Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH2:12]([O:14][C:15](=[O:27])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[CH:25]=[O:26])[CH3:13].[NH4+].[Cl-]>C1COCC1.CCOCC>[CH2:12]([O:14][C:15](=[O:27])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[CH:25]([OH:26])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)COc1ccc(Br)cc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Br)cc1C(O)C#C[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
To a cooled (−78° C.) solution of (trimethylsilyl)acetylene (3.93 g, 40.0 mmol) in dry THF (40 mL) was slowly added a 2.5 M solution of butyllithium in hexanes (14.54 mL, 36.36 mmol). After stirring for 30 minutes at −78° C., the mixture was transferred to a cooled (−78° C.) solution of (4-bromo-2-formylphenoxy)acetic acid ethyl ester (10.44 g, 36.36 mmol) in dry THF (120 mL). Upon completion, the reaction mixture was stirred at −78° C. for 45 minutes. Saturated aq. NH4Cl (40 mL) was slowly added to the reaction mixture followed by Et2O (40 mL). The quenched reaction mixture was allowed to warm up to room temperature. The phases were separated and the aqueous phase was extracted with Et2O (2×). The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude oil was purified by column chromatography (SiO2), then was stirred for 90 min with polystyrene-supported trisamine (PS-Trisamine, 4.17 mmol/g, 8 g) in CH2Cl2 (160 mL). The resin was filtered off and the filtrate was concentrated in vacuo to give the title compound as pale yellow oil (7.6 g, 19.7 mmol, 54%). LC/MS (an10p8) Rt 4.30 min, m/z 408 [M+Na]+; 1H NMR (CDCl3): δ 0.24 (s, 9H), 1.31 (t, 3H), 4.27 (q, 2H), 4.71 (s, 2H), 5.79 (s, 1H), 6.74 (d, 1H), 7.39 (dd, 1H), 7.79 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:43]=[CH:44][C:45]([C:48]#[N:49])=[CH:46][CH:47]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(C#N)cc2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C#N)cc4)c3)c2cc1OC
Yield: 4.6 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-ylcarbamate (108 mg, 0.3 mmol) described in Example 328A, to afford 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (8 mg, 4%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.28 (s, 9H), 3.99 (m, 6H), 6.41 (s, 1H), 7.24-7.41 (m, 6H), 7.79 (d, J=8.7 Hz, 2H), 7.98 (d, J=8.7 Hz, 2H), 8.62 (s, 1H), 8.69 (s, 1H), 9.25 (s, 1H); LC-MS (ESI) m/z 580 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH2:32][CH3:33])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29](O)=[O:30])[CH2:24]2)[O:12]1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:68]([C:72]1[CH:73]=[C:74]([NH2:79])[C:75]([NH2:78])=[CH:76][CH:77]=1)([CH3:71])([CH3:70])[CH3:69]>C(Cl)Cl.O>[NH2:79][C:74]1[CH:73]=[C:72]([C:68]([CH3:71])([CH3:69])[CH3:70])[CH:77]=[CH:76][C:75]=1[NH:78][C:29](=[O:30])[CH2:28][CH2:27][CH:25]1[CH2:26][CH:23]([N:22]([CH2:21][C@@H:13]2[C@@H:14]3[C@@H:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]3)[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH2:1])[O:12]2)[CH2:32][CH3:33])[CH2:24]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CCN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: CCN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)Nc2ccc(C(C)(C)C)cc2N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(ethyl)amino)cyclobutyl)propanoic acid (2 g, 4.35 mmol), HOAT (768 mg, 5.65 mmol), HATU (2.2 g, 5.65 mmol) and TEA (3 mL, 21.3 mmol) in DCM (40 mL) was added 4-tert-butylbenzene-1,2-diamine (785 mg, 4.79 mmol) and the mixture was stirred at rt for 2 h. Water (15 mL) was added and the mixture was extracted with DCM (30 mL×2). The combined organic phase was washed with H2O (20 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude was purified by SGC (DCM: MeOH=70:1-20:1) to obtain the target (1.6 g, yield: 61%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.28-8.27 (m, 1H), 8.24-8.23 (m, 1H), 7.10-6.92 (m, 2H), 6.81-6.76 (m, 1H), 6.22 (s, 1H), 5.54-5.52 (m, 1H), 5.03 (s, 1H), 4.36 (s, 1H), 3.03-2.50 (m, 5H), 2.32-2.26 (m, 2H), 2.16-1.80 (m, 4H), 1.73-1.69 (m, 2H), 1.59 (s, 3H), 1.39 (s, 3H), 1.28-1.24 (m, 9H), 0.94-0.85 (m, 3H) ppm; ESI-MS (m/z): 607.3 [M+1]+.
