Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:18])[C:5](=[CH:11][NH:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:18])=[C:14]2[S:15][CH:16]=[CH:17][C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccsc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2ccsc2c1O
Temperature: 25 °C
Yield: 76 %

Procedure:
Add 2-(thiophen-3-ylaminomethylene)-malonic acid diethyl ester (7.66 g, 28.4 mmol) to refluxing phenyl ether (100 ml) over a period of 5 min under nitrogen. After the addition is complete, keep the reaction under reflux for 30 min. Cool the reaction mixture to room temperature, and then pour it into ethyl acetate (1000 ml). Collect the brown precipitate by filtration to obtain 7-hydroxy-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (4.82 g, 76%). MS (ES+): 224 (M+H); (ES−): 222 (M−H).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](/Cl)\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:4][CH3:5].C([Li])(C)(C)C.[CH2:35]1[O:38][CH2:37][CH2:36]1.O>O1CCCC1>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)/[CH2:35][CH2:36][CH2:37][OH:38])=[CH:13][CH:14]=1)[CH2:4][CH3:5]
Reactant: CCN(CC)CCOc1ccc(/C(=C(/Cl)c2ccccc2)c2ccccc2)cc1
Reactant: C1COC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CCOc1ccc(/C(=C(/CCCO)c2ccccc2)c2ccccc2)cc1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Clomiphene (3.8 g, 9.3 mmol) was dissolved in tetrahydrofuran (50 ml), cooled to -40° C. and then treated with t-butyl lithium (1M in pentane, 20 mmol). After 10 minutes, trimethylene oxide (6 ml, 93 mmol) was added, the mixture stirred for 16 hours at room temperature, and then poured into water. The product was extracted with ether and chromatographed on a silica gel column using 1:1:0.1 ether/petroleum ether/triethylamine as eluant to yield purified trans-product (1 g, 25%), m.p. 93°-95° C. and cis- product (N,N-diethylhydroxymethyl tamoxifen) (1.0 g, 25%), m.p. 85°-87° C. Anal. (C29H35NO2)C,H,N. Calc., C:81.08, H:8.21, N:3.26; Found, C:80.56, H:7.94, N:3.32. Values for aliphatic protons are presented in Table 3.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([CH:14]=[O:15])[CH:3]=1.O.P([O-])(O)(O)=[O:18].[Na+].OO.Cl([O-])=O.[Na+]>C(#N)C.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([C:14]([OH:18])=[O:15])[CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: COc1c(C=O)cc(F)c2ccccc12
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1c(C(=O)O)cc(F)c2ccccc12
Reaction time: 2.5 h
Yield: 280.5 %

Procedure:
9.3 g of 4-fluoro-1-methoxynaphthalene-2-carbaldehyde were dissolved in 100 mL of acetonitrile. 2.1 g sodium dihydrogenphosphate monohydrate in 10 mL of water were added, followed by the addition of 9.5 mL hydrogen peroxide (30%). 8.9 g sodium chlorite, dissolved in 20 mL water were added dropwise while maintaining an internal temperature between 5° C. and 15° C. The reaction was then allowed to come to room temp over 2.5 h. The precipitated solid was filtered with suction, and the solid was washed with water, and dried in vacuo at 40° C. to yield 9.4 g of 4-fluoro-1-methoxynaphthalene-2-carboxylic acid. The filtrate was treated with 60 mL of cold 10% aqueous sodium bisulfite solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was washed with 0.2 N NaOH twice. The washes were acidified with 6 N HCl to pH 3, whereupon crystallization occurred. The precipitating product was filtered, washed with water and dried in vacuo at 40° C. to yield a second batch of 1.0 g of 4-fluoro-1-methoxynaphthalene-2-carboxylic acid.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[CH:12][CH2:13][CH2:14][NH:15][CH3:16])[C:9]3[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=1)=[O:28].C(=O)(O)[O-].[K+].[ClH:44]>CN(C=O)C.O.CC(O)C.CCOCC>[ClH:44].[CH:1]1[C:11]2[C:10](=[CH:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=3)=[O:28])[C:9]3[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CNCCC=C1c2ccccc2COc2ccccc21
Reactant: CC(C)(C)c1ccc(C(=O)CCCCCBr)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: O
Product: CN(CCC=C1c2ccccc2COc2ccccc21)CCCCCC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-dibenz[b,e]oxepin-11(6H)-ylidene-N-methyl-1-propanamine (10.0 g, 0.033 mol) in DMF (80 mL) were added 6-bromo-1-[4-(1,1-dimethylethyl)phenyl]-1-hexanone (10.3 g, 0.033 mol) and potassium bicarbonate (6.6 g, 0.066 mol). The mixture was heated to 75°-80° C. under nitrogen for 28 hours. The reaction was cooled to ambient temperature, diluted with water (300 mL) and extracted with ethyl acetate (2×150 mL). The combined ethyl acetate extracts were washed with water (3×150 mL) and saturated NaCl (100 mL) and dried over magnesium sulfate. Removal of solvent gave an oil of 17.1 g. This oil was dissolved in 2-propanol (100 mL) and acidified with HCl gas. The solution was diluted to 400 mL with anhydrous ether and cooled. The solid was collected by filtration, recrystallized twice from ethyl acetate-methanol (15:1),and vacuum dried at 70° C. for 92 hours to provide 5.69 g of 3-dibenz[b,e]oxepin-11(6H)-ylidene-N-methyl-N-[6-[4-(1,1-dimethylethyl)phenyl]-6-oxohexyl]-1-propanamine hydrochloride, mp 159°-161° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][CH2:12][CH2:13]O>OS(O)(=O)=O.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:13][CH2:12][Cl:11])=[O:6]
Reactant: OCCCl
Reactant: O=C(O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(OCCCl)c1cccc(O)c1

