Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=1.[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]#[N:38])#[N:30].[Cl-].[NH4+]>O1CCCC1>[Br:28][C:24]1[CH:23]=[C:22]([C:29]2([C:2]3[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=3)[C:31]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:37]([NH2:38])=[N:30]2)[CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1ccccc1C#N
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: Brc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a −78° C. cooled solution of (4-bromo-phenoxy)-tert-butyl-dimethyl-silane (3.82 mL, 15.61 mmol) in tetrahydrofuran (50 mL) was added 2.5 M n-butyllithium in hexanes (6.2 mL, 15.61 mmol) and the anion stirred 20 minutes. At the same time in a separate round bottom flask containing 1,3-dibromobenzene (2.83 mL, 23.41 mmol) and tetrahydrofuran (50 mL) cooled in a −78° C. bath was added 2.5 M n-butyllithium in hexanes (9.37 mL, 23.41 mmol) and the anion stirred 20 minutes. The first anion was cannulated into a −78° C. solution of 1,2-dicyanobenzene (2.00 g, 15.61 mmol) in tetrahydrofuran (20 mL) and this mixture stirred 10 minutes. The second anion was cannulated into the reaction and the mixture stirred 45 minutes. The reaction was poured into saturated ammonium chloride (100 mL) and extracted twice with ethyl acetate. The combined organic layers were washed with aqueous saturated sodium chloride, dried over magnesium sulfate and removed of solvent under reduced pressure to give an amber foam. The crude material was placed on a 180 g silica gel column and eluted with a gradient of dichloromethane to dichloromethane/methanol (9:1) over 30 minutes at 40 mL/min and the combined purified fractions were removed of solvent under reduced pressure to give the titled compound as a off white solid (1.64 g, 21%). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (d, J=7.4 Hz, 1 H), 7.60-7.47 (m, 3 H), 7.42 (s, 2 H), 7.28 (d, J=7.5 Hz, 2 H), 7.14 (d, J=8.6 Hz, 2 H), 6.76 (d, J=8.6 Hz, 2 H), 0.92 (s, 9 H), 0.16 (s, 6 H); MS (APCI+) m/z 493 [M+1]+; tR=2.79 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([N:1]([CH2:7][C:6]1[CH:11]=[CH:2][CH:3]=[CH:4][CH:5]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cccc2c1C(=O)NCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1NCCc2cccc(N(Cc3ccccc3)Cc3ccccc3)c21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
1.466 g (9.039 mmol) 8-amino-3,4-dihydro-2H-isoquinolin-1-one are dissolved in 15 ml DMF and combined with 3.226 g (23.340 mmol) potassium carbonate and with 3.808 ml (31.420 mmol) benzylbromide. This reaction mixture is stirred for 16 h at 50° C. The reaction mixture is diluted with ethyl acetate and extracted with sodium hydrogen carbonate solution. The organic phases are dried and the solvent is eliminated in vacuo.
Reaction SMILES: C([O:9][C:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]([C:18]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])([CH3:20])[CH3:19])=[N:12][C:11]=1[C:32]([O:34]C)=O)(=O)C1C=CC=CC=1.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1>>[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH:42][C:32]([C:11]2[N:12]=[C:13]([C:18]([NH:21][C:22](=[O:23])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([CH3:20])[CH3:19])[N:14]([CH3:17])[C:15](=[O:16])[C:10]=2[OH:9])=[O:34])=[CH:39][CH:38]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(C(C)(C)NC(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Product: Cn1c(C(C)(C)NC(=O)OCc2ccccc2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
To a methanolic solution of methyl 5-(benzoyloxy)-2-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate, p-fluoro benzylamine (3 eq) was added and mixture was refluxed over night. After evaporation of methanol, residue was taken in EtOAc, washed with 1N HCl and brine, dried (Na2SO4), filtered and evaporated to obtain the title product.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([CH2:17][OH:18])([CH2:12][O:13][CH2:14][CH:15]=[CH2:16])[CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:26]1([CH:34]=[CH:35][C:36](Cl)=[O:37])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=1>C1(C)C=CC=CC=1>[CH2:9]([O:8][CH2:7][C:6]([CH2:17][OH:18])([CH2:12][O:13][CH2:14][CH:15]=[CH2:16])[CH2:5][O:4][CH2:1][CH:2]=[CH2:3])[CH:10]=[CH2:11].[C:26]1([CH:34]=[CH:35][C:36]([OH:37])=[O:4])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=1
