Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:11]O>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: CO
Product: COC(=O)c1cnc(C)cn1
Reaction time: 8 h
Yield: 93 %

Procedure:
The reaction was carried out, under nitrogen, in a 1 L×4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet), and a thermocouple. The reactor was charged with 5-methylpyrazinecarboxylic acid (100 g), and acidic cation exchange resin (20 g), and methanol (300 g). The mixture was stirred at reflux for about 20 h. After the reaction was complete (analyze with GC or GC/MS), the resin was removed by pressure filtration. The resin was rinsed with methanol and about 75% of the solvent was removed under reduced pressure. The resulting suspension was allowed to stand at room temperature overnight, and then in an ice-bath for 3 h. The solid was collected by filtration and washed with ice-cold methanol (2×80 g). Drying under vacuum at room temperature (25 inches of Hg) yielded 102.4 g (93%) of 5-methyl-2-pyrazinecarboxylic acid, methyl ester that was suitable for further use.
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]\[CH2:4][OH:5].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([O:5][CH2:4]/[CH:3]=[CH:2]\[CH2:1][OH:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: OC/C=C\CO
Product: OC/C=C\COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
14.6 g of sodium hydride (60 % in oil) was washed with n-pentane under an argon gas. After drying, 150 ml of dry dimethylformamide (hereinafter referred to simply as DMF) was added thereto to form a suspension. 75 g of (Z)-2-buten-1,4-diol was dropwise added thereto at 0° C. under stirring over a period of 30 minutes. The mixture was stirred at room temperature for 1.5 hours, and 44 g of benzyl bromide was added at 0° C. under stirring. The mixture was stirred at the same temperature for 30 minutes, and then the temperature was returned to room temperature. The mixture was stirred at 50° C. overnight. The reaction solution was poured into ice water and extracted with diethyl ether. The ether solution was washed sequentially with water and with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to distillation under reduced pressure (2.5 mmHg, 134°-138° C.) to obtain 29 g of (Z)-4-benzyloxy-2-buten-1-ol as colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[C:16](=S)=[S:17].II>C(O)C.O1CCOCC1>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[C:16]=[S:17]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: S=C=S
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1ccc(N=C=S)cc1
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
A mixture comprising 4-aminobenzoic acid (0.20 g, 1.5 mmol), dioxane (5 mL), a saturated sodium hydrogencarbonate aqueous solution (5 mL) and carbon disulfide (0.37 mL, 6.1 mmol) was stirred in a nitrogen atmosphere at room temperature for 19 hours and then concentrated under reduced pressure to dryness. The obtained residue was dissolved in water (8.0 mL), and 1M sodium hydroxide aqueous solution (1.5 mL) was added. With stirring at room temperature, an ethanol (8.0 mL) solution of iodine (0.38 g, 1.5 mmol) was dropwise added thereto over a period of 8 minutes, followed by stirring at room temperature for further 12 minutes. Then, the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to remove ethanol and dioxane as far as possible. Then, 1M hydrochloric acid (4.5 mL) was added, and the precipitated solid was collected by filtration to obtain 4-isothiocyanatobenzoic acid as a ocher solid (0.20 g, yield: 78%). The HPLC purity was 62%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1NC1CCCCC1
Yield: 61.5 %

