Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:36][CH2:35][N:10]2[C:11]3[C:16]([C:17]([C:18]4[C:19](=[O:34])O[C:21](=[O:33])[C:22]=4[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)=[C:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2].C[N:38](C)C=O>N>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:36][CH2:35][N:10]2[C:11]3[C:16]([C:17]([C:18]4[C:19](=[O:34])[NH:38][C:21](=[O:33])[C:22]=4[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)=[C:9]2[CH2:8]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Reactant: CN(C)C=O
Agent: N
Product: CC(=O)OCCC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)c3ccccc32)C1

Procedure:
A solution of 115 mg of 3-[8-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 1 ml of dimethylformamide and 2 ml of 33% aqueous ammonia was heated to 140° C. for 4 hours. The cooled mixture was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (2:1). Crystallization from ethyl acetate/petroleum ether gave 13 mg of 3-[8-(2-acetoxyethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 272°-274° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([C:20]4[S:21][C:22]([CH2:25][NH:26]S(C)(=O)=O)=[CH:23][CH:24]=4)=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:32])([CH3:31])[NH:3]1.C(N(CC)CC)C.[CH3:41][O:42][CH2:43][C:44](Cl)=[O:45]>C1COCC1>[CH3:41][O:42][CH2:43][C:44]([NH:26][CH2:25][C:22]1[S:21][C:20]([C:18]2[S:19][C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]4[CH2:7][C:2]([CH3:1])([CH3:33])[NH:3][C:4]([CH3:31])([CH3:32])[CH2:5]4)[N:14]=3)=[CH:16][CH:17]=2)=[CH:24][CH:23]=1)=[O:45]
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(-c4ccc(CNS(C)(=O)=O)s4)s3)n2)CC(C)(C)N1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NCc1ccc(-c2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)s2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound of Example 68 (133 mg, 0.31 mmol) was dissolved in 7 ml THF and 0.2 ml triethylamine and 37 mg (0.35 mmol) methoxyacetylchloride added. This mixture was stirred at room temperature for 3 hours. Afterwards the solution was evaporated and the crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:95/5/0.5). Yield: 137 mg (88%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CN(C)C=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)[nH]cnc2cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
10% Palladium on carbon (8.3 g) was added to a suspension of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (50 g, 0.177 mol) in dimethylformamide (800 ml) under nitrogen. Ammonium formate (111.8 g, 1.77 mol) was then added in portions over 5 minutes. The reaction mixture was stirred for one hour at ambient temperature then heated to 80° C. for a further hour. The reaction mixture was filtered hot through diatomaceous earth and the residues washed with dimethylformamide. The filtrate was then concentrated and the residue suspended in water. The pH was adjusted to 7.0 using 2M sodium hydroxide and the resulting mixture was stirred at ambient temperature for one hour. The solid was filtered, washed with water and dried over phosphorus pentoxide yielding 7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one as a white solid (20.52 g, 60%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]=1[NH2:24])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CC[C:27]([C:29](Cl)=[O:30])=[O:28].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]=2[NH:24][C:27](=[O:28])[C:29]1=[O:30])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCC(=O)C(=O)Cl
Reactant: CCOP(=O)(CNc1c(N)cc([N+](=O)[O-])c2ccccc12)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c3ccccc3c21)OCC
Temperature: 25 °C

