Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:26][N:27]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[N:28]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([C:30]4[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=4)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COC(=O)C1(c2ccc(Nc3nc(-c4cnn(C)c4)nc4c3CCC4)cc2)CCC1
Temperature: 100 °C
Yield: 47.8 %

Procedure:
A glass tube was charged with 1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid methyl ester (0.5 g, 1.4 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.42 g, 2 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) (0.081 g, 0.1 mmol) and alternatively purged and backfilled with nitrogen. After addition of anhydrous toluene (10 mL), EtOH (5 mL), and sodium carbonate (2M, 2 mL) the glass tube was sealed and heated at 100° C. under stirring until the reaction was complete as evidenced by the disappearance of starting chloro compound (TLC). The resulting mixture was cooled to a temperature in the range of 15° C. to 40° C., diluted with ethyl acetate (20 mL), filtered through Celite, washed with ethyl acetate, and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel to afford the title compound as a light yellow solid (0.27 g, 48%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:23]([OH:26])([CH3:25])[CH3:24]>>[CH:23]([O:26][C:2]([C:4]1([OH:3])[CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]1)([CH3:11])[CH3:1])([CH3:25])[CH3:24]
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1=CCC(O)(C(C)(C)OC(C)C)CC1

Procedure:
By procedures similar to those described in Embodiments 57 and 58, 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene was treated with isopropyl alcohol in the presence of p-toluenesulfonic acid to obtain 1-(1-isopropoxy-1-methylethyl)-4-methyl-3-cyclohexen-1-ol. This alcohol was treated with vanadium(IV) bis(2,4-pentanedionate)oxide and tert-butyl hydroperoxide followed by p-toluenesulfonic acid to obtain (±)-2-exo-hydroxy-4-(1-isopropoxy-1-methylethyl)-1-methyl-7-oxabicyclo[2.2.1]heptane. This intermediate was treated with benzyl chloride to yield the desired product, b.p. 120°-130° C. (0.2 mm).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[CH2:7]2)([O-])=O.C(Cl)Cl>CO.[Pd]>[N:13]1([CH:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=3)[CH2:9]2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(N1CCOCC1)C2
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc2c(c1)CC(N1CCOCC1)C2
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 4-(5-nitro-indan-2-yl)-morpholine (210 mg, 0.85 mmol) in 20 mL of methanol was added Pd/C 10% (20 mg). The mixture was placed under a H2 atmosphere with stirring for 2 h. TLC showed 2 spots. CH2Cl2 was added to dissolve the ppt. that had formed and the hydrogenation continued further 2 h. The catalyst was removed by filtering, and the filtrate evaporated to give 188 mg of 2-morpholin-4-yl-indan-5-ylamine. The crude amine was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A mixture of 3-fluoro-4-methoxyaniline (56.4 g; 400 mmol) and triethylamine (56 ml; 400 mmol) in dichloromethane (400 ml) is cooled down using an ice bath. Acetic anhydride (57 ml; 600 mmol) is added dropwise and the reaction mixture is agitated for 3 hours at ambient temperature. The reaction medium is then washed successively with water, with an aqueous solution of 10% sodium bicarbonate then with an aqueous solution saturated in sodium chloride. The organic fraction is dried over sodium sulphate and concentrated under reduced pressure. The residue is recrystallized from an ethyl acetate/pentane mixture in order to produce 66.5 g (91%) of a white solid, m.p. 120° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:3]=1.[CH3:27][NH:28][CH3:29]>C(O)C>[CH3:27][N:28]([CH3:29])[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[N:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(F)cc2)cc1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Temperature: 70 °C
Reaction time: 24 h

Procedure:
2-Chloro-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile (Example 7) (200 mg, 0.52 mMol) in ethanol (150 ml) was charged with dimethylamine. The solution was shaken for 24 hours at 70° C. and a pressure of 22 psi in a Parr shaker. The solution was concentrated. The residue was titurated with methyl alcohol and filtered to give a yellow solid: m.p. (DSC) : 205.02° C. Anal. Calc'd. for C21H18N3O2SF (395.46): C, 63.78; H, 4.59; N, 10.63. Found: C, 64.02; H, 4.58; N, 10.77.
Reaction SMILES: [CH:1]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:40]([OH:42])=O)[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:39])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:30]=1)[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:46])=O>>[Cl:46][C:40]([C@:7]12[CH2:6][CH2:5][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:39])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:27])([CH3:28])[C@@H:16]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:30]=2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)=[O:42]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)O)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)Cl)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask containing (1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.154 g, 0.267 mmol) was added oxalyl chloride (2M in dichloromethane) (5 mL, 10.00 mmol). The solution was stirred at rt for 3 h. The mixture was concentrated under reduced pressure and was dissolved in dichloromethane and concentrated two additional times. The crude product was used in the next step with no additional purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-])=O.CO.[H][H]>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1

