Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([CH3:25])([CH3:24])[C:3](C1C=CC(C23CCC(CC(OC)=O)(CC2)CC3)=CC=1)=[O:4].[C:26]1([C:32]23[CH2:41][CH:36]4[CH2:37][CH:38]([CH2:40][C:34]([CH2:42][C:43]([O:45][CH3:46])=[O:44])([CH2:35]4)[CH2:33]2)[CH2:39]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Br:1][C:2]([CH3:25])([CH3:24])[C:3]([C:29]1[CH:28]=[CH:27][C:26]([C:32]23[CH2:41][CH:36]4[CH2:37][CH:38]([CH2:40][C:34]([CH2:42][C:43]([O:45][CH3:46])=[O:44])([CH2:35]4)[CH2:33]2)[CH2:39]3)=[CH:31][CH:30]=1)=[O:4]
Reactant: COC(=O)CC12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Reactant: COC(=O)CC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Product: COC(=O)CC12CC3CC(C1)CC(c1ccc(C(=O)C(C)(C)Br)cc1)(C3)C2
Yield: 35 %

Procedure:
Prepared according to the procedure described for Intermediate 9 using methyl (3-phenyl-1-adamantyl)acetate, the title compound being isolated in 35% yield: 1H NMR (CDCl3) δ 1.66 (d, 4H), 1.71 (s, 2H), 1.77 (s, 2H), 1.87 (s, 4H), 2.04 (s, 6H), 2.18 (s, 2H), 2.20-2.22 (m, 2H), 3.65 (s, 3H), 7.41 (d, 2H), 8.12 (d, 2H); GC-MS CI m/e MH+ 433.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:9])[C:6]=1[NH:7][NH2:8].N1C=CC=CC=1.[OH2:16].Cl.[CH2:18]([O:20][CH2:21]C)C>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:9])[C:6]=1[NH:7][NH:8][C:18]([O:20][CH3:21])=[O:16]
Reactant: CCOCC
Reactant: Cc1csc(C)c1NN
Reactant: O
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)NNc1c(C)csc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 35.5 g (0.25 mol) 2,4-dimethylthien-3-yl-hydrazine, 27.6 g (0.35 mol) pyridine and 83 ml water are added within 15 minutes at room temperature 23.6 g (0.25 mol) methyl chloroformiate. 83 ml water are further added, and the mixture is stirred for 3 hours at room temperature. After the addition of 300 ml diethylether, the mixture is acidified with 2 N HCl, the organic phase separated, washed with water, dried and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C[C@@H](CCl)CBr
Product: C[C@@H](CCl)COc1ccc(Cl)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-chlorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[N:17]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:21][C:18]1[N:17]=[C:16]([N:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[O:20][N:19]=1
Reactant: Cc1ccc(CNc2nc(C)no2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccc(CN(C(=O)C2CC2)c2nc(C)no2)cc1

