Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[CH2:13][CH2:14]O)=[CH:3][N:2]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:18][CH2:14][CH2:13]/[CH:12]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=[N:2][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCC/C=C/c1cncc2ccccc12
Solvent: ClC(Cl)Cl
Product: ClCC/C=C/c1cncc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3.3 g of (E)-4-(4-isoquinolinyl)-3-buten-1-ol in 15 mL of dry chloroform was added to a cold solution of 1.8 mL of thionyl chloride in 5 mL of dry chloroform. After 15 minutes, the cooling bath was removed and the reaction was stirred at room temperature for 1 hour and then at reflux for 3 hours. The cooled mixture was washed with NaHCO3 solution and with brine, then was dried (Na2SO4) and evaporated. The residue was purified by chromatography over silica gel (ethyl acetate-toluene; 3:17) to yield 2.2 g of (E)-4-(4-chloro-1-butenyl)isoquinoline as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].O>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][C:28]([NH:27][CH2:25][CH3:26])=[O:29])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CCN=C=O
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)NCC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 55.8 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.5 g, 1.53 mmol) in dichloromethane (10 ml) was stirred with ethyl isocyanate (0.12 ml, 1.53 mmol) at room temperature for two hours. Water was added and the organic phase separated, dried and evaporated to give crude product, which was chromatographed on silica gel, eluting with dichloromethane/methanol (95/5) to give 0.34 g of 6-nitro-2,2-dimethyl-3-(N'-ethylureido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 197° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6]/[CH:7]=[C:8](/[CH3:15])\[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:4][CH3:5])[CH3:2]>O1CCCC1>[CH2:1]([N:3](/[CH:6]=[CH:7]/[C@H:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)C/C=C(/C)CCC=C(C)C
Solvent: C1CCOC1
Product: CCN(/C=C/[C@H](C)CCC=C(C)C)CC
Temperature: 65 °C
Reaction time: 20 h
Yield: 102.2 %

Procedure:
A mixture of 11.37 g (50 mmol) of (Z)-N,N-diethyl-3,7-dimethyl-2,6-octadienylamine, 101.5 mg (0.25 mmol) of bis[η4 -(Z,Z)-1,5-cyclooctadiene]rhodium(I) tetrafluoroborate, 160 mg (0.275 mmol) of (R)-(6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphine) and 25 ml of tetrahydrofuran was heated to 65° C. while stirring for 20 hours. The brownish-red reaction mixture was evaporated and the residue was distilled in a bulb-tube at about 150° C./0.2 mbar, whereby 10.7 g of (1E,3R)-N,N-diethyl-3,7-dimethyl-1,6-octadienylamine were obtained as a light yellowish oil. The distillate was diluted with 20 ml of hexane, treated with 50 ml of 50% acetic acid and the two-phase mixture was stirred vigorously for 1 hour. After working-up in an analogous manner to Example 14 and distillation in a bulb-tube at 140° C./15 mbar there were obtained 7.18 g of (R)-citronellal as a colourless liquid: e.e=98.6%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([O:32]C)=[O:31])[CH:24]=3)[NH:19]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]2[C:27]([CH3:28])([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=3)[NH:19]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1cccc(F)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1NS(=O)(=O)c1cccc(F)c1
Reaction time: 5 h
Yield: 71.1 %

