Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH2:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32].ClCCl>O.C([O-])(O)=O.[Na+]>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:34][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)CCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)CCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Sodium triacetoxyborohydride (24.9 g, 117.48 mmol) is added to a stirred solution of 1-Boc-4-piperidone (15.6 g, 78.3 mmol), iso-amyl amine (10.0 ml, 86.15 mmol), and dichloromethane (400 ml). The reaction is stirred overnight at room temperature under nitrogen. The reaction is diluted with water and aqueous saturated NaHCO3, and extracted with dichloromethane (150 ml×3). The dichloromethane is concentrated under vacuum, diluted with ethyl acetate and washed with aqueous saturated NaHCO3, dried over Na2SO4, filtered, and concentrated to yield (19.99 g) of 4-(3-methyl-butylamino)-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=271 (M+1); 1H NMR (CDCl3): δ=4.05 (2H, brs), 2.84-2.73 (2H, brm), 2.67-2.55 (2H, m), 1.84 (2H, brd), 1.67-1.58 (1H, m), 1.51-1.44 (10H, m), 1.41-1.33 (2H, m), 1.30-1.18 (2H, m), 0.90 (6H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].O.[F:14][C:15]([F:19])([F:18])[CH:16]=O.C(=O)CC>>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:16][C:15]([F:19])([F:18])[F:14]
Reactant: O=CC(F)(F)F
Reactant: COc1cc([N+](=O)[O-])ccc1N
Solvent: CCC=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1NCC(F)(F)F

Procedure:
This compound was prepared in a similar fashion as that described in Example 2, General Procedure IV but using 2-amino-5-nitroanisole and trifluoroacetaldehyde hydrate in place of Compound 200 and propionaldehyde. Compound 465 was isolated as a light brown crystalline solid after recrystallization (1:1 EtOAc:hexanes, 30 mL): Rf 0.52 (2:1 hexanes:EtOAc); 1H NMR (400 MHz, acetone-d6) 7.87 (dd, J=8.9, 2.4, 1H), 7.69 (d, J=2.4, 1H), 6.96 (d, J=8.9, 1H), 6.38 (broad s, 1H), 4.20 (qd, J=9.3, 7.1, 2H), 4.00 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:11]=3[C:12]([NH2:20])=[N:13][N:14]4[CH3:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:19][N:14]1[C:15]2[C:11](=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([C:29](=[O:30])[CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:2][CH2:3]4)[CH:18]=[CH:17][CH:16]=2)[C:12]([NH2:20])=[N:13]1
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: Cn1nc(N)c2c(-c3ccc4c(c3)CCN4)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cccc5c4c(N)nn5C)ccc32)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 106.2 %

Procedure:
To a clear solution of 4-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-indazol-3-amine (200 mg, 0.76 mmol, 1 equiv), (3-methylphenyl)acetic acid (114 mg, 0.76 mmol, 1 equiv), and DIEA (145 uL, 0.83 mmol, 1.1 equiv) in 4 mL of DCM was added at rt in one portion solid HATU (316 mg, 0.83 mmol, 1.1 equiv). The mixture as stirred at rt for 20 h. LCMS showed conversion complete. The suspension was filtered. The filtrate was absorbed onto a dryload cartridge. Purification was done on an SF25-24 g silica gel cartridge using gradient elution of 1% EtOAc in hexane to 100% EtOAc. The product eluted in the 100% EtOAc as a broad but well-defined peak. Concentration in vacuo gave a white foam (320 mg). LCMS showed it was only 84% pure with a major impurity at 11%. This material was dissolved in EtOAc (75 mL), and washed with water (25 mL) and brine (15 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. LCMS showed the impurities still present. The material was dissolved in EtOAc (1 mL) with some material still sticked to the wall of the 100 mL recovery flask, to which was added 3 mL of MTBE. The mixture turned cloudy initially, and was immersed in a water bath at (40° C.). The cloudiness disappeared and then solids began to form on the walls. A spatula was used to scratch the flask. The mixture was then cooled to room temperature and the suspension was filtered. The solids (light tan colored) was washed with MTBE (2 mL). Both LCMS and NMR showed this lot was quite pure. The solid was dried under vacuum at 65° C. for 16 h to give 210 mg as tan-colored solids. LC-MS (ES) m/z=397 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H), 3.23 (t, J=8.3 Hz, 2H), 3.78 (s, 3H), 3.83 (s, 2H), 4.23 (t, J=8.6 Hz, 2H), 4.38 (s, 2H), 6.78 (d, J=5.8 Hz, 1H), 7.05-7.15 (m, 13H), 7.20-7.26 (m, 2H), 7.28-7.38 (m, 3H), 8.16 (d, J=8.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][S:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1.[CH3:25][CH:26]1[CH2:31][CH2:30][CH:29]([NH:32][CH2:33][C:34]([CH3:42])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH3:35])[CH2:28][CH2:27]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:18]([N:32]([CH:29]2[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]2)[CH2:33][C:34]([CH3:42])([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35])=[O:19])=[N:8][CH:7]=1
Reactant: COC(=O)CSc1cnc(N)s1
Reactant: CC1CCC(NCC(C)(C)c2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CSc1cnc(NC(=O)N(CC(C)(C)c2ccccc2)C2CCC(C)CC2)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.1 %

