Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=O)=[N:9]2)=[CH:4][CH:3]=1.[CH3:20][C:21]([NH2:30])([CH3:29])[CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:29][C:21]([NH:30][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:5]2[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:19])([CH3:20])[CH2:22][N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CC(C)(N)CN1CCOCC1
Reactant: O=C(O)c1nn(-c2ccc(Br)nc2)c2c1C[C@H]1C[C@@H]21
Product: CC(C)(CN1CCOCC1)NC(=O)c1nn(-c2ccc(Br)nc2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using (1aR,5aR)-2-(6-bromopyridin-3-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 2-methyl-1-morpholinopropan-2-amine. LCMS m/z=460.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.46 (td, J=4.7, 3.4 Hz, 1H), 1.27 (td, J=7.8, 4.8 Hz, 1H), 1.48 (s, 6H), 2.32-2.37 (m, 1H), 2.63-2.67 (m, 1H), 2.77 (d, J=16.4 Hz, 1H), 2.90 (dd, J=16.4, 6.6 Hz, 1H), 3.14-3.94 (m, 10H), 7.70 (s, 1H), 7.86 (dd, J=8.7, 0.5 Hz, 1H), 8.24 (d, J=7.7 Hz, 1H), 8.97 (s, 1H), 9.39 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH:13]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][N:11]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)[C:10]1=[O:27].C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][N:11]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)[C:10]1=[O:27]
Reactant: CN1C(=O)N(c2nccn2C)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1C(=O)N(c2nccn2C)CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (0.200 g, 1.00 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-bromo-1-methyl-1H-imidazole (0.146 ml, 1.500 mmol) in 1,4-dioxane (8 ml) was added potassium phosphate (1.062 g, 5.00 mmol), copper(I) iodide (0.190 g, 1.000 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.155 ml, 1.000 mmol) and the mixture heated at reflux under argon overnight. The mixture was cooled to room temperature and diluted with dichloromethane. The solid was filtered off, washed with dichloromethane and the filtrate reduced under vacuum. The residue was re-dissolved in dichloromethane and washed with 0.880 ammonia solution (×2), water then brine and passed through a hydrophobic frit and the organic layer reduced under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-10% methanol in dichloromethane to give 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-2-yl)-2-oxo-4-imidazolidinecarboxylate (145 mg, 37.8% yield). LC/MS [M+H]+=281. (ii) Trifluoroacetic acid (0.059 ml, 0.517 mmol) was added to a solution of 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-2-yl)-2-oxo-4-imidazolidinecarboxylate (145 mg, 0.517 mmol) in DCM (2 ml) and the reaction stirred at room temperature overnight. The reaction mixture was co-evaporated with toluene and dried to give 3-methyl-1-(1-methyl-1H-imidazol-2-yl)-2-oxo-4-imidazolidinecarboxylic acid (assume ˜0.517 mmol) which was used which was used in the next step. LC/MS [M+H]+=225.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]3=S)=[N:14][C:15]=2[C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:10]=[CH:11][N:12]=1.[CH:39]1([C:42]([NH:44][NH2:45])=O)[CH2:41][CH2:40]1.C(Cl)Cl>C1COCC1.[Hg](OC(C)=O)OC(C)=O>[CH:39]1([C:42]2[N:28]3[CH2:29][CH2:30][CH2:31][C@@H:26]([C:13]4[N:9]5[CH:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]6[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:3]=6[O:2][CH3:1])[C:8]5=[C:15]([C:16]5[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=5)[N:14]=4)[C:27]3=[N:45][N:44]=2)[CH2:41][CH2:40]1
Reactant: NNC(=O)C1CC1
Reactant: COC(=O)c1ccc(-c2nc([C@@H]3CCCNC3=S)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nc([C@@H]3CCCn4c(C5CC5)nnc43)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
To a solution of (S)-methyl 4-(8-((2,4-dimethoxybenzyl)amino)-3-(2-thioxopiperidin-3-yl) imidazo[1,5-a]pyrazin-1-yl)benzoate (600 mg, 1.13 mmol) in THF (20 mL) was added cyclopropanecarbohydrazide (339 mg, 3.39 mmol) and Hg(OAc)2 (360 mg, 1.13 mmol). The mixture was stirred at RT for 20 minutes and then heated to 65° C. overnight. The reaction mixture was filtered and the filtrate was evaporated, the residue was purified by column chromatography on silica gel eluted with EA:DCM:THF=1:1:1 to give (S)-methyl 4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzoate (300 mg, yield 46%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[F:13].[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[CH2:16]([O:15][P:14]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[F:13])([O:18][CH2:19][CH3:20])=[O:21])[CH3:17]
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(C(=O)OC)cc1F)OCC
Temperature: 145 °C

