Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7](=[O:15])[C:6]=2[CH:16]=1.[N+:17]([C:20]1[C:25](F)=[CH:24][CH:23]=[CH:22][N:21]=1)([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:25]3[C:20]([N+:17]([O-:19])=[O:18])=[N:21][CH:22]=[CH:23][CH:24]=3)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: O=[N+]([O-])c1ncccc1F
Reactant: CCOC(=O)C1Oc2ccc(Br)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2cccnc2[N+](=O)[O-])Oc2ccc(Br)cc2C1=O
Temperature: 87.5 °C

Procedure:
A mixture of ethyl 5-bromo-3-oxo-2,3-dihydro-1-benzofuran-2-carboxylate (1.42 g, 5.0 mmol), 2-nitro-3-fluoropyridine (0.71 g, 5 mmol) and potassium carbonate (0.83 g, 6.0 mmol) in DMSO (15 mL) is heated at 85-90° C. for 18 h. The mixture is cooled to ambient temperature and partitioned between EtOAc and brine. The layers are separated and the aqueous layer is further extracted with EtOAc. The combined organic extracts are dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient elution with hexanes-EtOAc) to afford the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.C[N:21](C=O)C>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:21])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Product: NC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-naphthoic acid (25 g, 0.145 mol) in MC (200 ml), oxalyl chloride (38 ml, 0.4356 mol) and a catalytic amount of DMF were added and stirred at room temperature for 2 hrs. After the solvent was evaporated, the crude acyl chloride was diluted with MC (200 ml), to which a solution of ammonium hydroxide in water (160 ml) was dropwise added at an ice bath temperature. After stirring for 1 hr, the precipitated product was collected by suction filtration, triturated in hexane and dried to obtain the title compound, which was used next step without further purification.
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][CH2:11][CH:12]([O:15][N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25])[CH2:13][OH:14])([O:6]CC)=[O:5])C.Br[Si](C)(C)C.N>CN(C)C=O>[OH:14][CH2:13][CH:12]([O:15][N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25])[CH2:11][O:10][CH2:9][P:4]([OH:5])([OH:6])=[O:3]
Reactant: CCOP(=O)(COCC(CO)On1cnc2c(N)ncnc21)OCC
Agent: C[Si](C)(C)Br
Agent: N
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2OC(CO)COCP(=O)(O)O
Temperature: 20 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
A solution of 9-(1-diethoxyphosphorylmethoxy-3-hydroxyprop-2-oxy)adenine (100 mg, 0.27 mmol) in N,N-dimethylformamide (5 ml) was treated with bromotrimethylsilane (0.36 ml, 2.7 mmol) and stirred for 16 hours at 20° C. After this time, t.l.c. (isopropyl alcohol-water-0.88 ammonia, 60:30:10) showed some monoester still present. More bromotrimethylsilane (0.18 ml, 1.35 mmol) was added and the reaction mixture stirred at 20° C. for 2 hours. The solvent was evaporated and the residual brown oil chromatographed on reverse-phase silica, eluting with water, affording 9-(1-hydroxy-3-phosphonomethoxyprop-2-oxy)adenine (65 mg, 76%) as a white solid; m.p. 222°-225° C.; λmax (H2O) 259(ε12,600)nm; νmax (KBr) 3420, 1700, 1650, 1620, 1120, and 1060 cm-1 ; δH [(CD3)2SO] 2.7-4.2(3H, v.br.s, D2O exchangeable, 3 ×OH), 3.64(2H, dJ8.5 Hz, CH2P), 3.67(2H, d, J4.9 Hz, CH2OH), 3.81(2H, d, J4.9 Hz,CH2OCH2P), 4.47(1H, m, CHON), 7.43(2H, br.s, D2O exchangeable, NH2), 8.16(1H, s, H 2/H-8), 8.35(1H, s, H-2/H-8); m/z(FAB+veIon) 320(M+, 100%), 342(MNa+, 24%); Found: C,31 77; H,4.67; N.20.83%; C9H14N5O6P.1.0H2O requires C,32.05; H,4.78; N,20.77%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:29]=[C:30]([CH:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([OH:45])[CH:41]=3)[O:36]2)[CH:31]=[C:32]([F:34])[CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([CH:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:45][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:41]=3)[O:36]2)[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: Oc1ccc2c(c1)CCC(c1cc(F)cc(F)c1)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cc(F)cc(F)c2)O3)nc1

