Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([NH:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:12]=3)[N:7]=[C:6]([CH:26]([F:28])[F:27])[C:5]=2[C:4](=[O:29])[CH2:3]1.C([OH:33])C.CS(C)=O.[OH-].[Na+].OO>O>[CH3:1][C:2]1([CH3:30])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:33])=[C:13]([NH:19][CH:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:12]=3)[N:7]=[C:6]([CH:26]([F:27])[F:28])[C:5]=2[C:4](=[O:29])[CH2:3]1
Reactant: CCO
Reactant: CC1(C)CC(=O)c2c(C(F)F)nn(-c3ccc(C#N)c(NC4CCOCC4)c3)c2C1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CC(=O)c2c(C(F)F)nn(-c3ccc(C(N)=O)c(NC4CCOCC4)c3)c2C1
Yield: 93 %

Procedure:
To a solution/suspension of 4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile (897 mg, 2.16 mmol, 1.0 eq) in 10.8 mL of 4:1 mixture of ethanol-dimethyl sulfoxide was added 1 mL of 1 M aqueous sodium hydroxide and 1 mL of 30% hydrogen peroxide. After 30 minutes the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound, 4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, (869 mg, 93%) as a tan solid: LC/MS (m/z): [M+H]+ 433.3.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([N:23]1[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]1)[CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=2)[CH:15]=[CH:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH2:39][CH2:40][CH3:41].O>CN(C=O)C>[CH2:38]([O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[CH:14][N:13]2[CH2:12][CH2:11][C@@H:10]([N:23]2[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]2)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:17][CH:18]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCI
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(O)cc21)n1cnc(C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc2ccn(CC[C@H](CO[Si](C)(C)C(C)(C)C)n3cnc(C(N)=O)c3)c2c1
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
Under N2, to a solution of 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(6-hydroxyindol-1-yl)-2-butyl]imidazole-4-carboxamide (80 mg, 0.187 mmol) in DMF (5 ml) was added potassium carbonate (38.7 mg, 0.280 mmol) at room temperature. The reaction mixture was stirred for 30 minutes. And then 1-iodobutane (51.5 mg, 0.280 mmol) was added and the resulting mixture was stirred for 24 hours at 60-80° C. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (3 g) chromatography eluting with chloroform/methanol (50:1) to give 1-[(R)-4-(6-butoxyindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (66.3 mg, 73.3%).
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1>>[S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:29][CH:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=3)[CH3:28])=[O:16])=[CH:17][CH:18]=2)(=[O:8])=[O:9])=[N:4][CH:3]=[N:2]1
Reactant: CC(N)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ncns2)cc1
Product: CC(NC(=O)c1ccc(S(=O)(=O)Nc2ncns2)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from 4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]benzoic acid (Preparation 29) and 1-[4-(trifluoromethyl)phenyl]ethanamine following the procedure described in Example 309. The reaction mixture was extracted from saturated sodium hydrogen carbonate into DCM and the crude product purified by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]1=[O:16].CN(C)[CH:19]=[O:20].O.Cl>P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([CH:19]=[O:20])[S:11][C:5]=2[N:4]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:3]1=[O:16]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Reactant: CN(C)C=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C=O)sc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine (300 mg; WO98/54190) was dissolved in phosphorus oxychloride (4 ml) and dimethylformamide (2 ml) was added. The mixture was then heated to 100° C. with stirring under nitrogen for 1 hour. The mixture was allowed to cool to ambient temperature and then added dropwise to vigorously stirred hot water (˜50° C.), containing a small amount of 2M hydrochloric acid. The mixture formed was allowed to cool to ambient temperature and filtered to give the title compound as a brown solid (210 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[O:3]1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH:8]=[CH:15][C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[O:3]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccc(F)cc2)=CC1=O
Temperature: 50 °C
Yield: 60.1 %

Procedure:
To a solution of 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) and 4-fluorobenzaldehyde (1.6 g, 13.2 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 50° C. for four hours. After the reaction solution was cooled to room temperature and diluted with saturated aqueous sodium chloride (200 mL) and water (200 mL), the aqueous solution was extracted with diethyl ether (2×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford a dark yellow crystalline solid. The crude product was recrystallized from hexane to give light yellow crystals (1.8 g, 45% yield), m.p. 55°-57° C.
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:11][C:12]1[C:13]([OH:18])=[CH:14][C:15]2[C:2]([CH3:10])([CH3:3])[CH2:4][CH2:5][C:6]([CH3:8])([CH3:7])[C:16]=2[CH:17]=1
Reactant: Cc1ccccc1O
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 25 °C