Procedure:
A mixture of methyl 4-bromomethyl-3-fluorobenzenecarboxylate (240 mg) and triethyl phosphite (0.32 mL) was heated at 145° C. for 2 hours. The reaction solution was purified through silica gel column chromatography (ethyl acetate/methanol=9/1) to obtain the entitled compound (300 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[N:20][C:21]4[N:22]([N:31]=[CH:32][C:33]=4[C:34]([OH:36])=O)[C:23]=3[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:17])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH3:1][C:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[N:20][C:21]4[N:22]([N:31]=[CH:32][C:33]=4[C:34]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:36])[C:23]=3[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:17])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)O)cnn3c1Nc1ccccc1)CC2
Product: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)NS(C)(=O)=O)cnn3c1Nc1ccccc1)CC2
Yield: 74.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(2-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)-7-phenylaminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.030 g, 0.063 mmol) obtained in step 4 and methanesulfonamide (0.030 g, 0.313 mmol), the title compound (0.026 g, 60%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[CH:12]=1.CO.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:23][OH:24]>O>[Cl:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7](=[N:23][OH:24])[C:6]=2[CH:12]=1
Reactant: O=C1CCOc2cc(Cl)c(Cl)cc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: ON=C1CCOc2cc(Cl)c(Cl)cc21
Temperature: 0 °C

Procedure:
A mixture of 6,7-dichloro-2,3-dihydro-4H-1-benzopyran-4-one (59.7 g), methanol (750 ml), water (75 ml), potassium carbonate (76 g), hydroxylamine HCl (76.4 g) was heated at reflux for 4 hours, then poured into ice-water: the oxime of 6,7-dichloro-2,3-dihydro-4H-1-benzopyran-4-one was filtered off, washed with water, with a small volume of ether, then dried in air. Yield: 62.7 g; m.p. 192°-193°.
Reaction SMILES: Br[C:2]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][C:2]2([N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][OH:22])[CH2:26][CH2:27]3)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]2=[O:10])=[CH:15][CH:16]=1
Reactant: COc1ccc(CCCC2(Br)C(=O)NC(=O)NC2=O)cc1
Reactant: OCCN1CCNCC1
Solvent: CCO
Product: COc1ccc(CCCC2(N3CCN(CCO)CC3)C(=O)NC(=O)NC2=O)cc1
Yield: 3.7 %