Reactant: O=C(Cl)C=CC1=Cc2ccccc21
Agent: C=CCOCC(CO)(COCC=C)COCC=C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)C=CC1=Cc2ccccc21
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A 1000 mL three necked round bottomed flask outfitted with a mechanical stirrer (Teflon paddle), a pressure equalizing addition funnel was charged with pentaerythritol triallyl ether (NEOALLYL P-30) (111.9 g, 436.5 mmol), toluene (300 mL) and triethylamine (56.61 g, 559.4 mmol). The addition funnel was charged with a solution of BCB-AA acid chloride (88.96 g, 461.8 mmol) from Example 6 in toluene (100 mL), which was then added dropwise to the reaction mixture over 45 min. The solution was then heated to 90° C. for 9.5 hr. The solution was then filtered through a 38 mm (1.5 inch) thick silica gel plug on a 350 mL fritted glass funnel. Hexane:ethyl acetate (80:20, 200 mL) was used as the washing solvent. The filtrate was condensed to afford an orange colored viscous oil, which was taken up in hexanes (300 mL) and placed into a freezer for 3 days. The solution was filtered and condensed to afford the product as a viscous dark yellow colored oil. Yield: 178.0 g (93.97%). 1H NMR (500 MHz, Chloroform-d) δ 7.67 (dd, J=15.9, 3.1 Hz, 1H), 7.36 (dd, J=7.6, 1.5 Hz, 1H), 7.31-7.18 (m, 1H), 7.13-6.94 (m, 1H), 6.39 (d, J=16.0 Hz, 1H), 5.97-5.78 (m, 2H), 5.27 (dd, J=17.3, 1.7 Hz, 2H), 5.15 (dd, J=10.5, 1.6 Hz, 2H), 4.30 (s, 2H), 3.97 (d, J=5.4 Hz, 4H), 3.52 (s, 4H), 3.20 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([CH2:24][N:25]1CN(C[Si](C)(C)C)CN(C[Si](C)(C)C)[CH2:26]1)(C)C.[C:41]1([CH2:47][C:48](F)=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClC(Cl)CCl.ClCCl>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]3[CH:11]([CH2:24][N:25]([C:48](=[O:49])[CH2:47][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:26]3)[C:10](=[O:13])[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(F)Cc1ccccc1
Reactant: C[Si](C)(C)CN1CN(C[Si](C)(C)C)CN(C[Si](C)(C)C)C1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: ClCC(Cl)Cl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3)CC12
Temperature: 120 °C
Yield: 12.8 %

Procedure:
A solution of 4,4-diphenylcyclohex-2-en-1-one (25 g) and 1,3,5-tris-trimethylsilylmethyl-1,3,5-triazine (1.65 g) in 1,1,2-trichloroethane (17 cc) is treated with a solution of phenylacetyl fluoride (1.8 g) in 1,1,2-trichloroethane (5 cc) and the mixture is then heated at 120° C. for 22 hours. The reaction mixture is diluted with dichloromethane (100 cc), washed with saturated sodium bicarbonate solution (100 cc) and with saturated sodium chloride solution (100 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 3 cm, height 27 cm), eluting with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 35 cc fractions. Fractions 33 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-diphenyl-2-(phenylacetyl)-4-perhydroisoindolone (0.25 g) in the form of white crystals melting at 212° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](N(OC)C)=[O:9])[C:5]([CH:14]=[CH2:15])=[C:4]([NH:16][CH3:17])[N:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])[C:5]([CH:14]=[CH2:15])=[C:4]([NH:16][CH3:17])[N:3]=1
Reactant: C=Cc1c(NC)nc(Cl)nc1C(=O)N(C)OC
Reactant: Br[Mg]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1c(NC)nc(Cl)nc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-N-methoxy-N-methyl-6-(methylamino)-5-vinylpyrimidine-4-carboxamide (136 mg) in THF (1.8 mL) at 0° C. was added phenylmagnesium bromide (1 M solution in THF, 1.3 mL)) dropwise, and the reaction mixture was stirred at 0° C. for 30 min. The reaction was worked up with EtOAc/sat. NH4Cl, and the crude product was purified by preparative TLC eluting with 40% EtOAc/Hexanes to give the title compound as a colorless oil (87 mg). LC-MS (M+H)+=274.03.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([C:16]#[CH:17])=[CH:14][N:13]=[C:12]([C:18]4[S:22][C:21]([C:23]#N)=[CH:20][CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:25]([O-])([O-])=[O:26].[K+].[K+].[ClH:31].C[OH:33]>>[ClH:31].[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([C:16]#[CH:17])=[CH:14][N:13]=[C:12]([C:18]4[S:22][C:21]([C:23]([O:26][CH3:25])=[O:33])=[CH:20][CH:19]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnc(-c2ccc(C#N)s2)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CO