Procedure:
To a mixture of (2-amino-thiazol-5-ylsulfanyl)-acetic acid methyl ester (416 mg, 2.04 mmol) in CH2Cl2 (30 mL) was added CDI (496 mg, 3.06 mmol) and DMAP (25 mg, 0.21 mmol) at room temperature. The reaction mixture was stirred at rt for 1.5 h, then (4-methyl-cyclohexyl)-(2-methyl-2-phenyl-propyl)-amine (500 mg, 2.04 mmol) was added. The mixture was stirred for 16 h at room temperature. The solvent was removed at reduced pressure and the residue was purified by preparative HPLC to give {2-[3-(4-methyl-cyclohexyl)-3-(2-methyl-2-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid methyl ester (350 mg).
Reaction SMILES: [CH:1]([NH:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][O:8]1)([CH2:3][CH3:4])[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][CH2:25][C:26](Cl)=[O:27]>O>[CH:1]([N:5]([CH2:6][CH:7]1[O:8][CH2:9][CH2:10][O:11]1)[C:26](=[O:27])[CH2:25][Cl:24])([CH2:3][CH3:4])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCC(C)NCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCC(C)N(CC1OCCO1)C(=O)CCl

Procedure:
N-Sec-Butyl-N-(1,3-dioxolan-2-ylmethyl)amine (12.0 grams, benzene (100 ml), water (100 ml) and sodium carbonate (10 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (6.0 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-sec-butyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:16]3[N:20]([CH3:21])[N:19]=[N:18][N:17]=3)=[CH:11][N:12]2[CH3:15])=[CH:7][CH:6]=1.CO>O>[CH3:1][O:2][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:16]3[N:20]([CH3:21])[N:19]=[N:18][N:17]=3)=[CH:11][N:12]2[CH3:15])=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(=O)c(-c3nnnn3C)cn(C)c2c1

