Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]([OH:20])[CH2:18][C:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[CH:4]([OH:39])[C:5]([C:7]1([CH3:38])[CH:12]([CH:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][CH:10]2[CH2:9][CH:8]1[OH:37])=[O:6].CC1[C@@H](O)C[C@]2(O)C(C)(C)C=1[C@@H](OC(C)=O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O>>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6]
Reactant: CC(=O)OC12COC1CC(O)C1(C)C(=O)C(O)C3=C(C)C(O)CC(O)(C(OC(=O)c4ccccc4)C21)C3(C)C
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C

Procedure:
Alternatively, C-7 CBZ baccatin III can be synthesized directly from 10-deacetylbaccatin III as follows: ##STR9## Here, 10-DAB III is dissolved in THF to form a first solution which is cooled to a reduced temperature of less than -20° C., and preferably to -40° C., under a nitrogen atmosphere. At least two equivalents of n-butyl lithium (1.6 M in hexane) are then added dropwise to the first solution to form a second solution which is then stirred for approximately five minutes at the reduced temperature. Preferably, acetyl chloride (one equivalent) is added to the second solution to form a third solution which is stirred at the reduced temperature for approximately thirty minutes. Alternatively, acetic anhydride (one equivalent) may possibly be used in place of the acetyl chloride to acylate the 10-DAB III. In either case, benzyl chloroformate (one equivalent) is next added, and this fourth solution is stirred for an additional thirty minutes at the reduced temperature and then warmed to 0° C. over thirty minutes. The fourth solution is then quenched with cold saturated ammonium chloride at the reduced temperature to remove any excess n-butyl lithium, acetyl chloride and CBZ-Cl; this mixture is then warmed to room temperature. The solvent is removed under vacuum to yield an initial residue which is taken up in ethyl acetate and washed with water to remove unwanted salts. The organic layer is then washed with brine, dried and concentrated under vacuum to yield a final residue. The final residue is chromatographed (silica gel hexanes:ethyl acetate) to yield C-7 CBZ baccatin III. It is important to note that this method represents a direct synthesis of C-7 CBZ baccatin III from 10-DAB III, as the intermediate formed in this reaction is a C-7 lithium alkoxide of baccatin III, that is, the intermediate is not baccatin III itself.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:31])[C:13](=C(C1C=CC=CC=1)C1C=CC=CC=1)[NH:14][NH:15][C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Cl.NO>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:31])[CH2:13][NH:14][NH:15][C:16]#[CH:17])([CH3:2])([CH3:4])[CH3:3]
Reactant: C#CNNC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: NO
Solvent: c1ccncc1
Product: C#CNNCC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 83.4 %

Procedure:
As reported for the synthesis of 19b in reference 46, benzhydrylidene aza-propargylglycinyl-proline tert-butyl ester 18a (100 mg, 0.23 mmol) was stirred with hydroxylamine hydrochloride (29 mg, 0.42 mmol) in 20 mL of pyridine overnight at 60° C. The volatiles were removed by rotary evaporation followed by co-evaporation with dichloromethane and ethyl acetate until solidification. Purification by flash chromatography on silica gel using a 1:1 mixture of ethyl acetate in hexane afforded amine 19a (51.3 mg, 84%) as a pale yellow foam: Rf=0.39 (hexane/EtOAc 1:1); [α]20D −48° (c 1.15, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 1.46 (s, 9H), 1.84-1.99 (m, 3H), 2.13-2.20 (m, 1H), 2.31 (s, 1H), 3.64 (m, 2H), 4.16 (d, J=17.2 Hz, 1H), 4.24 (d, J=17.2 Hz, 1H), 4.43 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ23.3, 27.6, 30.1, 42.6, 48.8, 61.5, 73.0, 78.1, 80.3, 159.8, 172.5. HRMS m/z calculated for C13H21N3O3 Na [M+Na]+ 290.1475. found 290.1488.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]>CO.[C].[Pd]>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH2:7][CH2:8][NH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnccn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1=CNCCN1
Yield: 85.5 %

Procedure:
At room temperature, 2-methoxycarbonylpyrazine (1.00 g) was dissolved in methanol. The resulting solution was subjected to catalytic reduction by the addition of 10% palladium-carbon (100 mg) for 2 hours under normal pressure. After the removal of the catalyst by filtration, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (5% methanol-dichloromethane), whereby 6-methoxycarbonyl-1,2,3,4-tetrahydropyrazine (880 mg, 86%) was obtained as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][C:5](=[O:12])[NH:4][NH:3]1.[CH3:13]O.Cl>O1CCOCC1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][C:5](=[O:12])[NH:4][NH:3]1
Reactant: O=C(O)Cc1cc(=O)[nH][nH]c1=O
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cc(=O)[nH][nH]c1=O
Reaction time: 8 h