Procedure:
A of 5-Bromo-5-[3-(4-Methoxyphenyl)propyl]barbituric Acid (710 mg) and N-(2-hydroxyethyl)piperazine (281 mg) in 25 ml of ethanol is refluxed for 4 hours. The solvent is evaporated under reduced pressure and the residue is partitioned between 1 N hydrochloric acid and ethyl acetate. The aqueous phase is basified to pH=6-7 and extracted with ethyl acetate. The organic phase is concentrated to dryness and the residue is crystallized from ethyl acetate to give 30 mg of the product.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([OH:12])[CH:11]=1)(=[O:3])[CH3:2].[C:22]([O:25][C@@H:26]1[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:37]([O:43][C:44](=[O:46])[CH3:45])[C@@H:36]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:35][C@@H:27]1OC(=N)C(Cl)(Cl)Cl)(=[O:24])[CH3:23]>ClCCl>[C:22]([O:25][C@@H:26]1[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:37]([O:43][C:44](=[O:46])[CH3:45])[C@@H:36]([CH2:47][O:48][C:49](=[O:51])[CH3:50])[O:35][C@H:27]1[O:12][C:10]1[CH:11]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:7]=[CH:8][C:9]=1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=1)(=[O:24])[CH3:23]
Reactant: CCc1ccc(Cc2ccc(COC(C)=O)cc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Product: CCc1ccc(Cc2ccc(COC(C)=O)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of 5-acetoxymethyl-2-(4-ethylbenzyl)phenol (0.59 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (1.1 g) in dichloromethane (15 mL) was added boron trifluoride diethyl ether complex (0.31 mL), and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1-3/2) to give 5-acetoxymethyl-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (1.0 g).
Reaction SMILES: [NH2:1][CH2:2]CNC1N=CC(C#N)=CC=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([N+]([O-])=O)=[CH:33][N:32]=2)[CH:24]=[CH:23][C:22]=1[C:40]1[NH:41][CH:42]=[CH:43][N:44]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[N:32]=[CH:33][C:34]([C:2]#[N:1])=[CH:35][CH:36]=2)[CH:24]=[CH:23][C:22]=1[C:40]1[NH:44][CH:43]=[CH:42][N:41]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: N#Cc1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
6-[(2-{[6-(2,4-dichlorophenyl)-5-imidazol-2-yl-2-pyridyl]amino}ethyl)amino]pyridine-3-carbonitrile was prepared from 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile using the general method for [6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[K].[SH:18][CH2:19][CH2:20][OH:21].CN(C)C(=O)C.Cl>>[OH:21][CH2:20][CH2:19][S:18][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Reactant: OCCS
Agent: Cl
Agent: [K]
Solvent: CC(=O)N(C)C
Product: O=c1c2ccccc2sc2ccc(SCCO)cc12

Procedure:
5.6 g (0.0225 mol) of 2-chlorothioxanthone and 2.6 g (0.0225 mol) of the potassium salt of 2-mercaptoethanol are stirred for 18 hours in 20 mol of N,N-dimethylacetamide at 100° C. The reaction mixture is then poured into 2N hydro-chloric acid and extracted with ethyl acetate. After conventional work-up and chromatographic purification, 3.5 g of the analytically pure compound IIIa of melting point 94° C. are obtained.
Reaction SMILES: Br.[F:2][C:3]1[CH:16]=[CH:15][C:6](C(C2CCNCC2)=O)=[CH:5][CH:4]=1.[C:17]([N:20]1[CH2:25][CH2:24][CH:23]([C:26](=O)[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)(=O)[CH3:18].[OH-:35].[Na+].[ClH:37]>>[ClH:37].[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:17][CH2:18][O:35][C:6]3[CH:15]=[CH:16][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:21][CH2:22]2)=[CH:28][CH:29]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: [OH-]
Agent: Br
Agent: Cl
Agent: [Na+]
Product: Fc1ccc(CC2CCN(CCOc3ccc(F)cc3)CC2)cc1
Yield: 98 %