Procedure:
A solution of 65 g of 3-hydroxybenzoic acid (0.47 mol) in 500 mL of 2-chloroethanol and 3 mL of H2SO4 was refluxed for 4 hours. The cooled solution was diluted with 500 mL of water and extracted with ethyl acetate (3×250 mL). The ethyl acetate was extracted twice with aqueous NaHCO3 and then with water. The ethyl acetate solution was dried and evaporated under reduced pressure yielding 85 g of product as a thick oil; 1H NMR (CDCl3) δ3.814 (t,2H, J=6 Hz), 4.569 (t,2H, J=6 Hz), 5.36 (br s,1H), 7.06-7.67 (m,4H). ##STR12##
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([O:19]CC)=[O:18])=[CH:15][N:16]=3)[CH:13]=2)=[C:5]([CH3:7])[N:6]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([OH:19])=[O:18])=[CH:15][N:16]=3)[CH:13]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: CCOC(=O)c1cnc2ccc(-c3sc(C)nc3C)cn12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C)c(-c2ccc3ncc(C(=O)O)n3c2)s1
Temperature: 60 °C

Procedure:
A mixture of ethyl 6-(2,4-dimethylthiazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylate (145) (190 mg, 0.630 mmol) and 2N LiOH (1 mL) in THF:MeOH (4:1, 4 mL) was heated at 60° C. for 30 minutes. The reaction was cooled to room temperature and the pH was adjusted between 4-5 with 10% citric acid. The solvent was partially reduced and the resulting solid was collected by vacuum filtration to give 6-(2,4-dimethylthiazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (146). 1H NMR (400 MHz, d6-DMSO) δ 9.34 (s, 1H), 8.29 (s, 1H), 7.87 (dd, J=0.8, 9.2 Hz, 1H), 7.62 (dd, J=2.0, 9.2 Hz, 1H), 2.66 (s, 3H), 2.41 (s, 3H). MS m/z 274.06 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17](Cl)[N:16]=1>C1COCC1.O>[Cl:21][C:19]1[CH:20]=[C:15]([Cl:14])[N:16]=[C:17]([NH:9][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:8]=[CH:7][N:6]=2)[CH:18]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccnc(Nc2cc(Cl)cc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(trifluoromethyl)pyridin-2-amine (3.24 g, 20.0 mmol) and sodium hydride (1.2 g, 30 mmol) in THF (60 mL) was stirred at 0° C. under nitrogen for 1 hour, and then 2,4,6-trichloropyridine (3.62 g, 20.0 mmol) was added. The reaction was stirred at 25° C. for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give 4,6-dichloro-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine. MS ESI calc'd. for C11H7Cl2F3N3 [M+H]+ 308. found 308. 1H NMR (400 MHz, CD3OD): δ 8.49 (d, J=5.6 Hz, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.19 (d, J=1.2 Hz, 1H), 7.05 (d, J=1.2 Hz, 1H).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]=[CH2:23])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:24])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H][H]>[Pd].C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH2:22][CH3:23])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:24])[CH:14]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C=Cc1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 42 h
Yield: 74.5 %

