Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH3:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1>O>[F:1][CH:2]([F:5])[CH2:3][NH:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([CH3:6])=[CH:8][CH:9]=1
Reactant: FC(F)CCl
Reactant: Cc1ccc(CN)cc1
Solvent: O
Product: Cc1ccc(CNCC(F)F)cc1
Yield: 58 %

Procedure:
An amount of 26.2 g (242 mmol) of 2,2-difluoro-1-chloroethane and 10 g of 4-methylbenzylamine (80.8 mmol) are heated in an autoclave at an internal temperature of 120° C. for 16 hours. Subsequently, 50 g of water are added and the aqueous phase is separated. The aqueous phase is again extracted with 2,2-difluoro-1-chloroethane and the combined organic phases are distilled as described in Example 1.1. Here also, the 4-methylbenzylamine hydrochloride which is present in the aqueous phase can be converted back into free 4-methylbenzylamine by addition of sodium hydroxide solution. After distillation, 4.3 g of 2,2-difluoro-N-(4-methylbenzyl)ethanamine are obtained, which corresponds to a yield of 58%, based on reacted 4-methylbenzylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Br)ccc1Oc1ccc(F)cc1
Yield: 98.3 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (4.1 g, 20 mmol) (Alfa) was reacted with 4-fluorophenol (2.5 g, 22 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(4-fluoro-phenoxy)-benzaldehyde as a yellow solid (Yield 5.8 g, 97%).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([CH3:29])=[C:24]([CH2:30][O:31][CH3:32])[N:23]=1>CN(C)C=O>[CH3:32][O:31][CH2:30][C:24]1[N:23]=[C:22]([Cl:21])[N:27]=[C:26]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)[CH:2]2[CH3:1])[C:25]=1[CH3:29]
Reactant: COc1ccc2c(c1)CCNC2C
Reactant: COCc1nc(Cl)nc(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1nc(Cl)nc(N2CCc3cc(OC)ccc3C2C)c1C
Yield: 91.3 %

Procedure:
After 1-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline(1.2 g, 6.8 mmol) and triethylamine(0.96 ml, 6.9 mmol) were added to a suspension of 2,4-dichloro-6-methoxymethyl-5-methylpyrimidine(1.3 g, 6.3 mmol) in dimethylformamide, 2.0 g of the titled compound was obtained in accordance with the same procedure as in Step 1 of Example 35. (Yield: 73.6%)
Reaction SMILES: [C:1](O)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:24][C:25]([CH3:38])([CH2:36][CH3:37])[C:26](=[O:35])[C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][NH:30]1)=[O:28]>C(Cl)Cl>[C:1]([N:30]1[CH:29]([C:27](=[O:28])[C:26](=[O:35])[C:25]([CH3:38])([CH3:24])[CH2:36][CH3:37])[CH2:34][CH2:33][CH2:32][NH:31]1)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: CCC(C)(C)C(=O)C(=O)C1CCCNN1
Reactant: C#CCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCC(=O)N1NCCCC1C(=O)C(=O)C(C)(C)CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.8 %

