Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[CH2:17]([N+:21]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1.CO>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[O-:15])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([N+:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cccc(C(C)(C)C)c1[O-]
Temperature: 25 °C

Procedure:
A solution of 22.69 g (110 mmol, 1.1 equivalents) of 2,6-di-t-butylphenol in 10 mL of toluene was treated with 100 mL (100 mmol) of a 1M solution of tetrabutylammonium hydroxide in methanol under nitrogen with stirring at ambient temperature. The resulting dark green solution was stirred for 1 hour and concentrated under vacuum to a thick residue. Two 100 mL portions of toluene were added and removed by evaporation under vacuum yielding 52.08 g of wet, crude title compound as a green solid which was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[N:25]([S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])[C:24]([Si](C(C)(C)C)(C)C)=[N:23][CH:22]=1.O>CN(C)C=O>[CH3:28][N:27]([CH3:29])[S:26]([N:25]1[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:22][N:23]=[CH:24]1)(=[O:30])=[O:31]
Reactant: CN(C)S(=O)(=O)n1c(CCCCCCCBr)cnc1[Si](C)(C)C(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)S(=O)(=O)n1cncc1CCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 92.9 %

Procedure:
Potassium phthalimide (1.67 g, 9.00 mmol) was added to a solution of the product from step b (2.10 g, 4.50 mmol) in dry N,N-dimethylformamide (10 ml), under an atmosphere of argon. The mixture was stirred and heated at 100° C. for 18 h and allowed to cool to room temperature. Water (75 ml) was added and the mixture extracted with dichloromethane (3×40 ml). The combined extracts were evaporated, the residue dissolved in ethyl acetate (75 ml) and the solution washed five times with brine. The solvent was evaporated and the residue purified by flash column chromatography (silica; ethyl acetate), from which the product was isolated as a yellow oil (1.75 g, 93%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH:21]=[CH:22]S(C2C=CC=CC=2)(=O)=O)[CH:15]=[CH:16][C:17]=1[CH3:18].COC(C)(C)C>C1COCC1>[CH2:1]([O:8][CH:22]=[CH:21][C:20](=[N:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=1)[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(OC(C=CS(=O)(=O)c2ccccc2)=Nc2ccc(C)c(C)c2)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cccc(OC(C=COCc2ccccc2)=Nc2ccc(C)c(C)c2)c1
Reaction time: 0.5 h
Yield: 114.8 %

Procedure:
To a solution of benzyl alcohol (0.78 g) in THF (15 mL) was added 60% sodium hydride (90 mg) under a nitrogen atmosphere under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added dropwise to a solution of 3-methylphenyl N-(3,4-dimethylphenyl)-3-(phenylsulfonyl)acrylimidate (0.78 g) in anhydrous THF (15 mL) under ice-cooling. The mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added tert-butyl methyl ether (80 mL), which was washed with a 1N aqueous sodium hydroxide solution, water and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 3-methylphenyl 3-benzyloxy-N-(3,4-dimethylphenyl)acrylimidate (0.82 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]2[CH:19]3[CH:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]3)[CH:14]([N:22]3[CH:30]=[N:29][C:28]4[C:23]3=[N:24][CH:25]=[N:26][C:27]=4Cl)[O:13]2)[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.[CH3:41][NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]2[CH:19]3[CH:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]3)[CH:14]([N:22]3[CH:30]=[N:29][C:28]4[C:23]3=[N:24][CH:25]=[N:26][C:27]=4[N:42]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:41])[O:13]2)[CH:6]=1)=[O:4]
Reactant: CNCc1ccccc1
Reactant: COC(=O)c1cc(OCC2OC(n3cnc4c(Cl)ncnc43)C3OC(C)(C)OC23)no1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(OCC2OC(n3cnc4c(N(C)Cc5ccccc5)ncnc43)C3OC(C)(C)OC23)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (0.106 g, 0.23 mmol) in tetrahydrofuran (1.2 mL) was added polymer-bound diisopropylethylamine (PS-DIEA; Argonaut Tech., 3.83 mmol/g, 0.190 g, 3 eq), followed by addition of 0.040 mL of N-methyl-N-benzylamine (1.2 eq). The resulting mixture was stirred at room temperature overnight. The PS-DIEA resin was washed three times with dichloromethane and the solution obtained from the washes was concentrated to yield 3-{6-[6-(N-Benzyl-N-methyl-amino)-purin-9-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-isoxazole-5-carboxylic acid methyl ester as yellow oil. This material (0.23 mmol) was dissolved in 1,4-dioxane (1.2 mL) and 0.250 mL of an aqueous 2M lithium hydroxide solution added. The mixture was stirred at room temperature for 4 h. The crude product, isolated after acid workup, was used without further purification in the following step. MW calculated for C25H26N6O7 (MH+): 523, found 523 by LCMS.
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O.C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1OCC(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccccc1OCC(F)F
Yield: 90 %

