Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na][Na].[C:11]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]#[N:22])=[O:19])#[N:12]>CN(C)C=O>[C:21]([N:20]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]([N:13]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]#[N:12])=[O:23])#[N:22]
Reactant: BrCc1ccccc1
Reactant: N#CNC(=O)CCCC(=O)NC#N
Agent: [Na][Na]
Solvent: CN(C)C=O
Product: N#CN(Cc1ccccc1)C(=O)CCCC(=O)N(C#N)Cc1ccccc1

Procedure:
359.2 g (2.0 mols+5% excess) of benzyl bromide are added dropwise to a suspension of 224.1 g (1.0 mol) of the disodium salt of glutaric acid bis-(N-cyanamide) and 1 liter of dimethylformamide at 20°-27° C. in the course of 40 minutes, the components are reacted at 68°-78° C. for 3 hours and 50 minutes and the mixture is then filtered with suction. The filtrate is concentrated on a rotary evaporator at 100° C. in vacuo and the residue is recrystallised from 800 ml of toluene. 253.7 g (70.4% of theory) of a colourless, crystalline product which has a melting point of 97.5°-100.4° C. are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])=[N:37][CH:38]=5)[CH:30]=4)[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[CH3:56][O:57][C:58]([NH:60][C:61]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([CH3:65])[C:62](O)=[O:63])=[O:59].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:53][O:52][C:50](=[O:51])[NH:49][CH:45]([C:44]([N:40]1[CH2:41][CH2:42][CH2:43][CH:39]1[C:36]1[NH:35][C:34]([C:29]2[CH:28]=[CH:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([C:21]4[CH:20]=[CH:19][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:62](=[O:63])[C:61]([NH:60][C:58]([O:57][CH3:56])=[O:59])([C:66]6[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=6)[CH3:65])=[N:17][CH:16]=5)=[CH:23][CH:22]=4)[CH:25]=3)[CH:30]=2)=[CH:38][N:37]=1)=[O:54])[CH:46]([CH3:47])[CH3:48]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C)(C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(C)(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.205 mmol) in CH2Cl2 (2 mL) and MeOH (0.2 mL) was added HCl (in dioxanes, 4 M, 1.0 mL, 4.1 mmol). The solution was stirred at room temperature for 1 h and concentrated to dryness. The resulting solid was dissolved in DMF (2.3 mL). 2-Methoxycarbonylamino-2-phenyl-propionic acid (0.06 g, 0.29 mmol), COMU (0.12 g, 0.27 mmol) and DIPEA (0.2 mL, 1.15 mmol) were added. The reaction was stirred at room temperature for 18 h before HCl (6M, 0.1 mL) was added. The solution was purified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid)) and lyophilized to provide [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.072 g, 42%). LCMS-ESI+: calc'd for C48H52N8O6: 836.40 (M+); Found: 837.87 (M+H+).
Reaction SMILES: [C:1]([N:4]1[CH:7]([S:8][CH3:9])[CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)Cl>[C:1]([N:4]1[CH:7]([S:8]([CH3:9])=[O:19])[CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2]
Reactant: CSC1CC(=O)N1C(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)N1C(=O)CC1S(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.8 %