Procedure:
To a solution of 5-hexynoic acid (0.467 g, 4 mmol) in 10 ml CH2Cl2 was added triethylamine (0.56 ml, 4 mmol), followed by isobutyl chloroformate (0.53 ml, 4 mmol) at 0° C. After stirring for 5 minutes, a solution of 3,3-dimethyl-1-perhydropyridazinyl pentane-1,2-dione (0.424 g, 2 mmol) in 1 ml CH2Cl2 was added. The reaction was gradually warmed up to room temperature. The crude material was subject to silica gel purification to yield final product as clear oil (0.385 g, 63%). 1H NMR (CDCl3, 400 MHz) δ 0.91 (t, 3H, J=7.0); 1.26 (s, 6H); 1.76(m, 8H); 2.28 (m, 2H); 2.50 (m, 2H); 2.88 (m, 2H); 3.60 (m, 1H); 4.50 (m, 2H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Mg]Cl)CCC.O1CCCC1.[Cl:21][CH2:22][C:23]([OH:25])=O.C(OC)(=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1>[CH2:22]([Cl:21])[C:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]
Reactant: COC(=O)c1ccccc1
Reactant: O=C(O)CCl
Agent: CCCC[Mg]Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=C(CCl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
To 5 mL of tetrahydrofuran was added hexamethyldisilazane (6.6 mmol) under the atomosphere of nitrogen gas and after the solution was cooled to 0° C., 6.67 mL of 0.9 M n-butylmagnesium chloride/tetrahydrofuran (6 mmol) was added. The mixture was stirred at 0° C. for 10 minutes. Then, after cooling to -30° C., a solution of 284 mg (3.0 mmol) of monochloroacetic acid and 136 mg (1 mmol) of methyl benzoate in 5 mL of tetrahydrofuran was added dropwise for 5 minutes. This mixture was stirred at -30° C. for 30 minutes and, while the temperature was allowed to rise to room temperature, was further stirred for 1 hour. This reaction mixture was poured in 1N-HCl (50 mL) and extracted with ethyl acetate (50 mL×2). The extract was washed with saturated aqueous NaHCO3 solution (50 mL×1) and water (30 mL×1) in that order and dries over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to provide a light-yellow oil. Comparative HPLC analysis of this oil with an authentic sample revealed that the oil was predominantly composed of the objective phenacyl chloride (reaction yield 84.3%). Methylbenzoate (reaction yield 17.5%) was obtained as a byproduct.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH:58]([CH3:60])[CH3:59])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.CO>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH:61][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH:58]([CH3:60])[CH3:59])=[N:56][C:52]=2[CH:51]=1
Reactant: CC(C)[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@H](c2nc3cc(Cl)ccc3[nH]2)C(C)C)ccc1C(=O)N1CCCC1
Yield: 72 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methylpropylamine in tetrahydrofuran. Yield: 72%; Rf value: 0.43 (silica gel; dichloromethane/methanol=9:1); C24H27ClN4O2 (438.96); Mass spectrum: (M+H)+=439 (chlorine isotope) and (M−H)−=437 (chlorine isotope).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][S:11][C:4]=2[CH2:3]1.[Br:12]Br.Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Br:12][C:10]1[S:11][C:4]2[CH2:3][N:2]([CH3:1])[CH2:7][CH:6]([OH:8])[C:5]=2[CH:9]=1
Reactant: CN1Cc2sccc2C(O)C1
Reactant: BrBr
Agent: Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1Cc2sc(Br)cc2C(O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
6-Methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (1.2 g) prepared in Reference Example 6 was dissolved in 60 mL of acetic acid, a solution of 2.72 g of bromine in 10 mL of acetic acid was added thereto by dropping, then 0.1 mL of 33% solution of hydrogen bromide in acetic acid solution was added thereto and the mixture was stirred for 3 hours at room temperature. To the reaction solution was added 10 mL of 10% aqueous solution of sodium thiosulfate and then the reaction solution was concentrated in vacuo to evaporate acetic acid. The residue was made basic by addition of 25% aqueous ammonia with cooling followed by extracting with ethyl acetate. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 0.74 g of the objective compound.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CCO>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(Cc2ccc(I)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Yield: 794.3 %

Procedure:
To a mixture of 1-(4-iodobenzyl)-4-methoxybenzene (0.300 g, 0.925 mmol), 2N aqueous NaHCO3 solution (1.85 mL, 3.7 mmol), and 2-thiopheneboronic acid (0.237 g, 1.85 mmol) in a solution of toluene/EtOH (17.6/0.8 mL) at ambient temperature under an atmosphere of nitrogen was added tetrakis(triphenylphosphine)palladium(0) (0.107 g, 0.093 mmol). The procedure in Example 15, Step 1 was followed to give the title product as a white solid (2.06 g, 79%): 1H NMR (400 MHz, CDCl3): δ 7.52 (d, 2H, J=8.4 Hz), 7.25 (m, 2H), 7.18 (d, 2H, J=8.4 Hz), 7.11 (d, 2H, J=8.8 Hz), 7.05 (m, 1H), 6.84 (d, 2H, J=8.8 Hz), 3.93 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.[Li]C(C)(C)C.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([B:18]([OH:23])[OH:19])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(B(O)O)ccc1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A mixture of 4-Bromo-2-ethoxy-1-methoxybenzene (4.00 g, 17.3 mmol) in THF (75 mL) was cooled to −78° C.; during cooling, a precicipitate formed. t-BuLi (22.4 mL, 1.7 M in pentane, 38.1 mmol) was added dropwise, while maintaining the temperature at −78° C. The mixture was stirred at −78° C. for 1 hour following completion of the addition. B(Oi-Pr)3 (9.76 g, 51.9 mmol) was added. The mixture was allowed to gradually warm to room temperature, and then stirred under nitrogen for 16 hours. 3N HCl (20 mL) was added, and the mixture stirred for 10 minutes. The mixture was poured into water (100 mL) and extracted with diethyl ether (3×75 mL), and the combined ethereal layers were washed with water (3×75 mL), dried (MgSO4) and evaporated, providing 3.15 g of the product in 93% yield: 1H NMR (DMSO-d6) δ 1.32 (t, J=7.0 Hz, 3H), 3.75 (s, 3H), 3.99 (q, J=7.0 Hz, 2H), 6.90 (d, J=8.3 Hz, 1H), 7.35-7.37 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:25][CH2:26][CH2:27][CH3:28])[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[CH2:25]([N:11]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:22])([CH3:21])[O:16][C:15]2([CH3:23])[CH3:24])[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:29])=[O:3])=[CH:10][CH:9]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN(c1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)OC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)OC2(C)C
Temperature: 55 °C
Yield: 41.3 %

