Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1([C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([C:32](OC)=[O:33])[C:25](=[CH:30][CH:31]=3)[C:26](OC)=[O:27])[CH:17]=[CH:18][CH:19]=2)[O:13][CH2:12][CH2:11][O:10]1)[CH3:8].O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[CH2:7]([C:9]1([C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:25]([CH2:26][OH:27])=[C:24]([CH2:32][OH:33])[CH:23]=3)[CH:17]=[CH:18][CH:19]=2)[O:10][CH2:11][CH2:12][O:13]1)[CH3:8]
Reactant: CCC1(c2cccc(CCc3ccc(C(=O)OC)c(C(=O)OC)c3)c2)OCCO1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCC1(c2cccc(CCc3ccc(CO)c(CO)c3)c2)OCCO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2.9 g (75 mmol) of lithium aluminum hydride are suspended in 20 ml of ethyl ether. A solution of 7.5 g (19 mmol) of dimethyl 4-{2-[3-(2-ethyl[1,3]dioxolan-2-yl)phenyl]ethyl}phthalate in 100 ml of ethyl ether is added drop by drop. After stirring at ambient temperature for 20 minutes, the reaction medium is treated by addition of 15 ml of water, 1.5 ml of 15% sodium carbonate and 4.5 ml of water, then filtered and concentrated under reduced pressure. A colorless oil is obtained (m=6.4 g; Y=99%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:5][CH2:4]1.Cl[C:14]1[N:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=1.C(N(C(C)C)C(C)C)C.[Na+].[I-]>CC(N(C)C)=O>[CH2:20]([C:17]1[CH:16]=[N:15][C:14]([N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:7][CH2:8]2)=[N:19][CH:18]=1)[CH3:21]
Reactant: CCc1cnc(Cl)nc1
Reactant: CN[C@H]1CC[C@H](C#CCO)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N(C)[C@H]2CC[C@H](C#CCO)CC2)nc1

Procedure:
A solution of 0.24 g (1.44 mmol) of trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol, 0.7 ml (5.74 mmol) of 2-chloro-5-ethylpyrimidine, 0.83 ml (4.88 mmol) N-ethyldiisopropylamine and a catalytic amount of NaI in 1.5 ml DMA was heated in the microwave oven for 3.75 h at 120° C. The reaction was cooled and partitioned between aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (hexane/EtOAc 9:1 to 1:1) gave 0.24 g (61%) of trans-3-{4-[(5-Ethyl-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol, MS: 274 (MH+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[C@H:4]([NH2:7])[CH2:5][OH:6].N1C=CC=CC=1.[S:20]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]([F:12])([F:13])[CH:3]([C:8]([F:9])([F:10])[F:11])[C@H:4]([NH:7][S:25]([C:22]1[CH:23]=[CH:24][S:20][CH:21]=1)(=[O:27])=[O:26])[CH2:5][OH:6]
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: N[C@H](CO)C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(N[C@H](CO)C(C(F)(F)F)C(F)(F)F)c1ccsc1
Temperature: 25 °C
Yield: 35 %

Procedure:
A solution of (1S)-3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propylamine (prepared according to the method of Example 13, 0.100 g, 0.4 mmol) in CH2Cl2 (1 mL) was stirred under nitrogen at 25° C. Pyridine (0.097 mL, 1.2 mmol) was added followed by 3-thiophenesulfonyl chloride (0.072 g, 0.4 mmol) in CH2Cl2 (0.5 mL), and the resulting solution stirred for 18 h at 25° C. The crude reaction mixture was loaded onto the TsOH Syntage™ samplet and after concentration was purified by the Biotage Flash™ 12 chromatography system, eluent: 30:70 EtOAc:hexanes, to obtain N-[(1S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]thiophene-3-sulfonamide as a white solid (0.053 g, 35% yield).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.N12CCCN=C1CCCCC2.[Cl:37][CH2:38][C:39](Cl)=[O:40]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:37][CH2:38][C:39]([NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=2)[N:14]=[C:13]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:2](=[O:1])(=[O:25])[CH2:3][CH2:4]2)[CH:22]=1)=[O:40]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N)c2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CCl)c2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 19.9 %

