Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:7]2
Reactant: Oc1cnc2c(Cl)ccnc2c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cnc2c(Cl)ccnc2c1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 56.3 %

Procedure:
A resealable pressure bottle was charged with 8-chloro-1,5-naphthyridin-3-ol (80 mg, 0.44 mmol), cesium carbonate (433 mg, 1.3 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (360 mg, 1.55 mmol), and DMF (0.9 ml). Vessel sealed and placed in a pre-heated at 50° C. oil bath. Reaction allowed to stir at this temperature for 45 minutes. LC/MS shows complete conversion. Quench with water, dilute with aqueous sodium bicarbonate solution and dichloromethane. Layers separated, organic layer collected and dried over sodium sulfate. This was concentrated to afford yellow oil; which was purified by ISCO silica gel chromatography (20-40% EtOAc/Hexanes) to afford 8-chloro-3-(2,2,2-trifluoroethoxy)-1,5-naphthyridine (65 mg, 56% yield). MS [M+H]=263.0@1.89 minutes. Calc'd for C10H6ClF3N2O=262.6.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)=[C:16]=[O:17]>C(OCC)C>[CH:23]1[C:24]2[C:19](=[C:18]([NH:15][C:16]([NH:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][CH:11]=3)=[O:17])[CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][N:22]=1
Reactant: NCc1ccc(N2CCOCC2)cc1
Reactant: O=C=Nc1cccc2cnccc12
Solvent: CCOCC
Product: O=C(NCc1ccc(N2CCOCC2)cc1)Nc1cccc2cnccc12

Procedure:
The product from Example 66B (285 mg, 1.48 mmol) in diethyl ether (10 mL) was treated with the product from Example 61A. The mixture was filtered and the filter cake purified by chromatography (95:5 CH2Cl2—MeOH, eluant) to provide that title compound as a white solid. The corresponding di-hydrochloride salt was prepared using methanolic HCl to afford a yellow solid (505 mg, 78%). 1H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.67 (s, 1H), 8.52-8.55 (m, 1H), 8.32 (dd, J=7.8 Hz, 1.1 Hz, 1H), 7.92 (d, J=6.1 Hz, 1H0, 7.73 (d, J=8.2 Hz, 1H), 7.60 (m, 1H), 7.23 (d, J=8.8 Hz, 1H), 6.92-6.96 (m, 3H), 4.26 (d, 5.4 Hz, 2H), 3.72-3.75 (m, 4H), 3.06-3.12 (m, 4H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[C:6](F)[C:7]=1[F:8].Cl.C(Cl)Cl.[C:15]([O-])([O-])=[O:16].[Na+].[Na+]>C[O-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[C:6]([O:16][CH3:15])[C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(F)c(F)c(F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(N)cc(F)c1F

