Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Br[CH:28]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:35][CH:34]=1)[C:29]([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][C:29]([CH3:31])([CH3:32])[CH:28]([C:33]1[CH:34]=[CH:35][C:36]([CH2:39][CH:40]([CH3:41])[CH3:42])=[CH:37][CH:38]=1)[O:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CC(C)Cc1ccc(C(Br)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(c3ccc(CC(C)C)cc3)C(C)(C)C)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 20 h
Yield: 47.7 %

Procedure:
A mixture of ethyl 4-[3-(4-hydroxybenzoyl)indol-1-yl]butyrate (0.50 g), 1-bromo-2,2-dimethyl-1-(4-isobutylphenyl)propane (0.74 g) and potassium carbonate (0.59 g) in N,N-dimethylformamide (10 ml) was stirred at 60° C. for 20 hours. The reaction mixture was filtered, and the filtrate was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting a mixture of n-hexane and ethyl acetate (5:1) to give ethyl 4-[3-[4-[2,2-dimethyl-1-(4-isobutylphenyl)-propyloxy]benzoyl]indol-1-yl]butyrate (376 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH3:13])[C:10]([NH2:12])=[NH:11].[C:14]([N:18]=[C:19]=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH3:13])[C:10]([NH:12][C:19]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[NH:11]
Reactant: CC(C)(C)N=C=O
Reactant: Cc1cccc(C)c1N(C)C(=N)N
Solvent: Cc1ccccc1C
Product: Cc1cccc(C)c1N(C)C(=N)NC(=O)NC(C)(C)C

Procedure:
To a mixture of 8.7 g. (0.05 mole) of 1-(2,6-dimethylphenyl)-1-methylguanidine and 10 ml. xylene is added 5 g. of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooled, triturated with heptane and filtered. Recrystallization from 1:1 isopropanol/water results in 1-(2,6-dimethylphenyl-N-methylamidino)-3-(t-butyl)urea.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=3)[N:19]=2)=[CH:14][C:13]=1[C:31]([F:34])([F:33])[F:32].[NH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C(Cl)Cl>CO.C(O)(=O)C>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:30]=[CH:29][C:26]([CH2:27][NH:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:25][CH:24]=3)[N:19]=2)=[CH:14][C:13]=1[C:31]([F:34])([F:33])[F:32]
Reactant: NCCCC(=O)O
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C=O)cc3)no2)cc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(CNCCCC(=O)O)cc3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium cyanoborohydride (18 mg, 0.28 mmol) was added to a solution of 4-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (0.25 mmol) and 4-aminobutanoic acid (0.25 mmol) in a mixture of methanol (3 mL), DCM (3 mL) and acetic acid (38 μl). The mixture was stirred at room temperature overnight and was filtered through a frit under positive pressure. The solvent was removed in vacuo and the residue purified by reverse phase HPLC to give the title compound as a off-white solid. LC/MS (Method A): 494 (M−H)−, 496 (M+H)+. HPLC (Method K) Rt=17.93 min (Purity: 93.64%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([CH2:8][NH:9][NH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([S:21]([NH:24][C:25]([NH:27][C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=2)=[O:26])(=[O:23])=[O:22])[CH:12]=1)=[O:7])#[N:2].[Na]>O>[C:1]([CH2:3][CH2:4][O:5][C:6]([CH:8]=[N:9][NH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([S:21]([NH:24][C:25]([NH:27][C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=2)=[O:26])(=[O:23])=[O:22])[CH:12]=1)=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(NNCC(=O)OCCC#N)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Agent: [Na]
Solvent: O
Product: COC(=O)c1ccc(NN=CC(=O)OCCC#N)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1

Procedure:
0.7 g (1.25 mmol) of methyl 4-(cyanoethoxycarbonylmethylhydrazino)-2-[3-(4,6-dimethoxypyrimidin-2-yl)ureidosulfonyl]benzoate, sodium salt, are dissolved in 15 ml of water. The few undissolved components are filtered off and the filtrate is acidified to pH 1 using 2N hydrochloric acid. The precipitated solid is filtered off with suction, washed with water and dried. This gives 0.5 g (75% of theory) of methyl 4-(cyanoethoxycarbonyl-methyldenhydrazino)-2-[3-(4,6-dimethoxypyrimidin-2-yl) ureidosulfonyl]benzoate of m.p. 145° C. (decomp.)
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7]3[S:8][C:9](Br)=[CH:10][C:11]=3[C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]=2[CH:3]=1.C(O[CH2:28][CH3:29])C>>[C:4]1([C:2]2[S:6][C:5]3[C:7]4[S:8][C:9]([C:29]5[CH:28]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:10][C:11]=4[C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]=3[CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:7][CH:5]=1
Reactant: CCOCC
Reactant: CCCCCc1c(CCCCC)c2cc(Br)sc2c2sc(Br)cc12
Product: CCCCCc1c(CCCCC)c2cc(-c3ccccc3)sc2c2sc(-c3ccccc3)cc12
Yield: 67 %

