Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([O:25]CC)=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO>[NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 30 ml of MeOH is dissolved 2.8 g of BOC-Tyr-(D)-Met-Gly-OEt, after cooling 12 ml of 1 N-aqueous sodium hydroxide is added and the mixture is stirred at room temperature for 1 hour. After cooling, 60 ml of 0.2 N-aqueous HCl is added and resulting crystals are recovered by filtration and washed with cold water. Yield 2.3 g; m.p. 184°-186° C.; Rf1 =0.24; [α]D21 +13.3° (c=0.46; DMF).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]([C@@H:12]2[N:16]([C@H](C3C=CC=CC=3)[C@@H](O)C3C=CC=CC=3)[C@H:15]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C@@:14]3([C:44]4[C:39](=[CH:40][C:41]([Cl:45])=[CH:42][CH:43]=4)[NH:38][C:37]3=[O:46])[C@H:13]2[C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[C:48]=2[F:54])=[O:11])[CH2:4][CH2:3]1.C(#N)C.[N+]([O-])([O-])=O.[NH4+].[Ce].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CC(C)=O.O>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]([C@@H:12]2[NH:16][C@@H:15]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C@:14]3([C:44]4[C:39](=[CH:40][C:41]([Cl:45])=[CH:42][CH:43]=4)[NH:38][C:37]3=[O:46])[C@H:13]2[C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[C:48]=2[F:54])=[O:11])[CH2:6][CH2:7]1
Reactant: CC(C)(C)C[C@H]1N([C@H](c2ccccc2)[C@@H](O)c2ccccc2)[C@@H](C(=O)NC[C@H]2CC[C@H](O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Solvent: O
Solvent: CC#N
Solvent: CC(C)=O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC[C@H]2CC[C@H](O)CC2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C

Procedure:
In a three-neck 50 mL flask were successively introduced 0.70 g (0.91 mmol) of (2′R,3′S,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-1′-((1R,2S)-2-hydroxy-1,2-diphenyl-ethyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (trans-4-hydroxy-cyclohexylmethyl)-amide, 7.0 mL of acetonitrile, 3.5 mL of distilled water and 3.5 mL of acetone. The resulting mixture was stirred and cooled to 0° C. and 0.99 g (1.81 mmol) of cerium ammonium nitrate was added in small portions. The reaction mixture was stirred at 0° C. for 20 minutes, upon which 89 mg (1.06 mmol) of sodium hydrogencarbonate were added and stirring was maintained for 5 minutes. The mixture was diluted with 60 mL of ethyl acetate and decanted. The organic phase was separated and the aqueous phase was extracted twice with 10 mL of ethyl acetate. The combined organic extracts were washed with 20 mL of water, dried with magnesium sulfate and then concentrated to dryness under reduced pressure. The residue was purified by flash chromatography on a 30 g silica cartridge (15-40 μm silica gel; eluting solvent: dichloromethane; flow: 30 mL/min) followed by a second purification by flash chromatography on a 15 g silica cartridge (15-40 μm silica gel; eluting solvent: dichloromethane/methanol/28% ammonia 97/2/1 v/v/v; flow: 30 mL/min) 87 mg of (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (trans-4-hydroxy-cyclohexylmethyl)-amide were obtained as a white solid. mp: 192° C. (Kofler); LC-MS: tR (min)=0.84; [M+H]+: m/z 576; [M−H]−: m/z 574 (method A); 1H NMR (CHLOROFORM-d, 400 MHz): mixture of isomers: 0.90 (s, 9H); 0.99 to 2.09 (m partially hidden, 11H); 3.05 to 3.27 (m, 2H); 3.59 (m, 2H); 4.39 (d, J=8.8 Hz, 1H); 4.59 (m, 1H); 6.76 (s large, 1H); 6.99 (t, J=7.8 Hz, 1H); 7.06 to 7.56 (m, 6H); 7.82 (t broad, J=6.1 Hz, 1H).
Reaction SMILES: [N:1]1([C:6]2[N:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]3=[N:8][N:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.[Cl:22][C:23]1[C:31]([F:32])=[C:30]([Cl:33])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C([O-])(O)=O.[Na+]>ClCCl.C(OCC)(=O)C>[Cl:22][C:23]1[C:31]([F:32])=[C:30]([Cl:33])[CH:29]=[CH:28][C:24]=1[C:25]([N:13]1[CH2:12][CH2:11][N:10]2[C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[N:7][N:8]=[C:9]2[CH2:14]1)=[O:26]
Reactant: c1cnn(-c2nnc3n2CCNC3)c1
Reactant: O=C(Cl)c1ccc(Cl)c(F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-n2cccn2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(1H-pyrazol-1-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (I107)(14.3 mg, 0.075 mmol) and triethylamine (0.016 ml, 0.113 mmol) was stirred in Dichloromethane (DCM) (1 ml) at 0° C. and 2,4-dichloro-3-fluorobenzoyl chloride (18.81 mg, 0.083 mmol) in DCM (0.5 ml) was added and the mixture was stirred at 0° C. After 1 h, sat. NaHCO3 (1 ml) and ethyl acetate (30 ml) were added and the product was extracted into ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. Chromatography (SP4 50-100% ethyl acetate in isohexane) gave a crude product which was passed through an SCX column (elution with 2M NH3 in MeOH) to give clean desired product as a gum. This was triturated with ether/hexane to give a white solid in 22.4 mg.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4].[Cl:8][GeH:9]([Cl:11])[Cl:10]>C(OCC)C>[CH3:1][CH:2]([CH:6]([Ge:9]([Cl:11])([Cl:10])[Cl:8])[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: C/C=C(\C)C(=O)O
Reactant: Cl[GeH](Cl)Cl
Solvent: CCOCC
Product: CC(C(=O)O)C(C)[Ge](Cl)(Cl)Cl
Reaction time: 2 h
Yield: 76.5 %

