6.3 Hz, 2H), 2.22 (s, 3H), 2.01 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C18H20N4O5S: 405.1 (M+H), 427.1 (M+Na). Found: 405.1, 427.0.
Reaction SMILES: ClC1C(Cl)=CC(NC2C3C(=CC(OCCOCC)=C(N)C=3)N=CN=2)=C(F)C=1.[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][C:32]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][C:43]([O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67]O)=[C:44]([N+:47]([O-])=O)[CH:45]=3)[N:40]=[CH:39][N:38]=2)=[C:31]([F:69])[CH:30]=1>>[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][C:32]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][C:43]([O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH3:67])=[C:44]([NH2:47])[CH:45]=3)[N:40]=[CH:39][N:38]=2)=[C:31]([F:69])[CH:30]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCOCCOCCO
Agent: CCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1N
Product: CCOCCOCCOCCOCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1N

Procedure:
Compound 41c was prepared as described hereinabove for Compound 41a, using Compound 29c as a starting material.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([OH:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.C(OC=C)(=O)C>CCCCCC>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C@@H:10]([OH:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(O)Cc1cccc(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: C=COC(C)=O
Product: C[C@H](O)Cc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 47 %

Procedure:
One gram of 1-(3-trifluoromethylphenyl)-propan-2-ol, (±)-(1), is dissolved in 100 ml of hexane, then is added with 0.5 g of Novozym (lipase from Candida antarctica) and 1 ml of vinyl acetate. The suspension is then incubated at 45° C. in a rotating stirrer (300 rpm). After 1 h, when the reaction mixture contains only two compounds in 1:1 ratio, the reaction is stopped and the solvent is distilled off under vacuum. The resulting residue is subjected to chromatographic separation on silica gel, eluting with ethyl ether/petroleum ether gradient, to yield 0.627 g of (R)-1-(3-trifluoromethylphenyl)-propan-2-ol acetic ester, (−)-(2), (52% yield, 92% ee) and (S)-1-(3-trifluoromethylphenyl)-propan-2-ol, (+)-(1), 0.470 g (47% yield, >98% ee). The (−)-(2) ester is dissolved in 50 ml of hexane containing 1.5 ml of butanol and added with 0.5 g of Novozym. The suspension is then incubated at 45° C. in a rotating stirrer (300 rpm). After 5 h, the reaction is stopped to yield (R)-1-(3-trifluoromethylphenyl)-propan-2-ol, (−)-(1), 0.488 g (94% yield, >98% ee).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH:34]([O:36][Si](C(C)(C)C)(C)C)[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH:34]([OH:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cc(C(C)O)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine*.
Reaction SMILES: Cl[CH:2]([O:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[N-:9]=[N+:10]=[N-:11].[Na+]>C(COC)OC>[N:9]([CH:2]([O:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C(Cl)OC
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C(N=[N+]=[N-])OC
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A mixture of methyl 2-chloro-2-methoxyacetate (13.86 g., 0.1 mole), powdered sodium azide (8.46 g., 0.13 mole) and dry dimethoxyethane (80ml.) is stirred and heated at reflux for 39 hours. After cooling to room temperature, the mixture is filtered to remove salts which are washed with dry ether. Evaporation of the solvents at aspirator pressure leaves a yellow liquid which is distilled to give methyl 2-azido-2-methoxyacetate (10.5 g.) as a water-white liquid (b.p. 75°-77°C./17 mm.).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[OH-].[Na+].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>O.O1CCOCC1.O1CCOCC1>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:6]2[CH2:7][CH2:8][NH:3][CH:4]([C:9]([OH:11])=[O:10])[CH2:5]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CCNC(C(=O)O)C2)cc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a suspension of piperazine-2-carboxylic acid dihydrochlorid (13.95 g, 68.70 mmol) in water/dioxane 1:1 (280 ml) at 0° C., NaOH 5 N (48 ml) was added to achieve complete dissolution. 4-tert-butylbenzenesulfonylchloride (17.586 g, 75.57 mmol) in dioxane (140 ml) was then added dropwise at 2° C. In 1 h. The reaction mixture was stirred overnight at 2° C. and over the week-end at room temperature. Solvents were removed in vacuo and the residue obtained was crystallized in EtOH to give 17.3 g of crude 4-(4-tert-butylphenyl-sulfonyl)piperazine-2-carboxylic acid. This material was dissolved in DCM (340 ml) and triethylamine (23 ml, 158 mmol) followed by di-tert-butyl-dicarboxylate (11.5 g, 52.7 mmol) were added. The mixture was stirred at mom temperature overnight, washed with HCl 1N, and brine. Organic phase was then dried over magnesium sulfate, filtered and concentrated to give 23.5 g of a white solid. This crude was purified by flash chromatography using DCM/MeOH 95:5 then DCM/MeOH/AcOH 90:10:0.1.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:45][C:46]1[C:50]([CH3:51])=[N:49][O:48][N:47]=1>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:42])([F:43])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:45][C:46]3[C:50]([CH3:51])=[N:49][O:48][N:47]=3)[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: Cc1nonc1CBr
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: Cc1nonc1Cn1nc2nc(NC(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole. MS (m/e): 394.4 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccccc2)nc2ccc(F)cc12
Product: Fc1ccc2nc(-c3ccccc3)cc(Cl)c2c1

