Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[CH:9]\[CH2:10][OH:11])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:57][O:58][C:59](=[O:70])[CH2:60][O:61][C:62]1[CH:67]=[CH:66][C:65](O)=[CH:64][C:63]=1[CH3:69]>O1CCCC1>[CH3:57][O:58][C:59](=[O:70])[CH2:60][O:61][C:62]1[CH:67]=[CH:66][C:65]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)/[C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)=[CH:64][C:63]=1[CH3:69]
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: OC/C=C(\c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(F)cc2)c2ccc(C#Cc3ccccc3)cc2)cc1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above alcohol (100 mg, 0.305 mmol) in dry tetrahydrofuran (20 ml), was added tributylphosphine (0.11 ml, 0.61 mmol). The mixture was cooled to 0° C. and added 1,1′-(azodicarbonyl)dipiperidine (153 mg, 0.61 mmol), and after 10 min. (4-hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (65 mg, 0.34 mmol) were added. The reaction mixture was stirred for 1.5 hours at 0° C. and then allowed to warm up to ambient temperature overnight. To the reaction mixture was added silica gel Fluka 60 (10 g) and the reaction mixture was evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving {4-[(Z)-3-(4-fluoro-phenyl)-3-(4-phenylethynyl-phenyl)allyloxy]-2-methyl-phenoxy}-acetic acid methyl ester as an oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(O[C:36]1(O[Si](C)(C)C)[CH2:38][CH2:37]1)C.C([BH3-])#N.[Na+]>C1COCC1.C(O)(=O)C>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([CH:36]6[CH2:38][CH2:37]6)[CH2:24][CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1cc2c3cnc(Nc4ccc(N5CCN(C6CC6)CC5)cn4)nc3n(C3CCCC3)c2cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a solution of compound 7 (207 mg, 0.50 mmol) in THF (5 mL) were added water (0.05 mL), (1-ethoxy-1-cyclopropyloxy)-trimethylsilane (1174 mg, 1.0 mmol), acetic acid (0.55 mL) and sodium cyanoborohydride (1 mL, 1 M in THF, 1.0 mmol). The mixture was stirred at 60° C. overnight. The reaction mixture was concentrated and the residue was disolved in ethyl acetate and washed with saturated NaHCO3 and brine then dried. The solvent was evaporated and the residue was purified by chromatography on silica gel eluting with CH2Cl2:methanol:NH4OH (400:10:1) to give compound 187 as a yellow solid (60 mg, 26% yield). 1H NMR (500 MHz, CDCl3) δ 9.08 (1H, s), 8.90 (1H, s), 8.51 (1H, d, J=5 Hz), 8.39 (1H, d, J=10 Hz), 8.18 (1H, bs), 8.07 (1H, d, J=2 Hz), 7.84 (1H, d, J=5 Hz), 7.39 (1H, dd, J=10 Hz, J=2 Hz), 5.38 (1H, p, J=10 Hz), 3.17 (4H, q, J=5 Hz), 2.83 (2H, t, J=5 Hz), 2.42 (2H, m), 2.21-2.14 (4H, m), 1.88 (2H, m), 1.71 (1H, m), 0.53-0.46 (4H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 454.2, Calculated 454.3.
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-:15])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:16]12[CH2:23][CH2:22][CH2:21][C:20]1([CH2:24][CH2:25][NH2:26])[CH2:19][CH2:18][CH2:17]2>>[N:16]12[CH2:23][CH2:22][CH2:21][C:20]1([CH2:24][CH2:25][NH:26][C:2]1[CH:3]=[N+:4]([O-:15])[C:5]3[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:19][CH2:18][CH2:17]2
Reactant: O=[N+]([O-])c1c(Br)c[n+]([O-])c2ccccc12
Reactant: NCCC12CCCN1CCC2
Product: O=[N+]([O-])c1c(NCCC23CCCN2CCC3)c[n+]([O-])c2ccccc12
Yield: 87.4 %

Procedure:
3-Bromo-4-nitroquinoline 1-oxide and 2-(1-azabicyclo[3.3.0]octan-5-yl)ethylamine were reacted in the same manner as in Example 1 to obtain the titled compound in a yield of 87.4%.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][CH:16]([F:35])[C:17]1[N:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:33][CH3:34])=[CH:25][CH:24]=2)[C:19]([SH:22])=[N:20][N:21]=1>ClCCl>[F:35][CH:16]([F:15])[C:17]1[N:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:33][CH3:34])=[CH:25][CH:24]=2)[C:19]([S:22][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:20][N:21]=1
Reactant: CCc1ccc(-n2c(S)nnc2C(F)F)c2ccccc12
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CSc1nnc(C(F)F)n1-c1ccc(CC)c2ccccc12
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Triethylamine (0.11 mL, 0.786 mmol) and ethyl 2-bromoacetate (80 μL, 0.72 mmol) were added to a stirred solution of 5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.2 g, 0.655 mmol) in dichloromethane (2.6 mL). The resulting mixture was stirred for 2 h. The crude reaction mixture was purified by SGC (0-50% EtOAc/Hexanes) to afford ethyl 2-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate as an off-white solid (0.246 g, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]=[CH:10]OCC>ClC1C=CC=CC=1>[Br:1][C:2]1[C:3]2[S:8][CH:9]=[CH:10][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=CSc1ccccc1Br