Procedure:
Cyclopropane carboxylic acid chloride (3.45 g, 0.033 mole) was added dropwise to a solution of 5-(4-methylphenyl)methylamino-3-methyl-1,2,4-oxadiazole (6.1 g, 0.03 mole) and triethylamine (3.45 g, 0.035 mole) in dry benzene keeping the temperature below 10° C. After the addition the temperature was allowed to reach room temperature and then refluxed overnight. On cooling the reaction mixture was washed twice with 2 N HCl and twice with a saturated solution of NaHCO3 and dried over MgSO4 and charcoaled. The product was purified by column chromatography--silica gel (110 g) eluting with petroleum ether 40°-60° C. increasing polarity to 10% ether in petroleum ether. The title compound was recrystallised from petroleum ether 60°-80° C. as white needles. m.p. 49.5°-50.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=3)[C:11]3[CH:24]([CH3:27])[CH2:25][CH2:26][C:10]=3[N:9]=2)[CH:7]=1.[CH2:29]([N:31](CC)CC)C.CN.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:20]([C:21]([NH:31][CH3:29])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=3)[C:11]3[CH:24]([CH3:27])[CH2:25][CH2:26][C:10]=3[N:9]=2)[CH:7]=1
Reactant: CC1CCc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(=O)O)c21
Reactant: CCN(CC)CC
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1C(C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-nicotinic acid (20 mg, 0.05 mmol, 1 eq) in DMF (2 ml) was added triethylamine (8 μl, 0.05 mmol, 1.1 eq) followed by methylamine (250 μl, 3.89 mmol, 2M solution in THF, 10 eq). To the suspension was added a solution of PyBOP (40 mg, 0.08 mmol, 1.5 eq) in DMF (1 ml) dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the residue was triturated with ether (2×20 ml). The crude residue was purified by flash column chromatography (100% ethylacetate) to afford 4-[2-(5-chloro-2-fluorophenyl)-5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-N-methyl-nicotinamide, 47 (12 mg, 58%) as a white solid.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH2:18][CH2:17][S:16][CH2:15]2)=[O:13])=[CH:5][CH:4]=1.[N:19]#[C:20][NH2:21]>C(O)C>[ClH:1].[NH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH2:18][CH2:17][S:16][CH2:15]2)=[O:13])=[CH:7][CH:8]=1)[C:20]([NH2:21])=[NH:19]
Reactant: N#CN
Reactant: Nc1ccc(CCCC(=O)N2CCSC2)cc1
Agent: Cl
Solvent: CCO
Product: N=C(N)Nc1ccc(CCCC(=O)N2CCSC2)cc1
Temperature: 70 °C
Yield: 64 %

Procedure:
1 mmol of N-[4-(4-aminophenyl)butanoyl]thiazolidine hydrochloride prepared in Example 20 and 1 mmol of cyanamide were dissolved with 5 ml of anhydrous ethanol. The solution was stirred under heating at 70° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a crystalline residue, which was recrystallized from an ethanol-ether mixed solvent to obtain 210 mg of colorless crystals of N-[4-(4-guanidinophenyl)butanoyl]thiazolidine hydrochloride (yield: 64%).
Reaction SMILES: [CH:1](/[CH:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C1(C)C=CC=CC=1.C([O-])(=O)C.[NH2+]1CCCCC1>O>[C:13]([C:15](=[C:9]1[CH2:10][CH2:11][CH:6](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: CCC/C=C/C1CCC(=O)CC1
Reactant: CCOC(=O)CC#N
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC/C=C/C1CCC(=C(C#N)C(=O)OCC)CC1

Procedure:
A mixture of 33.3 g of 4-(1E-pentenyl)cyclohexanone (prepared in accordance with EP-A-168683), 42 ml of ethyl cyanoacetate, 300 ml of toluene and 2.9 g of piperidinium acetate is boiled for 1.5 hours on a water separator. After cooling the reaction mixture is washed with three 50 ml portions of water, dried over sodium sulphate and concentrated. Chromatographic purification of the residue on 750 g of silica gel with hexane/ethyl acetate (vol. 19:1) gives ethyl cyano-[4-(1E-pentenyl)cyclohexylidene]-acetate.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([O:31][C:28]3[CH:29]=[CH:30][C:25]([CH2:24][C:16]4[NH:15][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[N:17]=4)=[CH:26][CH:27]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1cc(-c2cccnc2F)ccn1
Reactant: Oc1ccc(Cc2nc3ccccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Cc1cc(-c2cccnc2Oc2ccc(Cc3nc4ccccc4[nH]3)cc2)ccn1
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-3-(2-methylpyridin-4-yl)pyridine (1.00 g, 5.31 mmol), 4-((1H-benzo[d]imidazol-2-yl)methyl)phenol (1.43 g, 6.38 mmol) and cesium carbonate (2.60 g, 7.97 mmol) was heated to 80° C. for 16 h. After cooling to room temperature, the mixture was diluted with H2O and extracted with 25% i-PrOH/CHCl3 (3×). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (Acetone/Hexanes=0→80%) to give the title compound. MS (ESI, pos. ion) m/z: 393 (M+1). IC50 (uM) ++++.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:16][C:17]#[N:18]>>[N:9]1([CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][N:4]([CH2:16][C:17]#[N:18])[CH2:5][CH2:6]2)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: N#CCBr
Reactant: C1CN(CCN2CCOCC2)CCN1
Product: N#CCN1CCN(CCN2CCOCC2)CC1

