Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=3[Cl:21])[C:6]=2[CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][C:12]=3[Cl:21])[C:6]=2[CH:5]=[CH:4][N+:3]=1[O-:30]
Reactant: FC(F)(F)c1ccc(-n2ccc3c(Cl)nccc32)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: [O-][n+]1ccc2c(ccn2-c2ccc(C(F)(F)F)cc2Cl)c1Cl
Reaction time: 2 h
Yield: 29.8 %

Procedure:
4-chloro-1-(2'-chloro-4'-trifluoromethylphenyl)-pyrrolo[3,2-c]pyridine (1.10 g, 33 mmol) and meta-chloroperbenzoic acid (approximately 80-85%, 1.15 g) were stirred together in chloroform (20 ml) at room temperature overnight. A further quantity of meta-chloroperbenzoic acid (1.15 g) was added, and stirring continued for 2 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution. The organic portion was dried over magnesium sulfate, filtered, and the filtrate evaporated in vacuo. The residue was triturated with hexane to give 4-chloro-1-(2'-chloro-4'-trifluoromethylphenyl)-pyrrolo[3,2-c]-pyridine 5-oxide (0.69 g) as a tan solid, m.p. 119°-123° C. (with dec.)
Reaction SMILES: Cl.C([O:6][C:7](=[O:39])[CH2:8][CH2:9][O:10][CH:11]([CH3:38])[CH:12]([O:14][C:15]1[C:16]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:21][C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:13])(C)(C)C>O1CCOCC1>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]2[C:16]3[C:15]([O:14][CH:12]([CH3:13])[CH:11]([CH3:38])[O:10][CH2:9][CH2:8][C:7]([OH:39])=[O:6])=[N:20][CH:19]=[N:18][C:17]=3[O:21][C:22]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)C(C)OCCC(=O)OC(C)(C)C)c23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)C(C)OCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add 4.0 ml 4 N hydrogen chloride in dioxan to 500 mg (0.96 mmol) 3-(2-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-1-methylpropoxy)propionic acid tert.-butyl ester and stir for 16 h at RT. After concentrating the reaction solution by evaporation under vacuum, purify the residue by preparative RP-HPLC (gradient: water/acetonitrile). 249 mg (56% of theor.) of the desired product is obtained as (R,S/S,R) racemate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14]([NH2:16])=[O:15]>O1CCOCC1>[C:13]([C:14]1[O:15][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:16]=1)([CH3:18])([CH3:17])[CH3:12]
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1nc(-c2ccc(F)cc2)co1
Yield: 1254.2 %

