Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH:32]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][N:6]2[CH2:5][CH2:4][N:3]([C:9]3[C:13]4[CH:14]=[N:15][CH:16]=[CH:17][C:12]=4[O:11][N:10]=3)[CH2:8][CH2:7]2)[CH2:29][CH2:30]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: c1cc2onc(N3CCNCC3)c2cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccncc34)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution in CH2Cl2 (10 ml) of 3-piperazin-1-yl-isoxazolo[4,5-c]pyridine dihydrochloride (840 mg, 3.0 mmol) and trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (904 mg, 3.7 mmol; intermediate H; prepared according to WO2007/093540) was treated with Et3N (629 mg, 6.2 mmol) before addition of Na(AcO)3BH (1.03 g, 5 mmol). The reaction mixture was stirred 16 h at r.t., then sat. aq. NaHCO3 was added and the product was extracted with 2 portions of CH2Cl2. After drying (MgSO4) and evaporation of the solvent the product was purified by flash chromatography (50 g SiO2, EtOAc/MeOH 100:0→80:20) to obtain 930 mg (71%) of the title compound as an off white solid. m/z=430.3 ([M+H]+).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[CH2:13][C:11](=[O:12])[N:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:8]1=[O:9].N1C=CC=CC=1>C1(C)C=CC=CC=1>[O:9]=[C:8]1[N:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:3](=[O:4])[CH3:2])[C:11](=[O:12])[CH2:13][N:7]1[CH3:6]
Reactant: COc1ccccc1NCN1C(=O)CN(C)C1=O
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccccc1N(CN1C(=O)CN(C)C1=O)C(C)=O
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
A solution of 4.5 g of chloroacetyl chloride in 10 ml of toluene was added dropwise to a solution of 7 g of the 1-methyl-3-(2-methoxyphenylaminomethyl)hydantoin and 2.8 g of pyridine in 40 ml of toluene at -10° C. The suspension was stirred on an ice-bath for 1.5 hrs. The resulting precipitate was filtered and thoroughly washed with 5% hydrochloric acid, water, and recrystallized from chloroform-ether to give 6.0 g of N-(2,4-dioxo-1-methylimidazolidin-3-ylmethyl)-N-(2-methoxyphenyl)acetamide, mp 169°-172° C; M+ = 325.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH2:21]([N:28]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Solvent: ClC(Cl)Cl
Product: O=C1CCc2cc(C(=O)N3CCC(=NCc4ccccc4)CC3)ccc2N1

Procedure:
0.8 Gram of 6-(4-oxo-1-piperidyl)carbonyl-3,4-dihydrocarbostyril, 1.6 ml of benzylamine and 1 g of Molecular Sieve 3A (a trademark for synthetic feldspar manufactured by Linde Co., U. S. A.) were dispersed in 15 ml of chloroform and refluxed by heating for 6 hours. Molecular Sieve 3A was removed by filtration, the filtrate was concentrated, then the residue obtained was washed several times with diethyl ether, next, purified by means of a silica gel column chromatography to obtain 6-(4-benzylimino-1-piperidyl)carbonyl-3,4-dihydrocarbostyril.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([CH:19]([CH3:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:26](Cl)(=[O:28])[CH3:27].C([O-])(O)=O.[Na+]>O1CCCC1.O>[C:26]([CH:20]([CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:25])[C:21]([O:23][CH3:24])=[O:22])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: COC(=O)CC(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: COC(=O)C(C(C)=O)C(C)c1ccccc1
Reaction time: 0.17 h