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: C#Cc1cnc(-c2ccc(C(=O)OC)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 20 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
To a solution of 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophene-2-carbonitrile (80 mg, 0.24 mmol, 1.0 equiv.) in MeOH (5 mL) was added K2CO3 (133 mg, 0.96 mmol, 4.0 eq). After being stirred at 20° C. for 4 h, HCl (10%, 5 mL) was added, and the reaction mixture was stirred at 20° C. for 30 min. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with water, dried (Na2SO4) and evaporated and crystallized with petroleum ether/ethyl acetate to afford the product compound methyl 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophene-2-carboxylate hydrochloride (Compound 151 (21.2 mg, 22%). LC-MS (m/z)=366 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.79 (m, 2H), 0.99-1.02 (m, 2H), 1.95-1.99 (m, 1H), 3.87 (s, 3H), 4.92 (s, 1H), 6.46 (s, 1H), 7.85 (dd, J=4.0 Hz, J=3.6 Hz, 2H), 8.54 (s, 1H), 8.99 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[C:10]=2[F:17])[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:16][C:11]1[C:10]([F:17])=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1F
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: O
Solvent: COCCOC
Product: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3F)ccn2)cn1
Temperature: 70 °C
Yield: 55.1 %

Procedure:
Nitrogen was bubbled though a solution of 4-(2-chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (2 g, 7.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.6 g, 7.8 mmol) and Na2CO3 (1.65 g, 15.6 mmol) in DME (12 mL) and H2O (4 mL) for 20 min. Pd(PPh3)4 (450 mg, 0.4 mmol), was added and then resulting mixture was degassed in vacuo, blanketed with nitrogen and heated to 70° C. for 16 h. The reaction was concentrated to dryness under reduced pressure. The crude product was suspended in water and extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to give 2,3-difluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine (1.3 g, 55% yield). 1H NMR (400 MHz, DMSO-d6), δ 8.40 (d, J=6.0 Hz, 1 H), 8.32 (s, 1 H), 8.02 (s, 1 H), 7.26 (s, 1 H), 6.96 (t, J=8.8 Hz, 1 H), 6.71-6.68 (m, 2 H), 5.62 (s, 2 H), 3.92 (s, 3 H); MS (ESI) m/z: 303.2[M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.Br.Br.[OH:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>CN(C)C=O>[OH:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Oc1cccc(N2CCNCC2)c1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2cccc(O)c2)CC1
Temperature: 20 °C
Yield: 27.3 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (11.2 g), triethylamine (16.8 cc) and 4- (3-hydroxyphenyl)piperazine dihydrobromide (13.6 g) in dimethylformamide (250 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 6 hours at this temperature. After purification by crystallization from isopropyl oxide (30 cc), then recrystallization from boiling acetonitrile (125 cc), 2-{3-[4-(3-hydroxyphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.6 g) is obtained, m.p. 175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.[CH3:21][NH2:22].O>O1CCCC1.C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:22][CH3:21])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1

Procedure:
(i) A solution of 200 g of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 2 litres of tetrahydrofuran and 250 ml of benzene was saturated with methylamine with cooling in an ice-bath. A solution of 190 g of titanium tetrachloride in 250 ml of benzene was added through a dropping funnel within 15 minutes. After completion of the addition, the mixture was stirred and refluxed for 3 hours. 600 ml of water were added slowly to the cooled mixture. The inorganic material was separated by filtration and was washed well with tetrahydrofuran. The water layer was separated and the organic phase dried over sodium sulphate and evaporated. The crystalline residue was collected to give 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine of melting point 204°-206° C. An analytical sample was recrystallised from methylene chloride/ethanol and had a melting point of 204°-206° C.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[CH:3]([NH:36]C(=O)OCC1C=CC=CC=1)[C:4]([NH:6][C@@:7]([C:22]1[CH:27]=[C:26]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:25]=[C:24]([F:35])[CH:23]=1)([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[Si](I)(C)(C)C>C(Cl)Cl>[NH2:36][CH:3]([C:2]([F:47])([F:48])[F:1])[C:4]([NH:6][C@@:7]([C:22]1[CH:27]=[C:26]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:25]=[C:24]([F:35])[CH:23]=1)([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5]
