Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24]1([S:34](Cl)(=[O:36])=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][S:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)(=[O:36])=[O:35])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 1-naphthalenesulfonyl chloride (107 mg, 0.47 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (109 mg, 50%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31]O)=[N:9]1)=O)(C)(C)C.C[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.S(Cl)(C)(=O)=O.N1CCOCC1>C1COCC1.C(N(CC)CC)C>[CH3:25][C:21]1[NH:20][C:19]([CH3:26])=[C:18]([C:27]#[N:28])[CH:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[C:10]3[NH:29][CH2:30][CH2:31][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:22]=1[C:23]#[N:24]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(NCCO)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Reactant: CN1CCOCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(NCCN4CCOCC4)c3c2)C(C#N)=C(C)N1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a stirred and chilled (ice/water bath) solution of crude 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-(2-hydroxy-ethylamino)-indazole-1-carboxylic acid tert-butyl ester (1 g) in THF (157 mL), under argon, was added sequentially 4-methylmorpholine (5.2 mL) and mesyl chloride (MsCl, CH3SO2Cl, 0.89 mL) dropwise. The mixture was allowed to warm to room temperature overnight before morpholine (41 mL) was added. Stirring was continued overnight before heating to 35° C. On cooling, triethylamine was added, the mixture concentrated to ca. one third the volume and the residue cooled (ice/water bath). The mixture was quenched with ice and aqueous sodium carbonate solution and the extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was taken up in THF (15 mL), HCl (15 mL) was added and the mixture was heated for 1.5 h at 60° C. (bath temperature). On cooling, the mixture was poured carefully onto aqueous sodium hydrogencarbonate solution and extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was purified by preparative reverse phase HPLC to give 1,4-dihydro-2,6-dimethyl-4-[3-[[2-(4-morpholinyl)ethyl]amino]-1H-indazol-5-yl]-3,5-pyridinedicarbonitrile (60 mg) (Cpd. No. 307, Table 8). 1H-NMR (DMSO-D6, 300 MHz): δ=11.46 (br s, 1H), 9.50 (br s, 1H), 7.56 (s, 1H), 7.25 (d, 1H), 7.17 (dd, 1H), 5.93 (t, 1H), 4.40 (s, 1H), 3.60 (m, 4H), 3.40 (partially obscured by solvent, 2H), 2.59 (t, 2H), 2.44 (m, 4H), 2.05 (s, 6H) ppm.
Reaction SMILES: C(NC1N=C(C2O[N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)C=C(C)N=1)C.[CH2:30]([NH:34][C:35]1[N:40]=[C:39]([C:41]([OH:43])=O)[CH:38]=[C:37]([CH3:44])[N:36]=1)[CH:31]([CH3:33])[CH3:32]>>[CH2:30]([NH:34][C:35]1[N:40]=[C:39]([C:41]2[O:43][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:38]=[C:37]([CH3:44])[N:36]=1)[CH:31]([CH3:32])[CH3:33]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Reactant: Cc1cc(C(=O)O)nc(NCC(C)C)n1
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)nc(NCC(C)C)n1

Procedure:
rac-3-{4-[5-(2-Isobutylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 2-isobutylamino-6-methyl-pyrimidine-4-carboxylic acid; white crystalline solid; LC-MS: tR=0.90 min*; [M+H]+=428.25; 1H NMR (D6-DMSO): δ 0.93 (d, J=6.8 Hz, 6H), 1.91 (m, 1H), 2.35 (s, 6H), 2.41 (s, 3H), 3.18 (m, 2H), 3.50 (t, J=5.5 Hz, 2H), 3.75 (dd, J=5.5 and 8.8 Hz, 1H), 3.79-3.91 (m, 2H), 4.64 (t, J=5.5 Hz, 1H), 4.96 (d, J=5.0 Hz, 1H), 7.28 (s, 1H), 7.65 (s br, 1H), 7.76 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[N:6][C:7]=1F.[CH:22]([O:25][C:26]1[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=1)([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[C:7]([NH:31][C:28]2[CH:27]=[C:26]([O:25][CH:22]([CH3:24])[CH3:23])[NH:30][N:29]=2)=[N:6][C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: C[C@H](Nc1nc(F)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c([N+](=O)[O-])cc2F)n[nH]1
