Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH-].[Na+]>CCO>[CH3:1][NH:2][C:3]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOC(=O)c1cc2cccnc2nc1NC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1nc2ncccc2cc1C(=O)O
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Ethyl 2-(methylamino)-1,8-naphthyridine-3-carboxylate (58 mg, 0.25 mmol) was dissolved in EtOH. NaOH (0.75 ml, 1M aqueous solution) was added to the solution and the mixture stirred at 40° C. for 5.0 h. The organic solvent was removed under vacuo. The remaining aqueous residue was treated with HCl (1M aqueous solution) until slightly acidic and the product extracted with EtOAc. The combined organic phases were dried over MgSO4, filtered and concentrated yielding 50.0 mg (quant) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:7][O:8][C:9]1[C:10]([N+:15]([O-])=O)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4]>CO.[Pd]>[CH3:1][C:2]([CH3:18])([CH2:7][O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)COc1cccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)(C)COc1cccnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 611.7 %

Procedure:
A suspension of methyl 2,2-dimethyl-3-(2-nitropyridin-3-yloxy)propanoate (9.1 g, 6 mmol) and Pd/C (800 mg) in methanol (500 mL) was stirred at rt overnight under hydrogen. The cooled mixture was filtered through celite, washed with methanol and evaporated in vacuo to afford the title compound (8.23 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ 7.51 (d, J=1.3 Hz, 1H), 7.03 (d, J=1.3 Hz, 1H), 6.47 (m, 1H), 5.47 (s, 2H), 3.94 (s, 2H), 3.62 (s, 3H), 1.17 (s, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[C:6]1=[O:15])=[O:4].[H][H]>CO.[Pt]=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]1[OH:15])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1CCCC2(CCCC2)C1=O
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)C1CCCC2(CCCC2)C1O
Yield: 100.2 %

Procedure:
To a solution of 6-oxo-spiro[4.5]decane-7-carboxylic acid methyl ester (9.99 g) obtained in Step 2 in methanol (200 mL) was added platinum oxide (0.2 g) in an atmosphere of hydrogen (<0.3 Mpa) at room temperature overnight. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated. After adding ethyl acetate (30 mL) and n-hexane (30 mL) to the residue, the resulting insolubles were filtered off. The filtrate was concentrated and then dried in vacuo to give 6-hydroxy-spiro[4.5]decane-7-carboxylic acid methyl ester (10.11 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:12]=[CH:13]\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6](/[CH:12]=[CH:13]\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Reaction time: 1 h
Yield: 49.1 %

Procedure:
700 mg of (Z)-1-(3-nitro-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) ethene were dissolved in 35 ml of acetic acid, and 7 g of zinc were added thereto and stirred for one hour. The reaction liquid was filtered, concentrated and purified by silica gel column chromatography (dichloromethane:hexane=2:1 by volume) to obtain 314 mg of the intended compound. The yield was 49.3%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH:14]([OH:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH:14]([O:16][C:30](=[O:32])[CH3:31])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(O)c2ccccc21
Product: CC(=O)OC1C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc21

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (described above, 3.0 g) in acetic anhydride (50 ml) was heated at 80° under a dry nitrogen atmosphere for 2 hours. The acetic anhydride was evaporated. The residue was dissolved in ethyl acetate (75 ml) and washed with saturated sodium bicarbonate (50 ml), water (50 ml), and saturated sodium chloride (50 ml). The organic phase was dried (sodium sulfate), evaporated, and the residue triturated with ether (50 ml) to give 3-(S)-t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-5-acetoxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 164°-166.5° C., [α]D =-169° (c=0.36 in DMF).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)=[N:4][N:3]=[N:2]1.[NH2:20][C@H:21]([C:25]([OH:27])=[O:26])[CH:22]([CH3:24])[CH3:23].[OH-].[Na+]>CO.[Pt]>[CH3:23][CH:22]([CH3:24])[C@H:21]([NH:20][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[NH:1][N:2]=[N:3][N:4]=2)=[CH:17][CH:16]=1)[C:25]([OH:27])=[O:26]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde (0.79 g; 3.2 mmol) and L-Valine (0.4 g; 3.4 mmol) are suspended in 15 ml methanol. Then sodium hydroxide is added (0.27 g; 6.72 mmol) and the reaction mixture is stirred at room temperature until a clear solution is obtained. 5% Pt/C (15.8 mg; 2 wt/wt-%) is added. The autoclave is sealed and flushed with argon and hydrogen. The pressure is set to 5 bars and the reaction is stirred at 60° C. The reaction completion is monitored by HPLC. Then the autoclave is flushed with argon and the catalyst is filtered off. Further work-up and crystallisation are done similar to example 1 b2).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1
Reactant: OC1CCNCC1
Reactant: Clc1ccccn1
Product: OC1CCN(c2ccccn2)CC1
Yield: 49.7 %