Procedure:
To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (500 mg, 1.4 mmol) in chloroform (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL, 2.8 mmol) followed by chloroacetyl chloride (0.17 mL, 2.1 mmol) at room temperature. The resulting solution was heated with stirring at 70° C. for 2 hours under nitrogen. After being cooled to room temperature, the reaction was diluted with ethyl acetate (50 mL), washed with water (50 mL×3), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 25% ethyl acetate in petroleum ether) to give 120 mg of the product as an off-white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][C:21]([C:30]([O:32]C)=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCCN3CCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCCN3CCC)cc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 52.5 %

Procedure:
To methyl 9-(4-(2-butoxyethoxy)phenyl)-1-propyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.1 g) was incorporated with tetrahydrofuran (27 ml) and methanol (27 ml), followed by adding aqueous 1N sodium hydroxide solution (9 ml), and the mixture was stirred at 90° C. for 7 hours. After cooling to 0° C., water was added and the mixture was neutralized with 1N hydrochloric acid. After extracting with ethyl acetate, the organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from hexane-ethyl acetate to give 9-(4-(2-butoxyethoxy)phenyl)-1-propyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylic acid (1.07 g) as yellow crystals.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:38])[C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:46][C:41]1[CH:40]=[C:39]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:38])[C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[CH2:21]2)[CH:44]=[CH:43][C:42]=1[Cl:45]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc(C(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: CC#N
Product: COc1cc(C(=O)N2CC[C@@](CCN3CCC(N4CCCCC4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]([CH3:16])[CH2:5][NH:4]1)[CH3:2].C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([C@@H:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]([CH3:16])[CH2:5][N:4]1[CH3:19])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC[C@@H]1CN(Cc2ccccc2)[C@H](C)CN1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H]1CN(Cc2ccccc2)[C@H](C)CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of (2R,5R)-5-ethyl-2-methyl-1-(phenylmethyl)piperazine (prepared according to procedures in J. Med. Chem. 2006, 49, 716-726, utilizing Boc-D-2-aminobutyric acid in place of N-Boc-L-alanine) (902 mg, 4.13 mmol) in dichloromethane (25 mL) at 0° C. was added formaldehyde (0.435 mL, 37% water solution, 5.78 mmol) followed by sodium triacetoxyborohydride (1050 mg, 4.96 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were washed with brine, dried (MgSO4) and evaporated to yield (2R,5R)-2-ethyl-1,5-dimethyl-4-(phenylmethyl)piperazine (875 mg, 91%). LCMS: (M+H)+: 233.3.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[C:18]([CH3:21])[C:19]=2[CH3:20])[CH:10]([CH3:29])[CH2:9]1)C1C=CC=CC=1>CCO.[Pd]>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:17]2[N:16]=[N:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]3[CH3:29])=[C:19]([CH3:20])[C:18]=2[CH3:21])=[CH:27][CH:26]=1
Reactant: Cc1c(-c2ccc(F)cc2)nnc(N2CCN(Cc3ccccc3)CC2C)c1C
Agent: [Pd]
Solvent: CCO
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCNCC2C)c1C
Reaction time: 10 h
Yield: 14.5 %