Procedure:
To a stirred solution of methyl 2-(2-(3-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (1.99 g, 4.2 mmol, 1.0 eq.) in tetrahydrofuran/methanol (25 mL/25 mL) was added sodium hydroxide (24 mL, 22.63 mmol, 5.4 eq.). The mixture was heated to reflux and stirred for 5 h. LC-MS indicated that 2005467-032-01 was consumed. The mixture was concentrated and the residue was dissolved in water. The aqueous layer was basified to pH=4 by 1M hydrochloric acid. The precipitation was filtered, washed with water and dried to give 1.357 g of 2-(2-(3-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as off-white solid. yield: 92.7% (for two steps). MS (ESI+APCI) M+1=455.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)#[N:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)[N:21]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([C:22]3[N:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[CH:31][N:30]=2)=[O:19])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)#[N:2]
Reactant: N#Cc1cc(CC(=O)O)ccc1-c1ccnc(F)c1
Reactant: Nc1ccc(-c2cccnn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[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: N#Cc1cc(CC(=O)Nc2ccc(-c3cccnn3)cn2)ccc1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 206-6 (38 mg, 0.15 mmol), was dissolved in DMF (2 mL), 5-(pyridazin-3-yl)pyridin-2-amine (31 mg, 0.18 mmol) and DIEA (131 uL, 0.75 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (86 mg, 0.23 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 214. MS m/z 411.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.14 (s, 1H), 9.23 (dd, 1H), 9.13 (d, 1H), 8.56 (dd, 1H), 8.42 (d, 1H), 8.30 (dd, 1H), 8.23 (d, 1H), 8.02 (d, 1H), 7.86-7.78 (m, 2H), 7.74 (d, 1H), 7.63 (dt, 1H), 7.50 (s, 1H), 3.97 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[C:31]([O:33][CH3:34])=[O:32]>N1C=CC=CC=1>[CH3:34][O:33][C:31]([N:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:21]=[CH:22][C:17]3[N:18]([C:14]([CH:12]([C:11]4[C:2]([F:1])=[C:3]5[C:8](=[CH:9][C:10]=4[F:29])[N:7]=[CH:6][CH:5]=[CH:4]5)[CH3:13])=[CH:15][N:16]=3)[N:19]=2)[CH2:24][CH2:25]1)=[O:32]
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)N1CCN(c2ccc3ncc(C(C)c4c(F)cc5ncccc5c4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(rac)-5,7-Difluoro-6-[1-(6-piperazin-1-yl-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-quinoline (Example 6, 35 mg, 0.089 mmol) was dissolved in pyridine (0.89 mL) and methyl chloroformate (0.010 mL, 0.133 mmol) was added. The RM was stirred at RT for 1.5 h. The mixture was concentrated and the residue was purified by flash chromatography and afforded the title compound as a beige foam (tR 3.70 min (conditions 1), MH+=453).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(NC(C)C)(C)C.[CH3:17][O:18][CH2:19]Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][O:18][CH3:19])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: COCCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COCOc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 4-bromo-3-methylphenol (14 g) and N,N-diisopropylamine (39.1 mL) in dichloromethane (150 mL) was added chloromethyl methyl ether (11.4 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 days. The reaction mixture was poured into a saturated aqueous citric acid solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-bromo-3-methyl-1-(methoxymethoxy)benzene (16.7 g). This material was dissolved in tetrahydrofuran (250 mL). To the solution was added n-butyl lithium (2.64 mol/L n-hexane solution, 32.7 mL) at −78° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added N,N-dimethylformamide (16.6 mL), and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-methyl-4-(methoxymethoxy)benzaldehyde (12.9 g). This material was dissolved in tetrahydrofuran (70 mL)—methanol (10 mL). To the solution was added concentrated hydrochloric acid (6 mL), and the mixture was stirred at 50° C. for 1.5 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) with heating at 60° C. n-Hexane (100 mL) was added to the solution gently, and the mixture was stirred at the same temperature for 10 minutes. The mixture was cooled to room temperature. n-Hexane (170 mL) was added to the mixture, and the resulting mixture was stirred overnight. The precipitated crystals were collected by filtration, and washed with n-hexane and dried under reduced pressure to give the title compound (5.6 g).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[S:3](OC1C(C)(C)[C@H]2[C@](C)(CC=1)[C@@H]1[C@](C)([C@@]3(C)[C@H](CC1)[C@H]1[C@H](C(C)=C)CC[C@]1(NCCN1CCS(=O)(=O)CC1)CC3)CC2)(=[O:5])=[O:4].[CH3:49][C:50]1[CH:51]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:52][CH2:53][C:54](=[O:56])[CH:55]=1>>[CH3:49][C:50]1[CH:51]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:52][CH:53]=[C:54]([O:56][S:3]([C:2]([F:48])([F:47])[F:1])(=[O:5])=[O:4])[CH:55]=1
Reactant: CCOC(=O)C1CCC(=O)C=C1C
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: CCOC(=O)C1CC=C(OS(=O)(=O)C(F)(F)F)C=C1C
Yield: 62.7 %

Procedure:
The title compound was prepared following the procedure described in Method 2 for the preparation of Intermediate 1, Step 6, using ethyl 2-methyl-4-oxocyclohex-2-enecarboxylate as the reactant. (62.7% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.93 (t, J=1.3 Hz, 1H), 4.30-4.09 (m, 2H), 2.83-2.68 (m, 2H), 2.62-2.43 (m, 2H), 2.18 (t, J=1.9 Hz, 3H), 1.37-1.20 (m, 3H). 19F NMR (376 MHz, CHLOROFORM-d) δ −73.63 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4](=[O:16])[C:3]=1[C:17]#[N:18].[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:19][CH2:8][C:6]1[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4](=[O:16])[C:3]([C:17]#[N:18])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(C#N)c(=O)n1-c1ccccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1c(Cl)cc(CBr)n(-c2ccccc2Cl)c1=O
Temperature: 25 °C
Yield: 61.9 %