Solvent: Clc1ccccc1
Product: Brc1cccc2ccsc12
Temperature: 70 °C
Yield: 35 %

Procedure:
1-Bromo-2-(2-ethoxyvinylsulfanyl)benzene is dissolved in chlorobenzene (50 mL) and the solution is heated to 70° C. PPA (10.5 mL) is then added carefully and the biphasic mixture is heated at 150° C. overnight. The resulting dark syrup is allowed to cool down and the supernatant solvent removed by pipette. Chlorobenzene (15 mL) is added to the residue and heated to 150° C. for 30 min. The solvent is removed again and the residue washed with small amounts of dichloromethane until the washings are clear. The organic fractions are combined and filtered through celite to afford a clear yellow solution. Concentration under vacuum followed by LC using cyclohexane as the eluent provided the title compound as a viscous colourless oil (1.21 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH:23]([CH3:29])[C:24](OCC)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[H-].C([Al+]CC(C)C)C(C)C.C1CCCCC1.[Cl-].[NH4+]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH:23]([CH3:29])[CH2:24][OH:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: CCOC(=O)C(C)n1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(CO)n1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43.4 %

Procedure:
To a cooled (0° C.) stirred solution of ethyl 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)propanoate (72 mg, 0.177 mmol) in THF (0.5 mL) was added dropwise a 1.1 M solution of diisobutylaluminum hydride in cyclohexane (1 mL, 1.1 mmol). After 15 minutes, a saturated solution of ammonium chloride and CH2Cl2 were added at 0° C. to the reaction mixture. The aqueous phase was extracted with CH2Cl2 and the organic phases combined, dried over MgSO4, filtered and evaporated. Purification using preparative HPLC gave Compound 96 as an off-white solid (28 mg).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:36]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)[C:14]([C:17]([NH2:18])=[O:36])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc2ncccc2c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (97 mg, 0.241 mmol), 6-aminoquinoline (50 mg, 0.347 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. Water was added to induce precipitation. The precipitate was collected, and dried on vacuum to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(quinolin-6-ylamino)pyrazine-2-carbonitrile as a solid. The solid 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(quinolin-6-ylamino)pyrazine-2-carbonitrile was dissolved in EtOH (4 mL) and DMSO (2 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (26 mg). MS 414.2 (M+H); UV 200.0, 263.4, 296.0, 356.1 nm; t 0.335 min.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][OH:8].[C:9]1(=[O:19])[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.OS(O)(=O)=O>O>[CH:17]1[CH:18]=[C:10]([C:9]([OH:14])=[O:19])[C:11]([C:12]([O:7][OH:8])=[O:13])=[CH:15][CH:16]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: OO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1C(=O)OO
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
Deionized water (125 ml), Na2CO3 (31.0 g, 0.25 mol) and 35% H2O2 (29.15 g, 0.3 mol) are successively charged in a 500 ml four-neck flask, and the mixture was stirred in a dry ice-methanol bath at −5° C.-0° C. Thereto was added phthalic anhydride (37.0 g, 0.25 mol) and the mixture was stirred for 30 min. The bath was removed, ethyl acetate (100 ml) was added to the mixture, and the reaction system was neutralized in a solution obtained by diluting 98% H2SO4 (15 ml) with deionized water (50 ml). After partitioning, the aqueous layer was extracted with ethyl acetate (60 ml). The obtained organic layer (0.64 g) was taken up and saturated NaI-IPA (isopropyl alcohol) solution (5 ml) and 10% acetic acid-IPA solution (20 ml) were added thereto. The mixture was boiled for 5 min. It was titrated with 0.1N aqueous sodium thiosulfate solution. As a result, mono-perphthalic acid was present in 33.5 g and the yield was 76.9%.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)=[C:27]=[O:28]>C1COCC1>[CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:27]([NH:26][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=3)=[O:28])=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)s1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(5-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 120 mg) in THF (2.4 ml) was added 1-isocyanato-3-(trifluoromethyl)benzene (101 mg) and the mixture was stirred overnight at RT. The mixture was concentrated, purified by column chromatography (EtOAc:Pet ether, 2:8) and crystallized in CHCl3/pet ether to give the title compound. Yield: 156 mg (83%); 1HNMR (DMSO-d6, 300 MHz): δ 9.12 (s, 1H), 9.08 (s, 1H), 8.36 (s, 1H), 8.03 (d, 1H), 7.74 (d, 2H), 7.61 (d, 2H), 7.55 (dd, 1H), 7.5 (m, 1H), 7.32 (dd, 1H), 4.33 (m, 1H), 3.68 (s, 3H), 2.26 (m, 1H), 0.92 (d, 6H); MS (ES+): m/z 521 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([N:26]=[CH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N=Cc4ccccc4)c(Cl)cc3n2COCCOC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3cc(NCc4ccccc4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Yield: 81 %