Procedure:
A mixture of sodium methoxide (0.47 g), 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (2.0 g) and methanol (40 ml) was boiled under reflux for 43 hours. The mixture was cooled and poured into water (100 ml). The solid was collected by filtration, washed with boiling industrial methylated spirit (50 ml) and dried to give the novel compound 7-methoxy-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 270°-273°.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:16](=[O:29])[C:15]=1[Cl:30].CN1CCOCC1.[S:43]1[CH:47]=[CH:46][C:45]([CH2:48]O)=[CH:44]1.[H-].[Na+]>CC(N(C)C)=O.C(O)(=O)C>[Cl:30][C:15]1[C:16](=[O:29])[N:17]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][C:11]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:10]=1[CH2:9][NH:8][C:3](=[O:4])[O:5][CH2:48][C:45]1[CH:46]=[CH:47][S:43][CH:44]=1
Reactant: Cc1cc(OCc2ccc(F)cc2CN)c(Cl)c(=O)n1-c1c(F)cccc1F
Reactant: O=C(O)C(F)(F)F
Reactant: OCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Product: Cc1cc(OCc2ccc(F)cc2CNC(=O)OCc2ccsc2)c(Cl)c(=O)n1-c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one trifluoroacetate (0.26 g, 0.50 mmol) and 1,1-carbonyldiimidazole (0.10 g, 0.60 mmol) in DMA (2.0 mL) was added 4-methylmorpholine (0.06 mL, 0.55 mmol). After 1 h at RT, 3-thiophenemethanol (0.09 mL, 0.99 mmol) was added. No product was observed after 2 h at RT. NaH (0.01 g, 0.50 mmol) was added and the reaction stirred at 60° C. Reaction was complete after 20 min. The reaction mixture was cooled (0° C.) and acetic acid added to quench the reaction. Solvent removed by distillation. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (30 mL) and extracted in DCM (3×25 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to a white foam, dried in vacuo (0.20 g, 73%). 1H NMR (CD3OD/400 MHz) δ7.61 (m, 1H), 7.52 (m, 1H), 7.34 (s, 2H), 7.23 (t, 3H, J=8.4 Hz), 7.10 (m, 2H), 6.71 (s, 1H), 5.40 (s, 2H), 5.07 (s, 2H), 4.43 (s, 2H), 2.10 (s, 3H). ESHRMS m/z 549.0858 (M+H calculated for C26H21ClF3N2O4S requires 549.0857).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24]O)[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].CC(OC(/N=N/C(O[CH:41]([CH3:43])[CH3:42])=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:63]1CCN[CH2:65][CH2:64]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][N:63]4[CH2:42][CH2:41][CH2:43][CH2:65][CH2:64]4)[C:21](=[O:23])[N:22]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:26]([F:27])([F:28])[F:29]
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: C1CNCCN1
Reactant: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1CN1CCCCC1
Temperature: 45 °C
Yield: 47.7 %

Procedure:
To a solution of 2-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]thio}-5-(hydroxymethyl)-4(1H)-pyrimidinone (51 mg, 0.115 mmol) in dry DMF (3 mL) was added DIAD (0.034 mL, 0.173 mmol), triphenylphosphine (45.3 mg, 0.173 mmol) and piperizine (19.61 mg, 0.230 mmol) under argon. The mixture was heated with a microwave reactor at 45° C. for 0.5 h. Purification via MDAP then afforded the title compound (28 mg, 47.7% yield). LCMS: rt=3.02 min, [M+H+]=510
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:11][CH2:12][CH3:13])=[CH:2]1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)(Cl)Cl>[CH2:23]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:15]=2)[CH2:11][CH2:12][CH3:13])=[CH:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCC(c1c[nH]c2ccccc12)c1c[nH]c2ccccc12
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCC(c1cn(Cc2ccccc2)c2ccccc12)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
ST 1385 1,1-di-indol-3-yl-butane, 290 mg (1 mmol), was thoroughly mixed and blended with potassium tertbutylate (280 mg) and tetrabutylammonium bromide (20 mg). The mixture thus obtained was held under ultrasonic stirring at ambient temperature. 640 mg (5 mmol) of benzylchloride at 0° C. were then added and the ultrasonic stirring was continued for 2 hours at room temperature. At the end of this period, the reaction mixture was treated with H2O/CHCl3; the chloroform phase was separated, washed with a small amount of water, dried on Na2SO4, filtered and concentrated to dryness. The end product was isolated and purified chromatographically on silica gel, eluting with hexane:ethyl ether 95:5.351 mg of product were obtained with a 78% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9](SC2C=CC=CC=2)[CH2:8][C@H:7]1[C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])=[O:5])[CH3:2].Cl[C:27]1[CH:32]=[CH:31][CH:30]=[C:29](C(OO)=O)[CH:28]=1.[OH:37][S:38]([O-:40])=O.[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:38]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)(=[O:40])=[O:37])[CH2:8][C@H:7]1[C:18]([N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)=[O:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)N1CCOCC1
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)C[C@H]1C(=O)N1CCOCC1

