Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][C:12]=1/[C:21](/[CH3:28])=[CH:22]/[C:23](OCC)=[O:24]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:11]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][C:12]=1/[C:21](/[CH3:28])=[CH:22]/[CH2:23][OH:24]
Reactant: CCOC(=O)/C=C(\C)c1ccc2c(c1)CCCC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C/C(=C\CO)c1ccc2c(c1)CCCC2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
A solution of diisobutylaluminum hydride in toluene (1.5M, 25 ml) was added dropwise to a solution of ethyl (E)-3-(5,6,7,8-tetrahydro-2-naphtyl)crotonate (3.72 g) in CH2Cl2 at −78° C. and the mixture was stirred at −78° C. for 15 minutes. The reaction mixture was washed with 1N HCl and brine, dried and concentrated to give the titled compound (2.65 g) as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[C:22]([Br:28])[CH:21]=2)=[O:19])=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(S)C>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Br:28])[CH:21]=2)=[O:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OC)c(Br)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: O=C(c1ccc(O)c(Br)c1)c1c(-c2ccc(O)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.2 %

Procedure:
A 0° C. solution of 6.5 g (14.3 mmol) of 3-bromo-4-methoxyphenyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ketone in 300 mL of dichloromethane was treated with 15.3 g (115 mmol) of AlCl3, followed by 17 mL (230 mmol) of ethanethiol. The cold bath was removed and the reaction was stirred at ambient temperature for 3.5 h. The reaction mixture was cooled to 0° C. and poured into cold water. The layers were separated and the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic layers were dried over Na2SO4 and evaporated to give 5.9 g (13.9 mmol, 97%) of an oil which crystallized out when mixed with CH2Cl2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]#[CH:18])[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:19]([C@@H:22]1[CH2:31][CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([C:32]([O:34][CH3:35])=[O:33])[CH:25]=[CH:24][C:23]1=2)=[N+:20]=[N-:21].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O>[CH3:35][O:34][C:32]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[C@H:22]([N:19]1[CH:18]=[C:17]([CH2:16][C@@H:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[C:13]([OH:15])=[O:14])[N:21]=[N:20]1)[CH2:31][CH2:30][CH2:29]2)=[O:33]
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccc(C)cc1)C(=O)O
Reactant: COC(=O)c1ccc2c(c1)CCC[C@H]2N=[N+]=[N-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCC[C@H]2n1cc(C[C@@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)O)nn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (R)-2-(4-methylbenzenesulfonamido)pent-4-ynoic acid (6.25 g, 23.4 mmol) and (R)-methyl 5-azido-5,6,7,8-tetrahydronaphthalene-2-carboxylate (5.4 g, 23.4 mmol) in 80 mL t-BuOH was treated with sodium ascorbate (0.47 g, 2.34 mmole in 24 mL H2O) and CuSO4.5H2O (0.58 g, 2.34 mmol in 24 mL H2O). An additional portion of H2O (50 mL) was then added to the reaction mixture. After stirring for 48 h at RT, the reaction mixture was diluted with H2O. A precipitate had formed that was filtered and air-dried. MS (m/z): 499.4 (m+H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][N:13]1[C:18]2=[CH:19][NH:20][C:21]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])=[C:17]2[C:16](=[O:30])[N:15]([CH3:31])[C:14]1=[O:32].[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35]>C(#N)C>[C:25]([C:24]1[CH:23]=[C:22]([C:21]2[N:20]([CH2:35][CH2:34][C:33]([O:37][CH3:38])=[O:36])[CH:19]=[C:18]3[C:17]=2[C:16](=[O:30])[N:15]([CH3:31])[C:14](=[O:32])[N:13]3[CH3:12])[CH:29]=[CH:28][CH:27]=1)#[N:26]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Reactant: C=CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
DBU (0.656 mL, 4.35 mmol) was added to a solution of 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9 Step 4) (1.22 g, 4.35 mmol) and methyl acrylate (0.392 mL, 4.35 mmol) in acetonitrile (15 mL). The mixture was stirred at room temperature for 4 days. Further portions of methyl acrylate (0.392 mL, 4.35 mmol) and DBU (0.656 mL, 4.35 mmol) were added as required to allow the reaction to run to completion. The reaction was quenched with saturated NH4Cl(aq) and extracted with DCM (2×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc/hexane afforded a crude material which was triturated with DCM/diethyl ether/hexane to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:18]([F:23])([F:22])C([O-])=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:18]([F:23])[F:22])[CH:5]=[O:6]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Product: O=Cc1ccc(OC(F)F)c(Br)c1
Temperature: 65 °C
Reaction time: 5.5 h

