Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[Cl:23]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccccc2Cl)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.182 mmol) was used in general procedure 1 with 2-chlorobenzoyl chloride (0.228 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(2-chlorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 469 (M)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)([CH2:13][OH:14])[CH2:11][O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][OH:14])([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[CH2:11][O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(CO)(CCc2ccc(OCc3ccccc3)cc2)COC1(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(CO)(CCc2ccc(O)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[2-(4-benzyloxy-phenyl)-ethyl]-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (25 mg, 0.05 mmol) in methanol (10 ml) is added a catalytic amount of paladium on charcoal (10% wt). The reaction mixture is stirred under H2 atmosphere at room temperature for 2 hours. 4-Hydroxymethyl-4-[2-(4-hydroxy-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester is isolated as a white solid after filtration of the suspension through celite and concentration to dryness.
Reaction SMILES: [OH:1][C:2]1([CH2:15][O:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][CH2:3]1.[H][H]>[Pd].C(O)C>[OH:1][C:2]1([CH2:15][O:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCC2(O)CCNCC2)cc1
Yield: 100 %

Procedure:
A mixture of 23 parts of ethyl 4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]-methoxy]benzoate and 200 parts of ethanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 17 parts (100%) of ethyl 4-[(4-hydroxy-4-piperidinyl)methoxy]benzoate as a residue (int. 79).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26](Br)=[C:25]([CH3:31])[CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[CH2:34](B(O)O)[CH3:35]>>[CH2:34]([C:26]1[C:27]([CH3:29])=[CH:28][C:23]([O:22][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:33])=[O:32])=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:24][C:25]=1[CH3:31])[CH3:35]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2cc(C)c(Br)c(C)c2)cc1
Reactant: CCB(O)O
Product: CCc1c(C)cc(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc1C

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and ethyl boronic acid. MS: 464.2 [M−H]−.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:27]([CH3:28])=[CH:26][S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:27]([CH3:28])=[CH:26][S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1csc2nc(-c3ccno3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[NH:33][C@H:34]([C:38]([OH:40])=[O:39])[CH:35]([CH3:37])[CH3:36]>CCOCC>[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[NH:33][C@H:34]([C:38]([OH:40])=[O:39])[CH:35]([CH3:37])[CH3:36].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[NH:33][CH:34]([CH:35]([CH3:37])[CH3:36])[C:38]([O:14][CH2:13][C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:39]
Reactant: OCc1[nH]ccc1Cc1ccccc1
Agent: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OCc1[nH]ccc1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-benzylpyrrolylmethyl alcohol (0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of N-(2-chloro-4-trifluoromethylphenyl)valine (1.5 mmol) in ether. The mixture is stirred for 30 minutes and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography using a circular chromatography, eluting with 20% ether/hexane, gives the 3-benzylpyrrolylmethyl ester of N-(2-chloro-4-trifluoromethylphenyl)valine, [3-benzylpyrrolylmethyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate].
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[C:14]12([N:24]=[C:25]=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:25]([NH:24][C:14]23[CH2:23][CH:18]4[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]4)[CH2:21]2)[CH2:15]3)=[O:26])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)NC23CC4CC(CC(C4)C2)C3)c1O
Yield: 56.5 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (120 mg, 0.54 mmol) and 1-adamantyl isocyanate (115 mg, 0.64 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), gave the desired product (122 mg, 56%). LC-MS (m/z) 400.0 (M+).
Reaction SMILES: C([O:5][CH2:6][CH:7]1[N:11]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([Cl:20])[CH:13]=2)[C:10](=[O:21])[C:9]([CH3:23])([CH3:22])[C:8]1=[O:24])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>O>[Cl:20][C:14]1[CH:13]=[C:12]([N:11]2[CH:7]([CH2:6][OH:5])[C:8](=[O:24])[C:9]([CH3:22])([CH3:23])[C:10]2=[O:21])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: CC(C)(C)OCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(CO)N(c2ccc(C#N)c(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To 4-[5-(tert-butoxy methyl)-3,3-dimethyl-2,4-dioxopyrrolidin-1-yl]-2-chlorobenzonitrile (900 mg) was added trifluoroacetic acid (10 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was cooled to 0° C., and neutralized with saturated sodium hydrogen carbonate solution. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:4), and recrystallized from hexane-ethyl acetate to give the title compound as colorless crystals (yield: 655 mg, 87%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].[ClH:8].[CH2:9]([OH:11])[CH3:10]>>[ClH:8].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:7])[O:11][CH2:9][CH3:10]
Reactant: CCO
Reactant: N#Cc1cccs1
Agent: Cl
Product: CCOC(=N)c1cccs1