Procedure:
To a solution of (1R,2R,4S)-2-(morpholine-4-carbonyl)-4-phenylsulfanyl-cyclopentanecarboxylic acid ethyl ester (0.1 mmol) in dichloromethane (1 ml) was added a solution of m-chloroperbenzoic acid (70%, 0.4 mmol) in dichloromethane (2 ml) and stirring was continued at 22° C. until completion of the reaction. The mixture was vigorously shaken with aqueous NaHSO3, the organic layer was washed with aqueous Na2CO3 and water, the organic layer was dried, evaporated and the residue chromatographed on silica using mixtures of cyclohexane and ethyl acetate to give the title compound as a colorless oil. MS: 396.1 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:8]2[N:9]=[CH:10][CH:11]=[C:12]([C:13]#[N:14])[C:7]=2[CH:6]=[CH:5]1)(=[O:3])[CH3:2].CCN(CC)CC.[C:22](OC(=O)C)(=[O:24])[CH3:23]>[Pd].CCOC(C)=O>[C:1]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:22](=[O:24])[CH3:23])=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1ccc2c(C#N)ccnc21
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccnc2c1CCN2C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-acetyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (0.691 g, Example 15, Step D), 10% Pd/C (0.702 g), 5 mL of Et3N, and 20 mL of EtOAc was added acetic anhydride (1.0 mL). The mixture was stirred at RT under balloon pressure of H2 for overnight. Solid was removed by filtration through a pad of Celite® and the filtrate was concentrated to yield a white residue, which was purified by chromatography through silica gel (150 g, 1 to 5% MeOH/CHCl3 with 1% NH4OH, stepwise gradient) to afford N-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-acetamide (0.50 g) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:31](=[O:32])[CH2:30][N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Reactant: CN1CCN(CC(=O)O)CC1
Product: CN1CCN(CC(=O)Nc2ccc3nc(NC4CCc5cc(F)ccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and (4-methyl-piperazin-1-yl)-acetic acid; MS: m/e=434.3 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[CH2:24]([O:26][C:27](=[O:34])/[CH:28]=[CH:29]\[CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:25]>C(Cl)Cl>[CH2:24]([O:26][C:27]([C@H:28]1[C@@H:29]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12]1)=[O:34])[CH3:25]
Reactant: CCOC(=O)/C=C\CC(C)C
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CC(C)C
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
N-Benzyl-N-(methoxymethyl)trimethylsilylmethylamine (4.0 g, 16.8 mmol), followed by TFA (1.0 M solution in CH2Cl2, 1.0 mL, 1 mmol) were added to a solution of (Z)-5-methyl-hex-2-enoic acid ethyl ester 8 (3.0 g, 19.2 mmol) in methylene chloride (30 mL) maintained at −5° C. under nitrogen atmosphere. After 15 minutes, the bath was removed and stirring was continued overnight. The reaction mixture was washed with saturated NaHCO3 (10 mL), water (15 mL), brine (20 mL), and dried. The product was purified by chromatography on silica gel, and compound was eluted with 20% ethyl acetate in hexane to give (cis)-1-benzyl-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester 9 as an oil (2.25 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:14][C:15]1[CH:16]=[C:17]([S:21]([CH2:24][CH2:25][OH:26])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH2:24][CH2:25][OH:26])(=[O:23])=[O:22])[CH:16]=1)=[O:8]
Reactant: Nc1cccc(S(=O)(=O)CCO)c1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(S(=O)(=O)CCO)c1
Reaction time: 8 h