Temperature: 55 °C
Yield: 40.6 %

Procedure:
To a solution of (S)-5,6-difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method 23; 0.60 g, 2.0 mmol) in THF (10 ml) at room temperature was added 5-isopropoxy -1H-pyrazol-3-amine (0.50 g, 3.0 mmol), and DIEA (0.29 g, 2.2 mmol). The reaction was then heated to 55° C. for 24 hours, cooled to room temperature, and quenched with water. The reaction was then extracted with DCM (2×75 ml), and the combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.34 g, 40%). 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J=10.9 Hz, 1H), 7.45-7.35 (m, 2H), 7.07-7.03 (m, 2H), 5.88-5.71 (m, 1H), 5.48-5.30 (m, 1H), 4.58-4.29 (m, 1H), 1.68-1.56 (m, 3H), 1.34-1.28 (m, 6H). MS: Calcd.: 418. Found: [M+H]+ 419.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH:26][CH2:27][C@H:28]1[C@@H:32]([F:33])[CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:29]1)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:53]([O:56][C@@H:57]([CH3:61])[C:58](Cl)=[O:59])(=[O:55])[CH3:54]>ClCCl>[C:53]([O:56][C@@H:57]([CH3:61])[C:58]([N:26]([CH2:27][C@H:28]1[C@@H:32]([F:33])[CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35])[CH2:29]1)[C@@H:21]([C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[O:12][C:8]=1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:59])(=[O:55])[CH3:54]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CC(C)(C)C(NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)O[C@@H](C)C(=O)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
To a solution of (±)-(3R,4R)-benzyl 3-((1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (37 mg, 0.063 mmol) in dichloromethane (0.63 mL, 0.1 M solution) at room temperature was added N,N-diisopropylethylamine (55 μL, 0.313 mmol). (S)-1-Chloro-1-oxopropan-2-yl acetate (15.8 μL, 0.125 mmol) was then added dropwise over 2 min. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Two diastereomers were separated on preparative TLC (2% MeOH in dichloromethane). The polar diastereomer, (3R,4R)-benzyl 3-(((S)-2-acetoxy-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate, was obtained in 17% yield (7.5 mg). LC/MS (uplc): MH+ 706.4, 1.34 min. The nonpolar diastereomer, (3R,4R)-benzyl 3-(((S)-2-acetoxy-N—((S)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate, was obtained in 16% yield (7.0 mg). LC/MS (uplc): MH+ 706.4, 1.35 min.
Reaction SMILES: [O:1]([C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C@@H:24]([CH2:25][CH2:26][C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[C:23](=[O:36])[N:22]2[C:37]2[CH:42]=[CH:41][C:40]([C:43]#[C:44][Si](C)(C)C)=[CH:39][CH:38]=2)=[CH:17][CH:16]=1)[C@@H:2]1[O:10][C@H:9]([C:11]([O:13]C)=[O:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]>CO.O.C(N(CC)CC)C>[O:1]([C:15]1[CH:16]=[CH:17][C:18]([C@@H:21]2[C@@H:24]([CH2:25][CH2:26][C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[C:23](=[O:36])[N:22]2[C:37]2[CH:38]=[CH:39][C:40]([C:43]#[CH:44])=[CH:41][CH:42]=2)=[CH:19][CH:20]=1)[C@@H:2]1[O:10][C@H:9]([C:11]([OH:13])=[O:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](O)c4ccc(F)cc4)C(=O)N3c3ccc(C#C[Si](C)(C)C)cc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: C#Cc1ccc(N2C(=O)[C@H](CC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)cc2)cc1