Procedure:
Reflux a solution of commercially available 2-bromo-4′-fluoroacetophenone (100.00 g, 460 mmol), 2,2-dimethyl-propionamide (93.06 g, 20 mmol) in 1,4-dioxane (600 mL) for 2 days. Filter precipitate, concentrate filtrate, and purify (silica gel chromatography, eluting with hexanes:EtOAc 60:1) to give the title compound (55 g, 55%).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].CN(/[CH:12]=[N:13]/[C:14]1[C:15]([C:26]([O:28]C)=O)=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[CH:18]=2)C.C(O)(=O)C>O1CCCC1>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][C:22]2[CH:23]=[C:14]3[C:15]([C:26](=[O:28])[C:7]([C:6]#[N:8])=[CH:12][NH:13]3)=[CH:16][C:17]=2[CH:18]=1
Reactant: COC(=O)c1cc2cc(OC)ccc2cc1/N=C/N(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2cc3[nH]cc(C#N)c(=O)c3cc2c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4.75 mL (11.88 mmol) of n-butyllithium (2.5M in hexane) in 4.0 mL of tetrahydrofuran at −78° C. is added dropwise a solution of 0.68 mL (13.1 mmol) of acetonitrile in 6.8 mL of tetrahydrofuran. After completion of addition, the suspension is stirred for 10 minutes. To this is added 1.36 g (4.75 mmol) of methyl 3-{[(E)-(dimethylamino)methylidene]amino}-7-methoxy-2-naphthoate in 32 mL of tetrahydrofuran dropwise. The resulting reaction mixture is stirred at −78° C. for 1 hour, at −5° C. for 1 hour and at room temperature for 15 minutes. The reaction mixture is again cooled to −78° C. and 1.72 g (28.6 mmol) of acetic acid is added dropwise. After addition of the acetic acid, the reaction mixture is allowed to warm to room temperature. The precipitate is collected by filtration and washed sequentially with water, acetonitrile and methanol. After drying in vacuo, this yields 796.9 mg (67%) of 7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a deep yellow solid, mp>260° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[CH2:34]([O:33][C:31]([C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:22]([C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:6][N:7]=1)[CH:23]=[CH:24]2)=[O:32])[CH3:35]
Reactant: CCOC(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CCOC(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate and ethyl 1H-indole-5-carboxylate (0.21 g, 36%); MS: 466.2 (M+1).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[NH2:30][C:31]1[CH:36]=[C:35]([C:37]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=2[OH:44])[CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O.Cl>CS(C)=O.ClCCl.C(OCC)(=O)C>[NH2:30][C:31]1[CH:36]=[C:35]([C:37]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=2[O:44][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([NH:6][C:19]3[S:23][N:22]=[CH:21][N:20]=3)(=[O:8])=[O:9])=[C:11]([F:18])[CH:12]=2)[CH:34]=[CH:33][N:32]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: Nc1cc(-c2cc(Cl)ccc2O)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1cc(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3ncns3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 647, 10 g, 22.45 mmol), 2-(2-aminopyridin-4-yl)-4-chlorophenol (Preparation 258, 5 g, 22.67 mmol) and potassium carbonate (3.72 g, 26.94 mmol) in dimethyl sulfoxide (150 mL) was stirred at room temperature for 2 hours. The reaction was partitioned between ethyl acetate (150 mL) and saturated aqueous sodium chloride solution (150 mL). The organic layer was collected and concentrated in vacuo to afford an orange residue. This was dissolved in dichloromethane (145 mL) and trifluoroacetic acid (8.48 mL) was added. The reaction was stirred at room temperature for 24 hours before concentrating in vacuo to afford a pink residue. This was taken up in ethyl acetate (200 mL) to form a white slurry that was washed with saturated sodium bicarbonate solution (200 mL). Filtration yielded a white solid that was dried in vacuo, slurried in water and hydrochloric acid (1 N aqueous solution, 1.05 eq) and extracted with ethyl acetate. The organic layer was collected and concentrated in vacuo to yield the title compound.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[O:24][N:23]=[C:22]([CH3:25])[C:21]=2[CH3:26])(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(NCC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:7]#[C:8][C:10]2[CH:11]=[CH:12][C:13]([S:16]([NH:19][C:20]3[O:24][N:23]=[C:22]([CH3:25])[C:21]=3[CH3:26])(=[O:17])=[O:18])=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1noc(NS(=O)(=O)c2ccc(I)cc2)c1C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: Cc1noc(NS(=O)(=O)c2ccc(C#Cc3ccccc3)cc2)c1C
Temperature: 25 °C
Yield: 163.7 %