Procedure:
100 mg of (2-amino-4-nitro-1-naphthylamino)-methanephosphonic acid diethyl ester is dissolved in a few ml of tetrahydrofuran and treated with 95 microliters of distilled ethyloxalyl chloride and 118 microliters of triethylamine at ice-bath temperature. The solution is stirred first to room temperature and then the reaction is allowed to be completed at 55° oil bath temperature. The batch is concentrated by evaporation, taken up in ethyl acetate and washed with brine, dried and spun in. The crude product is chromatographed on silica gel with ethanol as mobile solvent. 76 mg or 67% of theory of product is obtained as polar fraction. NMR (DMSO,Delta in ppm): 1.03 (6H tr), 3.8 (4H dq), 4.93 (2H d), 7.73 (2H dd), 8.2, 8.35, 8.47 each 1H.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[CH:33][C:32]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:37]([C:35]1[CH:34]=[CH:33][C:32]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[C:31]([O:30][CH3:29])[CH:36]=1)#[N:38]
Reactant: COc1cc(C#N)ccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cc(C#N)ccc1O[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.5 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-methoxy-4-cyanophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (5.50 mg, 76.5% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.38 (s, 1H), 7.37 (d, 2H, J=2.4 Hz), 7.20 (m, 4H), 7.10 (d, 1H, J=2.4 Hz), 7.08 (s, 1H), 6.99 (apparent d, 1H, J=8.3 Hz), 6.76 (apparent d, 1H, J=8.3 Hz), 5.43 (apparent dd, 1H, J=5.1, 8.0 Hz), 3.91 (s, 3H), 3.34 (m, 2H), 2.63 (m, 2H), 2.63 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=7.7 Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.28 (d, 6H, J=6.8 Hz); ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=O)#[N:2].Cl.[O:13]([NH2:15])[CH3:14]>>[CH3:14][O:13][N:15]=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([F:11])=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(F)c(C#N)c1

Procedure:
Reaction of 3-cyano-4-fluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (94% yield). 1HNMR indicated a 93:7 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 4.02 (3H, s, OCH3), 7.26 (1H, m, aromatic), 7.85 (2H, m, aromatics), 8.03 (1H, s, CH).
Reaction SMILES: [CH3:1][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[S:41][C:42]([CH3:45])=[N:43][N:44]=1)=[C:22]2[C:26]([O:28]CC1C=CC([N+]([O-])=O)=CC=1)=[O:27])([O:4]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].C(O)C.P([O-])([O-])(O)=O.[K+:54].[K+].O>O1CCOCC1.O.[Pt](=O)=O>[OH:4][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[S:41][C:42]([CH3:45])=[N:43][N:44]=1)=[C:22]2[C:26]([O-:28])=[O:27])([CH3:3])[CH3:1].[K+:54]
Reactant: Cc1nnc(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@@H](C(C)(C)OC(=O)OCc4ccc([N+](=O)[O-])cc4)[C@H]3C2)s1
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nnc(SC2=C(C(=O)[O-])N3C(=O)[C@@H](C(C)(C)O)[C@H]3C2)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50 mg) and platinum (IV) oxide monohydrate (50 mg) in a mixture of dioxane (6 ml), ethanol (0.5 ml), 0.1M aqueous dipotassium hydrogen phosphate (2.28 ml) and water (2.5 ml) was shaken for 1.5 hours under a hydrogen atmosphere (40 psi) at ambient temperature. The catalyst was filtered off and the filtrate was concentrated to half of the original volume. The aqueous concentrate was washed three times with diethyl ether and evaporated in vacuo. The residue was dissolved in water (25 ml) and potassium chloride (1.25 g) was added. The aqueous solution was chromatographed on non-ionic adsorption resin, "Diaion HP-20 AG" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.) (1.2×22 cm), eluting with water (150 ml) and aqueous isopropyl alcohol (5 to 30%, 100 ml). The fractions, whose UV spectra showed λmax 293 nm, were combined and lyophilized to give potassium (5R,6R)-6-(1-hydroxy-1-methylethyl)-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (16.9 mg).
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.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>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]([O:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(O)c1cnc(OC2CCC2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Temperature: 100 °C