Procedure:
To a solution of 4-chloro-1-(2-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (1.55 g) in carbon tetrachloride (69.4 mL) were added N-bromosuccinimide (1.19 g) and 2,2′-azobis(isobutyronitrile) (0.0910 g) at room temperature. The reaction mixture was refluxed for 3 hr, and cooled to room temperature. The reaction mixture was diluted with dichloromethane, and the mixture was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.23 g).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)[CH:27]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Reactant: O=Cc1cccc(-c2ccccn2)c1
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with commercially available 3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.52 min.; [M+H]+: 403.81 g/mol.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2=[N:18]O)[CH2:2][CH2:3][CH3:4]>CO.C1COCC1.N.[Ni]>[NH2:18][CH:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=2)[O:12][C:11]([CH3:16])([CH3:17])[CH2:10]1
Reactant: CCCCOc1ccc2c(c1)C(=NO)CC(C)(C)O2
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc2c(c1)C(N)CC(C)(C)O2
Yield: 72.2 %

Procedure:
A solution of 30 g of 6-butoxy-2,2-dimethylchroman-4-one oxime in 500 ml of methanol, 500 ml of THF and 30 ml of ammonia solution was hydrogenated in a shaking duck for 8 h in the presence of Raney nickel. After filtering off the catalyst and concentrating in vacuo, 20.5 g of 4-amino-6-butoxy-2,2-dimethylchroman were obtained.
Reaction SMILES: [C:1]([O:5]C(N1C[C@@H](N(C)C)C[C@H]1CO)=O)(C)(C)C.O[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:23]([O:25][O:5][CH3:1])(=[O:24])[C:22]1[CH:27]=[CH:28][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(C)[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COOC(=O)c1ccccc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
To a stirred solution of cis-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-hydroxymethylpyrrolidine (555 mg, 2.27 mmol), methyl 4-hydroxybenzoate (380 mg, 2.5 mmol), and Ph3P (1.07 g, 4.09 mmol) in THF (10 ml) was added DIAD (826 mg, 4.09 mmol) at 0° C. The reaction mixture was stirred at 70° C. for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1/2, v/v) MeOH—CH2Cl2(5/95, v/v) as eluent to give methyl 4cis-1-tert-butoxycarbonyl diethylamino-(2S)-pyrrolidinyl)methoxy benzoate (260 mg, 30%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.45 (s, 9H), 1.70-1.90 (m, 1H), 2.26 (s, 6H), 2.33 (m, 1H), 2.57 (m, 1H), 3.06 (m, 1H) 3.85-4.23 (m, 4H), 388 (s, 3H), 6.93 (m, 2H), 7.95 (m, 2H).
Reaction SMILES: [N:1]1[C:2](=[O:10])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O>N1CCCCC1.C(O)C>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: COc1ccc(C=O)cc1F
Reactant: O=C1C=c2ccccc2=N1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1F
Temperature: 25 °C

Procedure:
A mixture of 1.33 g of indole-2-one (10 mmol), 1.54 g of 3-fluoro-4-methoxybenzaldehyde (10 mmol) and 3 drops of piperidine are refluxed in 40 ml of ethanol for 5 hours. The desired product precipitates as a yellow crystalline solid during the reaction. After cooling to room temperature, the product is filtered off, washed with ethanol and dried in vacuo. Yield 2.2 g (82%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:30][O:31][CH2:32][C@H:33]([CH3:53])[O:34][C:35]1[CH:36]=[C:37]([OH:52])[CH:38]=[C:39]([C:41]2[NH:42][C:43]([C:46]3[O:47][C@@H:48]([CH3:51])[CH2:49][N:50]=3)=[CH:44][CH:45]=2)[CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[S:8]([C:5]2[CH:4]=[CH:3][C:2]([O:52][C:37]3[CH:38]=[C:39]([C:41]4[NH:42][C:43]([C:46]5[O:47][C@@H:48]([CH3:51])[CH2:49][N:50]=5)=[CH:44][CH:45]=4)[CH:40]=[C:35]([O:34][C@@H:33]([CH3:53])[CH2:32][O:31][CH3:30])[CH:36]=3)=[CH:7][N:6]=2)(=[O:10])=[O:9])=[CH:14][CH:15]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(Cl)cn2)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
5-Chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (288 mg, 0.67 mmol) synthesized in Example (120b) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (220 mg, 0.67 mmol) synthesized in Example (116d) were dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (434 mg, 1.33 mmol) was added, followed by stirring at 100° C. for 1 hour under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0.5%-5%) to afford the desired compound (160 mg, yield 33%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][CH:6]=1.[Na]>C1COCC1.C(O)C>[C:11]([NH:10][C:8]1[S:9][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:6][N:7]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Yield: 102 %

