Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([N+:21]([O-])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([NH2:21])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc([N+](=O)[O-])cc2Cl)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(N)cc2Cl)CC1
Yield: 62.8 %

Procedure:
Place 4-(3-chloro-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.09 g, 9.01 mmol) in methanol (50 mL). Add nickel(II) chloride hexahydrate (10.7 g, 45.1 mmol) and cool the reaction to 0° C. Add sodium borohydride (5.11 g, 135.15 mmol) in portions and stir at 0° C. for 2 hours. Add CH2Cl2 and filter through a pad of Celite®. Wash filter cake with CH2Cl2 and collect filtrate. Add saturated aq. sodium bicarbonate solution to the filtrate and separate organic layer. Extract aqueous layer with CH2Cl2 (2×30 mL). Combine organic extracts, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 0-70% EtOAc:hexane to yield 1.77 g (63%) of the title compound. MS(ES): m/z=311.2 [M−H].
Reaction SMILES: [CH3:1][C:2]([CH3:39])([O:4][C:5](=[O:38])[NH:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[C:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([O:27]CC1C=CC=CC=1)=[O:26])[CH3:3].[H][H]>CO.[C].[Pd]>[CH3:3][C:2]([CH3:39])([O:4][C:5](=[O:38])[NH:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([OH:27])=[O:26])[CH3:1]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCOCC#Cc1cccc(C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of benzyl 3-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicos-19-yn-20-yl)benzoate (16 g, 29.52 mmol, 1.00 equiv) in methanol (200 mL), Palladium carbon (10 g). Hydrogen gas was introduced into the reaction vessel. The resulting solution was stirred for 3 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:1). This resulted in 7 g (52%) of 3-(2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azaicosan-20-yl)benzoic acid as pale-yellow oil. LC-MS (ES, m/z): 456 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 7.76 (dd, J=6.0 Hz, 2H), 7.37-7.47 (m, 2H), 6.73 (s, 1H), 3.35-3.52 (m, 16), 3.05 (dd, J=11.7 Hz, 2H), 2.69 (t, J=7.5 Hz, 2H), 1.76-1.85 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:31][C:10]1([CH3:32])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:30])[NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)Nc3ccccc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)Nc2ccccc2)c1
Temperature: 45 °C
Reaction time: 48 h
Yield: 46.7 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.8 g, 1.87 mmol) in methanol (15 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 45° C. for 48 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (350 mg, 46%) as a white solid: LC/MS m/e calcd for C25H24N2O3 (M+H)+: 401.48, observed: 401.1.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H][H]>CC(O)=O.C(OCC)(=O)C.O=[Pt]=O>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:4]2[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1ccc2ccncc21
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2CCNCC21
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.8 %

Procedure:
To a solution of tert-butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.5 g, 2.3 mmol) in AcOH (15 mL) was added PtO2 (0.25 g, 1.1 mmol). The mixture was treated with an atmosphere of hydrogen atmosphere (60 psi) and stirred for 12 h at rt. The suspension was filtered through a pad celite and concentrated in vacuo to afford a residue. The crude material was diluted with ethyl acetate (50 mL) and washed with sat. NaHCO3 (100 mL), the organic phase was separated, dried (Na2SO4) filtered and concentrated in vacuo to afford the title compound (0.53 g, 99% yield). 1H NMR (400 MHz, CDCl3) δ=6.07-5.58 (m, 1H), 4.03-3.68 (m, 1H), 3.57-3.22 (m, 3H), 3.05-2.66 (m, 2H), 2.49-2.19 (m, 1H), 1.96 (s, 4H), 1.77-1.64 (m, 1H), 1.45 (s, 9H). LC/MS (m/z): calc; d. For C12H22N2O2 (M+1H) 227. found 227.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[CH:13]1([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:23][C:22]2[CH:24]=[CH:25][C:19]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:20][CH:21]=2)=[CH:6][CH:5]=1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CO
Product: COC(=O)c1ccc(C=Nc2ccc(C3CCCCC3)cc2)cc1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
