Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:26]([CH:28]=1)[NH2:27]>CN(C)C1C=CN=CC=1.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[C:26]([NH:27][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:28]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(Cl)ccc1N1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Cl)ccc1N1CCCCC1)c1ccncc1
Reaction time: 19 h
Yield: 31.8 %

Procedure:
Isonicotinoyl chloride hydrochloride (350 mg, 1.96 mmol, commercially available product), triethylamine (740 μl, 5.30 mmol), and a catalytic amount of 4-(dimethylamino)pyridine were sequentially added at room temperature to a dichloromethane (10 ml) solution of 5-chloro-2-(1-piperidinyl)aniline (378 mg, 1.79 mmol), obtained as described in Referential Example 15-2. The resulting mixture was stirred for 19 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (200 g, hexane/ethyl acetate=1/1). Thus, N-[5-chloro-2-(1-piperidinyl)phenyl]isonicotinamide (GIF-0341) (180 mg, 31.8%) was yielded as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22]>C1(C)C=CC=CC=1.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)=[O:22]
Reactant: O=Cc1ccc(-c2ccc(Br)cc2)o1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1ccc(-c2ccc(-c3ccc(C=O)o3)cc2)cc1
Temperature: 80 °C
Yield: 85 %

Procedure:
To a stirred solution of 5-(4-bromophenyl)-furan-2-carboxaldehyde (5 mmol), and tetrakis(triphenylphosphine) palladium (200 mg) in toluene (10 mL) under a nitrogen atmosphere was added 5 mL of a 2 M aqueous solution of Na2CO3 followed by 4-formylphenylboronic acid (6 mmol) in 5 mL of methanol. The vigorously stirred mixture was warmed to 80° C. for 12 h. The solvent was evaporated, the precipitate was partitioned between methylene chloride (200 mL) and 2 M aqueous Na2CO3 (15 mL) containing 3 mL of concentrated ammonia. The organic layer was dried (Na2SO4), and then concentrated to dryness under reduced pressure to afford 1 in 85% yield; mp 173-174° C. (SiO2, hexanes/EtOAc, 70:30). 1H NMR (DMSO-d6); δ 7.42 (d, J=3.6 Hz, 1H), 7.70 (d, J=3.6 Hz, 1H), 7.93-8.01 (m, 8H), 9.64 (s, 1H), 10.07 (s, 1H). 13C NMR (DMSO-d6); δ 192.7, 177.9, 157.6, 151.8, 144.6, 139.6, 135.3, 130.2, 128.6, 127.9, 127.3, 125.7, 109.5. MS (ESI) m/e (rel. int.): 276 (M+, 100), 247 (5), 219 (25), 189 (25). Anal. Calc. for C18H12O3: C %, 78.24; H %, 4.37; Found. C %, 77.99; H %, 4.44.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[CH3:9][CH:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]([S:26][C:27]2[CH:32]=[C:31]3[O:33][CH2:34][O:35][C:30]3=[CH:29][C:28]=2I)=[N:24][C:18]2[C:19]([NH2:23])=[N:20][CH:21]=[N:22][C:17]1=2)[CH3:11].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:1]1[CH:5]=[CH:4][C:3]([C:28]2[C:27]([S:26][C:25]3[N:16]([CH2:15][CH2:14][CH2:13][NH:12][CH:10]([CH3:11])[CH3:9])[C:17]4[C:18]([N:24]=3)=[C:19]([NH2:23])[N:20]=[CH:21][N:22]=4)=[CH:32][C:31]3[O:33][CH2:34][O:35][C:30]=3[CH:29]=2)=[CH:2]1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Reactant: OB(O)c1ccoc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccoc2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 90.3 %

