Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:39])[C:28]=1[C:29]1[C:33]([CH2:34]O)=[C:32]([CH:36]([CH3:38])[CH3:37])[O:31][N:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:39][C:27]1[CH:26]=[N:25][CH:24]=[C:23]([Cl:22])[C:28]=1[C:29]1[C:33]([CH2:34][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:32]([CH:36]([CH3:37])[CH3:38])[O:31][N:30]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: CC(C)c1onc(-c2c(Cl)cncc2Cl)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 100 °C
Yield: 50.7 %

Procedure:
Methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (100 mg, 0.36 mmol), [3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methanol (103 mg, 0.36 mmol), triphenyl phosphine (94 mg, 0.36 mmol), diisopropyl azodicarboxylate (0.07 mL, 0.36 mmol) and dichloromethane (3.6 mL) were placed in a microwave reaction tube, sealed and heated in a microwave reactor to 100° C. for 10 minutes. The solution was concentrated then slurried in a 3:7 mixture of acetone: hexane. The resulting off-white solid was purified by chromatography (silica gel, 3:7 acetone:hexanes) to provide methyl 6-[4-({[3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (0.10 g, 52%). 1H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 2H), 8.55 (d, J=9 Hz, 1H), 8.29 (d, J=2 Hz, 1H), 8.18-8.10 (m, 3H), 7.74 (d, J=9 Hz, 2H), 6.89 (d, J=9 Hz, 2H), 4.97 (s, 2H), 3.94 (s, 3H), 3.49 (septet, 7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). ESI-LCMS m/z 548 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.O.[I-].[K+]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Oc1ccc(F)cc1Br
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(F)cc1Br
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Scheme IA, step A: 2-bromo-4-fluorophenol (15.0 g, 78.5 mmol) was dissolved in THF (200 mL) and treated with potassium carbonate (13.0 g, 94.2 mmol) and ethyl 2-bromopropionate (11.2 mL, 86.4 mmol). The reaction mixture was heated at reflux for 3 hours. Potassium iodide (0.1 g) was added and the reaction mixture was stirred for an additional 2 hours at reflux. The reaction was then cooled, diluted with water and extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography to provide ethyl 2-(2′-bromo-4′-fluorophenoxy)propionate (19.8 g) as a clear oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:36]=[CH:35][C:34]([N:31]6[CH2:32][CH2:33][O:28][CH2:29][CH2:30]6)=[CH:42][CH:41]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
The title compound, white solid (16.3 mg, 38.4%), MS (ISP) m/z=421.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 4-morpholinobenzoic acid.
Reaction SMILES: IC.[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([OH:17])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([O:17][CH3:27])=[O:16])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
Iodomethane (554 mg) was added to a suspension of (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionoic acid (1.1 g) and potassium carbonate (539 mg) in N,N-dimethylformamide (7 mL). The mixture was stirred for 2 hours at ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give methyl (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionate (1.2 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Cc1cc(N)c2ncccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2ncccc2c1
Yield: 22.9 %

Procedure:
In a similar fashion using route 14 general procedure 26, 6-methylquinolin-8-amine (Intermediate 31) (70 mg, 0.44 mmol), benzenesulfonyl chloride (0.07 ml, 0.53 mmol) gave the title compound (30 mg, 23%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>[OH-].[Na+]>[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:23]2[CH2:24][CH2:25][C:26]3[N:27]=[C:19]([NH:18][C:8]4[CH:9]=[CH:10][C:11]([N:12]5[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]5)=[C:6]([O:5][CH3:4])[CH:7]=4)[S:20][C:21]=3[CH2:22]2)=[O:37])=[CH:31][CH:30]=1
Reactant: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3c(s2)CN(C(=O)Cc2ccc(F)cc2)CC3)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