Reaction SMILES: C(N1CCN([NH:14][C:15](=[O:32])[CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][N:23]=[C:24]([N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)[CH:25]=3)[NH:20][CH:19]=2)CC1)C1C=CC=CC=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([NH:14][C:15](=[O:32])[CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][N:23]=[C:24]([N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)[CH:25]=3)[NH:20][CH:19]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(CCc1c[nH]c2cnc(-n3cncn3)cc12)NN1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)CCc2c[nH]c3cnc(-n4cncn4)cc23)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl) propionic acid (0.34 g, 1.3 mmol) (prepared as described in Example 53 Step 7) in anhydrous DMF (5 ml) was added 1-tert-butyloxycarbonylpiperazine (0.5 g, 2.7 mmol), 1-hydroxybenzotriazole (225 mg, 1.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.45 g, 2.3 mmol) and triethylamine (0.23 ml, 1.7 mmol). The mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue partitioned between ethyl acetate (25 ml) and water (20 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate (3×20 ml). The combined organic layers were dried (Na2 SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (90:10) to afford the title compound, with some impurities, as a pale yellow foam.
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]2[NH:19][C:20](=[O:44])[C:21]3[C:25]=2[C:24](=[O:26])[NH:23][C:22]=3[C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:31]=2)[S:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].I[CH2:46][CH:47]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:48][CH2:49][CH2:50][CH3:51].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:48]([CH:47]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:46][N:23]1[C:22]([C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:31]=2)=[C:21]2[C:25](=[C:18]([C:15]3[S:16][CH:17]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]=3)[N:19]([CH2:17][CH:13]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:14][CH2:15][CH2:18][CH2:25][CH2:21][CH3:20])[C:20]2=[O:44])[C:24]1=[O:26])[CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCC(CI)CCCC
Reactant: CCCCCCCCCCCCc1csc(C2=C3C(=O)NC(c4cc(CCCCCCCCCCCC)cs4)=C3C(=O)N2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCCCCCCCCCCc1csc(C2=C3C(=O)N(CC(CCCC)CCCCCC)C(c4cc(CCCCCCCCCCCC)cs4)=C3C(=O)N2CC(CCCC)CCCCCC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
A 100 mL flask was charged with 3,6-bis-(4-dodecyl-thiophen-2-yl)-2,5-dihydro-pyrrolo[3,4-c]pyrrole-1,4-dione 4 (4.3 g, 6.75 mmol), 5-iodomethyl-undecane (6.22 g, 21.0 mmol), Cs2CO3 (7.82 g, 24.0 mmol) and then purged with argon for 10 minutes before 150 mL of dimethylformamide (DMF) was added. The mixture was heated at 60° C. for 36 hours, then at 90° C. for 8 hours, and cooled to room temperature before 200 mL of hexane was added. The organic layer was washed with water (200 mL, 3 times), then dried over anhydrous Na2SO4. Black solids were obtained after removal of the solvent and precipitation from methanol. The product was purified by column with dichloromethane/hexane (v/v: 2/1 with Rf=0.25) as the eluent and weighed 1.43 g (21.7% yield from 4-dodecyl-thiophene-2-carbonitrile 3) after drying.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C1COCC1>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][C:23]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:14][CH2:13]2)=[O:24])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2F)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
1-(2,4-Difluoro-phenyl)-piperazine (3.70 g, 18.9 mmol) and triethylamine (2.8 mL, 19.8 mmol) were dissolved in anhydrous THF (30 mL) under nitrogen and the reaction mixture was cooled to 0° C. 4-Nitrophenyl chloroformate (3.8 g, 18.9 mmol), dissolved in anhydrous THF (25 mL), was added dropwise and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue triturated with water, and then filtered. The yellow solid was recrystallised from a mixture of hexane and toluene(3:7) using charcoal to give 4-(2,4-difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (4.3 g, 63%) as a yellow crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:12][C:4]=2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(N(C(C)C)CC)(C)C.[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37])([O-:33])=[O:32]>O1CCCC1>[CH2:10]([O:9][C:7]([N:5]1[C:4]2[S:12][C:13]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])=[CH:14][C:3]=2[C:2]([NH:1][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=2[N+:31]([O-:33])=[O:32])=[N:6]1)=[O:8])[CH3:11]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)n1nc(N)c2cc(C(=O)OC(C)(C)C)sc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(NC(=O)c2ccccc2[N+](=O)[O-])c2cc(C(=O)OC(C)(C)C)sc21