Procedure:
20.02 g (0.2 mol) of (E)-2-methyl-2-butenoic acid was dissolved in 100 ml of dry ethyl ether. 36.0 g (0.2 mol) of trichlorogermane was added to the solution and stirred for 2 hrs. Crystals thus formed were recrystallized from n-hexane to obtain 42.86 g (yield: 76.5%) of 2-methyl-3-(trichlorogermyl)butanoic acid in the form of colorless plate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=[C:5]2[CH:4]=[CH:3]1.[F:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]([F:22])[N:16]=1.O>C(Cl)Cl.N1C=CC=CC=1>[F:14][C:15]1[C:20]([NH:21][C:11]([C:9]2[CH:10]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:6]3=[N:7][CH:8]=2)=[O:13])=[CH:19][CH:18]=[C:17]([F:22])[N:16]=1
Reactant: Nc1ccc(F)nc1F
Reactant: Cn1ccc2cc(C(=O)O)cnc21
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cn1ccc2cc(C(=O)Nc3ccc(F)nc3F)cnc21
Yield: 72.5 %

Procedure:
To a suspension of 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (3.54 g, 20.1 mmol) in CH2Cl2 (400 mL) was added 1-chloro-N,N-2-trimethylpropenylamine (5.26 mL, 40.2 mmol). Following formation of the resulting acid chloride, the reaction mixture was concentrated affording a residue that was dissolved in pyridine (100 mL) before 2,6-difluoro-pyridin-3-ylamine (2.61 mg, 20.1 mmol) was added in one portion. After an additional 30 minutes the reaction mixture was concentrated to dryness affording a residue, to which was added water causing precipitation of analytically pure 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2,6-difluoro-pyridin-3-yl)-amide (4.2 g, 72.5% yield). ES MS (M+H+)=289.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[C:10]1([CH2:16][C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>[OH-].[Na+]>[C:10]1([CH2:16][C:17]([NH:1][CH:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)C(N)C(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)C(NC(=O)Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of DL-tert-leucine (2 g, 15.3 mol) in aqueous sodium hydroxide (2 M, 25 ml) was added dropwise phenylacetyl chloride (646 mg, 20.8 mmol), simultaneously with sodium hydroxide (2 M, 25 ml), at 0° C. over a period of 5 min. The solution was allowed to warm to room temperature and stirred for an additional 60 min until complete dissolution occurred. The reaction was then cooled to 0° C., acidified to pH 4 with conc. HCl, and stirred for 30 min. The resulting precipitate was collected by filtration, dried, and recrystallised from ethanol/water (1:1 v/v) to yield the product as a white solid (2.06 g, 54%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[S:3]1.Cl>CC(O)=O>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[CH:27][CH:28]=2)[S:3]1
Reactant: COC(=O)c1ccc(OCCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(OCCOc3ccc(C(=O)O)cc3)cc2)S1
Temperature: 120 °C
Yield: 99.1 %

Procedure:
To a solution of methyl ester 359 (872 mg, 2.17 mmol) in glacial AcOH (30 mL) was added conc. HCl (10 mL). The mixture was heated at 120° C. for 3 hours. The solvents were remove under reduced pressure to afford the title compound (833 mg, 99%). 1H NMR: (DMSO-d6) δ (ppm): 12.61 (bs, 1H), 12.01 (s, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.91 (dd, J=9.2, 4.4 Hz, 1H), 4.40-4.42 (m, 2H), 4.33-4.36 (m, 2H), 3.32 (d, J=4.0 Hz, 1H), 3.10 (dd, J=14.0, 9.6 Hz, 1H). LRMS (ESI): (calc.) 387.4; (found) 386.2 (M−H)−.
Reaction SMILES: Cl([O-])=O.[Na+].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[F:14].S(N)(=O)(=O)[OH:16].C(O)(C)(C)C>C(OCC)(=O)C.O>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:16])=[O:11])=[CH:8][C:7]=1[F:14]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 101.7 %