Procedure:
A mixture of 4-(adamantan-1-ylmethoxy)-2-fluoro-5-vinylbenzoic acid (1.00 g, 3.03 mmol) and 10% palladium on activated carbon (0.10 g) in ethyl acetate (150 mL) was fitted with a hydrogen balloon. The reaction mixture was stirred at ambient temperature for 42 h. The mixture was filtered through a pad of diatomaceous earth, and washed with ethyl acetate (50 mL). The filtrate was concentrated in vacuo, the residue was recrystallized from ethyl acetate and hexanes to afford the title compound as an off-white solid (0.75 g, 74%): 1H NMR (300 MHz, DMSO-d6) δ 12.80 (br s, 1H), 7.63 (d, J=8.6 Hz, 1H), 6.87 (d, J=13.2 Hz, 1H), 3.61 (s, 2H), 5.57 (d, J=7.5 Hz, 2H), 1.99 (s, 3H), 1.75-1.63 (m, 12H), 1.14 (t, J=7.5 Hz, 3H); MS (ES+) m/z 333.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([CH3:49])(=[O:47])=[O:48])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(O)cc(NS(C)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 84.1 %

Procedure:
(S)—N-(3-Hydroxy-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (40 mg, 0.05 mmol) was treated with trifluoroacetic acid (920 μl, 11.94 mmol) and a solution of ammonia (7N in methanol, 920 μl, 6.44 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 6% dichloromethane-2-propanol) to obtain 24 mg (78% yield) of the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24](O)=[O:25])=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:68][C:69]1[S:70][CH:71]=[CH:72][N:73]=1>CN(C=O)C.O>[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24]([NH:68][C:69]3[S:70][CH:71]=[CH:72][N:73]=3)=[O:25])=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1
Reactant: Nc1nccs1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
DIPEA (0.25 mL, 1.5 mmol) was added to a suspension of 3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (243 mg, 0.5 mmol), HATU (248 mg, 0.65 mmol) and 2-amino-1,3 thiazole (150 mg, 1.5 mmol) in DMF (3 mL). The resulting mixture was stirred at RT for 16 hours, water (45 mL) was added and the mixture extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (284 mg).
Reaction SMILES: CN(C)CCN1C2C(=CC([N+]([O-])=O)=CC=2)CC1.[H][H].[N+](C1C=C2C(=CC=1)N(CCN1CCCC1)CC2)([O-])=O.O1CCN(CCN2C3C(=CC(N)=CC=3)CCC2)CC1.O=[C:59]1[N:65]([CH2:66][CH2:67][N:68]2[CH2:73]CCC[CH2:69]2)[C:64]2[CH:74]=[CH:75][C:76]([NH:78][C:79]([C:81]3[S:82][CH:83]=[CH:84][CH:85]=3)=[NH:80])=[CH:77][C:63]=2[CH2:62]CC1>C(O)C.C([O-])(O)=O.[Na+].[Pd]>[CH3:73][N:68]([CH3:69])[CH2:67][CH2:66][N:65]1[C:64]2[C:63](=[CH:77][C:76]([NH:78][C:79]([C:81]3[S:82][CH:83]=[CH:84][CH:85]=3)=[NH:80])=[CH:75][CH:74]=2)[CH2:62][CH2:59]1
Reactant: [H][H]
Reactant: N=C(Nc1ccc2c(c1)CCCC(=O)N2CCN1CCCCC1)c1cccs1
Agent: [Pd]
Agent: CN(C)CCN1CCc2cc([N+](=O)[O-])ccc21
Agent: Nc1ccc2c(c1)CCCN2CCN1CCOCC1
Solvent: CCO
Product: CN(C)CCN1CCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C