Procedure:
To 2,4-dichlorophenoxyacetic acid (110.6 mg, 0.5 mmol), 2-(3-amino-benzenesulfonyl)-ethanol (151.0 mg, 0.75 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (102.1 mg, 0.75 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.13 ml, 0.75 mmol). The mixture was stirred overnight and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by preparative (CH2CH2:MeOH=30:1) to give 2-(2,4-dichloro-phenoxy)-N-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-acetamide as a yell foam (21.5 mg, 10.6% yield).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[CH:23]([CH2:26][CH3:27])[CH2:24][N:25]=[C:20]2[C@H:19]([NH2:28])[CH2:18][CH2:17]1.[O:29]=[C:30]1[NH:38][C:33]2=[N:34][CH:35]=[CH:36][CH:37]=[C:32]2[N:31]1[CH:39]1[CH2:44][CH2:43][N:42]([C:45](Cl)=[O:46])[CH2:41][CH2:40]1.C(=O)(O)[O-].[Na+]>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[CH:23]([CH2:26][CH3:27])[CH2:24][N:25]=[C:20]2[C@H:19]([NH:28][C:45]([N:42]2[CH2:41][CH2:40][CH:39]([N:31]3[C:32]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:38][C:30]3=[O:29])[CH2:44][CH2:43]2)=[O:46])[CH2:18][CH2:17]1
Reactant: O=C(Cl)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: CCC1CN=C2[C@H](N)CC[C@@H](c3cccc(F)c3F)CN21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1CN=C2[C@H](NC(=O)N3CCC(n4c(=O)[nH]c5ncccc54)CC3)CC[C@@H](c3cccc(F)c3F)CN21
Reaction time: 18 h
Yield: 42.5 %

Procedure:
Triethylamine (17 μL, 0.124 mmol) was added to a solution of the (6S,9R)-6-(2,3-difluorophenyl)-3-ethyl-2,5,6,7,8,9-hexahydro-3H-imidazo[1,2-a]azepin-9-amine (13 mg, 0.035 mmol) and 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbonyl chloride (15 mg, 0.053 mmol) in dichloromethane (1 mL). After 18 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by reverse phase HPLC(C-18, 95% water/acetonitrile 30% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (8 mg). MS 538.2710 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.[CH3:20][NH:21][CH3:22].[OH-].[Na+]>C(Cl)Cl.O1CCOCC1.O>[CH3:20][N:21]([CH3:22])[C:7](=[O:8])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A mixture of 5-methyl-2-nitrobenzoic acid (10 g, 55.2 mmol) and oxalyl chloride (6 mL, 68.8 mmol) in 100 mL of methylene chloride was stirred under argon at room temperature for 2 hours. The mixture was concentrated and the residue was co-evaporated twice with toluene. The residue was dissolved in 60 mL of dioxane and the solution was added dropwise to a mixture of aqueous dimethylamine (8.2 g, 40% w/w, 72.7 mmol) and sodium hydroxide (2.2 g, 55 mmol) in 20 mL of dioxane at 0° C. The mixture was stirred at room temperature for 1 hour and then poured into water. The mixture was extracted with ethyl acetate (2×150 mL), dried (Na2SO4), filtered and concentrated to give N,N,5-trimethyl-2-nitrobenzamide (11 g, 52.8 mmol).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[O:9]=[C:10]1[NH:14][C:13]([CH2:21][OH:22])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[O:23])[N:11]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([O:32][CH3:33])[CH:25]=1>CN(C=O)C>[O:9]=[C:10]1[N:14]([CH3:1])[C:13]([CH2:21][OH:22])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12](=[O:23])[N:11]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([O:32][CH3:33])[CH:25]=1
Reactant: COc1cc(N2C(=O)NC(CO)(c3ccccc3)C2=O)ccc1C#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(N2C(=O)N(C)C(CO)(c3ccccc3)C2=O)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
173 mg potassium carbonate and 86 μL methyl iodide are added to a solution of 141 mg 4-[2,5-dioxo-4-hydroxymethyl-4-phenylimidazolidin-1-yl]-2-methoxybenzonitrile in 2 mL DMF. The mixture is stirred overnight at room temperature, evaporated to dryness, The residue is taken in water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered, evaporated and chromatographed over silica gel while eluting with 70/30 heptane/ethyl acetate mixture to give the expected product.