Procedure:
A suspension of 3-bromo-4-hydroxy-benzaldehyde (4.97 mmol; 1.0 eq.), cesium carbonate (7.46 mmol; 1.5 eq.) and sodium chlorodifluoroacetate was stirred at 65° C. for 5.5 h. The mixture was partitioned with ethyl acetate and water, and the aqueous portion extracted with diethyl ether. The combined extracts were washed with successive portions of water and brine, dried over magnesium sulfate, filtered and concentrated to afford the title compound, I-286, as a yellow oil. 1H NMR (400 MHz, DMSO-d6): 7.49 (t, J=72.4 Hz, 3H), 7.54 (d, J=8.4 Hz, 1H), 8.00 (dd, J=8.4, 2.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 9.96 (s, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:59]1[CH:64]=[C:63]([O:65][CH2:66][C:67]([F:70])([F:69])[F:68])[N:62]=[C:61]([S:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([F:79])[C:74]=2[F:80])[N:60]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:59]2[CH:64]=[C:63]([O:65][CH2:66][C:67]([F:68])([F:70])[F:69])[N:62]=[C:61]([S:71][CH2:72][C:73]3[CH:78]=[CH:77][CH:76]=[C:75]([F:79])[C:74]=3[F:80])[N:60]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(N)(=O)=O)CC1
Reactant: Fc1cccc(CSc2nc(Cl)cc(OCC(F)(F)F)n2)c1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)Nc2cc(OCC(F)(F)F)nc(SCc3cccc(F)c3F)n2)CC1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 4-(aminosulfonyl)-1-piperazinecarboxylic acid-1,1-dimethylethyl ester (the product from example 15, step i), 0.40 g), tris(dibenzylideneacetone)dipalladium (0) (91 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (48 mg), cesium carbonate (0.49 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-(2,2,2-trifluoroethoxy)-pyrimidine (the product from example 16, step i) (0.37 g) in dioxane (6 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:9 to 2:8 gradient) as eluent to give the subtitle compound as a yellow solid. Yield: 0.22 g
Reaction SMILES: [N:1]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][CH2:20][C:21](O)=[O:22])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:34][C@@H:35]([C:46]([NH:48][C@H:49]([C:54]([NH:56][C@H:57]([C:62]([NH2:64])=[O:63])[CH2:58][CH2:59][S:60][CH3:61])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1.FC(C(O)=O)(F)F.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[N:1]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][CH2:20][C:21]([NH:34][C@@H:35]([C:46]([NH:48][C@H:49]([C:54]([NH:56][C@H:57]([C:62]([NH2:64])=[O:63])[CH2:58][CH2:59][S:60][CH3:61])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)=[O:22])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 36 %

