Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C[Si]([C:17]#[N:18])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:18][CH2:17][C:8]1([OH:12])[C:9]2[C:4](=[CH:3][C:2]([NH2:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: C[Si](C)(C)C#N
Reactant: Nc1ccc2c(c1)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1(O)CCCc2cc(N)ccc21

Procedure:
6-amino-1,2,3,4-tetrahydro-1-naphthalenone is reacted with trimethylsilylcyanide followed by lithium aluminum hydride to obtain 1-aminomethyl-1-hydroxy-6-amino-1,2,3,4-tetrahydronaphthalene. This diamine is di-acetylated with acetic anhydride, chlorinated with chlorine and acetic acid, and then heated to dehydrate the alcohol. The resulting di-chloro-di-acetamide is hydrolyzed in HCl to obtain 1-aminomethyl-6-amino-5,7-dichloro-3,4-dihydronaphthalene HCl.
Reaction SMILES: [CH:1]1([C:7]2[N:8]([C:12]3[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=3[N+:26]([O-:28])=[O:27])[C:15]([NH:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:16])[CH:9]=[CH:10][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:31]I>CN(C)C(=O)C.O>[CH:1]1([C:7]2[N:8]([C:12]3[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=3[N+:26]([O-:28])=[O:27])[C:15]([N:17]([CH2:18][CH2:19][O:20][CH2:21][CH3:22])[CH3:31])=[O:16])[CH:9]=[CH:10][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: CCOCCNC(=O)c1ccc([N+](=O)[O-])c(-n2ccnc2C2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOCCN(C)C(=O)c1ccc([N+](=O)[O-])c(-n2ccnc2C2CCCCC2)c1
Reaction time: 1.8 h

Procedure:
To the solution of 3-(2-cyclohexyl-1H-imidazol-1-yl)-N-(2-ethoxyethyl)-4-nitrobenzamide as synthesized in above Production Example 48, 3.86 g in N,N-dimethylacetamide 32 mL, sodium hydride (formed by washing 60% sodium hydride, oiliness 600 mg with hexane) was added under cooling with ice. Then methyl iodide 1.55 mL was added and the ice bath was removed. After 1.8 hours' stirring, sodium hydride (formed by washing 60% sodium hydride, oiliness 200 mg with hexane) was added, followed by 5 hours' stirring. The reaction liquid was poured in water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. Distilling the solvent off, 3.35 g of the title compound was obtained.
Reaction SMILES: [NH2-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1>O1CCCC1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[NH2:12])=[CH:16][CH:17]=1
Reactant: NNc1ccc(F)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NN(Cc1ccc(Br)cc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (253 mg, 6.15 mmol; Aldrich) and chilled to 0° C. (4-Fluorophenyl)hydrazine hydrochloride (500 mg, 3.08 mmol; Aldrich) was added in portions. After 5 minutes the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 1-(bromomethyl)-4-bromobenzene (845 mg, 3.38 mmol; Aldrich) was added dropwise. After 30 minutes the ice bath was removed and the reaction was heated to 50° C. overnight. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NH3) m/z 279 (M+H−NH3)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[CH:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.CO.O.[NH2:28][NH2:29]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:28][NH2:29])[CH:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: NN
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1CC(C)C
Solvent: O
Solvent: CO
Product: CC(C)CC1N=C(c2ccccc2)c2cc(Cl)ccc2N=C1NN