Procedure:
A mixture of 130 mg (0.82 mM) N-acetyl-4-methylthioazetidinone and 200 mg (0.93 nM) 80% m-chloroperbenzoic acid in 5 ml methylene chloride was stirred at room temperature 5 minutes. After removing the solvent in vacuo. The residue was chromatographed on 2-2000μ silica gel plates in hexane/ethyl acetate to yield 57 mg (40%) of 1-acetyl-4-methylsulfinylazetidine-2-one.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:17])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: Cc1nn(-c2ccccc2)c2cc(Br)ccc12
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ccccc2)c2cc(N3CCNCC3)ccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-bromo-3-methyl-1-phenyl-1H-indazole (1 g, 3.50 mmol, 1.00 equiv) in toluene (20 mL), piperazine (600 mg, 6.98 mmol, 2.00 equiv), Cs2CO3 (1.7 g, 5.21 mmol, 1.50 equiv), Pd(AcO)2 (20 mg, 0.09 mmol, 0.03 equiv), BINAP (20 mg, 0.03 mmol, 0.03 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was cooled, the solids were filtered out. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue (300 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC (UV-Directed)): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, water with 0.05% TFA and MeOH (10% MeOH up to 42% in 4 min, hold 42% in 3.5 min, up to 100% in 0.1 min, hold 100% in 1.4 min); Detector, UV 220NMnm to yield 3-methyl-1-phenyl-6-(piperazin-1-yl)-1H-indazole as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15]C)=[O:13])[NH:6]2.[Mg]>>[CH3:15][O:14][C:12]([CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=2[Cl:1])[NH:6]1)=[O:13]
Reactant: CCOC(=O)c1cc2c(Cl)c(Cl)ccc2[nH]1
Agent: [Mg]
Product: COC(=O)C1Cc2c(ccc(Cl)c2Cl)N1

Procedure:
This compound was prepared from ethyl 4, 5-dichloroindole-2-carboxylate as described in Example 1, using 6-7 eq. of magnesium turnings instead of 2-3 eq. of magnesium turnings.
Reaction SMILES: CN1CCN(C2C=CC(N[CH:15]=[C:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([C:27]5[CH:28]=[C:29]([NH:33][C:34]([C:36]6[C:40]([Cl:41])=[CH:39][N:38]([CH2:42][CH3:43])[N:37]=6)=[O:35])[CH:30]=[CH:31][CH:32]=5)=[O:26])=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:44])=CC=2)CC1.C1COCC1.[NH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][CH2:59][C:60]([OH:62])=[O:61])=[CH:53][CH:52]=1>CCOC(C)=O.CCCCCC>[Cl:41][C:40]1[C:36]([C:34]([NH:33][C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=2)[C:25]([C:21]2[CH:20]=[C:19]3[C:24]([C:16](=[CH:15][NH:50][C:51]4[CH:52]=[CH:53][C:54]([CH2:57][CH2:58][CH2:59][C:60]([OH:62])=[O:61])=[CH:55][CH:56]=4)[C:17](=[O:44])[NH:18]3)=[CH:23][CH:22]=2)=[O:26])=[O:35])=[N:37][N:38]([CH2:42][CH3:43])[CH:39]=1
Reactant: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)n1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCCC(=O)O)cc3)c2)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
A small screw cap test tube was charged with 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylic acid [3-(3-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 342, 100 mg, 0.229 mmol) and THF (2.5 mL). To the resulting solution was added 4-(4-Amino-phenyl)-butyric acid (41.4 mg, 0.231 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (5 mL) and Hexane (˜40 mL). The solid that precipitated was collected by filtration and washed with 0° C. acetone (˜10 mL) affording the title compound in 45% yield (0.061 g, 0.102 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:15][C@@H:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:13][C@H:12]1[CH2:11][O:10][NH:9]2.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C.[Zn]>[NH2:9][C@@:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:15][C@@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:13][C@H:12]1[CH2:11][OH:10]
Reactant: Fc1ccc(CO[C@H]2C[C@H]3CON[C@@]3(c3ccccc3F)C2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N[C@@]1(c2ccccc2F)C[C@@H](OCc2ccc(F)c(F)c2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
Zinc (3.0 g) was added to a solution of (3aR*,5S*,6aS*)-6a-(2-fluorophenyl)-5-(3,4-difluorobenzyloxy)-hexahydrocyclopenta[c]isoxazole (620 mg) in acetic acid (25 mL), and the mixture was stirred at room temperature for two hours. A saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and zinc was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (630 mg).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([NH:10][CH2:11][CH3:12])[CH:3]=1.[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[NH:9][C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1
Reactant: CCNc1cc(Br)sc1C(N)=O
Reactant: O=C1CCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CCN1c2cc(Br)sc2C(=O)NC12CCCC2
Temperature: 90 °C
Reaction time: 24 h
Yield: 55.8 %