Procedure:
50.8 g (0.27 mol) of 2,5-dichloro-2,5-dimethylhexane, 30 g (0.27 mol) of 2-methylphenol and 500 ml of dichloromethane are introduced into a three-necked flask. 14.8 g (0.11 mol) of aluminium chloride are added portionwise, at 0° C., and the mixture is stirred at room temperature for twelve hours. The reaction medium is poured into ice-cold water, the mixture is extracted with dichloromethane and the organic phase is separated out after settling has taken place, washed with bicarbonate solution, dried over magnesium sulphate and evaporated. The residue obtained is triturated in hexane and filtered off and, after drying, 54.4 g (90%) of the expected phenol, with a melting point of 125-6° C., are collected.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14]Br)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCCOc1ccc(Br)c2ccccc12
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCOc2ccc(Br)c3ccccc23)cc1

Procedure:
The solution of 7.0 g. of 2-(4-bromo-1-naphthyloxy)ethyl bromide and 7.9 g. of ethyl 4-aminobenzoate in 50 ml. of hexamethylphosphoramide is heated for 18 hours, then cooled and diluted with 50 ml. of water. The precipitate is collected and crystallized from 200 ml. of methylcyclohexane and then from 100 ml. of ethanol, m.p. 126°-127° C.
Reaction SMILES: OC1C=CC(/C=C/C[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.[CH3:32][O:33][C:34]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[CH:39]=[CH:38][C:35]=1[CH:36]=O.C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([CH2:36][C:35]3[CH:38]=[CH:39][C:40]([O:44][CH3:45])=[C:41]([O:42][CH3:43])[C:34]=3[O:33][CH3:32])[CH2:16][CH2:15]2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COc1ccc(CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)c(OC)c1OC
Temperature: 120 °C
Yield: 73 %

Procedure:
A mixture of 1.27 g of the compound (9) synthesized in Example 2 and 0.8 g of 2,3,4-trimethoxybenzaldehyde was stirred at 120° C., then, 0.18 ml of formic acid was added dropwise. This was stirred for one hour at the same temperature, then ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added and the results were shaken. The organic layer was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain the above-referenced compound (29) in an amount of 1.46 g (yield 73%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:5]=[N:6][S:7][C:8]=1[C:9]([NH:11][NH2:12])=[O:10].[C:13](=S)=[S:14]>O.C(O)C>[SH:14][C:13]1[O:10][C:9]([C:8]2[S:7][N:6]=[N:5][C:4]=2[CH3:3])=[N:11][N:12]=1
Reactant: Cc1nnsc1C(=O)NN
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nnsc1-c1nnc(S)o1
Reaction time: 6.5 h
Yield: 59 %

Procedure:
A solution of 0.3 g of potassium hydroxide in 1 ml water and 0.6 ml of carbon disulfide were successively added to a solution of 1.1 g (7.2 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbohydrazide in 15 ml ethanol. The mixture was stirred for 6.5 hours with heating under reflux. After the reaction was completed, the solvent was distilled off under reduced pressure, water was added to the residue, acetic acid was added for the sake of acidification, and the deposited crystalline product was collected by filtration. Thus, 0.82 g of the objective compound was obtained.
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.[CH2:14]([N:16]=[C:17]=[O:18])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:17]([NH:16][CH2:14][CH3:15])=[O:18])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 44.7 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (150 mg, 0.67 mmol) and ethyl isocyanate (64 μL, 0.81 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), followed by recrystallization from acetone and hexane, gave the desired product (88 mg, 44%). LC-MS (m/z) 294.0 (M+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(O[C@H]2CC[C@H](N)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of trans-4-aminocyclohexanol (3 g, 26 mmol) in DMF (130 mL) at 0° C. was added 60% sodium hydride in oil. The reaction mixture was stirred at 0° C. for 1 h and then 4-fluorobenzonitrile (3.9 g, 32.6 mmol) was added. It was heated to 60° C. for 2 h and stirred for 12 h at room temperature. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried, filtered, and concentrated under reduced pressure to provide the titled compound (2.5 g, 44% yield). 1H NMR (300 MHz, DMSO-d6): δ7.72 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 4.48-4.34 (m, 1H), 2.68-2.55 (m, 1H), 2.07-1.94 (m, 2H), 1.85-1.71 (m, 2H), 1.46-1.11 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([OH:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.[CH2:14](O)[CH3:15]>S(=O)(=O)(O)O.C(N(CC)CC)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][CH2:14][CH3:15])[C:7]([CH3:11])([CH3:12])[C:6]=2[CH:13]=1
Reactant: CCO
Reactant: CC1(C)c2cc(Br)ccc2OC1O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC1Oc2ccc(Br)cc2C1(C)C
Yield: 86 %

