Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[O:28]1[C:32]2[CH:33]=[CH:34][C:35](B(O)O)=[CH:36][C:31]=2[CH2:30][CH2:29]1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:35]2[CH:34]=[CH:33][C:32]3[O:28][CH2:29][CH2:30][C:31]=3[CH:36]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.20 g, 90%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23](Br)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.[CH:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O)=[CH2:36]>COCCOC.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>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH:35]=[CH2:36])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: C=Cc1ccccc1B(O)O
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
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: COCCOC
Product: C=Cc1ccccc1-c1oc2ncnc(NCCCCCC(=O)OC)c2c1-c1ccc(OC)cc1
Reaction time: 15 h

Procedure:
Add 0.5 ml of 2 M aqueous potassium carbonate solution to a mixture of 224 mg (0.50 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 29 mg (0.03 mmol) tetrakis(triphenylphosphine)palladium(0) in 2.5 ml 1,2-dimethoxyethane. Next, add 92 mg (0.63 mmol) (2-vinylphenyl)boronic acid and stir the mixture for 15 h under reflux. Filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 82 mg (35% of theor.) of the desired product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[N:6][CH:7]=1.CN1CCOCC1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][NH:11][C:21](=[O:22])[CH2:20][Cl:19])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: NNC(=O)c1cncc(Br)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CCl)NNC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
To an ice-cold suspension of 5-bromo-3-pyridinecarbohydrazide (3.0 g, 13.88 mmol) in anhydrous CH2Cl2 (60 mL) was added 4-methyl-morpholine (2.1 g, 20.82 mmol), followed by dropwise addition of chloroacetyl chloride (1.88 g, 16.67 mmol). The cold bath was then removed and the mixture stirred at rt for 15 h. Heavy precipitation occurred and the mixture was diluted with additional CH2Cl2 (50 mL) and stirring continued for 24 h. The solids were collected by filtration and washed with CH2Cl2 to afford the title compound (3.66 g, 90% yield): MS (ES) m/z 292 and 294 (M+1 Br isotopes).
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1>O>[C:24]1([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OCCO
Reactant: FC(F)(F)c1cccc(C(=CCBr)c2ccccc2)c1
Agent: [Li]CCCC
Solvent: O
Product: OCCOCC=C(c1ccccc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of n-butyllithium in hexanes (16 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to dry ethylene glycol (40 ml) at 10° C. When addition was complete the mixture was stirred for 0.5 h at room temperature. 3-Bromo-1-phenyl-1-(3-(trifluoromethyl)phenyl)-1-propene (12.0 g, 35 mmol, prepared similarly to the method described in Example 23) was added and the reaction mixture was stirred at room temperature for 72 h. The mixture was poured into water (300 ml) and extracted with ethyl acetate (2×100 ml). The combined organic extracts was dried over sodium sulphate and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (150 g) using a mixture of cyclohexane and ethyl acetate (7:3) as eluent provided 5.9 g (52%) of 2-(3-phenyl-3-(3-(trifluoromethyl)phenyl)-2-propen-1-yloxy)ethanol. 2-(3-phenyl-3-(3-(trifluoromethyl)phenyl)-2-propen-1-yloxy) ethanol (5.0 g, 15.5 mmol) was dissolved into dry dioxan (80 ml) and stirred under an atmosphere of hydrogen for 18 h at room temperature in the presence of 10% palladium on carbon catalyst (50% aqueous paste) and then filtered. The filtrate was evaporated in vacuo to give 4.0 g (95%) of 2-(3-phenyl-3-(3-trifluoromethyl)phenyl)-1-propyloxy)ethanol. 1H NMR (CDCl3)δ 4.20 (t, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][NH:13][CH2:12][CH2:11]2.Br[C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[C:22]([NH:29][C:30](=[O:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[C:21]([Cl:37])[CH:20]=1>C1(C)C=CC=CC=1>[Cl:37][C:21]1[CH:20]=[C:19]([N:13]2[CH2:12][CH2:11][C:10]3[C:15](=[CH:16][CH:17]=[C:8]([F:7])[CH:9]=3)[CH2:14]2)[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[C:22]=1[NH:29][C:30](=[O:36])[CH2:31][C:32]([CH3:34])([CH3:33])[CH3:35]
Reactant: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Reactant: Fc1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(N2CCc3cc(F)ccc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl biphenyl-2-yl)dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (122 mg, 1.08 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (96 mg, 0.65 mmol), and N-(4-bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide (200 mg, 0.54 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid. m/z=441 [M−1]−.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:16]([OH:18])=[O:17]>CC(C)=O>[C:1]([NH:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:16]([OH:18])=[O:17])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc(N)cc(C(=O)O)c1
Solvent: CC(C)=O
Product: COc1cc(NC(=S)NC(=O)c2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C

