Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:3]1=O.[BH4-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2
Reactant: Cc1cc(C)c2c(c1)CC(C)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=Cc2c(C)cc(C)cc2C1
Yield: 95.6 %

Procedure:
20.4 g (117 mmol) of 2,5,7-trimethyl-l-indanone (1) were dissolved in 300 ml of a mixture of tetrahydrofuran/methanol (2:1), and 6.6 g (175 mmol) of NaBH4 were added at room temperature. The mixture was stirred for a further hour, 50 ml of half-concentrated HC1 were added and the mixture was extracted with ether. The combined organic phases were dried over sodium sulfate and freed from the solvent. The residue was transferred to a distillation apparatus, and 13 g of magnesium sulfate were added. A vacuum of about 10mbar was applied and the mixture was heated up until the product distilled over (130°-150° C). The distillation gave 17.7 g of the indene as a colorless oil. The yield was 96%. Mass spectrum: 158 M+, correct disintegration pattern.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[C:5]([NH:21][CH2:22][CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[N:4]=1.[CH:38]([N:41]([CH:52]([CH3:54])[CH3:53])[CH2:42][CH2:43][NH:44][C:45](N1C=CN=C1)=[O:46])([CH3:40])[CH3:39]>>[Cl:30][C:26]1[CH:25]=[C:24]([CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[CH2:22][NH:21][C:5]2[N:4]=[C:3]([CH2:2][NH:1][C:45]([NH:44][CH2:43][CH2:42][N:41]([CH:52]([CH3:54])[CH3:53])[CH:38]([CH3:39])[CH3:40])=[O:46])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Reactant: NCc1nc(NCC(c2cccc(Cl)c2)c2cccc(Cl)c2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Product: CC(C)N(CCNC(=O)NCc1nc(NCC(c2cccc(Cl)c2)c2cccc(Cl)c2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)C(C)C

Procedure:
The title compound was prepared from (2R,3R,4S,5R)-2-(2-(aminomethyl)-6-{[2,2-bis(3-chlorophenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol (Preparation 62) and N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 27) in a similar procedure to that used in Example 36.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].[CH3:19][O:20][C:21]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1)=[O:22]>CN(C=O)C>[CH3:19][O:20][C:21]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][NH:30][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:25][CH2:24]1)=[O:22]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(NC[C@H]2CC[C@H](C(=O)OC)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
K2CO3 (9.04 g, 65.5 mmol) was added to a solution of 2-Fluoro-4-methoxy-1-nitro-benzene (5.6 g, 32.7 mmol) in DMF (20 ml). The mixture was stirred at room temperature for 30 minutes and then trans-4-Aminomethyl-cyclohexanecarboxylic acid methyl ester (5.60 g, 32.7 mmol) was added. The reaction mixture was heated for 2 hours at 50° C. and then at room temperature overnight. The solvent was removed under reduced pressure and the crude product dissolved in DCM (150 ml) and washed with water (2×150 ml) and then with a solution of citric acid (2×150 ml). The organic solution was dried over Na2SO4, filtered and the solvent removed by evaporation to give 9.6 g of the titled compound.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Br:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>ClCCl.O>[Br:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:32][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: Oc1ccc(F)cc1Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(OC2CCCCO2)c(Br)c1
Reaction time: 24 h