4-Formylbenzoic acid methyl ester (6.65 g, 40.5 mmol) was dissolved in hot methanol (175 mL). To this mixture, 4-cyclohexylaniline (7.1 g, 40.5 mmol) was added. To the resulting suspension, more methanol (75 mL) was added and the mixture was heated at reflux for 1 hour. After cooling to 0° C., the mixture was filtered and the solid was washed with ice-cold methanol and dried in vacuo at 40° C. for 16 hours to afford 10.95 g of 4-[(4-cyclohexylphenylimino)-methyl]benzoic acid methyl ester. This compound (10.93 g, 34 mmol) was suspended in methanol (200 mL) and glacial acetic acid (27 mL) was added followed by sodium cyano borohydride (1.9 g, 30 mmol) in small portions. The mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was dissolved in DCM (200 mL) and washed with 5% aqueous sodium carbonate (5×80 mL), dried (magnesium sulphate) and concentrated in vacuo. The residue was added ethyl acetate (100 mL) and n-heptane (200 mL) and concentrated in vacuo to half the original volume. The solid was filtered, washed with n-heptane and dried in vacuo at 40° C. for 16 hours to afford 9.52 g (87%) of 4-((4-cyclo-hexylphenylamino)methyl)benzoic acid methyl ester.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[C:21]1([CH3:33])[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:33])=[CH:22][CH:23]=3)[CH2:28][CH2:29]2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(c3ccc(C)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-p-tolyl-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C23H28N2O5 [M+H]+: 413.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1.N1CCCCC1>[F:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=Cc1ccc(F)c(O)c1F
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccc(F)c(O)c1F
Yield: 86.7 %

Procedure:
A mixture of 2,4-difluoro-3-hydroxybenzaldehyde (0.255 g, 1.613 mmol) and malonic acid (0.168 g, 1.613 mmol) in pyridine (6 ml) and piperidine (0.06 ml) was heated to reflux for 1 h. All the volatile were removed and the residue was partitioned between NaHCO3 sat. and Et2O. The aqueous phase was acidified with 37% HCl until pH <3 and extracted with AcOEt. The organic layer was dried over sodium sulphate and evaporated to give (E)-3-(2,4-difluoro-3-hydroxyphenyl)acrylic acid (280 mg) as pale a brown solid. The compound was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:15]1([S:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of indole (2.4 g, 20 mol) in dry THF (20 ml) under argon at −78° C. was added dropwise via syringe over 10 min n-butyllithium (1.6M in hexanes; 14 ml). The cooling bath was removed and the solution was stirred for 1 h while warming to 0° C. The resulting indole anion precipitated as a very fine white solid in a cloudy colorless solution. After the suspension was recooled to −78° C., benzenesulfonyl chloride (2.8 ml, 22 mmol) was added via syringe over 20 min, keeping the temperature below −60° C. The resulting colorless mixture was allowed to warm slowly to room temperature overnight, poured into 2% aqueous sodium bicarbonate (30 ml), and extracted with ethyl acetate (2×25 ml). The combined extracts were washed with 2% aqueous sodium bicarbonate(30 ml), water (2×25 ml), dried over anhydrous sodium sulphate, and evaporated to give a light amber oil which crystallized when triturated with 2:1 hexane/ether (15 ml). After standing in the cold (−20° C.) for several hours, the product was collected by filtration, washed with hexane, and dried in vacum to provide pure 1-phenylsulfonyl-indole (60) as white crystals (4.8 g, 90.6%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[NH4+].[Cl-]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]([S:20]([CH3:19])(=[O:22])=[O:21])[S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cc1I)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
To a solution containing 2-iodo-4-nitroaniline (25 g; 95 mmol) and triethylamine (43 ml; 312 mmol) in CH2Cl2 (250 ml), a solution containing methanesulphonyl chloride (36 g; 312 mmol) was added dropwise. The reaction mixture was left under stirring at room temperature for 18 hours, then NH4Cl (saturated solution) was added (250 ml). The biphasic solution was transferred into a separating funnel, the organic phase was separated, dried over Na2SO4 and the solvent was removed by evaporation under reduced pressure. The residue was suspended in EtOH (200 ml) and heated under stirring until a yellow solid precipitated. The crude product was filtered, washed with EtOH (750 ml), and dried under vacuum to give N-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)methanesulfonamide (32 g) which was used in the following reaction without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O-:16])=O)[CH:7]=[C:8]([C:10]([O:12]C)=[O:11])[CH:9]=1)([O-:3])=[O:2].[OH-].[NH4+:18].N>O>[NH2:18][C:14]([C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:10]([OH:12])=[O:11])=[O:16]
