Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](Cl)(=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:13]([O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)Cl
Reactant: O=C(OCCO)c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)OCCOC(=O)c1ccccc1

Procedure:
2-Benzoyloxyethyl erucate was prepared by the procedure of Example 1 from 16 gms (0.1 mole) of ethylene glycol monobenzoate and 35.5 gms (0.1 mole) of erucoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [Li].[CH3:2][C:3]1([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[O:7][CH2:6][CH2:5][O:4]1.[CH3:14][Li]>O1CCCC1>[CH3:2][C:3]1([CH2:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:14])[O:4][CH2:5][CH2:6][O:7]1
Reactant: CC1(CCCC(=O)O)OCCO1
Reactant: [Li]C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(=O)CCCC1(C)OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
348 Mg. of the lithium salt of the ketal acid, 4-(2-methyl-1,3-dioxolan-2-yl)butanoic acid was dissolved in 5 ml. anhydrous tetrahydrofuran. The solution was cooled to 0° C and 1.25 ml. of a 1.6 molar solution of methyllithium in dicthylether was added dropwise over a period of 1 hour while stirring under a nitrogen atmosphere. The solution was allowed to rise approximately to 20° C and kept at this temperature over a period of 2 hours. The reaction mixture as added to crushed ice and the organic solvents were removed in vacuo. The residue was extracted with ether, the extract was washed with a saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated in vacuo to give crude 5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][O:30][CH2:31]Br>C(Cl)Cl>[CH3:29][O:30][CH2:31][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: COCBr
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice-bath cooled solution containing 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2 -a]imidazole prepared as in Example 16 and 0.5 ml (3.6 mmole) of triethylamine in 10 ml of methylene chloride is added 0.27 ml (3.5 mmole) of bromomethyl methyl ether. The reaction is allowed to warm to room temperature and stirred at room temperature for several hours. Workup and chromatography in a manner analogous to that outlined in example 18 affords the desired titled compound.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][S:25](=[O:32])(=[O:31])[N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:23]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([C:18]3[CH:23]=[C:22]([O:24][S:25](=[O:31])(=[O:32])[N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[CH:21]=[N:20][CH:19]=3)[NH:8]2)=[CH:12][CH:13]=1
Reactant: CCN(CC)S(=O)(=O)Oc1cncc(-c2cc3ccc(Cl)cc3n2C(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)Oc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Reaction time: 1 h

Procedure:
6-Chloro-2-(5-diethylsulfamoyloxy-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester is redissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) is added. After 1 h, saturated aqueous sodium bicarbonate is added and following extraction with dichloromethane, the organic layer is dried over sodium sulfate and concentrated to give diethyl-sulfamic acid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl ester, which is used in the next step without further purification. MS (ESI) m/z 378.1 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:43])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=1)([CH3:7])[CH3:6])[CH3:2].Cl[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]>>[CH2:1]([O:3][C:4](=[O:43])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[CH2:25][CH2:26][N:27]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:36][CH:37]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccc(NS(C)(=O)=O)cc3)c2c1
Reactant: O=C(Cl)OCc1ccccc1
Product: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc(NS(C)(=O)=O)cc3)C(=O)OCc3ccccc3)c2c1
Yield: 72 %

Procedure:
The reaction of 2-(2-(3,5-dimethylphenyl)-3-{2-[4-(4-methanesulfonylaminophenyl)butylamino]ethyl}-1H-indol-5-yl)-2-methylpropionic acid ethyl ester with benzyl chloroformate was carried out according to the procedure of Example 4, Step C, to give the titled compound in 72% yield as a stiff foam; homogeneous by TLC in 95:5 CH2Cl2-MeOH. 500 MHz 1H NMR was complex, owing to the existence of rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e=738 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[S:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:22])=[O:21]
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1
Yield: 73.8 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 5, Step A using methyl 3-aminobenzoate (16 g, 105.9 mmol) in DCM (150 mL) and 2,5-difluorobenzene-1-sulfonyl chloride (24.7 g, 116.5 mmol) the title compound was obtained (25.6 g, 73.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.06-11.13 (br, 1H), 7.42-7.52 (m, 2H), 7.52-7.77 (m, 4H), 7.78-7.80 (m, 1H), 3.88 (s, 3H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([CH:20]=[O:21])[CH2:14]2)([CH3:10])([CH3:9])[CH3:8].CI>CCOCC>[C:7]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]([CH3:1])([CH:20]=[O:21])[CH2:14]2)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)c1ccc2c(c1)CC(C=O)C2
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Product: CC1(C=O)Cc2ccc(C(C)(C)C)cc2C1
Yield: 6.6 %

