Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C.C1COCC1.O.CCOCC.CCCCCC>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:6]=[CH:5]2)[CH3:28]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc2c(ccn2Cc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)CCCOc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 0.17 h
Yield: 40.4 %

Procedure:
A solution of 850 mg (4.0 mmol) of 5-hydroxy-1-(phenylmethyl)-1H-indole in 75 mL of DMF and 20 mL of THF was treated with 200 mg (5.0 mmol) of 60% NaH/mineral oil and after stirring for 0.17 hours, 0.7 mL (4.9 mmol) of ethyl 4-bromobutyrate was added. After 2.75 hours, the mixture was diluted with water and extracted with EtOAc. The EtOAc solution was washed with water, saturated NaCl solution, dried(Na2SO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and the 545 mg (40% yield) of 4-[[l-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester by eluting with a gradient, 15% ether/hexane→50% ether/hexane.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[OH:27])[C:21]([OH:23])=O)=[O:17].ON1C(=O)CCC1=O.Cl.[CH3:37][O:38][C:39](=[O:49])[C@H:40]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH2:41].C(N(CC)CC)C>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:37][O:38][C:39](=[O:49])[C@H:40]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:41][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][C:26]([OH:27])=[C:18]([CH:16]=[O:17])[CH:19]=1
Reactant: O=Cc1cc(C(=O)O)ccc1O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(O)c(C=O)c1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
87 mmol of dicyclohexylcarbodiimide are added to a stirred suspension, cooled to 10° C, containing 80 mmol of 3-formyl-4-hydroxybenzoic acid (prepared according to H. WYMBERG, J. Am. Chem. Soc., 76, 4998, 1954) and 87 mmol of N-hydroxysuccinimide in 320 ml of chloroform. After re-equilibrating to room temperature, the mixture is kept stirring overnight. The precipitate is then filtered. The filtrate is cooled to 8° C. and treated dropwise, with stirring, with a suspension containing 160 mmol of phenylalanine methyl ester hydrochloride and 160 mmol of triethylamine in 100 ml of anhydrous dimethylformamide. The mixture is stirred for 3 hours at 20° C. and then for 5 hours at 50° C. After cooling and evaporation of the solvents, the residue is taken up in 400 ml of ethyl acetate. After washing this solution with 1N hydrochloric acid and then with water, the organic phase is dried and evaporated. The oily residue leads to the expected product by crystallization from toluene.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](B(CC)CC)[CH3:32]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:31][CH3:32])[N:13]=[C:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCB(CC)CC
Reactant: CC(C)(C)OC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)cc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(NC(=O)OC(C)(C)C)n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
tert-Butyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-chloropyridin-2-ylcarbamate (11-4, 0.496 g, 1.33 mmol) was dissolved in 2 mL DMF. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.087 g, 0.11 mmol), cesium carbonate (2.601 g, 7.98 mmol), and triethylborane (1M in hexanes) (3.190 mL, 3.19 mmol) were added and the solution was heated to 50° C. After 24 hours the reaction was allowed to cool to room temperature and was concentrated to afford a brown oil. The oil was filtered through celite and washed with CH2Cl2. The filtrate was concentrated to afford a light brown oil. The oil was purified by flash column chromatography (10:90 EtOAc/hexanes) to afford tert-butyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-ethylpyridin-2-ylcarbamate as a light yellow oil. Free base: 1H NMR (CDCl3) δ 7.60 (s, 1H), 7.14 (bs, 1H), 6.91 (s, 1H), 4.71 (s, 2H), 2.68 (q, 2H, J=7.63 Hz), 1.51 (s, 9H), 1.25 (t, 3H, J=7.63 Hz), 0.95 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]([CH3:18])[N:10]=2)=[CH:5][C:4]=1[CH3:19].Br>C(O)(=O)C>[CH3:19][C:4]1[CH:5]=[C:6]([C:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]([CH3:18])[N:10]=2)[CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccc(-c2cc(C(F)(F)F)n(C)n2)cc1C
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(F)(F)F)n(C)n2)ccc1O
Yield: 527.4 %

Procedure:
A mixture of 3-(4-methoxy-3-methyl-phenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole (described in Reference Preparation example 78) 0.4 g, 47% hydrobromic acid 24 ml and acetic acid 24 ml was stirred with heating under reflux for twelve hours. The solvent was distilled off and to the resulting residues was added ice water 70 ml. The precipitates were filtered and were washed with ice water 70 ml, and then were concentrated under, reduced pressure to give 2-methyl-4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenol 2 g.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH2:15])([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O1CCOCC1.[OH-].[Na+].C(O)(C(F)(F)F)=O>[CH2:20]([O:19][C:17](=[O:18])[NH:15][C:11]1([CH3:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC1(NC(=O)OCc2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
4-Amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester 80E (4.19 g, 19.6 mMol) was dissolved in a solution of 50 mL of dioxane and 20 mL of aqueous 2 N NaOH under an atmosphere of dry N2. To this solution was slowly added benzyl chloroformate (5.6 mL, 39 mMol) and the reaction was stirred for 3 hours at ambient temperature. The reaction mixture was concentrated under vacuum. The reaction mixture was dissolved in DCM and successively washed three with aqueous 1 N NaOH. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum to give a yellow oil. The oil was dissolved in 15 mL of TFA under an atmosphere of dry N2. The reaction mixture was concentrated under vacuum and partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum to give 3.06 g of an oil. The oil was chromatographed on flash silica gel eluting with DCM to remove less polar impurities then with MeOH/DCM/NH4OH (20179.90.1) to give 2.85 g of the title compound 80F as an oil.