Procedure:
5-Bromo-6-cyclobutoxy-nicotinic acid (example 78 a; 1.531 g, 5.63 mmol), 4-chloro-phenylboronic acid (968 mg, 6.19 mmol), potassium carbonate (1.56 g, 11.3 mmol) and tetrakis(triphenylphosphine)palladium (325 mg, 281 μmol) were suspended in THF (38 mL) and water (38 mL). The reaction mixture was stirred at reflux temperature (100° C.) over the weekend. THF was removed and the residue was partitioned between water (pH=2) and ethyl acetate; the organic phases were combined, dried with MgSO4 and concentrated in vacuo to obtain the title compound (quant.) as off-white solid; MS (ESI) 302.2 (M−H)−.
Reaction SMILES: [ClH:1].[CH3:2][S:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:12]#[N:13])[CH2:11][CH2:10]2)[CH:8]=1.[CH2:14]([OH:16])[CH3:15]>>[ClH:1].[CH3:2][S:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:12](=[NH:13])[O:16][CH2:14][CH3:15])[CH2:11][CH2:10]2)[CH:8]=1
Reactant: CCO
Reactant: CSc1cnn(C2(C#N)CC2)c1
Agent: Cl
Product: CCOC(=N)C1(n2cc(SC)cn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a saturated solution of hydrogen chloride in ethanol (3.5 mL) at 0° C. was added a solution of 1-(4-(methylthio)-1H-pyrazol-1-yl)cyclopropanecarbonitrile (125 mg, 0.697 mmol) in ethanol (0.5 mL). The reaction mixture was stirred at room temperature for 1.5 h. The solvent was removed under a stream of nitrogen to afford the title compound (210 mg). The material was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:20]1[CH2:21][CH2:22][CH:17]([CH3:16])[CH2:18][CH2:19]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: CC1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(C)CC1

Procedure:
Prepared analogously to Example 1.1 C. from 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 4-methylpiperidine. Yield: 0.7 g (88.2% of theory); C15H22N2O4 (M=294.35); calc.: molecular ion peak (M+H)+: 295; found: molecular ion peak (M+H)+: 295; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:30]([Li])CCC.IC>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:15])([CH3:16])[N:12]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C@H:11]1[CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Solvent: CI
Solvent: C1CCOC1
Product: Cc1nc(C[C@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)cs1
Temperature: -50 °C
Reaction time: 0.67 h

Procedure:
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (0.100 g, 0.23 mmol) was dissolved in THF (2.5 mL) and cooled to −78° C. n-Butyllithium (0.12 ml, 0.29 mmol) was added and the reaction was stirred at −50° C. for 40 minutes followed by the addition of iodomethane (0.018 ml, 0.29 mmol). After stirring 40 minutes the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over sodium sulfate to afford the title compound. MS m/z: 457.3 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([SH:25])[CH:20]=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:25][C:21]2[CH:20]=[C:19]([CH3:18])[CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:12]=1
Reactant: Cc1cccc(S)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Product: Cc1cccc(SCC(=O)c2c(C)noc2-c2ccc(Br)cc2)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and m-thiocresol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=O)[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 80.6 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.09 g, 0.4 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (0.1 g) to give 0.14 g (81%) of the title compound as a yellow-orange solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=O)=[C:10]([CH3:22])[CH:9]=2)=[CH:4][C:3]=1[C:23]1[N:24]=[N:25][N:26]([CH:28]([CH3:30])[CH3:29])[CH:27]=1.[BH4-].[Na+].CO>C1COCC1.O>[CH:28]([N:26]1[CH:27]=[C:23]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)=[C:10]([CH3:22])[CH:9]=3)[CH:4]=2)[N:24]=[N:25]1)([CH3:30])[CH3:29]
Reactant: Cc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)N1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
BF3Et2O in THF (47-49%) (0.87 mL, 2.46 mmol) was added to a solution of [4-[6-amino-5-(1-isopropyltriazol-4-yl)-3-pyridyl]-2-methyl-phenyl]-morpholino-methanone (200 mg, 0.46 mmol) in THF (10.0 mL) at 0° C. The reaction mixture was stirred for 30 min, NaBH4 (93.5 mg, 2.46 mmol) was added at 0° C., reaction mixture was slowly warmed to RT, stirred for 16 h. Reaction mixture was again cooled to 0° C., added MeOH (5.0 mL) and heated to 70° C. for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 2% MeOH in DCM. Product was further purified by Prep.HPLC furnished 30 mg (Yield: 15.5%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:54][CH2:55][C@@H:56]([OH:58])[CH3:57]>O.CN(C)C=O>[OH:58][C@@H:56]([CH3:57])[CH2:55][NH:54][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1
Reactant: C[C@H](O)CN
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC[C@H](C)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 40 h
Yield: 68.2 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), (2S)-1-aminopropan-2-ol (100 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 40 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was washed with ethyl acetate-diethyl ether to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (230 mg, 68%) as colorless prisms. MS 519 (MH+). mp 185-186° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.Cl.C(N)CN.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncc(F)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl (6S)-5′-fluoro-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (300 mg, 0.656 mmol) in MeOH (15 mL) was saturated with HCl (g) and aged for 30 min at ambient temperature. The resulting mixture was concentrated to dryness in vacuo. The residue was dissolved in MeOH (10 mL), ethylenediamine (0.044 mL, 0.656 mmol) was added, and the solution was adjusted to pH 10 by addition of 1 N sodium hydroxide. The resulting mixture was stirred at ambient temperature for 30 min, poured into water (20 mL) and extracted with CHCl3 (2×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH-100:0 to 90:10, to give the title compound, which contained some of the corresponding methyl ester. MS: m/z=328.2 (M+1).
Reaction SMILES: [N:1]1([C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([N:11]2[CH2:12][CH2:13][CH2:14][C@@H:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C([C@@H]1CCCNC1)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@@H](C(=O)N3CCOCC3)C2)CC1
Yield: 69 %

