Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:23])(OC1C=CC=CC=1)[O:2][CH2:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.C([O-])(=O)C.[NH4+:28]>C(O)(=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([C:4]2[NH:28][C:1](=[O:23])[O:2][CH:3]=2)=[CH:6][CH:7]=1
Reactant: O=C(OCC(=O)c1ccc(C(F)(F)F)cc1)Oc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)co1
Yield: 84.9 %

Procedure:
A mixture of 2-oxo-2-(4-trifluoromethylphenyl)ethyl phenyl carbonate (18.0 g), ammonium acetate (20 g) and acetic acid (100 ml) was stirred with heating under reflux for 1 hour. The reaction mixture was concentrated, and poured into ice water (200 ml). The solid precipitates were filtered, washed with water, and air-dried to give crystals of 4-(4-trifluoromethylphenyl)-2-oxazolone (10.8 g, 85%). Melting point decomposed at 250° C. or more.
Reaction SMILES: [C:1]1([CH2:14][C@H:15](O)[CH3:16])[C:9]2[C:8]3[CH:10]=[CH:11][CH2:12][O:13][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C1COCC1>[N:34]([C@@H:15]([CH3:16])[CH2:14][C:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH2:12][O:13][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](O)Cc1n[nH]c2ccc3c(c12)C=CCO3
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](Cc1n[nH]c2ccc3c(c12)C=CCO3)N=[N+]=[N-]
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
To a stirred solution of the product from Step E (0.16 g, 0.70 mmol) and triethylamine (0.28 g, 0.39 mL, 7.51 mmol) in anhydrous THF (50 mL) at 0° C. was added methanesulfonic anhydride (0.24 g, 1.4 mmol). The mixture was stirred for about 30 minutes and an additional 1 eq of methanesulfonic anhydride was added. After 30 minutes sodium azide (1.10 g, 7.0 mmol) was added to the reaction mixture. The THF was evaporated and anhydrous dimethyl sulfoxide (20 mL) was added to the residue, which was heated at 90° C. for 1 hour. The reaction mixture was cooled, poured into a saturated solution of sodium bicarbonate (80 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were dried (MgSO4), filterd and evaporated to an oil. Chromatography on silica (gradient, 10% to 20% of ethyl acetate in hexane) gave an oil (0.09 g, 51%): LC/MS (+APCI) m/z 256 (M+H).
Reaction SMILES: [OH2:1].[F:2][C:3]([F:18])([F:17])[C:4]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([F:16])[CH:7]=1)=O.O.[N:20]1C=CC=CC=1>C(O)C>[F:2][C:3]([F:18])([F:17])[C:4]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([F:16])[CH:7]=1)=[N:20][OH:1]
Reactant: O=C(c1cc(F)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: O
Reactant: c1ccncc1
Solvent: CCO
Product: ON=C(c1cc(F)cc(C(F)(F)F)c1)C(F)(F)F
Yield: 51.5 %

Procedure:
4.00 g (15.37 mmol) of 2,2,2-trifluoro-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone hydrate from Stage 1 were stirred in a mixture of 37.3 ml of pyridine and 26.9 ml of ethanol, and stirred at reflux temperature for approx. 18 hours. After cooling, the entire reaction mixture was admixed with water and then concentrated under reduced pressure. The remaining residue was purified by means of column chromatography using silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm; cyclohexane/acetone gradient) to obtain 2.18 g (51.5% of theory) of 2,2,2-trifluoro-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone oxime as a syn/anti isomer mixture.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)C=1O)(=O)[CH3:2].C[O:18]C1C=C(C=C(OC)C=1OC)C=O.N1CC[CH2:34][CH2:33][CH2:32]1.N1C=CC=CC=1>C(O)C>[O:14]1[C:15]2[C:1](=[CH:2][CH:32]=[CH:33][CH:34]=2)[C:4](=[O:18])[CH2:13][CH:12]1[C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1cc(C(C)=O)c(O)c2ccccc12
Reactant: C1CCNCC1
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1CC(c2ccccc2)Oc2ccccc21
Yield: 45 %