Procedure:
n-Butyllithium (2.5 M hexanes 12.4 ml, 30.9 mmol) is added to N,N-diisopropylamine (4.4 ml, 31.4 mmol) in tetrahydrofuran (THF, 50 ml) at 0° C. After 10 minutes, the resultant solution is transferred via cannula to a cooled (−78° C.) solution of methyl 3-phenylbutyrate (5.0 g, 28.05 mmol) in THF (50 ml). After 40 minutes, the resultant solution is transferred via cannula to a solution of acetyl chloride (19.15 ml) in THF (50 ml). The resultant mixture is stirred at −78° C. for 1.5 hours, then warmed to 0° C. after which water is added and the mixture is then poured into saturated NaHCO3 and extracted with EtOAc. The combined organic phases are washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (12:1 EtOAc-hexane elution) affords the title compound. δH 1.3 (d J 7 3H), 2.3 (s 3H), 3.4 (s 3H), 3.6 (m 1H), 3.8 (m 1H), 7.2-7.4 (m 5H)
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1>CC(N(C)C)=O.[Na+].[Cl-].CCOC(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH:12]=[CH:11][N:10]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: c1nc[nH]n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Clc1cc(-n2cncn2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60 wt. %. in mineral oil, 400 mg, 10.0 mmol, 5.0 eq) was carefully suspended in 5 mL of DMA (caution: intensive gas development). To the mixture was added carefully 1,2,4-triazole (691 mg, 10.0 mmol, 5.0 eq) and the mixture was stirred at room temperature for 30 min. 2,4-Dichloropyridine (300 mg, 2.0 mmol, 1.0 eq) was added in portions and the reaction mixture was heated at 100° C. for 3.5 hours. The mixture was allowed to cool to room temperature and diluted with saturated NaCl solution (25 mL) and EtOAc (15 mL). The separated aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic layers were washed with saturated NaCl solution (25 mL), dried over sodium sulfate and concentrated under reduced pressure. Purification by silica column chromatography with EtOAc/hexanes (3/1) provided 2-chloro-4-(1H-1,2,4-triazol-1-yl)pyridine as a white solid. Yield: 290 mg. ES/MS m/z 181.1 (MH+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:25](O)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC(OCC(C)C)=O.CCN(C(C)C)C(C)C.[N+:45](=[CH2:47])=[N-:46]>C1COCC1.CCOCC>[C:21]([O:20][C:18](=[O:19])[O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C:25](=[O:26])[CH:47]=[N+:45]=[N-:46])=[CH:16][CH:15]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)OC(C)(C)C)cc1)C(=O)O
Reactant: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)OC(C)(C)C)cc1)C(=O)C=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
N,O-Bis-Boc-(S)-tyrosine (6.00 g, 15.73 mmol) was dissolved in THF (40 mL), the solution stirred under an argon atmosphere and cooled in an ice bath. Isobutyl chloroformate (3.0 6mL, 23.59 mmol) was added followed by DIEA (8.22 mL, 47.19 mmol). Additional isobutyl chloroformate (1 mL) was added after 1.5 and 2.5 h. To the cold suspension was then added a ca 0.6M Et2O solution of diazomethane (80 mL) by portions. After 15 min. of stirring, nitrogen was diffused in the solution for 0.5 hr. The solvent was evaporated, the residue taken into EtOAc (75 ml) and the solution washed with 0.5M aqueous citric acid (2×50 mL), 5% aqueous sodium bicarbonate (2×50 mL) and brine (50 mL). After drying (MgSO4) and evaporation of the solvent under reduced pressure, the residue was purified by flash chromatography (20% EtOAc/hexane) to give the title compound (5.52 g) of a yellowish solid.
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[O:7])[CH:5]=[CH:4]N=[CH:2]1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:22]2CNCC[C:17]=2[C:16]=1[CH:25]=[O:26]>O1CCCC1>[N:8]1([C:6]([N:1]2[CH2:2][CH2:22][C:17]3[C:16]([CH:25]=[O:26])=[C:15]([O:14][CH3:13])[CH:24]=[CH:23][C:4]=3[CH2:5]2)=[O:7])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2c(c1C=O)CCNC2
Solvent: C1CCOC1
Product: COc1ccc2c(c1C=O)CCN(C(=O)n1ccnc1)C2
Temperature: 80 °C
Reaction time: 14 h
Yield: 88.2 %

Procedure:
To a solution of freshly dried di-imidazol-1-yl-methanone (276 mg, 1.7 mmol) in anhydrous tetrahydrofuran (20 mL) the solution of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde (325 mg, 1.7 mmol) in anhydrous tetrahydrofuran (10 mL) was added and the mixture was stirred at 80° C. oil bath for 14 h. The solution was concentrated and the residue was dissolved in dichloromethane, washed with water (2×10 mL), dried over MgSO4 and concentrated. In this manner the title compound (426 mg, 1.50 mmol, 88.2%) was obtained as a brownish yellow foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].C(N(C(C)C)CC)(C)C.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:10]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc(CCCCO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(CCCCO)c1
Reaction time: 65 h