Procedure:
To a solution of 1.6 parts of 7-chloro-3-isobutyl-2-methylmercapto-5-phenyl-3H-1,4-benzodiazepine in 150 parts by volume of methanol is added 40 parts of 100% hydrazine hydrate. The mixture is refluxed for 4.5 hours and poured into water, followed by extraction with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with diethyl ether yields 7-chloro-2-hydrazino-3-isobutyl-5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from a mixture of chloroform and n-hexane yields colorless crystals melting at 168° C to 169° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)[CH3:2].ClC(Cl)C.[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>CO>[Br:23][CH:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)Cl
Solvent: CO
Product: CC(Br)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To the solution dissolved 15.0 g of 2-ethylanthraquinone (63 mmol; produced by Wako Pure Chemical Industries, Ltd.) into 100 mL of dichloroethane, 11.3 g of N-bromosuccinimide (NBS) (63.5 mmol; produced by Wako Pure Chemical Industries, Ltd.) and 1.0 g of 2,2′-azobis(isobutyronitrile) (AIBN) (6.1 mmol; produced by Wako Pure Chemical Industries, Ltd.) were added, then, the solution was reacted by stirring for 2 hours at 60° C. After completing reaction, the reaction solution was condensed, and 120 mL of methanol was poured into the condensed residue, and after the resultant crystal was filtered, the resultant crystal was dried to obtain 18.0 g of 2-(1-bromo-1-ethyl)anthraquinone (yield: 90%) as pale yellow crystal. Measurement results of 1H-NMR are shown as the follows:
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.C[Si](C)(C)Cl.[CH3:25][CH:26]([CH:28]([Cl:33])[O:29][C:30](Cl)=[O:31])[CH3:27]>ClCCl>[Cl:33][CH:28]([O:29][C:30]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:31])[CH:26]([CH3:27])[CH3:25]
Reactant: CC(C)C(Cl)OC(=O)Cl
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
To a mixture containing gabapentin (1.71 g, 10 mmol) and triethylamine (3.06 mL, 22 mmol) in dichloromethane (150 mL) was added trimethylchlorosilane (1.4 mL, 11 mmol) and the resulting mixture was stirred until clear (about 20 min). A solution containing 1-chloro-2-methylpropylchloroformate (1.27 mL, 11 mmol) in dichloromethane (10 mL) was then added at 0° C. and stirred at room temperature for 60 min. The reaction mixture was washed with 10% citric acid (30 mL) and the organic layer separated. The aqueous layer was further extracted with ether (3×20 mL) and the combined organic phases were dried over MgSO4 and then concentrated in vacuo. Chromatography of the residue on silica gel, eluting with hexane:ethyl acetate (1:4) gave 2.37 g (77%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.04 (d, J=6.4 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 1.36-1.53 (m, 10H), 2.15 (m, 1H), 2.34 (s, 2H), 3.24 (m, 2H), 5.39 (t, 1H), 6.32 (d, J=5.6 Hz), 1H). MS (ESI) m/z 306.34 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
4-Bromobenzyl alcohol (50.00 g, 267.3 mmol), tert-butyldimethylsilyl chloride (52.38 g, 347.5 mmol), and imidazole (23.66 g, 347.5 mmol) were dissolved in anhydrous DMF (300 mL). This solution was allowed to stir at room temperature overnight and then poured into ice-water (600 mL). The organic layer was separated off and washed with saturated aqueous sodium bicarbonate (2×200 mL) and water (2×200 mL). We obtained colorless oil (71.9 g, 88%): 1H NMR (CDCl3): δ 0.10 (s, (CH3)2Si), 0.94 (s, (CH3)3C), 4.7 (s, CH2O), 7.20 (d, J=7.8 Hz, C6H4), 7.45 (d, J=7.8 Hz, C6H4); 13C NMR (CDCl3): δ.
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=[N:2]1.Cl.[CH3:10][O:11][NH:12][CH3:13].CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C.CN1CCOCC1.Cl>ClCCl>[CH3:10][O:11][N:12]([CH3:13])[C:6]([C:5]1[O:1][N:2]=[CH:3][CH:4]=1)=[O:8]
Reactant: O=C(O)c1ccno1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccno1
Yield: 75.8 %

Procedure:
A solution of isoxazole 5-carboxylic acid (2.81 g), N-methoxy-N-methylamine hydrochloride (2.49 g), EDCI (4.96 g), dimethylaminopyridine (3.15 g) and 4-methylmorpholine (2.8 ml) in dichloromethane (20 ml) was stirred for 18 h. 2M Hydrochloric acid was added and the mixture was extracted with dichloromethane (three times). The organic layers were washed with aqueous sodium hydrogen carbonate and then brine, combined, dried (magnesium sulphate), evaporated and purified by chromatography on silica eluting with petrol-ether to give the sub-title compound as a colourless oil (2.94 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:15])[C:10](=[CH2:14])[CH2:11][CH2:12][Cl:13])[CH:5]=[CH:4][C:3]=1[O:16][CH3:17]>C(Cl)Cl>[Cl:13][CH2:12][CH2:11][CH:10]1[CH2:14][C:5]2[C:6](=[C:7]([Cl:8])[C:2]([Cl:1])=[C:3]([O:16][CH3:17])[CH:4]=2)[C:9]1=[O:15]
Reactant: C=C(CCCl)C(=O)c1ccc(OC)c(Cl)c1Cl
Solvent: ClCCl
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCl)C2