Reactant: [NH4+]
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Agent: N
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
The ammonium salt of 3-(aminocarbonyl)-5-nitrobenzoic acid (Compound I or C-I) is prepared from 5-nitro-1,3-benzenedicarboxylic acid, 1-methyl ester (“MME”) with ammonium hydroxide. The reaction is preferably carried out in an aqueous solvent, e.g., ammonia in water, and at elevated temperatures. Preferably, the reaction mixture contains a molar excess of ammonia relative to MME. In one embodiment, the product, C-I, is obtained as a solid, centrifuged or filtered, washed with cold aqueous ammonia then by cold water and finally dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([CH3:23])[N:22]=[C:4]2[CH:3]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[CH:20]=[C:21]([CH3:23])[N:22]=[C:4]2[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1cn2c(NCCNc3ccc(C#N)cn3)nc(Cl)cc2n1
Product: Cc1cn2c(NCCNc3ccc(C#N)cn3)nc(-c3ccc(Cl)cc3Cl)cc2n1

Procedure:
In analogy to the procedure described for Example 7, 11.9 mg (7% of theory) of the product are obtained starting from 120 mg (0.36 mmol) of 6-({2-[(7-chloro-2-methylimidazo[1,2-c]pyrimidin-5-yl)amino]ethyl}amino)nicotinonitrile (Example 30A) by coupling with 68.4 mg (0.36 mmol) of (2,4-dichlorophenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.C(N)(=[S:15])C.Cl.O>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH2:10])=[S:15])=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: CC(N)=S
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=S)c1ccc(C(F)(F)F)cc1
Temperature: 95 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
A solution of α,α,α-trifluoro-p-tolunitrile (603.5 g, 3.53 mol) in dry DMF (2 L) under N2 was heated at 70° C. and the Thioacetamide (505 g, 1.9 eq.) was added. The reaction mixture was treated with HCl gas before 15 minutes and was stirred at 95° C. for 6 hours. This treatment was operated 3 times and the mixture was stirred at rt for 24 hours. After cooling at 0° C., water was added and the residue was extracted with diethyl ether (4*1 L). The organic layer was washed with water (3*1 L), dried over Na2SO4 and then evaporated off. The brownish powder was washed with pentane (3 L) to give the title compound (530.3 g, 2.59 mol) as brown solid in a 73% yield.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=3)[O:25][C:26]=2[CH3:27])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2cc[nH]c2c1)OCC
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Product: CCOC(Cc1ccc2ccn(Cc3nc(-c4ccc(C(C)C)cc4)oc3C)c2c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(1H-indol-6-yl)-propionic acid ethyl ester (preparation 11) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole to give rac-2-ethoxy-3-{1-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-6-yl}-propionic acid as light yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([OH:32])[CH2:18][O:19][C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[NH:28][C:29](=[O:31])[CH3:30])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.CN(C=O)C.B(Br)(Br)[Br:41]>C(Cl)Cl>[Br:41][C:23]1[C:24]([O:26][CH3:27])=[CH:25][C:20]([O:19][CH2:18][C@@H:17]([OH:32])[CH2:16][N:13]2[CH2:12][CH2:11][CH:10]([N:6]3[C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][C:4]=4[NH:8][C:7]3=[O:9])[CH2:15][CH2:14]2)=[C:21]([NH:28][C:29](=[O:31])[CH3:30])[CH:22]=1
Reactant: COc1ccc(NC(C)=O)c(OC[C@@H](O)CN2CCC(n3c(=O)[nH]c4cc(F)ccc43)CC2)c1
Reactant: BrB(Br)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(OC[C@@H](O)CN2CCC(n3c(=O)[nH]c4cc(F)ccc43)CC2)c(NC(C)=O)cc1Br
Reaction time: 8 h
Yield: 45 %

Procedure:
To a stirred suspension of N-[2-({(2S)-3-[4-(5-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]-2-hydroxypropyl}oxy)-4-methoxyphenyl]acetamide (Example 32 iii)) (0.17 g, 0.36 mmol) in CH2Cl2 (5 ml) with some drops of DMF a solution of boron tribromide (BBr3) in dichloromethane (CH2Cl2) (1M, 1.08 mmol, 1.08 ml) was added dropwise under nitrogen. The stirring was continued overnight art room temperature. Then the reaction mixture was quenched with methanol, diluted with water and extracted with dichloromethane (CH2Cl2) (2×10 ml) and ethyl acetate (2×10 ml). The combined organic extracts were dried with sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography of silica gel (CH2Cl2/MeOH, 9:1) to give a colourless solid (89 mg, 0.16 mmol, 45%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:22])=O)=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.[NH2:44][C:45]1([C:48]#[N:49])[CH2:47][CH2:46]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:48]([C:45]1([NH:44][C:20]([C:19]2[C:13]3[C:14](=[N:15][CH:16]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=3)[NH:17][CH:18]=2)=[O:22])[CH2:47][CH2:46]1)#[N:49]
