Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)NCCC2

Procedure:
A solution of 7-nitro-1,2,3,4-tetrahydroquinoline (396 mg, 0.0022 mol) in 4 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with PdC 10% (40 mg) at rt for 2 h. Filtration over celite 330 mg (100%) of 7-amino-1,2,3,4-tetrahydroquinoline. Data for 7-amino-1,2,3,4-tetrahydroquinoline: 1H NMR (400 MHz, CDCl3) 6.72 (d, J=7.9, 1H), 6.00 (dd, J=7.9, 2.3, 1H), 5.84 (d, J=2.3, 1H), 3.67 (bs, 1H), 3.42 (bs, 2H), 3.24 (t, J=5.0, 2H), 2.65 (t, J=6.4, 2H), 1.91 (quintet, J=6.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[NH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:14]=1[C:19]([C:18]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:17]=1[F:16])=[O:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(F)cc1F
Product: Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1F
Yield: 20 %

Procedure:
In a manner similar to that described above for compound 1aa, 4-Chloro-N-Boc-aniline and 2,4-difluoro-benzoyl chloride were converted to 1w (20% yield) MS m/z=268 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:14]#[CH:15])=[CH:13][C:8]=2[C:7](=[O:16])[N:6]([CH3:17])[C:5]2[CH:18]=[CH:19][CH:20]=[N:21][C:4]1=2)[CH3:2].Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:14]#[C:15][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][C:8]=2[C:7](=[O:16])[N:6]([CH3:17])[C:5]2[CH:18]=[CH:19][CH:20]=[N:21][C:4]1=2)[CH3:2]
Reactant: C#Cc1cnc2c(c1)C(=O)N(C)c1cccnc1N2CC
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCN1c2ncc(C#Cc3cccnc3)cc2C(=O)N(C)c2cccnc21
Temperature: 85 °C
Yield: 66.2 %

Procedure:
A mixture containing 5,11-dihydro-11-ethyl-8-ethynyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.19 g, 0.68 mmol), 3-bromopyridine (0.07 mL, 0.73 mmol), tetrakis(triphenylphosphine)palladium(0), triethylamine (2 mL), and 1 crystal of BHT was heated at 85° C. in a sealed tube for 7 hours. Solvent was removed, and the residue was purified by flash chromatography, eluting with ethyl acetate/hexanes, and recrystallization from ethanol/hexanes to give 0.16 g of the title compound as yellow crystals, m.p. 178°-180° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[N:6]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:7]2[C:12]([N:13]=1)=[C:11]([NH2:14])[N:10]=[C:9]([O:15][C@@H:16]([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])[N:8]=2>CO>[CH3:1][O:2][C:5]1[N:6]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:7]2[C:12]([N:13]=1)=[C:11]([NH2:14])[N:10]=[C:9]([O:15][C@@H:16]([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])[N:8]=2
Reactant: CCCC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1

Procedure:
A solution of sodium methoxide in methanol (0.5M, 20 ml, 10 mmol) was added to a solution of 8-bromo-2-{[(1S)-1-methylpentyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.368 g, 5.95 mmol) in methanol (10 ml) and the mixture heated under reflux for 5 hours. More sodium methoxide in methanol (4 ml, 2 mmol) was added and the mixture refluxed for a further 2 hours and then cooled and evaporated. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was dissolved in dichloromethane and purified on an aminopropyl (NH2) cartridge (100 g) using a 0-100% ethyl acetate in cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.725 g).
Reaction SMILES: [NH2:1]C(OCC)=O.[F-].[Cs+].[CH3:9][O:10][CH2:11][C@H:12]1[CH2:16][O:15][C:14](=O)[O:13]1>CN(C)C=O>[CH3:9][O:10][CH2:11][C@@H:12]1[O:13][C:14](=[O:15])[NH:1][CH2:16]1
Reactant: CCOC(N)=O
Reactant: COC[C@H]1COC(=O)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COC[C@H]1CNC(=O)O1
Temperature: 140 °C
Reaction time: 72 h
Yield: 63731.8 %

Procedure:
Urethane (37.4 g, 0.420 mmol) was dissolved in N,N-dimethylformamide (200 mL), and thereto were added cesium fluoride (5.80 g, 38.2 mmol) and (S)-4-methoxymethyl-1,3-dioxolan-2-one (50 g, 0.382 mol, optical purity 97.7%ee), in order. The mixture was stirred for 72 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by distillation to give the subject (R)-5-methoxymethyloxazolidin-2-one (35.1 g, yield 69.6 %, optical purity 97.3%ee).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(C(=O)N2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccccc2)cc1