Procedure:
A solution of the acetonaphthone 12 (1.08 g, 5 mmol) and trimethoxybenzaldehyde (2) (1.08 g, 5.5 mmol) in ethanol (25 mL) was treated with piperidine (3 mL) and pyridine (3 mL) and refluxed for 24 h. On cooling, the product, 13 precipitated out of solution and was collected by filtration and washed with ethanol to yield 488 mg of 13 as the first crop. The filtrate was further purified by flash chromatography and the product eluted with hexanes/CH2Cl2/EtOAc (6:3:1) to give a light orange solid, which was recrystallized from ethanol to afford an additional 399 mg of a second crop. Combined yield 45%. 1H NMR (300 MHz, CDCl3): δ 2.99 (m, 1H, 3-H), 3.19 (m, 1H, 3-H), 3.91, 3.93, 4.03 (3s, 12H, OCH3), 5.57 (m, 1H, 2-H), 6.80 (s, 2H, 2′,6′-Ar—H), 7.18 (s, 1H, Ar-5-H) 7.57 (m, 1H, Ar—H), 8.26 (d, 1H, Ar—H), 8.33 (d, 1H, Ar—H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12](Cl)=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1.C1COCC1.[CH2:24]([NH2:26])[CH3:25]>O>[CH2:24]([NH:26][C:12]([C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:5]=2)=[CH:8][CH:9]=1)=[O:13])[CH3:25]
Reactant: CCN
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(C(=O)Cl)s1
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-c2cc(C(F)(F)F)nn2C)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(1-Methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonyl chloride (150 mg) and THF (2 ml) were added to a mixture of 70% ethylamine aqueous solution (1 ml) and THF (2 ml), followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was recrystallized from a mixed solvent ethyl acetate and n-hexane to give N-ethyl-5-(1-methyl-3-trifluoromethy-1H-pyrazol-5-yl)thiophene-2-carboxamide (96 mg) as colorless powder crystals.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN(C=O)C.C(Cl)Cl.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>N1C=CC=CC=1>[CH2:24]([O:23][C:21]([NH:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1nccn1N
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)Nn1ccnc1C(=O)OCC
Temperature: 12.5 °C
Reaction time: 1.5 h

Procedure:
(I9C): In 10 lit, round bottom flask charged ethyl 1-amino-1H-imidazole-2-carboxylate (70 g, 451 mmol) along with DMF and DCM (1200 ml) was added and cooled to 10-15° C. Then pyridine was added (35 ml) at single lot. Followed by slow addition of ethyl chloroformate (30 ml) and stirred at same temperature for 1.5 hrs. After 1.5 hrs additional pyridine (25 ml) and ethyl chloroformate (20 ml) was added. The reaction mixture was stirred for additional 30 minutes. The reaction mixture was concentrated under high vacuum and the crude residue was diluted with ethyl acetate and given saturated aqueous citric acid (250 ml) washing. The organic layer was separated. The citric acid layer was extracted with EtOAc (3×500 ml). All organic layers combined and washed with brine (2×150 ml), dried with sodium sulphate and concentrated to get the syrupy gel. The syrupy gel was triturated with ether-hexane mixture to give 65 g of ethyl 1-((ethoxycarbonyl)amino)-1H-imidazole-2-carboxylate as pale yellow solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]([CH3:13])[N:6]=1)([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].Cl.[NH2:20][OH:21]>CO>[OH:21][NH:20][C:11]([C:9]1[CH:8]=[C:7]([CH3:13])[N:6]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[N:10]=1)=[NH:12]
Reactant: Cc1cc(C#N)nc(NC(C)C)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=N)NO)nc(NC(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.2 %

Procedure:
2-Isopropylamino-6-methyl-pyrimidine-4-carbonitrile (2.8 g, 16.0 mmol) is added to a suspension of NaHCO3 (4.71 g, 56.1 mmol) and hydroxylamine hydrochloride (3.34 g, 48.1 mmol) in MeOH (20 mL). The reaction mixture is stirred at rt for 1 day and is filtered and evaporated. The residue is dissolved in DCM, washed with water followed by brine and dried to give N-hydroxy-2-isopropylamino-6-methyl-pyrimidine-4-carboxamidine as a yellow oil (1.38 g); LC-MS: tR=0.55; [M+H]+=209.96.
Reaction SMILES: ClC1C=C[C:9]2[C:8]([CH:12]=[O:13])=[C:7]([OH:14])[CH:6]=[CH:5][C:4]=2N=1.C1N2CN3[CH2:24][N:18](C2)CN1C3.CC(O)=[O:27]>>[OH:14][C:7]1[C:8]([CH:12]=[O:13])=[C:9]2[N:18]=[CH:24][O:27][C:4]2=[CH:5][CH:6]=1
Reactant: O=Cc1c(O)ccc2nc(Cl)ccc12
Reactant: CC(=O)O
Reactant: C1N2CN3CN1CN(C2)C3
Product: O=Cc1c(O)ccc2ocnc12
Temperature: 90 °C
Yield: 25 %