Procedure:
A mixture of 478.0 ml (5.24 mol) of 3,4-dihydropyran and 750 ml of dichloromethane was admixed with 65.4 g (260 mmol) of pyridinium p-toluenesulfonate. Subsequently, a solution of 500.0 g (2.62 mmol) of 2-bromo-4-fluorophenol in 500 ml of dichloromethane was added dropwise. After stirring for 24 h, the reaction mixture was admixed with a solution of 50 g of potassium carbonate in 500 ml of water, and then with 500 ml of saturated sodium chloride solution. The organic phase was removed, dried over potassium carbonate and, after freeing it of the solvent and potassium carbonate, fractionally distilled (approx. 1 mbar, top temperature from 79 to 82° C.) by means of a Vigreux column (40 cm). The product was obtained as a colorless, low-viscosity oil. The yield was 520.5 g (72.2%) at a purity of greater than 98.0% by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1.CC(=CC)C.Cl([O-])=[O:31].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:31])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3cnc(N4CCOCC4)nc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3cnc(N4CCOCC4)nc3)cc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
6-chloro-5-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-indole-3-carbaldehyde (159 mg, 0.464 mmol) was dissolved in acetonitrile (6 mL) and warm tert-butanol (6 mL) and treated with 2-methyl-2-butene. The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (630 mg, 9.27 mmol) and sodium phosphate monobasic dihydrate (1.45 g, 9.30 mmol) in water (5 mL) via addition funnel. The mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo to remove the organics and extracted with EtOAc (3×20 mL). The combined organics were washed with brine (20 mL), dried and concentrated in vacuo to give a crude, which was purified by prep-HPLC to give 6-chloro-5-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-indole-3-carboxylic acid (67.6 mg, 40.60% yield) as a white solid. MS (ES+) 359.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1 H), 12.03 (s, 1 H), 8.49 (m, 2 H), 8.12 (m, 1 H), 7.97 (s, 1 H), 7.69 (s, 1 H), 3.78 (m, 4 H), 3.70 (m, 4 H).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[C:14]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[CH2:19][CH2:18]1)(=[O:16])[CH3:15]>ClCCl.[Cl-].[NH4+]>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[CH2:19][CH2:18]2)([OH:16])[CH3:15])=[N:8][CH:9]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: ClCCl
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2ccc(Cl)cn2)CC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Tert-butyllithium (1.6 M in hexane, 3.3 mL, 5.28 mmol) was added dropwise over a period of 1 minute to a solution of 2-bromo-5-chloropyridine (0.8 g, 4.16 mmol) in dichloromethane (21 mL) at −78° C. The mixture was stirred for 90 minutes at −78° C., then a solution of trans-butyl 4-acetylcyclohexanecarboxylate (1.035 g, 4.57 mmol) in dichloromethane (1 mL) was added. The reaction was then allowed to warm to 23° C. over a period of 16 hours and subsequently diluted with saturated aqueous ammonium chloride solution. The resulting slurry was extracted with dichloromethane (3×70 mL), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (EtOAc/hexanes) afforded racemic trans-butyl 4-(1-(5-chloropyridin-2-yl)-1-hydroxyethyl)cyclohexanecarboxylate as a brown oil. MS ESI calcd. for C18H27ClNO3 [M+H]+ 340. found 340. 1H NMR (500 MHz, CDCl3) δ 8.47 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 4.68 (s, 1H), 4.03 (t, J=6.6 Hz, 2H), 2.22-1.85 (m, 4H), 1.66-1.53 (m, 4H), 1.48 (s, 3H), 1.42-1.05 (m, 6H), 0.91 (t, J=7.5 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:13])([F:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)C.[BH4-].[Na+]>C(O)C>[F:13][C:5]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(F)(F)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(F)(F)c1ccccn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
To the solution of difluoro-pyridin-2-yl-acetic acid ethyl ester (example 59a, 10 g, 50 mmol) in ethanol (100 mL) was added sodium borohydride (2 g, 52.5 mmol) in 5 portions at 0° C. After stirring at 0° C. for 1 h and room temperature for 1.5 h, the reaction was quenched by slow addition of hydrochloric acid (2 N) at 0° C. The pH was adjusted to 8.5 with 4N NaOH. The product was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The product was crystallized with heptane afforded 2,2-difluoro-2-pyridin-2-yl-ethanol (6.7 g, 84%) as a white solid.
Reaction SMILES: ClC1C(Cl)=C(Cl)C(Cl)=C2C=1C(=O)[N:5]([CH2:15][CH2:16][C:17]1([OH:33])[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH2:19][CH2:18]1)C2=O.C(N)CN>C(#N)C.O1CCCC1.O.C(O)C>[NH2:5][CH2:15][CH2:16][C:17]1([OH:33])[CH2:18][CH2:19][N:20]([C:23]2[N:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][N:24]=2)[CH2:21][CH2:22]1
Reactant: O=C1c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)N1CCC1(O)CCN(c2nccc(C(F)(F)F)n2)CC1
Solvent: O
Solvent: CCO
Solvent: NCCN
Product: NCCC1(O)CCN(c2nccc(C(F)(F)F)n2)CC1
Yield: 76 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.4.). Starting with 0.38 g (0.68 mmol) of 4,5,6,7-tetrachloro-2-{2-[4-hydroxy-1-(4-trifluoromethylpyrimidin-2-yl)piperidin-4-yl]ethyl}isoindole-1,3-dione), obtained in the preceding step, dissolved in an acetonitrile/tetrahydrofuran/water mixture (2/1/1) and 0.18 g (3.06 mmol) of ethylenediamine in 4.50 mL of ethanol, and after chromatography on silica gel, eluting with a 90/10/1 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.15 g of expected product is obtained in the form of a wax.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:9][C:8]=2[C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CI.[C:40](OCC)(=O)C>CN(C=O)C>[CH:1]1([O:6][C:7]2[C:8]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:9][C:10]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:11][C:12]=2[N:13]([CH3:40])[C:14](=[O:19])[C:15]([F:17])([F:16])[F:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: COC(=O)CCc1cc(NC(=O)C(F)(F)F)c(OC2CCCC2)c(-c2ccc3ccccc3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCc1cc(-c2ccc3ccccc3c2)c(OC2CCCC2)c(N(C)C(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of Intermediate 54 (208 mg) in DMF (5 ml) was added with 60% sodium hydride (21 mg) under ice cooling, and stirred for 20 minutes. This reaction mixture was added dropwise with methyl iodide (150 μl), stirred for 10 minutes, then warmed to room temperature, and further stirred for 1 hour. The reaction mixture was poured into ice water, and ethyl acetate (100 ml) was added for extraction. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate 5:1) to obtain the title compound (Intermediate 55, 200 mg).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H][H]>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C

