Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[O:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(-c2ncco2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1ccc(-c2ncco2)cc1
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of methyl-4-(oxazol-2-yl)-benzoate (0.203 g, 1 mmol) in CH2Cl2 (10 mL) 0° C. was added DIBAL-H (4 mL of a 1.0M solution in dichloromethane, 4 mmol) over 10 minutes. The resultant solution was stirred at 0° C. for 2 hours then quenched with an aqueous saturated solution of sodium potassium tartrate (20 mL) and the biphasic mixture stirred rapidly for 60 minutes. The phases were separated and the aqueous layer extracted with CH2Cl2 (3×10 mL). The combined organic fractions were dried (Na2SO4), filtered, concentrated and purified by chromatography on silica gel (10:1 CH2Cl2/MeOH) to afford the title alcohol (0.156 g, 89%). 1H NMR (CDCl3) δ 3.42 (t, 1H, J=6.0 Hz (OH)), 4.77 (s, 2H, J=6.0 Hz), 7.24 (s, 1H), 7.47 (d, 2H, J=7.8 Hz), 7.71 (s, 1H), 8.05 (d, 2H, J=7.8 Hz).
Reaction SMILES: C1(O[C:8](=[O:23])[NH:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[C:13]([C:21]#[N:22])=[CH:12][N:11]=2)C=CC=CC=1.C(C1C=CC(NC([N:35]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]3[CH:42]=[CH:43][C:44]([CH:46](OC)[O:47]C)=[N:45][C:36]2=3)=O)=NC=1)#N>>[C:21]([C:13]1[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:15][C:10]([NH:9][C:8]([N:35]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]3[CH:42]=[CH:43][C:44]([CH:46]=[O:47])=[N:45][C:36]2=3)=[O:23])=[N:11][CH:12]=1)#[N:22]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCCC2
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Product: COCCOc1cc(NC(=O)N2CCCCc3ccc(C=O)nc32)ncc1C#N

Procedure:
From intermediates 108 and 237, coupled and deprotected in an analogous manner to intermediate 236 and Example 201. The title compound was obtained as a white solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>CO>[CH2:9]([NH:16][CH:3]([CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CC(C)NCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
Ru(OCOCH3)2((R)-dm-binap)(20.5 mg, 0.0215 mmol), methyl acetoacetate (500 mg, 4.305 mmol), benzylamine (461 mg, 4.305 mmol) and methanol (2.5 mL) were placed in a 2.5 mL-stainless autoclave under atmosphere of nitrogen, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled down to room temperature, and acetic acid (259 mg, 4.305 mmol) was added thereto. The mixture was further stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation in vacuo, and the residue was purified by column chromatography on silica gel (eluent:hexane ethyl acetate/triethylamine=75/25/5) to give the objective methyl (−)-3-(benzylamino)butanoate (141 mg) as a colorless oil in 15.8% yield. The enantiomeric excess of the resulting methyl (−)-3-(benzylamino)butanoate was determined to be 44.5% ee by HPLC analysis using a CHIRALCEL OD-H column.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:49])[CH:6]([O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:25][NH:26][C:27]([C:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][C:30]=3[CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])[CH:21]=2)[C:16]=1[C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.Cl>CO>[CH2:38]([C:30]1[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:29]=1[C:27]([NH:26][CH2:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)=[C:15]([O:14][CH:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:49])=[O:4])[CH:24]=[CH:23]2)=[O:28])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(Cl)cc3)c(OC(Cc3ccccc3)C(=O)OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(Cl)cc3)c(OC(Cc3ccccc3)C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
1 N NaOH (300 μL, 0.30 mmol) was added under nitrogen to a solution of 2-[6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-(4-chloro-phenyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl ester (182 mg, 0.28 mmol), prepared in the previous step, in 30 mL of methanol plus 2.5 mL of water at room temperature. After the addition the reaction was stirred at room temperature overnight. If starting material remains additional 1 N NaOH is added until the reaction is complete. A total of 900 μL of 1 N NaOH was added. The reaction was acidified by the addition of 1.6 mL of 1 N HCl and then concentrated under reduced pressure. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (166 mg, 94%) as a white solid, mp 169-172° C.
Reaction SMILES: [C:1]([C:3]1([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:3]1([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CC2CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(CC2CC2)CCNCC1