Procedure:
Methyl(2-tritylamino-1,3-thiazole-5-yl)acetate (2 g, 4.8 mmol) in THF (10 ml) and ethanol (10 ml) was reacted with sodium hydroxyde (1N, 7.2 ml, 7.2 mmol) at room temperature for 1.5 hour. The solvent was evaporated, HCl (6N) was added, the solid recovered by filtration to give title compound (1.96 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:60].Cl>>[ClH:1].[ClH:30].[ClH:60].[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)=[CH:18][CH:17]=2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Yield: 77 %

Procedure:
Following general procedure II, 1-(6-chloro-4-(4-((4-methylpiperazin-1-yl)methyl)-phenylamino)-1,5-naphthyridin-3-yl)ethanone (74 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) followed by formation of the dihydrochloride salt to afford the desired product (84 mg, 77%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.33 (s, 1H), 8.45 (d, J=9.1 Hz, 1H), 8.36 (d, J=9.0 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.38 (br s, 2H), 4.45 (s, 2H), 3.55 (br s, 8H), 2.99 (s, 3H), 2.81 (s, 3H); ESI MS m/z 536 [M+H]+; HPLC>99% (AUC), tR=9.57 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.ClC(Cl)C.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([CH:31]=O)[O:29][CH:30]=2)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:34][C:19]([F:18])([F:33])[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[C:28]([CH2:31][NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]4[CH2:10][C@H:9]4[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=3)[O:29][CH:30]=2)=[CH:24][CH:25]=1
Reactant: O=Cc1cc(-c2ccc(C(F)(F)F)cc2)co1
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cc(-c3ccc(C(F)(F)F)cc3)co2)cc1
Reaction time: 7 h
Yield: 111 %

Procedure:
A mixture of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.060 g, 0.339 mmols) and dichloroethane was heated slightly and allowed to cool before addition of 4-[4-(trifluoromethyl)phenyl]-2-furancarbaldehyde (0.075 g, 0.312 mmols). The mixture was stirred for 7 h, followed by addition of sodium triacetoxyborohydride (0.104 g, 0.491 mmols). After 12 h, the mixture was partitioned between water and CH2Cl2 (10 mL each). The aqueous phase was extracted with CH2Cl2 (1×10 mL). The combined organics were dried with MgSO4 and concentrated to give the title compound as a yellow solid (0.139 g, quant). 1H NMR (400 MHz, DMSO-d6): δ 12.01 (s, 1H), 8.23 (s, 1H), 7.75 (d, J=8.24 Hz, 2H), 7.68 (d, J=8.42 Hz, 2H), 6.85 (d, J=8.42 Hz, 2H), 6.81 (s, 1H), 6.56 (d, J=8.61 Hz, 2H), 6.05 (t, J=5.95 Hz, 1H), 4.22 (d, H=5.86 Hz, 2H), 2.18 (m, 1H), 1.58 (m, 1H), 1.27 (m, 1H), 1.16 (m, 1H). APCI m/z 399.93 (MH−).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[C:14]2([CH3:21])SC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].O.O1CCCC1>[C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]2[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC1(C)C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: CC1C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Yield: 89 %

Procedure:
A stirred solution of 8 g. (0.027 mole) of 7-benzoyl-3-methyl-3-methylthioindolin-2-one in 80 ml. of tetrahydrofuran was treated under N2 with 40 g. of a commercial Raney nickel-water mixture over a 2 hr. period. At the end of this period the mixture was filtered and the residue washed thoroughly with tetrahydrofuran. One drop of concentrated hydrochloric acid was added to the filtrate and the dark orange solution turned pale yellow. The solution was stripped under vacuum to a yellow oil which crystallized on seeding. The material was recrystallized from toluene petroleum ether to give a white crystalline material. The solid (6.0 g., 89% yield) melted at 125°-127°C.