Procedure:
4-(4-Fluorobenzoyl)piperidine hydrobromide. A solution of 1-acetyl-4-(4-fluoro-benzoyl)piperidine (1.20 g, 4.80 mmol) in HCl (6N, 15 mL) was refluxed for 2 h. The cooled solution was made basic (NaOH) and then extracted with benzene (2×40 mL). The collected organic phase was washed with brine (50 mL), dried and was concentrated under reduced pressure. The free amine was dissolved in HBr (saturated solution in MeOH, 10 mL). The precipitated hydrobromide salt was collected, washed with ether (2×4 mL) and dried in vacuo to afford the title compound as a colorless solid (1.54 g, 98%): mp 198° C.; 1H NMR (CD3OD) 1.80-2.00 (m, 2H), 2.05-2.18 (m, 2H), 3.12-3.28 (m, 2H), 3.40-3.50 (m, 2H), 3.70-3.85 (m, 1H), 4.85 (s, 2H), 7.24 (t, J=8.3 Hz, 2H), 8.10 (dd, J=5.7 and 8.7 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:39]1([N:45]=[C:46]=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(OCC)C>[C:39]1([NH:45][C:46]([C:2]2[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[C:4]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:3]=2)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN(Cc1ccccc1)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(Cc1ccccc1)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
1.00 g (0.0023 mol) of 2-bromo-4-{methyl(phenylmethyl) amino}-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 20 ml of diethyl ether. While cooling the solution in a dry ice-acetone bath in an argon atmosphere, 2.2 ml of a 1.6M-hexane solution of BuLi (0.0023×1.5 mol) was added to the solution, followed by stirring the obtained mixture for about 10 minutes. After 0.62 g (0.0023×2.3 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then subjected to precipitation using hexane, thereby obtaining an aimed product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C1COCC1>[C:23]1([O:22][C:20](=[O:21])[NH:4][C:3]2[CH:5]=[C:6]([C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:8][C:2]=2[F:1])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a stirred solution of 2-fluoro-5-(trifluoromethyl)aniline (3.00 g, 16.7 mmol) in THF (80 mL) was added pyridine (2.71 mL, 33.5 mmol), followed by phenyl chloroformate (3.15 mL, 25.1 mmol) at rt. Some solid precipitated out. The mixture was stirred at rt overnight. Water was added to the reaction and it was extracted with EtOAc. The organic solution was washed with water (2×) and dried over MgSO4 and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (10:90 to 30:70 v/v EtOAc-hexanes) to afford the title compound (3.1 g, 62%). 1H-NMR (DMSO-d6) δ 10.36 (br s, 1H), 8.15 (d, J=7.1 Hz, 1H), 7.59 to 7.47 (m, 2H), 7.46 to 7.38 (m, 2H), 7.30 to 7.20 (m, 3H); TLC Rf=0.39 (9:1 v/v hexanes-EtOAc).
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]([N:34]2[CH2:43][C:42]3[CH:41]=[N:40][N:39]([CH3:44])[C:38]=3[NH:37][C:36]3[CH:45]=[CH:46][CH:47]=[CH:48][C:35]2=3)=[O:33])[CH:29]=[CH:28][C:27]=1[CH2:49][CH2:50][C:51](O)=[O:52].[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([CH2:67][NH:68][CH:69]2[CH2:71][CH2:70]2)[CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:56])[CH3:55].CCN(C(C)C)C(C)C>ClCCl.CCOC(C)=O>[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([CH2:67][N:68]([CH:69]2[CH2:70][CH2:71]2)[C:51](=[O:52])[CH2:50][CH2:49][C:27]2[CH:28]=[CH:29][C:30]([C:32]([N:34]3[CH2:43][C:42]4[CH:41]=[N:40][N:39]([CH3:44])[C:38]=4[NH:37][C:36]4[CH:45]=[CH:46][CH:47]=[CH:48][C:35]3=4)=[O:33])=[CH:31][C:26]=2[CH3:25])[CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:55])[CH3:56]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(CNC2CC2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 73 %

Procedure:
PyBroP (238 mg, 0.51 mmol) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (200 mg, 0.51 mmol) and 4-cyclopropylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.51 mmol) in dichloromethane (10 ml) and DIEA (0.18 ml, 1.02 mmol). The mixture was stirred for 4 days at room temperature, diluted with EtOAc, washed with 5% KHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (235 mg, 73%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2.[CH:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([CH3:22])[CH3:21].N1C=CC=CC=1.O>ClCCl.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[CH:20]([C:23]1[CH:28]=[C:27]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:19])=[CH:12][CH:11]=3)[CH:7]=[C:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)ccc2n1-c1cccc(C(C)C)c1
Yield: 35 %