Procedure:
To a slurry of 1-[5-(benzylidene-amino)-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.177 g, 0.366 mmol) in ethanol (7 mL) was added sodium borohydride (41.6 mg, 1.10 mmol) at 0° C. The yellow slurry was warmed to 23° C. over 24 h. The reaction mixture was concentrated and saturated aqueous sodium bicarbonate (25 mL) was added to the residue. The reaction mixture was extracted with EtOAc (3×25 mL) and the combined organic layers were washed with brine (20 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-45% EtOAc/hexanes) to yield the titled compound as a 6:5 mixture of regioisomers (0.144 g, 81% yield). MS (ESI/CI): mass calcd. for C24H26ClN5O4, 483.2; m/z found, 484.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.79 (s, 1H), 8.14 (s, 1H), 7.58 (s, 1H), 7.43-7.27 (m, 5H), 6.92 (s, 1H), 6.03 (s, 2H), 4.75 (t, J=6.0 Hz, 1H), 4.49-4.43 (m, 2H), 4.34 (q, J=7.2 Hz, 2H), 3.65-3.61 (m, 2H), 3.47-3.44 (m, 2H), 3.32 (s, 1H), 1.36 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][S:13][C:7]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]1=[O:18]>ClCCl>[Br:1][C:12]1[S:13][C:7]2[N:6]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:5](=[O:18])[N:4]([CH3:3])[C:9](=[O:10])[C:8]=2[CH:11]=1
Reactant: BrBr
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Br)sc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (2.79 ml) in dry dichloromethane (25 ml) was added dropwise to a solution of 3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (12.0 g, WO 98/54190) in dry dichloromethane (100 ml) and stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with sodium metabisulfite solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the sub-title compound as a cream solid. (15.85 g)
Reaction SMILES: [CH:1]([O-:3])=O.[Na+].[Cl-].[Na+].C1N(CCCS(O)(=O)=O)CCOC1.[NH2:20][CH:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22]#[N:23]>>[CH:1]([NH:20][C@@H:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22]#[N:23])=[O:3]
Reactant: N#CC(N)Cc1ccccc1
Reactant: O=C[O-]
Agent: O=S(=O)(O)CCCN1CCOCC1
Agent: [Cl-]
Agent: [Na+]
Product: N#C[C@H](Cc1ccccc1)NC=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 27 mL buffer-solution of pH 7.4 (containing 0.1 mg/mL catalase, 6 M sodium formate, 0.25 M sodium chloride and 100 mM MOPS buffer) was added 25 mg PDF and 1.0 g rac-2-amino-3-phenylpropionitrile.HCl-salt. This solution was adjusted to pH 6.7. After 20 h of shaking at ambient temperature the reaction was stopped at 38% conversion. A small amount of the heterogeneous reaction mixture was extracted with CH2Cl2. (S)-2-Formamido-3-phenylpropionitrile with e.e.>99% (HPLC) was isolated from the organic layer. The precipitate in the remaining part of the reaction mixture was filtered yielding (S)-2-formamido-3-phenylpropionitrile (e.e.>99.5%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])[O:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[C:7]([OH:13])[CH:6]=2.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>>[Cl:1][C:2]1[C:3](=[O:14])[O:4][C:5]2[CH:6]=[C:7]([O:13][CH2:16][C:17]3([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:18][C:5](=[O:4])[C:10](=[CH2:9])[CH2:11]3)[CH:8]=[CH:9][C:10]=2[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)c(=O)oc2cc(O)ccc12
Reactant: O=C(CBr)c1ccccc1
Product: C=C1CC(COc2ccc3c(C)c(Cl)c(=O)oc3c2)(c2ccccc2)OC1=O
Yield: 71 %

Procedure:
Compound 7 was prepared from 3-chloro-7-hydroxy-4-methylcoumarin and 2-bromoacetophenone according to the procedure given for 4, yield: 71%;
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:10])=[C:5]([Cl:9])[C:6]=1[CH:7]=O.[C:11]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:13])[CH3:12]>C(#N)C.O.[Br-].[Li+]>[Cl:1][C:2]1[S:3][C:4]([Cl:10])=[C:5]([Cl:9])[C:6]=1/[CH:7]=[CH:12]/[C:11](=[O:13])[CH3:14]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(Cl)sc(Cl)c1Cl