Procedure:
The title compound is synthesized by coupling of 4-(2-piperazin-1-yl-ethyl)-morpholine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=239.3; 1HNMR(DMSO-d6) 3.70 (s, 2H), 3.30 (bs, 4H), 2.60-2.30 (m, 16H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-])=O.C(N(CC)CC)C>CN(C=O)C>[NH2:14][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1

Procedure:
1-Boc-piperazine and 4-nitrobenzoyl chloride were allowed to undergo the reaction in DMF in the presence of triethylamine, and then the nitro group was reduced in the sama manner as the catalytic hydrogenation shown in Reference Example 3 to obtain tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate. ESI: 307.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:27][CH2:26][C@:12]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])[N:13]=[C:14]([NH:17]C(=O)C4C=CC=CC=4)[S:15][CH2:16][C@@H:11]3[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].N12CCCN=C1CCCCC2>CO.C(=O)(O)[O-].[Na+]>[NH2:17][C:14]1[S:15][CH2:16][C@@H:11]2[CH2:10][C@H:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[O:27][CH2:26][C@:12]2([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[N:13]=1
Reactant: N#Cc1ccc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(F)cc3F)CO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: N#Cc1ccc([C@H]2C[C@H]3CSC(N)=N[C@@]3(c3ccc(F)cc3F)CO2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
N-[(4aR,6R,8aS)-6-(4-Cyanophenyl)-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C26) (37 mg, 76 μmol, 1 equiv.) was dissolved in methanol (1.9 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.01 mL, 0.06 mmol, 0.8 equiv) was added. The reaction was stirred at 80° C. for 16 hours. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×20 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 50% ethyl acetate in heptane) afforded the product as a white solid. Yield: 27 mg, 91%. LCMS m/z 386.2 [M+H]. 1H NMR (400 MHz, CDCl3) δ 7.64-7.67 (m, 2H), 7.53-7.55 (m, 2H), 7.4 (td, J=9.0, 6.7 Hz, 1H), 6.82-6.95 (m, 2H), 4.73 (dd, J=11.4, 2.2 Hz, 1H), 4.25 (dd, J=11.4, 2.2 Hz, 1H), 4.00 (d, J=11.5 Hz, 1H), 3.11-3.17 (m, 1H), 3.04 (dd, J=12.5, 4.1 Hz, 1H), 2.66 (dd, J=12.5, 2.9 Hz, 1H), 1.95-2.05 (m, 1H), 1.78-1.83 (m, 1H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1.[NH:27]1[CH2:33][CH2:32][CH2:31][CH:30]([OH:34])[CH2:29][CH2:28]1>>[OH:34][CH:30]1[CH2:31][CH2:32][CH2:33][N:27]([CH2:2][CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[C:19]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH:18]=[CH:17][CH:16]=4)=[O:12])[CH2:8][CH2:9]2)[CH2:28][CH2:29]1
Reactant: OC1CCCNCC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCO)CC3)cc12
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to example 150 from 4-isobutoxy-1H-indole-2-carboxylic acid [1-(2-hydroxy-ethyl)piperidin-4-yl]-amide, 190 and azepan-4-ol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3C(=O)C4C(=CC=CC=4)C3=O)=[N:8][C:6]=2[N:7]=1.NN.O>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[N:8][C:6]=2[N:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: NN
Solvent: CO
Solvent: O
Product: NCc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C