Procedure:
A mixture of 3,4,5-trifluorobenzenamine (40 g; 272 mmol) in NaOMe (30% in MeOH) (250 ml) was heated at reflux for 16 h. The reaction mixture was then poured onto ice with 37% aqueous HCl (150 ml)( ). CH2Cl2 was added and the pH of the reaction mixture was adjusted to pH=7-8 using an aqueous solution of Na2CO3. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography over silica gel (eluent: 50:50 heptane/CH2Cl2 to pure CH2Cl2). The pure fractions were collected and the solvent evaporated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH:12]([OH:28])[CH2:11][CH2:10]1.C(#N)C>O.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][C:12](=[O:28])[CH2:11][CH2:10]1
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(O)CCN3c1ccc(Cl)cc1Cl
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: O
Solvent: CC#N
Product: CCN(CC)c1cccc2nc3n(c12)CC(=O)CCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
A mixture of 1-(2,4-dichlorophenyl)-7-(diethylamino)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-4-ol (Example 70; 60.0 mg, 0.143 mmol), tetra-n-propylammonium perruthenate (5.0 mg, 0.014 mmol), 4-methylmorphorine N-oxide (41.9 mg, 0.358 mmol), molecular sieves 4A (60 mg) and acetonitrile (1.5 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, filtered and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound as a solid (26.5 mg, 0.0635 mmol, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:13][C:14]1[C:15]([O:24][CH3:25])=[C:16]([O:22][CH3:23])[CH:17]=[C:18]([CH:21]=1)[CH:19]=O.[C:26](#[N:30])[CH2:27][C:28]#[N:29].C1N2CCN(CC2)C1>C(O)C.O>[NH2:30][C:26]1[O:12][C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][N:7]=3)[C:2]([Cl:1])=[CH:11][C:10]=2[CH:19]([C:18]2[CH:17]=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[C:14]([Br:13])[CH:21]=2)[C:27]=1[C:28]#[N:29]
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: Oc1ccc(Cl)c2cccnc12
Reactant: N#CCC#N
Agent: C1CN2CCN1CC2
Solvent: CCO
Solvent: O
Product: COc1cc(C2C(C#N)=C(N)Oc3c2cc(Cl)c2cccnc32)cc(Br)c1OC
Temperature: 80 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
5-Chloro-8-hydroxyquinoline (790.2 mg, 4.4 mmol), 5-bromo-3,4-dimethoxy-benzaldehyde (1.077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 μl, 1.46 mmol) and then stirred at 80° C. under LC-MS control for 18 h. The reaction mixture was cooled down to room temperature, diluted with water to about 100 ml and the solid were collected by filtration. It was washed with 50% aqueous ethanol. The solids were taken in 15 ml 2-propanol and stirred at 60° C. for 10 minutes, cooled down by dipping the flask in an ice bath, the solids were filtered and dried under vacuum to get the pure title compound (1.25 g, 2.64 mmol, 60%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:19][C:18]=3[CH3:29])=[C:13]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:12]2=[O:35])=[CH:2]1.[CH3:36]N(C)C(=O)C>CC(O)C.[Zn]>[CH:30]([OH:32])=[O:31].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:19][C:18]=3[CH3:29])=[C:13]([C:30]([O:32][CH:33]([CH3:36])[CH3:34])=[O:31])[C:12]2=[O:35])=[CH:2]1
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)C1=C(Nc2ccc(OCCN(C)C)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [Zn]
Solvent: CC(C)O
Product: Cc1cc(OCCN(C)C)ccc1NC1=C(C(=O)OC(C)C)C(=O)C(=Cc2c[nH]c3ncccc23)O1
Product: O=CO
Temperature: 25 °C
Yield: 11 %

Procedure:
A solution of ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.070 mmol) which similarly prepared according to the procedure described in the Example 111, and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0033 g, 0.0035 mmol) in 2-propanol (0.5 mL) and N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0046 g, y. 11%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C([O-])(=O)C.[Na+].[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(OCC)(=O)C>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Br)cc1
Temperature: 25 °C
Yield: 26.2 %

Procedure:
10 g (49.5 mmol) of 2-bromonitrobenzene, 13 g (163 mmol) of sodium acetate, and 10 g (59 mmol) of 4-bromoaniline were stirred at 180° C. for 8 hours in an argon atmosphere. After cooling the reaction solution to room temperature, the reaction solution was diluted with ethyl acetate, and filtered. After concentrating the filtrate, the residue was washed with methanol to obtain 3.8 g of (4-bromophenyl)-(2-nitrophenyl)amine as an orange crystal (yield: 22%).
Reaction SMILES: C(O[C:4]1(O[Si](C)(C)C)[CH2:6][CH2:5]1)C.C1(P(=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:4]1(=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:5][CH2:6]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CC1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A suspension of 38.49 g (220.80 mmol) of [(1-ethoxycyclopropyl)oxy](trimethyl)silane, 100.0 g (287.04 mmol) of ethyl (triphenylphosphoranylidene)acetate and 3.51 g (28.70 mmol) of benzoic acid in 600 ml of toluene is stirred at a bath temperature of 90° C. for 18 hours. After cooling, the mixture is poured onto 800 g of silica gel 60 and eluted successively with in each case 3 liters of petroleum ether 40-60 and dichloromethane. The dichloromethane eluate is, after removal of the solvent, distilled at 160° C. and 14 mbar in a kugelrohr. This gives 17.95 g (64% of theory) of the title compound as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:36])([CH3:35])[C@@H:17]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].BrN1C(C)(C)C(=O)N(Br)[C:40]1=[O:41]>C1C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:36])([CH3:35])[C@@H:17]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH2:18][CH2:19]2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].[CH3:40][OH:41]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 106.1 %