Procedure:
A mixture of 30.4 g (0.127 mol) of 6-fluoro-2-phenyl-4-quinolinol, and 65 ml of phosphorus oxychloride was stirred and heated under reflux for 2 hr. This mixture was concentrated in vacuo, diluted with methylene chloride, and poured onto ice. The aqueous phase was neutralized with 3N sodium hydroxide. The organic phase was separated, and the aqueous phase extracted with methylene chloride. The organic phases were combined, washed with water and with brine, dried over sodium sulfate, and concentrated in vacuo to leave 34.8 g of residue. This was dissolved in methylene chloride, and the solution filtered through a plug of alumina. Concentration of the filtrate left 23.7 g of 4-chloro-6-fluoro-2-phenylquinoline, mp 96°-99°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][OH:19])[CH:16]=2)[NH:11][N:10]=1.O>CS(C)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[O:19])[CH:16]=2)[NH:11][N:10]=1
Reactant: OCc1ccc2[nH]nc(COC3CCCCO3)c2c1
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc2[nH]nc(COC3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazol-5-yl]-methanol (0.40 g, 1.50 mmol) in DMSO (3 mL), IBX (0.42 g, 1.50 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours under nitrogen. Water (50 mL) was added; the separated solid was filtered, and the solid was washed with ethyl acetate (100 mL). The filtrate was collected and the organic phase was separated, washed with brine (100 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazole-5-carbaldehyde as an off-white solid. Yield: 0.33 g (84%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH3:13])[C:7]=1[C:14]#[N:15])=[O:4].S(=O)(=O)(O)[OH:18]>>[CH3:16][N:2]([CH3:1])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH3:13])[C:7]=1[C:14](=[O:18])[NH2:15])=[O:4]
Reactant: O=S(=O)(O)O
Reactant: CCSc1nsc(NC(=O)N(C)C)c1C#N
Product: CCSc1nsc(NC(=O)N(C)C)c1C(N)=O

