Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[N:5]([C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=[C:16](Cl)[C:15]=1[N+:25]([O-:27])=[O:26])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2].[NH3:29]>C1COCC1>[CH2:1]([O:3][C:4](=[O:28])[N:5]([C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([NH2:29])[C:15]=1[N+:25]([O-:27])=[O:26])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(C(F)(F)F)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2-Chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (54 mg, 0.13 mmol) was dissolved in THF (1 ml) and transferred to a 10 ml reactivial. 880 Ammonia (1 ml) was added, the vessel sealed and the mixture stirred vigorously at ambient temperature for 16 h. The solution was concentrated in vacuo to give a crude oil which was purified directly by column chromatography on silica, eluting with 100% EtOAc to give 27 mg of the title compound as a yellow residue.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10](OC)=[O:11])=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[C:6]=2[CH:18]=1.O.[NH2:26][NH2:27]>CCO>[Br:1][C:2]1[C:3]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:26][NH2:27])=[O:11])=[C:7]([C:14]([NH:15][CH3:16])=[O:17])[C:6]=2[CH:18]=1
Reactant: CNC(=O)c1c(C(=O)OC)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: CNC(=O)c1c(C(=O)NN)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Yield: 100 %

Procedure:
To a suspension of compound methyl 5-bromo-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylate in EtOH was added hydrazine hydrate (421 mg, 7.16 mmol). The mixture was refluxed overnight. Then it was concentrated in vacuo and the resulting solid was washed with MeCN to give the compound 5-bromo-2-(hydrazinecarbonyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (600 mg, yield: 100%). It was used for the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 10.33 (br s, 1H), 8.60 (s, 1H), 7.96 (s, 1H), 5.03 (br s, 3H), 3.22 (s, 3H), 3.20 (s, 3H), 2.87 (d, J=4.8 Hz, 3H). MS (M+H)+: 419/421.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:5]=1[N+:17]([O-])=O)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:5]=1[NH2:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(C(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)COc1ccc(C(C)=O)c(N)c1
Reaction time: 0.5 h

Procedure:
Ethyl 2-(4-acetyl-3-nitrophenoxy)acetate (TU3205-034) (111 mg) in MeOH (5 mL) was hydrogenated using 10% palladium on charcoal (11 mg) under atomospheric pressure of H2 at ambient temperature. After 30 minutes LC-MS analysis revealed a clean complete reaction. The reaction was repeated using TU3205-034 (1.45 g), 10% palladium on charcoal (140 mg), and MeOH (80 mL). The two reaction mixtures were combined, and the spent catalyst was removed by filtration through a celite pad. The filtrate was concentrated under reduced pressure, affording ethyl 2-(4-acetyl-3-aminophenoxy)acetate (TU3205-036) as a dark yellow oil. MS (ESI+): calcd. 238.10. found 238.10 (MH+). H-NMR (400 MHz, CDCl3): 1.295 (3H, t, J=7.0 Hz), 2.507 (3H, s), 4.269 (2H, q, J=7.2 Hz), 4.603 (2H, s), 6.047 (1H, d, J=2.8 Hz), 6.236 (1H, dd, J=8.8 Hz, 2.8 Hz), 6.396 (2H, br.s), 7.647 (1H, d, J=9.2 Hz). C-NMR (100 MHz, CDCl3): 14.135, 27.658, 61.532, 64.939, 100.237, 104.030, 113.586, 134.286, 152.468, 162.294, 168.310, 199.055.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:11]3[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=3[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:36])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1>CS(C)=O>[CH3:24][O:25][C:26](=[O:36])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:15]2[C:10]3[C:9]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)[O:17][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:30]=1
Reactant: COC(=O)COc1cccc(N)c1
Reactant: Clc1ncnc2oc(-c3ccc(Br)cc3)c(-c3ccccc3)c12
Solvent: CS(C)=O
Product: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccc(Br)cc4)c(-c4ccccc4)c23)c1

