Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([O-])=[O:11])=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[BH4-].Cl>O1CCOCC1>[CH:1]1([C:6]2[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[CH:8][C:7]=2[C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C([O-])c1ccc(C2CCCC2)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Product: OCc1ccc(C2CCCC2)c(C(F)(F)F)c1
Temperature: 85.5 °C
Reaction time: 5.5 h
Yield: 54.7 %

Procedure:
To a solution of 4-cyclopentyl-3-(trifluoromethyl)benzoate (224 g, 823 mmol) in 1,4-dioxane (600 mL), LiBH4 (494 mL, 987 mmol, 2 M solution in THF) was added dropwise at 22° C. The resulting suspension was stirred at 85.5° C. for 5.5 h. The dark brown solution was cooled to 0° C. and the pH adjusted to 5 by slowly adding 6 N HCl (130 mL). The layers were separated and to the aqueous phase H2O (250 mL) and NaCl (20 g) were added. The combined aqueous layers were extracted with EtOAc (2×250 mL). The EtOAc layer was added to the previously separated organic phase and the combined organics were concentrated under reduced pressure. The resulting suspension was filtered through a pad of Celite®/Na2SO4 and the solids were washed with EtOAc (3×400 mL). The combined organics were rotary evaporated and the dark brown oily residue was subjected to chromatography on silica to give the title compound as colorless liquid (110 g). LCMS m/z=243.3 [M−H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.67-1.55 (m, 2H), 1.82-1.69 (m, 2H), 1.95-1.83 (m, 2H), 2.19-2.04 (m, 2H), 3.39 (quintet, J=8.0 Hz, 1H), 4.72 (s, 2H), 7.55-7.46 (m, 2H), 7.62 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH3:17])=[N:7][N:6]=[CH:5]2.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[NH2:26].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.CO.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]>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[NH:26][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH3:17])=[N:7][N:6]=[CH:5]2
Reactant: Nc1ccc(F)cc1F
Reactant: CC1CCCN1c1nncc2cc(Br)ccc12
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: CC(C)(C)O
Solvent: CO
Product: CC1CCCN1c1nncc2cc(Nc3ccc(F)cc3F)ccc12
Temperature: 110 °C

Procedure:
A mixture of 6-bromo-1-(2-methylpyrrolidin-1-yl)phthalazine (325 mg, 1.1 mmol), 2,4-difluorobenzenamine (287 mg, 2.2 mmol), Pd2(dba)3 (10.2 mg, 0.011 mmol), X-Phos (26.5 mg, 0.056 mmol), and potassium carbonate (384 mg, 2.8 mmol) in t-butanol (2.2 mL) was heated at 110° C. in an oil bath for 18 h. The mixture was cooled to RT, diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated. The resulting brown residue was purified by column chromatography (0-70% acetone in hexanes) to provide the title compound as a brown amorphous solid. MS (ESI, pos. ion) m/z: 341.2 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]1[C:16]([S:17][CH3:18])=[CH:15][C:14]([C:19]2[C:24]([CH2:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:27][CH3:28])=[N:13][C:12]=1[CH3:29])C>C1COCC1>[CH2:27]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25][CH3:26])[C:19]=1[C:14]1[N:13]=[C:12]([CH3:29])[C:11]([CH2:10][OH:9])=[C:16]([S:17][CH3:18])[CH:15]=1)[CH3:28]
Reactant: CCOC(=O)c1c(SC)cc(-c2c(CC)cccc2CC)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1-c1cc(SC)c(CO)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of LiAlH4 (1 M in THF, 1 mL, 1 mmol) is added to a solution of 6-(2,6-diethyl-phenyl)-2-methyl-4-methylsulfanyl-nicotinic acid ethyl ester (125 mg) in THF (5 mL) at 0° C. The mixture is warmed to room temperature and stirred for 1 hour, cooled to 0° C. and Na2SO4.10H2O is added to quench the reaction. The mixture is filtered through Celite and the filtrate is concentrated in vacuo to give [6-(2,6-diethyl-phenyl)-2-methyl-4-methylsulfanyl-pyridin-3-yl]-methanol.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2F)[N:7]=[C:6]([C:16]([O:18]CC)=[O:17])[CH:5]=1.[OH-:21].[Na+]>O1CCOCC1>[C:9]1([N:8]2[C:4]([NH:3][C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:21])=[CH:5][C:6]([C:16]([OH:18])=[O:17])=[N:7]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2F)n1
Reactant: [OH-]
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)Nc1cc(C(=O)O)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
145.3 mg (3.63 mmol, 1.2 Eq) of a 60% suspension of NaH in mineral oil are suspended in 25 ml of dioxane, 700 mg (3.03 mmol) of ethyl 5-amino-1-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylate are added and the resulting mixture is stirred for 10 minutes at RT: Then phenylisocanate (360.6 mg, 3.03 mmol, 1 Eq) is added and the resulting mixture is heated to 80° C. for 5 hours. After cooling 7 ml of 1M NaOH are added and the resulting mixture is stirred overnight at RT. The solvent is evaporated in vacuo and the obtained crude product is subjected to HPLC chromatography. 257 mg (26%) of the pure product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][N:19]=[C:20]=[S:21]>ClCCl>[CH3:18][NH:19][C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[S:21]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 47.7 %