Procedure:
A reaction was carried out in the same manner as in Example 11, except that 2,7-dibromo-4,5-di(n-pentyl)benzo[2,1-b:3,4-b′]dithiophene (124.9 mg (0.26 mmol)) was used instead of 2,7-dibromo-4,5-di(n-propyl)benzo[2,1-b:3,4-b′]dithiophene. The post-reaction solution was charged with diethyl ether (about 20 mL), and the resultant solution was then washed with water. Subsequently, the organic layer was dried over sodium sulfate, and then filtered. The solvent was removed from the filtrate by distillation, and then the remaining solid was purified by thin-layer column chromatography using hexane as a developing solvent to obtain the target product 2,7-diphenyl-4,5-di(n-pentyl)benzo[2,1-b:3,4-b′]dithiophene as a yellow solid (83.8 mg, 67% yield). The obtained target product 1H-NMR and HRMS measurement results were as follows.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH:4]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23](=[O:39])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:17][CH:16]=1)[N:5]1[CH2:9][CH2:8][CH:7]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH2:6]1.[Li+].[OH-]>CO>[C:35]([O:34][C:32]([NH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:23](/[CH:22]=[CH:21]/[C:18]1[CH:17]=[CH:16][C:15]([CH:4]([N:5]2[CH2:9][CH2:8][CH:7]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH2:6]2)[C:3]([OH:40])=[O:2])=[CH:20][CH:19]=1)=[O:39])=[O:33])([CH3:36])([CH3:38])[CH3:37]
Reactant: CCN(CC)C1CCN(C(C(=O)OC)c2ccc(C=CC(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)C1CCN(C(C(=O)O)c2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
To a solution of {4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-(3-diethylamino-pyrrolidin-1-yl)-acetic acid methyl ester (2.06 g, 3.75 mmol) in MeOH (30 mL) was added aqueous LiOH (1 N, 15 mL), This mixture was stirred for about 5 h at room temperature, and then evaporated to remove most of the MeOH. The aqueous layer was acidified with concentrated HCl to pH 5-6. The acidified aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain 1.40 g (70%) of yellow solid product. MS: calc'd 537 (MH+), exp 537 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[BH4-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:28][OH:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F

Procedure:
To a solution of diethyl 2-methyl-4-(2-trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.0 g) in ethanol (20 ml) was gradually added sodium borohydride (92 mg) under stirring and ice-cooling and the resultant mixture was further stirred for 25 minutes. The resultant mixture was adjusted with 0.1N hydrochloric acid to pH 4 to 5. The ethanol was removed under reduced pressure without heating so much, and water was added to the residue to give crystals. The crystals were collected by filtration to give crude crystals (1.2 g). These were recrystallized from a mixture of diethyl ether and n-hexane to give pure crystals of diethyl 2-methyl-4-(2-trifluoromethylphenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 147° to 148.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:17][C:10]=12.[CH3:41][C:42](=O)[CH3:43].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([CH:42]([CH3:43])[CH3:41])[CH2:22][CH2:23]3)[S:17][C:10]=12
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4CCNCC4)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 15.4 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-(piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 154, Step C, 35.0 mg, 0.0625 mmol), propan-2-one (36.3 mg, 0.625 mmol), NaBH(OAc)3 (66.3 mg, 0.313 mmol) and THF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford crude product. The crude product was further purified by preparative reverse phase HPLC to afford product (5.8 mg, 15.4%). LRMS (APCI pos): >99% purity, 254 nm, m/e 602 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.52 (d, 1H), 8.39 (d, 1H), 8.26 (d, 1H), 8.05 (m, 1H), 7.69 (m, 2H), 7.61 (m, 1H), 7.52 (m, 1H), 7.34-7.46 (m, 3H), 6.70 (d, 1H), 3.12-3.41 (m, 6H), 2.33 (m, 2H), 1.97 (m, 2H), 1.28 (d, 6H).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C@H:21]([C@@H:10]2[C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:12][NH:8][CH2:9]2)[CH3:22])=[N:25][CH:26]=1
Reactant: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(F)c(Cl)c1
Temperature: 100 °C
Yield: 63.7 %