Procedure:
Sodium chlorite (17 g) was added portionwise to a mixture solution composed of 4-chloro-3-fluorobenzaldehyde (10 g), amidosulfuric acid (18 g), tert-butyl alcohol (50 ml) and water (50 ml) under ice cooling, and the mixture was stirred for 4 days while the temperature of the system was gradually raised to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water, 1N hydrochloric acid and saturated aqueous solution of sodium chloride. After the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, the resultant residue was recrystallized from a mixed solvent of diisopropyl ether and hexane to obtain the title compound (11.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.ClCCl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: ClCCl
Solvent: O
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-Fluoro-2-nitrophenol (3.14 g; 20 mmol) and potassium carbonate (2.76 g; 20 mmol) are place in a round bottom flask and are flushed with argon. Dry dimethylformamide (60 mL) is added followed by dimethylsulfate (3.8 mL; 40 mmol). The reaction is stirred for 2 days at room temperature. Dichloromethane (120 mL) and water (60 mL) are then added. The aqueous phase is extracted with dichloromethane (100 mL) and the combined organic layers are washed three times with aq. sat. sodium hydrogencarbonate (50 mL), twice with aq. 1N hydrochloric acid (50 mL) and with brine (50 mL). The organic layer is then dried over magnesium sulfate and is concentrated under reduced pressure. The desired product is isolated in the presence of dimethylformamide (4.39 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Yield: 72.4 %

Procedure:
A mixture of 20.8 g of 4-bromonitrobenzene and 17.2 g of 2-methoxyphenyl boronic acid in 340 mL of ethylene glycol dimethyl ether and 170 mL of 2 M sodium carbonate solution was purged with argon gas and then 3.6 g of Pd(PPh3)2Cl2 was added under argon atmosphere. The reaction mixture was heated in a sealed flask at 120° C. overnight. The reaction mixture was cooled down to room temperature. The mixture was filtered through diatomaceous earth and the filtrate was diluted with water and the product was extracted three times with EtOAc. The organic layers were combined, dried over magnesium sulfate (MgSO4), and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield 17.1 g of 2-methoxy-4′-nitrobiphenyl as a solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:17]=O)=[CH:13][NH:14]2)=[CH:10][CH:9]=1)[CH3:3].P([O-])([O-])(O)=O.[NH4+].[NH4+].[N+:26](CCC)([O-])=O.[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][N:2]([CH2:4][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:17]#[N:26])=[CH:13][NH:14]2)=[CH:10][CH:9]=1)[CH3:3]
Reactant: CCC[N+](=O)[O-]
Reactant: CN(C)CC1CC1c1ccc2c(C=O)c[nH]c2c1
Agent: O=P([O-])([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CC1CC1c1ccc2c(C#N)c[nH]c2c1
Yield: 38 %

Procedure:
In 5 mL of acetic acid were combined the crude 6-(2-dimethylaminomethyl-cyclo-propyl)-1H-indole-3-carbaldehyde, ammonium hydrogen phosphate (0.99 g, 7.50 mmol), and nitropropane (0.09 g, 1.03 mmol.). The mixture was stirred and heated to a gentle reflux for 16 h. Water was added after cooling reaction to room temperature, and the mixture was made basic by the addition of 1 N NaOH. The mixture was extracted with methylene chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give a brown oil. The oil was purified by flash chromatography (50% methanol/ethyl acetate) to give 6-(2-dimethylaminomethyl-cyclopropyl)-1H-indole-3-carbonitrile as an amber oil (93 mg, 38%). 1H NMR (CDCl3): δ7.58 (m, 2H), 6.99 (m, 2H), 5.75 (s, 1H), 2.46 (m, 1H), 2.33 (s, 7H), 1.89 (m, 1H), 1.20 (m, 1H), 0.98 (m, 1H), 0.86 (m, 1H); FIMS: 238.2 (M−H); LCMS: 72% AP.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Cl)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>O1CCOCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([Br:22])=[CH:24][CH:25]=3)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2ncnc(Nc3ccc(Br)cc3)c2[N+](=O)[O-])CC1