Procedure:
51.5 g (0.27 mol) of 2,5-dichloronitrobenzene, 22.3 g (0.27 mol) of cyclohexylamine, 74.6 g (0.54 mol) of potassium carbonate and 0.5 g of 18-crown-in 300 ml of dimethylformamide were heated at 100° C. for 4 h. The mixture was then poured into water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from i-propanol, resulting in 42.3 g (62%) of the product. Melting point 101°-103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[NH2:28][C:24]1[N:25]=[C:26]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[CH:22][N:23]=1
Reactant: Nc1nccc(Cl)n1
Reactant: N#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1c[nH]c2nccc(Oc3ccc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
200 mg (0.66 mmol) of 4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 104 mg (0.72 mmol) of 4-chloropyrimidine-2-amine are suspended in 9 ml of water and 4.5 ml of ethanol. 0.33 ml (1.31 mmol) of 4N hydrochloric acid is added, and the mixture is heated at reflux for 2 h. The mixture is made alkaline using concentrated aqueous sodium hydroxide solution, diluted with water and extracted with ethyl acetate. The organic phase is separated off and concentrated. The crude product is purified by preparative HPLC. This gives the title compound as crystals.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:65][C:66]1[O:67][C:68]2[CH:74]=[CH:73][CH:72]=[CH:71][C:69]=2[N:70]=1>>[O:67]1[C:68]2[CH:74]=[CH:73][CH:72]=[CH:71][C:69]=2[N:70]=[C:66]1[S:65][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:51][CH2:52][CH2:53][CH2:54]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:45][CH2:46][CH2:47][CH2:48]2)=[O:36])[CH2:32][CH2:33]1
Reactant: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1
Reactant: Sc1nc2ccccc2o1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c(N2CCCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, to thereby yield the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1([CH3:38])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[C:17]([NH:26][C:27]4[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=4[CH3:35])[CH:18]=[C:19](Br)[CH:20]=3)[C:15](=[O:36])[C:14]=2[CH:13]=[C:12](Br)[CH:11]=1.[C:39]1([S-:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Na+].CO>CN(C=O)C>[C:1]1([CH3:38])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[C:17]([NH:26][C:27]4[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=4[CH3:35])[CH:18]=[C:19]([S:45][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:20]=3)[C:15](=[O:36])[C:14]=2[CH:13]=[C:12]([S:45][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:11]=1
Reactant: Cc1cc(C)c(Nc2cc(Br)cc3c2C(=O)c2cc(Br)cc(Nc4c(C)cc(C)cc4C)c2C3=O)c(C)c1
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C)c(Nc2cc(Sc3ccccc3)cc3c2C(=O)c2cc(Sc4ccccc4)cc(Nc4c(C)cc(C)cc4C)c2C3=O)c(C)c1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
16.5 g of 1,5-bis(mesitylamino)-3,7-dibromoanthraquinone are suspended at RT in 50 ml of DMF and heated to 120° C. After cooling to 50° C., a suspension of 8.5 g of sodium thiophenolate in 25 ml of DMF is added thereto. The mixture is then heated to 120° C. again and stirred at that temperature for 1.5 hours. After cooling the mixture to 60° C., 100 ml of methanol are added and the mixture is stirred overnight at RT. The precipitate is filtered off, washed with a methanol/water mixture (1:1) and dried in vacuo.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:7]([OH:15])[CH:8]([OH:14])[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:4].[C:29]([CH2:35][C@@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37](O)=[O:38])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C(N1CCOCC1)C.C(Cl)CCl>CN(C)C=O>[CH:17]1([CH2:16][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([CH2:35][C:29](=[O:34])[C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:23][C:24]2[N:25]=[CH:26][NH:27][CH:28]=2)[C@@H:7]([OH:15])[CH:8]([OH:14])[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCC(CC)C(O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCC(CC)C(O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
A mixture of 880 mg (2.23 mmol) of (S)-α-amino-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]imidazole-4-propionamide, 608 mg (2.45 mmol) of (R)-α-(pivaloylmethyl)hydrocinnamic acid (see EpA 0 184 550), 0.35 ml (2.76 mmol) of 4-ethylmorpholine, 662 mg (4.9 mmol) of HBT and 529 mg (2.76 mmol) of EDC in 20 ml of dimethylformamide is stirred at room temperature overnight. Thereafter, the reaction mixture is evaporated to dryness in a high vacuum, the residue is poured into a mixture of ice and 2N sodium bicarbonate solution and extracted three times with ethyl acetate. The extracts are washed in succession with saturated ammonium chloride solution, 2N sodium bicarbonate solution and saturated sodium chloride solution and combined. After drying the organic solution over magnesium sulphate the solvent is evaporated under reduced pressure and the residue (1.01 g), for purification, is chromatographed on 70 g of silica gel using a 20:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Crystallization of the thus-obtained crude product from methylene chloride/methanol/ether yields 900 mg of (S)-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide, melting point 160° , MS: 624 (M)+.
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][CH2:12][N:13]=[C:14]=[O:15]>C1COCC1>[CH2:1]([O:8][NH:9][C:14]([NH:13][CH2:12][CH2:11][Cl:10])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCCCl
Reactant: NOCc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCCl)NOCc1ccccc1
Yield: 97 %