Procedure:
Ethyl 2-thiophenecarboximidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, 2-thiophenecarbonitrile (25.2 g, 0.231 mol) was treated with hydrogen chloride in ethanol (250 mL) to give 16.3 g (37%) of the target compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)C(=O)C3C=NN(C4C=CC=C(C)C=4S)C=3N=2)=[CH:4][CH:3]=1.BrC1C=CC(C(Cl)=[O:39])=CC=1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:9][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[O:39])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1S
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-N-(4-chloro-phenyl)-benzamide (4) used is prepared by the following procedure. To a solution of 4-chloroaniline (2, 66.0 g, 517.4 mmol) and 4-bromobenzoyl chloride (3, 109.0 g, 497.5 mmol) in dichloromethane (1200 mL) is added triethyl amine (83.2 mL, 597.0 mmol). The reaction mixture is then poured into 0.05 N sodium hydroxide solution and the resulted suspension is stirred at rt for 1 h. The solid formed is filtered and washed well with water. It is dried in vacuo and used for the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18]3(OCC[O:27]3)[CH:17]=[CH:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH:17]=[CH:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1C=CC2=O
Yield: 51776.1 %

Procedure:
A solution of 1.04 g (2.57 mmol) of 43, 117 mg (0.617 mmol) of pTsOH in acetone (70.3 mL) and H2O (11.4 mL) was stirred at rt for 1.5 h. The reaction mixture was adjusted to pH 7 with 5% NaHCO3 and concentrated by rotovap to about 30 mL without heating. The solution was poured into H2O (50 mL) and extracted with EtOAc (3×, 70 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo giving a white solid. Crystallization of the residue from CH2Cl2/hexanes gave 477 g (52%) of 44 as fine white needles. Data for 44: TLC, T-1, Rf 0.5; 1H NMR (400 MHz, CDCl3) δ 1.12 (s, 3H, H-18), 5.05 (s, 2H, benzylic-H), 6.10 (dd, 1H, J=5.9, 3.2 Hz, H-15), 6.76 (d, 1H, J=2.7 Hz, H-4), 6.81 (dd, 1H, J=8.6, 2.7 Hz, H-2), 7.22 (d, 1H, J=8.6 Hz, H-1), 7.31–7.45 (m, 5H, Ar—H), 7.64 (dd, 1H, J=5.9, 1.1 Hz, H-16).
Reaction SMILES: CI.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]3=[CH:17][S:18][CH:19]=[C:13]3[NH:12][C:11]2=[S:20])=[CH:6][C:5]=1[CH:21]=[C:22]([Cl:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].[C:29](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]3=[CH:17][S:18][CH:19]=[C:13]3[N:12]=[C:11]2[S:20][CH3:29])=[CH:6][C:5]=1[CH:21]=[C:22]([Cl:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(Cl)=Cc1cc(-n2c(=S)[nH]c3cscc3c2=O)ccc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)C(Cl)=Cc1cc(-n2c(SC)nc3cscc3c2=O)ccc1Cl
Temperature: 10 °C
Reaction time: 48 h

