Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([CH2:9][C:10](Cl)=[O:11])([CH3:8])([CH3:7])[CH3:6].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:5]([CH2:9][C:10]([C:16]1[CH:17]=[CH:18][C:13]([CH3:19])=[CH:14][CH:15]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CC(C)(C)C)cc1

Procedure:
27 g of aluminum chloride and 100 ml of toluene were mixed and 25 g of t-butylacetyl chloride was added dropwise to this under ice cooling, After reaction at room temperature for 2 hours, the reaction solution was poured on ice. This was extracted with hexane, and the organic phase was rinsed with water and an aqueous sodium bicarbonate solution, dried and condensed. The crude product was purified by distillation under reduced pressure (95-96° C./2 mmHg) to obtain 32 g of 4-t-butylacetyltoluene. 20 g of 4-t-butylacetyltoluene, 19 g of sodium iodide and 13 g of triethylamine were mixed with 100 ml of acetonitrile, and 13.7 g of chlorotrimethylsilane was gradually added thereto The mixture was reacted at 60° C. for 5 hours, and left alone to be cooled. The reaction solution was poured on ice, this was extracted with diisopropyl ether, and the organic phase was rinsed with an aqueous sodium bicarbonate solution, dried and condensed. This was purified by distillation under reduced pressure (95-98° C./2 mmHg) to obtain 32 g of silylenol ether of 4-t-butylacetyltoluene. Under nitrogen flow, 23.9 g of silylenol ether and 14.8 g of dibutylsulfoxide were dissolved in 100 ml of chloroform. The solution was cooled to −30° C. or less, and to the solution, 19.1 g of trifluoroacetic anhydride was added over 30 min. After reaction at room temperature for one hour, a solution in which 30.8 g of potassium nonafluorobutane sulfonate was dissolved in acetonitrile/water was added to the reaction solution. This was extracted with chloroform, the organic phase was rinsed with distilled water until aqueous phase is neutral. The organic phase was condensed, and the crude product obtained was rinsed with hexane and then with water to precipitate a powder. This was further rinsed with hexane and water by slurry rinsing to obtain 21 g of the compound (I-39).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:35]=[CH:34][C:14]3[N:15]([CH3:33])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1.[CH3:36][C:37]1([CH3:40])[CH2:39][O:38]1.CCN(C(C)C)C(C)C>CN(C=O)C.CO.C(Cl)Cl>[OH:38][C:37]([CH3:40])([CH3:39])[CH2:36][N:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:35]=[CH:34][C:14]3[N:15]([CH3:33])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:30])([F:31])[F:32])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1
Reactant: CC1(C)CO1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCNC3)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCN(CC(C)(C)O)C3)ccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-pyrrolidin-3-yl]-amide (16 mg) was prepared using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid pyrrolidin-3-ylamide dihydrochloride (47 mg), 2,2-dimethyl-oxirane (excess) and DIEA (70 uL) in DMF (1 mL). The reaction was stirred at 80° C. overnight. The pure product was isolated through silica gel chromatography using DCM: (10%) methanol in DCM (from 100:0 to 0:100) as eluent system. LC/MS: m/z 548.7.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[NH2:14][C@@:15]1([CH3:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.CCN(C(C)C)C(C)C.CCOC(C)=O>CS(C)=O>[Cl:11][C:6]1[N:5]=[C:4]([S:12][CH3:13])[N:3]=[C:2]([NH:14][C@@:15]2([CH3:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:7]=1[CH2:8][CH2:9][OH:10]
Reactant: CSc1nc(Cl)c(CCO)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@](C)(N)C1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)c(CCO)c(N[C@@]2(C)CCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 110 °C
Reaction time: 42 h
Yield: 65 %

Procedure:
To a solution of 2-[4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-yl]ethanol (1.25 g, 5.23 mmol) and tert-butyl(3S)-3-amino-3-methylpyrrolidine-1-carboxylate (1.57 g, 7.84 mmol) in DMSO (13 mL) was added DIEA (4.6 mL, 26.1 mmol) at room temperature. The reaction mixture was stirred at 110° C. for 42 h, whereupon the mixture was poured into EtOAc and washed with water. The water layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified via ISCO normal phase silica gel chromatography (80 g column) eluting with a 0-100% gradient of EtOAc/Heptane to give the title compound (1.37 g, 65%) as a light yellow-white foamy solid. 1H NMR (400 MHz, DMSO-d6) δ 6.96 (d, J=17.0 Hz, 1 H), 5.06 (br s, 1 H), 3.75 (dd, J=20.6, 11.2 Hz, 1 H), 3.54 (br s, 2 H), 3.50-3.33 (m, 3 H), 2.77 (t, J=6.3 Hz, 2 H), 2.44 (s, 3 H), 2.40-2.23 (m, 1 H), 2.03-1.93 (m, 1 H), 1.47 (d, J=11.1 Hz, 3 H), 1.38 (d, J=13.4 Hz, 9 H). m/z (APCI+) for C17H27ClN4O3S 403.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.[C:21]1([CH3:28])[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][CH:22]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>CCCCC.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:24]=[CH:25][C:26]([OH:27])=[C:21]([CH3:28])[CH:22]=2)[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(O)c2cccc3ccccc23)cc1
Reactant: Cc1ccccc1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCCCC
Product: COc1ccc(C(c2ccc(O)c(C)c2)c2cccc3ccccc23)cc1
Reaction time: 5.5 h