Procedure:
A solution of tert-butyl 4-cyano-4-cyclopropylmethylpiperidine-1-carboxylate (I-2) (1.00 g, 3.78 mmol) in TFA (50 mL) and DCM (75 mL) was stirred at room temperature for 0.5 h then the volatile components removed in vacuo. The residue was partitioned between saturated sodium bicarbonate solution and DCM. The organic phase was separated and the aqueous phase re-extracted with DCM twice. The combined organic phase was washed with brine, dried (MgSO4) and the solvent removed in vacuo to leave 4-cyano-4-cyclopropylmethylpiperidine (I-8) as a glass. 1H NMR (500 MHz, CD3OD): δ 3.03 (d, J=13.1 Hz, 2 H), 2.88-2.82 (m, 2 H), 2.00 (d, J=11.7 Hz, 2 H), 1.55-1.49 (m, 4 H), 0.92-0.84 (m, 1 H), 0.57-0.55 (m, 2 H), 0.20 (q, J=5.0 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:16])[C:9]=1[NH:10]2.[F-].[Cs+].[C:19]([Si](C)(C)C)([F:22])([F:21])[F:20]>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:3]=1[C:4]1[CH:5]([C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:7][CH:8]([OH:16])[C:9]=1[NH:10]2
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCCc2c1[nH]c1c(Cl)ccc(Cl)c21
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: OC1CCC(C(F)(F)F)c2c1[nH]c1c(Cl)ccc(Cl)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.5 %