Procedure:
Heat 400 mg (1.04 mmol) of 6-(4-bromophenyl)-4-chloro-5-phenylfuro[2,3-d]pyrimidine (preparation according to WO 03/018589) and 225.5 mg (1.25 mmol) of 3-aminophenoxyacetic acid methyl ester to 150° C. in an oil bath for 1.5 h. After cooling, take up the residue in DMSO and filter through silica gel (eluent: cyclohexane/ethyl acetate 2:1). 140 mg (25.5% of theory) of the target compound are obtained as a yellowish solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:38]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:38][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=4)=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)Nc2ccc(N3CCNCC3)cc2)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=Cc1ccc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(C(=O)Nc2ccc(N3CCN(Cc4ccc[nH]4)CC3)cc2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
To a solution of 5-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (329 mg) in 1,2-dichloroethane (20 mL) was added 1H-pyrrole-2-carboxaldehyde (86 mg) and acetic acid (54 mg). The solution was cooled at 0° C. and sodium triacetoxy borohydride (238 mg) was added portionwise and the mixture was stirred at room temperature for 16 hours. The solution was then washed with a saturated solution of NaHCO3, with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/MeOH (95/5) and the oily residue obtained was crystallized from diisopropyl ether to give the title compound (210 mg) as white crystals.
Reaction SMILES: [CH3:1][C:2]([C:9]1[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[CH:12]=[C:11]([F:18])[CH:10]=1)([CH3:8])[C:3](OCC)=[O:4].C([NH2:21])=O.C[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]([C:9]1[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[CH:12]=[C:11]([F:18])[CH:10]=1)([CH3:8])[C:3]([NH2:21])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1cc(F)cc2ccoc12
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C(N)=O)c1cc(F)cc2ccoc12
Temperature: 100 °C
Yield: 43.7 %

Procedure:
A mixture of 0.156 gm (0.62 mMol) ethyl 2-methyl-2-(5-fluorobenzofur-7-yl)propionate, 0.095 gm (2.12 mMol) formamide, and 0.44 mL (0.44 mMol) sodium methoxide (1.0 M in methanol) in 3 mL dimethylformamide was heated at 100° C. for 45 minutes. The reaction mixture was diluted with ethyl acetate and the organics washed sequentially with water and saturated aqueous sodium chloride. The organics were then concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with 2:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.060 gm (25%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[C:9]=2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C=O)C.CCOC(C)=O>[C:33]([O:32][C:30](=[O:31])[CH2:29][N:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:9]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:10]2[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:11]1=2)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(Cl)cc3)c(C3CCCCC3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution (0.2 M) of methyl 5-(4-chlorophenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (prepared as described in example 13, step 4) in DMF was treated with NaH (2 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 30 min, then tert-butyl bromoacetate (3 eq.) was added. The reaction mixture was heated at 50° C. for 2 h then cooled down and diluted with AcOEt. The organic phase was washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine and dried. Evaporation of the solvent gave a residue that was purified by flash chromatography on silica gel (1:9 AcOEt/petroleum ether) to afford the title compound (93%).
Reaction SMILES: CN(C)C1C=C([CH:9]=[C:10]([CH3:12])[N:11]=1)C(O)=O.Cl[C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([CH3:24])[N:23]=1)[C:18]([OH:20])=[O:19].C(N)(C)C>>[CH:10]([NH:11][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([CH3:24])[N:23]=1)[C:18]([OH:20])=[O:19])([CH3:12])[CH3:9]
Reactant: Cc1cc(C(=O)O)cc(N(C)C)n1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Solvent: CC(C)N
Product: Cc1cc(C(=O)O)cc(NC(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-dimethylamino-6-methyl-isonicotinic acid starting from 2-chloro-6-methyl-isonicotinic acid and isopropylamine; LC-MS: tR=0.52 min, [M+1]+=195.09.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CN(C)C=O.C(OCC)C>[CH2:16]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCc1ccccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To an ice-bath cooled suspension of sodium hydride (60% dispersion in mineral oil, 0.40 g) in dimethylformamide (18 ml) were added dropwise methyl 3-(2-hydroxyphenyl)propionate (1.80 g) and benzyl bromide successively. After being stirred for 30 minutes, the mixture was poured into a mixture of diethyl ether (20 ml) and 1N hydrochloric acid solution (90 ml). The organic layer was separated and the aqueous layer was extracted by diethyl ether. The combined organic layer was washed with aqueous sodium bicarbonate solution, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography [eluting with ethyl acetate n-hexane (1:1)] to provide methyl 3-(2-benzyloxyphenyl)-propionate (2.33 g).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][CH:8]1[C:13](=[O:14])[N:12]2[CH:15]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:16](=[O:22])[N:17]([CH:19]([CH3:21])[CH3:20])[CH2:18][CH:11]2[N:10]([S:31]([C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=2[O:41][CH3:42])(=[O:33])=[O:32])[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH:15]2[N:12]3[C:13](=[O:14])[CH:8]([NH:7][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:9][N:10]([S:31]([C:34]4[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=4[O:41][CH3:42])(=[O:33])=[O:32])[CH:11]3[CH2:18][N:17]([CH:19]([CH3:21])[CH3:20])[C:16]2=[O:22])=[CH:25][CH:26]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CC(N)C(=O)N2C(Cc3ccc(Cl)cc3)C(=O)N(C(C)C)CC21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CC(NC(=O)C2CC2)C(=O)N2C(Cc3ccc(Cl)cc3)C(=O)N(C(C)C)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
11 mg (0.105 mmol) of cyclopropanecarbonyl chloride are added to a solution of 3-amino-6-(4-chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione (56 mg, 0.10 mmol) in 1 ml of dichloromethane and 26 mg (0.20 mmol) of diisopropylethylamine. After stirring at room temperature for two hours, the reaction mixture is purified by chromatography on 1 g of silica gel (eluent EtOAc/DCM; gradient 0-20%). 42 mg of the desired product are obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH:2]=[CH2:3].CO.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:4][C:5]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: C=CCOc1cc(N)ccc1C#N
Temperature: 65 °C
Reaction time: 0.83 h
Yield: 93.7 %