Procedure:
To a stirred solution of (4-methoxyphenyl)-naphth-1-yl carbinol of formula II (5.0 gm, 0.018 mol )and o-cresol (2.4 ml, 0.022 mol) in a mixture of anhydrous benzene, anhydrous pentane (50 ml, 1:1), and AlCl3 (2.5 gm) was gradually added, after addition stirring was continued for 5-6 hrs at 0-4° C. The reaction mixture was decomposed by adding crushed ice with conc. HCl (0.5 ml) and extracted with ethyl acetate. The organic layer was washed successively with water, dried over Na2SO4 and concentrated to give an oil, which was chromatographed over silica gel using benzene-hexane as the eluent to give the title compound of formula III, yield 4.5 gm (67.16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:40]=[CH:39][C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:40]=[CH:39][C:33]6[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=6[CH:31]=5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)ccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4ccc5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
99 mg (0.40 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.10 g (0.40 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3-methyl-3H-benzoxazol-2-one and 0.070 mL (0.40 mmol) DIPEA were combined in 2 mL DMF and shaken overnight at RT. The mixture was diluted with acetonitrile/water and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].CN(C)[CH:13]=[O:14].[NH4+].[Cl-]>O1CCCC1>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([CH:13]=[O:14])=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Br)c(F)cc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc(F)c(Br)cc1F
Temperature: -40 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To 1,4-dibromo-2,5-difluorobenzene (10.28 g, 37.81 mmol) in tetrahydrofuran (80 mL) at −40° C. was isopropylmagnesium chloride lithium chloride complex (29.1 mL, 37.81 mmol) added dropwise. After 1 h at −40° C. was N,N-dimethylformamide (58 mL, 756 mmol) added and the mixture was stirred for 30 minutes at −40° C. NH4Cl (2M, aq, 100 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was dried with MgSO4 and concentrated to give 4-bromo-2,5-difluorobenzaldehyde (6.20 g, 74%) as a solid.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[O:8]1)=[O:6])[CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:24][C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)NC(=O)C1OC1c1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NC(=O)C(O)C(Oc1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
This compound was prepared from N-(1-methylethyl)-3-(4-chlorophenyl)-2-oxiranecarboxamide (9.56 g.), p-chlorophenol (5.2 g.), sodium hydride (50% oil dispersion, 2.0 g.) 18-crown-6 (3.0 g.), and acetonitrile (300 ml.) as described in Example 12, and purified by recrystallization from ether. The compound melted at 177°-179°, and weighed 0.76 g.
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-:12])=[O:11])([CH3:9])[CH2:3][CH2:4][C:5](OC)=[O:6].[Cl-].[Li+].[BH4-].[Li+].Cl>C1COCC1.C(O)C.O>[CH3:1][C:2]([N+:10]([O-:12])=[O:11])([CH3:9])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: COC(=O)CCC(C)(C)[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(CCCO)[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
50 g (0.285 mol) methyl 4-methyl-4-nitro-pentanoate are dissolved in a 6:4 mixture of THF/ethanol (1000 mL). The solution is cooled to −10° C. and combined with 24.2 g (0.571 mol) lithium chloride. Then 21.6 g (0.571 mol) lithium borohydride are added batchwise. The mixture is stirred for 30 minutes at −10° C. and then heated overnight to ambient temperature. The reaction mixture is stirred for 6 hours at 60° C. and overnight at ambient temperature. It is combined with water and adjusted to pH 6 with dilute hydrochloric acid. The solvent is distilled off and the residue is combined with water. The mixture is extracted with dichloromethane, the combined organic phases are washed with water and ammonium chloride solution and dried with sodium sulphate. After elimination of the solvent the product is obtained as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([C:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=3)[C@@H:14]([CH3:31])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>CCO.C(Cl)Cl.[Pd]>[NH2:1][C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([C:24]([OH:30])([CH3:29])[C:25]([F:27])([F:28])[F:26])=[CH:20][N:19]=3)[C@@H:14]([CH3:31])[CH2:13]2)(=[O:10])=[O:11])=[CH:6][CH:5]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Product: C[C@H]1CN(S(=O)(=O)c2ccc(N)s2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Reaction time: 18 h
Yield: 22.7 %