Reaction SMILES: Cl.C(O)(=O)C.C([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([O:33]CC)=[O:32])=[CH:18]2)[CH:14]=[CH:13][C:12]=1[F:36])(C)(C)C>O>[NH2:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([OH:33])=[O:32])=[CH:18]2)[CH:14]=[CH:13][C:12]=1[F:36]
Reactant: CCOC(=O)c1cn(-c2ccc(F)c(NC(C)(C)C)n2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To 2 ml of mixed solution (1:1) of 4N hydrochloric acid and acetic acid was added 450 mg of ethyl 1-[6-(t-butyl-amino)-5-fluoropyridine-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 3 hours. After adding 1 ml of distilled water, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 342 mg of the title compound as a colorless powder.
Reaction SMILES: [CH:1]([C:19]([O:21]CC1C=CC=CC=1)=[O:20])([C:9]([O:11]CC1C=CC=CC=1)=[O:10])[C@@H:2]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:3]>CO.[Pd]>[CH2:7]([O:6][C:4](=[O:5])[C@H:2]([CH:1]([C:19]([OH:21])=[O:20])[C:9]([OH:11])=[O:10])[CH3:3])[CH3:8]
Reactant: CCOC(=O)[C@@H](C)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@H](C)C(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To the solution of (S)-1,1-dibenzyl 2-ethyl propane-1,1,2-tricarboxylate (23 g, 0.06 mol) in methanol (500 mL) was added palladium on carbon (10%, 2 g), and then the mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The catalyst was filtrated and the filtrate was concentrated under reduced pressure to afford the crude product (S)-2-(1-ethoxy-1-oxopropan-2-yl)malonic acid, which was purified by silica gel chromatography (10 g, yield 83%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:10]1([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[O:9][C:8]2=[O:17].[C:18]1([C:24]2[CH:25]=[N:26][C:27]([NH:30][C:31](=O)[O:32]C3C=CC=CC=3)=[N:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:10]1([CH2:11][CH2:12][N:13]([C:31]([NH:30][C:27]3[N:26]=[CH:25][C:24]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:29][N:28]=3)=[O:32])[CH2:14][CH2:15]1)[O:9][C:8]2=[O:17]
Reactant: O=C(Nc1ncc(-c2ccccc2)cn1)Oc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2c(F)cccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1OC2(CCN(C(=O)Nc3ncc(-c4ccccc4)cn3)CC2)c2c(F)cccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A mixture of 7-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (150 mg), phenyl N-(5-phenyl-2-pyrimidinyl)carbamate (170 mg) and triethylamine (0.24 mL) in chloroform (2 mL) was stirred at 60° C. for 2 hours. The reaction mixture was diluted with ethyl acetate. The whole was washed with 10% citric acid aqueous solution, saturated aqueous sodium bicarbonate and saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the reaction mixture left a residue, which was recrystallized from ethyl acetate to give the subject compound (202 mg) as colorless crystals (melting point 244-246° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)[CH2:27][CH2:28]CN=C=NCC.C(N(CC)CC)C.N1(C2C=CN=CC=2)CCCC1.C(O)C>C(Cl)Cl>[CH2:27]([O:22][C:21]([CH:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:23])[CH3:28]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a stirred solution of N,N'-di-tert-butyloxycarbonylpiperazine-2-carboxylic acid (4.6 g, 0.013 mol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (3.2 g, 0.016 mol), triethylamine (2.2 mL, 0.016 mol) and 4-pyrrolidinopyridine (0.23 g, 1.5 mmol) in CH2Cl2 (120 mL) was added ethanol (0.93 mL, 0.016 mol). The mixture was left stirring overnight, then the mixture was washed with water (2×50 mL), 5% aqueous acetic acid (2×300 mL) and water (2×50 mL). The organic phase was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with petrol:EtOAc (1:1) to give the ester (3.3 g, 72%) as a colourless oil. 1H NMR (360 MHz, CDCl3) δ 1.28 (3H, t, J=7.1 Hz), 1.44 (9H, s), 2.70-3.32 (3H, m), 3.70-4.12 (2H, m), 4.14-4.26 (2H, m), 4.46-4.76 (2H, m). MS (ES+) 359 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[SH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([S:11][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(O)c1ccc(O)cc1