Procedure:
Condensation of BocPro-DTrp-GlyOH (1.00 g.) and HDTrp-Leu-MetNH2 trifluoroacetate salt (1.10 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-DTrp-Gly-DTrp-Leu-MetNH2 in 36% yield. De-t-butoxycarbonylation of BocPro-DTrp-Gly-DTrp-Leu-MetNH2 (0.68 g.) using trifluoroacetic acid in methyl ethyl sulfide and ethanedithiol gave HPro-DTrp-Gly-DTrp-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (2:3) salt in 59% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([CH3:18])=[CH:20][CH:21]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1ccc(CN)cc1
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 4-methylbenzylamine in DME. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:29][OH:30])=[C:16]([NH:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:29]=[O:30])=[C:16]([NH:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=1
Reactant: O=C(CCc1ccccc1)Nc1cc(F)ccc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(F)cc1NC(=O)CCc1ccccc1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
To a solution of oxalyl chloride (4.46 g, 35.13 mmol) and methylene chloride (300 mL) at −78° C. was added dimethyl sulfoxide (3.29 g, 42.15 mmol) over 15 min. After 15 min at −78° C., a solution of N-[5-fluoro-2-hydroxymethylphenyl]benzenepropanamide from Step 2 (3.20 g, 11.7 mmol) and methylene chloride (300 mL) was added over 10 min. After 45 min at −78° C., triethylamine (8.53 g, 84.3 mmol) was added and the reaction was warmed to 23° C. After 20 min at 23° C., the reaction was washed with sat'd NaHCO3 (2×100 mL), brine (1×100 mL) and dried (MgSO4). After concentration in vacuo, the crude residue was purified by flash chromatography (ethyl acetate: hexane 1:3) which afforded the aldehyde as an oil (2.71 g, 85.4%): 1H NMR (CDCl3) δ2.79 (t, J=7 Hz), 3.06-3.16 (m), 6.85-6.93 (m), 7.17-7.37 (m), 7.63-7.69 (m), 8.52-8.58 (m), 9.84 (s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]=[C:37]=[O:38])=[CH:31][CH:30]=1>CN(C=O)C.O>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][NH:36][C:37](=[O:38])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: O=C=NCc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)NCc3ccc(F)cc3)cc2)C1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a stirred solution of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (100 mg) in DMF (3.5 ml) were added sequentially triethylamine (62 μl) and 1-fluoro-4-(isocyanatomethyl)benzene (58.4 μl) and the mixture was stirred at 60° C. for 17 h. The suspension was cooled to room temperature, then diluted with water and extracted twice with EtOAc. The combined organic phases were washed sequentially with water and saturated brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified was purified by flash chromatography (silica gel; gradient: EtOAc/heptane) to afford (S)-tert-butyl 2-(4-(3-(4-fluorobenzyl)ureido)phenyl)morpholine-4-carboxylate (164 mg, quant.) as a white solid. MS (ISP): 374.0 ([M+H—C4H8]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].ClCCl>O>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:11][CH:12]=1)([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)c1ccc(CCO)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(CCOS(C)(=O)=O)cc1
Yield: 107.6 %

Procedure:
In a reaction vessel, 2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid methylester (2.2 g) prepared in the Examples 1-3, triethylamine (1.2 g), methanesulfonylchloride (1.25 g) and dichloromethane (20 mL) were introduced, and the mixture was reacted at room temperature for 2 hours. Distilled water (50 mL) was added thereto, and the mixture was stirred to separate layers. The separated organic layer was dehydrated Na2SO4, and then condensed by filtration to obtain 2-[4-(2-methanesulfonyloxy-ethyl)-phenyl]-2-methyl-propionic acid methylester (3.2 g, yield 100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:8]([N:11]([CH2:19][C:20](O)=[O:21])[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:20](=[O:21])[CH2:19][N:11]([S:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:9])=[O:10])[C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)[CH3:24]
Reactant: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)c1
Reactant: CCNCc1ccccn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1cccc(C)c1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:2]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].N1CCCCC1>CN(C)C=O>[NH2:1][C@@H:2]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CCCCNC(=O)OC(C)(C)C)C(N)=O
Yield: 100 %

Procedure:
Condensation of FmocDLys(Boc)OH (1.00 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 0.63 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave FmocDLys(Boc)-Leu-MetNH2 in 87% yield. De-9-fluorenylmethoxycarbonylation of FmocDLys(Boc)-Leu-MetNH2 (1.00 g.) using piperidine in dimethylformamide gave HDLys(Boc)-Leu-MetNH2 in 100% yield.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:31])[CH2:10][CH2:9]1)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:31])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(OC(F)(F)F)cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3ccc(OC(F)(F)F)cc32)CC1

Procedure:
tert-Butyl(1-{2-[3-oxo-6-(trifluoromethoxy)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)carbamate (Intermediate 62) (790 mg, 1.72 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: C(O[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)C.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][C:4](=[O:11])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][CH:10]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1ccncc1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccncc1
Yield: 50 %