Procedure:
To a solution of 2-{(S)-1-[(3R,4S)-1-benzyl-4-(3-chloro-4-fluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine 88 mg (0.19 mmol) dissolved in toluene (2 mL) were added 0.06 mL (0.57 mmol) of 1-chloroethyl chloroformate and 0.10 mL of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (5 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 43 mg (61%) of the title compound as a light yellow oil. ES-MS m/e: 355.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:6](I)=[C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12]C)=[O:10])[N:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[O:36][CH2:35][CH2:34][CH2:33]3)O1.C(N(CC)CC)C.ClC(OC)=O>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].ClCCl>[Br:1][C:2]1[C:6]([C:30]2[CH:39]=[CH:38][C:37]3[O:36][CH2:35][CH2:34][CH2:33][C:32]=3[CH:31]=2)=[C:5]([C:8](=[O:14])[C:9]([O:11][CH3:12])=[O:10])[N:4]([CH3:15])[N:3]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Reactant: CCOC(=O)C(=O)c1c(I)c(Br)nn1C
Agent: [Pd]
Agent: COC(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C(=O)c1c(-c2ccc3c(c2)CCCO3)c(Br)nn1C
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A solution of ethyl 2-(3-bromo-4-iodo-1-methyl-1H-pyrazol-5-yl)-2-oxoacetate (11f) (750 mg, 1.94 mmol), potassium carbonate (536 mg, 3.88 mmol), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (494 mg, 1.90 mmol) in a mixture of dioxane (16 mL) and water (4 mL) was degassed for 5 minutes. Palladium tetrakis(triphenylphosphine) (157 mg, 0.14 mmol) was added and the reaction mixture was heated at 120° C. overnight. After concentrating in vacuo, the residue was dissolved in 1N sodium hydroxide (15 mL). The aqueous layer was washed with diethyl ether (20 mL), acidified with 1M hydrochloric acid until pH 3 and extracted with diethyl ether (2×15 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was dissolved in dichloromethane (7 mL), cooled to 0° C., and under a nitrogen atmosphere, triethylamine (0.41 mL, 2.91 mmol) and methyl chloroformate (0.22 mL, 2.91 mmol) were added. The reaction mixture was stirred at 0° C. for 30 minutes, and allowed to reach room temperature. Dichloromethane (10 mL) was added, and the mixture was successively washed with 1N hydrochloric acid (10 mL), a saturated solution of sodium hydrogenocarbonate (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide methyl 2-[3-bromo-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazol-5-yl]-2-oxoacetate (11g) (531 mg, 1.40 mmol, 72%) as a yellow solid.
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([CH:39]([OH:48])[C:40]2[N:47]3[C:43]([S:44][CH:45]=[CH:46]3)=[CH:42][N:41]=2)[CH2:37][C@H:36]([S:49][C:50]2[C@H:51]([CH3:74])[C@@H:52]3[C@@H:62]([C@H:63]([O:65][Si](C(C)(C)C)(C)C)[CH3:64])[C:61](=[O:73])[N:53]3[C:54]=2[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]>C1COCC1.C(OCC)(=O)C>[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([CH:39]([OH:48])[C:40]2[N:47]3[C:43]([S:44][CH:45]=[CH:46]3)=[CH:42][N:41]=2)[CH2:37][C@H:36]([S:49][C:50]2[C@H:51]([CH3:74])[C@@H:52]3[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:73])[N:53]3[C:54]=2[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 39 h