Procedure:
A mixture of compound 3 (350 mg, 1.05 mmol) and HMTA (560 mg, 4 mmol) in AcOH (35 mL) was heated to 90° C. under N2 for 1.5 h. The reaction was monitored by LCMS. After cooled to RT, the solvent was removed under vacuum. The residue was purified by prep-HPLC to give 5-hydroxybenzo[d]oxazole-4-carbaldehyde (152 mg, 25% yield). 1HNMR (DMSO, 400 MHz): δ 10.99 (s, 1H, OH), 10.53 (s, 1H, CHO), 8.86 (s, 1H, ArH), 8.00 (d, 1H, J=9.2 Hz, ArH), 7.05 (d, 1H, J=8.8 Hz, ArH). MS [ESI, MH+]: 164.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.CO>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:45])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 71 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 71% of theory, C27H29N7O3 (499.6); Rf value: 0.28 (silica gel; dichloromethane/methanol=5:1); EKA mass spectrum: (M+H)+=500; (M+H+Na)++=261.8; (M+2H)++=250.8.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[C:30]1([C:36]2[O:40][C:39]([C:41](Cl)=[O:42])=[N:38][N:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC#N>[C:30]1([C:36]2[O:40][C:39]([C:41]([OH:42])=[O:13])=[N:38][N:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH-:2])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1nnc(-c2ccccc2)o1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)c1nnc(-c2ccccc2)o1
Product: [NH-]Cc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 195 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.55 g, 4.8 mmol) in CH3CN (15 ml), was added triethyl amine (1.67 mL, 11.98 mmol) and 5-phenyl-1,3,4-oxadiazole-2-carbonyl-chloride (1.0 g, 4.8 mmol). The mixture was stirred at room temperature for 21 hours and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH3CN (20 mL), water (2×20 mL), EtOAc (20 mL) and MeOH (20 mL) to afford 5-phenyl-[1,3,4]oxadiazole-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethylamide as a white solid (1.34 g, 61%): mp, 279-281° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.90 min. (99%); 1H NMR (DMSO-d6): δ 2.08-2.10 (m, 1H), 2.53-2.64 (m, 2H), 2.86-2.98 (m, 1H), 4.98 (d, J=5 Hz, 1H), 5.18 (dd, J=5, 13 Hz, 1H), 7.62-7.72 (m, 3H), 7.85 (broad, 3H), 8.09-8.12 (m, 2H). 9.97 (t, J=5 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.90, 30.85, 38.24, 48.82, 122.07, 122.70, 126.98, 127.16, 129.46, 131.49, 132.58, 133.03, 134.77, 137.63, 153.51, 158.29, 164.94, 166.84, 167.42, 169.74, 172.67. Anal Calcd for C23H17N5O6: C, 60.13; H, 3.73; N, 15.24. Found: C, 56.69; H, 3.34; N, 15.41.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].I[CH2:18][CH3:19].C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH2:1]([N:13]([CH2:14][CH2:15][OH:16])[CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCI
Reactant: CCCCCCCCCCCCNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCCCCCCCCCCCN(CC)CCO
Yield: 73.4 %