Procedure:
In a 50-mL round bottomed flask, a mixture of 2-(2-((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (108 mg, 0.224 mmol), ammonium formate (30.1 mg, 0.478 mmol, Sigma-Aldrich, St. Louis, Mo.), and 10% Pd/C (25.4 mg, 0.024 mmol) in EtOH (10 mL) was stirred under an atmosphere of H2 (1 atm) for 18 h. Afterwards, the mixture was filtered through a plug of Celite and the filtrate was concentrated to give the crude product. The crude product was dissolved in CH2Cl2 and filtered through a plug of silica gel. The filtrate was concentrated to give 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (23 mg) as a mixture of two isomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][N:6]=[CH:5]2.[CH:13]1([NH:16][C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.ClCCl.[Pd+2].[Cl-].[Cl-].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=3[CH3:24])[C:17]([NH:16][CH:13]3[CH2:14][CH2:15]3)=[O:34])=[CH:11][CH:10]=2)[CH:5]=[N:6][N:7]=1
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (0.11 g, 0.5 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.1 g, 0.5 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) dichloromethane adduct (0.02 g, 0.02 mmol) in toluene (5 mL) was treated with 2 M aq. potassium carbonate (0.7 mL, 1 mmol). The mixture was stirred at 90° C. After about 15 hr, the mixture was cooled to RT and purified by flash chromatography (silica gel) eluting with 1/1 hexanes/ethyl acetate to 6% 2 M ammonia in MeOH/DCM to give the title compound as yellow solid. MS (ES+): 338 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]([C@@H:7]1[CH2:11][C:10](=[O:12])[CH2:9][C@@H:8]1[C:13]([O:15][CH3:16])=[O:14])=[O:6]>CO>[CH3:16][O:15][C:13]([CH:8]1[CH2:9][CH:10]([OH:12])[CH2:11][CH:7]1[C:5]([O:4][CH3:3])=[O:6])=[O:14]
Reactant: COC(=O)[C@H]1CC(=O)C[C@H]1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CC(O)CC1C(=O)OC
Yield: 75.6 %

Procedure:
Sodium borohydride (1.11 g, 0.029 mol) was added to a stirred solution of (1R,2S)-4-oxo-cyclopentane1,2-dicarboxylic acid dimethyl ester (4.88 g, 0.0244 mol) in methanol (300 mL) at 0° C. After 1 h the reaction was quenched with 90 ml brine, concentrated and extracted with ethyl acetate. The organic phases were pooled, dried, filtered and concentrated. The crude product was purified by flash column chromatography (toluene/ethyl acetate 1:1) which gave the title compound (3.73 g, 76%) as a yellow oil.
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[CH2:11][CH2:12][CH:13]=O.[Cl-].[CH2:16]([O:23][C:24]1[CH:49]=[CH:48][CH:47]=[CH:46][C:25]=1[CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH:13]=[CH:26][C:25]1[CH:46]=[CH:47][CH:48]=[CH:49][C:24]=1[O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CCCc1ccc2ccccc2c1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C(=Cc1ccccc1OCc1ccccc1)CCc1ccc2ccccc2c1
Yield: 82.7 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, 1.73 g of 3-(2-naphthyl)propanal prepared as described above, 4.65 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 2.15 g of 1,8 -diazabicyclo[5,4,0]undec-7-ene were reacted in 200 ml of acetonitrile. The reaction mixture was worked up and purified as described in the first part of Preparation 3, to obtain 2.83 g (yield 82%) of 4-(2-naphthyl)-1-(2-benzyloxyphenyl)-1-butene as a colorless oil.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]2[CH2:36][CH2:37][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:39][CH:40]=2)([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[CH2:41]([N:38]1[CH2:37][CH:36]=[C:35]([C:32]([CH3:34])([CH3:33])[CH2:31][CH:10]2[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[F:20])[C:11]2([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])[C:21]#[N:22])[CH2:40][CH2:39]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC(C)(C)C2=CCN(Cc3ccccc3)CC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1=CCN(Cc2ccccc2)CC1
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 127b (1.5 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (1.6 g, 98%).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)OC(=O)[CH:6]=[CH:5]2.[O:13]1C2C(=CC=CC=2)C=CC1=O>>[OH:13][C:11]1[CH:2]=[CH:3][C:4]([CH:5]=[CH2:6])=[CH:9][CH:10]=1
Reactant: O=c1ccc2cc(O)ccc2o1
Reactant: O=c1ccc2ccccc2o1
Product: C=Cc1ccc(O)cc1