Procedure:
0.28 g of methyl iodide in 5 ml of dimethylformamide was added to a solution of 0.8 g of 3-[4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)-phenyl]-4-oxo-2-thioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine and 0.27 g of potassium carbonate in 40 ml of dimethylformamide. Stirring was carried out for 2 days, after which the mixture was cooled to 10° C., 80 ml of water were added and stirring was effected for a further 2 hours. The resulting precipitate was removed, washed with water and dried.
Reaction SMILES: [C:1]1([OH:8])([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]1(O)CCCCC1.COC1CCCCC1O.C1(O)C=CC=CC=1.C1(OC)C(=CC=CC=1)O>CO>[CH3:9][O:7][C:1]1([OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1(O)CCCCC1
Reactant: OC1CCCCC1
Agent: COC1CCCCC1O
Agent: COc1ccccc1O
Solvent: CO
Solvent: Oc1ccccc1
Product: COC1(O)CCCCC1

Procedure:
Ruthenium Catalyzed Hydrogenations. For guaiacol hydrogenation in the presence of ruthenium catalyst the products were similar to those identified earlier in our laboratory. At 150° C., 30% of the guaiacol had already been converted by the time the reactor reached temperature, time zero in FIG. 1. The primary product was that resulting from saturation of the phenolic ring, 2-methoxycyclohexanol (60% yield @ 4 h). Cyclohexanediol was the secondary product (11%), although cyclohexanol was also significant (6%). The methanol byproduct was found (1%). There was little phenol formed at this temperature. At 200° C. the initial conversion of guaiacol during heatup was 44%. As shown in FIG. 2 the methoxycyclohexanols were still the main product (54% yield @ 4 h), but cyclohexanediol became less important (4%) while more cyclohexanol was formed (12%). More methanol was present (2%), as was more phenol. At 250° C., 60% of the guaiacol was converted by the time the reactor reached temperature. As shown in FIG. 3 cyclohexanol almost surpassed methoxycyclohexanols as the main product. Methoxycyclohexanol yield peaked at 17% in the 1 to 2 h range before reacting on to secondary products. The maximum cyclohexanol yield was 13%. Cyclohexanediol was only a minor product (1%). More phenol was evident and cyclohexane became a significant product (2%); however, the hexane recovery is likely limited by its low solubility in the water. More cyclohexane may have been actually produced and remained in the reactor as a separate light phase, which could not be sampled by our method. Over the period of the test, the amount of aqueous phase products is reduced. A large methane gas product was produced in this test, as has been reported for processing at these conditions of temperature and catalyst wherein phenol was extensively gasified at as low as 250° C.xi At 300° C., phenol is the primary product that was recoverable. Cyclohexanol and methoxycyclohexanol are early products which are reduced to low levels within the first hour at temperature. All three isomers of methyl-phenol (cresols) are significant byproducts, as is benzene. Cyclohexane is present in the water product only at low concentration, but is likely present as a significant product in a separate phase. Because of the large amount of methane gas formation, this test was hydrogen limited with the reactor pressure surpassing the pressure set point after 1 h of operation and this factor is expected to have skewed the mechanism away from the high-use hydrogenation pathways, such as saturation of the aromatic ring. xiElliott, D. C.; Hart, T. R.; Neuenschwander, G. G. “Chemical Processing in High-Pressure Aqueous Environments. 8. Improved Catalysts for Hydrothermal Gasification.” Ind Eng. Chem. Res. 45(11) 3776-81, 2006.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C(O)(=O)C.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[N:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1>C(O)C>[Cl:20][C:18]1[CH:19]=[C:14]2[C:15](=[CH:16][C:17]=1[Cl:21])[N:22]1[CH:23]=[CH:24][CH:25]=[C:26]1[C:5]1([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[NH:13]2
Reactant: Nc1cc(Cl)c(Cl)cc1-n1cccc1
Reactant: CN1CCC(=O)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCC2(CC1)Nc1cc(Cl)c(Cl)cc1-n1cccc12

