Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].C([Li])CCC.[CH2:16]([Mg]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]#[N:10]
Reactant: N#CCc1ccccc1F
Reactant: Br[Mg]Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CC(Cc1ccccc1)c1ccccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A solution of 2-(2-fluorophenyl)acetonitrile (2.1 g, 15.5 mol) in tetrahydrofuran (50 ml) and hexane (20 ml) was treated with n-butyl lithium (6.2 ml, 15.5 mol) at −78° C. The mixture was stirred at −78° C. for one hour. A solution of benzyl magnesium bromide (2.02 ml, 17.05 mmol) in hexane (10 ml) was added at −78° C. The mixture was stirred at −78° C. for two hours, then warmed to room temperature and stirred at room temperature overnight. The mixture was quenched with water and extracted in ether. The combined organic layers were washed with brine, dried with magnesium sulfate then filtered and evaporated. Purification by MPLC with 3 to 5% MeOH:CH2Cl2 afforded 2-(2-fluorophenyl)-3-phenylpropanenitrile, (Intermediate 11), (3.4 g).
Reaction SMILES: [C:1]12([C:11]3[C:12](=[O:17])[NH:13][NH:14][C:15]=3[CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[C:1]12([N:13]3[C:12](=[O:17])[CH:20]=[C:19]([CH3:21])[N:14]3[CH:15]([CH3:16])[CH3:11])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2.[C:1]12([C:11]3[C:12](=[O:17])[NH:13][N:14]([CH:19]([CH3:21])[CH3:20])[C:15]=3[CH3:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)Br
Reactant: Cc1[nH][nH]c(=O)c1C12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Product: Cc1c(C23CC4CC(CC(C4)C2)C3)c(=O)[nH]n1C(C)C
Product: Cc1cc(=O)n(C23CC4CC(CC(C4)C2)C3)n1C(C)C
Reaction time: 48 h
Yield: 34.5 %

Procedure:
A sealable tube was charged with 4-adamantan-1-yl-5-methyl-1,2-dihydro-pyrazol-3-one (0.05 g), 2-bromopropane (0.026 g) and DMF and purged with argon and sealed. The reaction vessel was immersed into a heated oil bath at 110 degrees C. for 48 hours. The reaction vessel was then cooled and opened carefully. The reaction mixture was diluted with EtOAc and aq. NaHCO3 solution and the phases were separated. The aqueous layer was extracted with further EtOAc and the combined organic layers were washed with sodium thiosulfate. The phases were then dried over sodium sulfate, filtered and reduced in vacuo. The crude gum was chromatographed by adsorption onto silica gel and subjection to Isco Combiflash chromatography. Evaporation of the desired fractions afforded the desired product 4-adamantan-1-yl-1-isopropyl-5-methyl-1,2-dihydro-pyrazol-3-one (0.01 g) as an off white material. MS (ESI+): 275.3 [M+H]+).