Procedure:
A solution of 3-(4-hydroxybutyl)benzoic acid (100 mg) in dry DMF (10 ml) was treated with diisopropylethylamine (0.134 ml) and benzyl bromide (106 mg) and the reaction mixture was stirred for 65 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with sat. NH4Cl(aq), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (SPE, gradient Cyclohexane to cyclohexane-EtOAc 1:1) to give the title compound LCMS RT=3.38 min.
Reaction SMILES: [CH:1]([N:4]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=O)[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:49]1[NH:54][CH2:53][CH2:52][N:51]2[CH2:55][CH2:56][CH2:57][C@H:50]12>ClCCl.CN(C)C=O.ClCCl>[CH2:49]1[N:54]([C:21]([C:20]2[CH:19]=[C:18]([N:4]([CH:1]([CH3:3])[CH3:2])[S:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)(=[O:7])=[O:6])[CH:26]=[CH:25][CH:24]=2)=[O:23])[CH2:53][CH2:52][N:51]2[CH2:55][CH2:56][CH2:57][C@H:50]12
Reactant: CC(C)N(c1cccc(C(=O)O)c1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: C1C[C@@H]2CNCCN2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(c1cccc(C(=O)N2CCN3CCC[C@@H]3C2)c1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 3-(N-isopropyl-3-(trifluoromethyl)phenylsulfonamido)benzoic acid (155 mg, 0.4 mmol) and 1-hydroxybenzotriazole hydrate (61 mg, 0.4 mmol) in dichloromethane/N,N-dimethylformamide (4:1, 6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 62 mg, 0.4 mmol) in dichloromethane (1 mL). After 5 minutes, (R)-octahydropyrrolo[1,2-a]pyrazine (50 mg, 0.4 mmol) in dichloromethane (1 mL) was added. The mixture was stirred at room temperature overnight. Then the mixture was concentrated. The residue was diluted with ethyl acetate (100 mL), washed with water (2×20 mL), dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (dichloromethane, then methanol/dichloromethane=1:12) to give the titled compound: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 (d, 6H, J=8 Hz), 1.35 (m, 1H), 1.65-2.10 (m, 6H), 2.80-3.05 (m, 4H), 3.45-3.55 (m, 1H), 4.40-4.50 (m, 1H), 4.60 (m, 1H), 6.98 (s, 1H), 7.15 (m, 1H), 7.50 (m, 2H), 7.88 (m, 2H), 8.10 (m, 2H); MS (ESI) m/z 496 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH2:5][N:6]=[C:7]=[O:8].[Cl:12][CH2:13][C:14]1[N:18]=[C:17]([NH2:19])[S:16][N:15]=1>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1.CCOC(C)=O>[Cl:12][CH2:13][C:14]1[N:18]=[C:17]([NH:19][C:7]([NH:6][CH2:5][C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)=[O:8])[S:16][N:15]=1
Reactant: O=C=NCc1cccc(F)c1
Reactant: Nc1nc(CCl)ns1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(NCc1cccc(F)c1)Nc1nc(CCl)ns1
Temperature: 25 °C
Yield: 72 %

Procedure:
3-Fluorobenzyl isocyanate (1.3 g, 8 mmol) was added into a mixture of Intermediate 38: 3-chloromethyl-[1,2,4]thiadiazol-5-ylamine (0.83 g, 5.5 mmol), and DMAP (22 mg, 0.14 mmol) in NMP (11 mL). The reaction mixture was heated in a microwave reactor for 1 hour at 100 C and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (75 mL) and washed with water (30 mL×2). The aqueous phase was extracted with EtOAc (40 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give the crude product, which was purified by silica gel column chromatography to afford 1-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-3-(3-fluoro-benzyl)-urea as an off-white solid (1.2 g, 72%). LC-MS (m/z): 303.0 (M+H)
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[OH:18][C:19]([C:25](=[O:32])[NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])([CH2:23][CH3:24])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH2:23]([C:19]([OH:18])([C:25]([NH:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[O:32])[C:20]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:21])[CH3:24]
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: CCC(O)(C(=O)O)C(=O)NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(O)(C(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A solution of 250 mg (1.12 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 256 mg (1.12 mmol) (RS)-2-hydroxy-2-(2,2,2-trifluoro-ethylcarbamoyl)-butyric acid in 24 ml tetrahydrofuran were cooled to 0° C. and 174 mg (0.94 mmol) 1-hydroxy-benzotriazole hydrate, 390 μl (2.23 mmol) diisopropylethylamine and 218 mg (1.12 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. Removal of the solvent by distillation and chromatography on silicagel with ethylacetate/heptane 2/8 yielded 330 mg (68%) (R/S)-2-ethyl-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,2-trifluoro-ethyl)-malonamide as a colorless oil, MS (m/e): 436.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:18](=O)([O-])[O-].[Na+].[Na+].C(OCC)C.CCCCCC>CO.O>[CH3:18][O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[OH:12]
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)C(O)c1ccc(Cl)cc1
Yield: 84.7 %