Procedure:
Add a solution of 3-(4-benzyl-2-methylpiperazin-1-yl)-6-(4-fluorophenyl)-4,5-dimethylpyridazine (200 mg, 3.25 mmol) in absolute EtOH (15 mL) to 10% Pd/C (46.8 mg) pre-wetted with EtOH (5 mL). Shake the mixture in a Parr bottle pressurized with H2 at 60 psi for 10 h. Filter the reaction mixture, and apply the solution directly to an SCX column (Varian, 2 g). Rinse the column with MeOH and CH2Cl2. Elute the product with a 1:1 mixture of 2 M NH3/MeOH and CH2Cl2. Concentrate the eluent under reduced pressure to afford the title compound as an off-white foam (142 mg, 92%). ES/MS m/z 301.2 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]>Cl>[CH2:14]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2)[CH2:15][CH3:16]
Reactant: CCCNCCC
Reactant: O=C1Cc2c(CCBr)cccc2N1
Agent: Cl
Product: CCCN(CCC)CCc1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
Under an atmosphere of nitrogen, a suspension of 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (245 mg, 102 mmol) was prepared by the addition of di-n-propylamine (1.00 g, 10 mmol, 1.35 ml) which has previously been degassed with a stream of nitrogen. After stirring for 30 minutes, degassed acetonitrile (5 ml) was added to give a pale yellow solution. After an additional hour the solution was heated, and maintained at reflux for 5 hours. After cooling to ambient temperature, the solution was poured into IN hydrochloric acid (35 ml) and extracted with ether (50 ml). The aqueous layer was made neutral to pH 7-7.5 with solid sodium bicarbonate and extracted with dichloromethane (50 ml). After drying separately, the ether layer was evaporated to give 4-vinyl-indol-2-one (60 mg, 37.7%) Evaporation of the dichloromethane layer gave 4-[2-(dipropylamino)ethyl]-1.3-dihydro-2H-indol-2-one (155 mg. 58.5%) as free-base which was then taken up in absolute ethanol (5 ml) and saturated with gaseous hydrogen chloride. The solvent was removed in vaccuo to give the crude hydrochloride salt (170 mg) as a light yellow solid. Recrystallisation from absolute ethanol (2 ml) gave light yellow crystals (110 mg 63% from the free-base) of 4-[2-(dipropylamino)ethyl]-1,3- dihydro-2H-indol-2-one hydrochloride m.p. 242-244° C.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][C:11](=[O:18])[O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][C:11](=[O:18])[O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)COC(=O)Nc1cccc(C)c1CO
Solvent: ClCCl
Product: COC(=O)COC(=O)Nc1cccc(C)c1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Methoxycarbonylmethyl (2-hydroxymethyl-3-methylphenyl)carbamate (6.8 g) is introduced in dichloromethane (60 ml) and treated dropwise with thionyl chloride (3.4 ml). The mixture is then stirred at RT for a further 1 h. The solvent is then distilled off and the residue is treated 2 times with dichloromethane (50 ml each) and the mixture is in each case concentrated again on a rotary evaporator. 7 g (96%) of the title compound of m.p. 114-116° C. are obtained.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:34]2([CH3:35])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:37][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:34]2([CH3:35])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:25][C:26]([OH:29])([CH3:27])[CH3:28])([CH3:22])[CH3:23])[CH2:12][C@@H:11]([OH:37])[CH2:10]1
Reactant: CC(C)(O)COC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)COC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 78.7 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(2-hydroxy-2-methylpropoxy)-20-methylpregna-5,7,16-triene (35.6 mg, 0.0552 mmol), a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (0.35 ml) and tetrahydrofuran (0.5 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (reflux under heating for 12 hours), worked up and the thus obtained residue was purified by preparative thin layer chromatography (1 sheet (0.5 mm thickness), dichloromethane:ethanol=15:1, developed three times) to give the titled compound (18.1 mg, 79%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccc1F
Temperature: 100 °C
Yield: 65.9 %