Procedure:
6-hydroxycoumarin:coumarin=0.23:0.52:0.15:0.10
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][N:33]2C(OC(C)(C)C)=O)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][C:25]([NH:27][CH3:28])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][C:25]([NH:27][CH3:28])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CNC(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-{N-[(1R)-1[(4-chlorophenyl)methyl]-2-(4-{2-[(methylamino)carbonylamino]phenyl}piperidyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step a) (397 mg, 0.59 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (266 mg). MS (ESI, pos. ion) m/z: 574 (M+1); (ESI, neg. ion) in/z: 572 (M−1). Calc'd for C32H36ClN5O3: 573.25. Anal. Calcd for C32H36ClN5O3.1.8C2HF3O2: C, 54.86; H. 4.89; N, 8.99. Found: C, 55.11; H, 5.04; N, 9.11.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]([CH3:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=1)=[O:4].[OH-].[Na+]>CO.O>[CH3:10][N:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=[C:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1nc2ccccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(C(=O)O)nc2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 1-methyl-1H-benzoimidazole-2-carboxylic acid methyl ester (81) (190 mg, 1.0 mmol) and NaOH (80 mg, 2.0 mmol) in MeOH/H2O (1:1, 20 mL) was stirred at 50° C. for 1 h. The mixture was concentrated, then diluted with water (15 mL), adjusted pH=2 with concentrated HCl. Then the precipitate was formed and filtered, washed with water and dried to give 1-methyl-1H-benzoimidazole-2-carboxylic acid (82) (176 mg, 1.0 mmol, yield 100%)
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[Br:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.CN(C)C=O.Cl>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:6]#[N:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1ccc(-n2cccc2)c(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cccc2C#N)c(Br)c1
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
Chlorosulfonyl isocyanate (1.2 ml) in methylene chloride (12 ml) was added dropwise to a stirred solution of 1-(2-bromo-4-methylphenyl)pyrrole (2.5 g) in methylene chloride (25 ml) kept about -20° C. under nitrogen atmosphere. The reaction mixture was stirred at -20° C. for 30 minutes and at room temperature for 1.5 hours, and then was added dropwise dimethylformamide (1.7 ml) keeping at about -20° C. The reaction mixture was stirred at -20° C. for 30 minutes and at room temperature for an hour. To the reaction mixture was added 4N-hydrochloric acid at 0° C., and stirred at 0° C. for 30 minutes. The organic layer was washed with water and saturated sodium hydrogencarbonate solution, and dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography with a mixture of ethyl acetate and n-hexane (1:10) as eluent to give 1-(2-bromo-4-methylphenyl)pyrrole-2-carbonitrile (2.4 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1>>[Cl:19][C:18]1[C:13]([O:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[N:14][CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: Oc1ccc2ncccc2c1
Product: O=[N+]([O-])c1cnc(Oc2ccc3ncccc3c2)c(Cl)c1

Procedure:
Quinolin-6-ol was reacted with 2,3-dichloro-5-nitro pyridine to obtain 6-(3-chloro-5-nitropyridin-2-yloxy)quinoline which was further converted to 5-chloro-6-(quinolin-6-yloxy)pyridin-3-amine as per the procedure described in preparation 1 step iii and iv.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19](OC)=[O:20])[CH:13]=[CH:14][CH:15]=1)#[N:10].O>CN(C)C=O>[C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([N:7]=[C:6]([NH2:8])[NH2:5])=[O:20])[CH:13]=[CH:14][CH:15]=1)#[N:10]
Reactant: N=C(N)N
Reactant: COC(=O)c1cccc(-n2cccc2C#N)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccn1-c1cccc(C(=O)N=C(N)N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
28% Methanolic sodium methoxide (122.2 ml) was added to a solution of guanidine hydrochloride (63.7 g) in dry N,N-dimethylformamide (300 ml) and the mixture was stirred for 20 minutes at ambient temperature. To the mixture was added methyl 3-(2-cyanopyrrol-1-yl)benzoate (30.5 g), and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water under stirring. The isolated precipitate was collected by filtration to give 2-[3-(2-cyanopyrrol-1-yl)benzoyl]guanidine (21.66 g).