Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:17]=2)=[CH:14][N:13]=[CH:12]1.N>N1C=CC=CC=1.CCOC(C)=O>[Cl:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[NH:22][C:18]1[N:17]=[C:16]([C:15]2[N:11]([CH2:10][CH2:9][NH:8][C:5](=[O:7])[CH3:6])[CH:12]=[N:13][CH:14]=2)[CH:21]=[CH:20][N:19]=1
Reactant: NCCn1cncc1-c1ccnc(Nc2cccc(Cl)c2)n1
Reactant: CC(=O)OC(C)=O
Agent: N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCCn1cncc1-c1ccnc(Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
Acetic anhydride (0.58 μl, 1.0 mmol) was added to solution of 2-(3-chloroanilino)-4-[1-(2-aminoethyl)imidazol-5-yl]pyrimidine (Example 13; 0.30 g, 0.63 mmol) in pyridine (2 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 2 hours. 7M Methanolic ammonia (0.5 ml) was added and the mixture diluted with EtOAc (10 ml). The precipitate was removed by filtration and the filtrate pre-absorbed on to silica gel and purified by column chromatography on silica gel eluting with DCM/2% methanolic ammonia (11:1) to give the title compound (88 mg, 39%) as a white solid. NMR 9.68 (s, 1H), 8.43 (d, 1H), 8.03-7.96 (m, 2H), 7.81 (s, 1H), 7.79 (s, 1H), 7.60 (dd, 1H), 7.33 (t, 1H), 7.12 (d, 1H), 6.98 (dd, 1H), 4.56-4.46 (m, 2H), 3.44-3.37 (m, 2H), 1.80 (s, 3H); m/z 357.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH2:15][NH2:16])=[C:10]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].CCCCCC.C[CH2:33][O:34]C(C)=O.CCOC(C)=O.CC(O)C>C(Cl)Cl>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH2:15][NH2:16])=[C:10]3[S:17][C:18]4[CH:23]=[CH:22][C:21]([O:34][CH3:33])=[CH:20][C:19]=4[C:8]([C:9]=23)=[N:7]1)[CH3:25]
Reactant: CCOC(C)=O
Reactant: CCN(CC)CCn1nc2c3c(c(CN)ccc31)Sc1ccccc1-2
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCCCCC
Product: CCN(CC)CCn1nc2c3c(c(CN)ccc31)Sc1ccc(OC)cc1-2
Yield: 90 %

Procedure:
The compound is prepared via the same procedure used to synthesize the compound of Example 8. Pure material is obtained by flash chromatography [hexane:EtOAc (50:50), EtOAc, CH2Cl2, 0.5-1% IPA in CH2Cl2 ] in 90% yield: mp 74°-76° C. 1H NMR (CDCl3) 0.96 (6H; t), 2.52 (4H; q), 2.88 (2H; t), 3.72 (2H; s), 3.82 (3H; s), 4.28 (2H; t), 6.70-6.80 (2H; m), 7.10 (1H; d), 7.62 (1H; d)ppm. MS m/z 383 (MH+). Anal (C21H26N4OS) C, H, N.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]2[CH:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][N:7]2[CH:15]=1)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40].[I:44]N1C(=O)CCC1=O>CN(C=O)C>[CH2:39]([N:41]([CH2:42][CH3:43])[C:12]([C:10]1[CH:9]=[CH:8][N:7]2[C:15]([I:44])=[C:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]2[CH:11]=1)=[O:14])[CH3:40]
Reactant: CCNCC
Reactant: CC(C)c1cn2ccc(C(=O)O)cc2n1
Reactant: O=C1CCC(=O)N1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)c1ccn2c(I)c(C(C)C)nc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 113 %