Procedure:
To a stirred solution of benzyloxyamine (36.63 g, 0.297 mol) in THF (250 ml) was added a solution of 2-chloroethyl isocyanate (25.4 ml, 1.0 equiv.) in THF (50 ml) over 20 minutes. The resulting cloudy solution was refluxed for 10 minutes, cooled and evaporated. Trituration of the residue with ether-hexane gave N-benzyloxy-N'-(2-chloroethyl)urea as a white solid (65.82 g, 97% yield), mp 67°-68° C. after recrystallization from hexane-ether. To a stirred solution of this urea (65.8 g, 0.287 mol) in the THF (500 ml) at room temperature was added sodium hydride (11.8 g of 60% dispersion in oil, 1.02 equiv.) in portions over 30 minutes. The cloudy solution was refluxed for 10 minutes, cooled and evaporated. To the resulting semi-solid was added 2% aqueous citric acid (60 ml) and hexane (250 ml). After vigorous agitation, the resulting solid was collected by filtration and washed with water and hexane, to give 1-benzyloxy-2-imidazolidinone as a tan solid (52.66 g, 93% yield), mp 64°-65° C. after recrystallization from water.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]1([C:17](=[O:18])[NH:16][C:15](=[O:19])[NH:14]1)[CH2:8][CH2:7]2)(O)=O.[N-:20]=[N+]=[N-].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[NH2:20][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]1([C:17](=[O:18])[NH:16][C:15](=[O:19])[NH:14]1)[CH2:8][CH2:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1NC(=O)C2(CCc3cc(C(=O)O)ccc3C2)N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O
Temperature: 50 °C

Procedure:
A stirred mixture of (±)-6′-carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione (described in Intermediate 1) (1.50 g, 5.76 mmol), and sodium azide (749 mg, 11.53 mmol) in conc. H2SO4 (30 mL) was heated to 50° C. for 2 h, then allowed to cool to ambient temperature. The mixture was adjusted to pH 8 by addition of 6 N aqueous NaOH and concentrated in vacuo to precipitate a solid. The precipitate was collected by filtration and washed extensively with H2O. Drying in vacuo afforded the title compound as a light brown solid. MS: m/z=232 (M+1).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](C1C=CC([C:20]2[C:28]([CH2:29][C@H:30]3[C@@H:35]([OH:36])[C:34]4[CH:37]=[C:38]([O:41][CH2:42][C:43]5[S:44][C:45]6[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:46]=6[N:47]=5)[CH:39]=[CH:40][C:33]=4[O:32][CH2:31]3)=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([O-])=[O:23])=CC=1)([O-])=O.[H-].[Na+]>>[F:52][C:49]1[CH:50]=[CH:51][C:45]2[S:44][C:43]([CH2:42][O:41][C:38]3[CH:39]=[CH:40][C:33]4[O:32][CH2:31][C@@H:30]([CH2:29][C:28]5[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=5)[C:22]([NH:10][S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])=[O:23])[C@@H:35]([OH:36])[C:34]=4[CH:37]=3)=[N:47][C:46]=2[CH:48]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C([O-])c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1-c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1

Procedure:
Synthesis was carried out as in example 1, but using 4.4 grams benzene sulfonamide instead of methane sulfonamide, and using 2.4 grams optically pure (-) cis-4-nitrophenyl-3-[[6-[(5-fluoro-2-benzothiazolyl)methoxy]-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-yl]methyl]benzoate and 628 milligrams sodium hydride. There was obtained 1.02 grams of product, m.p. 161°-162° C. αD =-30° ; c =0.005 in tetrahydrofuran.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25](Br)[C:24]=2[CH:29]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[CH2:1]([O:3][C:4](=[O:30])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25]([C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:24]=2[CH:29]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: C#CCCCCCCCCCC
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(F)(F)F)cc1)Cc1ccc2occ(Br)c2c1
Product: CCCCCCCCCCC#Cc1coc2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc12
Yield: 34 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step c) but using ethyl{[(3-bromo-1-benzofuran-5-yl)methyl][4-(trifluoromethyl)benzyl]amino}(oxo)acetate and 1-dodecyne gave the title compound as a yellow oil (34%). HPLC (Condition A), Rt: 6.39 min (HPLC purity: 99.2%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH2:30][CH2:31][CH3:32])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>C(OCC)(=O)C.CN(C)C=O>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH2:30][CH2:31][CH3:32])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CCCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Yield: 8.5 %