Procedure:
A mixture of 4.0 g of 1,1-dimethyl-3-(4-cyano-3-(ethylthio)-5-isothiazolyl)urea in 6 ml of concentrated sulfuric acid was heated at 100° during one hour. The reaction mixture was treated as described in Example XIII to give, after recrystallization from ethanol, 2.8 g of 1,1-dimethyl-3-(4-carbamoyl-3-(ethylthio)-5-isothiazolyl)urea, m.p. 147°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[NH:16][N:17]=[CH:18][CH:19]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:19]=[CH:18][N:17]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:16]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccc(F)cc1
Product: COc1ccc(CCn2ccc(-c3nc(C)c(C(=O)NCc4ccc(F)cc4)s3)n2)cc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)thiazole-5-carboxylic acid 4-fluoro-benzylamide and 1-(2-bromo-ethyl)-4-methoxy-benzene as describe in Example 83 and isolated as a white solid (0.045 g, 38% yield). 1H NMR (400 MHz, CDCl3) δ 7.30-7.35 (m, 2H), 7.14 (d, J=2 Hz, 1H), 7.04 (t, J=8 Hz, 2H), 6.97 (d, J=8 Hz, 2H), 6.80 (d, J=8 Hz, 2H), 6.71 (d, J=2 Hz, 1H), 6.03-6.09 (m, 1H), 4.57 (d, J=4 Hz, 2H), 4.32 (t, J=7 Hz, 2H), 3.77 (s, 3H); 3.12 (t, J=7 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=451.2; Rt=1.49 min; HRMS (M+H)+=451.16.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:4][O:5][C:6]=1[Si](C)(C)C.[NH4+].[OH-]>CCO>[Br:1][C:2]1[C:3]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:4][O:5][CH:6]=1
Reactant: C[Si](C)(C)c1onc(-c2cccnc2)c1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Brc1conc1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
To a solution of EtOH (20 ml) containing compound 63 (4.5 g, 15.4 mmol) were added 5 ml of 25% NH4OH. After the addition, the resulting solution was stirred for 10 minutes at room temperature. The reaction mixture was concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vauo. Purification by flash chromatography (diethyl ether) afforded the title compound (64) as an oil (2.76 g, 82%). (TLC diethyl ether Rf 0.4). 1H-NMR (400 MHz, CDCl3): δ 9.14 (d, J=2 Hz, 1H), 8.76 (dd, J=5 Hz, 2 Hz, 1H), 8.58 (s, 1H), 8.19 (dt, J=8 Hz, 2 Hz, 1H), 7.48-7.43 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH:10]([CH2:23][C:24]([OH:26])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>[Pt].CO.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][C:24](=[O:26])[CH2:23][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1CN(Cc2ccccc2)CCN1c1ccccc1[N+](=O)[O-]
Agent: [Pt]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: O=C1CC2CN(Cc3ccccc3)CCN2c2ccccc2N1
Reaction time: 18 h

Procedure:
Platinum on carbon (5%, 30 mg) was added to a solution of the product of Example 26B (0.67 g, 1.88 mmol) in methanol (100 mL). The reaction flask was evacuated and purged with nitrogen (5 cycles) and then with hydrogen (5 cycles), and the suspension was stirred under hydrogen (1 atm) for 18 hours. The reaction flask was evacuated and purged with nitrogen (5 cycles), and the mixture was filtered through diatomaceous earth with ethyl acetate (50 mL) and methanol (50 mL) rinses. The filtrate was concentrated under vacuum and the residue was dissolved in N,N-dimethylformamide (8 mL). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (720 mg, 1.89 mmol) and diisopropylethylamine (0.395 mL, 2.262 mmol) were added, and the solution was stirred at room temperature for 3 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed successively with 1 N NaOH (50 mL) and brine (40 mL), and then concentrated under vacuum. The residue was purified by flash chromatography (SiO2 eluted with CH2Cl2-CH3OH, 100:0-95:5) to provide the title compound: 1H NMR (300 MHz, CD3OD) δ ppm 1.98 (dd, J=13.4, 1.2 Hz, 1H), 2.27 (dt, J=11.4, 3.1 Hz, 1H), 2.40 (t, J=10.9 Hz, 1H), 2.67 (dd, J=13.2, 7.5 Hz, 1H), 2.82-2.89 (m, 1H), 2.89-2.97 (m, 1H), 3.01-3.09 (m, 1H), 3.22 (dd, J=11.5, 2.7 Hz, 1H), 3.35-3.44 (m, 1H), 3.61 (s, 2H), 6.98 (dd, J=8.1, 1.7 Hz, 1H), 7.03 (td, J=7.3, 1.7 Hz, 1H), 7.10-7.22 (m, 2H), 7.25-7.39 (m, 5H); MS (DCI) m/z 308 (M+H)+.