Procedure:
Iron powder-325 mesh (5.7 g, 98.0 mmol) was taken in a round bottom flask charged with a mixture of 2-(allyloxy)-4-nitrobenzonitrile (4.0 g, 19.6 mmol), absolute methanol (40 mL), water (8 mL) and ammonium chloride (5.2 g, 98 mmol). A water-cooled reflux condenser was attached to the flask and the heterogeneous mixture was heated to 65° C. with vigorous stirring for 50 min. The reaction mixture was filtered, and washed with methanol. The solvent was removed in vacuo. EtOAc was added to the residue, and the solution was washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 2-(allyloxy)-4-aminobenzonitrile (3.2 g, 94% yield) as a light-brown solid. LC-MS (M+H)+=175.2 1H NMR (400 MHz, CDCl3) δ ppm 7.29 (d, 1H, J=8.4 Hz), 6.22 (dd, 1H, J=2.0, 8.4 Hz), 6.14 (s, 1H), 6.07-5.98 (m, 1H), 5.48 (dd, 1H, J=1.6, 3.2 Hz), 5.44 (dd, 1H, J=1.6, 3.2 Hz), 4.59 (d, 2H, J=1.6 Hz).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]([O:15][CH3:16])=[O:14].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=1)[CH:8]=[C:7]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1c[nH]c2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(Cl)cc12
Temperature: 120 °C
Reaction time: 6 h

Procedure:
0.771 g (24 mmol) of sodium hydride at 75% by weight in liquid petroleum jelly is added to a solution of 5.03 g (24 mmol) of 5-chloro-3-methoxycarbonyl-1H-indole in 120 cm3 of dimethylformamide at a temperature in the region of 20° C. under an argon atmosphere. After the reaction mixture has been stirred for 0.5 hour at a temperature in the region of 40° C., 3.94 g (24 mmol) of 4-chloroquinoline are added. After stirring for 6 hours at a temperature in the region of 120° C., the reaction mixture is cooled to a temperature in the region of 20° C. and then poured into 400 cm3 of water and extracted with 500 cm3 of ethyl acetate. The organic phase is washed three times with 250 cm3 of water, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica gel (eluent: dichloromethane). After the fractions containing the expected product have been concentrated to dryness under reduced pressure, 2.5 g of 5-chloro-3-methoxycarbonyl-1-(quinolin-4-yl)-1H-indole are obtained in the form of a sticky beige-colored solid, which is used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16]3[C:17](=[O:29])[NH:18][C:19]4([CH2:26][CH2:25][N:24]([O:27][CH3:28])[CH2:23][CH2:22]4)[C:20]=3[OH:21])[CH:9]=2)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].N1C=CC=CC=1.Cl>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16]3[C:17](=[O:29])[NH:18][C:19]4([CH2:22][CH2:23][N:24]([O:27][CH3:28])[CH2:25][CH2:26]4)[C:20]=3[O:21][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(-c3ccc(Cl)cc3)c(F)cc1C)=C2O
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CON1CCC2(CC1)NC(=O)C(c1cc(-c3ccc(Cl)cc3)c(F)cc1C)=C2OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4′-chloro-6-fluoro-4-methyl-biphenyl-3-yl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (170 mg) and pivaloyl chloride (98 mg) in acetonitrile (5 ml) was added pyridine (64 mg) and the reaction mixture stirred at room temperature for 8 hours. The mixture was poured on diluted HCl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with heptane, filtered and dried. Yield: 100 mg of 2,2-dimethyl-propionic acid 3-(4′-chloro-6-fluoro-4-methyl-biphenyl-3-yl)-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound A82) as a solid, mp: 150-151° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:25]1[CH:26]=[CH:27][C:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:29][CH:30]=1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:29][CH:30]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(C(=O)OC(C)(C)C)nc2)cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (80.7 mg), bis(tri-tert-butylphosphine)palladium (0) (9.91 mg) and a 1 N potassium phosphate solution (388 μL) were added to a solution of tert-butyl 5-bromopyridine-2-carboxylate (50 mg) in 1,4-dioxane (2 mL). After replacement with nitrogen, the mixture was heated to 100° C. and stirred for eight hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a mixture (81 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(Cl)ccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C(=O)Cl
Reaction time: 3 h