Procedure:
2.79 Grams of Z-Leu-Gln-NHNHBoc was suspended in 80 ml of methanol, a small amount of palladium black was added to this suspension and the suspension was stirred for 32 hours under the condition of introducing hydrogen gas. After completion of the reaction, the catalyst was removed by suction filtration, the filtrate was subjected to distillation under a reduced pressure, the residue obtained was dried under a reduced pressure in a desiccator to obtain the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH:15]([OH:22])[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:3]=1>N1C=CC=CC=1.CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:22])[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(O)c1cccnc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.4 %

Procedure:
N-[4-chloro-2-(hydroxy-pyridin-3-yl-methyl)-phenyl]-2,2-dimethyl-propionamide (1.0 g, 3.14 mmol) was dissolved in 5 mL pyridine and treated with CrO3 (0.75 g, 7.5 mmol, 2.39 eq). The mixture was stirred under N2 at room temperature for five hours, diluted with 20 mL 1:2 EtOAc/H2O, and filtered through Celite. The aqueous phase was separated and discarded, then the organics dried under vacuum yielding product (680 mg, 70%). 1H NMR (CDCl3) δ 11.06 (s, 1H) 8.92 (d, J=2.4 Hz, 1H) 8.84 (d, J=8.0 Hz, 1H) 8.73 (d, J=9.2 Hz, 1H) 8.00 (d, J=8.0 Hz, 1H) 7.56 (dd, J=11.2 Hz, 2.0 Hz, 1H) 7.48 (m, 2H) 1.36 (s, 9H) MS (ES) m/z=317.1 (MH)+
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5](=O)[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([F:15])[CH:7]=1.C(OCC)C.Cl>O>[F:15][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=1)[CH2:5][OH:4]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc(CO)c1
Yield: 82.3 %

