Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[C:27]([O:30][C@H:31]1[CH2:36][C:35](=[O:37])[O:34][C:32]1=[O:33])(=[O:29])[CH3:28].C(O)(=O)C>C1C=CC=CC=1>[C:27]([O:30][C@@H:31]([CH2:36][C:35]([NH:26][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][CH2:19]2)[N:11]=3)=[C:2]([F:1])[CH:3]=1)=[O:37])[C:32]([OH:34])=[O:33])(=[O:29])[CH3:28]
Reactant: CC(=O)O[C@H]1CC(=O)OC1=O
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=O)O[C@@H](CC(=O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (70 mg, 0.194 mmol) and (S)-(−)-2-acetoxysuccinic anhydride (34 mg, 213 μmol) was added benzene (1.9 mL) and acetic acid (55 μl, 0.968 mmol) before it was stirred at 80° C. for 1 h. The reaction mixture was concentrated before the regioisomers were separated via SFC (Column: Chiralpak IC, Mobile Phase: liquid CO2/40% MeOH) to give (2S)-2-acetoxy-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)phenylamino)-4-oxobutanoic acid. MS (ESI) m/z: Calculated: 519.1; Observed: 520.1 (M++H).
Reaction SMILES: C[C@@H](PC)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[CH2:31]([C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:48][CH3:49])[CH:46]=2)[CH2:41][CH2:40][C:39]=1[N:50]1[CH2:54][CH2:53][CH2:52][C:51]1=[O:55])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H][H]>[Rh+].ClC1CCCCC=CC=1.CO>[CH2:31]([C@@H:38]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:48][CH3:49])[CH:46]=2)[CH2:41][CH2:40][C@@H:39]1[N:50]1[CH2:54][CH2:53][CH2:52][C:51]1=[O:55])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)=C(N1CCCC1=O)CC2
Agent: [Rh+]
Agent: CP[C@H](C)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CO
Product: COc1ccc2c(c1)[C@@H](Cc1ccccc1)[C@@H](N1CCCC1=O)CC2
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (3.70 mg, 15.0 μmol of Rh), Josiphos SL-J216-2 (10.16 mg, 16.0 μmol), and N-(1-benzyl-7-methoxy-3,4-dihydronaphthalen-2-yl)pyrrolidin-2-one (500.8 mg, 1.50 mmol) were combined in a glass-lined metal reactor, and the vessel was inerted with argon. Degassed methanol (5.0 ml) was added, and the mixture was agitated under 20 psi of argon at 50° C. for 20 min. The vessel was pressurized with 90 psig of hydrogen and stirred at 100° C. for 45 hrs. HPLC analysis indicated 99.8% conversion and 90.7% ee. The mixture was concentrated and diluted with water to yield 415 mg (yield: 82%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)[CH:5]=1.[Li]CCCC.[Cl:21]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:21][C:13]1[O:14][C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH:2][CH3:1])=[O:15])=[CH:11][N:12]=1
Reactant: CNC(=O)c1cccc(-c2cnco2)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(-c2cnc(Cl)o2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
To a round bottom flask was added N-methyl-3-(oxazol-5-yl)benzamide (0.50 gm, 2.47 mmol) and THF (25 mL). The reaction was cooled to −78° C. and 1.6 M nBuLi (3.86 mL, 6.18 mmol) was added dropwise. The reaction turned orange-red in color. After 60 min, a solution of hexachloroethane (0.88 gm, 3.71 mmol) in THF (5 mL) was slowly added. The reaction was slowly warmed to rt over 30 min. After 2 h at rt the reaction was quenched by slow addition of sat. NH4Cl (10 mL). The mixture was concentrated to remove most of the THF. The mixture was then partitioned between EtOAc (40 mL) and water (20 mL). The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes to give the product, 3-(2-chlorooxazol-5-yl)-N-methylbenzamide, (123 mg, 0.52 mmol, 21% yield) as a light yellow solid. Anal. Calcd. for C11H9ClN2O2 m/z 236.0, found: 237.0 (M+H)+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(C(=O)c2cc(Cl)cc(Cl)c2)C(Cc2ccccc2)C1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](NC(c2ccccc2)c2ccccc2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
A solution of 200 mg (0.551 mmol) of (2R*,45*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine and 110 mg (0.606 mmol) of benzophenone in 5 ml of toluene are kept at reflux for 18 hours. The reaction mixture is then concentrated in a rotary evaporator and dissolved in 3 ml of methanol, and 69 mg (1.10 mmol) of sodium cyanoborohydride are added at RT. The reaction mixture is adjusted to pH=5 with 80 μl of acetic acid and stirred at RT for 68 hours. The title compound ##STR98## is obtained as white foam (120 mg, 41%). TLC:toluene/ethyl acetate (7:3) Rf =0.79, FD-MS:M+ =528, 530; IR:1630 cm-1.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH2:15][C:16]1[C:21]([NH:22][C:23]([C:25]2[N:29]([CH3:30])[CH:28]=[N:27][C:26]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=O)=[C:20]([NH2:37])[N:19]=[CH:18][N:17]=1.P(=O)(O)(O)O.N>>[CH3:30][N:29]1[C:25]([C:23]2[NH:15][C:16]3[C:21]([N:22]=2)=[C:20]([NH2:37])[N:19]=[CH:18][N:17]=3)=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=[CH:28]1
Reactant: Cn1cnc(-c2ccccc2)c1C(=O)Nc1c(N)ncnc1N
Agent: N
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cn1cnc(-c2ccccc2)c1-c1nc2c(N)ncnc2[nH]1
Temperature: 160 °C
Yield: 96.9 %

