Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]N1C(=O)CCC1=O)=O.[CH3:16][O:17][C:18]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:19]=1[CH2:20][NH:21][CH2:22][C:23]#[CH:24].C([O-])(O)=O.[Na+]>CC#N.O>[CH3:16][O:17][C:18]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:19]=1[CH2:20][N:21]([CH2:22][C:23]#[CH:24])[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc[nH]1
Reactant: C#CCNCc1ccc(OC)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C#CCN(Cc1ccc(OC)cc1OC)C(=O)c1ccc[nH]1

Procedure:
A solution of 1-[(1H-pyrrol-2-ylcarbonyl)oxy]pyrrolidine-2,5-dione (1 eq), N-(2,4-dimethoxybenzyl)prop-2-yn-1-amine (1.05 eq) and NaHCO3 (1 eq) in a mixture of CH3CN and H2O (20:1) was heated at reflux for 12 hrs and then the MeCN was removed under reduced pressure. The resulting residue was partitioned between DCM and sat. aq. NaHCO3 solution. The organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and the resulting brown oil was purified by Biotage system eluting with EtOAc/petrol ether to obtain the desired amide. MS (ES) C17H18N2O3 requires: 298, found: 299 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ: 11.56 (1H, br. S), 7.40 (1H, d, J=8.3 Hz), 6.91 (1H, s), 6.60 (1H, d, J=2.1 Hz), 6.52 (1H, dd, J=8.3, 2.1 Hz), 6.48-6.35 (1H, m), 6.09 (1H, s), 4.68 (2H, s), 4.22 (2H, s), 3.80 (3H, s), 3.76 (3H, s), 3.24 (1H, s).
Reaction SMILES: Cl.[F:2][C:3]([F:22])([F:21])[C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10]([CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])=[CH:6][CH:5]=1.[CH:23]([C@@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH2:28][N:27]([C@H:37]([CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[C:38]([O:40]CC2C=CC(OC)=CC=2)=[O:39])[CH2:26]1)=O>>[F:22][C:3]([F:2])([F:21])[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:23][C@@H:25]3[C@@H:29]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)[CH2:28][N:27]([C@H:37]([CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)[C:38]([OH:40])=[O:39])[CH2:26]3)[CH2:15][CH2:14]2)=[O:11])=[CH:19][CH:20]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3cccc(F)c3)[C@@H](C=O)C2)cc1
Reactant: O=C(CC1CCNCC1)NCc1ccc(C(F)(F)F)cc1
Agent: Cl
Product: O=C(CC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2cccc(F)c2)CC1)NCc1ccc(C(F)(F)F)cc1
Yield: 37.8 %

Procedure:
The title compound was prepared from 4-((N-(4-(trifluoromethyl)benzyl)carbamoyl)methyl)-piperidine hydrochloride (34 mg, 0.1 mmol, from Step A) and 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)-pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (25 mg, 0.06 mmol, Aldehyde 6) according to the method described in Example 1, Step C to give 14 mg (38%) of the title compound. ESI-MS: 618.4 (M+H); HPLC A: 2.30 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27](=[O:31])([O:29][CH3:30])[NH2:28]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([NH:28][C:27](=[O:31])[O:29][CH3:30])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: COC(N)=O
Product: COC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following the procedure of Example 61, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and methyl carbamate were coupled to give 149. MS: (ESI+) 443.1
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[CH:12]=[C:11]([CH2:20]Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.CO.C([O-])([O-])=O.[K+].[K+].[C:35]([O:38][CH2:39]C)(=[O:37])C>O.CCCCCC>[CH3:39][O:38][C:35](=[O:37])[CH2:20][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[CH:12]=1
Reactant: Fc1ccc2cc(CCl)cc(OCc3ccccc3)c2c1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a stirred solution of 1-benzyloxy-3-chloromethyl-7-fluoro-naphthalene (19.3 g, 64.2 mmol) in a 2:1 THF-MeOH (300 mL) was added K2CO3 (9.75 g, 70.6 mmol) and PdCl2 (PPh3)2 (2.25 g, 3.2 mmol) at room temperature. The solution was degassed (by purging with argon for 5 minutes) and stirred under carbon monoxide (balloon pressure) at room temperature overnight. The solvents were distilled off under reduced pressure, and the obtained crude residue was diluted with water (150 ml) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product. Silica gel chromatography (100-200 mesh, 5% ethyl acetate in hexane) yielded (4-benzyloxy-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (18.5 g, 89%) as a white solid. MS cald. for C20H17FO3 [(M+H)+]: 325, obsd. 325.2.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:3]=1.[ClH:20].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[ClH:20].[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[O:10][CH2:11][C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: [H][H]
Reactant: N#Cc1ccc(F)cc1OCC(=O)N1CCOCC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCc1ccc(F)cc1OCC(=O)N1CCOCC1
Reaction time: 7 h
Yield: 29.2 %