Procedure:
A solution of compound 2 (183 mg, 0.778 mmol) and Pd—C (82 mg, 0.078 mmol, 10% wt) in dry ethanol (5 mL) was purged with hydrogen gas. The reaction was stirred at room temperature over night under hydrogen atm. (balloon pressure). Then the reaction mixture was filtered through a celite pad and washed with ethanol (35 mL). The filtrate (compound 3) was treated with imidate 4 (444 mg, 1.559 mmol) and stirred over night at room temperature. The reaction was diluted with saturated NaHCO3 solution (50 mL) and product was extracted into CH2Cl2 (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel: 2% methanol: 98% CH2Cl2 followed by 2.5% 2M NH3 in methanol: 97.5% CH2Cl2 followed by 5% 2M NH3 in methanol: 95% CH2Cl2, to give a greenish/yellow solid (90 mg, yield). 1H-NMR (DMSO-d6) δ 7.68 (d, J=2.7 Hz, 1H), 7.56 (dd, J=5.1, 1.2 Hz, 1H), 7.07 (dd, J=3.6, 5.1 Hz, 1H), 6.62 (s, 1H), 6.55-6.46 (m, 2H), 6.28 (s, 2H), 3.32-3.27 (m, 2H), 3.09 (t, J=6.6 Hz, 2H), 2.84 (t, J=8.1 Hz, 2H), 2.45 (t, J=6.9 Hz, 2H), 2.20 (s, 6H). ESI-MS (m/z, %): 315 (MH+, 100), 244 (29), 127 (38); ESI-HRMS calculated for C17H23N4S (MH+): calculated 315.1637, Observed: 315.1645: HPLC purity: 95.3%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:8][CH:9]=1)=[O:4].C(Cl)(Cl)[Cl:19]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:8]([Cl:19])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(OCCn2ccnc2)s1
Reactant: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)c(OCCn2ccnc2)s1
Temperature: -40 °C