Procedure:
2-[2-(3,5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 340 mg of 2-(3,5-difluorophenyl)chroman-6-ol. The product was purified on preparative TLC-plate covered with silica gel using toluene-ethyl acetate as an eluant and then crystallised from 2-propanol. 1H NMR (400 MHz, d6-DMSO) δ:9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.23-7.19 (m, 4H), 7.01-6.95 (m, 3H), 5.18 (dd, 1H, J 10.0, 2.1 Hz), 2.97 (ddd, 1H, J −16.9, 10.9, 5.7 Hz), 2.76 (ddd, 1H, J −16.9, 8.4, 4.7 Hz), 2.22 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.CC(C)=O.[CH3:11][NH:12][CH3:13]>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH3:13])[C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: CNC
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC(=O)CC(=O)N(C)C

Procedure:
A solution of 9 ml (0.05 mmol) of diketene-acetone adduct in 20 ml of toluene was treated with gaseous dimethylamine at room temperature until the reaction was complete. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (EtOAc/MeOH 0%→10%) yielding 7.0 g of the title compound.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC.N1C2C(=CC=CC=2)C=CC=1>>[C:17]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2)(=[O:19])[CH3:18]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CCc2ccccc2N1
Solvent: c1ccc2ncccc2c1
Product: CC(=O)c1ccc2c(c1)CCC(=O)N2

Procedure:
The 3,4-dihydro-1H-quinolin-2-one derivative of Formula 5 is reacted with tributyl(1-ethoxyvinyl)tin to introduce an acetyl group into the 6 position of the quinoline nucleus and to provide a 6-acetyl-3,4-dihydro-1H-quinolin-2-one derivative of Formula 6. The R3 group (R3 is as defined in connection with Formula 1) is introduced into the molecule by treatment of the compound of Formula 6 with a reagent of the formula R3—I and a strong base, such as sodium hydride in a polar aprotic solvent, such as dimnethylformamide (DMF). Instead of the iodo derivative R3—I, other alkylating agents of the formula R3—X1 (where X1 is a leaving group) could also be used in this reaction to provide a 6-acetyl-1-alkyl (or 1-phenylalkyl) 3,4-dihydro-1H-quinolin-2-one derivative of Formula 7. The 6-acetyl-1-alkyl (or 1-phenylalkyl) 3,4-dihydro-1H-quinolin-2-one derivative of Formula 7 is reacted with a bromophenyl or bromo heteroaryl aldehyde of Formula 8 to give the 1-alkyl-6-[3-(bromo phenyl or bromo-heteroaryl)-acryloyl]-3,4-dihydro-1H-quinolin-2-one of Formula 9. The bromo compound of Formula 9 is reacted with carbon monoxide in the presence of 1,3-bis(diphenylphosphino)propane (DPPP), palladium acetate (Pd(OAc)2), triethylamine (TEA) in dimethylformamide and ethanol and thereafter with base (such as NaOH or KOH) to provide [3-(1-alkyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3-oxo-propenyl]-benzoic or heteroaryl carboxylic acids of Formula 10.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:15]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[O:30]1[CH2:35][CH2:34][N:33]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:32][CH2:31]1>>[CH3:16][C:15]1[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:13]=[CH:12][C:11]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([N:39]2[CH2:40][CH2:41][CH:36]([N:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)[CH2:37][CH2:38]2)=[C:3]([N+:27]([O-:29])=[O:28])[CH:4]=1)=[O:10]
Reactant: Cc1c(C(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)cnn1-c1ccc(C(F)(F)F)cc1
Reactant: C1CC(N2CCOCC2)CCN1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c([N+](=O)[O-])c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 9.1 %