Procedure:
A mixture of 15.3 g. (0.05 moles) of ethyl 3-nitro-4-cyclohexylphenylglyoxylate in 100 ml. methanol containing 0.05 mole citric acid and 1.5 g. of 5% palladium-on-carbon is shaken with hydrogen at 3 atm. pressure and 27° C. until 3 moles of hydrogen are absorbed. The mixture is filtered, washed with methanol and the filtrate concentrated in vacuo to obtain ethyl 3-amino-4-cyclohexylphenylglyoxylate, isolated as the citrate salt.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)[C:10]2=[O:13])[CH:18]=1
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Reactant: Brc1cccnc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(C(F)(F)F)ccc2CCN1c1cccnc1
Yield: 22.1 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-16c: 150 mg, 0.698 mmol) was reacted with 3-bromo-pyridine (220 mg, 1.395 mmol), 1,4-dioxane (10 mL), copper iodide (13.29 mg, 0.0698 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (29.33 mg, 0.209 mmol) and potassium phosphate (369.9 mg, 1.745 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 45 mg of the product (22.05% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Br:12]Br>C(O)(=O)C.O>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([Br:12])=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1N
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1nc(Br)cnc1N
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
Methyl 3-amino-2-pyrazine-carboxylate (10 g, 65.3 mmol) was dissolved in glacial acetic acid (50 mL) by warming to approximately 45° C. To the warm solution was added bromine (3.7 mL) in acetic acid (5 mL) dropwise and the resulting mixture was stirred at room temperature for 20 minutes. The solution was diluted with water (300 mL) and then stirred at room temperature for 30 minutes, which resulted in a precipitate. The precipitate was then filtered, washed with water and dried to afford methyl 3-amino-6-bromo-2-pyrazine-carboxylate as a yellow solid (14.2 g, 94%). 1H NMR (300 MHz, CDCl3) δ3.99 (s, 3H), 8.30 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 53.02, 123.49, 124.85, 150.24, 154.70, 166.04.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:40])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[N:24](C(OC(C)(C)C)=O)[C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:40])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
t-Butyl 2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (7.16 g, 12.2 mmol) synthesized in Example (1h) was dissolved in dichloromethane (15 mL), and cooled to 0° C. Trifluoroacetic acid (30 mL) was added dropwise with stirring under nitrogen atmosphere. Stirring was carried out at room temperature for 30 minutes, followed by further stirring at 40° C. for 30 minutes. The solvent was distilled off under reduced pressure followed by dilution with ethyl acetate (300 mL), a saturated aqueous sodium hydrogencarbonate solution (200 mL) was added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-50%) to afford the desired compound (5.21 g, yield 88%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CN.C[CH2:15][N:16](C(C)C)C(C)C>CS(C)=O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:16][CH3:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Agent: CN
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CNc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-1-fluoro-2-nitrobenzene (832 mg, 4.7 mmol) in DMSO (10 mL) is added a 2M solution of methylamine (3.56 mL, 7.1 mmol) in tetrahydrofuran, followed by Hunig's base (1.2 mL, 7.1 mmol). The reaction flask is sealed and heated to 80° C. for 16 h. The reaction is cooled to room temperature and poured over ice water. The resulting solid is isolated by filtration to afford the title compound (713 mg, 81%).
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H-].[Na+].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[NH:18][C:19](=O)[O:20]C1C=CC=CC=1.Cl>CN(C)P(=O)(N(C)C)N(C)C>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[NH:18][C:19]([CH:3]1[C:2](=[O:1])[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]1=2)=[O:20]
Reactant: O=C(Nc1cccs1)Oc1ccccc1
Reactant: O=C1Cc2ccccc2S1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(Nc1cccs1)C1C(=O)Sc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 7.5 g of 2,3-dihydro-2-oxo-benzo[b]thiophen in 50 ml of hexamethylphosphoric acid triamide is added dropwise, with cooling, to a suspension of 2.4 g of a 50% sodium hydride/mineral oil dispersion in 100 ml of hexamethylphosphoric acid triamide, the temperature being kept below 15° during the addition. After stirring for half an hour at room temperature, 52 g of phenyl N-(2-thienyl)-carbamate, dissolved in 50 ml of hexamethylphosphoric acid triamide, are added dropwise, with external cooling. The reaction mixture is stirred for a further 16 hours at room temperature and is poured into a mixture of 200 ml of 2 N hydrochloric acid and 1000 ml of ice-water. An oil separates out and this crystallises after about 2 hours. The crystalline product, which contains solvent, is dissolved in 2 N sodium hydroxide solution and the solution is washed four times with ethyl acetate. The organic phase is washed with water, the aqueous phases are combined and acidified to a pH of 1 and the crude product is filtered off with suction and recrystallised from tetrahydrofuran/ether. N-(2-Thienyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophen-carboxamide with a melting point of 142°-144° (decomposition) is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccc(F)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 3-fluorobenzene boronic acid according to the general procedure B. Obtained as a yellow solid (3.87 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([NH2:46])=[NH:45])[CH2:40][CH2:39]1.CS(C)=O>CN(C=O)C>[C:44]([N:41]1[CH2:42][CH2:43][CH:38]([CH2:37][NH:36][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH2:39][CH2:40]1)(=[NH:45])[NH2:46]
Reactant: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Reactant: N=C(N)N1CCC(CN)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1ccc(C(=O)NCC2CCN(C(=N)N)CC2)cc1OCCc1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 21.4 %