Reaction SMILES: C(N1C(=O)CCC1=O)(=O)C.C[Si](C)(C)N1C(=O)CCC1=O.C[Si](C)(C)[O:24][C:25]([CH:27]([N:31]1[CH:34]([S:35][N:36]2[C:40](=[O:41])[CH2:39][CH2:38][C:37]2=[O:42])[CH:33]([NH:43][C:44](=[O:52])[CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:32]1=[O:53])[C:28]([CH3:30])=[CH2:29])=[O:26].C>C1C=CC=CC=1>[C:25]([CH:27]([N:31]1[CH:34]([S:35][N:36]2[C:37](=[O:42])[CH2:38][CH2:39][C:40]2=[O:41])[CH:33]([NH:43][C:44](=[O:52])[CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:32]1=[O:53])[C:28]([CH3:30])=[CH2:29])([OH:26])=[O:24]
Reactant: C=C(C)C(C(=O)O[Si](C)(C)C)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Agent: CC(=O)N1C(=O)CCC1=O
Agent: C[Si](C)(C)N1C(=O)CCC1=O
Solvent: c1ccccc1
Product: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
A mixture of 5.3 g of benzylpenicillin-S-sulphoxide, 50 g of N-acetylsuccinimide, 12.5 ml of N-trimethylsilylsuccinimide and 35 ml of benzene was refluxed for 16 hours. The reaction mixture (containing 1-(1-trimethylsilyloxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one) was then allowed to cool to room temperature, diluted with benzene (200 ml), treated with decolourizing charcoal, and evaporated to dryness. The residue was purified by column chromatography on silica gel using 5% acetic acid in ethyl acetate as eluent. The fractions containing the major component of the original residue were combined, evaporated to dryness and the residue triturated with diethyl ether. The precipitate was chromatographed a second time to obtain 1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothioazetidin-2-one in a pure state. The structure was confirmed by PMR and IR spectroscopy.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[NH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>>[CH3:31][C:28]([NH:27][C:22]([C:21]1[CH:25]=[CH:26][C:18]([C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:5]3[C:4]([NH:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:11][CH2:12]2)=[O:17])=[N:19][CH:20]=1)=[O:23])([CH3:32])[CH2:29][OH:30]
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: CC(C)(N)CO
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(C)(C)CO)cn2)CC1
Yield: 70 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2-amino-2-methyl-1-propanol. And then, the product was recrystallized to give a desired compound.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[CH3:13][C:3]1[C:2]([N:24]2[CH2:23][CH2:22][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:26][CH2:25]2)=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1ccnc(Cl)c1C
Product: CCOC(=O)c1ccnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C

Procedure:
Step (i) of Example 106 was repeated, except that the compound prepared in step (a) of Example 109 was used instead of 3-bromo-7,8-dihydro-6H-1,6-naphthyridin-5-one and 1-tert-butoxycarbonylpiperazine was used instead of 3,3-diphenyl-1-propylpiperazine. Thus, ethyl 3-methyl-2-[4-(tert-butoxycarbonyl)piperazin-1-yl]isonicotinate was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:14][C:15]1[CH:19]=[N:18][N:17]([CH3:20])[C:16]=1[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]([CH3:35])([N+:32]([O-])=O)[CH3:31])[NH2:24].C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH2:32])([CH3:35])[CH3:31])=[C:21]([C:16]3[N:17]([CH3:20])[N:18]=[CH:19][C:15]=3[Br:14])[CH:22]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)Nc2ccc(OCC(C)(C)N)c(-c3c(Br)cnn3C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