Procedure:
The reaction and treatment in the same manner as in Example 162 using N-(4-chloro-3-nitrophenyl)-5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxamide (1.0 g) and 4-morpholinopiperidine (1.4 g), the title compound (0.12 g) was obtained, melting point: 225–230° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]=[C:6]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:21]=1.[CH3:34][S:35]([Cl:38])(=[O:37])=[O:36].C(N(CC)CC)C>C1COCC1>[ClH:38].[CH:28]1([CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([NH:2][S:35]([CH3:34])(=[O:37])=[O:36])[CH:4]=4)[N:9]=[C:8]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:7]=3)=[CH:25][CH:24]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2nc(-c3ccccc3)cc(Nc3ccc(OCC4CCCCC4)cc3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc2nc(-c3ccccc3)cc(Nc3ccc(OCC4CCCCC4)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a suspension of 6-amino-4-(p-cyclohexylmethoxyanilino) -2-phenylquinoline hydrochloride (0.21 g, 0.5 mmol) in anhydrous THF (10 ml) at 0° C. was added methanesulfonyl chloride (69 mg, 0.6 mmol) followed by addition of triethylamine (61 mg, 0.6 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The solvent was removed by rotary evaporation and the residue partitioned between ethyl acetate (EtOAc) and 1M hydrochloric acid. The layers were separated, the organic layer was washed with saturated sodium bicarbonate and dried (Na2SO4) and the solvent was removed by rotary evaporation. The crude material was dissolved in warm methanol and treated with 1M HCl in ether. After 2 hours at room temperature, the solvent was removed by rotary evaporation and the residue recrystallized from methanol/ether to give 4-(p-cyclohexylmethoxyanilino)-6-methylsulfonamido-2-phenylquinoline hydrochloride (38%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:18]([NH:20][NH2:21])=[O:19])=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.O.C1C[O:39][CH2:38]C1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:18]1[O:19][C:38](=[O:39])[NH:21][N:20]=1)=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C1CCOC1
Reactant: NNC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1[nH]nc(-c2c(N3CCCCC3)nc3ccc(Cl)cc3c2-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-4-phenyl-2-piperidin-1-yl-quinoline-3-carboxylic acid hydrazide (30 mg, 70.9 μmol, Eq: 1.00) and N,N′-carbonyldiimidazole (13.8 mg, 85.1 μmol, Eq: 1.2) were dissolved in THF (1 ml). Then triethylamine (10.0 mg, 13.8 μL, 99.2 μmol, Eq: 1.4) was added and the reaction mixture was stirred for 2 h at RT. Water was added and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, DCM/EtOAc 97:3) to afford the title compound as yellow solid (25 mg). MS (ESI): 407.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C@H:5]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:4](=O)[O:3]1.[NH2:20][OH:21]>C(OCC)(=O)C>[OH:21][N:20]1[C:2](=[O:1])[C@@H:6]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C@H:5]([O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:4]1=[O:3]
Reactant: NO
Reactant: CC(C)C(=O)O[C@@H]1C(=O)OC(=O)[C@H]1OC(=O)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)C(=O)O[C@@H]1C(=O)N(O)C(=O)[C@H]1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of compound (2a) (5.98 g, 22 mmol) in ethyl acetate (50 mL) at 0° C. was added a 50% aqueous solution of hydroxylamine (1.75 g, 26.4 mmol). The resulting mixture was stirred at room temperature for 3 h and washed successively with aqueous citric acid solution and brine, then dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the residue was suspended in toluene and the reaction mixture heated under reflux for 5 h, with the azeotropically liberated water being collected in a Dean-Stark apparatus. Toluene was removed in vacuo to afford the title compound (2b) (6.3 g, quantitative yield). 1H-NMR (400 MHz, CDCl3): δ 1.22 (d, J=6.8 Hz, 12H), 2.69 (hept, J=6.8 Hz, 2H), 5.48 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[NH2:14][CH2:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18].CCN(CC)CC>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:14]([CH2:15][CH2:16][C:17]([OH:19])([CH3:20])[CH3:18])[CH2:12]2
Reactant: CC(C)(O)CCN
Reactant: COC(=O)c1ccc(Br)cc1CBr
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(O)CCN1Cc2cc(Br)ccc2C1=O
Temperature: 85 °C