Procedure:
To a solution of 5,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.1 g, 0.39 mmol) in anhydrous THF (8 mL) at 0° C., CsF (59 mg, 0.39 mmol) and CF3TMS (0.56 g, 3.93 mmol) were added. The reaction mixture was slowly warmed to room temperature and stirred for 18 h. After the volatiles were removed in vacuo, the residue was diluted with water and extracted with EtOAc (2×15 mL) to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (1:4) as eluant] to give the title compound (0.127 g, 16%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.07 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.62 (s, 1H), 3.01-3.0 (m, 2H), 2.22-2.19 (m, 1H), 1.97-1.92 (m, 3H).
Reaction SMILES: [CH:1]1([C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:18])(=O)=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(OCC)C>[Cl:18][CH:8]([C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)C1CCCCC1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of ethyl 3-cyclohexyl-3-oxopropanoate (1.0 g, 5.0 mmol) in diethyl ether (15 mL) was added sulfuryl chloride (750 mg, 5.5 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (150 mL) were added to the reaction solution, and the mixture was stirred for 30 min. The organic layer was washed with saturated brine (10 mL) and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (870 mg, 60%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17])[C:6]([NH:8][CH2:9][CH2:10][OH:11])=O)#[N:2].S(Cl)(Cl)=O>C(Cl)Cl>[O:11]1[CH2:10][CH2:9][N:8]=[C:6]1[C:5]1[CH:12]=[CH:13][C:14]([O:15][CH:16]([CH3:18])[CH3:17])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)NCCO)cc1C#N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)Oc1ccc(C2=NCCO2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
3-cyano-N-(2-hydroxyethyl)-4-isopropoxybenzamide was dissolved in DCM (30 mL) and thionyl chloride (1.43 g, 12 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 1 h and then quenched at 0° C. with water (200 μL) and 6N NaOH solution (1 mL). The mixture was stirred for 30 min. The aqueous layers were extracted with DCM and the combined organic extracts were washed with brine and dried over MgSO4 to afford 570 mg (61% for two steps) of 5-(4,5-dihydrooxazol-2-yl)-2-isopropoxybenzonitrile INT-31. LCMS-ESI (m/z) calculated for C13H14N2O2: 230.3; found 231.0 [M+H]+, tR=2.50 min. 1H NMR (400 MHz, CDCl3) δ 8.17-7.86 (m, 2H), 6.91 (d, J=8.9 Hz, 1H), 4.65 (dt, J=12.2, 6.1 Hz, 1H), 4.37 (dd, J=14.3, 4.9 Hz, 2H), 3.98 (t, J=9.5 Hz, 2H), 1.36 (t, J=5.5 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:41][OH:42])[C@@H:21]([OH:40])[C@@H:22]([OH:39])[C@H:23]([OH:38])[C:24]([NH:26][C@H:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][C:29](O)=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:44]1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.N>C(#N)C.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:41][OH:42])[C@@H:21]([OH:40])[C@@H:22]([OH:39])[C@H:23]([OH:38])[C:24]([NH:26][C@H:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][C:29]([NH2:44])=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
A solution of (S)-3-[(2S,3R,4R,5S)-5-(N-benzyloxycarbonyl-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionic acid (295 mg), N-hydroxysuccinimide (58 mg) and N,N′-dicyclohexylcarbodimide (103 mg) in acetonitrile (10 ml) was stirred at room temperature for 3 hours and the formed insoluble solid was filtrated off. Removal of the organic solvent gave a residue, which was dissolved in dimethylformamide (5 ml), followed by addition of 25% aqueous ammonia solution (1 ml). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine respectively. After drying over anhydrous sodium sulfate, removal of the organic solvent gave a residue, which was recrystallized from methanol-diethylether to give the title compound (97 mg).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>CO>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:31][CH:28]([CH3:30])[CH3:29])=[N:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)N
Reactant: Fc1cccc(F)c1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1
Solvent: CO
Product: CC(C)NC(=Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of N-[3-(2,6-difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.0 g, 0.0025 mol), yellow mercuric oxide (0.64 g, 0.003 mol) and isopropylamine (0.43 g, 0.0074 mol) in methanol (20 ml) was stirred at room temperature for 96 hours, and then heated at 50 ° C. for 8 hours. After cooling, the solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 0.24 g (23%), m.p. 112°-113 ° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:9]([F:16])[C:10](F)=[C:11]([F:14])[C:12]=1[F:13])[C:6]([OH:8])=[O:7].[CH3:18][O-:19].[Na+].Cl>CO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:9]([F:16])[C:10]([O:19][CH3:18])=[C:11]([F:14])[C:12]=1[F:13])[C:6]([OH:8])=[O:7]
Reactant: C[O-]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(F)c(F)c(OC)c(F)c1C(=O)O
Reaction time: 1 h
Yield: 87.2 %

Procedure:
Into a 100 ml glass reactor equipped with a reflux condenser, a stirrer and a dropping funnel, 20 ml of a methanol solution of 10 g (0.0397 mol) of the 3,4,5,6-tetrafluorophthalic acid-monomethyl ester prepared in Example 14, was charged. Then, 44.9 g (0.0833 mol) of a 10% methanol solution of sodium methoxide was dropwise added thereto. The mixture was stirred for one hour under reflux. After completion of the reaction, the reaction mixture was neutralized with a 10% hydrochloric acid aqueous solution and extracted with ethyl acetate. Then, the solvent was distilled off to obtain 9.14 g of 4-methoxy-3,5,6-trifluorophthalic acid-1-methyl ester. (=5-methoxy-3,4,6-trifluorophthalic acid-2-methyl ester.) The yield was 87.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13]2=[N:14][CH2:15][CH2:16][N:12]2[CH:11](O)[CH2:10]1>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13]2=[N:14][CH2:15][CH2:16][N:12]2[CH:11]=[CH:10]1
Reactant: Cc1cccc(Cl)c1N1CC(O)N2CCN=C12
Agent: Cl
Product: Cc1cccc(Cl)c1N1C=CN2CCN=C21
Reaction time: 0.08 h
Yield: 23.5 %