Procedure:
3-Furanylboronic acid (9.8 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 20:1) to give 23.9 mg (90%) of DZ3-27. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.17 (s, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.07 (s, 1H), 6.97 (s, 1H), 6.49 (s, 1H), 6.08 (s, 2H), 4.17 (t, J=6.9 Hz, 2H), 2.93 (septet, J=6.4 Hz, 1H), 2.64 (t, J=7.1 Hz, 2H), 2.02 (m, 2H), 1.17 (d, J=6.4 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.1, 151.8, 151.0, 149.7, 149.0, 147.8, 142.6, 140.4, 131.7, 124.2, 118.9, 117.8, 114.8, 111.5, 110.7, 102.1, 49.2, 42.6, 40.6, 28.0, 20.7; HRMS (ESI) m/z [M+H]+ calcd. for C22H25N6O3S, 453.1709; found. 453.1711; HPLC: method A Rt=6.18, method B Rt=6.67.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>CN(C)C=O>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([CH2:17][N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[CH:19][CH:20]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)cc1
Temperature: 100 °C
Yield: 61.2 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 250 mg, 1.21 mmol) and methyl 4-(bromomethyl)-benzoate (0.27 g, 1.18 mmol) in N,N-dimethylformamide (12 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-4-(1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-ylmethyl)-benzoic acid methyl ester (256 mg, 61%) as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])[C:6]=2[C:5](=[O:18])[NH:4][C:3]1=[O:19].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:29])[CH3:28].O>CS(C)=O>[O:29]=[C:27]([CH3:28])[CH2:26][CH2:25][CH2:24][CH2:23][N:4]1[C:5](=[O:18])[C:6]2[N:7]([C:11](=[O:17])[C:12]([CH3:15])([CH3:16])[CH2:13][CH3:14])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:19]
Reactant: CC(=O)CCCCBr
Reactant: CCC(C)(C)C(=O)n1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(C)(C)C(=O)n1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Reaction time: 0.25 h
Yield: 49.7 %

Procedure:
3-Methyl-7-(methylpivaloyl)xanthine (406 mg, 1.5 mmol) was added to a stirring suspension of NaH (36 mg, 1.5 mmol) in DMSO (20 ml) and stirred for 15 min. 6-Bromo-2-hexanone (260 mg, 1.5 mmol) was added and the reaction mixture was stirred for 20 hrs. The reaction mixture was poured into 100 ml of water and extracted with 25% ethanol/dichloromethane (3×40 ml). The combined organic extracts were combined, dried with magnesium sulfate and the solvent was removed under vacuum to give a brown oil. The brown oil was chromatographed (10 g silica gel, ethyl acetate) to give 1-(5-oxohexyl)-3-methyl-7-(methylpivaloyl)xanthine (270 mg, 49% yield)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C=O.[C:32]([BH3-])#N.[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH3:32])[CH2:26]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: [BH3-]C#N
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51.5 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (chiral intermediate in Example 212, Step 6) (0.30 g, 0.73 mmol) in methanol (7.3 mL) was treated with formaldehyde (37% in water) (0.54 mL, 7.3 mmol) and this was stirred at room temperature for 5 min. The reaction mixture was treated with sodium cyanoborohydride (0.092 g, 1.5 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.16 g, 50%). The product was isolated as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.48 (s, 1H), 6.27-6.18 (m, 1H), 4.10-3.98 (m, 1H), 3.96-3.86 (m, 2H), 3.83-3.74 (m, 1H), 3.72-3.64 (m, 1H), 3.10-2.98 (m, 2H), 2.54 (s, 3H), 2.20 (s, 3H), 1.71 (d, J=6.9 Hz, 3H), 1.32 (t, J=6.7 Hz, 3H). LCMS for C21H25ClN7O (M+H)+: m/z=426.2; Found: 426.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])=[CH:15][CH:14]=1.Cl>C(OCC)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)[C@@H](C)c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: COc1ccc(C[C@@H](C)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84.8 %