Procedure:
Benzoyl isothiocyanate (169 μl, 1.25 mmol) was added to a solution of 3-amino-5-methoxy-benzoic acid (0.2 g, 1.19 mmol) in acetone (10 mL). The reaction was stirred at ambient temperature and a thick precipitate formed after 10 minutes. LCMS indicated complete conversion of the starting material. The solvent was removed in vacuo and the crude material triturated with iso-hexane, dried under reduced pressure and used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][OH:11]>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: OCCC#Cc1ncccn1
Agent: [Pd]
Solvent: CCO
Product: OCCCCc1ncccn1
Yield: 85.7 %

Procedure:
4-(2-Pyrimidinyl)-3-butynol (1.5 g) in ethanol (40 ml) was added to pre-reduced 10% palladium on charcoal (50% aqueous paste) in ethanol (60 ml) and hydrogenated at room temperature and atmospheric pressure. The catalyst was removed by filtration through hyflo and the solvent evaporated in vacuo. The residual oil was purified by FCC. Elution with System C (19:1) and (9:1) gave the title compound as a pale yellow oil (1.32 g).
Reaction SMILES: [CH2:1]([N:4]([C:38]1[S:39][CH:40]=[CH:41][N:42]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([O:19][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[C:15]2=[O:37])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH2:1]([N:4]([C:38]1[S:39][CH:40]=[CH:41][N:42]=1)[S:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([OH:19])[C:15]2=[O:37])=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O)C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a stirring solution of (R)—N-allyl-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (78.7 g, 127 mmol) and THF (300 mL) under N2, at 0° C., was added tetrabutylammonium fluoride (1.0 M in THF, 255 mL, 255 mmol) dropwise over 20 minutes. The mixture was stirred at ambient temperature for 2 hours. To this solution was added H2O (5 mL) followed by evaporation to dryness. The residue was purified via silica gel using 30% EtOAc in hexanes to obtain the desired alcohol as a white solid (39.5 g, 104 mmol, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.37 (d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.92-5.83 (m, 2H), 5.17 (dd, J=1.3, 10.3 Hz, 1H), 4.98 (q, J=1.4 Hz, 1H), 4.55 (dt, J=5.3, 1.7 Hz, 2H), 4.36-4.30 (m, 1H), 3.81-3.76 (m, 1H), 3.70 (td, J=9.5, 5.4 Hz, 1H), 2.45-2.38 (m, 1H), 1.90-1.80 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C3CCCCO3)=[CH:16][CH:15]=2)=O)=[N:10][CH:11]=1.[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)[CH2:29][CH3:30]>>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH3:30])=[N:10][CH:11]=1
Reactant: CN(C)CCOc1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)nc1
Reactant: CCC(=O)c1ccccc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN(C)C)cn1)c1ccccc1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, (5-(2-(dimethylamino)ethoxy)pyridin-2-yl)(4-(tetrahydro-2H-pyran-2-yloxy) phenyl)methanone (1 eq) was reacted with propiophenone (2 eq) to give the desired product (Z/E=1/1). m/z=389[M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35]Br)=[CH:31][CH:30]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:35][C:32]2[CH:33]=[CH:34][C:29]([Br:28])=[CH:30][CH:31]=2)[C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (4.0 g) synthesized in Example 265-1 and 1-bromo-4-(bromomethyl)benzene (2.94 g) were dissolved in N,N-dimethylformamide (40 mL), potassium tert-butoxide (1.32 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was 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 silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (4.65 g) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:17]([CH3:49])[C:18]([N:20]([CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[N:44]([CH3:48])[N:43]=[CH:42]3)CC2C=CC(OC)=CC=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:1]([C:5]1[CH:6]=[C:7]([N:17]([CH3:49])[C:18]([NH:20][CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[N:44]([CH3:48])[N:43]=[CH:42]3)=[O:19])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(Cc2cc(F)ccc2Oc2ccc3c(cnn3C)c2)C(=O)N(C)c2cc(C(C)(C)C)nn2-c2ccc(C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N(C)C(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3C)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Intermediate (31t) (85 mg, 0.131 mmol) was dissolved in 5 mL of solution of 2% (v/v) anisole in trifluoroacetic acid and stirred at room temperature for 1.5 hour. After evaporation the crude residue was dissolved in EtOAc (80 mL) and neutralized with saturated NaHCO3, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The obtained crude oil was purified on silica gel with EtOAc/hexane (2:3) to obtain compound (32t) as a white amorphous (68.6 mg, 99% yield). 1HNMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.32 (d, J=9.4 Hz, 1H), 7.25 (d, J=7.8 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.07 (t, J=10.2 Hz, 1H), 7.20-6.96 (m, 1H), 6.93 (td, J=8.6, 3.1 Hz, 1H), 6.85 (td, J=8.6, 3.1 Hz, 1H), 6.68 (dd, J=8.6, 4.7 Hz, 1H), 6.11 (s, 1H), 5.31 (t, J=6.3 Hz, 0.8H), 5.17 (t, J=6.3 Hz, 0.2H), 4.48-4.26 (m, 2H), 4.05 (s, 3H), 3.00 (s, 3H), 2.33 (s, 2.4H), 2.32 (s, 0.6H), 1.36 (s, 1.8H), 1.29 (s, 7.2H) ppm.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:10][O:9][C:7]([C:5]1[N:6]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:23][CH2:22]2)[S:3][CH:4]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1csc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)c1csc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 150 °C
Yield: 35.1 %