Procedure:
To a mixture of phenylacetylene (34.8 ml, 0.32 mmol) and copper(I) iodide (0.25 mg) in diethylamine (2 ml) stirred at room temperature was added 4-iodo-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide (1 00 mg, 0.26 mmol) and bis(triphenylphosphine) palladium(II) chloride (1.86 mg). The brown mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the brownish residue was extracted into 50 ml of ethyl acetate. The organic extract was washed with 1N HCl (2×20 ml) and brine (25 ml). After drying with magnesium sulfate, the solvent was removed to give a brown crystalline solid which was chromatographed on silica gel with 1.5% methanol in chloroform to give 150 mg (81%) brown solid. Recrystallization from ethyl acetate/hexanes gave a white powder, m.p. 198°-200° C. (dec.).
Reaction SMILES: [Na+].[I-].[C:3]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br)#[N:4].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:35]([O:42][C:43]1[CH:48]=[C:47](I)[CH:46]=[CH:45][C:44]=1[N:50]1[S:54](=[O:56])(=[O:55])[N:53]([CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[C:52](=[O:63])[CH2:51]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.CCOC(C)=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:35]([O:42][C:43]1[CH:48]=[C:47]([CH:46]=[CH:45][C:44]=1[N:50]1[CH2:51][C:52](=[O:63])[N:53]([CH2:57][CH2:58][Si:59]([CH3:60])([CH3:61])[CH3:62])[S:54]1(=[O:55])=[O:56])[CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[C:3]#[N:4])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: N#Cc1ccccc1CBr
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3C#N)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc dust (240 mg, 3.69 mmol) is placed in a flask and heated under vacuum to remove traces of water. DMF (10 mL) is then added under nitrogen atmosphere. Dibromoethane (0.03 mL) is added and the mixture heated until effervescence occurs. The mixture is allowed to cool to RT and chlorotrimethylsilane (0.03 mL) is added. After 30 min, NaI (165 mg, 1.1 mmol) is added followed by 2-cyanobenzyl bromide (216 mg, 1.1 mmol) and the mixture is stirred at RT for 30 min. To this mixture is added tri-o-tolylphosphine (33.5 mg) and Pd2(dba)3 (20.2 mg) followed by the dropwise addition of a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (400 mg, 0.74 mmol) in DMF (10 mL). The reaction mixture is stirred at RT for 18 h and then diluted with EtOAc and filtered through Celite. The filtrate is washed with 0.1N HCl and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by column chromatography using a gradient of 0-10% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: C([O:5][C:6](=[O:34])[C@H:7]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:26])=[CH:17][N:18]=[C:19]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C.[C:35]([C:39]([OH:41])=[O:40])([F:38])([F:37])[F:36]>C(Cl)Cl.C1(C)C=CC=CC=1>[F:36][C:35]([F:38])([F:37])[C:39]([OH:41])=[O:40].[Cl:26][C:16]1[C:15]2[C:20](=[CH:21][C:12]([S:9]([NH:8][C@H:7]([C:6]([OH:34])=[O:5])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:10])=[O:11])=[CH:13][CH:14]=2)[C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@@H](Cc3ccccc3)C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-phenylalanine t-butyl ester (30 mg, 0.060 mmol) was dissolved in CF3CO2H (2.5 mL) and the mixture stirred at room temperature for 2.5 h. The mixture was diluted with CH2Cl2 and PhMe, concentrated in vacuo, azeotroping with PhMe, and the residue triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-phenylalanine trifluoroacetate (24.4 mg, 0.42 mmol) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[NH:4][CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1>>[C:32]([O:31][C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:4]2[C:5]3[C:10](=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)[C:2]([CH3:1])=[CH:3]2)=[CH:18][CH:19]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc2[nH]cc(C)c2c1
Product: COC(=O)c1ccc2c(c1)c(C)cn2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 2, Example 38, using the methyl 3-methyl-1H-indole-5-carboxylate instead of the methyl 1H-indole-5-carboxylate, and the tert-butyl 4′-(bromomethyl)biphenyl-2-carboxylate instead of the 1-bromo-4-(bromomethyl)benzene. ESI-MS (m/z): 456 [M+H]+.
Reaction SMILES: C(OCC1C2C(=CN=C(C([NH:21][OH:22])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.ClC1C=C(F)C=CC=1OCC1C2C=NC(C(OCC)=O)=CC=2N(CC)C=1.[Cl:58][C:59]1[C:60]([OH:83])=[C:61]([CH:79]=[C:80]([F:82])[CH:81]=1)[CH2:62][C:63]1[C:67]2[CH:68]=[N:69][C:70]([C:72](OCC)=[O:73])=[CH:71][C:66]=2[N:65]([CH2:77][CH3:78])[CH:64]=1>>[Cl:58][C:59]1[C:60]([OH:83])=[C:61]([CH:79]=[C:80]([F:82])[CH:81]=1)[CH2:62][C:63]1[C:67]2[CH:68]=[N:69][C:70]([C:72]([NH:21][OH:22])=[O:73])=[CH:71][C:66]=2[N:65]([CH2:77][CH3:78])[CH:64]=1
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CCOC(=O)c1cc2c(cn1)c(Cc1cc(F)cc(Cl)c1O)cn2CC
Agent: CCOC(=O)c1cc2c(cn1)c(COc1ccc(F)cc1Cl)cn2CC
Product: CCn1cc(Cc2cc(F)cc(Cl)c2O)c2cnc(C(=O)NO)cc21

Procedure:
Ethyl 3-(3-chloro-5-fluoro-2-hydroxybenzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate. The title compound can be prepared from ethyl 3-hydroxymethyl-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and 2-chloro-4-fluorophenol using methods similar to that set forth in Example 55. (b) 3-(3-Chloro-5-fluoro-2-hydroxybenzyl)-1-ethyl-N-hydroxy-1H-pyrrolo[3,2-c]pyridine-6-carboxamide. The title compound can be prepared from the mixture of ethyl 3-(2-chloro-4-fluoro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and ethyl 3-(3-chloro-5-fluoro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate in a manner similar to step (e) of Example 11. Purification by HPLC can provide the pure title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:33]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:37]5[CH2:38][CH2:39][N:34]([CH2:32][CH3:33])[CH2:35][CH2:36]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:31])[F:30])[CH:3]=1
Reactant: CCN1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-ethyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-ethyl-piperazine following General Procedure C.
Reaction SMILES: [C@@H:1]1([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[OH:9]>ClCCl>[CH:1](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[O:9]
Reactant: O[C@@H]1CCCCCC[C@@H]1O
Solvent: ClCCl
Product: O=CCCCCCCC=O
Temperature: 25 °C