Procedure:
2-Isopropylimidazo[1,2-a]pyridine-7-carboxylic acid (3.00 g, 14.7 mmol) obtained in step 2 was dissolved in DMF (15 mL), and the solution was stirred at 60° C. for 2 hours after adding EDC.HCl (4.20 g, 22.0 mmol), HOBt.H2O (3.00 g, 22.0 mmol), and diethylamine (2.70 mL, 29.4 mmol). The reaction mixture was extracted with ethyl acetate after adding a saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed with a saturated ammonium chloride aqueous solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was dissolved in DMF (20 mL), and stirred under light shielding at room temperature for 1 hour after adding N-iodosuccinimide (4.20 g, 18.5 mmol). The reaction mixture was extracted with ethyl acetate after adding a saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was slurried with heptane. The resulting crystals were collected by filteration, and dried to give N,N-diethyl-3-iodo-2-isopropylimidazo[1,2-a]pyridine-7-carboxamide (6.40 g, yield 99%).
Reaction SMILES: [CH2:1]([C:4]1([CH2:7][CH2:8][CH3:9])[CH2:6][O:5]1)[CH2:2]C.[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C:19]#[N:20])[CH:14]=[CH:15][CH:16]=1>>[Si:22]([O:21][CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][CH2:6][C:4]2([OH:5])[CH2:1][CH2:2][CH2:9][CH2:8][CH2:7]2)[CH:12]=1)[CH2:18][C:19]#[N:20])([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:24])[CH3:23]
Reactant: CCCC1(CCC)CO1
Reactant: CC(C)(C)[Si](C)(C)OC(CC#N)c1cccc(N)c1
Product: CC(C)(C)[Si](C)(C)OC(CC#N)c1cccc(NCC2(O)CCCCC2)c1

Procedure:
Epoxide ring opening of 2,2-dipropyloxirane with 3-(3-aminophenyl)-3-(tert-butyldimethylsilyloxy)propanenitrile following the method used in Example 67 gave 3-(tert-butyldimethylsilyloxy)-3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)propanenitrile as a colorless oil. Yield (1.5 g, 56%); 1H NMR (400 MHz, DMSO-d6) δ 7.01 (t, J=7.6 Hz, 1H), 6.63 (s, 1H), 6.57 (d, J=7.6 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 5.22 (t, J=5.2 Hz, 1H), 4.91 (t, J=6.4 Hz, 1H), 4.21 (s, 1H), 2.84 (d, J=5.6 Hz, 2H), 2.78-2.75 (m, 2H), 1.77-1.39 (m, 10H), 0.87 (s, 9H), 0.05 (s, 3H), −0.05 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:10][O-:11].[Na+:12].C[OH:14]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O-:14])=[O:11])[C:4]=2[N:3]=[N:2]1.[Na+:12]
Reactant: C[O-]
Reactant: c1ccc2[nH]nnc2c1
Reactant: CO
Agent: [Na+]
Product: O=C([O-])c1cccc2[nH]nnc12
Yield: 97 %

Procedure:
29.8 g (0.25 mol) of benzotriazole was reacted in 200 ml methanol with an equivalent quantity of sodium methanolate solution in methanol by the method described for catalyst 1. The reaction mixture was processed as described and 34.2 g sodium benzotriazoleate was obtained (yield 97%) in the form of a virtually colorless powder. The product was pure according to the 1H-NMR spectrum and free of starting material.
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([CH:23]([CH3:25])[CH3:24])[N:3]=1.[Br:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[C:12]3[CH2:11][CH2:10][N:9]([C:13]4[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=4)[CH2:8][CH2:7][C:6]=3[N:5]=[C:4]([CH:23]([CH3:24])[CH3:25])[N:3]=2)=[CH:29][CH:28]=1
Reactant: CC(C)c1nc(Cl)c2c(n1)CCN(c1ncccc1C(F)(F)F)CC2
Reactant: Nc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(c(Nc3ccc(Br)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Temperature: 130 °C
Yield: 80.4 %