Procedure:
A solution of lithium borohydride (2M in THF, 7.3 ml) was added slowly to a mixture of methyl-3-fluoro-5-nitrobenzoate (JCS Chem. Comm., 1993, 921-922; 2.9 g) and diethyl ether (60 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. Water and a 2N aqueous hydrochloric acid solution were added in turn and the mixture was extracted with diethyl ether. The organic solution was evaporated and the residue was purified by column chromatography on silica using methylene chloride as eluent. There was thus obtained an oil which crystallised on standing to give 3-fluoro-5-nitrobenzyl alcohol (2.05 g); 1H NMR: (DMSOd6) 4.64 (s, 2H), 5.65 (s, 1H), 7.64 (m, 1H), 7.96 (m, 1H), 8.06 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.CC([O-])(C)C.[K+].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1>O1CCOCC1>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[N:14]=1
Reactant: c1cn[nH]c1
Reactant: Brc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Brc1cccc(-n2cccn2)n1
Yield: 89.7 %

Procedure:
To a solution of 1H-Pyrazole (10.0 mmol, 680 mg) in distilled dioxane (30 mL) were added KOtBu (11.0 mmol, 1.26 g), and followed by addition of 2,6-dibromopyridine (10.0 mmol, 2.37 g). The reaction mixture was refluxed for 48 hour, and then quenched with 5 mL of water. Solvent was removed under reduced pressure and water was added to the residue, then the mixture was extracted with DCM. The combined organic layers were washed with brine and dried over MgSO4. After solvent evaporation, the crude product was purified by column chromatography on silica gel (Hexanes:ethyl acetate=20:1 as eluent) to afford a white solid (2.01 g, 90%). 1H NMR (400 MHz, CDCl3, ppm): 8.53 (s, 1H), 7.92 (d, 1H, J=7.6 Hz), 7.73 (s, 1H), 7.67 (t, 1H, J=7.8 Hz), 7.35 (d, 1H, 7.6 Hz), 6.46 (s, 1H). 13C NMR (100 MHz, CDCl3, ppm): 162.72, 140.73, 139.91, 127.58, 125.25, 110.89, 108.23.
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([OH:9])=O)=[O:4].CN1CCOCC1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>C1COCC1.CCOC(C)=O>[N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])=[O:9])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)O
Reactant: NCCCO
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)NCCCO
Temperature: 25 °C

Procedure:
To a cold (−15° C.) solution of Boc-Pro-Gly-OH (610 mg, 2.24 mmol) and NMM (369 μl, 3.36 mmol) in THF (8 mL) was added ECF (2201 μl, 2.3 mmol) and stirred vigorously. After 2 min. a solution of 1-amino-3-propyl alcohol (220 mg, 2.68 mmol) in THF (2 mL) was added to it followed by NMM (505 mg, 5 mmol) and stirred for further 30 minutes. The mixture was warmed to r.t. and stirred for 8 h. The solvent was removed under reduced pressure to give a residue which was diluted with EtOAc and washed with saturated citric acid, saturated NaHCO3 and the organic layer was dried over Na2SO4 and concentrated under vacuum to give a residue, which was purified by silica gel flash column chromatography (EtOAc:MeOH—50:1) to give the desired product as a thick oil in good yields (633 mg, 80%). TLC (MeOH:DCM—1:4; Rf—0.5).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C@H:4](/[CH:7]=[CH:8]/[CH2:9][C:10]([CH3:23])([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C@H:3]1[CH2:24][CH2:25][S:26][C:27]1[S:28][CH:29]=[C:30]([C:32]([OH:34])=[O:33])[N:31]=1.[I-].[CH4:36]>>[OH:1][C@H:2]1[CH2:6][CH2:5][C@H:4](/[CH:7]=[CH:8]/[CH2:9][C:10]([CH3:23])([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C@H:3]1[CH2:24][CH2:25][S:26][C:27]1[S:28][CH:29]=[C:30]([C:32]([O:34][CH3:36])=[O:33])[N:31]=1
Reactant: CCCCCC(C)(C/C=C/[C@H]1CC[C@H](O)[C@@H]1CCSc1nc(C(=O)O)cs1)OC1CCCCO1
Reactant: C
Agent: [I-]
Product: CCCCCC(C)(C/C=C/[C@H]1CC[C@H](O)[C@@H]1CCSc1nc(C(=O)OC)cs1)OC1CCCCO1