Procedure:
0.175 g (0.321 mmol) of (2R*,4S*)-2-benzyl-1-(4-methoxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.047 g (1.25 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR100## is obtained (0.100 g, 69%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.21, FD-MS: M+ =465; IR: 1620 cm-1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27]Br)[CH2:9][CH3:10]>>[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7])[CH2:9][CH3:10]
Reactant: O=C1CCCCN1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2CCCCC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
1-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one was prepared as for Example 10 from piperidin-2-one and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:21][C:8]2=[C:9]3[C:14](=[C:15](Br)[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH2:11][C:10]3([CH3:20])[CH3:19])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[O:21][C:8]2=[C:9]3[C:14](=[CH:15][CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH2:11][C:10]3([CH3:19])[CH3:20]
Reactant: CC1(C)CC(=O)Nc2c(Br)cc3c(c21)OC(CN=[N+]=[N-])C3
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(=O)Nc2ccc3c(c21)OC(CN)C3
Yield: 80.1 %

Procedure:
2-Azidomethyl-5-bromo-9,9-dimethyl-2,3,6,7,8,9-hexahydrofuro[2,3-f]quinoline-7-one (997 mg, 2.84 mmol) was dissolved in methanol (50 ml). To the solution, 10% palladium-on-carbon (1.0 g) was added, followed by stirring in a bath at 50° C. for 1 hour in the atmosphere of hydrogen. The catalyst was filtered off, and the filtrate was condensed under reduced pressure. Recrystallization from a solvent mixture of methanol-ether yielded 560 mg of the title compound as a yellow powder (80.4%).
Reaction SMILES: C(O[C:4](=O)[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O.P(Cl)(Cl)([Cl:30])=O>>[C:6]([C:5]1[CH:11]=[N:12][C:13]2[C:18]([C:4]=1[Cl:30])=[CH:17][C:16]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)=[CH:15][CH:14]=2)([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=CNc1ccc(C2CCCCCC2)cc1)C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cnc2ccc(C3CCCCCC3)cc2c1Cl
Reaction time: 2 h

Procedure:
10 g of p-cycloheptyl-anilinomethylene-malonic acid diethyl ester are dissolved in 50 ml of phosphorus oxychloride, 0.2 g of polyphosphoric acid is added and the mixture is boiled for 2 hours under reflux, with exclusion of water. The mixture is then evaporated to dryness in vacuo, the evaporation residue is partitioned between 3 times 100 ml of methylene chloride and 3 times 100 ml of 2 N sodium hydroxide solution and the organic solution is washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. The evaporation residue is treated with active charcoal and a little silica gel and crystallised from petroleum ether to give 3-carboethoxy-4-chloro-6-cycloheptyl-quinoline of melting point 61°-62°C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.[Br:21]C(Br)(F)C(F)(F)F>O1CCCC1>[Br:21][CH:13]1[CH2:12][CH:11]1[O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:14])([F:15])[F:1])=[CH:9][CH:8]=1
Reactant: FC(F)(F)C(F)(Br)Br
Reactant: FC(F)(F)Oc1ccc(OC2CC2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(OC2CC2Br)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
4-(Trifluoromethoxy)cyclopropoxybenzene (3 g) was dissolved in tetrahydrofuran (100 ml) and the solution was cooled to −78° C. under a nitrogen atmosphere. tert-Butyllithium (22.9 ml, 1.5M in pentane) was added dropwise and the solution was stirred for 3 hours. Dibromotetrafluoroethane (8.2 ml) was added dropwise and the reaction mixture was stirred at −78° C. for 2 hours. The reaction was quenched by the dropwise addition of water (50 ml). The product was extracted with diethyl ether. The combined organic fractions were dried (brine, MgSO4) and concentrated in vacuo. The residue was purified on silica using hexane as eluant, to yield the product as a colourless oil (2.2 g). 1H NMR (360 MHz, CDCl3) δ 0.86 (4H, m), 3.79 (1H, m), 7.15 (1H, dd, J 8.9, 2.7 Hz), 7.24 (1H, d, J 8.9 Hz), 7.42 (1H, d, J 2.7 Hz).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:5][CH:4]=1)=O.C(O)(=O)C.[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[C:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=3[O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:7][CH:8]=2)[CH2:37][CH2:36]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C=O)cc2)c(OCCCOC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)CCc1ccc(-c2ccc(CN3CCN(C(C)=O)CC3)cc2)c(OCCCOC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Ethyl 3-[4′-formyl-2-(3-methoxypropoxy)biphenyl-4-yl]propanoate (1 g, 2.7 mmol) was dissolved in dichloroethane (20 mL). At 0° C., acetic acid (0.02 mL, 0.4 mmol) was added, followed by N-acetylpiperazine (0.38 g, 3 mmol) and sodium triacetoxyborohydride (0.86 g, 4 mmol) portionwise. The mixture was stirred at room temperature overnight. At 0° C., saturated aqueous sodium bicarbonate was added. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with brine and water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 1.02 g (78%) of the desired product as a brown oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: O=Cc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using 4-formylphenylboronic acid (252 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Brown solid. Yield: 150 mg, 0.57 mmol, 68%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.21 (s, 2H), 6.94 (t, J=1.3 Hz, 1H), 7.14 (t, J=0.9 Hz, 1H), 7.53 (dd, J=8.2, 2.0 Hz, 1H), 7.60 (brs, 1H), 7.79 (dd, J=8.2, 0.6 Hz, 1H), 7.98 (d, J=8.4 Hz, 2H), 8.16 (d, J=8.4 Hz, 2H), 8.63 (d, J=2.0 Hz, 1H), 10.08 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 119.0, 121.2, 127.5, 130.2, 130.5, 131.3, 135.9, 136.7, 137.3, 144.0, 148.8, 156.1, 191.8; MS (ESI): m/z=264.16 [M+H]+.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])[CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c(Cl)c1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2cc(O)c(O)c(Cl)c2)S1
Temperature: 100 °C