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of 5-tert-butyl 1-ethyl 3-amino-1H-thieno[2,3-c]pyrazole-1,5-dicarboxylate (500 mg, 1.606 mmol) and diisopropylethylamine (DIEA, 0.824 mL, 4.818 mmol) in tetrahydrofuran (THF, 20 mL) at 0° C., 2-nitro-benzoyl chloride (0.318 mL, 2.409 mmol) was added. The reaction mixture was kept at the same temperature for 10 minutes then allowed to reach room temperature and let react overnight. The solvent was removed under vacuum, the residue was dissolved in dichloromethane (DCM) and washed with a 10% solution of acetic acid (AcOH), water, saturated NaHCO3 and brine. The crude was purified on silica gel (eluant dichloromethane/methanol 96/4) yielding 512 mg (69%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][CH:8]=1.[CH3:11][C:12](=[N:16][OH:17])[C:13](=O)[CH3:14].[ClH:18]>C(O)(=O)C>[ClH:18].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:13]([CH3:14])=[C:12]([CH3:11])[N+:16]=2[O-:17])=[CH:5][CH:4]=1
Reactant: CC(=O)C(C)=NO
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Reaction time: 3 h

Procedure:
A mixture of 68.07 g of anisaldehyde, 50.5 g of 2,3-butanedione mono-oxime and 150 ml of acetic acid was saturated with hydrogen chloride gas and the mixture was allowed to stand at room temperature for 3 hours. The solid product was collected and recrystallized from methanol to give 2-(4-methoxyphenyl)-4,5-dimethyloxazole N-oxide hydrochloride, m.p. 194°-196° C. The latter was converted to the free base for use in the next reaction by treatment with sodium bicarbonate solution.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(C)=O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=1)[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(NC(C)=O)c1
Temperature: 100 °C

Procedure:
To a solution of N-(3-hydroxy-phenyl)-acetamide (0.5 g, 3.3 mmol) in acetone (5 ml) was added K2CO3 (0.46 g, 3.3 mmol), ethyl bromoacetate (0.67 g, 4.0 mmol) and 10 4A molecular sieves. The reaction mixture was then heated in the microwave for 1 h at 100° C. (150 W, 200 psi). The reaction mixture was filtered and the acetone layer evaporated in vacuo. This residue was dissolved in EtOAc (10 ml) and washed with 2M KOH (5 ml×2). The organic layer was dried (Na2SO4), filtered and the solvent removed in vacuo to give the title compound as a colourless oil which solidified upon standing.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]([I+]C1C=CC=CC=1)=[C:13]2[OH:28].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:13]2[OH:28]
Reactant: Nc1ccccc1
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (6-bromo-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)(phenyl)iodoniumtrifluoromethane sulfonate (1.40 g, 2.36 mmol, Intermediate 8, step b) and aniline (1 mL) was stirred for 4 hours at room temperature. To this was added DCM and the resulting suspension was filtered. The solid was washed first with DCM followed by water and air dried under vacuum at 50° C. to yield the title compound.
Reaction SMILES: [NH:1]([C:3](=[O:16])[CH2:4][CH:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1)[NH2:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[C:20]([F:27])[CH:19]=1>ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:2][NH:1][C:3](=[O:16])[CH2:4][CH:5]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:6]2)=[O:26])=[C:20]([F:27])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)NN)C1
Reactant: O=C=Nc1ccc(Br)cc1F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CC(=O)NNC(=O)Nc2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a round bottom flask under nitrogen, a solution of 1,1-dimethylethyl 3-(2-hydrazino-2-oxoethyl)-1-azetidinecarboxylate (15.18 mmol) in dichloromethane (20 mL) at 0° C. was treated with 4-bromo-2-fluorophenylisocyanate (15.18 mmol). The cooling bath was removed and the clear yellow solution was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to afford the crude title compound as a white foamy solid. This material was used directly without further purification. MS(ES)+ m/e 445.2, 447.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[CH:14][C:13]=1[C:24]([F:27])([F:26])[F:25].[OH-].