Procedure:
262 ml of aqueous NaIO4 was added drop wise to a vigorously stirred suspension of 105 g chromatographic grade silica gel in 500 ml dichloromethane whereby a white suspension was formed. To the suspension a solution of 6.1 g cis-1,2-cyclo-octanediol in 100 ml dichloromethane was added. The reaction mixture was stirred over night at room temperature, after which the mixture was filtered whereby the residue was washed 3 times with 100 ml dichloromethane. Finally the filtrate was dried over NaSO4, after which the solvent was removed under reduced pressure.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.C[O:10][C:11]([C:13]1[CH:17]=[C:16]([Br:18])[N:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])O)=O.ClC1C=C(C=CC=1F)N.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O.O(S(C)(=O)=O)S(C)(=O)=O>CCN(CC)CC>[Br:18][C:16]1[N:15]([CH:19]([CH3:21])[CH3:20])[C:14]2[CH:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[F:31])[N:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:8])[CH:5]=3)[C:11](=[O:10])[C:13]=2[CH:17]=1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1F
Reactant: Cc1cc(N)n(C)n1
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: Nc1ccc(F)c(Cl)c1
Solvent: CCN(CC)CC
Product: Cc1cc(N2C(=O)c3cc(Br)n(C(C)C)c3C2c2ccc(Cl)cc2F)n(C)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate D but in the step corresponding to Step D2, 2,5-dimethyl-2H-pyrazol-3-ylamine [3524-32-1] and 5-bromo-2-[(4-chloro-2-fluoro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step BI1) were used instead of 3-chloro-4-fluoroaniline and 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester respectively. Moreover, in this step, the procedure described for Step L3 using Ms2O and Et3N was used. The title compound (containing some of the corresponding 2-chloro analog) was obtained as a solid. ESI-MS: tR=1.14 min, [M+H]+ 465/467/469 (LC-MS 1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]2[CH:28]=[C:27]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:26]([C:37]3[CH:42]=[CH:41][C:40]([CH:43]=O)=[CH:39][CH:38]=3)=[N:25][C:24]=12)=[O:19]>>[CH3:16][O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]2[CH:28]=[C:27]([C:29]3[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=3[F:35])[C:26]([C:37]3[CH:38]=[CH:39][C:40]([CH2:43][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:41][CH:42]=3)=[N:25][C:24]=12)=[O:19]
Reactant: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(C=O)cc3)nc12
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Product: COC(=O)c1cnn2cc(-c3c(F)cccc3F)c(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)nc12

Procedure:
The compound is prepared in analogy to example 27.0. 348.5 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are reacted with 500 mg (1.27 mmol) 6-(2,6-difluorophenyl)-5-(4-formylphenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester. After the usual work-up and purification 254 mg (32.9%) of the title compound are obtained.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl>ClCCl>[CH2:1]([N:4]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCNc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCN(C(=O)OCc1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
Under nitrogen, to a solution of allylphenylamine (3 ml) in dichloromethane (30 ml) were added pyridine (2.1 ml) and benzyl chloroformate (3.5 ml) at 5° C., and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into aqueous 1N hydrogen chloride and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1 to 10:1) to give N-allyl-N-phenylbenzyloxycarbonylamine (5.5 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[CH3:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:27]=1
Reactant: Cc1c[nH]cn1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: Cc1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])cn1
Yield: 43 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (25 mg, 0.0786 mmol) is reacted with 4-methyl-1H-imidazole according to the GPB affording 12.6 mg (43%) of a yellowish powder as a 5 to 1 regioisomer mixture. Rt=2.11 min.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)[CH2:7][CH2:6]1.[BrH:20]>>[BrH:20].[OH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]([OH:19])=[O:2])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CN1CCC(c2cccc(OC)c2)CC1
Agent: Br
Product: O=C(O)CN1CCC(c2cccc(O)c2)CC1

Procedure:
A mixture of [4-(3-methoxy-phenyl)-piperidin-1-yl]-acetic acid methyl ester and HBr (48%, 2 mL) was refluxed for 1 h. The reaction mixture was concentrated in vacuo, azeotroped with toluene twice and washed with ether to give white solid (1.2 g, quantitative yield). MS(ESI) 236.0 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:27]=[C:26]([CH2:28][CH2:29][C:30](O)=[O:31])[O:25][N:24]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:30](=[O:31])[CH2:29][CH2:28][C:26]3[O:25][N:24]=[C:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=4)[N:27]=3)[CH2:14][CH2:15]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](c1ccc(Br)cc1)N1CCC(N)CC1
Reactant: O=C(O)CCc1nc(-c2ccccn2)no1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC(c1ccc(Br)cc1)N1CCC(NC(=O)CCc2nc(-c3ccccn3)no2)CC1
Yield: 5.8 %

Procedure:
Prepared following a method as hereinbefore described using (R)-1-[1-(4-bromophenyl)ethyl]-4-piperidinamine (449 mg), 3-(2-pyridinyl)-1,2,4-oxadiazole-5-propanoic acid (0.31 g), 1-hydroxybenzotriazole (0.20 g), 4-(N,N-dimethylamino)-pyridine (0.13 g) and 1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride (0.30 g) to give the title compound (40 mg). m.p. 153-155° C.