Procedure:
A solution of intermediate 130, 4-fluoro-2-(2-morpholino-2-oxoethoxy)benzonitrile, (500 mg, 1.89 mmol) in warm ethanol (30 mL) and ethyl acetate (30 mL) was mixed with conc.HCl (0.32 mL, 3.78 mmol, 2 eq.). To this was added 10% Pd—C (100 mg; Aldrich), and the mixture was hydrogenated at 1 atm of hydrogen for 20 hrs at room temperature. To this mixture was added an additional amount of 10% Pd—C (50 mg) and stirring continued for another 7 hrs. The mixture was filtered through Celite and the filtrate concentrated in vacuo to dryness. The residue was triturated with ethyl acetate, then with ethanol to obtain the title compound (168 mg, Yield 29%) as an off-white powder: 1H NMR (CD3OD, 500 MHz) δ ppm: 3.55 (2H, t, J=5 Hz, NCH2), 3.62 (2H, t, J=5 Hz, NCH2), 3.70 (2H, t, J=5 Hz, OCH2), 3.75 (2H, t, J=5 Hz, OCH2), 4.17 (2H, s, NCH2), 5.17 (2H, s, OCH2), 6.82 (1H, dt, J=2.5, 8.5 Hz, Ar—H), 7.05 (1H, dd, J=2.5, 10.5 Hz, Ar—H), 7.43 (1H, dd, J=6.5, 8.5 Hz, Ar—H); 13C NMR (CD3OD, 125.77 Hz) δ ppm: 39.40, 42.49, 44.97, 66.11, 66.46, 66.59, 101.38, 101.59, 108.40, 108.57, 118.40, 132.53, 132.62, 158.43, 158.52, 63.87, 165.83, 168.27. HRMS (ESI) calcd for C13H18N2O3F (M+H) 269.1301, found 269.1301.
Reaction SMILES: C(OC(=O)[NH:7][S:8]([O:11][CH2:12][C@@H:13]1[CH2:17][C@@H:16]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH:27][C@H:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[C:21]=3[CH:20]=[CH:19]2)[CH2:15][C@@H:14]1[OH:37])(=[O:10])=[O:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[S:8](=[O:10])(=[O:9])([O:11][CH2:12][C@@H:13]1[CH2:17][C@@H:16]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH:27][C@H:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[C:21]=3[CH:20]=[CH:19]2)[CH2:15][C@@H:14]1[OH:37])[NH2:7]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)OC[C@@H]1C[C@@H](n2ccc3c(N[C@@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)OC[C@@H]1C[C@@H](n2ccc3c(N[C@@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.5 %