Procedure:
5 gm (0.02 mol) of 7-(2-chloro-6-methyl-phenyl)-5-hydroxy-2,3,5,6-tetrahydro-imidazo[1,2-α]-imidazole were slowly heated to 180° C. on an oil bath, while stirring, and allowed to remain at that temperature for about 5 minutes. The molten mass was allowed to cool, was then dissolved in dilute hydrochloric acid, and the solution was extracted once with ether. The ethereal extract solution was discarded. The acidic aqueous phase was made alkaline with 2 N sodium hydroxide and was then extracted several times with ether while salting out (common salt). The combined ethereal extracts were dried over anhydrous calcium sulfate and evaporated in vacuo, leaving 2.9 gm (63% of theory) of slightly impure reaction product, as determined by thin-layer chromatography. For further purification the product was twice stirred with ether and suction-filtered off, yielding 1.1 gm (23.9% of theory) of 7-(2-chloro-6-methyl-phenyl)-2,3-dihydro-imidazo[1,2-α]-imidazole, m.p. 105°-107° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C1COCC1>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]6[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=6)=[O:22])=[CH:16][CH:15]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:38][CH:37]=2)[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)s1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCOCC4)cc3)cc2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 50 mg, 0.116 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (20.0 mg, 0.1122 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜2 mL of i-prOH affording the title compound in 64% yield (0.044 g, 0.0742 mmol).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.S(=O)(=O)(O)O>C(O)(=O)C.O>[I:1][C:14]1[CH:13]=[C:12]([O:11][C:10]([F:19])([F:20])[F:9])[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(OC(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.5 %

Procedure:
To a suspension of N-iodosuccinimide (6.95 g, 31 mmol) in glacial acetic acid (2 ml) was added 4-trifluoromethoxy phenol (4.0 ml, 31 mmol) and, after 5 minutes, concentrated sulphuric acid (0.5 ml, 9 mmol). The pale brown suspension was stirred at ambient temperature under nitrogen for 48 hours before diluting with water and extracting with dichloromethane. The organic extract was washed with water, saturated aqueous sodium thiosulfate solution and water, dried over anhydrous magnesium sulfate and decolorizing charcoal added. The resulting suspension was left to stand for 30 minutes before filtering through a short pad of silica gel eluting with dichloromethane. The solvent was concentrated in vacuo to afford the title compound as an oil (1.18 g, 12%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([F:22])[CH:21]=1)[NH:18][CH:17]=[C:16]2[C:23]#[N:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.OCCC(N1C2C(=CC=CC=2)C(C#N)=C1)C1C=CC=CC=1>>[F:22][C:20]1[CH:21]=[C:13]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][OH:3])[CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[C:16]2[C:23]#[N:24]
Reactant: CCOC(=O)CC(c1ccccc1)c1cc(F)c2[nH]cc(C#N)c2c1
Agent: N#Cc1cn(C(CCO)c2ccccc2)c2ccccc12
Product: N#Cc1c[nH]c2c(F)cc(C(CCO)c3ccccc3)cc12