Procedure:
A mixture of (3,6-dioxo-1,2,3,6-tetrahydro-4-pyridazinyl)acetic acid, (5.0 g), methanol (75 ml) and 4M hydrochloric acid in 1,4-dioxane (20 ml) was stirred overnight. Evaporation afforded a white solid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=2)=[O:7])C.O1CCCC1>CO>[Cl:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:6]([OH:7])=[O:5])=[C:16]2[CH3:17]
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2N NaOH (20 mL) was added to a suspension of 5-chloro-3-methyl-1H-indole-2-carboxylic acid ethyl ester (7.0 g, 29.4 mmol) in methanol (50 mL) and the resulting mixture stirred at 25° C. for 18 hours. Tetrahydrofuran (100 mL) was added and the resulting solution heated at reflux for 30 minutes and concentrated. The residue was dissolved in water and the resulting solution extracted twice with ethyl acetate. The aqueous layer was acidified and the precipitate collected by filtration and washed with water (5.24 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:33][CH2:32][C:11]2[N:12]=[C:13](Cl)[N:14]=[C:15]([N:16]3[C@H:21]([CH3:22])[CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:18]([CH3:30])[CH2:17]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH2:33][CH2:32][C:11]2[N:12]=[C:13]([C:36]3[C:37]([CH3:41])=[CH:38][CH:39]=[CH:40][C:35]=3[CH3:34])[N:14]=[C:15]([N:16]3[C@H:21]([CH3:22])[CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:18]([CH3:30])[CH2:17]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
Reactant: Cc1cccc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(C)c1-c1nc2c(c(N3C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]3C)n1)CN(Cc1ccccc1)CC2
Temperature: 140 °C

Procedure:
To a solution of racemic tert-butyl 4-(6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-(trans)-2,5-dimethylpiperazine-1-carboxylate (0.54 g, 1.14 mmol) in DME (9 mL) was added 2,6-dimethylphenylboronic acid (0.257 g, 1.72 mmol), Pd(Ph3P)4 (0.198 g, 0.172 mmol) and a 2 M aq solution of sodium carbonate (1.9 mL). The reaction was heated at 140° C. in a microwave reactor for 1.75 h. The reaction was filtered and diluted with EtOAc and brine. The organic layer was separated and then dried (Na2SO4), filtered and concentrated. The residue was then purified by FCC (55-80% EtOAc/heptane) to give the title compound. MS (ESI+) m/z 542.5 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+](=[CH2:17])=[N-]>>[CH3:17][O:13][C:12](=[O:14])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: C=[N+]=[N-]
Product: COC(=O)Cc1ccc(S(C)(=O)=O)cc1