Procedure:
A solution of 4-[n-butyl-(1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 82, 0.224 g, 0.6 mmol) in 20 mL of ethanol was treated with 2 mL of 5M sodium hydroxide solution and the resulting solution was heated at 55° C. for 2 hours. The volatiles were removed by distillation in vacuo and the residue was acidified using hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate and evaporated to a residue which was subjected to flash column chromatography on silica gel using ethyl acetate as the eluent to afford the title compound (0.091 g, 50%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 2H, J=9.1 Hz), 7.12 (d, 1H, J=8.2 Hz), 7.09 (d, 1H, J=8.1 Hz), 6.91 (s, 1H), 6.67 (d, 2H, J=9.0 Hz), 3.71 (t, 2H, J=7.8 Hz), 1.72-1.64 (m, 2H) 1.56 (s, 6H), 1.52 (s, 6H), 1.34-1.45 (m, 2H), 0.95 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=1.P(Br)(Br)([Br:21])=O>>[Br:21][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(=O)[nH]1
Reactant: O=P(Br)(Br)Br
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(Br)n1

Procedure:
The title compound was prepared from 6-methyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (example A.30 step 1) (118.1 g, 466.4 mmol) and phosphoryl bromide (267.4 g, 933 mmol) according to the general procedure Ia to d preparation of bromides. Obtained as an off-white solid (109.67 g, 74%). MS (ISP) 316.0 [(M+H)+] and 318.0 [(M+2+H)+]; mp 74-76° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].Br[CH2:12][C:13]([C:15]1([CH3:18])[CH2:17][CH2:16]1)=O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:7]([CH:12]=[C:13]([C:15]3([CH3:18])[CH2:17][CH2:16]3)[NH:6]2)=[CH:8][C:9]=1[CH3:10]
Reactant: CC1(C(=O)CBr)CC1
Reactant: COc1cc(N)ccc1C
Agent: Cl
Solvent: CCO
Product: COc1cc2[nH]c(C3(C)CC3)cc2cc1C
Yield: 54.6 %

Procedure:
A solution of 3-methoxy-4-methylaniline (2.26 g) in ethanol (7 mL) was heated under reflux while stirring. To the solution was added slowly a solution of 2-bromo-1-(1-methylcyclopropyl)ethan-1-one (885 mg) in ethanol (3 mL), and this mixture was heated under reflux for 3 hours while stirring. The reaction mixture was left to be cooled. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (588 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:24][CH3:25])=[CH:4][C:5]2[CH2:14][CH:13]3[N:8]([CH2:9][CH2:10][C:11]4[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:12]=43)[CH2:7][C:6]=2[CH:23]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH3:22][O:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:11]2[CH2:10][CH2:9][N:8]3[CH:13]([CH2:14][C:5]4[CH:4]=[C:3]([O:24][CH3:25])[C:2]([O:1][C:26](=[O:28])[CH3:27])=[CH:23][C:6]=4[CH2:7]3)[C:12]=2[CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1O)CN1CCc3cc(OC)c(OC)cc3C1C2
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C1Cc3cc(OC)c(OC(C)=O)cc3CN1CC2
Yield: 33.3 %

Procedure:
0.8 g. of 10-hydroxy-2,3,11-trimethoxy-5,6,13,13a-tetrahydro-8H-dibenzo[a, g]quinolizine was dissolved in 8 ml of anhydrous pyridine. To the resulting solution 2 ml of acetic anhydride was added dropwise with stirring, while cooling in an ice-bath. After the mixture was stirred at room temperature for 5 hours, the excessive acetic anhydride was distilled off under reduced pressure, and the residue obtained was extracted with chloroform. The chloroform layer was washed with a 1N-sodium hydroxide solution and then with water, dried over potassium carbonate and evaporated to dryness. Recrystallization of the residue from ethanol-petroleum ether afforded 0.3 g. (33.3% yield) of 5,6,13,13a-tetrahydro-2,3,11-trimethoxy-10-acetoxy-8H-dibenzo [a,g]quinolizine as colorless needles having a melting point of 162° to 164°C.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(Cl)([Cl:15])=O.CN(C)C=O>C(Cl)Cl>[CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)Cl)cc1
Reaction time: 1 h