Procedure:
(3R)-Morpholin-4-yl-piperidin-3-yl-methanone (2.25 g, 11.4 mmol) was reacted with tert-butyl 4-oxo-1-piperidinecarboxylate (1 eq., 2.27 g) under conditions analogous to those described above for the preparation of Intermediate 1 to give (3R)-3-(morpholine-4-carbonyl)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester (3.00 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7]([NH2:12])=[C:6]([F:13])[C:5]=1[F:14].[CH2:16]([CH2:20][C:21](=O)[CH3:22])[C:17]([CH3:19])=O>C(O)C.Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5]([F:14])=[C:6]([F:13])[C:7]([N:12]2[C:21]([CH3:22])=[CH:20][CH:16]=[C:17]2[CH3:19])=[C:8]([F:11])[C:9]=1[F:10]
Reactant: COC(=O)c1c(F)c(F)c(N)c(F)c1F
Reactant: CC(=O)CCC(C)=O
Agent: Cl
Solvent: CCO
Product: COC(=O)c1c(F)c(F)c(-n2c(C)ccc2C)c(F)c1F
Temperature: 95 °C

Procedure:
To the solution of 4-amino-2,3,5,6-tetrafluoro-benzoic acid methyl ester (0.5 g, 2.24 mmol) in absolute ethyl alcohol (20 mL) containing 2 drops of conc. HCl was added followed by acetonyl acetone (0.233 g, 2.041 mmol). The reaction mixture was then refluxed at 95° C. for 18 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated and the obtained residue was purified by column chromatography using 0.5% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: C[CH:2]1[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[N:10]1([CH:16]2CCCN2CC(O)=O)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>O1CCOCC1>[CH3:16][N:10]1[CH2:15][CH2:14][N:13]([C:7](=[O:9])[CH2:8][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:12][CH2:11]1
Reactant: O=C(O)CN1CCCC1N1CCNCC1
Reactant: CC1CC(=O)OC(=O)C1
Solvent: C1COCCO1
Product: CN1CCN(C(=O)CCCC(=O)O)CC1
Reaction time: 8 h
Yield: 171 %

Procedure:
1.6 g of 3-methylglutaric anhydride and then 2.62 g of piperazin-1-ylcarboxymethylpyrrolidine are added to 20 cm3 of dioxane. After stirring for 8 hours, an additional 320 mg of 3-methylglutaric anhydride are added and then the stirring is continued at 20° C. for 18 hours. The solvent is evaporated under reduced pressure and then the resulting oil is dried at 45° C. (90 Pa) to give 4.5 g of 5-(4-methylpiperazin-1-yl)-5-oxopentanoic acid in the form of an orange-colored oil which is used as it is.