Procedure:
To a solution of potassium tert-butoxide (Fluka, 0.45 g, 4 mmole) and of 5-tert-butyl-2-indancarbaldehyde (ex. 4; 0.71 g, 3.5 mmole), there was added at room temperature and under N2, methyl iodide (0.56 g, 4 mmole) and reaction was allowed at room temperature, under stirring. The mixture was taken in ether and washed with NH4Cl and brine, dried over Na2SO4 and concentrated (0,9 g). Chromatography on SiO2 (30 g), with toluene as eluting agent, provided 50 mg (purity>99%, yield 7%) of the desired aldehyde.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]2[C:26](=[O:30])[N:27]([CH3:29])[CH3:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:64]([O:68][C:69]([N:71]1[CH:76]2[CH2:77][CH2:78][CH:72]1[CH2:73][NH:74][CH2:75]2)=[O:70])([CH3:67])([CH3:66])[CH3:65]>CN(C=O)C>[C:64]([O:68][C:69]([N:71]1[CH:72]2[CH2:78][CH2:77][CH:76]1[CH2:75][N:74]([C:21]([C:20]1[CH:19]=[N:18][C:17]([NH:16][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([C:26](=[O:30])[N:27]([CH3:29])[CH3:28])[N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:25][CH:24]=1)=[O:22])[CH2:73]2)=[O:70])([CH3:67])([CH3:65])[CH3:66]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a 1 mL DMF solution of 6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (50 mg, 0.122 mmol) was added DIPEA (32 mg, 0.043 mmol) and HBTU (49 mg, 0.129 mmol). After stirring for 15 m at room temperature 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (31.2 mg, 0.147 mmol) was added and the reaction mixture was left to stir at room temperature for 4 h. The reaction was quenched by pouring into brine and extracted with EtOAc. The organic extracts were dried with Na2SO4, filtered and concentrated. The crude product was purified by NP-LC (Analogix, 10% MeOH in EtOAc) to yield 3-[6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (60 mg, 0.10 mmol). MS m/z 603.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@@H:23]([OH:26])[CH2:24][OH:25])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@@H:23]([O:26][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H](CSC[C@@H](O)CO)NC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@H](CSC[C@H](COS(C)(=O)=O)OS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((S)-2,3-dihydroxypropylthio)propanoate (1 eq) was stirred in dry DCM (0.1M) in an ice bath (0° C.) under an atmosphere of N2. Pyridine (8.0 eq) was then carefully added at 0° C. Methanesulfonyl chloride (4.0 eq) and DMAP (0.1 eq) were added with the reaction slowly warming to room temperature, then stirred overnight. The crude reaction mixture was then loaded directly onto a silica column and purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 100% Hex, 0-20% EtOAc/Hex, 20-50% EtOAc/Hex, 100% EtOAc to afford the title compound as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:28][C:29]([NH2:31])=[O:30]>CN(C)C=O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CCl
Reactant: c1ccc(CN2CCNc3ccccc32)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CN1CCN(Cc2ccccc2)c2ccccc21
Temperature: 100 °C
Yield: 97.5 %