4-Acetamidobenzoyl chloride (11 mg, 0.06 mmol) was added to a solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (18 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μl, 0.06 mmol) in dichloromethane (0.5 mL) and the mixture was stirred at room temperature. After 1 h, the solution was diluted with dichloromethane, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in methanol (0.5 mL). Acetic acid (0.1 mL) was added followed by zinc dust (33 mg) and the mixture was stirred at room temperature. After 4 h, the suspension was made basic with ammonium hydroxide and extracted twice with ethyl acetate. The combined extracts were evaporated to dryness, purified by preparative LCMS and lyophilized to give the product (5.6 mg, 22%) as a TFA-salt. LCMS m/z (%)=502.3 (M+H 81Br 42.9%), 500.4 (M+H 79Br 52.1%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (s, 3 H), 1.18 (s, 3 H), 2.08 (s, 3 H), 3.67 (s, 3 H), 3.82 (d, J=9.60 Hz, 1 H), 3.98 (d, J=9.85 Hz, 1 H), 7.27 (d, J=9.09 Hz, 1 H), 7.67 (s, 1 H), 7.69 (d, J=2.78 Hz, 1 H), 7.71 (d, J=8.84 Hz, 2 H), 7.85-7.91 (m, 3 H), 7.91 (d, J=8.84 Hz, 2 H), 7.95 (dd, J=8.97, 2.65 Hz, 1 H), 10.22 (s, 1 H), 10.23 (s, 1 H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[N:8][CH:7]=1>>[OH:16][C:9]1[C:10]2[C:15](=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=[CH:12][CH:11]=2)[N:6]=[CH:7][N:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ncnc2ccccc12
Product: O=S(=O)(Cl)c1cccc2c(O)ncnc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 581.7 %

Procedure:
Chlorosulfonic acid (4.10 mL, 62.6 mmol) was slowly added to quinazolin-4-ol (1.09 g, 0.26 mmol). The resulting mixture was heated to 140° C. and stirred for 3 hours at the same temperature. After cooling to room temperature, the reaction mixture was poured into crushed ice. The mixture was extracted with DCM (100 mL×3), the combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified via flash chromatography (5% PE:Ethyl Acetate) to give 370 mg of 4-hydroxyquinazoline-8-sulfonyl chloride. 1H NMR (400 MHz, DMSO-d6) δ: 7.76 (t, J=7.79 Hz, 1 H) 8.26 (ddd, J=9.67, 7.92, 1.48 Hz, 2 H) 9.02 (s, 1 H). LC-MS: m/z 245.7 (M+H)+
Reaction SMILES: C([O:5][C:6]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)=[O:7])(C)(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](OC2C=CC=CC=2)=[O:33])[C:24](=[CH:29][CH:30]=1)[C:25](OC)=[O:26]>>[C:6]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([S:16]([N:19]2[C:25](=[O:26])[C:24]3[C:23](=[CH:22][C:21]([Cl:20])=[CH:30][CH:29]=3)[NH:31][C:32]2=[O:33])(=[O:17])=[O:18])[CH:13]=[CH:14][CH:15]=1)([OH:5])=[O:7]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)CNc1cccc(S(N)(=O)=O)c1
Product: O=C(O)CNc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Yield: 9 %

Procedure:
From 1.62 g (5.65 mmol) of 3-t-butoxycarbonylmethylaminobenzenesulfonamide and 1.73 g (5.65 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate in a similar manner to Preparation Example 7, 209 mg (yield 9%: 4 steps) of the title compound was obtained. Property: colorless crystals, melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6): 3.86 (2H, s), 6.88 (1H, s), 7.12 (1H, s), 7.24 (1H, d), 7.30-7.38 (3H, m), 7.86 (1H, d), 11.61 (1H, br).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH2:27].O=O>CN(C=O)C.Cl[Cu].Cl[Pd]Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:1][C:2](=[O:27])[CH3:3])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: CN(C)C=O
Product: CC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Yield: 92 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (5 g, 12 mmol) and CuCl (2.75 g, 27.8 mmol) in dry DMF (50 mL) was added H2O (20 mL) and PdCl2 (950 mg, 3.2 mmol) at room temperature. The mixture was vigorously stirred under a balloon of oxygen for 24 h. After TLC showed the starting material had disappeared, the solid was filtered off. Water (200 mL) and EtOAc (50 mL) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (5.25 g, 92%), which was purified by column chromatography. 1H NMR (CDCl3): 1.47 (s, 3H), 2.06 (s, 3H), 2.10-2.36 (m, 3H), 2.58 (m, 1H), 2.90 (m, 2H), 5.58 (m, 1H), 6.69 (m, 1H), 6.79 (m, 1H), 7.02 (m, 2H), 7.19-7.33 (m, 4H).