Procedure:
To a solution of 10.0 mg (0.0437 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole in 3.0 mL dichloromethane were added 6.2 mg (0.0874 mMol) methyl isothiocyanate. The reaction was mixed for 48 hours and to it were then added 0.15 gm (0.0874 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the volatiles evaporated to give 6.3 mg (48%) of the title compound.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]([OH:21])[CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]([OH:21])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(O)CC#Cc1ccccn1
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(O)CCCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A solution of 1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)-4-(pyridin-2-yl)but-3-yn-1-ol (286 mg, 1.00 mmol) in ethanol (6.0 mL) was flushed with nitrogen. Palladium on carbon (10%, 100 mg) was added and the reaction was again flushed with nitrogen. The reaction was then stirred at room temperature under an atmosphere of hydrogen overnight. The reaction was filtered through a pad of silica and purified by silica chromatography to give the desired hydrogenation product (190 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[NH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>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]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:29][CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34])[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: CC(=O)NCCN
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC(=O)NCCNc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 16.1 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd2(dba)3 (66 mg, 0.072 mmol), N-(2-Amino-ethyl)-acetamide (147 mg, 1.44 mmol), Xphos (69 mg, 0.144 mmol) in dioxane (2 mL) was added to a MW tube. The mixture was bubbled N2 for about 2 min, tBuONa (142 mg, 1.44 mmol), was added followed and bubbled N2 for another 2 min. The mixture was stirred at 120° C. for 45 min under the irradiation of microwave. The mixture was filtered though a ceilite, the filtrate was concentrated to dryness and purified by pre-TLC (pure EtOAc) and pre-HPLC to afford 56 mg of 392. (yield=16%). 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1H), 7.50-7.44 (m, 1H), 7.19-6.99 (m, 4H), 6.25-6.17 (m, 2H), 4.55 (s, 1H), 4.18-4.16 (m, 2H), 3.46-3.40 (m, 2H), 3.06-3.04 (m, 2H), 1.80-1.79 (m, 1H). ESI-MS: m/z=483 [M+H+]
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:13]([Cl:27])[C:12]2=[O:28])=[CH:6][CH:5]=1.[NH3:30]>CO>[Cl:27][C:13]1[C:12](=[O:28])[N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH2:30])=[O:2])=[CH:5][CH:6]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: N
Reactant: COC(=O)c1ccc(Cn2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)cc1
Solvent: CO
Product: NC(=O)c1ccc(Cn2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)cc1
Temperature: 75 °C
Yield: 60 %