Procedure:
Methyl 2-chlorothiazole-4-carboxylate (500 mg, 2.82 mmol), N-Boc-piperazine (655 mg, 3.52 mmol) and DIPEA (736 uL, 4.22 mmol) were dissolved in DMA (10 mL) and the reaction mixture was heated in a microwave reactor at 150° C. for 45 min. The reaction mixture was partitioned between EtOAc (40 mL) and water (40 mL) and the organic fraction was washed with water (40 mL) and brine (40 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound as a white solid (324 mg, 35.1%). LCMS (ES+): 350.1 [MNa]+. HPLC: Rt 6.04 min, 100% purity.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:9]([C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])[CH2:10][CH2:11][C:12](=O)[OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+].C(OC(N(C(O)CCCC(C1NCCS1)=O)C(OC(C)(C)C)=O)=O)(C)(C)C>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCC(=O)O)C(=O)N1CCSC1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(O)CCCC(=O)C1NCCS1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(CCCO)C(=O)N1CCSC1
Temperature: -20 °C

Procedure:
3-[N,N-Di-(tert-butyloxycarbonyl)-L-glutamyl]thiazolidine (912 mg, 2.2 mmol) was dissolved in tetrahydrofuran (30 mL). This solution was cooled to −20° C., N-methylmorpholine (300 mg, 2.96 mmol) and isobutyl chloroformate (387 mg, 2.83 mmol) were added. After 20 mins at −20° C. the reaction mixture was added to a solution of sodium borohydride (182 mg, 4.8 mmol) in water (5 mL) at 0° C. After 1 hour the reaction mixture was diluted with ethyl acetate (150 mL). This solution was washed with water (1×20 mL) and brine (1×20 mL), dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as 3-[2-(N,N-di-(tert-butyloxycarbonyl)amino-5-hydroxy-pentanoyl]thiazolidine (800 mg, 2.0 mmol, 92%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(OCC)(=O)C.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15].C(N(CC)CC)C>C(O)C>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COC(CN)OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(CNC(C)=O)OC
Reaction time: 1 h