Procedure:
The title compound (3.5 g, 50%) was prepared as a semi solid from 2-chloropyridine (6.7 g) and 4-piperidinol (4 g) by an analogous procedure to that described in preparation 1.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=1.C([O-])(O)=O.[Na+].[CH:31]([OH:34])([CH3:33])[CH3:32]>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=[C:2]([O:34][CH:31]([CH3:33])[CH3:32])[N:7]2[N:8]=1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reactant: CC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc(OC(C)C)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 80 °C

Procedure:
To a suspension of 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 150 mg, 0.384 mmol) in isopropanol (5 ml) was added solid NaHCO3 (129 mg, 1.5 mmol), and the mixture was heated at 80° C. overnight. After cooling, the suspended solids (150 mg) were collected by filtration and the filtrate was concentrated, in vacuo, to give a solid (95 mg). The suspended solids were extracted from saturated aqueous NaHCO3 with ethyl acetate, the organic layers were dried (MgSO4) and then concentrated, in vacuo, to give a solid. The combined solids were then purified on a Biotage™ Flash 12M column using 0-10% ethyl acetate in hexanes to afford 13A-1 (91 mg, 60%) as an off-white solid: +ESI MS (M+1) 413.4; 1H NMR (400 MHz, CD2Cl2) δ 7.50-7.34 (m, 6H), 7.24 (d, J=8.7 Hz, 2H), 5.73 (septuplet, J=6.2 Hz, 1H), 2.62 (s, 3H), 1.55 (d, J=6.2 Hz, 6H).
Reaction SMILES: C(Cl)(=O)[C:2]([Cl:4])=O.[CH3:7][O:8][C:9]([CH:11]1[O:15][CH:14]([C:16]([OH:18])=O)[CH2:13][CH2:12]1)=[O:10]>ClCCl.CN(C)C=O>[Cl:4][CH2:2][C:16]([CH:14]1[O:15][CH:11]([C:9]([O:8][CH3:7])=[O:10])[CH2:12][CH2:13]1)=[O:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)C1CCC(C(=O)O)O1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1CCC(C(=O)CCl)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.55 ml) was added to a stirred solution of (2RS, 5SR) -5-methoxycarbonyltetrahydrofuran-2-ylcarboxylic acid (2.00 g) in dichloromethane (30 ml). Dimethylformamide (1 drop) was added and the mixture stirred at room temperature for 1 h, and then heated to reflux for 10 min. The mixture was cooled and the solvent removed on a rotary evaporator. Chloroform was then evaporated from the residue twice. The residue was dissolved in dichloromethane (100 ml) and the solution cooled in an ice bath, then excess diazomethane was passed into the solution. The mixture was stirred at 0° C. for 15min and then excess hydrogen chloride was passed into the solution. The solution was washed with brine, dried over magnesium sulphate and evaporated. The title compound (2.02 g) was isolated by column chromatography of the residue using gradient elution (silica gel, 4:1 going to 1:1 hexane:ethyl acetate); νmax (CHCl3) 1740 cm-1 ; δH (CDCl3) 1.9-2.5 (4 H, m), 3.71 (3 H, s), 4.45-4.8 (2 H, m), 4.54 (1 H, d, J 18 Hz) and 4.89 (1 H, d, J 18 Hz).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH2:17][CH3:18])([CH3:16])[C:13](=[O:19])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH2:17][CH3:18])([CH3:16])[C:13](=[O:19])[C:12]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=O
Reactant: OB(O)c1ccccc1
Product: CCC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2ccccc2)C1=O
Yield: 34.2 %