Procedure:
0,15 g of 5-[2-(1-imidazolyl)-1-ethoxy]-thiophene-2-carboxylic-acid methyl ester (formula I: R=H, R1 =CH3) were dissolved in 5 ml of absolute chloroform, cooled to -40° C. and 0,16 g (1,19 mol) of SO2Cl2 were dropped thereto such that the temperature did not exceed -35° C. After standing over night it was evaporated in vacuo, the residue was partioned between 2N HCl and ether, the aqueous phase was extracted several times with ether, neutralized with sodium hydrogen carbonate and extracted several times with methylene chloride. The combined methylene chloride phases were dried (sodium sulfate) and evaporated, the residue from the evaporation was separated by column chromatography (eluant: benzene/ethanol 9:1). Yield 73 mg (43%), melting point 97°-99° C. (benzene/ether), colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:31]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]([F:41])([F:40])[F:39])[CH2:34][CH2:33]2)=[CH:30][C:8]2[N:9]([CH3:29])[C:10]([NH:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([CH2:20][NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]=3[Cl:28])=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[Cl:28][C:14]1[C:15]([CH2:20][NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[NH:12][C:10]1[N:9]([CH3:29])[C:8]2[CH:30]=[C:31]([N:32]3[CH2:33][CH2:34][CH:35]([C:38]([F:41])([F:40])[F:39])[CH2:36][CH2:37]3)[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c2cc1N1CCC(C(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester (2.54 g, 4.17 mmol), 50% aq NaOH-solution (10.3 ml) and MeOH (41 ml) is stirred for 2.5 h at rt and concentrated. The concentrate is acidified with 4N HCl (to pH ˜6) and the precipitate is filtered, washed with water and dried.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.[CH3:34][C:35]1([CH3:42])[C:39]([CH3:41])([CH3:40])[O:38][BH:37][O:36]1.[C:43]([NH:46][C:47]([C@@H:59]1[CH2:63][CH2:62][N:61]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[CH2:60]1)([CH2:55][CH2:56][CH:57]=[CH2:58])[C:48]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])(=[O:45])[CH3:44]>C(=O)(O)[O-].[Na+].C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Ir].[Ir]>[C:43]([NH:46][C:47]([C@@H:59]1[CH2:63][CH2:62][N:61]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[CH2:60]1)([CH2:55][CH2:56][CH2:57][CH2:58][B:37]1[O:38][C:39]([CH3:41])([CH3:40])[C:35]([CH3:42])([CH3:34])[O:36]1)[C:48]([NH:50][C:51]([CH3:54])([CH3:52])[CH3:53])=[O:49])(=[O:45])[CH3:44]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)[C@@H]1CCN(Cc2ccc(F)cc2)C1
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: C1=CCCC=CCC1
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)[C@@H]1CCN(Cc2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of bis(1,5-cyclooctadiene)diiridium(I) dichloride (35.0 mg, 0.0520 mmol) and 1,2-bis(diphenylphosphino)-ethane (44 mg, 0.11 mmol) in tetrahydrofuran (5 mL, 60 mmol) was cooled to 0° C. After stirring for 10 min 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (120 uL, 0.83 mmol) was added in a single portion via syringe and the reaction mixture was stirred at 0° C. for 5 min before warming to room temperature and stirring an additional 15 min. The reaction mixture was recooled to 0° C. and treated with 2-acetamido-N-tert-butyl-2-[(3R)-1-(4-fluorobenzyl)pyrrolidin-3-yl]hex-5-enamide (210 mg, 0.52 mmol) in tetrahydrofuran (3 mL, 40 mmol) in a single portion. After stirring for 10 min at 0° C., the reaction was warmed to room temperature and stirred an additional 4 h. The mixture was diluted with aqueous sodium bicarbonate, extracted with DCM (3×50 mL), dried over Na2SO4, filtered and concentrated to give 2-acetamido-N-tert-butyl-2-((R)-1-(4-fluorobenzyl)pyrrolidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide as a light orange oil that was used without further purification. ESI MS found for C29H47BFN3O4 m/z 532.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[C:19]([CH3:25])=[N:20][N:21]([CH3:24])[C:22]=1[Cl:23]>CN(C=O)C>[Cl:23][C:22]1[N:21]([CH3:24])[N:20]=[C:19]([CH3:25])[C:18]=1[CH2:17][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1nn(C)c(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2c(C)nn(C)c2Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (437 mg, 3.0 mmol) was dissolved in anhydrous DMF (25 mL), then potassium carbonate (1.27 g, 9.2 mmol) and crude 4-(bromomethyl)-5-chloro-1,3-dimethyl-1H-pyrazole (1.03 g, 4.6 mmol) were added. The mixture was stirred for 3 hours at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM/MeOH to afford 2-{[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (190 mg, 22% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.17 (s, 3H), 2.20 (s, 3H), 3.70 (s, 3H), 4.20 (s, 2H), 5.76 (bs, 1H); LRMS (ES+) m/z 285 (80%, M+1), 287 (30%, M+3).
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@@H:15]([C@H:17]2[CH2:22][CH2:21][CH2:20]C[N:18]2C(C2C=CC=CC=2)C2C=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2].N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@@H]1N(C(C2C=CC=CC=2)C2C=CC=CC=2)C[C@H](O)C1)[OH:61].FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H](O)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.[Li+].[OH-]>CCO.O>[C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:38]=[C:39]([F:44])[CH:40]=[C:41]([F:43])[CH:42]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:22][C@@H:21]([OH:61])[CH2:20][NH:18]2)=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](O)CN1C(c1ccccc1)c1ccccc1
Agent: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](O)CN2)C1=O
Temperature: 25 °C

Procedure:
Step 14 (A): (3R,5R)-5-((1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl)-1-benzhydrylpyrrolidin-3-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)oxazolidin-2-one (Preparation J, 129 mg, 0.278 mmol) in EtOH (10 mL) was added a solution of LiOH (133 mg, 5.56 mmol) in H2O (2.5 mL). This reaction mixture was stirred at reflux for 3.5 h. After cooling down to rt, the mixture was concentrated to remove EtOH and the mixture was extracted with ethyl acetate and the organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-10% MeOH/chloroform) gave the title compound: 1H NMR (CDCl3, 500 MHz) δ 2.00-2.05 (1H, m), 2.13-2.21 (1H, m), 2.40-2.61 (2H, m), 2.79-2.91 (2H, m), 3.21 (2H, d, J=15 Hz), 3.51 (1H, d, J=15 Hz), 4.26 (1H, m), 4.79 (1H, s), 6.62-6.70 (3H, m), 7.14-7.26 (4H, m), 7.30-7.35 (3H, m), 7.37-7.43 (3H, m). HPLC retention time: 1.19 min (method A). MS (ESI) (M+H)+ 439.22.