Procedure:
A sealed tube containing a solution of 4-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzoic acid methyl ester (0.25 g, 0.60 mmol) and NH3 (20 mL of a 7 N solution in MeOH, 140 mmol) was heated at 75° C. for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Trituration with Et2O/MeOH afforded 4-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzamide as a white solid (0.14 g, 60%): mp 235-238° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.93 (d, J=8 Hz, 2H), 7.79 (d, J=8 Hz, 2H), 7.60 (app q, J=8 Hz, 1H), 7.35-7.27 (m, 4H), 7.20-7.10 (m, 1H), 6.61 (d, J=8 Hz, 1H), 5.28 (s, 2H), 5.14 (s, 2H). ESHRMS m/z 405.0788 (M+H C20H16ClF2N2O3 requires 405.0812)
Reaction SMILES: C([N:4]1[C:18]2[C:19]3[C@@H:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[C:15]([Br:20])=[CH:16][CH:17]=2)[CH2:12][C@H:11]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:10][N:9]4[CH3:29])[CH2:5]1)(=O)C.N>Cl>[Br:20][C:15]1[C:14]2=[C:19]3[C:18]([NH:4][CH2:5][C@@H:6]3[CH2:7][C@@H:8]3[C@@H:13]2[CH2:12][C@H:11]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:10][N:9]3[CH3:29])=[CH:17][CH:16]=1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Br)ccc4c3[C@@H](C[C@H]2N(C)C1)CN4C(C)=O
Agent: Cl
Agent: N
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Br)ccc4c3[C@H](CN4)C[C@H]2N(C)C1
Temperature: 0 °C
Yield: 18.3 %

Procedure:
A solution of 1.8 g of 3-(1-acetyl-12-bromo-2,3α-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea in 50 ml of 1N hydrochloric acid is stirred for 4 hours at 70°-80° C. The reaction mixture is poured on 100 ml of ice, combined with 25% strength ammonia solution until the reaction is alkaline, and extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel with dichloromethane/methanol in a ratio of 97:3, thus isolating 300 mg of an oily product which, for complete purification, is crystallized from ethyl acetate/diisopropyl ether. Yield: 200 mg of 3-(12-bromo-2,3α-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[S:18][C:19]([C:22]4[CH:27]=[CH:26][C:25](F)=[C:24]([C:29]#[N:30])[CH:23]=4)=[N:20][N:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][CH:33]([CH3:35])[O-:34].[Na+]>CC(O)C>[C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[S:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:34][CH:33]([CH3:35])[CH3:32])=[C:24]([C:29]#[N:30])[CH:23]=4)=[N:20][N:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3nnc(-c4ccc(F)c(C#N)c4)s3)cccc21
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NC(=O)OC(C)(C)C)s2)cc1C#N
Temperature: 60 °C
Yield: 42 %

Procedure:
Prepared using General Procedure 2. To a solution of (S)-tert-butyl(4-(5-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (2.5 g 5.7 mmol) in IPA (30 mL) was added sodium isopropoxide (0.61 g, 7.4 mmol). The reaction mixture was heated at 60° C. for 4 h. Upon cooling, the mixture was concentrated to 50% volume and the suspension was cooled to 0° C. The resulting solid was filtered and dried under high vacuum to afford 1.14 g (42%) of (S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate as off-white solid. LCMS-ESI (m/z) calculated for C26H28N4O3S: 476.2; found 477.2 (M+H). tR=4.12 min. 1H NMR (400 MHz, CDCl3) δ 8.26-8.04 (m, 2H), 7.82 (d, J=7.7 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 5.38-5.08 (m, 1H), 4.94-4.62 (m, 1H), 3.54-3.32 (m, 1H), 3.21 (s, 1H), 2.80-2.59 (m, 1H), 1.97-1.74 (m, 1H), 1.52-1.35 (m, 15H). 13C NMR (101 MHz, CDCl3) δ 166.93, 165.54, 161.59, 155.65, 145.84, 142.05, 133.28, 128.71, 127.59, 126.64, 126.33, 122.72, 115.54, 113.86, 103.69, 79.59, 72.50, 60.35, 55.73, 33.78, 31.27, 28.39, 21.74.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:22][C:23]1[S:27][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH:31]=O)=[N:25][CH:24]=1>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[CH:2]1[N:1]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([C:26]3[S:27][C:23]([CH3:22])=[CH:24][N:25]=3)[CH:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)ccc2ccccc12
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Product: COc1ccc2ccccc2c1C1CCCC(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to general procedure 1 (GP1) using methyl 5-amino-5-(2-methoxynaphthalen-1-yl)pentanoate and 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 443.13 g/mol.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([N+:20]([O-])=O)[CH:12]=2)=[CH:5][CH:4]=1.[CH3:25][N:26]([CH3:44])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])=[CH:29][CH:28]=1>>[CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:11]2[CH:16]=[CH:15][C:14]3[NH:17][C:40]([C:39]4[CH:38]=[CH:37][C:36]([C:34](=[O:35])[NH:33][C:30]5[CH:31]=[CH:32][C:27]([N:26]([CH3:44])[CH3:25])=[CH:28][CH:29]=5)=[CH:43][CH:42]=4)=[N:20][C:13]=3[CH:12]=2)=[O:23])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(NC(=O)c2ccc(C=O)cc2)cc1
Reactant: CN(C)c1ccc(NC(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: CN(C)c1ccc(NC(=O)c2ccc(-c3nc4cc(C(=O)Nc5ccc(N(C)C)cc5)ccc4[nH]3)cc2)cc1