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (5 g, 0.02 mole) was heated under reflux in ethanol (30 ml) with sulphuric acid (4 drops) for 11/2 hour. The solution was cooled, neutralised with a few drops of triethylamine and run down. The residue was redissolved in ether and the solution washed with water, dried over magnesium sulphate and the solvent removed under vacuum leaving 4.7 g (86%) title product as a buff-coloured oil. The structure was confirmed by NMR.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([F:28])[CH:24]=[CH:25][C:26]([F:27])=[C:19]3[C:18]2=[O:29])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:43][OH:44]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([F:28])[CH:24]=[CH:25][C:26]([F:27])=[C:19]3[C:18]2=[O:29])[CH2:13][C:14]([NH:43][OH:44])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3c(F)ccc(F)c3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3c(F)ccc(F)c3C2=O)ccc1OC
Yield: 56.6 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-3-(3,6-difluorophthalimido)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(3,6-difluorophthalimido)propanoic acid (580 mg, 1.43 mmol), carbonyldiimidazole (255 mg, 1.57 mmol) and hydroxylamine hydrochloride (120 mg, 1.73 mmol) in tetrahydrofuran (8 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-3-(3,6-difluorophthalimido)-N-hydroxypropionamide as a white solid (340 mg, 57% yield): mp, 171.0-172.0° C.; 1H NMR (DMSO-d6) δ1.32 (t, J=6.9 Hz, 3H, CH3), 3.03 (dd, J=7.9, 14.8 Hz, 1H, CHH), 3.16 (dd, J=8.1, 14.9 Hz, 1H, CHH), 3.71 (s, 3H, CH3), 3.91 (q, J=6.9 Hz, 2H, CH2), 5.62 (t, J=7.8 Hz, 1H, NCH), 6.878-6.95 (m, 2H, Ar), 6.99 (br s, 1H, Ar), 7.74 (t, JH-F=5.8 Hz, 2H, Ar), 8.81 (br s, 1H, OH), 10.61 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.64, 33.88, 50.29, 55.44, 63.71, 111.64, 112.44, 118.02 (t, JC-F=9.2 Hz), 119.77, 125.47 (t, JC-F=15 Hz), 130.42, 147.65, 148.59, 152.93 (dd, JC-F=4.2, 261 Hz), 163.49, 165.84; Anal Calcd for C20H18N2O6F2: C, 57.14; H, 4.32; N, 6.66. Found: C, 56.93; H, 4.37; N, 6.31.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]([C:31]1[CH:32]=[C:33]([C:42]2[N:43]=[C:44]([CH:47]=O)[S:45][CH:46]=2)[CH:34]=[C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:36]=1[OH:37])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C(OC(=O)C)(=O)C>[C:27]([C:31]1[CH:32]=[C:33]([C:42]2[N:43]=[C:44]([CH:47]=[C:2]3[CH2:6][CH2:5][NH:4][C:3]3=[O:7])[S:45][CH:46]=2)[CH:34]=[C:35]([C:38]([CH3:39])([CH3:40])[CH3:41])[C:36]=1[OH:37])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1cc(-c2csc(C=O)n2)cc(C(C)(C)C)c1O
Reactant: O=C1NCCC1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(-c2csc(C=C3CCNC3=O)n2)cc(C(C)(C)C)c1O
Temperature: 70 °C

Procedure:
16.0 g (91 mmol) of 3-bromopyrrolidin-2-one were heated to boiling in 30 ml of acetic anhydride for 1 hour. After evaporating the reaction mixture t dryness under reduced pressure, the residue was dissolved in 50 ml of tetrahydrofuran and, after adding 26.2 g (0.1 mol) of triphenylphosphine, heated under reflux for 5 hours. It was then concentrated again, the residue was dissolved in 300 ml of ethanol and 24.7 g (78 mmol) of the aldehyde from Example 2 b1) and 27 ml (0.36 mol) of triethylamine were added. After heating the mixture at 70° C. for 2 hours, the yellow precipitate was filtered off and washed with ethanol. The crystal magma is dissolved in about 2 1 of chloroform, the solution is washed several times with saturated sodium chloride solution and dried over Na2SO4, and the chloroform phase is concentrated to a third. Yellow crystals deposit on allowing to stand for a relatively long time.
Reaction SMILES: Cl[CH2:2][CH:3]=O.C([O:9][C:10](=[O:28])[C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[C:15]([F:26])[C:14]([NH2:27])=[N:13][CH:12]=1)(C)(C)C>CCO>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:16]2[C:11]([C:10]([OH:9])=[O:28])=[CH:12][N:13]3[CH:2]=[CH:3][N:27]=[C:14]3[C:15]=2[F:26])=[C:19]([Cl:25])[CH:20]=1
Reactant: O=CCCl
Reactant: CC(C)(C)OC(=O)c1cnc(N)c(F)c1Nc1ccc(Br)cc1Cl
Solvent: CCO
Product: O=C(O)c1cn2ccnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 70 °C
Reaction time: 10 h
Yield: 73.7 %