Procedure:
100 mg of 5-{4-(aminosulfonyl)phenyl}-2-ethyl-4-iodo-2-methyl-3(2H)-furanone was reacted with 90 mg of benzeneboronic acid by following a procedure similar to Step 2 of Example 35 to give 30 mg of 5-{4-(aminosulfonyl)phenyl}-2-ethyl-2-methyl-4-phenyl-3(2H)-furanone as a solid. mp: 153-154° C. NMR: δ0.95 (t, J=7.5 Hz, 3H), 1.54 (s, 3H), 1.97 (m, 2H), 4.89 (br s, 2H), 7.26 (m, 2H), 7.36 (m, 3H), 7.79 (d, J=8.7 Hz, 2H), 7.90 (d, J=8.7 Hz, 2H). IR (cm−1): 3340, 3256, 1684, 1616, 1392, 1342, 1161.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.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](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:32]4[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1ccc(Br)cc1
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: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 150 °C
Yield: 10 %

Procedure:
A mixture of [4-(4-bromo-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (44 mg, 0.10 mmol), 4-methoxy-phenylboronic acid (3 mg, 0.15 mmol), sodium carbonate (21 mg, 0.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) in N,N-dimethylformamide (0.5 mL) was heated in a microwave oven at 150° C. for 30 minutes under an argon atmosphere. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford [4-(4′-methoxy-biphenyl-4-sulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (4.7 mg, 10%) as a white solid. MS cald. for C24H27N3O5S 469, obsd. (ESI+) [(M+H)+] 470.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2[N:23]=[CH:24][N:25]=[C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)[C:21]=2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([NH:50][C@H:51]([CH3:56])[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[C:21]4[CH:20]=[CH:19][N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([NH:50][C@H:51]([CH3:56])[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: C[C@@H](NC(=O)c1cnc(Cl)cn1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C(F)(F)F
Temperature: 125 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (0.11 mL, 0.62 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (110 mg, 0.22 mmol) and 5-chloro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide (52 mg, 0.21 mmol) in NMP (2.0 mL). The reaction mixture was stirred at 125° C. for 2 h. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-70%) to afford the desired product. LCMS (M+H)+: m/z=627.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16](OC)[CH:15]=3)[C:9]=2[C:22]([N:24]2[CH2:27][C:26]([F:29])([F:28])[CH2:25]2)=[O:23])=[CH:4][CH:3]=1.[Cl:30]C1C=CC=C(I)C=1.ClC1C=CC(C2C(C)=CNC=2C(N2CC(F)(F)C2)=O)=CC=1>>[Cl:30][C:16]1[CH:15]=[C:14]([N:10]2[CH:11]=[C:12]([CH3:13])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]2[C:22]([N:24]2[CH2:27][C:26]([F:29])([F:28])[CH2:25]2)=[O:23])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-n2cc(C)c(-c3ccc(Cl)cc3)c2C(=O)N2CC(F)(F)C2)c1
Reactant: Clc1cccc(I)c1
Agent: Cc1c[nH]c(C(=O)N2CC(F)(F)C2)c1-c1ccc(Cl)cc1
Product: Cc1cn(-c2cccc(Cl)c2)c(C(=O)N2CC(F)(F)C2)c1-c1ccc(Cl)cc1
Yield: 89 %