Reaction SMILES: N[C:2]1S[C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1C(OCC)=O.[C:14]([C:19]1[CH:23]=[C:22]([CH2:24][CH3:25])[S:21][C:20]=1[NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])([O:16][CH2:17][CH3:18])=[O:15].C(I)CCCCC>>[CH2:13]([N:26]([C:20]1[S:21][C:22]([CH2:24][CH3:25])=[CH:23][C:19]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])[CH2:12][CH2:4][CH2:5][CH2:6][CH3:2]
Reactant: CCOC(=O)c1cc(CC)sc1N
Reactant: CCOC(=O)c1cc(CC)sc1NC(=O)C(C)C
Solvent: CCCCCCI
Product: CCCCCCN(C(=O)C(C)C)c1sc(CC)cc1C(=O)OCC

Procedure:
Ethyl 2-amino-5-ethyl-3-thiophenecarboxylate (Chemische Berichte 99, 94 (1966)) was converted into N-(3-carbethoxy-5-ethyl-2-thienyl)-2-methylpropanamide by the method described in Example 41. Alkylation of the unpurified product with n-hexyl iodide as described in Example 43 gave the title compound as a light yellow oil, b.p. 145°-147° C./0.25 mm. NMR showed that the material was the correct product.
Reaction SMILES: [C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[S:28](=[O:32])(=[O:31])([OH:30])[OH:29]>>[S:28]([O-:32])([OH:31])(=[O:30])=[O:29].[C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH+:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=S(=O)(O)O
Reactant: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: C[NH+]1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: O=S(=O)([O-])O
Yield: 84.9 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and sulfuric acid (0.15 mL, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium hydrogensulfate as a crystalline white solid (1.07 g, 85% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:23]=[C:22]2[C:9]([C:10]3[CH:34]=[C:14]([C@@H:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:16][CH:17]=[CH:18][C@@H:19]([CH3:25])[C:20](=[O:24])[NH:21]2)[N:13]=[CH:12][CH:11]=3)=[CH:8][CH:7]=1)=[O:4].C([O-])(=[O:37])C.[Na+].OO>C1COCC1.O>[OH:37][CH:17]1[CH2:16][C@H:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:14]2=[CH:34][C:10](=[CH:11][CH:12]=[N:13]2)[C:9]2[C:22](=[CH:23][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:7][CH:8]=2)[NH:21][C:20](=[O:24])[C@H:19]([CH3:25])[CH2:18]1
Reactant: CC(=O)[O-]
Reactant: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)C=CC[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Agent: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)/C=C/C[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CC(O)C[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl N-[(10R,11E,14S)-5-[(methoxycarbonyl)amino]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(18),2,4,6,11,15(19),16-heptaen-14-yl]carbamate (634 mg, 1.36 mmol) 1H in THF (13.6 mL) at 0° C. was added borane tetrahydrofuran complex (4.08 mL, 4.08 mmol) dropwise. The reaction was allowed to warm up to rt and stirred for 2.5 h. The reaction mixture was cooled to 0° C. and added sodium acetate (9.06 ml, 27.2 mmol), followed by hydrogen peroxide (4.16 mL, 40.8 mmol) dropwise. The reaction was warmed up to rt and stirred at for 8 h. The mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to yield a mixture of two products 22A and 22B (323 mg, 49%) as a light grey solid. MS (ESI) m/z: 485.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[NH:5][CH:6]=1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][C:15](=[O:16])[N:5]2[CH:6]=1
Reactant: Cc1c[nH]c(Cc2ccccc2N)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1cn2c(n1)Cc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 18.61 g of 4-methyl-2-(2-aminobenzyl)imidazole, 16.12 g of 1,1'-carbonyldiimidazole and 375 ml of methylene chloride is stirred at room temperature overnight. The methylene chloride is evaporated to a small volume, the mixture is cooled to 0° and the solids are filtered and washed with ether to give 2-methyl-11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-one, m.p. 234.5°-236.5°.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=O)C.O.[NH2:22][NH2:23]>CO>[NH:22]([C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=[O:3])[NH2:23]