Procedure:
Step E A mixture of 4-chloro-2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (50 mg, 0.14 mmol), 4-bromoaniline (35 mg, 0.36 mmol), and p-toluenesulfonic acid (51 mg, 0.27 mmol) in toluene (2 mL) was heated in a sealed tube at 130° C. for 18 h. The mixture was cooled, diluted with satd. aq. NaHCO3, and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated. The residue was purified (FCC) to give the title compound (57 mg, 77%). MS (ESI): mass calcd. for C23H23BrF3N5, 505.11; m/z found, 506.1 [M+H]+. 1H NMR (CDCl3): 8.41-8.39 (m, 1H), 7.90-7.87 (m, 1H), 7.61-7.56 (m, 2H), 7.48-7.43 (m, 2H), 6.99-6.95 (m, 1H), 6.49 (s, 1H), 3.68-3.65 (m, 2H), 3.63-3.60 (m, 2H), 3.25-3.21 (m, 2H), 3.08-2.99 (m, 1H), 2.98-2.94 (m, 2H), 1.32 (d, J=6.9 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[S:14])[N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:7]=1[NH2:8].[CH:16]1([C:20](O)=[O:21])[CH2:19][CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[S:14])[N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:7]=1[NH:8][C:20]([CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:21]
Reactant: O=C(O)C1CCC1
Reactant: CCCCCn1c(N)c(N)c(=O)[nH]c1=S
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCn1c(NC(=O)C2CCC2)c(N)c(=O)[nH]c1=S
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
The mixture of 5,6-diamino-1-pentyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1060 mg, 0.00464 mol), cyclobutane carboxylic acid (0.55 g, 5.5 mmol), benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate (2.2 g, 5.1 mmol) and triethylamine (1.3 mL, 9.3 mmol) in DMF (20 mL) was stirred at room temperature for 4 hours. The mixture was diluted with water. The precipitate formed was filtered and dried to yield the desired product (1.20 g, 83.27%). LCMS calculated for C14H23N4O2S(M+H): 311.2; found 311.2.
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.[CH:36]1[CH:41]=[CH:40][C:39]([C@H:42]([NH2:45])[CH2:43][OH:44])=[CH:38][CH:37]=1>C(Cl)Cl>[C:14]([NH:13][C@H:12]([C:11]([NH:45][C@H:42]([C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1)[CH2:43][OH:44])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: N[C@H](CO)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Prepared according to the method described in Example 4(b) above from Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (4.0 g; 9.22 mmol; see Example 4(a) above) and (S)-(+)-phenylglycinol (1.26 g; 9.22 mmol; 1 eq.) and CH2Cl2 (160 mL). The reaction mixture was stirred overnight and then washed with saturated aqueous KHSO4, saturated aqueous Na2CO3, brine, dried with Na2SO4, filtered and concentrated to dryness. The residue was triturated with ether to obtain 3.8 g of the sub-title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31]([N:33]=[C:34]=[S:35])[CH3:32]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:34]([NH:33][CH2:31][CH3:32])=[S:35])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: CCN=C=S
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCNC(=S)NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccc2OC)CC1
Yield: 34.6 %

Procedure:
188 mg (0.5 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 326 mg (1 mmol) of cesium carbonate were heated in 5 ml of N-methyl-2-pyrrolidone with 0.1 ml (1.1 mmol) of ethyl isothiocyanate at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid and extracted three times with 10 ml of dichloromethane each time. The combined organic phases were washed with water until neutral, dried over sodium sulfate and filtered after addition of activated carbon. The crude product obtained after removal of the solvent was recrystallized from methanol/water. 80 mg (35%) of the title compound were obtained as a colorless solid.
Reaction SMILES: Cl.[NH2:2]O.[C:4](=[O:7])([O-:6])O.[Na+].[C:9]([C@@H:11]1[CH2:16][C@H:15]([N:17]([C:22]([C:24]2[N:28]([CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:27]3[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=3[N:25]=2)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][N:13]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:12]1)#[N:10]>CS(C)=O.O>[CH3:34][O:33][CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:27]2[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=2[N:25]=[C:24]1[C:22]([N:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[C@H:15]1[CH2:16][C@@H:11]([C:9]2[NH:2][C:4](=[O:7])[O:6][N:10]=2)[CH2:12][N:13]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:14]1)=[O:23]
Reactant: NO
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C#N)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3noc(=O)[nH]3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Hydroxylamine hydrochloride (418 mg) was dissolved in dimethyl sulfoxide (10 ml), and the mixture was stirred at 40° C. for 30 min. Sodium hydrogen carbonate (506 mg) was added, and the mixture was stirred at 50° C. for 1 hr. A solution of tert-butyl (3R,5S)-3-cyano-5-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate (308 mg) in dimethyl sulfoxide (10 ml) was further added, and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 ml). 1,1′-Carbonylbis(1H-imidazole) (490 mg) and 1,8-diazabicyclo{5.4.0}undec-7-ene (450 μl) were added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with 0.5M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (5:95)-ethyl acetate was concentrated under reduced pressure to give the object product (256 mg).
Reaction SMILES: B(F)(F)F.[C:5]([N:7]1[C:13]2C=[CH:15][CH:16]=[CH:17][C:12]=2C([N+]([O-])=O)=[CH:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]1=2)#[N:6].[OH2:25].[C:26]([OH:29])(=O)[CH3:27]>[Fe]>[C:5]([N:7]1[C:13]2[CH:12]=[CH:17][CH:16]=[CH:15][C:27]=2[C:26](=[O:29])[CH2:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]1=2)(=[O:25])[NH2:6]
Reactant: N#CN1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Reactant: O
Reactant: CC(=O)O
Agent: [Fe]
Agent: FB(F)F
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Reaction time: 0.25 h