Procedure:
Isonicotinic acid ethyl ester (3.0 g, 20 mmol) was mixed with cyclopropylamine (2 ml) at 120° C. in a sealed vial for 40 h. The reaction mixture was triturated with ether to give 1.62 g (50%) of N-cyclopropyl-isonicotinamide as off-white solid. 1H-NMR(CDCl3) d (ppm): 8.73 (d, 2H), 7.60 (d, 2H) and 6.55 (w, 1H), 2.92 (m, 1H), 0.90 (m, 2H) and 0.66 (m, 2H). Step 2: N-Cyclopropyl-isonicotinimidoyl chloride hydrochloride: N-Cyclopropyl-isonicotinamide (1.62 g, 10 mmol) was reacted with SOCl2 (12 g, 100 mol) at 80° C. overnight. The reaction mixture was concentrated and triturated with dichloromethane to give 1.3 g (64%) of N-cyclopropyl-isonicotinimidoyl chloride hydrochloride as yellow solid. Step 3: 4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine: (R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid hydrazide (56 mg, 0.2 mmol) was mixed with N-cyclopropyl-isonicotinimidoyl chloride hydrochloride (40.6 mg, 0.2 mmol) and K2CO3 (60 mg, 0.43 mmol) in DMF (1 ml) at 100° C. for 3 h. The reaction mixture was dilute with dichloromethane and then washed with water. The organic layer was concentrated and purified with 5˜6% methanol in ethyl acetate to give 32 mg (39%) of the title comound. 1H-NMR(CDCl3) d (ppm): 8.78 (d, 2H), 8.05 (s, 1H), 7.96(d, 1H), 7.73(d, 2H), 7.45(m, 2H), 4.15 (q, 1H), 3.64 (dd, 1H), 3.31 (m, 2H), 1.68 (d, 3H), 1.25 (m, 2H) and 0.79 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:5][O:4][C:3]1=[O:17].[ClH:18]>C(O)C.[Pd]>[ClH:18].[CH3:1][N:2]1[C@@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5][O:4][C:3]1=[O:17]
Reactant: CN1C(=O)OC[C@@H]1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1C(=O)OC[C@@H]1Cc1ccc(N)cc1
Reaction time: 1 h

Procedure:
A suspension of the product from step (a) (4.0 g) and 10% w/w Pd/C (0.20 g) in a mixture of ethanol (70 ml) and dil. HCl (2N aqu. HCl (12 ml)+water (55 ml)) was hydrogenated at 45 psi for 1 hour. The mixture was filtered through Hyflo and the filtrate evaporated in vacuo to give the desired product as a foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([S:20][CH2:21][CH3:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1.CSC.B(F)(F)F.CCOCC>ClCCl>[CH3:1][O:2][C:3](=[O:23])[CH:4]([S:20][CH2:21][CH3:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: CCSC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CSC
Product: CCSC(Cc1ccc(O)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
3-(4-Benzyloxyphenyl)-2-ethylsulfanyl propanoic acid methyl ester (0,37 g; 1.12 mmole) was dissolved in dichloromethane (3.5 ml). Dimethylsulfide (3 ml), was added followed by addition of boron trifluoride etherate (1.6 g; 11 mmole), The reaction mixture was stirred for 3 hours at room temperature and then quenched with water (3 ml). More dichloromethane was added and the phases were separated. The organic phase was washed twice with brine and dried with sodium sulfate. Evaporation of the solvent gave 0.2 g (74.3% yield) of ethylsulfanyl-3-(4-hydroxyphenyl)propanoic acid methyl ester.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[F:40])[NH:36][CH2:35][CH2:34]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[F:40])[N:36]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=1)=[O:29])[CH2:35][CH2:34]2
Reactant: Fc1cc2c(cc1F)NCC2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cc(F)c(F)cc21

Procedure:
0.10 g (0.24 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 50 mg (0.26 mmol) 5,6-difluoro-2,3-di-hydro-1H-indole, 0.10 mL (0.72 mmol) TEA and 80 mg (0.25 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][CH:7]([P:16](=[O:23])([O:20]CC)[O:17]CC)[P:8](=[O:15])([O:12]CC)[O:9]CC.Br[Si](C)(C)C>C(#N)C.O>[OH2:9].[CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][CH:7]([P:8](=[O:9])([OH:15])[OH:12])[P:16](=[O:17])([OH:20])[OH:23].[CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][CH:7]([P:8](=[O:9])([OH:15])[OH:12])[P:16](=[O:17])([OH:20])[OH:23]
Reactant: CCOP(=O)(OCC)C(NCCCSC)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: O
Product: CSCCCNC(P(=O)(O)O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
To a solution of tetraethyl 3-methylthiopropylaminomethylenebisphosphonate (5.28 g) in acetonitrile (100 ml) was added bromotrimethylsilane (12.39 g) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with water (3.2 ml) and concentrated under reduced pressure. The solid residue was collected by filtration and recrystallized from water-methanol to give 3-methylthiopropylaminomethylenebisphosphonic acid hemihydrate (1.84 g, 47%). Colorless prisms, m.p. 120°-122° C.