Procedure:
A solution of 100 mg 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid in 2 ml DMF was activated by the addition of 53 mg carbonyldiimidazole. After stirring for 2 h at RT 90 mg of 4-Aminomethyl-piperidine-1-carboxamidine hydrochloride and 2 ml DMSO were added and the mixture was stirred overnight. Subsequent dilution with 3 ml water and filtration through a chem elut® cartridge, eluting with ethyl acetate yielded after concentration under reduced pressure a white solid. Purification by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.5% TFA) and lyophilisation afforded 30 mg (20%) of the title compound as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][NH:7]C(=O)OC(C)(C)C)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:17]=[CH:16][CH:15]=1)[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(CN)c1
Reaction time: 1 h

Procedure:
To tert-butyl 3-cyanobenzylcarbamate in CH2Cl2 (10 ml), TFA (3 ml) was added. After 1 h, volatiles were removed on a rotavap under reduced pressure. Crude residue 3-(aminomethyl)benzonitrile was dissolved in water, basified with 2N NaOH and extracted with CHCl3 (100 ml) and used without further purification.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].O[N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[O:21])[N:13]([CH3:22])[CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]1=[NH:29]>O.C(O)C>[NH2:29][C:11]1[CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:13]([CH3:22])[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:10]=1
Reactant: CN1C(=O)c2ccccc2N(O)C(=N)C1c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1C(=O)c2ccccc2N=C(N)C1c1ccccc1

Procedure:
A slow stream of a solution of 23.00 g (0.132 m) of sodium dithionite in 300 ml of water is added to a stirred solution of 16.87 g (0.06 m) of 1-hydroxy-2-imino-4-methyl-3-phenyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine-5-one in 700 ml of ethanol. The reaction mixture is refluxed for 2 hours and then concentrated in vacuo, to about 200 ml. The resulting solution is extracted once with chloroform. Some solid crude product, formed during this extraction, is filtered off. The aqueous layer is made basic and extracted with chloroform. The organic solutions are combined, dried and concentrated to dryness in vacuo to give additional solid product. The solids are combined and recrystallized twice from ethanol/ether (the solution is filtered while hot to clarify) to give the pure product, 2-amino-3,4-dihydro-4-methyl-3-phenyl-5H-1,4-benzodiazepine-5-one m.p. 282° - 286° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[C:4]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CCO.[Pd]>[F:1][C:2]1[C:3]([C:22]([F:24])([F:25])[F:23])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)c(F)c2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Reaction time: 72 h
Yield: 97.6 %

Procedure:
A mixture of tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (7, 59.0 g, 162.3 mmol) and 10% Pd/C (5.0 g) in EtOH (200 mL) was placed under an atmosphere of H2 (30 psi) at ambient temperature for 72 h. the mixture was filtered through a Celite, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (8) as a white solid (57.9 g, 97%): 1H NMR (300 MHz, CDCl3) δ7.36-7.28 (m, 1H), 7.12 (m, 1H), 4.24 (br, 2H), 3.06 (m, 1H), 2.80 (m, 2H), 1.78-1.52 (m, 4H), 1.48 (s, 9H); MS (ESI+) m/z 310 [M+H−C4H8]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH3:28])[CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][C:21]=2[CH3:28])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1-c1ccc(F)cc1C
Temperature: 70 °C
Reaction time: 15 h
Yield: 78.6 %

Procedure:
A solution of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (3.6 g, 0.014 mol) in toluene (80 mL) and EtOH (40 mL) was degassed 3 times before Pd(PPh3)4 (0.49 g, 0.425 mmol), 4-fluoro-2-methylphenylboronic acid (2.62 g, 0.017 mol) and an aqueous solution of Na2CO3 (2N, 14.2 mL, 0.028 mol) were added. The reaction mixture was stirred at 70° C. for 15 hours, cooled down to RT, filtered and the volatiles evaporated under vacuo. The residue was taken up in EtOAc and washed with aqueous NaOH (1N). The organic phase was dried over Na2SO4, concentrated under vacuo, before a purification on column chromatography (SiO2, EtOAc/Heptane, 1/3) yielded 3.6 g (77%) of the title compound as a colorless oil. ES-MS m/e: 328.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[O:11])=[C:5]([O:39][CH3:40])[CH:4]=1)#[N:2].[OH:41]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[O:11])=[C:5]([O:39][CH3:40])[CH:4]=1)(=[O:41])[NH2:2]
Reactant: OO
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To the solution of rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.16 g, 0.28 mmol) in DMSO (3 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.47 g, 4.2 mmol) aqueous solution (1N) of NaOH (1.4 mL, 1.4 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a white solid (Yield, 0.12 g, 73%)