Procedure:
Employing a 2 L four-necked flask equipped with a condenser tube, 7.25 g of lithium aluminum hydride was stirred in 290 mL of diethyl ether for 5 minutes. Then, 25.48 g of aluminum chloride as a 280 mL of diethyl ether solution was dropwise added thereto while cooling with ice. After stirring for 5 minutes, 38.26 g of (S)-(+)-1-(4-methoxyphenyl)-2-phenylpropane-1-one as a 245 mL diethyl ether solution was dropwise added thereto. Then, reflux under heating was carried out for 3 hours. After cooling to 0° C., treatment with diluted hydrochloric acid was carried out, extraction with diethyl ether was carried out for liquid separation, and drying over anhydrous sodium sulfate was carried out overnight. After the solvent was distilled off, purification by column chromatography (developing solvent: hexane) was carried out to obtain 30.55 g of (R)-(−)-1-(4-methoxyphenyl)-2-phenylpropane [H-Ph-CH(CH3)—CH2-Ph-OCH3] (yield: 85%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][C:9]=1[Cl:16]>CN(C)C=O>[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:1]=[N+:2]=[N-:3])=[CH:10][C:9]=1[Cl:16]
Reactant: COC(=O)c1ccc(CBr)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
Add sodium azide (2.44 g, 37.49 mmol) to crude 4-bromomethyl-2-chloro-benzoic acid methyl ester (7.6 g, 28.84 mmol) in anhydrous dimethylformamide (100 mL) at room temperature under argon gas. Stir the reaction mixture at 50° C. overnight. Quench the reaction mixture with water and extract with ether (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate to provide the crude product (5.8 g, 25.7 mmol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[CH:33]=4)[CH:27]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(-c3cc(C)no3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1ccnc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from (4-chloro-5-[(2-methoxy-ethyl)-methyl-amino]-2-{3-[2-(3-methyl-isoxazol-5-yl)-pyridin-4-yl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example M12) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (106 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:34])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[N+:31]([O-])=O)[C:5]2=[CH:4][CH:3]=1.[NH4+].[Cl-]>CO.[Zn]>[NH2:31][C:25]1[CH:26]=[CH:27][C:28]([I:30])=[CH:29][C:24]=1[CH:11]1[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:34])[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH2:14][C:13](=[O:23])[NH:12]1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2[N+](=O)[O-])N1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc(I)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a suspension of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-iodo-2-nitrophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in Example 201c (0.7 g, 1.15 mmol) in methanol (50 ml) was added aqueous NH4Cl solution (0.61 g, 11.5 mmol, 20 mL), followed by addition of Zn powder (0.75 g, 11.5 mmol). The reaction mixture was stirred at room temperature for 1 h, then filtered throught a short pad of celite. The filtrate was concentrated, extracted with ethyl acetate and dichloromethane. The organic layers were combined, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc, then EtOAc:MeOH=19;1) to give racemic (2′R,3R,4′S)-2′-(2-amino-5-iodophenyl)-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.41 g, 61%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:9][NH2:10])=[CH:6][C:7]=1[CH3:8].[CH:11](O)=O>>[CH3:8][C:7]1[C:2]([Cl:1])=[N:3][N:4]2[CH:11]=[N:10][N:9]=[C:5]2[CH:6]=1
Reactant: Cc1cc(NN)nnc1Cl
Reactant: O=CO
Product: Cc1cc2nncn2nc1Cl

Procedure:
13.4 Grams (0.0845 mole) of 3-chloro-4-methyl-6-hydrazinopyridazine are dissolved in 100 milliliters of aqueous 88 percent formic acid. The mixture is heated at the boiling temperature under reflux for 2 hours. The mixture is evaporated under reduced pressure and the 7-methyl-6-chloro-s-triazolo[4,3-b]pyridazine intermediate product is obtained as a residue. The residue is triturated with diethyl ether, and found to melt at a temperature of 157.5°-158° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:28]([CH3:41])[C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[Cl:40])=[O:30])[CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:40][C:34]1[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][NH:31][C:29](=[O:30])[N:28]([C@H:10]([CH2:9][OH:8])[CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]1)=[O:14])[CH3:41]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](CO)CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
To a solution of (S)-tert-butyl 4-(5-(tert-butyldimethylsilyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoyl)piperazine-1-carboxylate (14 g, 22.8 mmol) in THF (70 mL) was added TBAF (1M, 34.2 mL, 34.2 mmol). The reaction mixture was stirred at RT for 1 h and concentrated. The residue was dissolved in EtOAc (500 mL). The organic mixture was washed with 2% citric acid, NaOH (0.2 N), and brine, dried over Na2SO4, filtered, and concentrated to give (S)-tert-butyl 4-(4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-hydroxypentanoyl)piperazine-1-carboxylate (12.1 g, crude), which was used without further purification. LRMS (M+H) m/z 501.2.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([NH:1][C:2]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][C:3]=2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-phenylbenzoate 94 mg were added 4-bromotoluene 0.11 mL, cesium carbonate 0.23 g, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg at room temperature, and it was stirred at 110° C. for 6 hours. After the reaction mixture was cooled to room temperature, palladium acetate 1.6 mg, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg were added to it, and it was stirred at 110° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-methylanilino)-4-phenylbenzoate.
Reaction SMILES: Cl.[C:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[C:25]([NH:36][CH2:37][CH2:38][C:39]([OH:42])([CH3:41])[CH3:40])[CH:24]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]>O1CCOCC1>[C:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:36][CH2:37][CH2:38][C:39]([OH:42])([CH3:40])[CH3:41])[CH:24]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]
Reactant: CC(C)(O)CCNc1cc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)ccc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(O)CCNc1cc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)ccc1C(=O)O
Temperature: 100 °C
Yield: 14.9 %