Procedure:
[1-(3-chlorophenyl)-3-(4-chlorophenyl)-4-methyl-pyrrol-2-yl]-(3,3-difluoroazetidin-1-yl)methanone was synthesised according to the procedure described for [3-(4-Chlorophenyl)-1-(3-methoxyphenyl)-4-methyl-pyrrol-2-yl]-(3,3-difluoroazetidin-1-yl)methanone (SC-32) using 1-chloro-3-iodobenzene (1 mL, 8 mmol) and [3-(4-chlorophenyl)-4-methyl-1H-pyrrol-2-yl]-(3,3-difluoroazetidin-1-yl)methanone (200 mg, 0.6 mmol). The product was purified by preparative HPLC (preparative Agilent 1200 Series HPLC system using 30%-95% acetonitrile/water (0.1% Ammonia aq.) over 15 minutes, collecting at 254 nm) to afford the title compound as an off-white solid (223 mg, 89% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([N:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[C:25]1([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:34]5([C:32]([NH:31][C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)=[O:33])[CH2:36][CH2:35]5)=[O:38])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[N:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c(F)c1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)cc3F)cn2n1)C1CC1
Yield: 80 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy) [1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 0.367 mmol), 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (90.4 mg, 0.440 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (126 μL, 0.733 mmol) and HATU (209 mg, 0.550 mmol) and in the same manner as in Example 24, the title compound (151 mg, 80%) was obtained as white crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:12][CH3:13])[CH:6]=[N:7]2>CC(=O)OCC>[CH3:13][O:12][C:5]1[CH:6]=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([CH2:3][CH2:4][CH:5]=[O:12])[CH:11]=[CH:10][CH:9]=2
Reactant: COc1cnc2cccc(Br)c2c1
Solvent: CCOC(C)=O
Product: COc1cnc2cccc(CCC=O)c2c1
Yield: 30 %

Procedure:
This aldehyde was prepared using sequentially the protocols of Example 29, step 29.i and Example 33, steps 33.i to 33.ii and starting from 5-bromo-3-methoxy-quinoline (4 g, 16.7 mmol; prepared as in DE 10316081). After chromatography on SiO2 (Hex/EA 1:1, EA), the compound was obtained as a yellowish solid (0.95 g, 30% yield over 3 steps).
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=[O:3].[NH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1>CCOCC>[O:3]=[C:2]([CH3:4])[CH:1]=[N:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CC(=O)C=O
Solvent: CCOCC
Product: CCOC(=O)N1CCC(N=CC(C)=O)CC1
Reaction time: 0.33 h
Yield: 58.1 %

Procedure:
To a solution of pyruvaldehyde (40% w/w solution in water, 2.67 mL, 3.15 g, 17.5 mmol) in 50 mL of Et2O at room temperature was added dropwise ethyl 4-amino-piperidinecarboxylate (3.0 mL, 3.01 g, 17.5 mmol). After 20 min, the solution was diluted with 50 mL of Et2O and washed with 3×30 mL of water. The solution was concentrated in vacuo to yield 2.3 g (58%) of the imine product which was used as such in the subsequent step: 1H NMR (CDCl3) δ 7.58 (1H, s), 4.07 (2H, q, J=7.1 Hz)), 4.04 (2H, m), 3.39 (1H, m), 3.02 (2H, m), 2.31 (3H, s), 1.65 (4H, m), 1.19 (3H, t, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][N:25]=1.[F-].[Cs+]>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][C:11]([C:12]([NH:14][CH:15]3[CH2:16][CH2:17][N:18]([C:24]4[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:26][N:25]=4)[CH2:19][CH2:20]3)=[O:13])=[CH:21][CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)nc1
Reactant: O=C(NC1CCNCC1)c1ccc(-c2cccc(F)c2)nc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(NC(=O)c3ccc(-c4cccc(F)c4)nc3)CC2)nc1
Temperature: 100 °C
Yield: 97 %