Procedure:
4-Chloro-2-methylbenzoic acid (1.365 g, 8 mmol, commercially available from e.g. Maybridge, Fluorochem or Sigma-Aldrich) in dichloromethane (DCM) (40 mL) was cooled to 0° C., before oxalyl chloride (0.770 mL, 8.80 mmol) and a few drops of DMF (cat.) were added. The solution was then stirred under argon for 3 hours. The solvent was then evaporated in vacuo and the remaining residue was azeotroped with toluene (2×20 mL) to yield the product in 1.464 g.
Reaction SMILES: [H][H].[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd]>[CH:3]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: c1ccccc1
Agent: [Pd]
Product: c1ccc(C2CCCCC2)cc1
Temperature: 300 °C
Yield: 79 %

Procedure:
2 g of a hydroalkylation catalyst comprising 0.15 wt % Pd on alumina/MCM49 20/80 wt/wt was sized and loaded into the reactor as described above. The catalyst was activated by ramping its temperature at 60° C./hour heating rate to 300° C. and holding it there for 2 hours in 2028 GHSV of flowing hydrogen at 3.44 bar (50 psig, 344 kPag) total pressure. Other details of the experimental procedure and the reactor were as described above. This reference case was established by running two experiments (A and B) parallel at identical conditions. As the results in Table 1 indicate, the catalyst yielded 35%-37% benzene conversion with 79% cyclohexylbenzene selectivity.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:5][CH:6]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([NH:30]C(=O)OC(C)(C)C)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[NH2:30][C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:21]([C:2]1[N:3]=[C:4]([O:7][CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[S:5][CH:6]=1)[CH:22]=[CH:23]2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc(Br)cs2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(-n3ccc4cc(N)ccc43)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using tert-butyl 4((4-bromothiazol-2-yl)oxy)piperidine-1-carboxylate and tert-butyl 1H-indol-5-ylcarbamate; MS: 415.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[CH:12][C:13]#[N:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH3:15]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([NH2:15])([CH2:12][C:13]#[N:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: N
Reactant: CCOC(=O)N1CCC(=CC#N)CC1
Solvent: CO
Product: CCOC(=O)N1CCC(N)(CC#N)CC1

Procedure:
A solution of 51.38 g (264.53 mol) of 4-cyanomethylene-piperidine-1-carboxylic acid ethyl ester in 301 ml of an aqueous ammonia solution (29%) and 50 ml of methanol was heated at 110° C. in a sealed tube for 48 h. The reaction mixture was concentrated, and the residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 100/0 to 96/4 to afford 40 g of the product as a white solid.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[C:18]([C:19]3[CH:20]=[N:21][N:22]([CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:23]=3)=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][C@H:13]([CH3:34])[N:14]3[C:30]([O:32][CH3:33])=[O:31])=[C:6]([C:37]#[N:38])[CH:5]=1.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Cl:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[C:18]([C:19]3[CH:20]=[N:21][N:22]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:39])[CH2:26][CH2:25]4)[CH:23]=3)=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][C@H:13]([CH3:34])[N:14]3[C:30]([O:32][CH3:33])=[O:31])=[C:6]([C:37]#[N:38])[CH:5]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CCNCC4)c3)c(Oc3ccc(Cl)cc3C#N)c2CC[C@@H]1C
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C)CC4)c3)c(Oc3ccc(Cl)cc3C#N)c2CC[C@@H]1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
Formaldehyde (37% aqueous solution, 0.015 mL, 0.198 mmol) was added to a solution of (S)-methyl 5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.010 g, 0.020 mmol) in methanol (1.0 mL), and the reaction mixture stirred for 2 h. The mixture was cooled to 0° C. and sodium triacetoxyborohydride (8.4 mg, 0.040 mmol) was added. The reaction mixture stirred at 0° C. and was allowed to warm to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford (S)-methyl 5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.0095 g, 92%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06 (br d, J=6.74 Hz, 3H), 1.47-1.69 (m, 4H), 1.71-2.13 (m, 4H), 2.19 (s, 3H), 2.71-2.90 (m, 2H), 3.72 (s, 3H), 3.93-4.13 (m, 1H), 4.32-4.45 (m, 1H), 4.50-4.65 (m, 1H), 6.35-6.54 (m, 1H), 7.45-7.65 (m, 4H), 7.65-7.72 (m, 1H), 7.97 (s, 1H), 8.11 (d, J=2.64 Hz, 1H). MS (ESI, pos. ion) m/z 521 [M+H]+.