Procedure:
A solution of 1 g (4.46 mmol) 1-benzyl-1,2,3,4-tetrahydroquinoxaline in 10 ml of dimethylformamide was treated with 3.14 ml (18.15 mmol) of N-Ethyl-N-isopropylpropan-2-amine, and subsequently 863 mg (9.23 mmol) 2-chloroacetamide was added. The reaction mixture was heated in a microwave system at 100° C. for four hours. The resulting mixture was quenched with water and extracted once with ethylacetate. The aqueous phase was set to pH 10 with sodium hydroxide solution and extracted 3× with ethylacetate. The combined organic extracts were dried with magnesium sulfate, evaporated till dryness and directly purified by column chromatography on silica (eluent: starting with heptane and then up to 100% ethylacetate) to yield 1.224 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[CH:4][CH:3]=1.[NH2:15][C:16]1[S:17][C:18]([C:24]2[C:29]([F:30])=[CH:28][C:27]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:26][C:25]=2[F:35])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22]>>[F:35][C:25]1[CH:26]=[C:27]([C:31]([OH:34])([CH3:33])[CH3:32])[CH:28]=[C:29]([F:30])[C:24]=1[C:18]1[S:17][C:16]([NH:15][C:2]2[CH:3]=[CH:4][C:5]([CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[N:11]3)=[C:6]([CH3:8])[N:7]=2)=[C:20]([C:21]([NH2:23])=[O:22])[CH:19]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1Cn1ccnn1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1Cn1ccnn1

Procedure:
The title compound was synthesized from 6-chloro-2-methyl-3-(1H-1,2,3-triazol-1-ylmethyl)pyridine (83 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (130 mg, 0.42 mmol) according to the general procedure in Example 1.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:23])[CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25]>>[C:24]([C:26]1[CH:31]=[C:30]([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]5([OH:23])[CH2:22][CH2:21][CH2:20]5)[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH:29]=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(C4(O)CCC4)n3)c2n1
Product: N#Cc1cccc(-c2nc(N)nc3c2nnn3Cc2cccc(C3(O)CCC3)n2)c1

Procedure:
Prepared from 7-chloro-3-{6-[1-hydroxy-1-cyclobutyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 3-cyanophenylboronic acid by the method described for Example 7 to give the title compound (0.06 g) as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)(C)C>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: C1CCNCC1
Solvent: CC(C)O
Product: Cc1c(N2CCCCC2)nc2cc(F)cc(F)c2c1Cl
Temperature: 85 °C
Reaction time: 8 h

Procedure:
The 2,4-dichloro-5,7-difluoro-3-methylquinoline (300 mg, 1.21 mmol) was dissolved in isopropanol (3 mL) and piperidine (0.120 mL, 1.21 mmol) was added to the sealed tube. The mixture was heated to 85° C. and stirred overnight. The reaction was then cooled and concentrated to dryness. The residue was then purified by medium pressure chromatography (silica, 0 to 40% DCM:hexane) to give 4-chloro-5,7-difluoro-3-methyl-2-(piperidin-1-yl)quinoline. Mass Spectrum (ESI) m/e=297.1 (M+1).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][NH2:25].O>C(OCC)(=O)C>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:25][CH3:24])=[C:3]([N+:21]([O-:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1[N+](=O)[O-]
Reactant: CN
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1c([N+](=O)[O-])c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 55 °C
Yield: 92.1 %

Procedure:
A mixture of 5-bromo-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-nitro-1H-pyrazole-3-carbonitrile (EP 295118 A1, 50 mg, 0.12 mmol) and methylamine (2M in tetrahydrofuran, 1.0 mmol, 2.0 mmol) was heated at 55° C. for 2.5 h. To the reaction mixture was added water (5 ml), followed by ethyl acetate (5 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the titled compound (42 mg).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4]CC1.[CH3:23][N:24]1C(N)=CC=[N:25]1>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[N:24]([CH3:23])[N:25]=[CH:4][CH:5]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cn1nccc1N
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccnn2C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 1-methyl-1H-pyrazol-5-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 2.09 (s, 3H), 2.27 (s, 3H), 3.38 (s, 3H), 4.42 (s, 2H), 5.98 (s, 1H), 7.14 (d, J=7.5 Hz, 1H), 7.24 (t, J=6.7 Hz, 1H), 7.38 (s, 1H), 7.70 (t, J=7.0 Hz, 1H), 8.43 (d, J=5.2 Hz, 1H); MS (ESI) m/z 310.2 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]([NH2:21])=[O:20].[NH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][C:33](OCC)=O)[CH:30]=2)[NH:25][N:24]=1.[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:33]([CH2:32][C:29]3[CH:30]=[C:31]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[C:23]4[NH2:22])=[N:21][C:19](=[O:20])[C:3]2=[C:4]([CH:16]([CH3:18])[CH3:17])[NH:5]1
Reactant: CCOC(=O)Cc1ccc2[nH]nc(N)c2c1
Reactant: CC(C)c1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc4[nH]nc(N)c4c3)nc(=O)c1-2
Reaction time: 16 h