Procedure:
(4-Methanesulfonyl-phenyl)-acetic acid was treated with an etheral solution of diazomethane until completion of esterification by TLC. The solvent was evaporated, the residue triturated in hexane/ether and filtered to afford the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:17])[NH:5][C:6]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1.CCO>C(Cl)Cl>[OH:2][C:3]1[C:4](=[O:17])[NH:5][C:6]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1
Reactant: COc1cc(=O)c2cc(C)cc(C)c2[nH]c1=O
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C)c2[nH]c(=O)c(O)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 3-methoxy-7,9-dimethyl-1H-1-benzazepine-2,5-dione (272 mg, 1.18 mmol) in dry CH2Cl2 (3 mL, distilled from CaH2 under N2, there was added a solution of BBr3 in CH2Cl2 (3 mL, 1M, Aldrich) in one portion over 10 seconds at rt. The reaction instantaneously became homogeneous and orange, then an orange precipitate formed after a few seconds. The reaction bubbled vigorously during the addition. The reaction was allowed to stir under N2 at rt for 45 min. The reaction was added to saturated NaHCO3 (30 mL) and the resulting beige suspension was allowed to stir for 15 min to give a cloudy, yellow solution. The solution was filtered through glass wool to remove any suspended matter. The resulting solution was acidified with concd HCl (pH 2), the solid collected by filtration and washed to neutrality with water (6×5 mL). The damp filter cake was crystallized from 95% EtOH (dissolved in 20 mL, hot filtered, allowed to cool to rt) to yield yellow needles (176 mg, 69%, pure by TLC, 1H NMR and C,H,N analysis); mp 211°-213° C. (EtOH), 1H NMR (DMSO-d6) δ2.28 (s, 3H), 2.42 (s, 3H), 6.27 (s, 1H), 7.31 (s, 1H), 7.47 (s, 1H), 9.90 (s, 1H), 10.74 (bs, 1H); Anal. Calcd for C12H11NO3 : C, 66.35; H, 5.10; N, 6.45. Found: C, 66.34; H, 5.13; N, 6.48.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C([Li])CCC.C[O:16][B:17](OC)[O:18]C.[OH-].[Na+]>O1CCCC1>[CH3:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[B:17]([OH:18])[OH:16]
Reactant: Cc1cc(F)ccc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1B(O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
2-Bromo-5-fluorotoluene (52.9 mmol, 10 g) in 400 ml of tetrahydrofuran was cooled to −78° C. and n-butyllithium (2.5 M, 58.2 mmol) was added. The solution was stirred for 20 minutes, trimethoxy borane (3 eq, 0.16 mol) was added, and the reaction was allowed to warm to room temperature overnight. Sodium hydroxide (60 ml of 1.25 M) was added and the reaction was stirred for 30 minutes. The tetrahydrofuran was removed in vacuo. The remaining aqueous layer was diluted and extracted with diethyl ether. The aqueous layer was adjusted to pH 3 with 2N HCl and extracted with ethyl acetate, which was dried (MgSO4) and concentrated in vacuo to give 6.57 g (81%) of a colorless solid: MS(FAB) m/e (rel. intensity) 154(48), 136(100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]#[CH:12].I[C:14]1[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([OH:24])=[CH:16][CH:15]=1.C1C=CC=CC=1.C(N(CC)CC)C>O=O.[Cu]I>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[C:14]([C:12]#[C:11][C:4]2[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:15]=[CH:16][C:17]=1[OH:24]
Reactant: COC(=O)c1cc(I)ccc1O
Reactant: C#Cc1cc(OC)ccc1OC
Agent: [Cu]I
Agent: O=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#Cc2cc(OC)ccc2OC)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere 240 mg of 2,5-dimethoxyphenylacetylene and 493 mg of methyl 5-iodosalicylate are dissolved in 20 ml of oxygen-free and dry benzene. The mixture is treated with 85 mg of tetrakis (triphenylphosphine)palladium, 20 mg of copper(I)iodide and 450 mg of triethylamine, stirred at room temperature overnight and then poured onto 100 ml of aqueous pH 7 buffer. After extraction with ethyl acetate and purification by chromatography on silicagel, 5-[2-(2,5-dimethoxyphenyl)ethinyl]-2-hydroxybenzoic acid methyl ester is obtained (colorless crystals of M.P. 105°-108°).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:26][S:27][C:28]1[S:29][C:30]2[CH:36]=[C:35]([CH:37]=O)[CH:34]=[CH:33][C:31]=2[N:32]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH:7][CH2:37][C:35]1[CH:34]=[CH:33][C:31]2[N:32]=[C:28]([S:27][CH3:26])[S:29][C:30]=2[CH:36]=1
Reactant: CSc1nc2ccc(C=O)cc2s1
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccc(CNc3cc(Br)ccc3[N+](=O)[O-])cc2s1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a stirred mixture of 5-bromo-2-nitroaniline (714 mg, 4.0 mmol) in TFA (7 mL) at −15° C. under argon, was added NaBH(OAc)3 (1.2 g, 5.4 mmol) in small portions. The mixture was stirred for 15 min, then a solution of 2-(methylthio)benzo[d]thiazole-6-carbaldehyde in CH2Cl2 (2 mL) was added dropwise. The mixture was stirred for 30 min then concentrated under reduced pressure to give a red oil. The oil was partitioned between EtOAc (200 mL) and saturated aq NaHCO3 (100 mL). The organic layer was separated and washed with brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 50% hexanes in EtOAc to afford 5-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (1.1 g, 73%) as a yellow solid. LCMS (ESI) m/z 409, 411 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].Br[CH:31]([CH2:39][CH3:40])[C:32]([O:34]C(C)(C)C)=[O:33]>>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:31]([CH2:39][CH3:40])[C:32]([OH:34])=[O:33])=[CH:16][CH:17]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: CCc1cnc(N(CCc2ccc(O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1
Product: CCc1cnc(N(CCc2ccc(OC(CC)C(=O)O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol and t-butyl 2-bromobutyrate.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[H-].[Na+].O.[CH2:23](Br)[C:24]#[CH:25]>CN(C)C=O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[O:11])[N:10]([CH2:25][C:24]#[CH:23])[C:4]=2[CH:3]=1
Reactant: C#CCBr
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)c2cccc3c2N(CC3)c2ccc(Br)cc21
Reaction time: 0.5 h