Procedure:
To methyl 4-bromo-2-(bromomethyl)benzoate (0.220 g, 0.714 mmol) suspended in MeOH (6.0 mL) were added 4-amino-2-methylbutan-2-ol (0.077 g, 0.750 mmol) and Et3N (0.156 mL, 1.107 mmol). The mixture was heated to reflux (85° C.) for 24 hours, then cooled to RT, and concentrated in vacuo to give the title compound, which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[CH3:13][O:14][C:15]([CH:17]1[N:22]([C:23](=[O:37])[CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][C:20]2[N:38](CC(=O)C3C=CC=CC=3)[CH2:39][NH:40][C:19]=2[CH2:18]1)=[O:16].C(#N)C>CCOCC>[CH3:13][O:14][C:15]([CH:17]1[N:22]([C:23](=[O:37])[CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:21][C:20]2[N:38]=[CH:39][N:40]([CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=3)[C:19]=2[CH2:18]1)=[O:16]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: COC(=O)C1CC2=C(CN1C(=O)C(c1ccccc1)c1ccccc1)N(CC(=O)c1ccccc1)CN2
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)C1Cc2c(ncn2Cc2cccc(C(F)(F)F)c2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
A solution of 1.4 g 3-trifluoromethylbenzyl chloride, 3.0 g methyl-5-diphenylacetyl-3-(2-oxo-2-phenylethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate and 20 mL acetonitrile is heated at reflux 16 hr. An additional 1.4 mL 3-trifluoromethylbenzyl chloride is added and refluxing continued 24 hr. The cooled solution is added dropwise to 400 mL vigorously stirred ether and the resulting precipitate is collected by filtration. This precipitate is dissolved in 60 mL methanol and treated with 10 g zinc dust and 60 mL acetic acid. The resulting suspension is sonicated 2 hr then the solution is filtered from excess zinc. The filtrate is dissolved in 400 mL dichloromethane and treated dropwise with 520 mL 10% Na2CO3 with vigorous stirring. The organic phase is separated, dried, concentrated and the major product is isolated by chromatography on silica gel (chloroform-methanol, 99.5:0.5) as a crisp foam. NMR (CDCl3) 5.05 (s, 2H, NCH2Ar).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1.Cl.N[C@H:24]1[CH2:28]CN(S(C2C3C(Br)=CN=CC=3C=CC=2)(=O)=O)[CH2:25]1>>[CH2:28]([NH:2][CH:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1)[CH:24]=[CH2:25]
Reactant: N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: Cl
Product: C=CCNC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1

Procedure:
3-Amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine hydrochloride can be used in the method of Example 5-1 instead of (S)-3-amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine hydrochloride to obtain the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][NH:25][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCN)cc3)no2)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCNS(C)(=O)=O)cc3)no2)cc1C
Yield: 24.8 %

Procedure:
The title compound (3 mg) is prepared in analogy to Example 155 starting from 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethylamine (10 mg, 27 μmol) and methanesulfonyl chloride (4 mg, 35 μmol); LC-MS: tR=0.78 min; [M+1]+=448.99; 1H NMR (CDCl3): δ 1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.64 (q, J=7.3 Hz, 4H), 2.89 (s, 3H), 2.96-3.01 (m, 2H), 3.49 (q, J=6.8 Hz, 2H), 3.73 (s, 2H), 4.23 (t br, J=6.3 Hz, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.67 (s, 1H), 8.13 (d, J=8.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C@H:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:31]=[C:30](O)[CH:29]=[CH:28][C:25]=1[CH:26]=[O:27]>>[Cl:23][C:24]1[CH:31]=[C:30]([O:20][C@H:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=3)[N:14]=2)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:29]=[CH:28][C:25]=1[CH:26]=[O:27]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: CCCC[C@@H](O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Product: CCCC[C@H](Oc1ccc(C=O)c(Cl)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 35 %