Procedure:
To a solution of 2-((5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)methyl)isoindoline-1,3-dione 58 (100 mg, 0.24 mmol) in MeOH (7 mL) was added H2N—NH2.H2O. The reaction was heated at reflux for 1 h. After cooling to room temperature the reaction was quenched with water (10 mL) and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo to afford (5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)methanamine 59.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]1.FC(F)(F)C(O)=O>ClCCl>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N(CCC2CCCNC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a solution of tert-butyl 3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxylate (1.48 g, 3.0 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4 mL) at 0° C. The mixture was stirred at ambient temperature for 2 h and concentrated in vacuo to dryness. The residue was diluted in dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2×30 mL), water (30 mL), and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness to give 3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine (0.72 g, 60%): MS (ES+) m/z 393.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:5]=[N:6][C:7]=1[C:8]#[N:9]>CO.Cl.[C].[Pd]>[NH2:9][CH2:8][C:7]1[N:6]=[CH:5][C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: N#Cc1ncc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ncc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.9 %

Procedure:
In a solution of 0.32 g of 3-(5-chloro-6-cyano-3-pyridyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole in 12 mL of methanol, 0.5 mL of concentrated hydrochloric acid and 0.10 g of 5% palladium carbon were added, and stirred at room temperature under hydrogen atmosphere of normal pressure for 2.5 hours. After the completion of the reaction, the reaction mixture was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 0.30 g of the aimed product as brown resinous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]([O-:16])(=O)[CH3:14].[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.CCCCCO[N:49]=O>C(Cl)(Cl)Cl>[C:13]([N:12]1[C:11]2[C:2](=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=2)[CH:1]=[N:49]1)(=[O:16])[CH3:14]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: CCCCCON=O
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc2c(cnn2C(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
To a stirred mixture of methyl 3-methyl-4-aminobenzoate (5.0 g, 30.0 mmol) and potassium acetate (2.94 g, 30.0 mmol) in chloroform (50 mL) is added acetic anhydride (5.66 mL, 60.0 mmol). The mixture is stirred for 30 min at rt, followed by the addition of 18-crown-6 (1.58 g, 6.0 mmol) and n-amyl nitrite (7.78 g, 66.0 mmol). The mixture is heated to reflux for 16 h, followed by cooling to rt. The mixture is washed sequentially with aqueous sodium bicarbonate solution (2×), water and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel. Elution with hexanes-EtOAc (80:20) gives 3.1 g (47%) of methyl 1-acetyl-1H-indazole-5-carboxylate as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.52-8.50, 8.3, 8.2, 4.0, 2.8.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:5][CH2:4][O:3]1.[NH3:13]>CO>[OH:3][CH2:4][CH2:5][CH:6]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:2]([NH2:13])=[O:1]
Reactant: O=C1OCCC1N1CCCC1=O
Reactant: N
Solvent: CO
Product: NC(=O)C(CCO)N1CCCC1=O
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10.15 g (0.06 mol) of 1-(tetrahydro-2-oxo-3-furyl)-2-pyrrolidinone are dissolved in 100 ml of methanol and the solution is saturated with ammonia, the temperature rising spontaneously to 40° C. The mixture is kept at that temperature for 30 minutes, whereupon it is allowed to return to ambient temperature. The reaction mixture is then evaporated under reduced pressure and the resulting powder is recrystallized from absolute ethanol. 10 g of alpha-(2-hydroxyethyl)-2-oxo-1-pyrrolidineacetamide are obtained. M.P.: 164°-165° C.; yield: 90% of theory.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:15][NH2:16]>CCO>[NH:15]([C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[NH2:16]
Reactant: NN
Reactant: CN(C)S(=O)(=O)c1ccc(Cl)nc1
Solvent: O
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc(NN)nc1
Temperature: 80 °C
Yield: 85.1 %

Procedure:
A mixture of 1.9 g (8.8 mmol) of 6-chloro-N,N-dimethylpyridine-3-sulfonamide and 4.6 mL (91.5 mmol) of hydrazine monohydrate in 10 mL of EtOH is heated for 2 hours at 80° C. The precipitate obtained, after cooling to room temperature, is filtered off and then washed with 10 mL of EtOH and dried under vacuum. 1.62 g of 6-hydrazino-N,N-dimethylpyridine-3-sulfonamide are obtained in the form of a white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:20]1COCC1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH2:13][CH3:20])=[O:11])[CH:3]=[CH:2]1.[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][OH:11])[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCOC(=O)c1cccc2cc[nH]c12
Product: OCc1cccc2cc[nH]c12
Temperature: 25 °C
Yield: 98 %