Procedure:
8.2 mL of acetyl chloride were added to a solution of 150 ml of ethyl acetate, 11.2 mL of 2,2-dimethoxyethanamine and 21 mL of triethyl amine at room temperature. After 1 hour, 1.5 mL of ethanol were added. The resulting suspension was stirred for a further hour, and then filtered. Ethyl acetate was removed by evaporation from the filtration liquors yielding the title compound as an oil, which was used without further purifications . H1-NMR (DMSOd6), δ ppm: 7.85 (s broad, 1H); 4.30 (t; 1H); 3.25 (s, 6H); 3.10 (t, 2H); 1.80 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([Br:14])=[CH:9][CH:8]=2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH2:3][N:2]([CH3:15])[CH3:1])=[CH:13]2
Reactant: CN(C)C(=O)c1cc2cc(Br)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)Cc1cc2cc(Br)ccc2[nH]1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
5-Bromo-1H-indole-2-carboxylic acid dimethylamide (1.34 g, 5.00 mmol) was taken in anhydrous THF (50 mL) (suspension), and cooled to −20° C. A solution of lithium aluminium hydride (1.0 M solution in THF, 10.0 mL, 10.0 mmol) was added dropwise at −20° C. over a period of 15 minutes under nitrogen, and allowed to warm to 10° C.; stirring was continued at 10° C. for 1 hour. The reaction mixture was carefully quenched with aq. saturated ammonium chloride solution (10 mL). The reaction mixture was diluted with ethyl acetate (150 mL). The organic phase was separated, washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. Solvent was evaporated, to give (5-bromo-1H-indole-2-ylmethyl)-dimethyl amine as an off-white solid. Yield: 1.27 g (crude).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]3[C:19]([O:25][CH3:26])=[N:20][CH:21]=[CH:22][C:23]=3[I:24])[NH:15]2)=[CH:11][CH:10]=1)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[I:24][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([O:25][CH3:26])[C:18]=1[C:14]1[NH:15][C:16]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH:7][CH3:6])[CH:17]=2
Reactant: COc1nccc(I)c1-c1cc2ccc(N(C)C(=O)OC(C)(C)C)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc2cc(-c3c(I)ccnc3OC)[nH]c2c1
Yield: 92.8 %

Procedure:
A solution of [2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (520 mg, 1.08 mmol) in CH2Cl2 (5 mL) was added 2,2,2-trifluoroacetic acid (1 mL) at 25° C. The solution was heated to reflux for 3 h. The solution was concentrated in vacuo and poured into water. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded [2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-methyl-amine (380 mg, 92%) as a white product. MH+ 379.9.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I.O>C1COCC1.C(OCC)(=O)C>[CH3:15][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1ccc2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-nitroindole (500 mg, 3.1 mmol) in THF (15 mL) at 0° C. was treated portionwise with NaH (290 mg, 9.3 mmol), stirred for 30 minutes, treated dropwise with methyl iodide (0.95 mL, 15.5 mmol), warmed to room temperature for 18 hours, treated sequentially with water and ethyl acetate (200 mL), and washed with brine (100 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to provide the desired product, which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][N:5]1[C:9](=[O:10])[C:8]2([CH2:15][CH2:14][N:13]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:6]1.[OH-].[Na+].ClCCl.Cl>C(O)C>[C:17]1([CH2:16][N:13]2[CH2:14][CH2:15][C:8]3([N:7]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:6][N:5]([CH2:4][C:3]([OH:33])=[O:2])[C:9]3=[O:10])[CH2:11][CH2:12]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CN1CN(c2ccccc2)C2(CCN(Cc3cccc4ccccc34)CC2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)CN1CN(c2ccccc2)C2(CCN(Cc3cccc4ccccc34)CC2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.8 %

Procedure:
(8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl)-acetic acid methyl ester (44.40 g, 0.1 mol, prepared as described above) was dissolved in a mixture of 2 N sodium hydroxide (165 ml, 0.33 mol) and ethanol (500 ml) and stirred at room temperature for 16 h. Dichloromethane (700 ml) was added and pH was adjusted to 5 by the addition of 6 N hydrochloric acid. The organic phase was separated, washed with water (2×200 ml and concentrated to 300 ml in vacuo. Water (300 ml) and dichloromethane (100 ml) were added and the slurry was stirred overnight. The product was collected by filtration, washed successively with water (4×100 ml, dichloromethane (2×50 ml) and acetone (2×50 ml) and dried, affording the title compound as a powder (44.6 g, 97% yield).