Reactant: O=C(NC(C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)C(F)(F)F)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: NC(C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.9 %

Procedure:
To a solution of benzyl 1,1,1-trifluoro-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-3-oxopropan-2-ylcarbamate (10 mg, 0.014 mmol) in CH2Cl2 (0.5 m) was added TMSI (18 mg, 0.094 mmol). The reaction mixture was sealed and stirred at rt for 20 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep HPLC (Phenomenex Luna AXIA 5μ 21.2×100 mm, 10%-90% ACN/H2O containing 0.1% TFA, flow rate 20 mL/min, gradient time 10 min) to yield 2-amino-3,3,3-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)propanamide (Example 324) as a white solid (5 mg, 65% yield). HPLC: RT=1.90 min [M+H] 551.5 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.82-7.85, m, 1H, 7.19-7.23, m, 1H, 7.11-7.17, m, 2H, 7.07-7.11, m, 1H, 6.98-7.03, m, 3H, 6.89-6.93, m, 2H, 6.80-6.86, m, 1H, 6.61-6.64, m, 2H, 5.73-5.99, t, J=52, 1H, 4.00-4.03, J=12, d, 1H, 3.98, m, 1H, 3.63-3.67, d, J=12, 1H;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[CH3:50][NH:51][CH3:52].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:24])([F:25])[F:26])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:51]([CH3:52])[CH3:50])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN(C)C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
A mixed solution of 150 mg of the compound obtained in Example 218, a solution of 2 mol/L dimethylamine in THF (0.22 ml), 63 mg of acetic acid, 95 mg of sodium triacetoxy borohydride, in CHCl3 (1.5 ml) was stirred at room temperature for one hour. A saturated aqueous solution of NaHCO3 was added to the reaction solution, and the resulting mixture was extracted with CHCl3. The extract was dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. Purification was carried out by a preparative TLC plate (1 mm; mobile phase: CHCl3/MeOH=8/1; v/v) to obtain 75 mg of the title compound (colorless solid).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](O)=[O:20])[CH2:17][C:6]=2[CH:5]=1.Cl.[O:31]=[C:32]1[N:41]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](=[O:20])[N:45]3[CH2:44][CH2:43][CH:42]([N:41]4[CH2:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[NH:33][C:32]4=[O:31])[CH2:47][CH2:46]3)[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Yield: 27 %

Procedure:
(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (90 mg, 0.23 mmol) and 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine hydrochloride (75 mg, 0.28 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 27% yield.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[CH:11]=[CH:10][C:9]4[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][CH2:20]CCCC>>[CH2:19]([N:13]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:14]1=2)[CH3:20]
Reactant: Cc1cccc2c1[nH]c1ccc3ccccc3c12
Reactant: CCCCCC
Product: CCn1c2ccc3ccccc3c2c2cccc(C)c21
Yield: 79.1 %

Procedure:
Using the procedure outlined in Example 34A, 8-methyl-7H-benzo[c]carbazole (Cambridge Chemicals, Inc.) gave a 79.1% yield of 7-ethyl-8-methyl-7H-benzo[c]carbazole, mp 79°-83°, (hexane), (C,H,N).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][NH:64][C:65]([C@@H:67]1[CH2:71][CH2:70][CH2:69][NH:68]1)=[O:66]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH2:71][C@H:67]1[C:65]([NH:64][CH3:63])=[O:66])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:20]=[CH:26][C:25]([Cl:27])=[CH:24][C:23]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CNC(=O)[C@@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H]1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-methylaminocarbonyl-pyrrolidine in DMSO at ambient temperature.