Procedure:
By the same procedure as the reaction of Example 51 using the compound 55 instead of the compound 50 and using methane iodide instead of ethane iodide, the title compound having the following physical data was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11](=[O:35])[CH2:12][CH:13]1[CH:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:21]2[C:16](=[C:17]([F:34])[CH:18]=[CH:19][C:20]=2[F:33])[O:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](O)[CH2:37][OH:38].C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:12][CH:13]2[CH:22]([S:23]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)(=[O:25])=[O:24])[C:21]3[C:16](=[C:17]([F:34])[CH:18]=[CH:19][C:20]=3[F:33])[O:15][CH2:14]2)[O:38][CH2:37][CH2:36][O:35]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCOCc1ccccc1)CC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Reactant: OCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1CC1(CCOCc2ccccc2)OCCO1
Temperature: 25 °C

Procedure:
4-Benzyloxy-1-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-butan-2-one (10 g, 19.2 mmole), ethylene glycol (20 ml) and toluene sulfonic acid (1 g) were dissolved in 300 ml toluene. The reaction was refluxed for four hours with a Dean-Stark trap. The reaction was cooled to room temperature and 200 ml water and 200 ml EtOAc were added. The organic layer washed with brine (2×50 ml), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (EtOAc/hexane from 0/100 to 50/50 in 55 minute). Yield: 6.3 g, 58%. 1H NMR (CDCl3 400 MHz δ 7.74 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.20-7.39 (m, 5H), 7.02 (m, 1H), 6.42 (m, 1H), 4.89 (dd, J=11.0 and 2.9 Hz, 1H), 4.84 (s, 1H), 4.40 (d, J=2.0 Hz, 2H), 4.21 (d, J=11.7 Hz, 1H), 3.85 (m, 4H), 3.46 (t, J=5.9 Hz, 2H), 3.03 (d, J=8.1 Hz, 1H), 1.75-1.90 (m, 3H), 1.54-1.61 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[I-].[K+]>C1(N)CC1>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][NH:23][CH:24]5[CH2:26][CH2:25]5)=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Agent: NC1CC1
Agent: [I-]
Agent: [K+]
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC3CC3)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (37 mg) and potassium iodide (5 mg) were mixed in cyclopropylamine (3 ml) and the reaction stirred at room temperature for 18 hours. The excess amine was evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate/cyclohexane gradient. After evaporation of the solvent this gave N-cyclopropyl-4′-{5-[(cyclopropylamino)methyl]-1,3,4-oxadiazol-2-yl}-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH2:27][CH2:28][NH2:29])=[CH:23][NH:24]2)=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH2:27][CH2:28][NH:29][C:11]([C:8]3[CH:7]=[C:6]([CH2:5][C:4]4[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=4)[O:10][N:9]=3)=[O:13])=[CH:23][NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2cc(F)ccc12)c1cc(Cc2cccc(F)c2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A mixture of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g; 0.257 mmol), 2-(6-fluoro-1H-indol-3-yl)ethanamine (0.051 g; 0.284 mmol), HATU (0.108 g; 0.284 mmol) and N,N-diisopropylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.040 g (41%) of the title compound as a white solid.