Reactant: CCOC(=O)c1nc(-c2cccc3ccccc23)no1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc(-c2cccc3ccccc23)no1
Yield: 74.7 %

Procedure:
5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (10.0g.) was dissolved in methanol (150 ml.) and hydrazine hydrate (10.0g.) added dropwise with cooling. The mixture was stirred for fifteen minutes and the crystalline precipitate was filtered off, washed with methanol (10 ml.), and dried to give title compound (7.08 g), m.p. 211°-212° (decomp.) λmax. (EtOH) 302 nm (ε 10,100) νmax. (Nujol) 1680 cm.-1 (--CONH--).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:9][C:8]=1[F:22])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.B(OC)(OC)[O:31]C.C(O)(=O)C.OO.O>C1COCC1>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[C:8]([F:22])=[C:9]([OH:31])[CH:10]=[C:11]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]C(C)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-4-(tert-butyl-dimethyl-silanyloxymethyl)-1-fluoro-benzene (23.70 g, 63.9 mmol, 1.0 equiv) in anhydrous THF (130 mL) was added at −78° C. under Ar a solution of sec-BuLi (54.5 mL, 71.6 mmol, 1.1 equiv, 1.3 M solution in hexane) within 30 min. Then a solution of trimethyl borate (7.13 mL, 6.64 g, 63.9 mmol, 1.0 equiv) in anhydrous THF (30 mL) was added slowly within 30 min and the cooling bath removed. A solution of conc. acetic acid (5.49 mL, 5.76 g, 95.9 mmol, 1.5 equiv) was slowly added followed by addition of a solution of 35% hydrogen peroxide in water (6.2 mL, 6.83 g, 70.3 mmol, 1.1 equiv) and the reaction mixture kept at 0° C. for 30 min. After stirring at rt for an additional 4 h, the reaction was extracted with diethyl ether (2×100 mL) and the combined organic phases washed with a solution of 10% NaOH (2×100 mL) and a sat. solution of sodium chloride (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (19:1) providing 15.80 g (64%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 0.00 (s, 6H), 0.10 (s, 6H), 0.85 (s, 9H), 0.91 (s, 9H), 4.50 (s, 2H), 4.93 (br s, 1H), 6.37 (d, J=5.6 Hz, 1H), 6.47 (d, J=5.6 Hz, 1H). MS (EI): 329.2 [M-tert-Bu]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(/C=C/C(=O)O)cc2)c2ccc(O)c(F)c2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of Ethyl (2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(3,3,5,5-tetramethyl cyclohexylidene)methyl]phenyl}-2-propenoate (140) (0.235 g, 0.54 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Upon concentration and adding hexanes, compound 141 was obtained as pale yellow solid (0.182 g, 83%). mp 193-195° C. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (s, 6H), 0.89 (s, 6H), 1.25 (s, 2H), 1.88 (s, 2H), 1.91 (s, 2H), 6.45 (d, J=15.9 Hz, 1H), 6.76 (dd, J2=8.2 Hz, J2=1.6 Hz, 1H), 6.80-6.92 (m, 2H), 7.17 (d, J=8.0 Hz, 2H), 7.53 (d, J=16.1 Hz, 1H), 7.59 (d, J=8.2 Hz, 2H), 9.72 (s, 1H), 12.32 (s, 1H). LCMS (ES): m/z 407 (M−H)−. Anal. Calcd for C26H29FO3.⅙H2O: C, 75.89; H, 7.19. Found: C, 75.91; H, 7.17.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].Cl.[NH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[F:35].C(N(CC)CC)C>ClCCl>[CH3:29][N:24]1[C:23]2[NH:22][C:21]3[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:20]=3[N:19]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][NH:9][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[C:12]([F:35])[CH:13]=3)=[O:18])[CH2:28][C:27]=2[CH:26]=[N:25]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CN)c(F)c1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(C)ccc32)cc1F
Reaction time: 1 h
Yield: 51 %

Procedure:
1-Propanesulfonyl chloride (0.016 ml, 0.14 mmol) was added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E98.2 (50 mg, 0.12 mmol) in dichloromethane (2 ml) and triethylamine (0.038 ml, 0.27 mmol) at room temperature. The mixture was stirred for 1 h then concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white solid identified as the title compound (30 mg, 51%).