Procedure:
A solution containing 1.33 g of thiazolidine-2,4-dione, 1.72 g of 3,4-dihydroxy-5-chlorobenzaldehyde and 2 ml of piperidine in 20 ml of acetic acid was heated for five hours at 100 ° C. Yield 1.9 g (70%), mp 299°-301° C.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CN(CCN(C)C)C.Br[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CCCCCC.C1CCCCC1>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(C(CC2CC3CCN2CC3)c2ccccc2)cc1
Reactant: CCCCCBr
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CCCCCC(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1

Procedure:
Following the procedure which is described in Example 4, 2.91 parts of 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octane in 40 parts by volume of cyclohexane, 5.1 parts by volume of a 2.17 M solution of butyl lithium in hexane are reacted with 1.5 parts by volume of TMEDA and 1.65 parts of 1-bromopentane to provide 2-(2,2-diphenylheptyl)-1-azabicyclo[2.2.2]octane. This compound is then treated with 0.570 parts of maleic acid to give 2-(2,2-diphenylheptyl)-1-azabicyclo[2.2.2]octane maleate, melting at about 177°-178.5° C. This compound is represented by the following structural formula ##STR11##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:4][CH:3]=1.[O-:41][C:42]#[N:43].[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:6][CH:7]=1)[C:42]([NH2:43])=[O:41]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(N)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(NC(N)=O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 40 °C
Reaction time: 2.3 h
Yield: 56 %

Procedure:
4-(4-Aminophenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (39.2 mg, 0.0730 mmol) was dissolved in acetic acid (1.57 mL) and water (1.57 mL), and the solution was added with aqueous sodium cyanate solution (0.139 mol/L, 1.57 mL, 0.219 mmol), followed by stirring at 40° C. for 2.3 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol/7 mol/L ammonia-methanol solution=10/0.5/0.5) to obtain 4-(4-ureidophenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (23.7 mg, yield 56%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[C:2]=1[NH2:8].Cl.C(O[C:13](=N)[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1)C>CO>[NH:7]1[C:3]2[C:2](=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[C:13]1[CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]1
Reactant: Nc1cccnc1N
Reactant: CCOC(=N)CC1CCN(C(=O)OCC)CC1
Agent: Cl
Solvent: CO
Product: CCOC(=O)N1CCC(Cc2nc3ncccc3[nH]2)CC1
Yield: 52.7 %