Procedure:
Chloroacetaldehyde (23 μL, 0.360 mmol) was added to a mixture of 6-amino-4-(4-bromo-2-chlorophenylamino)-5-fluoronicotinic acid tert-butyl ester (45) (75 mg, 0.180 mmol) in EtOH (1 mL). After stirring the reaction mixture at 70° C. for 10 hours, an additional 10 μL chloroacetaldehyde was added and heating was continued for 33 hours. The reaction mixture was cooled to room temperature and desired product (46) was collected by filtration. The filtrate was diluted with EtOAc and washed with water, saturated NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated to give additional product (46) (51 mg, 74% combined recovery). MS APCI (−) m/z 382, 384, 386 (M-, Cl, Br pattern) detected. 1H NMR (400 MHz, CD3OD) δ 8.86 (s, 1H), 7.85 (s, 1H), 7.53 (s, 2H), 7.32 (d, 1H), 6.82 (t, 1H). 19F NMR (376 MHz, CD3OD)−148.3 (s).
Reaction SMILES: C([Mg]Cl)(C)C.[OH:6][CH2:7][C@H:8]([CH3:35])[C@@H:9]([NH:16][C:17]1[C:18](=[O:34])[N:19]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28]C)=O)[CH:20]=[CH:21][N:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>O1CCCC1>[CH:36]1([NH:39][C:26](=[O:28])[C:25]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:23]([N:19]3[CH:20]=[CH:21][N:22]=[C:17]([NH:16][C@@H:9]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C@@H:8]([CH3:35])[CH2:7][OH:6])[C:18]3=[O:34])[CH:24]=2)[CH2:38][CH2:37]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(N[C@@H](c3ccccc3)[C@@H](C)CO)c2=O)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)CO)c1=O

Procedure:
A solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 5.5 mL) was added dropwise to a stirred mixture of 3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid, methyl ester (Example 136c, 500 mg), cyclopropylamine (0.3 mL) and tetrahydrofuran (20 mL) at 0° C. After 15 min the reaction was quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give a crude title product (525 mg). Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound.
Reaction SMILES: [I-:1].[CH2:2]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][N+](C)(C)C)[CH3:3].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[I-:1].[CH2:2]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:3]
Reactant: CCn1cccc1C[N+](C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: CC#N
Product: CCn1cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 81.3 %

Procedure:
Subsequently, to a suspension of (1-ethylpyrrol-2-yl)methyl trimethylammonium iodide (20 g, 68.0 mmol) obtained above in acetonitrile (200 ml) was added triphenylphosphine (22.0 g, 83.9 mmol), and the resulting mixture was stirred at 80° C. for 9 hours. After cooling, the reaction mixture was concentrated to about one-half of its initial volume, to which was added ethyl acetate (100 ml). The crystals precipitated were collected by filtration, washed with ethyl acetate and dried in vacuo to afford the title compound (27.5 g,yield: 81%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][C:40]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41]>>[CH3:38][O:39][C:40]([CH:42]1[CH2:47][CH2:46][N:45]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:44][CH2:43]1)=[O:41]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COC(=O)C1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)OC)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was reacted with piperidine-4-carboxylic acid methyl ester (Aldrich) to give title compound. HR-MS (ES, m/z) calculated for C36H43Cl2N4O4 [(M+H)+] 665.2656, observed 665.2652.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH:20]=[CH2:21])C1C=CC=CC=1>C(O)C.O1CCOCC1.[OH-].[Pd+2].[OH-]>[CH2:20]([C:14]1[C:13]2[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=2)[N:17]=[C:16]([CH3:19])[CH:15]=1)[CH3:21]
Reactant: C=Cc1cc(C)nc2c(OCc3ccccc3)cccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CCc1cc(C)nc2c(O)cccc12
Temperature: 25 °C
Reaction time: 9 h
Yield: 48.5 %

Procedure:
A mixture of 8-benzyloxy-2-methyl-4-vinylquinoline (200 mg) and palladium(II) hydroxide (40 mg) in a mixture of ethanol (1.5 ml) and dioxane (1.5 ml) was stirred for 9 hours at ambient temperature under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (Ethyl acetate:n-hexane=1:2, V/V) to give 4-ethyl-8-hydroxy-2-methylquinoline (66 mg) as brown oil.