Procedure:
Phosphorous pentoxide (1.06 g) was added to N-(4,6diaminopyrimidin-5-yl)-1-methyl-4-phenyl-1H-imidazole-5-carboxamide (intermediate 7) (171 mg) followed by phosphoric acid (85%, 0.76 mL) and heated at 160° C. for 72 hours. Ice was added to the cooled mixture, which was then adjusted to pH 5 with aqueous NH3, the resultant precipitate filtered off, washed with water and dried at 60° C. in vacuo to give the title compound as a cream solid (156 mg, 89%);
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:23])=[C:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[C:12]#[N:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[S:31](Cl)([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>ClCCl>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([O:23][S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[C:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[C:12]#[N:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)N1CCC(C(O)=C(C#N)c2nc3ccccc3s2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(OS(=O)(=O)c2ccc(C)cc2)=C(C#N)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.9 %

Procedure:
To a solution of the above prepared 3-(1-acetylpiperidin-4-yl)-2-benzothiazol-2-yl-3-hydroxyacrylonitrile (415 mg, 1.27 mmol) in anhydrous dichloromethane (20 mL) at room temperature under argon were added triethylamine (193 mg, 1.9 mmol) and tosyl chloride (303 mg, 1.59 mmol) in small portions. The resulting mixture was stirred at room temperature for 6 hrs. The reaction mixture was diluted with dichloromethane. The organic phase was washed with 1% HCl, 0.5% NaOH, water, brine, and dried over anhydrous sodium sulfate, filtered, and evaporated. The resulting crude product was purified by flash column chromatography eluting with CH2Cl2:MeOH=20:1 to yield 140 mg (23%) of toluene-4-sulfonic acid 1-(1-acetylpiperidin-4-yl)-2-benzothiazol-2-yl-2-cyanovinyl ester. MS (m/z, ES+): 482.1 (M+1, 100%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[C:11]([OH:19])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)CCl.Cl.[NH2:25][CH:26]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28]>CN(C=O)C.CCN(C(C)C)C(C)C.CO>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:27](=[O:28])[CH:26]([NH:25][C:11](=[O:19])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:42][CH:43]([CH3:44])[CH3:45])[CH2:34][CH2:33]2)=[CH:36][CH:37]=1
Reactant: CC(C)CC(N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCCl
Product: CC(C)CC(NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reaction time: 0.25 h