Procedure:
1.6 ml of 1N hydrochloric acid are added to a solution of 0.15 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(3-hydroxy-3-methylbutyl)amino]benzoate in 8 ml of dioxane. The reaction mixture is heated at 100° C. in a microwave for 2 hours and then concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (97/3 by volume), so as to give 20 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(3-hydroxy-3-methylbutyl)amino]benzoic acid in the form of a pale yellow powder, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[C:11]([CH2:18][CH3:19])[CH:10]=2)=[CH:4][CH:3]=1.[CH:20]1[CH:25]=[C:24]2[C:26]([O:28][S:29](=[O:31])(=[O:30])[C:23]2=[CH:22][CH:21]=1)=[O:27]>ClCCl>[CH2:18]([C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:26]([C:24]3[CH:25]=[CH:20][CH:21]=[CH:22][C:23]=3[S:29]([OH:31])(=[O:30])=[O:28])=[O:27])=[CH:7][CH:6]=2)[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=1)[CH3:19]
Reactant: O=C1OS(=O)(=O)c2ccccc21
Reactant: CCc1cc(Nc2ccc(N)cc2)n2nccc2n1
Solvent: ClCCl
Product: CCc1cc(Nc2ccc(NC(=O)c3ccccc3S(=O)(=O)O)cc2)n2nccc2n1
Temperature: 25 °C

Procedure:
1.3 g (5.1 mmol) of the amine from Example 14, Step B and 940 mg (5.1 mmol) of 2-sulfobenzoic acid cyclic anhydride were dissolved in 20 ml dichloromethane. A solid material precipitated immediately from the clear solution, and the mixture was stirred at room temperature over night. The pale yellow crystals of the title compound were filtered by suction, heated with ethanol, filtered again after cooling to room temperature, and dried in vacuo, m.p.>320° C.
Reaction SMILES: [NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:38].[CH3:39][N:40]1[CH2:45][CH:44]2[CH2:46][CH:41]1[CH2:42][N:43]2[CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)=[O:31])[C:8]([N:50]2[CH2:49][CH2:48][CH:47]([N:43]3[CH2:42][CH:41]4[CH2:46][CH:44]3[CH2:45][N:40]4[CH3:39])[CH2:52][CH2:51]2)=[O:10])=[CH:4][C:3]=1[Cl:38]
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CN1CC2CC1CN2C1CCNCC1
Solvent: CCN(CC)CC
Product: CN1CC2CC1CN2C1CCN(C(=O)[C@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)Cc2cc(Cl)c(N)c(C(F)(F)F)c2)CC1

Procedure:
Prepared analogously to Example 10.26 from 100 mg (0.18 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 39.1 mg (0.2 mmol) 2-methyl-5-piperidin-4-yl-2,5-diaza-bicyclo[2.2.1]heptane using triethylamine as the base.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:16])[C@:9]([OH:15])([CH3:14])[C:10]([F:13])([F:12])[F:11])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)#[N:25]>CCOC(C)=O>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:16])[C@:9]([OH:15])([CH3:14])[C:10]([F:12])([F:13])[F:11])[CH2:4][CH2:3]2)=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: C[C@@](O)(C(=O)N1CCC(N)CC1)C(F)(F)F
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@](O)(C(=O)N1CCC(NC(=O)c2ccc(C#N)cc2)CC1)C(F)(F)F
Yield: 36.6 %

Procedure:
To a solution of (R)-[4-amino-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperidine] (Example 21, 170 mg, 0.71 mmol) and triethylamine (0.12 mg, 0.86 mmol) in EtOAc (15 ml) was added a solution of 4-cyanobenzoylchloride (130 mg, 0.78 mmol) in EtOAc (10 ml). The resultant mixture was stirred at ambient temperature for 4 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with 50% EtOAc/DCM as eluent to give the title compound as a solid (97 mg, 0.26 mmol). NMR: 1.45 (m, 2H), 1.65 (s, 3H), 2.1 (m, 2H), 3.05 (m, 2H), 4.2 (m, 1H), 4.4-4.6 (m, 2H), 5.1 (s, 1H), 6.2 (d, 1H), 7.65 (d, 2H), 7.8 (d, 2H); m/z 368.