Procedure:
2,3-Dichloro-4-(4-chloro-2-methylenebutyryl)anisole (14 gm, 0.037 mole) was dissolved in methylene chloride (7 ml) and added with stirring concentrated to sulfuric acid (55 ml) over a period of 20 minutes. The temperature rose to 39° C. The mixture was stirred for 16 hours at ambient temperature, then poured into ice water, extracted first with methylene chloride and then with ether. The combined organic extracts were washed with water, dried over MgSO4 and evaporated in vacuo. The residue (12 gm) was triturated with isopropyl alcohol, filtered and dried to give the product, m.p. 103°-105° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:19]3[N:20]=[CH:21][N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:9]=2)=[CH:4][C:3]=1[CH2:43][O:44][CH3:45].Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:19]3[N:20]=[CH:21][NH:22][CH:23]=3)([OH:18])[CH:15]([CH3:16])[CH3:17])[CH:9]=2)=[CH:4][C:3]=1[CH2:43][O:44][CH3:45]
Reactant: COCc1cc(-c2cccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)c2)ccc1F
Agent: Cl
Solvent: c1ccncc1
Product: COCc1cc(-c2cccc(C(O)(c3c[nH]cn3)C(C)C)c2)ccc1F
Yield: 78.4 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 1-[4′-fluoro-3′-(methoxymethyl)[1,1′-biphenyl]-3-yl]-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.35 g) and pyridine hydrochloride (469 mg), the colorless amorphous title compound (629 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][O:13][CH2:14][CH2:15][N:16]([CH3:17])[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCN(C)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 117.5 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (2.2 g, 12.7 mmol), (2-methoxy-ethyl)-methyl-amine (3.0 g, 33.7 mmol) and anhydrous potassium carbonate (1.93 g, 14 mmol) in N,N-dimethylacetamide (5 ml) was stirred at 115-120° C. under nitrogen for 2 days. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (20 ml) and stirred vigorously and cooled at 5° C. overnight. The resulting yellow brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting yellow brown solid was slurried in diethyl ether (20 mL), filtered, washed with additional diethyl ether, dried to afford N1-(2-methoxy-ethyl)-N1-methyl-4-nitro-benzene-1,3-diamine (2.1 g, 72%) as a yellow brown powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)=[N:8][N:9]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCOC1
Yield: 76.7 %

Procedure:
A solution of 4-methoxy-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (225 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (260 mg), tetrakis(triphenylphosphine)palladium(0) (70.8 mg) and 2M aqueous sodium carbonate solution (1.53 mL) in DME (15 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (176 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:21]2[CH:22]=[CH:23][C:24]([CH:26]([F:28])[F:27])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:34])=[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4]4)=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:33][CH2:32]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1S,3S)-3-aminocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f64) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH:10]2[O:14][CH2:15][C:16]([O:19][CH3:20])([O:17][CH3:18])[CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21]C([O-])(C)C.[K+].C(OCC)C>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:21])[CH:10]2[O:14][CH2:15][C:16]([O:17][CH3:18])([O:19][CH3:20])[CH:9]12)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[O-]
Reactant: COC1(OC)COC2C(=O)CN(C(=O)OC(C)(C)C)C21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1CN(C(=O)OC(C)(C)C)C2C1OCC2(OC)OC
Temperature: 0 °C
Yield: 47.9 %