Procedure:
A mixture of 5-bromo-3-(ethylamino)thiophene-2-carboxamide (500 mg, 2.0 mmol), cyclopentanone (0.53 mL, 6.0 mmol), CSA (46 mg, 0.20 mmol), MgSO4 (384 mg, 4.0 mmol) and DMA (1.5 mL) was stirred at 90° C. for 1 day. The mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to 50:50 hexane/EtOAc) to give a brown solid. The solid was washed with EtOAc to give the title compound (352 mg, 56%) as a pale brown solid:
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C:31]2=[O:36])=[CH:26][C:25]=1[F:37]>>[F:37][C:25]1[CH:26]=[C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C:31]2=[O:36])[CH:28]=[CH:29][C:24]=1[NH:23][C:4]([CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)=[O:22]
Reactant: CCOC(=O)CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Reactant: Nc1ccc(N2CCOCC2=O)cc1F
Product: CO[C@H]1CN(CC(=O)Nc2ccc(N3CCOCC3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
Using general procedure F {(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidin-1-yl}-acetic acid ethyl ester (example 25.2) was reacted with 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (CAS 438056-69-0) to give 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-1-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcar-bamoyl]-methyl}-4-methoxy-pyrrolidin-3-yl)-amide. Yellow solid. MS 511.3 ([M+H]+)
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9]([NH2:14])=[N:10][C:11]=2Cl)[N:6]([C@@H:15]2[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]2[O:17][C:18](=[O:20])[CH3:19])[C:5]1=[O:33])[CH:2]=[CH2:3]>C(O)(=O)C>[CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9]([NH2:14])=[N:10][CH:11]=2)[N:6]([C@@H:15]2[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]2[O:17][C:18](=[O:20])[CH3:19])[C:5]1=[O:33])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)n([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c2nc(N)nc(Cl)c21
Solvent: CC(=O)O
Product: C=CCn1c(=O)n([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c2nc(N)ncc21
Temperature: 70 °C
Yield: 59.6 %

Procedure:
Compound 41 (0.27 g, 0.56 mmol) was dissolved in acetic acid and Zn—Cu couple was added to the solution. The mixture was heated at 70° C. for 18 h. The suspended particles were filtered off and the filtrate concentrated under vacuum. The residue was purified by flash chromatography using 10% to 100% gradient of ethyl acetate in hexanes. The solvent was removed to give 150 mg (60%) of 42 as off-white solid: 1H NMR (400 MHz, CDCl3) δ 6.05 (t, J=4.0 Hz, 1H), 6.03 (d, J=4.0 Hz, 1H), 5.87 (t, J=6.0 Hz, 1H), 5.83 (m, 1H), 5.48 (br s, 2H), 5.33 (s, 1H), 5.29 (d, J=5.6 Hz, 1H), 4.49 (d, J=3.2 Hz, H), 4.46 (d, J=3.2 Hz, 1H), 4.41 (d, J=5.6 Hz, 2H), 4.27 (m, 2H), 2.12 (s, 3H), 2.10 (s, 3H), 2.05 (s, 3H); MS (+)-ES [M+H]+ 450.0 m/z.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:17]12[CH2:23][CH:20]([CH:21]=[CH:22]1)[CH2:19][CH:18]2[C:24](Cl)=[O:25]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:24]([CH:18]3[CH2:19][CH:20]4[CH2:23][CH:17]3[CH:22]=[CH:21]4)=[O:25])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: O=C(Cl)C1CC2C=CC1C2
Product: CCC(NC(=O)C1CC2C=CC1C2)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 120 mg (0.74 mmol) bicyclo[2.2.1]hept-5-ene-2-carbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:22])[CH2:13][CH2:14][NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17].[H-].[Na+]>>[CH3:11][N:12]([CH3:22])[CH2:13][CH2:14][N:15]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCS(=O)(=O)NCCN(C)C
Agent: [H-]
Agent: [Na+]
Product: CCCS(=O)(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 1-fluoro-4nitro-benzene, N-(2-dimethylamino-ethyl)-propanesulphonamide and sodium hydride as base
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH:3]1[CH2:6][N:5]([C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[C:9]([O:33][CH3:34])[CH:8]=2)[CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:35][N:2]([CH3:1])[CH:3]1[CH2:4][N:5]([C:7]2[CH:8]=[C:9]([O:33][CH3:34])[C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[CH:11][C:12]=2[NH2:13])[CH2:6]1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 79.6 %