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Product: CC(=O)/C=C/c1c(Cl)sc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a stirred solution of 2,4,5-trichloro-thiophene-3-carbaldehyde (10.3 g; 48 mmol) and lithium bromide (0.10 g; 1.2 mmol) in acetonitrile (100 mL) at 15° C. under nitrogen was added acetylmethylene-triphenylphosphorane (15.6 g; 49 mmol). The reaction mixture was stirred for 3 hours at ambient temperature then poured in water (200 ml) and extracted with dichloromethane (3×70 ml). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by chromatography over silica gel (eluant: cyclohexane/ethyl acetate 90:10) to afford 11.2 g (91% of theory) of (E)-4-(2,4,5-trichloro-thiophen-3-yl)-but-3-en-2-one as yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:22])[CH2:16][NH:17][C:18](=O)[CH2:19][CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([OH:22])[CH2:16][NH:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)NCC(O)c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCNCC(O)c1ccc(OCc2ccccc2)cc1
Yield: 97.8 %

Procedure:
To the amide from example 25 (27.5 g, 0.092 mol) in dry THF (100 ml) was added borane-methyl sulphide complex (17.5 ml, 0.18 mol) and the reaction mixture was stirred at reflux for 2 hours. The reaction mixture was cooled then quenched with methanol (30 ml). Water (50 ml) and c.HCl (35 ml) were added and the reaction mixture stirred until all bubbling ceased before concentrating in vacuo. To the residue water (250 ml) was added, before basifying by addition of NH4OH (30 ml). The aqueous layer was extracted with ethyl acetate (3×200 ml) and the combined organic extracts dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a white solid (26.1 g, 0.09 mol, 99%). 1H NMR (CD3OD, 400 MHz) δ: 0.95 (t, 3H), 1.58 (q, 2H), 2.62 (m, 2H), 2.81 (m, 2H), 4.72 (dd, 1H), 5.05 (s, 2H), 6.95 (d, 2H), 7.24 (m, 3H), 7.35 (t, 2H), 7.41 (d, 2H). LRMS: m/z 286 (M-H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23][CH3:24])[CH:15]=2)[CH:10]([F:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:23][CH3:24])[CH:15]=2)[CH:10]([F:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2F)ccc1N
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of (±)-3-fluoro-4-(3-methoxy-4-nitro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester in methanol (10 mL) was added palladium on carbon 10% (1:9 palladium:carbon black, 40 mg). The mixture was shaken in a Parr apparatus under an atmosphere of hydrogen (35 PSI) overnight. Filtration through Celite and evaporation of the solvent provided crude (±)-4-(4-amino-3-methoxy-phenyl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (180 mg, 98%), which was used without purification. 1H NMR (CDCl3): δ ppm 6.63-6.71 (m, 3H), 4.52 (br. s., 2H), 4.05-4.26 (m, 1H), 3.85 (s, 3H), 3.74 (br. s., 2H), 2.63-2.86 (m, 3H), 1.88 (d, J=13.4 Hz, 1H), 1.62-1.79 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: C([O:5][C:6](=[O:37])[C:7]([S:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([N:20]([CH2:35][CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)=[O:22])[CH2:14]2)([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([N:20]([CH:15]1[CH2:14][C:13]2[C:17](=[CH:18][CH:19]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:37])=[O:5])[CH:12]=2)[CH2:16]1)[C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=1)=[O:22])[CH3:36]
Reactant: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1Cc2ccc(SC(C)(C)C(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionic acid tert butyl ester (4.8 g; 8.91 mmol) dissolved in CH2Cl2 (15 mL) is added TFA (15 mL) and the reaction was stirred at RT for 2 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 3.13 g (73%) of 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionic acid as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:36]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C(NCC1CNCCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: O=C(NCC1CN(C(=O)CO)CCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (morpholin-2-ylmethyl)-amide (example A147) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C([O-])([O-])=O.[K+].[K+].[CH3:27][NH2:28]>C(Cl)Cl>[CH3:27][NH:28][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1ccc(-c2ccc([N+](=O)[O-])c(F)c2)cc1[N+](=O)[O-]
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1cc(-c2ccc(N)c([N+](=O)[O-])c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
3′-Fluoro-3,4′-dinitrobiphenyl-4-amine (285 mg, 1.03 mmol) was suspended in DCM (10 mL). K2CO3 (284 mg, 2.06 mmol) was added, followed by MeNH2 (40% in H2O, 10 mL). The mixture was stirred at room temperature for 72 h. The solution was then washed with H2O and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford the product as a red solid (296 mg, 100%).