Procedure:
2-[Dodecylamino]ethanol (2.0 g, 8.73 mmol), 1-iodoethane (1.63 g, 10.48 mmol) and N,N-diisopropylethylamine (2.51 g,17.5 mmol) in isopropanol (25 ml )were heated under reflux for 4 h. The solvent was then evaporated in vacuo and the residue was diluted with ethyl acetate washed with aqueous sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent followed by chromatography on silica gel (ethyl acetate/methanol 90:10 to 80:20) afforded the title compound (1.65 g, 73%) as a white solid.
Reaction SMILES: O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[CH:19]([O:24][CH3:25])([O:22][CH3:23])OC.[Cl:26][C:27]1[C:28]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39](C=O)[CH:38]=2)=[N:29][N:30]([CH3:36])[C:31]=1[O:32][CH:33]([F:35])[F:34]>ClCCl>[Cl:26][C:27]1[C:28]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([CH:19]([O:22][CH3:23])[O:24][CH3:25])[CH:38]=2)=[N:29][N:30]([CH3:36])[C:31]=1[O:32][CH:33]([F:34])[F:35]
Reactant: Cn1nc(-c2ccc(Cl)c(C=O)c2)c(Cl)c1OC(F)F
Reactant: COC(OC)OC
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: COC(OC)c1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 g of montmorillonite K10 were added to a solution of 16 ml of trimethyl orthoformate in 80 ml of dichloromethane. A solution of 6.4 g (20 mmol) of 4-chloro-3-(4-chloro-3-formylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 20 ml of dichloromethane was added dropwise at 5° C. to this mixture. The mixture was then stirred at room temperature overnight. The solids were then separated off and the clear reaction solution which remained was concentrated. Yield: 6.7 g.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C#N)=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[NH4+].[Cl-].C[N:17]([CH:19]=O)C>>[Br:1][C:2]1[CH:9]=[CH:8][CH:5]=[CH:4][C:3]=1[C:19]1[NH:17][N:12]=[N:11][N:10]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: CN(C)C=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Brc1ccccc1-c1nnn[nH]1
Temperature: 100 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
A mixture of 546 mg (3.0 mmol) of 4-(bromo)benzonitrile, 227 mg (3.5 mmol) of sodium azide and 187 mg (3.5 mmol) of NH4Cl in 5 mL of DMF was stirred at 100° C. for 20 h. The mixture was cooled and concentrated. The residue was dissolved in 20 mL of H2O and the pH adjusted to 2 with 2 N HCl solution. The solid that precipitated was filtered, rinsed with H2O, then ether and dried to afford 395 mg (58%) of the title compound: El-MS 226+224 (20%, M+H), 198+196 (100%, M−N2+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:34][C:35](=[O:47])[C:36]([NH:39]C(=O)OC(C)(C)C)([CH3:38])[CH3:37])[C:12]([N:14]2[CH2:33][CH2:32][CH2:31][C:16]3([C:20](=[O:21])[N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH:17]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:15]2)=[O:13])=[CH:2]1.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:34][C:35](=[O:47])[C:36]([NH2:39])([CH3:38])[CH3:37])[C:12]([N:14]2[CH2:33][CH2:32][CH2:31][C:16]3([C:20](=[O:21])[N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH:17]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:15]2)=[O:13])=[CH:2]1
Reactant: CC(C)N1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)C(C)(C)N)C2)C1=O

Procedure:
A mixture comprising tert-butyl 1-((2R)-3-(1H-indol-3-yl)-1-(2-isopropyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (450.21 mg, 0.699 mmol) (step 1) and TFA (0.539 ml, 6.99 mmol) in DCM (5 ml) was stirred at room temperature for 17 hours. The solvent was removed in vacuo to afford a purple oil. The oil was dissolved with methanol (3 ml) and passed through a 10 g SCX-2 cartridge eluting with 2M NH3 in methanol (70 ml). The solvent was removed in vacuo to yield the title compound as diastereomeric mixture.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22].[CH3:29][O-:30].[Na+]>[Cu]I.CO>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:6]3[S:5][C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]=3[O:30][CH3:29])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: C[O-]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3Br)c(C)nc12
Agent: [Cu]I
Agent: [Na+]
Solvent: CO
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3OC)c(C)nc12
Temperature: 130 °C
Yield: 35.9 %

Procedure:
100 mg of 3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.22 mmol), 24 mg of sodium methoxide (0.44 mmol) and 21 mg of CuI (0.11 mmol) are put into 4 ml vial with MeOH 3 ml and capped with a Teflon® lined cap. The reaction vial is heated at 130° C. overnight. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane: THF=10:1) to give 32.8 mg of the title compound. Yield 36%. Mass spectrum (m/e): 416 (M+1). 1H NMR (CDCl3): δ 6.64 (s, 1H), 3.96 (s, 3H), 3.86 (t, J=4.7 Hz, 4H), 3.53 (m, 4H), 3.34 (m, 1H), 2.82 (s, 3H), 2.48 (s, 3H), 1.82 (m, 4H), 0.85 (t, J=7.4 Hz, 6H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:18]=[C:17]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29]([NH:31][CH:32]4[CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH:33]4[C:44]([O:46][CH3:47])=[O:45])=[O:30])=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1>C(Cl)Cl>[CH3:8][C:9]1[CH:18]=[C:17]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29]([NH:31][CH:32]4[CH2:36][NH:35][CH2:34][CH:33]4[C:44]([O:46][CH3:47])=[O:45])=[O:30])=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC1NC(=O)c1ccc2c(ccn2Cc2cc(C)nc3ccccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CNCC1NC(=O)c1ccc2c(ccn2Cc2cc(C)nc3ccccc23)c1
Reaction time: 2 h
Yield: 186.4 %