Procedure:
In 5 ml of methylene chloride was suspended 0.25 g of 4-isopropylbenzoic acid. Then, at ambient temperature, 0.12 ml of thionyl chloride and 0.03 ml of N,N-dimethylformamide were added. After stirring the mixture at the same temperature as above for one hour, the solvent was distilled off under reduced pressure, and an azeotropic distillation treatment using toluene was carried out to obtain 0.25 g of 4-isopropylbenzoic acid chloride. To a suspension of 0.50 g of trifluoroacetic acid salt of 2-(4-benzyl-3-oxo-1-thia-4,8-diazaspiro[4.5]decan-2-yl]-acetic acid in 5 ml methylene chloride were successively added dropwise at 0-5° C. 0.64 ml of triethylamine and a solution of 0.25 g of 4-isopropylbenzoic acid chloride in 5 ml methylene chloride. The resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was poured into ice water, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluents: toluene:ethyl acetate=1:1, followed by chloroform] gave 0.30 g of 2-[4-benzyl-8-(4-isopropylbenzoyl)-3-oxo-1-thia-4,8-diazaspiro[4.5]-decan-2-yl]-acetic acid as a light yellow solid product.
Reaction SMILES: C(O)C.[CH3:4][C:5]1[S:9][C:8]([CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=[O:15])=[CH:7][CH:6]=1.[BH4-].[Na+]>O>[CH3:4][C:5]1[S:9][C:8]([CH2:10][C:11]2[CH:12]=[C:13]([CH2:14][OH:15])[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cc2cccc(C=O)c2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Cc2cccc(CO)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
To a solution of ethanol (5.0 mL) and 3-(5-methyl-thiophen-2-ylmethyl)-benzaldehyde (350 mg) described in Manufacturing Example 52-2 was added sodium borohydride (120 mg), which was stirred for 10 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The solvent was evaporated from the organic layer under a reduced pressure, and the residue was purified by silica gel chromatography (heptane:ethyl acetate=2:1) to obtain the titled compound (300 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][C@@H:13]2[O:16][C:17](=[O:26])[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:12]2[CH2:11]1)([O-])=O>CCO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][C@@H:13]2[O:16][C:17](=[O:26])[N:18]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C@@H:12]2[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3[N+](=O)[O-])C[C@H]21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3N)C[C@H]21
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of (3aR,7aS)-tert-butyl 5-(3-nitropyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate in EtOH and EtOAc (1:1, 0.15 M) was added Pd/C (10% by weight) and the reaction was stirred under a hydrogen balloon for 15 h. The solution was filtered through a pad of Celite, and the filtrate was concentrated to yield (3aR,7aS)-tert-butyl 5-(3-aminopyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate as a clear oil in >95% yield. LCMS (m/z): 335.0 (MH+), Rt=1.68 min.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH2:6][C:7](=[O:29])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C:23](=[O:27])[CH2:24]2)[C@:20]2([CH3:21])[C@H:15]([CH2:16][C:17](=[O:28])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)#[N:2]>O.Cl.Cl.Cl[Ir](Cl)(Cl)Cl>[C:1]([CH2:3][CH2:4][O:5][CH2:6][C:7](=[O:29])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C:23](=[O:27])[CH2:24]2)[C@:20]2([CH3:21])[C@H:15]([CH2:16][C@H:17]([OH:28])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)#[N:2]
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)COCCC#N)[C@@]3(C)CC(=O)[C@@H]12
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)COCCC#N)[C@@]3(C)CC(=O)[C@@H]12
Yield: 0.2 %

Procedure:
The product, crude 21-(2'-cyanoethoxy)-5α-pregnane-3,11,20-trione (0;80 g.) was treated with chloroiridic acid solution (24 ml.). The mixture was refluxed for 24 hours cooled and partitioned between water and ether. The organic layer was washed with saturated aqueous sodium bicarbonate, water, dried (Na2SO4) and evaporated. The residue was subjected to preparative t.l.c. EtOAc, petrol (1:1) to give title compound (0.2 g.) as a white foam, [α]D + 85° (c 1.1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][C:43]1([OH:59])[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[O:46][CH:45]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:44]1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:41][CH2:42][C:43]1([OH:59])[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[O:46][CH:45]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:44]1)=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCC1(O)CC(c2ccccc2)Oc2ccccc21
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCC1(O)CC(c2ccccc2)Oc2ccccc21
Yield: 13 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (82 mg, 0.15 mmol) and 4-(aminomethyl)-2-phenyl-4-chromanol (45 mg, 0.18 mmol) according to Method C with HPLC purification to give the title compound (15 mg). 1H-NMR (400 MHz, CD3OD) d 7.64 (s, 1H), 6.84 (dd, J=1.0 Hz, J=8.3 Hz, 1H), 5.33 (d, J=12.0 Hz, 1H), 4.64 (s, 2H), 4.63 (m, 1H), 4.28 (m, 1H), 3.95 (m, 1H), 3.19 (m, 1H), 1.35 (s, 3H), 1.32 (s, 6H); HRMS m/z 767.3084 (calc. of monoisotopic mass for C42H45N3O11 gives 767.3054).