To a solution of 90 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride and 35 mg (0.22 mmol) 4-fluorophenylacetic acid in DMF (2 ml) 121 mg (1.2 mmol) N-methyl morpholine and 114 mg (0.3 mmol) HBTU were added. The reaction was stirred over night at room temperature. The reaction was diluted with 2N aqueous NaOH solution (6 ml) and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 70 mg (73%) 2-(4-fluoro-phenyl)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl}-ethanone as a yellow viscous oil. MS ISP (m/e): 478.0 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.32 (s, 1H), 7.65 (s, 1H), 7.46 (s, 1H), 7.32-7.24 (m, 4H), 7.30 (d, 1H), 7.24 (d, 1H), 7.02 (s, 1H), 4.65 & 4.55 (br s, 2H), 3.84 (m, 2H), 3.78 (s, 3H), 2.89 (s, 2H), 2.62 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: C([N:4]1[CH2:8][CH:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:6]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:5]1)C=C.CC#N>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH:6]3[CH:7]([C:9]4[CH:13]=[CH:12][S:11][CH:10]=4)[CH2:8][NH:4][CH2:5]3)[CH2:20][CH2:19]2)=[CH:22][CH:23]=1
Reactant: C=CCN1CC(CN2CCC(c3ccc(F)cc3)CC2)C(c2ccsc2)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: Fc1ccc(C2CCN(CC3CNCC3c3ccsc3)CC2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 0.48 g (0.26 mmol) of 1-allyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(3-thienyl)pyrrolidine and 0.067 g (0.072 mmol) of Wilkinson's catalyst [Rh(PPh)3Cl] in 20 mL of an 85% solution of CH3CN and water was heated to 90° C. and stirred for 3 h. The reaction mixture was cooled to rt and concentrated. The residue was partitioned between EtOAc and water. The organic fraction was washed with sat. NaHCO3, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, CHCl3: MeOH: NH3, 90: 10:1) to give the title compound. 1H NMR CDCl3) δ7.28 (d of d, 1H, J=3.0, 4.8 Hz), 7.15-7.17 (m, 2H), 6.95-7.02 (m, 4H), 3.31-3.38 (m, 2H), 2.85-3.03 (m, 5H), 2.35-2.48 (m, 5H), 1.95-2.02 (m, 2H), 1.61-1.78 (m, 4H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C([O:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[N:28]=[C:27]2[NH:29][CH2:30][CH2:31][C:26]2=[CH:25][CH:24]=1)CCC>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:18](=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[N:28]=[C:27]2[NH:29][CH2:30][CH2:31][C:26]2=[CH:25][CH:24]=1)(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: CCCCOC(=O)CCCCc1ccc2c(n1)NCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCCCc1ccc2c(n1)NCC2)OC
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
A solution of dimethyl methylphosphonate (1.35 g, 10.9 mmol) in anhydrous THF (20 mL) was cooled to −78° and treated dropwise with 2.6 M n-BuLi (4.1 mL). After stirring at −78° for 15 min, a solution of ester 23-6 (0.750 g, 2.71 mmol) in THF (10 mL) was added dropwise and the resulting solution stirred for 15 min at −78°, quenched with sat. NH4Cl (25 mL), then extracted with CHCl3 (1×25 mL), and the organic layer was applied to PCTLC (4 mm, 10% MeOH/CHCl3) affording 0.79 g (89% yield) of 23-7.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]3[N:9]([C:13]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[CH:36]=[CH2:37].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:37]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:8]3[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:11]=[CH:10][N:9]3[C:13]=2[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:24]=2)=[CH:21][CH:20]=1)[CH:36]=[CH2:35]
Reactant: Oc1ccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C
Yield: 33.7 %

Procedure:
To a solution of 4-{8-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-2-yl}phenol (110 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL) was added allyl bromide (27 μL, 0.31 mmol) and cesium carbonate (160 mg, 0.48 mmol). The mixture was heated at 80° C. for 3 hours. The mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid. The residue was purified by flash chromatography (1:1 ethyl acetate:hexanes) to give 2-[4-(allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-8-amine (40 mg, 34%) as a yellow foam. 1H NMR (CDCl3): δ 8.87 (d, 1H), 8.04 (d, 1H), 7.57 (d, 2H), 6.95 (d, 2H), 6.75 (t, 1H), 6.40 (d, 1H), 6.26 (d, 1H), 6.1 (m, 1H), 5.43 (d, 1H), 5.30 (m, 3H), 4.58 (d, 2H), 4.35 (m, 1H), 3.92 (m, 1H), 2.10–2.00 (m, 4H), 1.76–1.45 (m, 12H); MS m/z 495 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl>ClCCl>[CH3:17][Si:18]([CH3:21])([CH3:20])[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Oc1ccc(F)cc1F
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)Oc1ccc(F)cc1F
Temperature: 0 °C

Procedure:
In a 2.51 sulfation flask, 260.2 g (2.0 mol) of 2,4-difluorophenol and 242.9 g (2.4 mol) of triethylamine are dissolved in 700 ml of dichloromethane and cooled to 0° C. 239 g (2.2 mol) of trimethylchlorosilane are added dropwise in the course of about 3 hours. The white suspension is allowed to react to completion for 8 hours (check using GC and TLC). The suspension is filtered, the residue is washed with a little dichloromethane, and the filtrate is evaporated on a rotary evaporator. The oil obtained is distilled at 56°-62° C. in vacuo (22 mbar). 280 g of a clear, colourless liquid are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[CH:5][C:3]=1[NH2:4].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:23])[CH:19]=[C:18]([Cl:39])[C:17]=1[N:40]1[C:44](=[O:45])[CH2:43][C:42](OCC)=[N:41]1.CS(O)(=O)=O>C(OCC)(=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:23])[CH:19]=[C:18]([Cl:39])[C:17]=1[N:40]1[C:44](=[O:45])[CH2:43][C:42]([NH:4][C:3]2[CH:5]=[C:6]([N:9]3[CH2:13][CH2:12][CH2:11][C:10]3=[O:14])[CH:7]=[CH:8][C:2]=2[Cl:1])=[N:41]1
Reactant: Nc1cc(N2CCCC2=O)ccc1Cl
Reactant: CCCCCCCCCCCCCCOC(=O)c1cc(Cl)c(N2N=C(OCC)CC2=O)c(Cl)c1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)c1cc(Cl)c(N2N=C(Nc3cc(N4CCCC4=O)ccc3Cl)CC2=O)c(Cl)c1
Temperature: 150 °C

Procedure:
A mixture of 4.4 g of 2-chloro-5-(2-oxo-pyrrolidin-1-yl)aniline, 10.2 g of 1-(2,6-dichloro-4-tetradecyloxycarbonylphenyl)-3-ethoxy-2-pyrazolin-5-one and 0.5 g of methanesulfonic acid was stirred with heating at 150° C. under reduced pressure for 12 hours. After cooling, the reaction mixture was dissolved in ethyl acetate and washed three times with water. After distilling off the solvent, the residue was separated by a silica gel chromatography (using a solvent mixture of ethyl acetate and chloroform as a spreading agent) to obtain the desired compound. By recrystallization from acetonitrile 9 g of crystals having a melting point of 143° to 146° C. were obtained.
Reaction SMILES: [C:1]1([C:7]2([OH:19])[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:21][C:22](=[O:45])[C@H:23]([C@@H:42]([CH3:44])O)[NH:24]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[C:1]1([C:7]2([O:19][C@H:42]([CH3:44])[C@@H:23]([C:22]([OH:45])=[O:21])[NH2:24])[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccccc2)c2ccccc2-c2ccsc21
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OC1(c2ccccc2)c2ccccc2-c2ccsc21)[C@H](N)C(=O)O

Procedure:
from 8-phenyl-8H-indeno[2,1-b]thiophen-8-ol (Example 1pp) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:11])([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.Cl[C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:20]([NH:2][C:3]([CH3:11])([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:27])[CH3:26]
Reactant: CCOC(=O)CC(C)(C)N
Reactant: CCOC(=O)CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)NC(C)(C)CC(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Ethyl 3-amino-3-methylbutanoate hydrochloride (0.87 g, 4.79 mmol) was suspended on methylene chloride (12 mL) and triethylamine (1.4 mL, 2.1 eq.). The mixture was cooled to 0° C. and treated dropwise with ethyl 3-chloro-3-oxopropanoate (0.64 mL, 1.05 eq.). The reaction was kept at room temperature for 2 hours, diluted with methylene chloride, washed with 1 N HCl and then with 5% NaHCO3, dried over Na2SO4 and evaporated to dryness to obtain ethyl 3-[(3-ethoxy-3-oxopropanoyl)amino]-3-methylbutanoate (1.2 g, Y=97%) as a red oil.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH:22]1([CH2:21][N:11]2[C:12]3[C:7](=[C:6]([OH:34])[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][C:13]=3[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:8]=[C:9]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:10]2=[O:27])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A mixture of 1-cyclopentylmethyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (38 mg, 0.084 mmol), β-alanine (595 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound as a pale yellow solid. MS: (+) m/z 513.47 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][CH:22]([SH:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([S:24][CH:22]([CH3:23])[CH3:21])=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1ccc2c(n1)OCCN(Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
A mixture of the compound obtained in Example 28, step 1 (0.50 g), isopropylthiol (0.20 potassium carbonate (0.51 g) and DMF (10 mL) was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed twice with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(isopropylthio)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.38 g, 63%) as a white powder.