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethylchol-5-en-24-oic acid methyl ester (9.75 g) is dissolved in a warm mixture of 122 ml of benzene and 475 ml of n-hexane, 1,3-dibromo-5,5-dimethylhydantoin (3.95 g) is added and the mixture is refluxed for 15 minutes. After cooling (fast) and evaporating to dryness under reduced pressure, 475 ml of o-xylene and 21.7 ml of quinaldine is added and the mixture is refluxed for 1 hour. After aqueous work-up and trituration with methanol 3β-tert-butyldimethylsilyloxy-4,4-dimethylchola-5,7-dien-24-oic acid methyl ester (8.22 g) is isolated. Melting point: 116-124° C. 1H-NMR (CDCl3, 300 MHz): δ=5.88 (1H, m); 5.52 (1H, m); 3.65 (3H, s); 3.32 (1H, m); 0.89 (9H, s); 0.04 (6H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.O.[N+:9]([CH:12]([CH:15]=O)[CH:13]=O)([O-:11])=[O:10].[Na].CC(O)=O>O>[CH3:1][C:2]1[C:6]2[C:5](=[N:7][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:15]=2)[NH:4][N:3]=1
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Cc1cc(N)[nH]n1
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: Cc1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 90 °C
Yield: 52.1 %

Procedure:
A 5 mL reaction vessel was charged with 3-methyl-1H-pyrazol-5-amine (68 mg, 0.70 mmol), sodium nitromalonaldehyde monohydrate (121 mg, 0.77 mmol) and AcOH (2 mL). The flask was heated to 90° C. under a nitrogen atmosphere overnight. The following day the mixture was poured into water (10 mL), and the precipitate was filtered and rinsed with water (3×5 mL). The precipitate was triturated with minimal Et2O to provide 3-methyl-5-nitro-1H-pyrazolo[3,4-b]pyridine as a solid (65 mg, 52% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 99.9 %

Procedure:
To a 250 ml round bottom flask fitted with a magnetic stirrer was added 4-bromophenylacetic acid (100.0 g; 0.465 mol) and 100 ml of thionyl chloride (163.1 g; 1.37 mol). The resulting slurry was stirred at room temperature for 22.5 hrs. The excess thionyl chloride was evaporated under vacuum to afford 108.5 g of the subtitle compound as a brown liquid.
Reaction SMILES: [N:1]1C=CC=C[C:2]=1C.Cl[S:9]([OH:12])(=O)=[O:10].[CH2:13]([O:20][CH2:21][C@@H:22]1[CH2:26][C@@H:25]([S:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][NH:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O=P(Cl)(Cl)Cl.CN>CCO.COCCOC>[CH3:2][NH:1][S:9]([N:23]1[CH2:24][C@H:25]([S:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:26][C@H:22]1[CH2:21][O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:10]
Reactant: Cc1ccccn1
Reactant: c1ccc(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1
Reactant: O=S(=O)(O)Cl
Agent: CN
Solvent: COCCOC
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CNS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 10 °C
Yield: 28.3 %

Procedure:
SO2NHR (via NSO2Cl) Following a procedure described in U.S. Pat. No. 4,868,308: 2.12 ml (21.5 mmol) Alpha-picoline and 0.19 ml (2.8 mmol) chloro sulfonic acid were added at −10° C. to 30 ml 1,2-dimethoxyethane, warmed up to 10° C. and treated with 431 mg (0.93 mmol) of (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine. The reaction was stirred at room temperature over night, treated with 0.32 ml (3.5 mmol) POCl3 and after 4 h at room temperature with 5 ml 8.03 M MeNH2 in EtOH. The reaction was stirred over night and extracted with aqueous 10% KHSO4/EtOAc (3×), the organic phases were washed with 10% NaCl. The crude product was crystallized from CH2Cl2/Et2O at −20° C. to give 147 mg (28%) of (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-sulfonic acid methylamide, mp 140–142° C., MS: 581 (M+Na+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Br:24][C:25]1[N:26]=[C:27]([CH3:33])[NH:28][C:29]=1[C:30]([OH:32])=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CN([CH:70]=[O:71])C>CCOC(C)=O>[F:20][C:19]([F:22])([F:21])[C:70]([OH:71])=[O:31].[Br:24][C:25]1[N:26]=[C:27]([CH3:33])[NH:28][C:29]=1[C:30]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:23])=[O:32]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Reactant: Cc1nc(Br)c(C(=O)O)[nH]1
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C(F)(F)F)c3)c2F)[nH]1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (33.6 mg, 0.098 mmol), 4-bromo-2-methyl-1H-imidazole-5-carboxylic acid (20 mg, 0.098 mmol) and HATU (37.1 mg, 0.098 mmol) in DMF (5 ml) was added diisopropylethyl amine (0.034 ml, 0.195 mmol) and the mixture was stirred for 20 minutes at rt. The mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-bromo-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-2-methyl-1H-imidazole-5-carboxamide trifluoroacetate (15.0 mg, 0.023 mmol, 24% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (t, 1H), 8.11 (s, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.50 (d, 1H), 7.36 (t, 1H), 4.49 (d, 2H), 2.26 (s, 3H). LC-MS (ES+) m/z 531.10, [M+H].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=O.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH2:20].[Na]>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][NH:20][CH2:19][CH2:18][CH:14]1[CH2:15][CH2:16][CH2:17][N:13]1[CH3:12]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CN1CCCC1CCN
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1cc2ccccc2[nH]1
Yield: 58.3 %