Procedure:
A reaction tube was charged with HOBt (13 mg), benzoic acid (9 mg) and EDC (18 mg) in DMF (0.75 mL) and then agitated for 15 min. After this time, a solution of 2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-4-methylpentan-1-one hydrochloride (21 mg) in DIEA (65 μL) and DMF (185 μL) was added to the reaction tube. After the reaction mixture was shaken overnight at rt., the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 187. MS found: (M+H)+=414.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.C1(C)C=CC(S([Cl:37])(=O)=O)=CC=1.O>O1CCCC1>[Cl:37][C:15]1[N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:11]2[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccncc2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-(4-fluorophenyl)-3-(4-pyridinyl)-pyrazolo[1,5-a]pyridine (from Example 26, 100 mg, 0.346 mmol) in dry tetrahydrofuran (4 mL) was cooled to about −78° C. under N2 and n-butyllithium in hexanes (2.5 M in hexanes, 0.27 mL, 0.7 mmol) was added dropwise. The mixture was stirred at −78° C. for about 30 min and a solution of p-toluenesulfonyl chloride (0.15 g, 0.76 mmol) in dry tetrahydrofuran (1 mL) was added. The mixture was allowed to warm to room temperature over 30 min and was stirred at room temperature for 1 hour. Water was added and the mixture was poured into a separatory funnel. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried using anhydrous magnesium sulfate, filtered and evaporated. Purification by silica gel chromatography yielded the title compound, 0.087 g (78.6%). 1H NMR (CDCl3): δ 8.65 (d, 2H, J=5.8 Hz), 7.55–7.69 (m, 3H), 7.30 (d, 2H, J=5.8 Hz), 7.11–7.21 (m, 1H), 7.04–7.13 (m, 3H). MS (ES+ve): 326 (25, M+3), 323 (50, M+), 290 (100).
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1>CN(C)C=O.[Cu]Cl>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: ClC1=NN(c2cccnc2)CC1
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 85 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a solution of 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (1.09 g, 6.00 mmol) in dry N,N-dimethylformamide (6.0 mL) in a 25 mL round bottom flask was added copper(I) chloride (0.178 g, 1.80 mmol) leading to a green suspension. Dried air was bubbled through the mixture. The resultant dark green mixture was stirred at 85° C. for 16 hours. The mixture was then cooled down and dispersed into water (20 mL) and ethyl acetate (20 mL). The mixture was filtered through a pad of Celite® and washed thoroughly with ethyl acetate (4×20 mL). Aqueous layer was extracted with ethyl acetate (4×20 mL). The combined organic extracts were dried over anhydrous sodium sulfate (Na2SO4) and concentrated to afford crude product (0.582 g, 51%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:14][CH:13]=1.C(Cl)(Cl)[Cl:24]>>[Cl:24][C:13]1[N:14]=[C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[NH:16][C:12]=1[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH3:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: ClC(Cl)Cl
Reactant: COC(=O)c1ccc(C)c(-c2cnc(C3CCOCC3)[nH]2)c1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C3CCOCC3)nc2Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of methyl 4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoate (compound 241.2, 260 mg, 0.87 mmol) in chloroform (3 mL) NCS (116 mg, 0.87 mmol) was added to the reaction. The reaction mixture was stirred for 4 h at 25° C., then concentrated under reduced pressure. The residue was dissolved in 50 mL of EtOAc, then was washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 313 mg (crude) of the title compound as brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[ClH:15].[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][Cl:23])=[CH:18][CH:17]=1.[OH-].[Na+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1>[ClH:23].[ClH:15].[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:5]2([CH2:22][C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)[C:4]3[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=1
Reactant: ClCc1ccncc1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2

Procedure:
The title compound was prepared following the procedure of Example 5 from 1.0 g (4.08 mmole) of 2-bromofluorene, 1.5 g of 4-picolylchloride hydrochloride, 100 mg of cetyl tri-n-butyl phosphonium bromide, 20 ml of 50% sodium hydroxide solution, and 20 ml toluene by reaction at 50° for 1 hr. The product was chromatographed (silica, CH2Cl2 /CH3OH, 100:1), m.p. (dihydrochloride) >300° NMR (200 MHz, CDCL3) δ: 3.39(dd,4H), 6.48(d,4H), 7.10-7.67 (m, 7H-arom.), 8.12(d,J=5.7 Hz,4H). HRMS calculated for C25H19BrN2 : 426.0758 Found: 426.0758
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:32]#[N:33])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=2[F:31])=[O:19])[CH:15]([CH3:17])[CH3:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.OB(O)[C:36]1[CH:41]=[CH:40][C:39]([C:42]2([C:45]([OH:47])=[O:46])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:32]([C@@H:21]([NH:20][C:18]([C@@H:14]([NH:13][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3([C:45]([OH:47])=[O:46])[CH2:44][CH2:43]3)=[CH:38][CH:37]=2)=[CH:3][CH:4]=1)[C:9]([F:12])([F:11])[F:10])[CH:15]([CH3:17])[CH3:16])=[O:19])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=1[F:31])#[N:33]
Reactant: O=C(O)C1(c2ccc(B(O)O)cc2)CC1
Reactant: CC(C)[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)N[C@H](C#N)Cc1ccc(C#N)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)[C@H](N[C@@H](c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1)C(F)(F)F)C(=O)N[C@H](C#N)Cc1ccc(C#N)cc1F
Temperature: 90 °C