Procedure:
Ethyl Indole-7-carboxylate was prepared according to literature procedure {Batcho B. and Leimgruber, K., Org. Syn. Vol IIV, page 34-40). To a solution of methyl 7-indolecarboxylate (13 g, 74.2 mmol) in 250 ml of anhydrous THF was added LiAlH4 (10.9 g, 0.288 mol) in portions, and reaction mixture was heated to reflux for 2 h. After cooling to room temperature, the excess hydride was quenched by addition of water (12 mL), 15% NaOH (12 mL) and water (26 mL). The solids were removed by filtration through a pad of Celite and filtrate was evaporated in vacuo to yield (1H-indol-7-yl)-methanol (10.7 g, 98%). 1HNMR (CDCl3). To a solution of the alcohol, (1H-indol-7-yl)-methanol (8.0 g, 54.3 mmol) in 400 mL of methylene chloride was added activated manganese (IV) oxide (85%, 41.0 g, 0.40 mol), and stirred at ambient temperature for 72 h. After additional of 200 mL of methylene chloride and 400 mL of methanol to the reaction mixture, the whole mixture was filtered through a pad of silica gel to remove solid materials. The filtrate was concentrated to afford a crude product, which was purified by a column chromatography on silica gel to yield 1H-indole-7-carbaldehyde, K-87 (6.55 g, 83%). 1HNMR (CDCl3).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([O:13]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3]2.N[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][CH:30]=[CH:29]2.C(=O)([O-])[O-].Cl.C[N:42](C=O)C>C(#N)C>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[CH:4]([CH2:10][C:11]([NH:42][C:35]1[CH:34]=[C:33]3[C:28]([CH:29]=[CH:30][CH:31]=[N:32]3)=[CH:27][CH:26]=1)=[O:13])[CH2:3]2
Reactant: Nc1ccc2ncccc2c1
Reactant: CN(C)C=O
Reactant: O=C(CC1CN2CCC1CC2)Oc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: O=C(CC1CN2CCC1CC2)Nc1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
90.3 mg (0.24 mmol) of pentafluorophenyl (1-azabicyclo[2.2.2]oct-3-yl)acetate hydrochloride are dissolved in 1 ml of DMF, mixed with 51.6 mg (0.36 mmol) of 6-aminoquinoline and stirred at room temperature overnight. 1 g of MP-carbonate (polymer-bound carbonate, capacity: 2.5-3.5 mmol/g; from Argonaut Technologies, USA) is added. After 1 h, the polystyrene resin is filtered off and washed with THF. The combined filtrates are concentrated in vacuo, and the crude product is purified by preparative HPLC. The hydrochloride is prepared by mixing the product with a mixture of 1 M hydrochloric acid and acetonitrile and concentrating again. Drying under high vacuum results in 44 mg (50.2% of theory) of the title compound. HPLC (method 2): Rt=2.8 min.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH:16]=[CH:17][C:18]=1[Cl:19].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:19][C:18]1[CH:17]=[CH:16][C:15]([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[CH:14][C:13]=1[NH:12][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(N)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(NC(=O)c3ccc(C#N)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 173.8 %

Procedure:
4-Cyanobenzoyl chloride (0.25 g) was added to a stirred mixture of N-(3-amino-4-chlorophenyl)-4-cyanobenzamide (0.39 g), triethylamine (0.51 ml), 4-dimethylaminopyridine (0.01 g) and methylene chloride (25 ml). The mixture was stirred at ambient temperature for 18 hours. The mixture was washed with 2M hydrochloric acid solution and with water. The organic phase was dried (MgSO4)and evaporated. The residue was purified by column chromatography on silica gel using a 49:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.1 1 g);