[K+].Cl>CN(C)C=O>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[CH:14][C:13]=1[C:24]([F:25])([F:27])[F:26])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccccc2[N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-nitroaniline (6.91 g.) and 2-chloro-3,5-dinitrobenzotrifluoride (13.53 g.) in dry dimethylformamide (150 ml.) potassium hydroxide (8.0 g, pellets) was added in small portions over 15 minutes. During the addition, the temperature rose from 20° C. to 80° C. When the addition was complete the mixture was stirred for two hours at 60° C., after which concentrated hydrochloric acid was added to acidify the mixture. Industrial methylated spirit (50 ml.) was then added and the mixture stirred for 15 minutes at the ambient temperature. The solid precipitate was collected by filtration, washed with water and dried to yield 2(2-nitroanilino)-3,5-dinitrobenzotrifluoride, melting point 154°-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][NH:13][C:12]3=[O:19])=[N:7][C:6]=12.CS(O[CH2:25][C@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=O)=O>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([CH:16]([CH3:17])[CH3:18])[CH2:14][N:13]([CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:12]3=[O:19])=[N:7][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COS(C)(=O)=O
Reactant: CC(C)[C@H]1CNC(=O)N1c1ccn2ncc(Br)c2n1
Product: CC(C)[C@H]1CN(C[C@H]2CCCN2C(=O)OC(C)(C)C)C(=O)N1c1ccn2ncc(Br)c2n1
Yield: 50 %

Procedure:
(R)-tert-butyl 2-(((S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrrolidine-1-carboxylate (94 mg, 50%) was prepared by the procedure described in Example 38, Step 1, using (S)-1-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-5-isopropylimidazolidin-2-one and (R)-tert-butyl 2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][CH2:37][CH2:38][OH:39])([CH3:35])([CH3:34])[CH3:33].O[C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][CH:45]=[CH:44]2>C(Cl)Cl.O>[C:32]([O:36][CH2:37][CH2:38][O:39][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][CH:45]=[CH:44]2)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OCCO
Reactant: Oc1ccc2[nH]ccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OCCOc1ccc2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.3 %

Procedure:
Add triphenylphosphine (600 mg, 2.29 mmol) to a solution of diethyl azodicarboxylate (0.36 mL, 2.29 mmol) in methylene chloride (10 ml) at 0° C. followed by ethylene glycol mono-t-butyl ether (0.30 mL, 2.29 mmol), and stir the mixture for 20 minutes at 0° C. Add 5-hydroxyindole (200 mg, 1.5 mmol), remove the cold bath, and stir for 5 hours. Add water (2 mL), transfer the resultant mixture to a separatory funnel, and separate the layers. Wash the organic layer with 0.1 N aqueous HCl and brine, then dry over sodium sulfate, filter, and concentrate. Purification by flash chromatography and eluting with hexane:ethyl acetate gives 127 mg (36%) of the title compound as a light yellow solid. Mass spectrum: electrospray (m/z) 232 (M−−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:39])([F:38])[C:27]1[CH:28]=[C:29]([OH:37])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:37][C:29]3[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:27]([C:26]([F:25])([F:38])[F:39])[CH:28]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(NC(=O)c1coc(Oc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 65.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (30 mg, 0.08 mmol) was reacted with 3,5-bis(trifluoromethyl)-phenol (30 mg, 0.13 mmol) to give the title compound (30 mg, 65%) after purification by flash chromatography on silica gel (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10]/[C:11](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:28]\[OH:29])=[CH:5][CH:4]=1
Reactant: Cc1cccnc1C(CC(=O)c1ccncc1)c1ccc(N(C)C)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cccnc1C(C/C(=N\O)c1ccncc1)c1ccc(N(C)C)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-3-(3-methyl-pyridin-2-yl)-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a yellow foam, MS (ESI+): m/z=361.3 ([M+H]+).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[NH:24][C:23](=[O:25])[C:21]3[C:22]4[C:14](=[CH:15][NH:16][C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH2:13]2)(=O)=O)=CC=1.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([N:33]2[CH2:38][CH2:37][N:36]([CH2:11][CH:12]3[NH:24][C:23](=[O:25])[C:21]4[C:22]5[C:14](=[CH:15][NH:16][C:17]=5[CH:18]=[CH:19][CH:20]=4)[CH2:13]3)[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c[nH]c4cccc(c34)C(=O)N2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Product: O=C1NC(CN2CCN(c3ccccc3)CC2)Cc2c[nH]c3cccc1c23
Temperature: 80 °C
Reaction time: 4 h

Procedure:
2.2 g of 4-(p-toluenesulfonyloxymethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole (for preparation see Example 7E) were mixed with 9 ml of 1-phenylpiperazine, and the mixture was stirred at a temperature of 80° C. for 4 hours. Subsequent cooling resulted in the crude title compound crystallising out. It was filtered out and washed with a mixture of equal parts of methanol and water. Drying resulted in 1.7 g of 4-(4-phenyl-1-piperazinylmethyl)- 3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole with a melting point of 184° to 185° C.