Reactant: N#CC1(N)CC1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(C#N)CC5)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 4.1 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), DIEA (200 mg, 1.55 mmol), EDCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) in 6 mL of DMF was added 1-aminocyclopropanecarbonitrile hydrochloride (100 mg, 0.84 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 35% acetonitrile/65% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(1-cyanocyclopropyl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (5 mg, 4.1%) as a yellow solid. MS: (M+H)+=358; 1H NMR (300 MHz, DMSO): δ 13.40 (s, 1H), 13.00 (s, 1H), 9.19 (s, 1H), 8.98 (s, 1H), 8.56 (d, 1H, J=3.0 Hz), 8.38 (d, 1H, J=8.1 Hz), 7.46 (s, 1H), 7.21 (d, 1H, J=8.4 Hz), 2.53 (s, 3H), 1.78-1.74 (m, 2H), 1.48-1.44 (m, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH:19]=2)=[CH:16][C:15]([CH2:44][N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]2)=[CH:14][N:13]=1.[CH3:55][O:56][C:57]1[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=1>C1COCC1>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:20]2[CH:19]=[C:18]([C:17]3[C:12]([NH:63][C:60]4[CH:61]=[N:62][C:57]([O:56][CH3:55])=[CH:58][CH:59]=4)=[N:13][CH:14]=[C:15]([CH2:44][N:45]4[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]4)[CH:16]=3)[N:23]=[C:22]([CH3:24])[N:21]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)nc(C)n2)cc1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)nc(C)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Lithium bis(trimethylsilyl)amide (Acros, Morris Plains, N.J.; 1.0M solution in THF/ethyl benezene) (0.599 mL, 0.599 mmol) was added dropwise to a solution of 6-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (124.0 mg, 0.200 mmol) and 6-methoxypyridin-3-amine (0.037 mL, 0.300 mmol) in THF (3.0 mL) at 0° C., and the resulting dark brown solution was stirred at 0° C. for 1 h. Excess LiHMDS was quenched by the addition of sat. aq. NH4Cl (5 mL), and the resulting mixture was partitioned between EtOAc (50 mL) and half-sat. aq. NH4Cl (15 mL). The organic layer was separated, washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (ISCO, 12 g, 0 to 10% MeOH/DCM) furnished N,N-bis(4-methoxybenzyl)-6-(2-(6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-2-methylpyrimidin-4-amine (137.7 mg, 0.190 mmol, 95% yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 11.67 (br. s., 1H); 8.36 (d, J=2.54 Hz, 1H); 8.06-8.11 (m, 2H); 7.54 (br. s., 1H); 7.18 (d, J=7.43 Hz, 4H); 6.84-6.90 (m, 4H); 6.75 (d, J=8.80 Hz, 1H); 6.56 (s, 1H); 4.77 (br. s., 4H); 3.93 (s, 3H); 3.80 (s, 6H); 3.42 (br. s., 2H); 3.19 (br. s., 4H); 2.76 (s, 3H); 2.65 (s, 3H); 2.50 (br. s., 4H). m/z (ESI, +ve ion) 561.2 (M-piperazine sulfonamide)+.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([CH:6]=[CH:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=O)[CH2:20][CH2:21]2)[CH:16]=[CH:15]3)[CH2:12][CH2:11]1)[CH3:9])[CH3:5])[CH3:3].Cl.[NH2:31][OH:32]>N1C=CC=CC=1>[CH3:1][CH:2]([C@H:4]([CH:6]=[CH:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[N:31][OH:32])[CH2:20][CH2:21]2)[CH:16]=[CH:15]3)[CH2:12][CH2:11]1)[CH3:9])[CH3:5])[CH3:3]
Reactant: NO
Reactant: CC(C)[C@@H](C)C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)[C@@H](C)C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=NO)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 50 %

Procedure:
100 mg of 4,6,22-ergosta-trien-3-one (0.25 mmol) is solubilized in 10 ml of pyridine in a 50 ml flask, then 100 mg of hydroxylamine hydrochloride is added. Stirring is maintained for 24 hours at ambient temperature, and the solvent is evaporated off under reduced pressure. Water then ethyl acetate are added in order to carry out an extraction. Then the organic phase is washed with an acidified aqueous solution (HCl 1%). The ethyl acetate is evaporated off under reduced pressure. A white powder is obtained with a yield greater than 50%.