Procedure:
TFA (2mL) was added to a solution of the coupled product (0.11 g, 0.2 mmol) from step (501c) in methylene chloride (3 mL) at room temperature. The reaction was complete after stirring for 2 h and was concentrated to give methyl 4-[({1-[(2-methyl-4-quinolinyl)methyl]-1H-indol-5-yl}carbonyl)amino]-3-pyrrolidinecarboxylate (0.165 g, 100%) as an oil, MS (M+2H)++=222.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10](Br)[C:11]#[CH:12].C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])[C:11]#[CH:10]
Reactant: N#Cc1cccc(N)c1
Reactant: C#CCBr
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNc1cccc(C#N)c1

Procedure:
11.8 g (0.1 mol) of 3-aminobenzonitrile and 12.3 ml (0.11 mol) of propargyl bromide (80% in toluene) are stirred in 250 ml toluene and 19.2 ml (0.11 mol) of N-ethyl-diisopropylamine for 18 hours at 90° C. After cooling the mixture is diluted with ethyl acetate and washed with water. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with dichloromethane/ethanol in the ratio 98:2.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:19]4[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[NH2:23][C:24]1[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=1>>[F:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[CH:11]([NH:10][C:7]1[O:8][CH2:9][C:4]3[CH:3]=[C:2]([NH:23][C:24]4[N:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][N:25]=4)[CH:22]=[CH:21][C:5]=3[N:6]=1)[CH2:12][CH2:13]2
Reactant: Nc1nccc(C(F)(F)F)n1
Reactant: Fc1ccc2c(c1)CCC2NC1=Nc2ccc(Br)cc2CO1
Product: Fc1ccc2c(c1)CCC2NC1=Nc2ccc(Nc3nccc(C(F)(F)F)n3)cc2CO1
Yield: 51 %

Procedure:
The title compound (113 mg, 51%), yellow foam, MS (ISP): m/e=444.2 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(5-fluoro-indan-1-yl)-amine (Example 53) (181 mg, 0.5 mmol) and commercially available 2-amino-4-trifluoromethyl-pyrimidine (163 mg, 1.0 mmol).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][C:18]1[CH:30]=[CH:29][C:21]2[O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:20]=2[CH:19]=1.O>CN(C=O)C>[CH:19]1[C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=2[CH:29]=[CH:30][C:18]=1[O:17][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3oc4ccccc4c3c2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2-hydroxydibenzofuran (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracted with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(dibenzofuran-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation .
Reaction SMILES: NN.[C:3]([O:7][C:8](=[O:44])[NH:9][C@H:10]([CH2:32][N:33]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:11][C:12]([CH3:31])([CH3:30])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]2[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]2)=[CH:17][CH:16]=1)([CH3:6])([CH3:5])[CH3:4].C(OCC)C>C1COCC1.C(O)C>[C:3]([O:7][C:8](=[O:44])[NH:9][C@H:10]([CH2:32][NH2:33])[CH2:11][C:12]([CH3:31])([CH3:30])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]2[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]2)=[CH:17][CH:16]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(CCc1ccc(OC[C@@H]2COC(C)(C)O2)cc1)C[C@@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: NN
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(CCc1ccc(OC[C@@H]2COC(C)(C)O2)cc1)C[C@@H](CN)NC(=O)OC(C)(C)C
Temperature: 45 °C

Procedure:
Hydrazine (2.2 ml of a 1M solution in THF, 2.2 mmol) is added to a solution of [(S)-5-[4-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3,3-dimethyl-pentyl]-carbamic acid tert-butyl ester (0.16 g, 0.28 mmol) in ethanol (5 ml), and the resulting colourless solution is heated at 45° C. overnight. The reaction is allowed to cool to room temperature, and diethyl ether (30 ml) is added and the resulting white suspension cooled at 0° C. for 30 minutes. The white solid is removed by filtration, and the solvent removed in vacuo to yield {(S)-1-Aminomethyl-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-3,3-dimethyl-pentyl}-carbamic acid tert-butyl ester as a colourless oil; [M+H]+ 451.