Procedure:
50 ml of a solution of 15% by weight of BF3 in acetic acid (=0.11 mole) are added to a suspension of 26.3 g (0.1 mole) of 5-cyano-10-nitro-5H-dibenz[b,f]azepine in 100 ml of acetic acid at room temperature. In the course of this the temperature rises slowly to 34° with complete dissolution of the starting material. 30 ml of water are added at 30° in the course of 5 minutes, resulting in a further increase in temperature to 37°. At this temperature 40 g of iron powder are added in portions over a period of 20 minutes, the temperature being maintained at 65°-70° by occasional cooling. After the exothermic reaction has subsided, stirring is continued for a further 15 minutes and then inorganic material is filtered off and washed three times with a little acetic acid. The total filtrate is added dropwise, while stirring well, to 11/2 l of water and, after stirring for 2 hours, the resulting precipitate is filtered off and washed neutral with water. After drying in vacuo at 60°, 5-carbamoyl-10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine is obtained, which according to the IR spectrum is identical to authentic material.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[CH:15]=[C:14]([OH:17])[CH:13]=[CH:12][C:11]=3[N:10]3[CH2:18][CH2:19][CH2:20][C:9]=23)[CH2:4][CH2:3]1.[OH-].[Na+].[C:23]1([S:29]([Cl:32])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[ClH:32].[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[CH:15]=[C:14]([O:17][S:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:31])=[O:30])[CH:13]=[CH:12][C:11]=3[N:10]3[CH2:18][CH2:19][CH2:20][C:9]=23)[CH2:4][CH2:3]1
Reactant: CN1CCC(c2c3n(c4ccc(O)cc24)CCC3)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c3n(c4ccc(OS(=O)(=O)c5ccccc5)cc24)CCC3)CC1
Product: Cl

Procedure:
By a method similar to Example 31, using 9-(1-methylpiperidin-4-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-ol (135 mg, 0.5 mmol), NaOH (3.25 mL, 0.65 mmol, 0.2 N), benzenesulfonyl chloride (99 mg, 0.564 mmol), and THF (1.5 mL) gave a crude residue which was purified by PCTLC (silica gel GF rotor; 95:5 CHCl3:2M NH3 in MeOH) and the hydrochloride was formed in EtOAc affording 196 mg (88%) of the title compound as an off-white powder: mp=202-204° C.; MS (ES+): m/e 411.0 (M+1); Calculated for C23H26N2O3S.HCl: C, 61.80; H, 6.09; N, 6.27. Found: C, 61.49; H, 6.10; N, 6.27.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[F:21])[CH:7]=1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:19]=[C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=3)[CH:17]=[CH:16][C:15]=2[F:21])=[O:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1

Procedure:
The phenyl bromide (78)(106 mg, 0.28 mmol) was coupled to 3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(OC([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=O)(C)(C)C.Cl>>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:14])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21
Agent: Cl
Product: O=C(Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21)N1CCNCC1