Procedure:
The keto compound 1e (1.10 g, 3.83 mmol) was dissolved in dry THF (30 mL) and the solution was cooled to 0° C. A solution of methyl triphenylphosphonium bromide (4.0 g, 11.2 mmol) and KOtBu (1.17 g, 10.5 mmol) in dry THF (40 mL) was added in 3 aliquots with 2 hours interval. After 6 hrs the solution was poured into a separatory funnel with diethyl ether (70 mL) and extracted with 10% citric acid (aq)(2*40 mL). The organic phase was washed with saturated aqueous NaHCO3 (40 mL), dried with Na2SO4, filtered and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (heptane:ethyl acetate 4:1) which gave the title compound (524 mg, 48%)
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.[CH2:10]([CH:17]1[CH:21]([CH2:22][CH2:23][CH3:24])[CH2:20][NH:19]C1=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:6][O:7][C:9]1[CH:17]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:21]([CH2:22][CH2:23][CH3:24])[CH2:20][N:19]=1
Reactant: CCCC1CNC(=O)C1Cc1ccccc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCC1CN=C(OC)C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.2 %

Procedure:
Trimethyloxonium tetrafluoroborate (0.85 g, 5.7 mmol) was added to a solution of 3-benzyl-4-propyl-2-pyrrolidinone (0.83 g, 3.8 mmol) in methylene chloride (15 ml) and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture to render it weekly basic and then extraction was performed with ethyl acetate. After washing the organic layer with brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (0.67 g) as a light yellow oil. 1H-NMR (CDCl3) δ(ppm) 0.75 (3H, t, J=7.2 Hz), 1.02-1.28 (4H, m), 2.02-2.16 (1H, m), 2.55-2.66 (1H, m), 2.69 (1H, dd, J=13.2 Hz, 8.4 Hz), 2.99 (1H, dd, J=13.2 Hz, 4.8 Hz), 3.10 (1H, dd, J=13.2 Hz, 5.2 Hz), 3.58 (1H, dd, J=13.2 Hz, 8.8 Hz), 3.83 (3H, s), 7.05-7.40 (5H, m)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]1>CN1C(=O)CCC1>[C:31]([NH:30][C@H:27]1[CH2:28][CH2:29][N:25]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:26]1)(=[O:33])[CH3:32]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CC(=O)N[C@H]1CCNC1
Solvent: CN1CCCC1=O
Product: CC(=O)N[C@H]1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 108.5 %

Procedure:
In a 2 mL microwave vial were placed N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 80 mg, 0.24 mmol) and (S)-N-(pyrrolidin-3-yl)acetamide (62 mg, 0.48 mmol). To the sealed vial were then added NMP (2 ml), and the mixture was then heated in the microwave at 100° C. for 15 minutes. After cooling to room temperature, the reaction mixture was filtered by syringe filter and was then directly purified by preparatory HPLC (20-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white powder (110 mg, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ=10.88 (s, 1 H), 8.24 (d, J=6.3 Hz, 1 H), 8.02 (d, J=2.3 Hz, 1 H), 8.01-7.96 (m, 2 H), 7.65-7.59 (m, 2 H), 6.87 (s, 1 H), 6.29 (d, J=2.0 Hz, 1 H), 4.41-4.31 (m, 2 H), 2.25-2.13 (m, 1 H), 2.03-1.91 (m, 1 H), 1.83 (s, 3 H), 1.46 (s, 6 H); ESI-MS: m/z 423.4 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:19][CH:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[CH:23][CH:22]=3)[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:29]1([CH2:28][O:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH:18]3[CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C@@H:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=4)[CH2:19]3)=[CH:22][CH:23]=2)[CH2:30][CH2:31]1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(N2CC(Oc3ccc(OCC4CC4)cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1ccc(N2CC(Oc3ccc(OCC4CC4)cc3)C2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
130 mg (0.30 mmol) (1-{4-[3-(4-cyclopropylmethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-carbamic acid tert-butyl ester are added to 2 mL DCM and the mixture is cooled to 0° C. 0.03 mL TFA is added and stirring is continued for 1 h at 0° C. The solution as such is used directly for subsequent reactions.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:3]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:3]=1
Reactant: COc1cccc(OC)c1B(O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(OC)c1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc12
Temperature: 120 °C

Procedure:
A mixture of (3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (40 mg, 0.068 mmol), 2,6-dimethoxyphenylboronic acid (18.6 mg, 0.102 mmol), tetrakis(triphenylphosphine)palladium(0) (3.9 mg, 0.0034 mmol) and sodium carbonate (2M aqueous solution, 0.102 mL, 0.204 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 120° C. for 30 minutes. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness to afford crude (3-(3-(2,6-dimethoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone, which was used in step 2 without further purification.