Procedure:
Experimental condition analogous to Example 5, from 1H-indole-2-carbaldehyde 0.14 g (2 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.3 g (2.4 mmol), and sodium triacethoxyborohydride 0.87 g (1.87 mmol), in 20 mL Dichloromethane. The compound was purified using silica gel chromatography elution, ethyl-acetate-methanol-amonium hydroxide: 9-1-0.1 to 8-2-0.2, yield to 0.3 g light brown oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.Cl>C(O)C>[CH:15]1([N:7]2[CH2:8][C:9]([F:14])([F:13])[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: Cl
Solvent: CCO
Product: O=C(O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3)cc1
Yield: 78.9 %

Procedure:
A mixture of 0.20 g (0.66 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20) and 0.11 g (0.79 mmole) of 4-aminobenzoic acid in a 1:4 mixture of 5 mL of ethanol and 1M hydrochloric acid was heated at 100 degrees for 18 hours. After cooling, the precipitate was collected by filtration, washed with water and dried to give 0.21 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-131).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19](O)(=[O:21])[CH3:20].O>O1CCOCC1>[C:19]([NH:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: Nc1cccc2c(=O)[nH]c3ccccc3c(=O)c12
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc2c(=O)[nH]c3ccccc3c(=O)c12

Procedure:
To 2.5 g 10-amino-5,6-dihydro-11H-dibenzo(b,e)azepine-6,11-dione in 50 ml dioxane are added 2 ml anhydrous acetic acid. This mixture is kept at reflux for 2 hours then brought almost to dryness under reduced pressure, and then poured into water, filtered and dried. Yield 2 g (ethanol): melting point 270°-2° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:11]([Si:15]([CH3:17])([CH3:16])[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
4-Nitrophenol (5.6 g, 40 mmol) was dissolved in CH2Cl2 (200 ml) and stirred at room temperature in the presence of tertbutyldimethyl-silyl chloride (7.8 g, 52 mmol), 4-dimethylaminopyridine (0.1 g, 0.8 mmol) and triethylamine (7.2 ml, 52 mmol). After 30 minutes at room temperature, the reaction mixture was washed with H2O (2×200 ml) and the resulting aqueous phases were extracted with CH2Cl2 (100 ml). The combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ether 9:1) to provide tert-Butyl-dimethyl-(4-nitro-phenoxy)-silane (10 g, 100%) as a yellow solid, m.p. 36°-38° C. and MS: m/e=253 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14](=O)[CH3:15])[C:9]2=O)=[CH:5][CH:4]=1.O.[NH2:18][CH2:19][C@H:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]3[CH:13]=[C:14]([CH3:15])[N:18]([CH2:19][C@H:20]([OH:22])[CH3:21])[C:9]=32)=[CH:5][CH:4]=1
Reactant: C[C@@H](O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC(C)=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(cc(C)n1C[C@@H](C)O)C2
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
A solution of 1.45 g of (RS)-6-methoxy-2-(2-oxopropyl)-1-indanone and 60 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 90 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.05 g (61%) of (R)-1-(7-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a yellow solid with m.p. 110°.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)[CH3:3].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH:5]1[C:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][C:4]=1[CH:2]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH3:3]
Reactant: c1c[nH]cn1
Reactant: CC(Cl)c1ccc2c(c1)Cc1ccccc1-2
Solvent: CN(C)C=O
Product: CC(c1ccc2c(c1)Cc1ccccc1-2)n1ccnc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The thus obtained 2-(1-chloroethyl)-9H-fluorene was dissolved in 20 ml of N,N-dimethylformamide, and the solution was mixed with imidazole (2.72 g), followed by stirring at 100° C. for 2 hours. The solvent was evaporated under a reduced pressure, and water was added to the resulting residue, followed by extraction with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure and then the resulting residue was purified by silica gel column chromatography to obtain crude crystals from the eluate of a mixed solvent of chloroform and methanol (200:1). By recrystallizing the crude crystals from a mixed solvent of ethyl acetate and ether, 0.6 g of 1-[1-(9H-fluoren-2-yl) ethyl]-1H-imidazole was obtained.