Reaction SMILES: [CH:1]1[C:6]2[C:7]#[C:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH:12]([OH:13])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20].N1C=CC=CC=1>C(Cl)Cl>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19](=[O:20])[O:13][CH:12]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=3[C:7]#[C:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11]2)=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1Cc2ccccc2C#Cc2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1Cc2ccccc2C#Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a solution of 45 (0.22 g, 1 mmol) in CH2Cl2 (30 mL) was added 4-nitro-phenyl chloroformate (0.4 g, 2 mmol) and pyridine (0.4 ml, 5 mmol). After stirring 4 hours at ambient temperature, the reacting mixture was washed with brine (2×10 mL), and the organic layer was dried (MgSO4). The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 10/1, v/v) to afford 47 (0.34 g, 89%). 1H NMR (300 MHz, CDCl3): δ 8.23-8.18 (2H, aromatics), 7.56-7.54 (2H, aromatics), 7.46-7.18 (8H, aromatics), 5.5 (1H, dd, J=3.9, 15.3 Hz, CHOH), 3.2 (1H, dd, J=3.9, 15.3 Hz, CH2), 2.9 (1H, dd, J=3.9, 15.3 Hz, CH2). 13C NMR (75 MHz, CDCl3): δ 154.5, 150.7, 149.1, 148.7, 129.0, 127.4, 127.3, 126.7, 126.5, 125.5, 125.2, 124.3, 124.0, 122.6, 122.4, 120.8, 120.6, 120.2, 112.2, 108.5, 80.6, 44.8. MALDI HRMS: m/z 408.0852 [M+Na+]. Calcd for C23H15NNaO5: 408.0848.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.CS(O[CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)=[CH:26][N:25]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)(=O)=O>CN(C=O)C>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]#[C:22][C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[N:13]([CH2:12][CH2:11][NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH:14]=[CH:15]4)=[N:25][CH:26]=2)=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)OCCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21
Reactant: NCC1CC1
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCNCC4CC4)c3)nc2)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
0.46 mL (5.4 mmol) C-cyclopropyl-methylamine are added to a solution of 2.03 g (4.5 mmol) 2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl methanesulphonate in 20 mL DMF and the reaction mixture is stirred for 4 h at 60° C. The mixture is evaporated down i. vac., the residue is stirred with DCM, the precipitate is suction filtered and dried in the air. The product is precipitated as the methanesulphonic acid salt.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>C(OCC)C>[CH3:21][Si:20]([CH3:23])([CH3:22])[N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN([Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 100.0 grams (0.64 mole) of ethyl piperidin-4-ylcarboxylate and 94 mL (0.67 mole) of triethylamine in 1400 mL of diethyl ether was cooled to 15° C., and a solution of 86 mL (0.68 mole) of chlorotrimethylsilane in 100 mL of diethyl ether was added dropwise during a 30 minute period. Upon completion of the addition, the thick reaction mixture was stirred vigorously for one hour while warming to ambient temperature. The reaction mixture was then filtered, and the collected solid was washed with diethyl ether. The combined wash and filtrate were concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure, yielding 115.0 grams (79% yield) of ethyl N-(trimethylsilyl)piperidin-4-ylcarboxylate, bp 75° C./0.1 mm Hg. The NMR spectrum was consistent with the proposed structure.