Procedure:
3.39 g (0.03 mole) of 1-methyl-4-piperidone and 5 ml. of glacial acetic acid are added to a solution of 6.81 g (0.03 mole) of 1-(2-amino-4,5-dichlorophenyl)pyrrole in 100 ml. of absolute ethanol. The solution is refluxed for 50 hours and concentrated, and the residue is dissolved in water. The solution is filtered and basified. A solid precipitates and is filtered, dried, and recrystallized from ethanol to give 7,8-dichloro-4,5-dihydro-1'-methylspiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine], m.p. 214°-215° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12].[F:15][C:16]1[C:21]([F:22])=[CH:20][C:19](B(O)O)=[C:18]([O:26][CH3:27])[CH:17]=1>C(Cl)Cl.CO>[F:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:18]([O:26][CH3:27])[CH:17]=1
Reactant: COc1cc(F)c(F)cc1B(O)O
Reactant: CS(=O)(=O)CCNc1cnccc1I
Solvent: CO
Solvent: ClCCl
Product: COc1cc(F)c(F)cc1-c1ccncc1NCCS(C)(=O)=O

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-amine and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of CH2Cl2:methanol (100:0 to 85:15) for the chromatographic purification. Light brown foam (76%). MS (ESI): m/z=343.09 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27](=[O:35])[CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[ClH:36]>CO.ClCCl.O1CCOCC1>[ClH:1].[ClH:36].[Cl:1][C:2]1[C:3]([NH:26][C:27](=[O:35])[CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(CC3CCNCC3)ccc12
Reaction time: 1 h

Procedure:
4-[[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]methyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (Example 1(b)) was dissolved in methanol (0.5 mL) and dichloromethane (3 mL). HCl in 1,4-dioxane (4M, 1 mL) was added and the mixture stirred for 1 hour. The resultant suspension was evaporated to dryness and recrystallised from methanol/ethyl acetate to give the title compound as a colourless solid (120 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: Nc1nccs1
Reactant: O=C(O)COc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1nc(-c2ccc(F)cc2)cs1)Nc1nccs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 90 mg (0.24 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 47 mg (0.47 mmol) of 2-amino-thiazole. Yield: 5 mg.
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:25]1([C:2]2[C:3]([O:16][CH2:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OC[C@H]2CC[C@H](C)CC2)cc1F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OC[C@H]2CC[C@H](C)CC2)cc1F
Temperature: 110 °C

Procedure:
To a solution of tert-butyl 5-chloro-2-fluoro-4-((trans-4-methylcyclohexyl)-methoxy)-benzoate (6.48 g, 18.16 mmol) in toluene-water (40 mL, v/v 20:1) was added cyclopropylboronic acid (2.34 g, 27.26 mmol) and tribasic potassium phosphate (17.37, 81.84 mmol). The reaction mixture was sparged with argon for 10 minutes and then charged with tricyclohexylphosphine tetrafluoroborate (1.35 g, 3.67 mmol) and palladium acetate (0.41 g, 1.82 mmol). The mixture was heated at 110° C. for 72 hours, then cooled to ambient temperature; filtered through a pad of diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (0% to 10% ethyl acetate) to give the title compound (5.95 g, 90%): 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=8.4 Hz, 1H), 6.50 (d, J=12.8 Hz, 1H), 3.78 (d, J=6.1 Hz, 2H), 1.91-1.70 (m, 8H), 1.56 (s, 9H), 1.41-129 (m, 2H), 1.14-0.95 (m, 6H), 0.65-0.60 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])=[O:23]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Br)c1
Reaction time: 21 h
Yield: 74.4 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-chlorophenyl isocyanate (0.29 ml, 2.40 mmol) in THF (2 ml) was added Et3N (33 ml, 0.24 mmol) at room temperature. After 21 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-chlorophenyl)ureido]phenylacetate (710 mg, 74%) as a pale brown powder. 1H-NMR (CDCl3) δ3.57 (s, 2H), 3.70 (s, 3H), 7.02-7.28 (m, 2H), 7.36 (d, J=6.8 Hz, 1H), 7.48 (s, 1H), 8.00-8.11 (m, 2H); MS (ESI) m/z 397 (M+), 399 (M++2), 401 (M++4).