Procedure:
7-Fluoro-5-(3-hydroxy-1-phenyl-propyl)-1H-indole-3-carbonitrile LXXXVIII (328 mg) was prepared from 3-(3-cyano-7-fluoro-1H-indol-5-yl)-3-phenyl-propionic acid ethyl ester using the procedure described above for preparation of -(3-Hydroxy-1-phenyl-propyl)-1H-indole-3-carbonitrile LX (Example 14).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH:3]([NH:14][CH2:15][CH2:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]1[C:5]([C:10]([F:13])([F:12])[F:11])=[N:6][CH:7]=[N:8][CH:9]=1.C(N(CC)CC)C.ClCCl.[C:35](Cl)(Cl)=[O:36]>O>[CH3:1][CH:2]([CH3:24])[CH:3]([N:14]1[CH2:15][CH2:16][N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:35]1=[O:36])[C:4]1[C:5]([C:10]([F:12])([F:11])[F:13])=[N:6][CH:7]=[N:8][CH:9]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)C(NCCNc1ccccc1)c1cncnc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)C(c1cncnc1C(F)(F)F)N1CCN(c2ccccc2)C1=O
Reaction time: 1 h
Yield: 68.6 %

Procedure:
1.05 g (4.2 mol) of 5-(1-chloro-2-methylpropyl)-4-trifluoromethylpyrimidine and 0.61 (4.2 mol) of N-phenylethylenediamine were added to 10 ml of isopropyl alcohol, followed by stirring at room temperature for 6 hours. After completion of the reaction, the reaction solution was concentrated, then poured into water and extracted with ethyl acetate, and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 to ethyl acetate) to obtain 0.38 g of N-[2-methyl-1-(4-trifluoromethylpyrimidin-5-yl)-propyl]-N′-phenylethane-1,2-diamine. Then, 0.38 g (1 mmol) of N-[2-methyl-1-(4-trifluoromethylpyrimidin-5-yl)-propyl]-N′-phenylethane-1,2-diamine and 0.5 g (5 mmol) of triethylamine were added to 10 ml of dichloromethane, and a dichloromethane solution containing 0.2 g (2 mmol) of phosgene was dropwise added under cooling with ice. After the dropwise addition, stirring was further continued at room temperature for 1 hour to terminate the reaction. After termination of the reaction, the product was poured into water, washed with an aqueous sodium hydrogencarbonate solution, dried and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 to ethyl acetate) to obtain 0.25 g (yield: 61%) of 1-[2-methyl-1-(4-trifluoromethyl-pyrimidin-5-yl)-propyl]-3-phenylimidazolin-2-one as colorless crystals (melting point: 126-128° C.).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:24]=[CH:25][N:26]=4)[N:20]=[C:21]([Cl:23])[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CO.Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[ClH:23].[C:1]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:24]=[CH:25][N:26]=4)[N:20]=[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)n1ccc(-c2cccc(Nc3cc(Cl)nn4ccnc34)n2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)n1ccc(-c2cccc(Nc3cc(-c4ccccc4)nn4ccnc34)n2)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 27.8 %

Procedure:
A mixture of N-(6-(1-tert-butyl-1H-pyrazol-3-yl)pyridin-2-yl)-6-chloroimidazo[1,2-b]pyridazin-8-amine (168 mg, 0.58 mmol), phenylboronic acid (105 mg, 0.86 mmol), Pd2(dba)3 (34 mg, 0.06 mmol), X-phos (114 mg, 0.24 mmol) and K2CO3 (240 mg, 1.74 mmol) in dioxane (10 mL) and water (1 mL) was heated to 100° C. with stirring for 4 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=180:1) to give crude product. This solid was further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give a white solid. This was dissolved in methanol and three drops of concentrated HCl added. The mixture was stirred for 5 minutes, then concentrated in vacuo to give the final product N-(6-(1-tert-butyl-1H-pyrazol-3-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine hydrochloride (72 mg, 39%) as an HCl salt. 1H NMR (300 MHz, DMSO): δ 10.26 (s, 1H), 8.58 (d, 1H, J=1.8 Hz), 8.32 (s, 1H), 7.83-7.79 (m, 2H), 7.56-7.51 (m, 4 h), 6.62 (s, 1H), 6.39 (d, 1H, J=1.5 Hz), 1.61 (s, 9H). LC-MS: [M+H]+, 333, tR=1.648 min, HPLC: 98.3% at 214 nm, 99.29% at 254 nm, tR=6.1 min.