Procedure:
A solution of 8a in methanol/water/triethylamine (0.25 mL:1.10 mL:0.40 mL) was stirred at room temperature for approximately 6 h. The volatiles were evaporated in vacuo and the crude residue purified by preparative reversed phase high performance liquid chromatography on YMC Pack Pro C18 phase (gradient elution; 10-65% acetonitrile/water as eluent, 0.1% TFA modifier) to give the title compound (8b); m/z (ES) 574 (M-OH)+, 398; HRMS (ES) m/z calc'd for C32H31FNO9 (MH+) 592.1983, found 592.1985.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[N:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].FC1C=CC=C(F)C=1C([N-]C1SC(C2C=CC=C(C(F)(F)F)C=2)=C(C)N=1)=O.[Na+:54]>>[CH3:12][C:10]1[N:11]=[C:7]([N-:6][C:4](=[O:5])[C:3]2[CH:23]=[CH:24][N:25]=[CH:26][C:2]=2[CH3:1])[S:8][C:9]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=1.[Na+:54]
Reactant: Cc1cnccc1C(=O)Nc1nc(C)c(-c2cccc(C(F)(F)F)c2)s1
Agent: Cc1nc([N-]C(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Product: Cc1cnccc1C(=O)[N-]c1nc(C)c(-c2cccc(C(F)(F)F)c2)s1

Procedure:
Compound 49 was prepared from Compound 11 as described for the preparation of Compound 48.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].II.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1.[Zn]>[Cl:1][CH2:2][CH2:3][C:4]([OH:5])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CBr
Reactant: O=C(CCCl)c1ccccc1
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(CCCl)c1ccccc1
Yield: 52.8 %

Procedure:
To a stirred suspension of 3-chloro-1-phenylpropan-1-one (10 g, 0.059 mol) and active Zinc power (19 g, 0.295 mol) in THF (200 mL) was added iodine (9 g, 0.035 mol), then ethyl bromoacetate (20 g, 0.118 mol) was added dropwise at rt. The formed mixture was heated to reflux for 30 min. The reaction was quenched with water, and the mixture was filtered through a celite pad. The filtrate was extracted with EtOAc. The organic phase was dried over Na2SO4, and concentrated to give the crude product, which was purified by column chromatography to afford ethyl 5-chloro-3-hydroxy-3-phenylpentanoate (8.0 g, 53%). 1H NMR (CDCl3): δ=1.02 (t, 3H), 2.13-2.28 (m, 2H), 2.73 (d, 1H), 2.90 (d, 1H), 3.11 (1, 2H), 3.54 (m, 1H), 3.94 (q, 2H), 7.18 (m, 1H), 7.29 (m, 4H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H:18]2[C@@H:22]([O:23][CH2:24]C)C[N:20]([C:26]3SC=C[N:30]=3)[CH2:19]2)=NC=1CC.[Cl:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:42]1[N:43]=[C:44]([CH2:59][CH3:60])[C:45]([NH:50][C@H:51]2[C@@H:55]([O:56][CH2:57][CH3:58])[CH2:54][NH:53][CH2:52]2)=[N:46][C:47]=1[CH2:48][CH3:49].ClC1N=C(OC)C=CN=1>>[Cl:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:42]1[N:43]=[C:44]([CH2:59][CH3:60])[C:45]([NH:50][C@H:51]2[C@@H:55]([O:56][CH2:57][CH3:58])[CH2:54][N:53]([C:26]3[N:30]=[C:22]([O:23][CH3:24])[CH:18]=[CH:19][N:20]=3)[CH2:52]2)=[N:46][C:47]=1[CH2:48][CH3:49]
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Agent: COc1ccnc(Cl)n1
Product: CCO[C@H]1CN(c2nccc(OC)n2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting 5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine and 2-chloro-4-methoxypyrimidine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ) 8.03, 7.25, 7.02, 6.90, 6.02, 5.25, 4.88, 4.22, 3.92–3.78, 3.55, 2.74, 2.50, 1.33–1.26, 1.16; IR (diffuse reflectance) 2972, 2475 (w), 2350 (w), 2310 (w), 2183 (w), 2069 (w), 1585 (s), 1568 (s), 1516 (s), 1482 (s), 1466 (s), 1397, 1393, 1292, 1231 cm−1 HRMS (ESI) calcd for C26H33N6O3Cl+H1 513.2380. found 513.2356.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29]COC)[CH:24]=1)=O)(C)(C)C.[ClH:33]>O1CCOCC1>[ClH:33].[OH:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COCOc1cccc(CCc2ccccc2OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1cccc(CCc2ccccc2OC[C@@H]2CCCN2)c1