Product: O=C(Sc1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 16 h
Yield: 24.4 %

Procedure:
A PPE (polyphosphate ester) solution (7 mL) was added to a mixture of 4-hydroxybenzoic acid (552 mg, 4 mmol) and 4-mercaptophenol (554 mg, 4.4 mmol). After stirring for 16 h, the solvents were removed by evaporation and the residue was purified by column chromatography (hexane-EtOAc 7:1 to 1:1). 4-Hydroxy-thiobenzoic acid S-(4-hydroxy-phenyl) ester (240 mg, 24%) was obtained as a white solid. MS (ES) m/z: 247.04 (M+1), 167.03, and 122.55. 13C-NMR (DMSO-d6): δ 188.24, 162.85, 158.82, 135.87, 129.59, 127.10, 116.33, 115.72, and 115.34.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C:6]2=[CH:7][CH:8]=1)=C.I([O-])(=O)(=O)=[O:33].[Na+].N1C(C)=CC=CC=1C.S([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O.O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C:6]2=[CH:7][CH:8]=1)=[O:33]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(C=O)cc12
Reaction time: 3 h
Yield: 81.5 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-vinylspiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (674 mg, 1.52 mmol) was dissolved in dioxane (15 mL). Thereafter, sodium periodate (1.30 g, 6.08 mmol), water (5 mL), 2,6-lutidine (0.35 mL, 3.01 mmol), and osmium tetroxide (1% t-butanol aqueous solution, 1 mL) were added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at the same temperature as above for 3 hours. Thereafter, an aqueous solution of sodium sulfite was added to the reaction solution, and the mixture was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=5:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-formylspiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (553 mg, 82%) in the form of a light yellow solid.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:18][Mg]Cl.FC1C=C(C=CC=1)/C=C1\CCC2NC(C(OC)=O)=CC\1=2>C(OCC)C.O=[Pt]=O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: Fc1cc(Cl)cc(C[Mg]Cl)c1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: O=[Pt]=O
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cccc(F)c1
Solvent: CCOCC
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cc(F)cc(Cl)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.40 g, 2.23 mmol) was reacted with 3-chloro-5-fluorobenzylmagnesium chloride ((0.25 M in diethyl ether, 23.0 mL, 5.6 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3-chloro-5-fluorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with PtO2). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound. 0.045 g The material was taken on to hydrolysis in impure form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>O1CCCC1.ClCCl>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 90 mg of 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide in 5 mL of tetrahydrofuran are added dropwise 50 μL of 2-fluoro-5-(trifluoromethyl)phenyl isocyanate. The reaction mixture is stirred for 16 hours at room temperature under an argon atmosphere and then concentrated under reduced pressure. The residue obtained is stirred for 30 minutes in 2 mL of dichloromethane. The suspended solid is filtered off and drained by suction. After drying under vacuum, at 40° C., 115 mg of 3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]-pyridine-2-carboxamide are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23]Br>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]2[Br:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: BrBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.8 %

Procedure:
To a suspension of ethyl 5-benzyloxyindole-2-carboxylate (21.9 g, 74.0 mmol) in DMF (30 mL) was added dropwise over 10 min a solution of bromine (11.83 g, 74.0 mmol, 3.8 mL) in DMF (40 mL). After stirring an additional 20 min at room temperature, the solution was partitioned between 3 N HCl and ethyl acetate. The organic layer was washed sequentially with water, saturated aqueous sodium bicarbonate, water and saturated brine, then dried (MgSO4), filtered and concentrated to leave a white solid. The solid was recrystallized from ethyl acetate to provide the title compound (19.6 g, 71%). 1H NMR (400 MHz, CDCl3) δ 8.96 (br s, 1H), 7.52-7.30 (m, 6H), 7.15-7.10 (m, 2H), 5.14 (s, 2H), 4.46 (q, J=7.1 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[Cl:9][C:10]1[C:11]([N+:21]([O-:23])=[O:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15](Cl)=[O:16].[OH-].[Na+]>O.ClC(Cl)Cl>[Cl:9][C:10]1[C:11]([N+:21]([O-:23])=[O:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15]([N:1]1[CH2:3][CH2:2]1)=[O:16]