Procedure:
A mixture of 0.2 g (0.73 mmol) of ethyl 5-trifluoromethyloxy-1H-indole-2-carboxylate, of 0.24 g (1.46 mmol) of 3-isopropylphenylboronic acid, of 0.2 g (1.1 mmol) of copper diacetate and of 0.12 ml (1.46 mmol) of pyridine in 5 ml of dichloromethane is stirred in the presence of 4 Å molecular sieve at ambient temperature for 4 days. The mixture is poured onto 100 ml of water and 50 ml of dichloromethane. The organic phase is separated, washed with 1N hydrochloric acid, dried over magnesium sulfate and then concentrated under reduced pressure. The residue is purified by chromatography on a silica column, elution being carried out with a mixture of cyclohexane and of ethyl acetate. 0.1 g of product is obtained, which product is used as is in the following stage.
Reaction SMILES: [CH2:1]1O[C:4]2([CH2:9][CH2:8][C@@H:7]([CH2:10][CH:11]=C)[C@H:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=3[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:5]2)[O:3][CH2:2]1.I([O-])(=O)(=O)=[O:38].[Na+].O1CCCC1.S([O-])([O-])=O.[Na+].[Na+].[OH2:54]>[Os](=O)(=O)(=O)=O.CCOCC>[CH2:2]1[O:3][C:4]2([CH2:9][CH2:8][C@@H:7]([CH2:10][CH:11]=[O:38])[C@H:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=3[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:5]2)[O:54][CH2:1]1
Reactant: C=CC[C@@H]1CCC2(C[C@H]1c1ccc(C(C)(C)CCCCCC)cc1OCc1ccccc1)OCCO2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC3(CC[C@H]2CC=O)OCCO3)c(OCc2ccccc2)c1
Yield: 59 %

Procedure:
A mixture of 17.0 g. (34.7 mmoles) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)cyclohexanone ethylene ketal, 44.5 g. (0.208 mmole) of sodium metaperiodate and 176 mg. (0.69 mmole) of osmium tetroxide in 340 ml. tetrahydrofuran and 100 ml. of water was stirred at room temperature for 3.5 hours. The reaction mixture was then added to 1000 ml. 15% sodium sulfite-1000 ml. ether. The organic phase was separated, washed twice with 500 ml. of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated (aspirator). The residue was purified by column chromatography on 400 g. of silica gel eluted with 33-75% ether-petroleum ether to yield 10.0 g. (59%) of the title compound as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5](I)[CH:6]=[CH:7][CH:8]=1.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1Br)([O-:12])=[O:11]>[Cu]>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CSc1cccc(I)c1
Agent: [Cu]
Product: CSc1cccc(-c2ccccc2[N+](=O)[O-])c1
Temperature: 120 °C

Procedure:
A mixture of 3-methylthioiodobenzene (30 g), 2-nitrobromobenzene (24 g) and copper powder (23 g) was heated at 120° C. for 34 hours to yield a residue which was purified by chromatography on a silica column eluted with hexane to give 3'-methylthio-2-nitrobiphenyl (m.p. 42°-43° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:26]12([CH2:36][NH2:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:37][CH2:36][C:26]12[CH2:35][CH:30]3[CH2:29][CH:28]([CH2:34][CH:32]([CH2:31]3)[CH2:33]1)[CH2:27]2)=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 2.5 h
Yield: 80.5 %

Procedure:
To a solution of 2-chloro-5-nitrobenzoic acid (1.22 g) in N,N-dimethylformamide (1.5 ml) was added carbonyldiimidazole (1.0 g). The resulting reaction mixture was stirred for 2.5 h and then 1-adamantanemethylamine (1.0 g) was added. After 14 h the reaction mixture was partitioned between ethyl acetate and water and the organic layer was separated, washed with water and brine and then dried over sodium sulphate (Na2SO4). The organic layer was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluting with 3-10% methanol in dichloromethane) to yield the subtitle compound as a yellow solid (1.7 g).