Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][N:33]1[C:37]([CH:38]=[O:39])=[CH:36][N:35]=[N:34]1.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([CH:38]([C:37]3[N:33]([CH3:32])[N:34]=[N:35][CH:36]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: Cn1nncc1C=O
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc2ccc(C(O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reaction time: 0.03 h

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 0.71 mL, 1.1 mmol) was added dropwise to a stirring solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (490 mg, 1.1 mmol, Intermediate 4: step d) in tetrahydrofuran (11 mL) at −78° C. After 2 minutes, a solution of 1-methyl-1H-1,2,3-triazole-5-carbaldehyde (140 mg, 1.1 mmol, Intermediate 18) in tetrahydrofuran (1 mL) was added dropwise. After 5 minutes, the flask was placed into an ice-water bath. After 1 hour, water (10 mL) and ethyl acetate (60 mL) were added. The biphasic mixture was stirred for 10 minutes. Half-saturated aqueous sodium chloride solution (50 mL) was added and the layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (4 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with 100% hexanes initially, grading to 100% ethyl acetate provided the title compound as a white foam which was impure. The foam was suspended in methanol (20 mL) and the suspension was sonicated for 5 minutes. The solids were collected by filtration and rinsed with methanol (5 mL). The collected solids were dried to provide the title compound as a white solid. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.42 (d, J=2.5 Hz, 1H), 8.21 (d, J=1.8 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.75-7.71 (m, 2H), 7.72-7.67 (m, 2H), 7.37-7.32 (m, 3H), 6.55 (d, J=5.2 Hz, 1H), 6.53-6.49 (m, 1H), 6.22 (d, J=5.2 Hz, 1H), 4.30 (s, 2H), 4.04 (s, 3H), 3.97 (s, 3H); MS (ESI): mass calcd. for C24H21ClN6O2, 460.1; m/z found, 461.1 [M+H]+.
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:17][C:18]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)=O)(=O)OC.O.[NH2:27][NH2:28]>>[CH3:25][N:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:18]1[N:28]=[N:27][C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]=2[CH:17]=1
Reactant: COP(=O)(CC(=O)c1cccn1C)OC
Reactant: O=C1CCCCCCC1=O
Reactant: NN
Solvent: O
Product: Cn1cccc1-c1cc2c(nn1)CCCCCC2

Procedure:
off-white solid. MS (ESI): 241.2 (M+). Prepared from cyclooctane-1,2-dione, [2-(1-Methyl-1H-pyrrol-2-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH2:23][O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[CH:32](OC)[N:33](C)C.[O:38]1[CH2:42]CCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:27])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][CH:32]=[N:33][O:38][CH3:42])=[O:19])=[C:16]([CH2:23][O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C1CCOC1
Reactant: COC(OC)N(C)C
Reactant: COCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Product: COCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC=NOC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a solution of 0.09 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methoxymethyl benzoic acid amide in 2 mL of tetrahydrofuran, 0.05 g of N,N-dimethylformamide dimethylacetal was added, and stirred at room temperature for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in 2 mL of tetrahydrofuran, a solution of 0.02 g of methoxyamine hydrochloride in 2 mL of water was added dropwise. After the completion of the addition dropwise, it was continued to stir at room temperature further for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, 5 mL of water was added in the residue, and extracted with ethyl acetate (10 mL×1). The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sulfuric acid, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (1:4) to obtain 0.07 g of the aimed product as white crystal.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:9]=[O:10])[NH:7][CH:8]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>C1COCC1.C(OCC)(=O)C>[Br:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:9]=[O:10])[N:7]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(Br)c[nH]c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c(C)c2C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Following a general procedure,50 a stirred suspension of 60% NaH (2.5 g, 62 mmol) in dry THF (42 mL, distilled) was cooled to 0° C. under argon. The mixture was treated portionwise with 3 (7.78 g, 41.4 mmol). The mixture was stirred for 30 min at 0° C. before treating all at once with p-toluenesulfonyl chloride (8.00 g, 41.4 mmol). The reaction mixture was stirred at room temperature for 3 h, whereupon water (100 mL) was slowly added to quench the reaction. Ethyl acetate (100 mL) was added, and the organic layer was separated. The organic layer was washed with brine, dried (Na2SO4), and concentrated to a solid. The solid was dried under high vacuum for 2 h. The crude solid material was dissolved in 100 mL hexanes/ethyl acetate (5:1) by refluxing in a hot water bath. Upon allowing the solution to cool to room temperature the product crystallized. The mixture was cooled overnight at −10° C. to promote additional crystallization. The mixture was vacuum-filtered, and the resulting light brown crystals were dried under high vacuum (9.73 g, 69%): mp 152-155° C.; 1H NMR δ 2.29 (s, 3H), 2.43 (s, 3H), 7.34 (d, J=8.5 Hz, 2H), 7.55 (s, 1H), 7.76 (d, J=8.5 Hz, 2H), 10.14 (s, 1H); 13C NMR δ 2.1, 22.0, 106.2, 126.8, 127.6, 129.1, 130.6, 135.2, 136.4, 146.5, 180.1; Anal. Calcd for C13H12BrNO3S: C, 45.63; H, 3.53; N, 4.09. Found: C, 45.71; H, 3.44; N, 4.11.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=4)[N:23]=3)[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+].CN(C=O)C.IC>O>[CH3:31][N:11]([C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=3)[N:23]=2)[CH:15]=[CH:16][CH:17]=1)[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CC(=O)Nc1cn2nc(-c3cccc(N(C)S(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a round-bottomed flask was added N-(6-(3-(4-methylphenylsulfonamido)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (from Example 1, Step 5) (0.027 g, 0.064 mmol), potassium carbonate (0.013 g, 0.096 mmol), DMF (1.0 mL) and iodomethane (0.0044 mL, 0.071 mmol). The mixture was stirred at 25° C. for 14 h, then poured into water and extracted with EtOAc (3×30 mL). The combined extracts were washed with water (2×50 mL) and brine (50 mL) then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0 to 3% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a light-yellow solid. MS (ESI positive ion) m/z: 436 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.92 (s, 1H), 8.27 (s, 1H), 8.07 (d, J=9.6 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.75 (t, J=1.9 Hz, 1H), 7.70 (d, J=9.6 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.39-7.47 (m, 4H), 7.23 (dd, J=8.0 Hz, 1.4 Hz, 1H), 3.20 (s, 3H), 2.41 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [CH:1]([C:4]([CH3:22])([N:7]1[C:19](=[O:20])[C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]=2)[C:8]1=[O:21])[C:5]#[N:6])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:24]>>[CH:1]([C:4]([CH3:22])([N:7]1[C:19](=[O:20])[C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]=2)[C:8]1=[O:21])[C:5]([NH2:6])=[O:24])([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C#N)N1C(=O)c2cc3ccccc3nc2C1=O
Reactant: O=S(=O)(O)O
Product: CC(C)C(C)(C(N)=O)N1C(=O)c2cc3ccccc3nc2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1,3-Dihydro-α-isopropyl-α-methyl-1,3-dioxo-2-H-pyrrolo[3,4-b]quinoline-2-acetonitrile (0.44 g, 0.0015 mol) is dissolved in conc. sulfuric acid (5 ml) at room temperature and stirred overnight. The reaction mixture is poured onto crushed ice (50 ml) and a white precipitate forms and is filtered off, washed with water, aqueous sodium bicarbonate and water and then vacuum dried. This gives 0.34 g (74%) of product, mp 237°-239° C. (dec.). Anal. calcd. for C17H17N3O3 : C, 65.58; H, 5.50; N, 13.50. Found: C, 65.03; H, 5.63; N, 13.19.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]([NH:15][NH2:16])=[O:14].C(N(CC)CC)C.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]1[O:14][C:24](=[O:25])[NH:16][N:15]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: NNC(=O)C=Cc1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(C=Cc2ccc3ccccc3c2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 3-naphthalen-2-yl-acrylic acid hydrazide (1.0 g, 4.71 mmol, prepared as described in example 5) and triethylamine (0.64 g, 6.28 mmol) in dry tetrahydrofuran (15 ml) was added carbonyl diimidazole (1.02 g, 6.28 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The resulting reaction mixture was evaporated in vacuo and to the residue was added water (25 ml). The precipitate was filtered off and washed with water (2×10 ml) and diethyl ether (2×10 ml) and recrystallised from ethyl acetate (100 ml) affording after drying in vacuo at 50° C. 0.5 g (45%) of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[F:12].C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27]>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[O:27][C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19].[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:27][C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[F:19])=[CH:4][C:3]=1[F:12]
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1F
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Br)c(F)cc1Oc1ccc(F)cc1F