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1C(=O)Cl
Reactant: C1CN1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc([N+](=O)[O-])c(Cl)cc1C(=O)N1CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To 230 parts of a solution of aziridine in water 0.875M are added 15 parts of sodium hydrogen carbonate while cooling at 0° C. Then there is added dropwise, during a 45 minutes-period, a solution of 42.5 parts of 5-chloro-2-methoxy-4-nitrobenzoyl chloride in 150 parts of trichloromethane at 0° C and while stirring vigorously. The mixture is diluted with about 150 parts of trichloromethane and the whole is stirred for 45 minutes without cooling. The reaction mixture is alkalized to pH 8 with a diluted sodium hydroxide solution. The product is extracted three times with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated, yielding 40 parts of 1-(5-chloro-2-methoxy-4-nitrobenzoyl)aziridine.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].Cl[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[S:16][C:9]=12.[F:26][C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[OH:36].C([O-])([O-])=O.[Na+].[Na+]>O(C1C=CC=CC=1)C1C=CC=CC=1.CO.C(Cl)Cl.CCOC(C)=O.CCCCCC.C(Cl)Cl>[F:26][C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[O:36][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[S:16][C:9]=12
Reactant: CN1CCN(C(=O)c2cc3nccc(Cl)c3s2)CC1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CN1CCN(C(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Temperature: 190 °C
Yield: 73.3 %

Procedure:
MgSO4 (1.41 g, 11.78 mmol) was added to a suspension of 436 (1.16 g, 3.93 mmol), 2-fluoro-4-nitrophenol (1.23 g, 7.85 mmol) and Na2CO3 (1.24 g, 11.78 mmol) in Ph2O (10 mL). The suspension was heated at 160° C. for 1.5 h and at 190° C. for 2 h. After cooling to room temperature, DCM (30 mL) was added and the reaction mixture was filtered and concentrated. The residue was purified by biotage (SNAP 25 g cartridge; AcOEt/Hexane:10/90 over 5 CV then MeOH/DCM: 0/100 to 10/90 over 20CV), to afford the title compound 437 (1.20 g, 2.88 mmol, 73% yield) as a yellow solid. MS (m/z): 417.2 (M+H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@@H:12]([CH3:16])[CH2:13][CH:14]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:28]1([CH2:14][CH2:13][C@@H:12]([C@@H:11]2[C@:17]3([CH3:25])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:21]([C:20]=4[CH2:19][CH2:18]3)([CH3:24])[CH2:22][CH2:23][C@H:2]([OH:1])[C:3]5([CH3:27])[CH3:26])=[CH:9][CH2:10]2)[CH3:16])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@@H](CCN1CCOCC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde was treated with morpholine and sodium tris(acetoxy)borohydride as described in Example 9d). (20S)-20-[(morpholin-4-yl)ethyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[CH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:15]1([S:12]([N:11]2[CH:3]=[CH:4][NH:5][C:6](=[O:21])[C@H:7]2[CH2:8][C:9]#[CH:10])(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)NCC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of (R)-N-(2,2-dimethoxyethyl)-2-(benzenesulfonamido)pent-4-ynamide (10.55 g, 30.99 mmol) and p-toluenesulfonic acid (1.47 g, 7.75 mmol) p-dioxane (100 mL) was heated to 60° C. for 36 h. The reaction mixture was cooled, concentrated and taken up in EtOAc. After the organic mixture had stirred, a precipitate had formed that was filtered to afford the product as a tan solid. 1H NMR (300 MHz, DMSO-d6): δ 2.98 (s, 1H), 3.35 (d, 7.0 Hz, 2H), 4.35 (t, 7.0 Hz, 1H), 5.98 (m, 2H), 7.71 (m, 5H), 9.65 (s, 1H).