Procedure:
Prepared according to the procedure used to prepare Intermediate 103 starting from (1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (202 mg, 0.65 mmol) and 2-chloro-4-hydroxybenzaldehyde (140, 0.89 mmol) to afford the title compound (102 mg).
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6][CH:5]1C(OCC)=O>O.C(O)C>[O:3]=[C:4]1[CH2:5][CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:9][CH2:10]1
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CCCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of potassium hydroxide (24.6 g, 375 mmol) in H2O (400 ml) was added to a solution of 1-benzyl 4-ethyl 5-oxo-1,4-azepanedicarboxylate (40.0 g, 125 mmol) in ethanol (400 ml). The resulting mixture was heated at reflux for 2.5 hours. Reaction was then cooled to rt., the ethanol was removed under reduced pressure, and was diluted with 200 ml brine and 300 ml ethyl acetate. The layers were separated, and the aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to an orange oil in vacuo. The product was isolated by flash chromatography (silica gel, 40% EtOAc/hexane) yielding a clear, colorless oil (22.6 g, 73%). 1H NMR(CDCl3) δ 7.31-7.30, 5.12, 3.65-3.63, 2.68-2.60, 1.81-1.78; IR (liq.) 1698, 1475, 1454, 1442, 1423, 1331, 1320, 1295, 1270, 1241, 1191, 1165, 1091, 900, 699 cm−1.
Reaction SMILES: [CH:1]([C:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].[C@H:19]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>CS(C)=O.ClCCl>[C@H:19]1([NH:28][C:11]2[N:10]=[C:9]([C:8]3[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][NH:6][CH:7]=3)[CH:14]=[CH:13][N:12]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: CC(C)c1n[nH]cc1-c1ccnc(S(C)(=O)=O)n1
Reactant: N[C@@H]1CCc2ccccc21
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)c1n[nH]cc1-c1ccnc(N[C@@H]2CCc3ccccc32)n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of 4-(3-isopropyl-1H-pyrazol-4-yl)-2-methanesulfonyl-pyrimidine (40 mg, 0.15 mmol) in anhydrous DMSO (0.25 mL) is added (R)-indan-1-ylamine (58 uL, 0.45 mmol). The reaction mixture is stirred at 150° C. overnight, diluted with dichloromethane, and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC to provide 20 mg of (R)-indan-1-yl-[4-(3-isopropyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine. (Example 83).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([CH3:11])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)cc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1cc(Br)cc2c1cnn2C1CCCCO1
Temperature: 70 °C
Yield: 57.7 %

Procedure:
6-Bromo-4-methyl-1H-indazole (1.0 g, 4.7 mmol, J&W PharmLab) and p-TSA (0.082 g, 0.47 mmol) were dissolved in THF (20 mL). 3,4-Dihydro-2H-pyran (1.99 g, 23.7 mmol) was added and the mixture was heated at about 70° C. for about 6 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (5:1 hexanes:EtOAc) to give 6-bromo-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.80 g, 41%): LC/MS (Table 2, Method g) Rt=2.28 min; MS m/z: 295, 297 (M+H)1.
Reaction SMILES: [CH3:1]N(C)C=O.[C:6]([C:8]1[CH:9]=[C:10]([NH:20][C:21]([C:23]2[C:24]([CH3:35])=[N:25][N:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH:27]=2)=[O:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:7].[H-].[Na+].CI>O>[C:6]([C:8]1[CH:9]=[C:10]([N:20]([CH3:1])[C:21]([C:23]2[C:24]([CH3:35])=[N:25][N:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH:27]=2)=[O:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:7]
Reactant: CN(C)C=O
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)N(C)c1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To dimethylformamide (5 ml) solution containing N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide (1.5 g) was added sodium hydride (60% content, 0.2 g) under ice-cooling and the mixture was stirred for 1 h. A solution of dimethylformamide (1 ml) containing methyl iodide (0.6 g) was added and the mixture was stirred under ice-cooling for 1 h. The mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:n-hexane=5:1) to give the title compound (0.5 g), melting point: 65–69° C.