Procedure:
A mixture of N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 117, 160 mg, 0.34 mmol), iron (113 mg, 2.03 mmol) and NH4Cl (13.56 mg, 0.25 mmol) in ethanol (5 mL) and water (1.67 mL) was heated at reflux for 2 h. The cooled mixture was purified by ion exchange chromatography, using an SCX column and eluting with 1:1 7M methanolic ammonia in CH2Cl2. Appropriate fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (120 mg, 80%) as a brown gum; m/z: ES+ MH+ 444.61.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)CC(C)=O
Product: CC(=O)C(=Cc1ccc(C(F)(F)F)cc1)C(C)=O

Procedure:
4-Trifluoromethylbenzaldehyde (8,7 g) was condensed with 2,4-pentanedione (5,01 g) in a similar manner as described above. The crude product was crystallized from a mixture of ether-petroleum ether (1:1), mp 46°-48° C., yield 3.8 g (30%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([Cl:27])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C([O-])(O)=O.[Na+]>[Cl:27][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[C:23]([F:24])([F:25])[F:26])[O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.9 %

Procedure:
Entire reaction was performed under argon atmosphere using syringe septa technique. {2-[4-(3-chloro-4-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3.703 mmol, 1 eq) was dissolved in dichloromethane (20 ml) and stirred at 0° C. for 5 min. TFA (18.517 mmol, 5 eq) was added and stirring was continued overnight. Reaction mixture was diluted with 10 ml NaHCO3 (sat.) and extraction with DCM (3×20 ml) followed. Organic layers were combined and evaporated in vacuo to give 2-[4-(3-chloro-4-trifluoromethyl-phenoxy)-phenyl]-ethylamine (2.661 mmol, yield=72%, purity=99%). [M+H]+=316.21 1H NMR (300 MHz, CDCl3) δ/ppm 2.68-2.82 (m, 2H), 2.91-3.05 (m, 2H), 6.81-6.91 (m, 1H), 6.93-7.07 (m, 4H), 7.16-7.23 (m, 1H), 7.52-7.63 (m, 1H)
Reaction SMILES: [NH:1]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO>[Pd].CC(O)=O>[NH:1]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Yield: 92.9 %