Procedure:
2-(4-Chlorophenyl)-2-hydroxyacetic acid (40 g; 0.2 mol) is dissolved in 100 ml of methanol and stirred at +20° C. At this temperature 5 ml of concentrated sulfuric acid are added dropwise. After the addition is complete the reaction mixture is heated up to +45° C. and stirred for further 30 minutes. Then the reaction mixture is poured into a cooled (0° C.) solution of sodium carbonate (42 g; 0.4 mol) in 300 ml of water. The product is extracted with toluene (3×50 ml) washed with brine (3×50 ml) dried (Na2SO4) and evaporated. After crystallization from diethylether/hexane (10 g/80 g) 2-(4-chlorophenyl)-2-hydroxyacetic acid methylester (34 g; 84% yield) is obtained as a colorless solid. M.p. 54-55° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[N:13]1[CH:12]=[CH:11][N:8]2[CH:9]=[CH:10][C:5]([CH2:3][OH:2])=[CH:6][C:7]=12
Reactant: COC(=O)c1ccn2ccnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccn2ccnc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −78° C. cooled solution of imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (1 eq.) in dry THF was slowly added a solution of LiAlH4 in THF (1M in THF, 2 eq.). The reaction mixture was warmed to 0° C. and stirred for 30 min. The reaction mixture was then poured onto a cooled aqueous solution of NaOH 2N, stirred for 5 min and filtered through a pad of celite. The filtrate was partitioned between water and EtOAc, the organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford imidazo[1,2-a]pyridin-7-yl-methanol which was used as such without further purification.
Reaction SMILES: [OH:1][C@H:2]([CH3:18])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[C:6]([C:16]#[N:17])=[N:5]1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:3][C@H:2]([OH:1])[CH3:18])[N:5]=[C:6]2[C:16]#[N:17]
Reactant: C[C@@H](O)Cn1nc(C#N)c2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@@H](O)Cn1nc(C#N)c2cc(N)ccc21
Temperature: 80 °C
Yield: 74.2 %