Product: O=[N+]([O-])c1cc(Br)c(Oc2ccc(F)cc2F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-bromo-2,4-difluoro-5-nitrobenzene (0.5 g, 2.10 mmol) and cesium carbonate (0.685 g, 2.10 mmol) in DMSO (10.50 mL) was treated dropwise with 2,4-difluorophenol (0.273 g, 2.10 mmol), stirred for 60 minutes at ambient temperature and partitioned between ethyl acetate and water, adjusting the pH to 6 with 1 M HCl. The organic layer was washed with water, saturated aqueous sodium chloride, dried (MgSO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-30% ethyl acetate in heptanes) afforded the title compound and 1-bromo-4-(2,4-difluorophenoxy)-2-fluoro-5-nitrobenzene as an inseparable mixture (0.59 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH:19]([C:21]1[NH:22][C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=2[C:29]=1[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=O>N1CCCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[CH:19][C:21]3[NH:22][C:23]4[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=4[C:29]=3[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reaction time: 4 h
Yield: 35.3 %

Procedure:
A mixture of 103 mg of 6-(2-methoxyphenyl)-2-oxindole, 95 mg of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid and piperidine (3 drops) in ethanol (2 mL) was held in a sealed tube at 90° C. for 4 hrs. The reaction mixture was concentrated and acidified with 6 N hydrochloric acid. The precipitate was collected by filtration and washed with water and hexane to give 67 mg of 3-{2-[6-(2-methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-4,5,6,7-tetrahydro-1H-indol-3yl}-propionic acid as a brown solid (35% yield).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[N:23][C:22]([C:25](O)=[O:26])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.[NH2:40][C:41]1[N:46]([CH2:47][CH2:48][CH2:49][CH3:50])[C:45](=[O:51])[N:44]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[F:59])[C:43](=[O:60])[C:42]=1[NH:61][C:62](=[O:71])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][CH:65]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:40][C:41]1[N:46]([CH2:47][CH2:48][CH2:49][CH3:50])[C:45](=[O:51])[N:44]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[F:59])[C:43](=[O:60])[C:42]=1[NH:61][C:62]([CH2:63][C:64]1[CH:65]=[CH:66][C:67]([NH:70][C:25]([C:22]2[N:23]=[CH:24][N:20]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:21]=2)=[O:26])=[CH:68][CH:69]=1)=[O:71]
Reactant: CCCCn1c(N)c(NC(=O)Cc2ccc(N)cc2)c(=O)n(Cc2ccccc2F)c1=O
Reactant: O=C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCn1c(N)c(NC(=O)Cc2ccc(NC(=O)c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(=O)n(Cc2ccccc2F)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
A solution of 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid (51 mg, 0.65 mmol) in N,N-dimethylformamide (0.8 mL) at 25° C. was treated with 1-hydroxybenzotriazole hydrate (19.3 mg, 0.14 mmol) and O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophosphate (54 mg, 0.14 mmol). The resulting mixture was cooled to 0° C. and then treated with the hydrochloric acid salt of N-[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-(4-amino-phenyl)-acetamide (62 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.65 mmol). The reaction was stirred at 0° C. for 1 h and then at 25° C. for 4.5 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×15 mL) and a saturated aqueous sodium chloride solution (1×20 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–00 mesh, 93:7 dichloromethane/methanol) afforded 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid (4-{[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-amide (67.9 mg, 68%) as a pale yellow solid: FAB-HRMS m/e calcd for C45H41N8O4F (M+Na)+ 799.3133, found 799.3113.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5]2.C([Li])CCC.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([Cl:35])=[C:31]([CH:34]=1)[CH:32]=[O:33]>C1COCC1>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([Cl:35])=[C:31]([CH:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH2:5]3)[OH:33])[CH:34]=1
Reactant: COc1ccc(CN2CCCc3cc(Br)ccc32)cc1
Reactant: O=Cc1cc(Br)ccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCc3cc(C(O)c4cc(Br)ccc4Cl)ccc32)cc1
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a cooled solution of 6-bromo-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinoline (2.5 g, 7.5 mmol) in THF (30 mL) was added 1.6 M n-butyl lithium in hexanes (4.7 mL, 7.5 mmol) at −78° C., stirred for 30 min. This was transferred to a stirred solution of 5-bromo-2-chlorobenzaldehyde (1.73 g, 7.9 mmol) in THF (30 mL) at −78° C. After stirring for 30 min, reaction was quenched by the addition of saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (2×50 mL). The ethyl acetate layer was washed with water, brine, dried over sodium sulphate, and concentrated. The resulting residue was purified by silica gel column chromatography to give (5-bromo-2-chloro-phenyl)-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-methanol (2.31 g).