Procedure:
tert-Butyl{[((1S,2S,4R)-4-{4-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methoxy]sulfonyl}carbamate (31.0 mg, 0.0570 mmol) was dissolved in DCM (0.803 mL) and trifluoroacetic acid (0.803 mL, 10.4 mmol) was added. The solution was stirred at rt for 15 min before being concentrated in vacuo. The residue was taken up in MeOH (5.00 mL), treated with solid sodium bicarbonate (300 mg) and stirred for 10 min. Filtration and silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM afforded the title compound (7.20 mg, 58%). 1H NMR (400 MHz, CD3OD, δ): 8.17 (s, 1H), 7.27-7.14 (m, 5H), 6.64 (d, J=3.5 Hz, 1H), 5.86 (t, J=7.5 Hz, 1H), 5.49-5.42 (m, 1H), 4.51-4.48 (m, 1H), 4.38 (dd, J=7.5, 9.8 Hz, 1H), 4.21 (dd, J=7.3, 9.8 Hz, 1H), 3.10-3.03 (m, 1H), 2.97-2.88 (m, 1H), 2.86-2.76 (m, 1H), 2.68-2.60 (m, 1H), 2.37-2.21 (m, 3H), 2.08-1.97 (m, 2H) ppm. LC/MS: Rt=1.16 min, ES+ 444 (FA standard).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([O:22][C:23]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:23]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: NCCc1ccc(-c2ccccc2)nc1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)NCCc1ccc(-c2ccccc2)nc1

Procedure:
A solution of 0.85 g (4.29 mmol) of 2-(6-phenylpyrid-3-yl)ethanamine, prepared in stage 1.2., and of 1.25 g (5.58 mmol) of ethyl [(phenyloxycarbonyl)oxy]acetate (J. Med. Chem., 1999, 42, 277-290) in 40 ml of toluene is heated at 60° C. for 12 hours. The mixture is allowed to return to ambient temperature, the insoluble material is separated by filtration and the filtrate is concentrated under reduced pressure. The residue thus obtained is purifed by chromatography on silica gel, elution being carried out with a 30/70 mixture of ethyl acetate and of cyclohexane.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[C:16]1([NH:15][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
To a solution of Boc-4-piperidone (4.0 g, 20 mmol), aniline (1.9 ml, 20 mmol), and acetic acid, glacial (1.4 ml, 24 mmol) in dichloroethane (60 mL) was added sodium triacetoxyborohydride (6.0 g, 28 mmol) portionwise at RT. The suspension was stirred at RT for 24 h, diluted with water and extracted with dichloromethane. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by ISCO using 0-30% EtOAc in Hexanes to give tert-butyl 4-(phenylamino)piperidine-1-carboxylate (2.5 g, 45% yield).
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:12][C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[C:9](=[O:25])[C:8]=2[CH:26]=1.O>CCOCC.O1CCCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:13]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[CH:12][C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[C:9]([CH3:1])([OH:25])[C:8]=2[CH:26]=1
Reactant: CN1CCN(c2cc3ccccc3c(=O)c3cc(Br)ccc23)CC1
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN1CCN(C2=Cc3ccccc3C(C)(O)c3cc(Br)ccc32)CC1
Reaction time: 3 h

Procedure:
Methyllithium, 35 ml. of a 1.6 M solution in ether, was added dropwise to a stirred solution of the product from Step C (18 g., 0.047 mole) in ether (200 ml) and tetrahydrofuran (60 ml) cooled in an ice bath and under nitrogen. Stirring was continued at room temperature for 3 hours. The mixture was cooled in ice and hydrolyzed by the dropwise addition of water. After dilution with ether and water, the layers were separated and the aqueous phase was re-extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate and evaporated. The mixture of 3-bromo-5-methyl-10-(4-methylpiperazinyl)-5H-dibenzo[a,d]cyclohepten-5-ol and 3-bromo-5-methyl-11-(4-methylpiperazinyl)-5H-dibenzo[a,d]cyclohepten-5-ol was obtained as a residual dark yellow glass; yield, 18 g, (96%).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[C:7]1([C:13]23[O:26][CH:14]2[CH2:15][CH2:16][C:17]2[C:22]3=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[C:7]1([CH:13]2[C:14](=[O:26])[CH2:15][CH2:16][C:17]3[C:22]2=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=3)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(C23OC2CCc2cc4c(cc23)OCO4)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: O=C1CCc2cc3c(cc2C1c1ccccc1)OCO3
Temperature: 80 °C