Procedure:
A solution of (R)-1-(2-hydroxypropyl)-5-nitro-1H-indazole-3-carbonitrile (0.76 g, 2.93 mmol) in EtOH (10 ml) was added to a suspension of iron (powder) (1.310 g, 23.46 mmol) and ammonium chloride (1.569 g, 29.3 mmol) in water (10 ml). The reaction mixture was heated in a microwave reactor at 80° C. for 15 min. The reaction vial was cooled to room temperature and the reaction mixture was filtered through celite, rinsing with EtOH, water, EtOH again, and then EtOAc. The filtrates were combined and diluted with EtOAc. The organic layer was washed with saturated aq. NaHCO3 solution, water, then brine, then dried over MgSO4, filtered, and evaporated to dryness. (R)-5-amino-1-(2-hydroxypropyl)-1H-indazole-3-carbonitrile (470 mg) was obtained as a pale yellow solid.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15].[Br:31][C:32]1[CH:37]=[CH:36][C:35](/[C:38](/[CH3:42])=[CH:39]/[CH2:40]O)=[CH:34][CH:33]=1>C1C=CC=CC=1.O.C(OCC)(=O)C>[Br:31][C:32]1[CH:37]=[CH:36][C:35](/[C:38](/[CH3:42])=[CH:39]/[CH2:40][O:30][C:27]2[CH:26]=[CH:25][C:24]([CH2:23][C@H:17]([O:16][CH2:14][CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:29][CH:28]=2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(Br)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.74 ml, 0.61 g, 3.0 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.500 g, 2.10 mmol) and (E)-3-(4-bromophenyl)-but-2-en-1-ol (0.454 g, 2.0 mmol) in dry benzene (20 ml), the mixture warmed to room temperature, and stirred for 2.5 days. The resulting mixture was diluted with water and ethyl acetate (50 ml each), the aqueous layer collected and further extracted with ethyl acetate (50 ml). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated. The crude product was then purified by column chromatography on silica gel (20% ethyl acetate in n-heptane eluent) to give (E)-(S)-ethyl 3-{4-[3-(4-bromophenyl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate as an oil; 0.780 g (87%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl[CH2:33][CH2:34][CH2:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])=[CH:37]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:50][O:49][C:47](=[O:48])[CH2:46][CH2:45][C:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:36]([CH2:35][CH2:34][CH2:33][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)[CH:37]=1
Reactant: COC(=O)CCc1cn(CCCCl)c2ccccc12
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CCc1cn(CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)OC(C)(C)C)c2)CN3c2ccccc2)c2ccccc12
Temperature: 81 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
A mixture of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (500 mg, 1.186 mmol, 1 equiv) and methyl 3-(1-(3-chloropropyl)-1H-indol-3-yl)propanoate (384.4 mg, 1.186 mmol, 1 equiv), sodium iodide (88.88 mg, 0.593 mmol, 0.5 equiv) and potassium carbonate (492 mg, 3.56 mmol, 3 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using preparative thin layer chromatography in 5% methanol in dichloromethane to afford the title compound as a white solid (442 mg, 56%); 1H NMR (400 MHz, DMSO-d6): δ 1.52 (s, 9H); 1.63 (d, 2H, J=12 Hz); 1.90-1.96 (m, 2H); 2.24 (bs, 2H); 2.61-2.70 (m, 8H); 2.96 (t, 2H, J=7.6 Hz); 3.57 (s, 3H); 4.20 (t, 2H, J=6.4 and 6.8 Hz); 4.59 (s, 2H); 4.61 (s, 2H); 6.77 (t, 1H, J=7.2 and 7.6 Hz); 6.87 (d, 2H, J=8.4 Hz); 6.99 (t, 1H, J=7.6 Hz); 7.10 (t, 1H, J=7.6 and 6.8 Hz); 7.17 (s, 1H); 7.24 (t, 2H, J=7.2 and 8.4 Hz); 7.46-7.53 (m, 4H); 7.79-7.84 (m, 2H); MS for C40H48N4O5 m/z 665 (M+H)+.
Reaction SMILES: [C:1](OC1C=CC(C2C=CC=CC=2)=CC=1)(=[O:4])[C:2]#[CH:3].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C#C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C>[C:1](=[O:4])([S:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]#[CH:3]
Reactant: Sc1ccccc1
Reactant: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Agent: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: C#CC(=O)Sc1ccccc1
Yield: 84 %

Procedure:
The compound 19 was prepared according to the method described for compound 1 employing thiophenol (1 g, 9.07 mmol), propargylic acid (0.64 g, 9.07 mmol), DCC (1.87 g, 9.07 mmol) and DMAP (7.3 mg, 0.06 mmol) to give brownish liquid compound 19 (1.24 g, 84%). 1H NMR (300 MHz, CD2Cl2) δ 3.40 (s, 1H), 7.46 (s, 5H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.C([O:23][C:24]1[C:25](=[O:35])[C:26](=O)[C:27]=1[NH:28][C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])CCC>O1CCCC1>[CH3:2][C:3]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:4]=1[CH2:5][NH:6][C:26]1[C:25](=[O:35])[C:24](=[O:23])[C:27]=1[NH:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH3:31]
Reactant: Cc1ccc(C)c(CN)c1
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)(C)Nc1c(NCc2cc(C)ccc2C)c(=O)c1=O
Yield: 87.2 %

Procedure:
Tetrahydrofuran (10 mL), 2,5-dimethylbenzylamine hydrochloride (0.858 g, 5.0 mmol, Example 94, Step 2), triethylamine (0.51 g, 5.0 mmol), and 3-butoxy-4-(1,1-dimethylpropylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5.0 mmol, Example 3) were stirred together at room temperature for approximately 18 hours. After removal of solvent the residue was triturated with water, with diethyl ether, and dried to give 1.31 g of a light yellow solid. Three recrystallizations of the crude product from acetonitrile provided 0.812 g of the title compound as a fluffy, white solid: mp 199°-200° C. (softens 195° C.). MS (m/z) 301 ([M+H]+). HPLC indicates a major component (>99%).