Procedure:
[6-chloro-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester (415 mg, 1.32 mmol) and 4-bromoaniline (309 mg, 1.80 mmol) were dissolved in anhydrous 1,4-dioxane (0.5-1 ml) and irradiated in a sealed microwave reaction tube at 250° C. for 300 seconds. The reaction mixture was passed through a silica plug [SiO2; EtOAc/hexane; 20:80]. Yield 0.070 g, 12%. Yellow solid. 1H NMR 400 MHz CDCl3 δ(ppm): 9.98 (s, 1H); 8.03 (s, 1H); 7.41 (m, 2H); 7.17 (m, 2H); 4.09 (m, 2H); 3.83 (m, 2H); 3.16 (m, 2H); 2.77 (m, 1H); 1.97 (m, 2H); 1.78 (m, 2H); 1.20 (m, 3H). LCMS (ESI) m/z 451, 452 (M+H+, 100%)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH2:14]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C)C1CCNC1
Product: CN(C)C1CCN(c2ccc(N)cn2)C1
Yield: 56.3 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with N,N-dimethylpyrrolidin-3-amine (400 mg, 3.5 mmol) followed by reduction to afford the desired product (360 mg, 56%) as a purple solid: ESI MS m/z 207 [C11H18N4+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3=[N:18][CH:19]=[CH:20][C:15]([C:8]4[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:16]3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: COc1ccc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f11) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]1[N:11]=[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9](B(O)O)=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:27]1[C:28]2[CH:35]=[CH:34][NH:33][C:29]=2[N:30]=[CH:31][N:32]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]1[N:11]=[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)(C)Oc1ncc(B(O)O)c(OC(C)(C)C)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)Oc1ncc(-c2ncnc3[nH]ccc23)c(OC(C)(C)C)n1
Temperature: 80 °C
Yield: 71.7 %

Procedure:
2,4-Di-tert-butoxypyrimidin-5-ylboronic acid (17.5 g, 65.4 mmol), tetrakis(triphenylphosphine) palladium(0) (7.6 g, 6.54 mmol) and sodium carbonate (20.8 g, 196 mmol) were added to a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10 g, 65.4 mmol) in DME (400 mL) and water (150 mL). With vigorous stirring, the mixture was heated to 80° C. for 24 h. The reaction mixture was cooled to RT and poured into water (100 mL). The mixture was extracted with EtOAc (100 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product. This was purified by flash chromatography to give 4-(2,4-di-tert-butoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (16.0 g, 72%) as a yellow solid. MS (APCI, pos. ion) m/z: 342.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.C1COCC1.C1(C)C=CC=CC=1.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34](=[O:39])N(OC)C)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34](=[O:39])[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
At 0° C. 4-chlorophenylmagnesiumbromide 0.9 molar in THF/toluene (66.7 ml, 60 mmol) was added over 15 minutes to a solution of (S)-2-(Methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester CAS 115186-37-3 (5.16 g, 20 mmol) in dry THF (50 ml). The reaction mixture was warmed to ambient temperature and stirred for another 4 hours. The reaction mixture was poured on 1N HCl/ice (150 ml) and then extracted with ethyl acetate (2×100 ml). The organic layers are washed with water (2×50 ml), saturated NaCl (50 ml) and then dried over Na2SO4. After evaporation of the solvent, the crude product (7.5 g in the form of a yellow oil) was purified by flash chromatography over silica gel 150 g, (eluent:cyclohexane/ethyl acetate 9:1) to afford 4.3 g (69.4% of theory) of (S)-2-(4-chloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a as a white solid m.p. 117-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[CH:38][C:39]([OH:50])=[C:40]([C:42]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:43])[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[OH:50][C:39]1[CH:38]=[CH:37][C:36]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:12]3=[N:13][CH:14]=2)=[CH:41][C:40]=1[C:42]([N:44]1[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1)=[O:43]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C(c1cc(Br)ccc1O)N1CCOCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(O)c(C(=O)N4CCOCC4)c3)cc12
Yield: 30 %

Procedure:
A mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.21 mmol), (5-bromo-2-hydroxy-phenyl)-morpholin-4-yl-methanone (66 mg (0.23 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (9 mg, 11 μmol) in acetonitrile (2 mL) and aqueous solution of sodium carbonate (2M, 2 mL) was irradiated in a Personal Chemistry Optimizer at 135° C. for 20 min. The crude reaction mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was then purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford {2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-morpholin-4-yl-methanone (35 mg, 30% yield) as a colorless solid. 1H-NMR (500 MHz, d6-DMSO) δ 8.86 (d, 1H), 8.27 (d, 1H), 7.64 (dd, 1H), 7.62 (dd, 1H), 7.54 (d, 1H), 7.49 (ddd, 1H), 7.24 (d, br, 1H), 7.11 (ddd, 1H), 7.00 (d, 1H), 5.84 (s, 2H), 3.84 (s, 3H), 3.69 (t, 2H), 3.7-3.2 (m, 8H), 0.86 (t, 2H), −0.08 (s, 9H). MS: m/z 583 [MNa+], 561 [MH+], 443 [MH+-(Me3Si(CH2)2O)]