Reaction time: 3 h
Yield: 66 %

Procedure:
630 mg of (S)-1-t-butoxycarbonyl-2-{2-[2-(3-methoxymethoxyphenyl) ethyl]phenoxymethyl }pyrrolidine [prepared as described in step (a) above] were dissolved in 10 ml of a 4N solution of hydrogen chloride in dioxane, whilst ice-cooling, and the solution was allowed to stand at room temperature for 3 hours. At the end of this time, the mixture was concentrated by distillation under reduced pressure, and the resulting oily residue was dissolved in a small amount of isopropyl alcohol; the solution was then allowed to stand, whilst ice-cooling. The crystals which precipitated were collected by filtration and dried in vacuo, to give 318 mg (yield 66%) of the title compound as colorless crystals, melting at 127°-129° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10](O)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)C(OCC)OCC)[C:5]([NH:25][C:26](=O)C(C)(C)C)=[CH:4][N:3]=1.C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]2[C:5](=[CH:4][N:3]=1)[N:25]=[CH:26][C:10]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[CH:9]2
Reactant: CCOC(OCC)C(O)(Cc1c(NC(=O)C(C)(C)C)cnc(Cl)c1C)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(Cl)ncc2ncc(-c3ccccc3)cc12

Procedure:
180.5 g (0.4 mol) of finely divided compound from Example I are intensively stirred under reflux for 5 h in 2.6 l of 2N HCl using a mechanical stirrer. The mixture is then neutralised with NaHCO3 and extracted several times with ethyl acetate, and the extracts are dried. 37.6 g of the title compound are obtained by crystallisation. Chromatography of the mother liquor (silica gel, toluene→toluene/ethyl acetate 2:1) yields a further 23.14 g of the title compound. Total yield: 60% M.p.: 136° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:13]([CH2:14][CH2:15][C:16]2=[CH:17][CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:24])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:23])[CH:6]=[CH:5]1.O[C@H]1C[C@@]2(C)[C@@H](CCC2=CCO)[C@H]2[C@H]1[C@]1(C)C([C@@H](C)C2)=CC(=O)C=C1>>[OH:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:13]([CH2:14][CH2:15][C:16]2=[CH:17][CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:24])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=CCO)CC[C@@H]12
Agent: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@]3(C)C(=CCO)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=CCO)CC[C@@H]12
Yield: 100 %

Procedure:
U.S. Pat. No. 3,770,586 claims an improved process for the production of 11β,21-dihydroxypregna-1,4,17(20)-trien-3-one (Example 1) and 11β,21-dihydroxy-6α-methylpregna-1,4,17(20)-trien-3-one (Example 5) whereby the alkali metal salts of the Δ4 -3-keto 21-hemiester substrates thereof where the acyl radical is that of a dicarboxylic acid of 3 to 12 carbon atoms are 1,2-dehydrogenated by use of S. affinis. Using shake flasks, 11β,21-dihydroxypregna-4,17(20)-dien-3-one 21-hemisuccinate potassium salt at a concentration of 5.0 g/l and medium 1, the desired Δ1,4 -product was produced in 100% yield after 5 days (Example 8). Example 1 uses larger stirred tanks and shows a lower yield. With medium 2, and 2.0-7.0 g/l of 11β,21-dihydroxypregna-4,17(20)-dien-3-one 21-hemisuccinate potassium salt yields of 91.1-96.6% were obtained in 6 days.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:22])[CH2:19][NH:20][CH3:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:22])[CH2:19][N:20]([CH3:21])[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:16][CH:17]=1