Procedure:
Acetic acid (0.19 ml) and 1.1 ml of a 1 M tetra-n-butylammonium fluoride/THF are added to a solution of 155 mg of the high polar component (stereoisomer A) of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-5-yl)methyl]pyrrolidin-3-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate in 3.3 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for 39 hr. The reaction solution is diluted with 30 ml of ethyl acetate, and the diluted solution is washed with semi-saturated saline and dried over anhydrous magnesium sulfate, followed by filtration and the removal of the solvent by evaporation to give a slightly yellow oil. This oil is successively purified by column chromatography on silica gel (ethyl acetate:methanol=95:5) and on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 117 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-5-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (stereoisomer A) as a yellow viscous material.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]1(B(O)O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[C:18]1([C:2]2[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=2)[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Cc1cnc(Cl)c(C)n1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cnc(-c2cccc3ccccc23)c(C)n1
Yield: 59 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 2.05 g of 2-chloro-3,5-dimethylpyrazine, 2.48 g of 1-naphthylboronic acid, 1.53 g of sodium carbonate, 0.066 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 15 mL of water, and 15 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 10 minutes, whereby heating was performed. After that, water was added to this solution, and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane as a developing solvent. Accordingly, Hdm1npr (a light orange powder, 59% yield), which was the substance to be produced, was obtained. Note that the irradiation with microwaves was performed using a microwaves synthesis system (Discover, produced by CEM Corporation). The synthesis scheme of Step 1 is shown in (a-1) below.
Reaction SMILES: C([O-])C.[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][C:17]#[N:18].[CH:19]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])=O>>[C:17](/[C:16](/[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([O:6][CH3:5])[CH:8]=2)[NH:12][CH:11]=1)=[CH:19]\[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])#[N:18]
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Reactant: N#Cc1cccc(C=O)c1
Agent: CC[O-]
Agent: [Na+]
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3cccc(C#N)c3)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of sodium ethanolate [prepared from sodium (30 mg, 1.3 mmol, 1.2 eq.) and anhydrous ethanol (8 mL)] were added, under an argon atmosphere, (5-methoxy-1H-indol-3-yl)-acetonitrile (200 mg, 1.1 mmol, 1.0 eq.) and, after 10 minutes stirring, 3-formyl-benzonitrile (200 mg, 1.5 mmol, 1.4 eq.). The reaction apparatus was protected from light and the mixture stirred at room temperature for 3 days. The solvent was removed under reduced pressure, and the crude purified by silica gel flash-column chromatography (eluent: heptane/CH2Cl2, 50:50 à 20:80). The residue was triturated with ethanol and diethyl ether to the compound (30) as a yellow powder (110 mg, 34%). mp: 149° C.; IR νmax (cm−1): 2227 (νCN), 3338 (νN—H); 1H NMR (DMSO, 500 MHz) δ (ppm): 3.84 (3H, s, 5′-methoxy), 6.90 (1H, m, H6′), 7.41 (1H, m, H7′), 7.49 (1H, s, H4′), 7.73 (1H, m, H5″), 7.76 (1H, s, H3), 7.79 (1H, s, H2′), 7.88 (1H, m, H6″), 8.24 (1H, m, H″), 8.28 (1H, m, H″), 11.70 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 55.8 (5′-methoxy), 102.2 (C4′), 108.6 and 110.3 (C2 and C3′), 112.0 (C3″), 112.6 (C6′), 113.3 (C7′), 118.0 and 118.6 (C1 and nitrile C), 124.1 (C3a′), 128.1 (C2′), 130.1 (C5″), 132.3 (C6″), 132.4 and 132.5 (C2″, C5″ and C7a′), 133.1 (C3), 136.2 (C1″), 154.8 (C5′); ESI-MS: m/z 322.1 ([M-Na]+); HRESI-MS: m/z 322.0946 (calcd for C19H13N3ONa, 322.0956).
Reaction SMILES: C1(C2OC(C(F)(F)F)=C(C(NC3C=CC(C4C=CC(C([C@@H]5CCC[C@H]5C(O)=O)=O)=CC=4)=CC=3)=O)N=2)C=CC=CC=1.[C:41]1([C:47]2[O:48][C:49]([C:78]([F:81])([F:80])[F:79])=[C:50]([C:52]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]4[CH:66]=[CH:65][C:64]([C:67]([CH:69]5[CH2:74][CH2:73][CH2:72][CH2:71][CH:70]5[C:75]([OH:77])=[O:76])=[O:68])=[CH:63][CH:62]=4)=[CH:57][CH:56]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1(C2OC(C(F)(F)F)=C(C(O)=O)N=2)C=CC=CC=1.NC1C=CC(C2C=CC(C([C@H]3CCCC[C@H]3C(O)=O)=O)=CC=2)=CC=1>>[C:41]1([C:47]2[O:48][C:49]([C:78]([F:80])([F:81])[F:79])=[C:50]([C:52]([NH:54][C:55]3[CH:56]=[CH:57][C:58]([C:61]4[CH:66]=[CH:65][C:64]([C:67]([C@H:69]5[CH2:74][CH2:73][CH2:72][CH2:71][C@H:70]5[C:75]([OH:77])=[O:76])=[O:68])=[CH:63][CH:62]=4)=[CH:59][CH:60]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Nc1ccc(-c2ccc(C(=O)C3CCCCC3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Nc1ccc(-c2ccc(C(=O)[C@H]3CCCC[C@H]3C(=O)O)cc2)cc1
Agent: O=C(Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(-c2ccc(C(=O)[C@H]3CCCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to that used for the preparation of racemic trans-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclopentanecarboxylic acid above, racemic 2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic cis-2-(4′-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid. The racemic product was separated by chiral SFC to afford (1R,2S)-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid (or enantiomer). [α]D: +11.70 in DMSO. LCMS calcd for C31H25F3N2O5 (m/e) 562, obsd 563 (M+H).