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) piperazine-1-carboxylic acid tert-butyl ester gave, after treatment with HCl, the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:63])[CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58](Br)[CH:57]=2)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:63])[CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[C:60]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)[CH:61]=2)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccc(Br)c2)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CC(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (150 mg) and 4-[2-(3-bromo-phenyl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (128 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-{2-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester was obtained, and further PMB group and BOC group were removed according to the above Deprotection method 2, to obtain the desired compound (D-171) as a colorless powder (4 mg, 3%).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:14][O:15][Si](C(C)(C)C)(C)C)[NH:7][C:6]1=[O:23])[CH3:3].Cl.[CH3:25][NH:26][S:27](=[O:36])([C:29]1[CH:34]=[CH:33]C(N)=[CH:31][CH:30]=1)=[O:28]>C(O)C>[OH:15][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C:5](=[CH:4][NH:2][C:3]1[CH:33]=[CH:34][C:29]([S:27]([NH:26][CH3:25])(=[O:36])=[O:28])=[CH:30][CH:31]=1)[C:6](=[O:23])[NH:7]2
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Reactant: CN(C)C=C1C(=O)Nc2cccc(CO[Si](C)(C)C(C)(C)C)c21
Agent: Cl
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(NC=C2C(=O)Nc3cccc(CO)c32)cc1
Temperature: 25 °C
Yield: 39.3 %

Procedure:
A solution of 1.2 g (3.7 mmol) of 3-methylsulfanyl-4-(t-butyldimethylsilyloxy)-methyl-1,3-dihydro-indol-2-one in THF (25 mL) was stirred with saturated ammonium chloride solution (20 mL), and activated zinc dust (5 g) was added. The mixture was stirred for 60 h at rt. The organic phase was separated, dried over MgSO4 and concentrated to give 1.16 g of impure 4-t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one as an off-white solid: 1H NMR (DMSO-d6): δ 0.11 (s, 6H), 0.86 (s, 9H), 3.42 (s, 2H), 4.67 (s, 2H), 6.74 (d, J=7.7 Hz, 1H), 695 (d, J=7.7 Hz, 1H) 7.18 (t, J=7.7 Hz, 1H), 10.40 (s, 1H). A solution of 0.64 g (2.3 mmol) of 4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in DMF dimethylacetal (5 mL) was heated to 100° C. for 1 h. The excess DMF dimethylacetal was removed under high vacuum, and the resulting dark oil was chromatographed on silica gel, eluting with EtOAc, to give 0.34 g (44%) of 3-dimethylaminomethylene-4-(t-butyldimethyl-silyloxy)methyl-1,3-dihydro-indol-2-one as a white solid: 1H NMR (DMSO-d6): δ −0.03 (s, 6H), 0.81 (s, 9H), 3.29 (s, 6H), 4.64 (s, 2H), 6.66 (d, J=7.3 Hz, 1H), 6.73 (d, J=7.3 Hz, 1H), 6.79 (t, J=7.3 Hz, 1H), 7.76 (s, 1H), 9.97 (s, 1H) ); APCI−MS m/z 333 (M+1)+. A solution of 0.115 g (0.34 mmol) of 3-dimethylaminomethylene-4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in ethanol (10 mL) was treated with 0.076 g (0.34 mmol) N-methylsulfanilamide hydrochloride. The solution was refluxed for 0.5 h and cooled to rt. The resulting yellow precipitate was isolated by filtration, washed with ethanol and dried to yield 0.048 g (38%) of the title compound: 1H NMR (DMSO-d6): δ 2.37 (d, J=5.0 Hz, 3H), 4.67 (s, 2H), 5.3 (bs, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 7.33 (q, J=5.0 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 8.32 (d, J=12.2 Hz, 1H), 10.67 (s, 1H), 11.26 (d, J=12.2 Hz, 1H); APCI−MS m/z 358 (M−1)−. Anal. Calcd for C17H17N3O4S: C, 56.81, H, 4.77; N, 11.69, S, 8.92. Found C, 56.89, H, 4.81; N, 11.70; S, 8.84.