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][C@@H:13]([C@H:15]([C:18]1[O:19][CH:20]=[C:21]([C:23]([OH:25])=O)[N:22]=1)[CH2:16][CH3:17])[CH3:14])=[O:11])([CH3:8])([CH3:7])[CH3:6].C1C=CC2N(O)N=[N:32]C=2C=1>ClCCl>[C:5]([O:9][C:10](=[O:11])[NH:12][C@@H:13]([C@H:15]([C:18]1[O:19][CH:20]=[C:21]([C:23](=[O:25])[NH2:32])[N:22]=1)[CH2:16][CH3:17])[CH3:14])([CH3:6])([CH3:7])[CH3:8]
Reactant: On1nnc2ccccc21
Reactant: CC[C@@H](c1nc(C(=O)O)co1)[C@@H](C)NC(=O)OC(C)(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC[C@@H](c1nc(C(N)=O)co1)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
1N aqueous sodium hydroxide (5.69 ml, 5.69 mmol) was added in one portion to a solution of methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylate (100 mg, 0.32 mmol) in anhydrous THF (1.11 ml). The reaction mixture was allowed to stir at room temperature for 3.5 hours before evaporating the organic in vacuo. The remaining aqueous portion was cooled to 0° C. and acidified to pH 4 using 1N HCl. The aqueous phase was then extracted with ethyl acetate (3×3 mL). The aqueous pH was re-checked and judged to be ˜pH 6-7. A small amount of 1N HCl was added to re-acidify the aqueous layer which was once again extracted with an additional portion of ethyl acetate (1×3 mL). The combined organics were dried (MgSO4) and evaporated in vacuo to give crude 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylic acid (95 mg, 0.32 mmol, 100% yield) as a white solid which was used immediately in the next reaction. EDC (86 mg, 0.45 mmol) was added in one portion to a mixture of 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylic acid (95 mg, 0.32 mmol) and HOBT (69 mg, 0.45 mmol) in anhydrous dichloromethane (5.0 ml) and the reaction allowed to stir at room temperature under a nitrogen atmosphere for 30 minutes. Ammonia was then bubbled through for approximately 5 minutes and the resulting white suspension allowed to stir at room temperature overnight. The reaction was then evaporated in vacuo and the residue partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was then dried (MgSO4) and evaporated in vacuo to give tert-butyl((2R,3R)-3-(4-carbamoyloxazol-2-yl)pentan-2-yl)carbamate (95 mg, 0.32 mmol, 100% yield) which was used immediately in the next step. LC/MS: M+H+436.11, ret. time=1.89 min. Column: Phenomenex, 2.0×30 mm, 2.5-μm particles; Mobile Phase A: 10:90 methanol:water with 0.05% TFA; Mobile Phase B: 90:10 methanol:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min. HPLC: ret. time=2.73 min. Column: YMC CombiScreen ODS-A, 4.6×50 mm; Mobile Phase A: 10:90 methanol:water with 0.2% H3PO4; Mobile Phase B: 90:10 methanol:water with 0.2% H3PO4; Temperature: 50° C.; Gradient: 0-100% B over 4 minutes, then a 0.75-minute hold at 100% B; Flow: 4 mL/min.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7](C(O)=O)[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:14][CH:15]=1
Reactant: O=C(O)C(Cc1ccc(F)cc1)C(=O)O
Solvent: CCOCC
Product: O=C(O)CCc1ccc(F)cc1

Procedure:
The 4-fluorobenzylmalonic acid is heated to 170° to 175° C. for 1.5 hours. After cooling, the reaction product is stirred with a little diethyl ether. 41.6 of 3-(4-fluorophenyl)propionic acid of m.p. 85° to 88° C. [from ethyl acetate/petroleum ether (1:4)] thereby crystallize out.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][CH:36]([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]2)=[N:31][CH:32]=1)#[N:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:39]([CH:36]3[CH2:35][CH2:34][N:33]([C:30]4[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][N:31]=4)[CH2:38][CH2:37]3)=[O:40])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:39]([CH:36]3[CH2:35][CH2:34][N:33]([C:30]4[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][N:31]=4)[CH2:38][CH2:37]3)=[O:41])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(F)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(F)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(F)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-[(3R,4S)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a brown semisolid. MS m/e: 562.1 [M]+. The racemate was then subjected to column chromatography on chiral phase to yield -[(3S,4R)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (MS (m/e): 546.3 [M+H]+) as a yellow waxy solid and -[(3R,4S)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (MS (m/e): 546.3 [M+H]+) as a yellow waxy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][NH2:13].[N:14]1([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:6])[N:13]([CH3:12])[C:27]([C:26]1[CH:29]=[CH:30][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:24][CH:25]=1)=[N:1]2
Reactant: CN
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: O=Cc1ccc(OCCCN2CCCC2)cc1
Product: Cn1c(-c2ccc(OCCCN3CCCC3)cc2)nc2cccc(F)c2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-6-fluorobenzoic acid, methylamine and 4-(3-pyrrolidin-1-ylpropoxy)benzaldehyde.