Procedure:
6.0 Grams (0.05 mols) of magnesium sulfate and 500 mL of toluene were added to 53.3 g (0.20 mols) of 8b-phenyl-1a,2,3,8b-tetrahydro-1,5,7-trioxacyclopenta[g]cyclopropa[a]naphthalene, and the mixture was heated at 80° C. for 2 hours. After cooled, the reaction product was washed two times each with 250 mL of water, and the organic layer was condensed under reduced pressure to obtain 5-phenyl-7,8-dihydro-5H-naphtho[2,3-d][1,3]dioxole-6-one represented by the following formula,
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]([O:41][C@H:42]1[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[CH:45](OC(=O)C)[O:44][C@@H:43]1[C:55]1[N:56]=[N:57][N:58]([CH2:60][CH3:61])[N:59]=1)(=[O:40])[CH3:39]>>[C:48]([O:47][C@@H:46]1[C@H:42]([O:41][C:38](=[O:40])[CH3:39])[C@@H:43]([C:55]2[N:56]=[N:57][N:58]([CH2:60][CH3:61])[N:59]=2)[O:44][C@H:45]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:22])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:50])[CH3:49]
Reactant: CCn1nnc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reactant: O=C(NCCN1CCCCC1)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNC(=O)NCCN5CCCCC5)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1

Procedure:
Prepared from N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-N′-[2-(1-piperidinyl)ethyl]urea (Preparation 42) and (2R,3R,4R)-4,5-bis(acetoxy)-2-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3-furanyl acetate (WO 9967265) by a similar procedure to Preparation 26. The title compound was obtained as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].O.Cl.[NH2:9][N:10]=[CH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:5]([O:4][C:2]([NH:9][N:10]=[CH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NN=Cc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)NN=Cc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl chloroformate (0.44 ml) was added slowly to a suspension of the product of Stage (ii) (0.8 g) and diisopropylethylamine (1.0 ml) in freshly distilled tetrahydrofuran (50 ml). The mixture was stirred at room temperature for 24 h and then reduced to dryness. The residue was chromatographed on silica (D) to give the title compound as an oil (0.4 g). T.l.c. SiO2 : ethyl acetate, Rf. 0.80 (Ceric).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(Cl)cccc23)CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc2c(C3CCNCC3)c[nH]c12
Temperature: 90 °C
Reaction time: 72 h
Yield: 199.9 %

Procedure:
A 100 mL round bottom flask was charged with 4-nitrophenyloxycarbonyloxyethyl polystyrene (4.0 g, 4.3 mmol), 7-chloro-3-(1-tert-butoxycarbonylpiperidin-4-yl)-1H-indole (2.7 g, 8.1 mmol), diisopropylethylamine (3.5 mL, 20.2 mmol), 4-dimethylaminopyridine (0.5 g, 4 mmol) and dry dimethyl formamide (50 mL). The mixture was stirred at 90° C. for 72 h. After cooling to room temperature, the resin was filtered off and washed with dry dimethyl formamide (3×25 mL), dry acetonitrile (3×25 mL) and dry dichloromethane (3×25 mL). The resin was transferred to a 250 mL glass cylinder with a fritte and a three way junction in the bottom. The resin was then treated for 20 minutes with 60 mL of a 1:1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2%, w/w) and methionine (0.2 %, w/w), using a flow of nitrogen to agitate the resin (Caution: Generation of carbon dioxide). The resin was filtered off and washed with dry dichloromethane (25 mL), a 1:1 mixture of dichloromethane:triethylamine (3×25 mL) and dry dichloromethane (3×25 mL). The resin was dried in vacuo (20° C., 20 h) to yield the title resin (3.8 g).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:14]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH2:49])=[CH:47][CH:48]=1)=[O:42])[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH:34]2[CH2:40][CH2:39][CH:38]1[CH2:37][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH:49][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:25])[CH3:1])[N:14]([CH:15]5[CH2:20][CH2:19][CH:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:47][CH:48]=1)=[O:42])[CH2:35]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1[C@H]1CC[C@H](C(C)(C)C)CC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCC(C(C)(C)C)CC1