Procedure:
(S)-1-[6-Fluoro-1-(2-fluorophenyl)-1H-benzoimidazol-2-yl]ethylamine (0.22 g, 0.81 mmol) was dissolved in n-butanol (5 mL) and 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.193 g, 0.81 mmol) and DIPEA (0.70 mL, 4.03 mmol) added. The reaction mixture was heated at 100° C. overnight. The resultant mixture was allowed to cool to RT and then concentrated in vacuo. The residue was passed down an Isolute® SCX-2 cartridge, eluting with DCM, MeOH and 2M NH3 in MeOH to afford a light yellow gum. This was purified by column chromatography (silica gel, gradient 0-5% MeOH in DCM) to afford 195 as an off-white solid (209 mg, 67%). LCMS (Method K): RT 3.34/3.52 min [M+H]+ 392.0 1H NMR (DMSO-d6, 400 MHz): δ 8.16-7.79 (3H, m), 7.77-7.64 (2H, m), 7.58-7.21 (3H, m), 7.16-7.09 (1H, m), 6.92-6.83 (1H, m), 5.63-5.38 (1H, m), 1.69 (1.5H, d, J=6.85 Hz), 1.58 (1.5H, d, J=6.86 Hz). NMR signals represent a mixture of rotamers
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][CH2:20][C:21]1([C@H:24]2[CH2:28][C:27](=[O:29])[N:26]([C@H:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:31])[CH2:25]2)[CH2:23][CH2:22]1.N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[O:19]([CH2:20][C:21]1([C@H:24]2[CH2:28][C:27](=[O:29])[N:26]([C@H:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH3:31])[CH2:25]2)[CH2:22][CH2:23]1)[Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](C2(CO)CC2)CC1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccccc1)N1C[C@@H](C2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)CC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
tert-Butyldiphenylsilyl chloride (2.83 ml, 10.88 mmol) was added to a solution of (3R)-3-[1-(hydroxymethyl)cyclopropan-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidine (2.35 g, 9.06 mmol) and imidazole (925 mg, 13.59 mmol) in N,N-dimethylformamide (30 mL), and the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate (150 mL), washed with water (50 mL×2) and brine (50 mL×2), dried over anhydrous sodium sulfate, and then filtered. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19→1:9→1:4→1:1) to give 3.88 g (86%) of the title compound as a colorless transparent gummy solid.
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][CH:12]3[C:16]([CH3:18])([CH3:17])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][CH:12]3[C:16]([CH3:17])([CH3:18])[CH2:15][N:14]([C:28]([C:25]4([C:23]#[N:24])[CH2:27][CH2:26]4)=[O:29])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: CC1(C)CNCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: N#CC1(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(C(=O)C2(C#N)CC2)CC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A solution of (+/−)-6-bromo-4-((4,4-dimethylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (50 mg, 0.104 mmol) in DMF (0.3 mL), was added 1-cyanocyclopropanecarboxylic acid (13.9 mg, 0.13 mmol), BOP (55.4 mg, 0.13 mmol), DIPEA (0.046 mL, 0.26 mmol). The mixture was stirred at rt for 3 h, quenched with water then filtered. The solid was rinsed with water, dried under vacuum to give 6-bromo-4-((1-(1-cyanocyclopropanecarbonyl)-4,4-dimethylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (36 mg, 78% yield) was obtained as a brown solid. MS (ES+) m/z: 444.1, 445.2 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:23][CH3:24])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=1)C1C=CC=CC=1.C(O)C>[C].[Pd].O1CCCC1>[CH2:23]([O:22][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][C:13]=1[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:24]
Reactant: CCOC(=O)/C=C/c1cc(OCc2ccccc2)ccc1OCC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(O)ccc1OCC
Yield: 96.3 %

Procedure:
A mixture of ethyl (E)-3-(5-benzyloxy-2-ethoxyphenyl)-2-propenoate (1.85 g), 5% palladium carbon (3.0 g), ethanol (50 mL) and tetrahydrofuran (30 mL) was subjected to catalytic hydrogenation at room temperature and 1 atm. After filtering off the catalyst, the solvents were evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate as a colorless oil (1.30 g, 96%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.ClCCl.O>C(#N)C.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Br)cnc21
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1-c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncc(Br)cc12
Temperature: 65 °C
Yield: 72.9 %

Procedure:
1.01 g (2.10 mmol) of 5-bromo-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine, 336 mg of 2-methoxyphenylboronic acid, and 75 mg of (1,1′-bis(diphenyl-phosphino)ferrocene)palladium(II)-dichloride dichloromethane adduct were placed in a Smith® vial and dissolved in a mixture of 15 ml of acetonitrile, 5 ml of toluene, and 7 ml of a saturated aqueous solution of sodium bicarbonate. The mixture was heated to 65° C. for 4 h and then cooled to room temperature. The crude was distributed between dichloromethane and water and the organic phase was dried over sodium sulfate and evaporated. The crude was then purified by flash chromatorgraphy on silica gel using a gradient of ethyl acetate in hexanes to afford 708 mg (1.53 mmol, 73%) of 5-bromo-3-(2-methoxy-phenyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine as a yellow oil (containing about 20% of residual starting material as an inseparable mixture). 1H-NMR (d6-DMSO): δ8.33 (d, J=2.4 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.76 (s, 1H), 7.55 (dd, J=1.3 Hz, 7.3 Hz, 1H), 7.33 (ddd, J=1.9 Hz, 7.3 Hz, 1H), 7.15 (dd, J=1.0 Hz, 8.3 Hz 1H), 7.06 (dt, J=1.0 Hz, 7.3 Hz, 1H), 3.82 (s, 3H), 1.88 (m, 3H), 1.10 (d, 18H).