Procedure:
In a manner similar to that of Example 1(g), starting with 600 mg (1.3 mmol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]-propylcarbamate in 7 ml of ethyl acetate and 7 ml of dimethylformamide, 50 mg (10%) of the desired product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([CH2:15][N:16]([C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH:17]([CH3:19])[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:36]1([NH2:39])[CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:15][N:16]([C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH:17]([CH3:18])[CH3:19])[C@H:11]([CH2:13][NH:39][CH:36]2[CH2:38][CH2:37]2)[CH2:12]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NC1CC1
Reactant: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)cc1OCCCOC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)cc1OCCCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,4S)-3-({[4-ethyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (described under step C in example 152) (6.9 g, 11.88 mmol) in dichloroethane (112 mL), cyclopropylamine (0.92 mL, 13.1 mmol) and NaBH(OAc)3 (3.52 g, 16.63 mmol) are added. The solution is stirred at RT overnight, then diluted with CH2Cl2. A saturated solution of NaHCO3 is added, the layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluent: AcOEt/MeOH 100:0 to 85:15) to give the title compound. MS (LC-MS): 532.3 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.58 min.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[Br:17][C:18]1[CH:19]=[C:20]([NH2:32])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[Br:17][C:18]1[CH:19]=[C:20]([NH:32][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:2]=2[Cl:1])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]
Reactant: CCN(CC)CCOc1ccc(N)cc1Br
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Br

Procedure:
Prepared analogously to Example 143 starting from (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 3-bromo-4-(2-diethylamino-ethoxy)-phenylamine (Z30b).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](Br)[C:6]([CH:10]2[CH2:12][CH2:11]2)=[C:5]([F:13])[C:3]=1[NH2:4].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:14])[C:6]([CH:10]2[CH2:12][CH2:11]2)=[C:5]([F:13])[C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cc(Br)c(C2CC2)c1F
Reactant: CB1OB(C)OB(C)O1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(Cl)c(N)c(F)c1C1CC1
Temperature: 25 °C

Procedure:
2-Chloro-4-bromo-5-cyclopropyl-6-fluoroaniline (14.0 g, 53 mmol), trimethylboroxine (13.4 g of 50% solution in THF, 53 mmol), tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.2 mmol) and potassium carbonate (14.0 g, 101 mmol) are combined and stirred in 250 mL of a 4:1 DME/water solution. The mixture is degassed by repeated alternating application of vacuum and positive nitrogen pressure (10×). The mixture is heated to reflux temperature for 2 days and then cooled to room temperature. Most of the DME is removed by rotary evaporator and the residual mixture is partitioned between Et2O (500 mL) and water (500 mL). The organic phase is washed with brine (3×250 mL), dried (MgSO4) and concentrated by rotary evaporator. The crude product is purified using flash chromatography (5% CH2Cl2/hexanes) to give 2-chloro-4-methyl-5-cyclopropyl-6-fluoroaniline a light yellow oil.
Reaction SMILES: [C:1]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][C:19]2=[O:31])[CH2:14][CH2:13]1)=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([CH:15]2[CH2:16][CH2:17][N:12]([C:10]([O:9][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:11])[CH2:13][CH2:14]2)[C:19](=[O:31])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(C(=O)OC(=O)c3ccccc3)CC2)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.8 %

Procedure:
tert-Butyl 4-{1-[(benzoyloxy)carbonyl]piperidin-4-yl}-3-oxopiperazin-1-carboxylate (0.42 g) obtained in Example 12b) was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (1 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated, toluene was added to the residue and it was concentrated again under reduced pressure. The residue was dissolved in dichloromethane (15 mL) and formalin (37%; 0.5 mL) was added. After the reaction mixture was stirred at room temperature for 2 hours, sodium triacetoxyborohydride (0.53 g) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was washed with an aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.38 g, quantitative) as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17]>C(OCC)C>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:16](=[O:18])[CH3:17])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(=O)N(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1cccc(Br)n1

Procedure:
29.7 g of 2,6-dibromopyridine were reacted with 86.1 ml of n-butyllithium (1.6-molar solution in n-hexane) and 12 g of N,N-dimethylacetamide in 300 ml of diethyl ether as described in the literature [J. Organomet. Chem. 56 (1973), 53-66; Chem. Ber. 125 (1992), 1169-1190] to give 2-bromo-6-acetylpyridine.