Procedure:
Following General N—C coupling procedure 1 trans-7-(4-tert-butyl-cyclohexyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (157 mg, 0.43 mmol), was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, which gave upon work up gave 3-{6-[7-(4-tert-Butyl-cyclohexyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butylester and was used as is.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22](Cl)=[C:23]([Br:25])[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[H-].[Na+].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.C(O)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22]([O:37][C:34]4[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=4)=[C:23]([Br:25])[CH:24]=3)(=[O:17])=[O:18])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Oc2ccc(Cl)cc2)c(Br)c1
Temperature: 100 °C
Yield: 52.6 %

Procedure:
The mixture of [4-(5-Bromo-6-chloro-pyridine-3-sulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (50 mg, 0.10 mmol), sodium hydride (60% dispersed in mineral oil, 20 mg, 0.50 mmol) and 4-chlorophenol (0.4 mL, 3.79 mmol) in N,N-dimethylformamide (1.5 mL) was heated in a microwave oven at 100° C. for 15 minutes, then acidified with acetic acid to pH 5, filtered through a glass funnel and purified by preparative HPLC to afford {4-[5-bromo-6-(4-chloro-phenoxy)-pyridine-3-sulfonylamino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (30 mg, 52.6%) as a white powder. MS calcd for C22H22BrClN4O5S 548, obsd (ESI+) [(M+H)+]: 569.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([CH3:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=2)[O:3]1.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH3:27][N:17]([CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:26])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)[CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H](CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution of (R)-tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (9.0 g, 24.93 mmol) in anhydrous THF (120 mL) was cooled to 0° C. and NaHMDS (30 mL, 29.9 mmol) was added. The mixture was stirred for 1 h, methyl iodide (1.9 mL, 29.9) in THF (40 mL) added and stirred for 14 h. The reaction mixture was quenched with water (20 mL) and diluted with ethyl acetate (250 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue purified by column chromatography (silica, 0-30% ethyl acetate/heptane) to afford the desired product (6.2 g, 66%) as light yellow oil: ESI MS m/z 376 [C21H13NO4+H]+.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17](C(OCC1C=CC=CC=1)=O)[C@H:16]([CH3:31])[CH2:15]2)=O)C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[CH3:31][C@@H:16]1[CH2:15][C:14]2[C:18](=[CH:19][CH:20]=[C:12]([NH2:11])[CH:13]=2)[NH:17]1
Reactant: C[C@@H]1Cc2cc(NC(=O)OCc3ccccc3)ccc2N1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1Cc2cc(N)ccc2N1

Procedure:
A mixture of benzyl (2R)-5-{[(benzyloxy)carbonyl]amino}-2-methyl-2,3-dihydro-1H-indole-1-carboxylate (PCT/US00/08224; WO00/73301, 3.36 g, 8.07 mmol) and 10% palladium-on-carbon (108 mg) in THF/MeOH (1:1, 60 mL) is shaken on a Parr apparatus under a 36 psi hydrogen atmosphere overnight. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure. Purification by chromatography on a Biotage Flash 40M 90 g silica gel cartridge (1-2% MeOH/CH2Cl2) affords the title compound, MS (ESI+) for C9H12N2 m/z 149 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)cn1
Yield: 74.2 %

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (362 mg, 1.2 mmol) and 3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H7) (300 mg, 1.0 mmol) according to the general procedure K. Obtained as a light yellow solid (392 mg).