Reactant: CNCC(=O)c1ccc(F)cc1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(CC(=O)c1ccc(F)cc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.26 g (12.5 mmol) of phenyl isocyanate are used to a suspension of 3 g (12.5 mmol) of the compound from Example 2 in 30 ml of toluene and 1.5 g (12.5 mmol) of triethylamine are slowly added dropwise at 0° C. The mixture is stirred overnight at 25° C. The toluene phase is washed with water, the product precipitating out. After drying 3.54 g are obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=4)[CH2:13][NH:12][C:11]3=[O:23])=[CH:9][C:4]=2[N:3]=[CH:2]1.B(Br)(Br)Br>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=4)[CH2:13][NH:12][C:11]3=[O:23])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1NCC(c2ccc(O)cc2)N1c1ccc2[nH]cnc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(1H-Benzo[d]imidazol-5-yl)-5-(4-methoxyphenyl)imidazolidin-2-one (308 mg; 1 mmol; 1 eq.) was dissolved in dry CH2Cl2 (20 ml) under Argon atmosphere and cooled to 0° C. BBr3 (0.285 ml; 3 mmol; 3 eq.) was added dropwise. After complete addition, the mixture was stirred for 1 h at 0° C. and then allowed to warm to room temperature. The reaction was quenched with water and the organic layer was separated. The aqueous layer was neutralized by addition of 1N NaOH. The resulting precipitate was filtered off, dried and used without further purification. Yield: 0.174 g (59.2%); MS m/z: 295.1 [M+H]+; 1H-NMR (400 MHz, DMSO d6): 3.04-3.06 (m, 1H); 3.72-3.77 (m, 1H); 5.30-5.33 (m, 1H); 6.62-6.64 (m, 2H); 6.84 (s, 1H); 7.09-7.11 (m, 2H); 7.17-7.19 (m, 1H); 7.34-7.36 (d, 1H, 3J=8.7 Hz); 7.46 (s, 1H); 8.03 (s, 1H); HPLC (P31/98): rt 6.66 min (100%)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]=[C:24]([C:26]([O:28]CC)=[O:27])[N:25]=1)[NH:6]2.[OH-].[K+]>O1CCCC1.CO.C(OCC)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[N:25]=1)[NH:6]2
Reactant: CCOC(=O)c1csc(-c2cc3c(C)ccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3nc(C(=O)O)cs3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
Ethyl 2-{4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazole-4-carboxylate (0.40 g) was dissolved in a mixed solution of tetrahydrofuran (15 mL) and methanol (15 mL), aqueous solution (5 mL) of 85% potassium hydroxide (0.20 g) was added, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (368 mg, yield 98%) as pale-yellow crystals. MS:434 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(N(CC)CC)C.[Cl:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])=[CH:38][CH:37]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 19.1 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (38.1 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (73 μL) was added followed by 4-chloroaniline (58.9 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58.0 mg) and 4-dimethylaminopyridine (˜1 mg). The mixture was stirred at room temperature for 45 min then eluted directly on silica gel column (98:2 CH2Cl2:MeOH) then on one 250 μm silica gel plate (1:1 hexanes:acetone) to yield 9.5 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.46 (br s, 1H); 8.39 (d, J=5.5 Hz, 1H); 7.98 (s, 1H); 7.90 (s, 1H); 7.82 (d, J=6.4 Hz, 1H); 7.75 (d, J=7.6 Hz, 1H); 7.65 (d, J=7.6 Hz, 1H); 7.58 (d, J=8.7 Hz, 2H); 7.51 (t, J=7.7 Hz, 1H); 7.33 (m, 3H); 6.80 (d, J=5.5 Hz, 1H); 5.94 (br s, 1H); 5.26 (br s, 1H); 1.67 (d, J=6.9 Hz, 3H). Mass Spectrum (ESI): m/e 469.2 (M+1).