Procedure:
A solution of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one (8.0 gm, 25.4 mmoles) in dimethylformamide (DMF, 120 ml) was stirred with sodium hydride (50% oil suspension, 1.9 gm, 1.6 eq) at ~0° C. (water bath) for 1.5 hours. Propargyl bromide (80% wt in toluene, 7.5 gm, 2 eq) was charged in one portion. The mixture was stirred for 30 minutes. After the starting material was consumed (TLC, dichloromethane), the solution was diluted with dichloromethane, then washed with water (3×500 ml) and brine (2×500 ml). The solution was dried over MgSO4, and concentrated on a rotary evaporator to an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.[CH2:21]([O:23][C:24]([C:26]1[N:27]=[CH:28][O:29][C:30]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2OC(C)(C)O[C:41](=[O:43])[CH:42]=2)[CH:32]=1)=[O:25])[CH3:22].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:21]([O:23][C:24]([C:26]1[N:27]=[CH:28][O:29][C:30]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH2:42][C:41](=[O:43])[NH:19][C:9]3[CH:10]=[C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:32]=1)=[O:25])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: CCOC(=O)c1ncoc1-c1cccc(C2=CC(=O)OC(C)(C)O2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncoc1-c1cccc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (164 mg) and 5-[3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-phenyl]-oxazole-4-carboxylic acid ethyl ester (Example L6) (206 mg) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (63 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[C:20]([F:23])([F:22])[F:21])=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(OCc2ccccc2)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-benzyloxy-3-chlorobenzaldehyde (4.9 g, 20 mmol) and trimethyl(trifluoromethyl)silane (4.4 mL, 30 mmol) in THF (0.10 L) was added a solution tetrabutylammonium fluoride (1.0 M in THF, 2.0 mL). After the reaction was stirred at 25° C. for 3 h, it was acidified with 2 N HCl to pH 2, diluted with ethyl acetate and washed with brine. The organic phase was dried and concentrated and the residue was purified by chramotography on silica gel eluting with 8:2 hexane:ethyl acetate to give 1-(4-benzyloxy-3-chlorophenyl)-2,2,2-trifluoroethanol.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[CH2:6]([Mg][Cl:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].Cl>CO>[ClH:14].[NH2:5][CH:1]([CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CC(C)C#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To 13.8 g (0.2 mol) of isobutyronitrile dissolved in 50 ml of anhydrous tetrahydrofuran(THF) was added 110 ml (0.22 mol) of 2.0M benzylmagnesiumchloride at room temperature, and the resulting mixture was refluxed for 1 hour and cooled to room temperature. Subsequently, 200 ml of methanol and 11.4 g (0.3 mol) of NaBH4 were added thereto and stirred for 1 hour at room temperature. The resultant was adjusted to about pH 11 by adding 1N HCl. The above mixture was extracted with chloroform and dried over anhydrous Na2SO4, and methanolic HCl was added to obtain 37.5 g of the title compound(yield 94%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[C@H:20]([OH:23])[CH2:21][OH:22].Cl[C:25]1C=CC(C2C(C=C)=C(C)C=C3C=2C=CC(C)=N3)=CC=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[C:3]([C@H:20]([OH:23])[CH2:21][OH:22])=[C:2]([CH3:25])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([CH3:12])=[N:9]3)=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](O)CO)c(Cl)cc2n1
Reactant: C=Cc1c(C)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](O)CO)c(C)cc2n1

Procedure:
Compound 2G was prepared following the procedure used to prepare compound 1H of Example 1, except that 5-(4-chlorophenyl)-2,7-dimethyl-6-vinylquinoline (2F) was used instead of compound 1G. LCMS-ESI+ (m/z): 328.2, 330.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[N:38]1([CH2:44][C:45]([NH2:47])=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:39][CH2:40]3)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and 2-piperazin-1-yl-acetamide (Matrix) in an analogous manner as described in example 25. LR-MS: 681.2 [(M+H)+]
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([C:8]([NH:10][C:11]2[C:12]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:18]=4[N:17]=3)=[N:13][NH:14][CH:15]=2)=[O:9])=[C:6]([O:31][CH2:32][CH3:33])[CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]([C:8]([NH:10][C:11]2[C:12]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:18]=4[N:17]=3)=[N:13][NH:14][CH:15]=2)=[O:9])=[C:6]([O:31][CH2:32][CH3:33])[CH:5]=1
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(=O)Nc1c[nH]nc1-c1nc2cc(OC)c(OC)cc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc(N)ccc1C(=O)Nc1c[nH]nc1-c1nc2cc(OC)c(OC)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A mixture of 4-nitro-N-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-ethoxy-benzamide (115 mg) and 10% Pd/C (20 mg) in EtOH (10 mL) was stirred under a hydrogen atmosphere for 2 h at r.t. The mixture was filtered through Celite and reduced in vacuo to give the title compound (95 mg). (LC/MS: Rt 2.11, [M+H]+ 423).