Procedure:
To a stirred solution of 139 mg (0.40 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 3 mL of absolute ethanol was added 329 mg (1.50 mmol) of ethyl 3-aminoindazol-5-ylacetate followed by 1.13 mL (3.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 16 h at reflux, and the heating mantle was then removed. The reaction was treated with 8 mL of 10% aq. HOAc, poured into water, and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4), concentrated under reduced pressure, and chromatographed on silica gel (gradient elution with 5% to 10% MeOH—CH2Cl2) to give, after removal of solvent, 123 mg (61%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-aminoindazol-5-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one as a white, amorphous solid. Mass spec.: 502.0712 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].FC1C=CC(C=O)=CC=1[C:25]#[N:26]>>[C:25]([C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9])#[N:26]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(C#N)c2)s1

Procedure:
The titled compound was prepared by an identical procedure to N-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) replacing 3,4-difluorobenzaldehyde in this procedure with 2-fluoro-5-formylbenzonitrile.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Yield: 53.3 %

Procedure:
To a solution of (2R)-2-methyl-piperizine (4.5 g, 45 mmol) in ethanol (80 mL) was added 4-fluorobenzyl chloride (5.38 mL, 45.0 mmol) and sodium hydrogen carbonate (11.3 g, 135 mmol). The reaction was refluxed overnight, cooled and concentrated. The remaining residue was diluted with dichloromethane and washed with water. The organic layer was separated and concentrated to give a clear oil. Chromatography on silica gel gave the title compound (5.0 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2)(=O)=O.[C-:20]#[N:21].[Na+]>C(#N)C.C(OCC)(=O)C.[Cu]I.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>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[C:7]([C:20]#[N:21])[CH:8]=[CH:9][CH:10]=2)[N:15]=1
Reactant: [C-]#N
Reactant: Cc1ccc2cccc(OS(=O)(=O)C(F)(F)F)c2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc2cccc(C#N)c2n1
Yield: 98.1 %

Procedure:
To a solution of 2-methylquinolin-8-yl trifluoromethanesulfonate (3.0 g, 10.3 mmol) in acetonitrile (26 mL) was added sodium cyanide (1.0 g, 20.6 mmol). The solution was degassed under nitrogen for 10 minutes, followed by addition of copper (I) iodide (0.20 g, 1.03 mmol) and Pd(PPh3)4 (0.60 g, 0.52 mmol) under nitrogen. The mixture was heated at reflux for 2 hours. After cooling the mixture was diluted with ethyl acetate (50 mL) and filtered through Celite and washed with ethyl acetate (50 mL). The filtrate was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 40 M; 20% ethyl acetate:hexanes) to afford 2-methylquinoline-8-carbonitrile (1.70 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:18].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:18]
Reactant: COc1cccc(C(=O)c2ccc(Br)c(F)c2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(c1cccc(O)c1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
The demethylation procedure described for 2 was employed. To a stirred solution of (4-bromo-3-fluorophenyl)[3-(methyloxy)phenyl]methanone (1.0 g, 2.5 mol) in toluene (50 mL) was slowly added AlCl3 (1.3 g, 9.7 mol) via a powder addition funnel under a nitrogen atmosphere at room temperature. The stirred reaction mixture was heated at reflux for 3 h. The reaction mixture was allowed to cool to room temperature and then poured into 10% aqueous HCl (200 mL). Standard work-up yielded 0.935 g (100%) of the title compound 196 as a tan solid. 1H NMR (300 MHz, CDCl3): δ 7.71 and 7.68 (dd, J1=6.6 Hz, J2=6.6 Hz, 1 H), 7.60 and 7.57 (dd, J1=8.7 Hz, J2=1.5 Hz, 1H), 7.50 and 7.47 (dd, J1=8.1 Hz, J2=1.2 Hz, 1H), 7.41-7.31 (m 3H), 7.15 and 7.13 (dd, J1=7.8 Hz, J2=1.8 Hz, 1H), 5.93 (s, 1H).