Procedure:
Compound 197 was prepared according to the procedure similar to that described in Scheme III from N-(4-dimethylaminophenyl)-3,4-dinitrobenzamide and 4-(4-dimethylaminophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C31H30N6O2: 519.24; found: 519.04.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].I[CH2:15][CH3:16].[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:15][CH3:16])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1cc(C(=O)OC)c2ccccc21
Yield: 77.6 %

Procedure:
A flask was charged with 1H-indole-3-carboxylic acid methyl ester (2 g, 11.41 mmol) and iodoethane (4.4 g, 28.5 mmol) in dry THF (25 mL). The mixture was stirred in a water bath and a 60% dispersion of sodium hydride (0.68 g, 17.12 mmol) in mineral oil was added in portions over 5 minutes. The reaction stirred for 48 hours and was quenched by careful addition of water. The mixture was extracted with dichloromethane (2×100 mL), dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica flash chromatography (10% ethyl acetate/heptane) to give 1-ethyl-1H-indole-3-carboxylic acid methyl ester (1.8 g). 1H NMR [CDCl3]: δ 8.22-8.15 (m, 1H), 7.87 (s, 1H), 7.42-7.33 (m, 1H), 7.31-7.25 (m, 2H), 4.22 (q, 2H), 3.92 (s, 3H), 1.52 (t, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].Cl.[N:20]1([C:26]2[O:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[N:20]1[CH2:21][CH2:22][N:23]([C:8]([C:7]2[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:10])[CH2:24][CH2:25]1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Agent: Cl
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3ccccc3o2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example 2.4) and 2-piperazin-1-yl-benzoxazole hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate) to yield the title compound as a slightly yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])[C:7]=1[F:8].[Cl:18][C:19]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:21][C:22]2[S:26][CH:25]=[N:24][C:23]=2[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(=O)OCC.[Cl-].[Na+].O>COCCOC.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:17][C:5]1[CH:4]=[CH:3][CH:2]=[C:7]([F:8])[C:6]=1[NH:9][C:10]([C:12]1[S:13][C:14]([C:20]2[C:19]([Cl:18])=[CH:27][C:23]3[N:24]=[CH:25][S:26][C:22]=3[CH:21]=2)=[CH:15][CH:16]=1)=[O:11]
Reactant: O=C(Nc1c(F)ccc(Br)c1F)c1cccs1
Reactant: CC1(C)OB(c2cc3scnc3cc2Cl)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1c(F)cccc1F)c1ccc(-c2cc3scnc3cc2Cl)s1
Temperature: 110 °C
Yield: 72.9 %