Procedure:
To N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-[(1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-L-valinamide (1 eq) in DMF (0.1M) were added 1-[4-(dihydroxyboryl)phenyl]cyclopropanecarboxylic acid (1.2 eq), Pd(dppf)Cl2 (0.05 eq) and 2M aqueous sodium carbonate (3 eq). The mixture was degassed by nitrogen bubbling for 5 min and heated to 90° C. for 2 h. The reaction mixture was cooled and diluted with EtOAc and 3N HCl was added to acidify the reaction mixture to pH 5. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and water, dried over Na2SO4 filtered and concentrated. The crude compound was purified by automated SiO2 flash chromatography system using solvent gradient of 40% EtOAc/Hex to 100% EtOAc/Hex.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CO.C([BH3-])#N.[Zn+2].C([BH3-])#N>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Zn+2]
Solvent: CO
Product: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A suspension of 3-nitrobenzaldehyde (30 g, 0.2 mol) in methanol (150 ml) was treated with morpholine and the resulting orange solution cooled to 0° C. The solution of zinc cyanoborohydride prepared above was then introduced by means of a double-ended needle and the reaction stirred to ambient temperature over 16 hours. The reaction was filtered and the filtrate evaporated to dryness. The residue was dissolved in diethyl ether (600 ml) and washed with 1N hydrochloric acid (1 l). The organic layer (containing 3-nitrobenzyl alcohol) was discarded. The aqueous layer was made basic with 4N sodium hydroxide and extracted with diethyl ether (750 ml). The organic layer was dried over anhydrous sodium sulphate, filtered and pre-adsorbed on to silica. Purification by dry flash chromatography eluting with dichloromethane/methanol/0.880 NH3 (95:4.5:0.5) gave 4-(3-nitrobenzyl)morpholine as a pale yellow oil which crystallised on standing (22.2 g, 50%). δH (360 MHz, CDCl3) 2.45-2.48 (4H, m), 3.59 (2H, s), 3.71-3.74 (4H, m), 7.49 (1H, t, J 8), 7.68 (1H, d, J 8), 8.12 (1H, d, J 8), 8.22 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].[CH:16]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)([CH3:18])[CH3:17].C(N=C=NCCCN(C)C)C>C1COCC1>[CH3:18][CH:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:8]2[NH:9][C:10]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[CH:7]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:17]
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc([N+](=O)[O-])ccc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-nitroindole-2 -carboxylic acid (0.86 g), 1-[3-(N-isopropyl)amino-2-pyridinyl]piperazine (0.43 g), 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.45 g) and THF (4 ml), the title compound is obtained, mp 153°-154°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].CNCC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH2:8][CH2:9][OH:4])[CH3:11])[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Agent: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCO)c4)cc23)CC1
Yield: 43.6 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-(methylamino)ethanol (75 mg, 1.0 mmol) for N-methylethanamine to afford 27.0 mg of the title compound (43.6%).
Reaction SMILES: [CH:1]([Si:4]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[C:5]1([CH2:18][OH:19])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)([CH3:3])[CH3:2].[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC=CC=1.C(N(CC)CC)C>[C:33](=[O:34])([O:19][CH2:18][C:5]1([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:20]([CH3:22])[CH3:21])[CH:23]([CH3:25])[CH3:24])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)C1(CO)c2ccccc2-c2ccccc21
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)[Si](C(C)C)(C(C)C)C1(COC(=O)Nc2ccccc2)c2ccccc2-c2ccccc21
Temperature: 82 °C
Yield: 100 %

Procedure:
To a mixture of 1.0 g of 9-triisopropylsilyl-9-fluorenemethanol and 0.3 mL of phenyl isocyanate in 10 mL of dry benzene was added 2 drops of triethylamine. The mixture was heated in an oil bath at 82° C. for one hour and cooled to room temperature. The solvent was evaporated in vacuo to give 1.30 g (100%) of the crude urethane as a yellow solid. Recrystallization from Skelly B gave 1.12 g (86.02%) of the pure urethane as colorless crystals, m.p. 152.5°-154° C.; IR (KBr): 3240 (NH), 1690 (C=O) cm-1 ; 1H NMR (CDCl3); δ 0.87 (d, 18H, Si-C-Me2), 1.18-1.44 (hept, 3H, C-Si-CH), 5.33 (s, 2H, CH2), 6.02 (b, 1H, NH), 6.70-7.95 (m, 13H, aryl).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:18]([NH:20][C@H:21]([C:26]([O:28]C)=[O:27])[C@H:22]([CH2:24][CH3:25])[CH3:23])=[O:19])[C:10]2=[O:30])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:31]>C(O)(=O)C>[ClH:31].[N:1]1([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:18]([NH:20][C@H:21]([C:26]([OH:28])=[O:27])[C@H:22]([CH2:24][CH3:25])[CH3:23])=[O:19])[C:10]2=[O:30])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC[C@H](C)[C@H](NC(=O)n1c(=O)n(CCN2CCOCC2)c2ccccc21)C(=O)OC
Agent: Cl
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)n1c(=O)n(CCN2CCOCC2)c2ccccc21)C(=O)O
Temperature: 25 °C
Yield: 81 %

Procedure:
A suspension of methyl N-{[3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-isoleucinate (Example 2) in 4N HCl (4 mL) and acetic acid (4 mL) was refluxed for 24 h. Then it was cooled to rt and evaporated to dryness. Recrystallization from ethyl acetate and hexane followed by filtration gave 510 mg (81%) of the title compound as white solid.