Procedure:
A mixture of 2,3-pyridinediamine (0.05 mol) and ethyl 4-(2-ethoxy-2-iminoethyl)-1-piperidinecarboxylate monohydrochloride (0.05 mol) in methanol (150 ml) was stirred and refluxed for 3 days. The solvent was evaporated and the residue was taken up in CH2Cl2. The organic solution was washed with K2CO3 10%, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 94/6/0.1). The pure fractions were collected and the solvent was evaporated, yielding 7.6 g of ethyl 4-[(1H-imidazo[4,5-b]pyridin-2-yl)methyl]-1-piperidinecarboxylate (52%) (interm. 9).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.CC(C)([O-])C.[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27].O>CS(C)=O>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(cc1OC)CC(=O)NCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1.1 gm (0.005 mol) of 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one were suspended in 15 ml of absolute dimethylsulfoxide, and the suspension was mixed with 0.67 gm (0.006 mol) of potassium tert. butoxide, while stirring. After 10 minutes, the suspension thus obtained was added dropwise to 0.64 ml (0.006 mol) of 1-bromo-3-chloro-propane in 10 ml of dimethylsulfoxide, while cooling with ice water. After one hour the mixture was poured into water. After a short time the viscous precipitate began to crystallize. The precipitate was suction-filtered off, dissolved in acetone, precipitated again with water, and then suction-filtered off and dried
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([O:5]N1C(=O)CCC1=O)=O.[CH:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:31])[CH2:29][OH:30])=[CH:24][CH:23]=1>C1COCC1>[OH:30][CH2:29][C@H:28]([NH:31][C:3](=[O:5])[C@@H:2]([CH3:1])[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: CC(CCCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](CO)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](CCCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Temperature: 48 °C
Reaction time: 40 h
Yield: 34 %

Procedure:
To a solution consisting of (±)-2,5-dioxopyrrolidin-1-yl 2-methyl-5-phenyl pentanoate (18mb(i), 85.6 g, 296 mmol) in THF (3000 mL) at 48° C. was added R-(−)-2-phenylglycinol (65.9 g, 480 mmol, Bridge Organics) in portions. The resulting reaction mixture was stirred at 48° C. for 40 hours. A white precipitate formed, which was filtered from the reaction mixture and washed with THF. The filtrate was concentrated under vacuum and the residue, comprising the diastereomeric pair, was chromatographed on silica gel. Elution with ethyl acetate-heptane (50:50 v/v) afforded the pure diastereomer title compound (31.3 g, 34%) as a colorless solid; TLC Rf 0.205 (solvent system: 50:50 v/v ethyl acetate-heptane); HPLC retention time 15.1 minutes, stationary phase: Gemini 5μ C18 250×4.6 mm, ultraviolet detector at 210 nm, mobile phase: 1 mL/min, 60:40:0.1 v/v methanol-water-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](Cl)=[O:25]>>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccn1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccn4)nc23)CC1
Yield: 22.5 %

Procedure:
Beginning with 0.30 gm (1.30 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.34 gm (1.56 mMol) 2-pyridinecarbonyl chloride, 0.098 gm (26%) of the title compound were prepared as a crystalline solid essentially by the procedure described in Example 4.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+].Cl>C(O)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[N:24][OH:25])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
In to a solution of 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzaldehyde (6.5 g, 22.2 mmol) in ethanol (300 mL) were added hydroxylamine hydrochloride (4.62 g, 66.55 mmol) and a solution of sodium acetate (7.27 g, 82.7 mmol) in H2O (40 mL). The mixture was stirred at room temperature for 12 h, then poured into H2O, acidified with 1N HCl and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether/hexane, gave a white solid (6.1 g, 89% yield, m.p. 192°-193° C.). Analysis for: C18H16N2O3Calc'd: C, 70.12; H, 5.23; N, 9.09 Found: C, 70.31; H, 5.27; N, 8.82
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14](I)[N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].[CH3:38][NH:39][CH3:40]>O.O1CCOCC1>[CH3:38][N:39]([CH3:40])[C:14]1[NH:13][C:10]2=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:26]([F:37])=[CH:27][CH:28]=[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:32])=[O:33])[C:2]=3[F:1])[CH:8]=[C:9]2[CH:15]=1
Reactant: CNC
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(I)n3S(=O)(=O)c2ccccc2)c1F
Solvent: O
Solvent: C1COCCO1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(N(C)C)cc3c2)c1F
Temperature: 100 °C
Yield: 18 %

Procedure:
2,6-Difluoro-N-(2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.050 g, 0.076 mmol) and 7.9M dimethylamine in water (0.240 mL) were combined in 1,4-dioxane (0.500 mL). The solution was heated at 100° C. for 18 hours in a sealed vessel. The reaction mixture was concentrated and purified via reverse phase chromatography to give N-(2-(dimethylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (5.9 mg, 18% yield) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 11.00 (s, 1H), 10.54 (s, 1H), 8.32 (s, 2H), 8.01 (d, 1H), 7.81 (d, 1H), 7.40 (m, 1H), 7.05 (m, 1H), 5.28 (s, 1H), 2.91 (s, 6H), 1.73 (m, 2H), 0.97 (m, 3H). m/z (API-pos) 438.2.