Procedure:
Boc-Phe-Gly-OBzl (6.2 g, 15 mmole) was suspended in the mixtured solvent of MeOH (80 ml) and AcOH (30 ml), and then H2 gas was passed through the solution in the presence of Pd-C for 4 hours. Pd-C was removed by filtration, and the solvent was distilled off. The thus-obtained residue was recrystalized two times with AcOEt/n-hexane to obtain the object product (4.49 g, 92.8%).
Reaction SMILES: [NH:1]([C:3]1[N:8](CC(C)C)C(=O)N(C)C(=O)C=1)N.ClC1C=C2C(=CC=1)NC=C2C=O.C(C1C=C(C=O)N(C)C=1)(=O)C.[C:39]([C:42]1[CH:43]=[C:44]([C:48]2[N:49]([CH2:64][C:65]3[C:73]4[C:68](=[CH:69][CH:70]=[C:71]([Cl:74])[CH:72]=4)[NH:67][CH:66]=3)[N:50]=[C:51]3[C:56]=2[C:55](=[O:57])[N:54]([CH3:58])[C:53](=[O:59])[N:52]3[CH2:60][CH:61]([CH3:63])[CH3:62])[N:45]([CH3:47])[CH:46]=1)(=O)[CH3:40].C[Si](N=C=N[Si](C)(C)C)(C)C>ClCCl.Cl[Ti](Cl)(Cl)Cl>[Cl:74][C:71]1[CH:72]=[C:73]2[C:68](=[CH:69][CH:70]=1)[NH:67][CH:66]=[C:65]2[CH2:64][N:49]1[C:48]([C:44]2[N:45]([CH3:47])[CH:46]=[C:42]([C:39](=[N:8][C:3]#[N:1])[CH3:40])[CH:43]=2)=[C:56]2[C:51]([N:52]([CH2:60][CH:61]([CH3:62])[CH3:63])[C:53](=[O:59])[N:54]([CH3:58])[C:55]2=[O:57])=[N:50]1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: CC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)c1cc(C=O)n(C)c1
Agent: C[Si](C)(C)N=C=N[Si](C)(C)C
Solvent: ClCCl
Product: CC(=NC#N)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
This compound was made in two steps following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first 5-chloro-1H-indole-3-carbaldehyde, followed by 4-acetyl-1-methyl-1H-pyrrole-2-carbaldehyde. The isolated 3-(4-acetyl-1-methyl-1H-pyrrol-2-yl)-2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione was treated with a cold solution of bis(trimethylsilyl)carbodiimide and TiCl4 at 0° C. in anhydrous dichloromethane. The mixture was stirred at room temperature for 4 h. The crude reaction product was purified by semi-prep RPHPLC eluting with water/acetonitrile/trifluoroacetic acid mixtures. 531.2 (M+H).
Reaction SMILES: [C:1]([CH2:4][C:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])([OH:12])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)(=[O:3])[NH2:2].[H-].[Na+].[CH3:23]I>O1CCCC1>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:5]([OH:12])([CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)[CH2:4][C:1](=[O:3])[NH:2][CH3:23]
Reactant: NC(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
1-Carbamoyl-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1.0 g) was dissolved in dry tetrahydrofuran (20 ml) and the reaction mixture was cooled to 0°-5° C. Sodium hydride (0.15 g, as a 50% dispersion in oil) was then added, the mixture stirred for 10 minutes and methyl iodide (0.45 g) added. Further quantities of methyl iodide (90 mg) and sodium hydride (375 mg, as a 50% dispersion in oil) were added. After stirring for a few minutes, yet further quantities of methyl iodide (90 mg) and sodium hydride (375 mg, as a 50% dispersion in oil) were added. The mixture was then quenched in water and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried (MgSO4) and evaporated to give the crude product as a gum. A solution of this gum in methylene chloride (20 ml) was chromatographed on a silica gel column (10 g), eluting with methylene chloride (100 ml), then with methylene chloride containing 2% isopropanol and 0.2% NH4OH (300 ml), and finally with methylene chloride containing 5% isopropanol and 0.5% NH4OH (500 ml). Appropriate fractions were collected to yield the title compound, which was recrystallized from cyclohexane (yield 41 mg, m.p. 151°-154° C.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(O)(=O)C>[F:20][C:8]1[C:9]([F:19])=[C:10]([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])=[C:12]([F:13])[C:7]=1[N:6]1[C:2]([NH:1][C:21]([CH3:22])=[O:23])=[CH:3][CH:4]=[N:5]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: CC(=O)O
Product: CC(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 7.48 grams (0.0250 mole) of 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)pyrazole, 21.0 mL of glacial acetic acid, and 3.1 mL of acetic anhydride was stirred at room temperature for approximately 18 hours. The reaction mixture was poured into 100 mL of ice-water, forming a white precipitate. This solid was collected by filtration and washed in succession with dilute acetic acid and water. The washed solid was dried to yield 8.1 grams of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonylaminopyrazole, m.p. 103-105° C. The nmr spectrum was consistent with the proposed structure.