Procedure:
To a microwave tube was added 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide (2.2 g, 7.35 mmol, tert-butyl 6-bromonicotinate (2.85 g, 11 mmol), DMA (5 mL), CsF(6.70 g, 44.1 mmol) and TEA (5 drops). After heating the reaction mixture on CEM microwave at fullpower (100° C. for 45 min), the solution was extracted with ethyl acetate and washed with water. The solvent was removed and the residue purified by chromatography (silica, 50% EtOAc: Hep) to give the desired product, tert-butyl 6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinate (3.39 g, 97%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.06 (1H, d, J=1.1 Hz), 8.58 (1H, d, J=1.6 Hz), 8.47 (1H, d, J=7.9 Hz), 8.27 (1H, d, J=8.4 Hz), 8.10 (1H, d, J=8.2 Hz), 7.98 (1H, d, J=8.4 Hz), 7.93 (1H, d, J=10.8 Hz), 7.86 (1H, d, J=9.1 Hz), 7.54 (1H, q), 7.29 (1H, t, J=8.6 Hz), 6.88 (1H, d, J=9.1 Hz), 4.41 (2H, d, J=13.5 Hz, 4.15 (1H, d, J=4.8 Hz), 3.10 (2H, t, J=12.3 Hz), 2.48 (2H, br. s.), 1.91 (2H, d, J=13.4 Hz), 1.50 (9H, s), HRMS (TOF, ES+) calculated 477.2302; observed 477.2515.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[O:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[C@@H]12N(C3C=NC4C(=CC=CC=4)N=3)C[C@@H]1CCNC2.[CH3:36][O:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[C:39]=1[C:40](Cl)=[O:41].C1(C2C=CC=CC=2)C(C(Cl)=O)=CC=CC=1>>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[N:8]1[CH:1]2[CH:6]([CH2:5][CH2:4][N:3]([C:40]([C:39]3[C:43]([O:47][CH3:48])=[CH:44][CH:45]=[CH:46][C:38]=3[O:37][CH3:36])=[O:41])[CH2:2]2)[CH2:7]1
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: c1ccc2oc(N3CC4CCNCC43)nc2c1
Agent: O=C(Cl)c1ccccc1-c1ccccc1
Agent: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Product: COc1cccc(OC)c1C(=O)N1CCC2CN(c3nc4ccccc4o3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Example 5, substituting 2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-benzooxazole (Intermediate 7) for (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline and 2,6-dimethoxy benzoyl chloride for biphenyl-2-carbonyl chloride. MS (ESI) mass calcd. for C22H23N3O4, 393.44; m/z found 394.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.54-7.27 (m, 2H), 7.25-7.06 (m, 3H), 6.57-6.01 (m, 2H), 5.12-4.00 (m, 5H), 3.98-3.33 (m, 7H), 3.20-2.94 (m, 2H), 2.24-1.72 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][N:24]=[C:23]([CH3:26])[C:22]=2[CH:27]=O)=[CH:17][CH:16]=1>C1COCC1>[CH3:3][O:4][C:5](=[O:6])/[CH:7]=[CH:27]/[C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1c(C)noc1-c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of sodium hydride (60% in mineral oil, 0.471 g, 11.03 mmol) in THF (10 mL) at 0° C. was added trimethyl phosphonoacetate (1.1 mL, 7.58 mmol). Additional THF (15 mL) was added to facilitate stirring and the solution was warmed to room temperature over 15 minutes. After cooling to 0° C., 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (1.834 g, 6.89 mmol) in THF (8 mL) was added and the reaction was stirred at room temperature for 10 minutes. The mixture was extracted with EtOAc and aqueous NH4Cl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [N:1]([CH:4]1[C:7]([CH3:9])([CH3:8])[N:6]([S:10]([OH:13])(=[O:12])=[O:11])[C:5]1=[O:14])=[N+]=[N-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.[Pd]>[NH2:1][CH:4]1[C:7]([CH3:9])([CH3:8])[N:6]([S:10]([OH:13])(=[O:11])=[O:12])[C:5]1=[O:14]
Reactant: CC1(C)C(N=[N+]=[N-])C(=O)N1S(=O)(=O)O
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Product: CC1(C)C(N)C(=O)N1S(=O)(=O)O
Reaction time: 1 h
Yield: 48.6 %

Procedure:
A solution of 0.155 g of (±)-3-azido-4,4-dimethyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium in 0.6 ml of methanol is hydrogenated over 10% palladium on charcoal for 20 minutes at 1 atmosphere. The catalyst is filtered off and rinsed with methylene chloride which is combined with the methanol solution. This clear solution is treated with 0.123 ml 97% formic acid. Upon addition of the acid the solution immediately becomes cloudy. After standing for 1 hour at 5° C., the solid is filtered off to yield 0.0664 g of the title compound.