Procedure:
A mixture of (5-bromo(2-thienyl)-N-(2,6-difluorophenyl)carboxamide (19 mg, 0.06 mmol), 5-chloro-6-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))benzothiazole (20) (17 mg, 0.06 mmol), tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 7 mg) and sodium carbonate (19 mg) in 0.5 ml DME, 0.5 ml EtOH and 0.25 ml water was heated under Ar in microwave reactor at 110° C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to silica gel flash chromatography (0-80% B; A: hexane; B: 50% EA in hexane) to furnish 17.8 mg of N-(2,6-difluorophenyl)[5-(5-chlorobenzothiazol-6-yl)(2-thienyl)]carboxamide (21) as white solid (yield: 72.9%; purity>95%). LC-MS: calcd. for C18H9F2ClN2OS2: 407 (M+1).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:29][C:26]([CH3:28])([CH3:27])[C:23]([CH3:25])([CH3:24])[O:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH3:27][C:26]1([CH3:28])[C:23]([CH3:24])([CH3:25])[O:22][B:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][O:12][C:10]3[CH:9]=[CH:8][C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=4[CH:11]=3)=[CH:20][CH:19]=2)[O:29]1
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(COc3ccc4nc(C#N)sc4c3)cc2)OC1(C)C
Temperature: 60 °C
Reaction time: 0.79 h
Yield: 82.1 %

Procedure:
2-Cyano-6-hydroxybenzothiazole (300 mg, 1.7 mmol) and 4-(bromomethyl)benzeneboronic acid pinacol ester (505.7 mg, 1.7 mmol) were dissolved in 30 mL dry DMF prior to the addition of cesium carbonate (610.25 mg, 1.87 mmol). The mixture was stirred at 60° C. for 45-50 minutes before it was allowed to cool to room temperature. 100 mL EtOAc was added to the reaction mixture, and the organic phase was washed three times with deionized water (DI H2O). The aqueous layers were combined and washed three times with EtOAc. All of the organic layers were combined, washed twice with brine, dried over sodium sulfate, and concentrated. The crude material was purified on a silica column (90:10 hexanes:ethyl acetate, dry loaded) to give 547.4 mg (82%) of the pure product. 1H NMR (400 MHz, CDCl3): δ 1.36 (1H, s), 5.21 (2H, s), 7.32 (1H, d, J=8.8 Hz), 7.40 (1H, s), 7.45 (2H, d, J=7.6 Hz), 7.86 (2H, d, J=7.2 Hz), 8.09 (1H, d, J=9.2 Hz). LRESI-MS: calculated for [C21H22BN2O3S]+393.1. found 393.1.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[NH:28][C:27](=[O:29])[O:26][N:25]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:36]>C(OCC)(=O)C>[ClH:36].[NH2:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[NH:28][C:27](=[O:29])[O:26][N:25]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3noc(=O)[nH]3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3noc(=O)[nH]3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.44 g, 0.9 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (10 ml) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the obtained crystals were recrystallized from methanol-diethyl ether to give 3-(aminomethyl)-4-butoxy-2-isobutyl-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1(2H)-isoquinolinone hydrochloride (0.36 g, 94.7%) as crystals.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([NH:18][CH2:19][P:20]([O:24][CH3:25])([O:22][CH3:23])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([NH:18][CH2:19][P:20]([O:24][CH3:25])([O:22][CH3:23])=[O:21])[C:3]([OH:26])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(OC)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COP(=O)(CN[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-3-(Biphenyl-4-yl)-2-[(dimethylphosphonomethyl)-amino]-propionic acid methyl ester (5 g, 13.2 mmol) is dissolved in methanol (60 mL) and cooled to 0°. 1N Sodium hydroxide (19.8 mL,19.8 mmol) is added dropwise. The solution is stirred at room temperature for 4 hours, then neutralized with 1N hydrochloric acid (20.2 mL, 20.2 mmol). The solvent is removed in vacuo at 10° from the gelatinous solution. The residue is extracted with methylene chloride (3×20 mL). The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude solid is triturated with acetonitrile, filtered and washed with ether. (S)-3-(Biphenyl-4-yl)-2-[(dimethylphosphonomethyl)-amino]-propionic acid is obtained as a white solid that is dried under vacuum at 60° for 16 hours, [α]D =+77.34 (c 0.83, MeOH).