Procedure:
The 1-(2,2-difluoro-ethoxy)-2-nitro-benzene (2.16 mmol) was dissolved in a 1:1-mixture of ethanol and ethyl acetate in order to obtain a final concentration of 0.05M. Hydrogenation was performed at 60° C., 1 bar of hydrogen and with palladium on charcoal (10%) as the catalyst. After evaporation of the solvent the title compound was obtained in 90% yield and could be used in the next step without further purification; (calculated) C8H9F2NO [173.16]; (found) [M+H]+=174.
Reaction SMILES: C(O[C:6]([N:8]([CH3:12])[N:9](C)[CH3:10])=O)(C)(C)C.[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16]>C(Cl)Cl>[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16].[CH3:6][N:8]([CH3:12])[NH:9][CH3:10]
Reactant: CN(C)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNN(C)C
Reaction time: 1 h

Procedure:
To a solution of N,N',N'-trimethylhydrazinecarboxylic acid tert-butyl ester (0.52 g, 2.99 mmol) in methylene chloride (4 ml) was added trifluoroacetic acid (4 ml) and the mixture was stirred for 60 min. The mixture was concentrated in vacuo and stripped three times with methylene chloride to give 0.61 g of N,N,N'-trimethylhydrazine trifluoroacetate as a thin oil.
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH:10][C@H:11]([CH2:16][C:17]#[CH:18])[C:12](OC)=[O:13])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[NH4+].[Cl-].CCN(CC)CC>CO.[Fe]>[CH2:16]([C@@H:11]1[C:12](=[O:13])[NH:1][C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]=2[NH:10]1)[C:17]#[CH:18]
Reactant: C#CC[C@@H](Nc1cccnc1[N+](=O)[O-])C(=O)OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CO
Product: C#CC[C@H]1Nc2cccnc2NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of (R)-methyl 2-(2-nitropyridin-3-ylamino)pent-4-ynoate (220 mg, 0.883 mmol), iron (296 mg, 5.30 mmol) and NH4Cl in 10 mL of MeOH was heated to reflux for 4 h. After cooling to room temperature, 0.5 mL of NEt3 was added and the solution was stirred overnight. The solvent was evaporated and the residue was redissolved with EtOAc and filtered through a pad of silica gel. The filtrate was evaporated to dryness the title compound that was used directly in the next step.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[CH2:15]([S:18]([NH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])(=[O:20])=[O:19])[CH2:16][CH3:17].O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:9]([C:25]([C:24]3[CH:23]=[C:22]([NH:21][S:18]([CH2:15][CH2:16][CH3:17])(=[O:20])=[O:19])[CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:10][NH:11][C:12]2=[N:13][CH:14]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To aluminum trichloride (4.8 g, 36.0 mmol) in methylene chloride (70.0 mL), under an atmosphere of nitrogen, was added 5-bromo-1H-pyrrolo[2,3-b]pyridine (67, 797 mg, 4.04 mmol) dissolved in methylene chloride (5.0 mL). The reaction was stirred at room temperature for 30 minutes, followed by addition of 3-(propane-1-sulfonylamino)-benzoyl chloride (77, 1.10 g, 4.20 mmol) dissolved in methylene dichloride (4.0 mL). The reaction was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid (P-1116, 300.0 mg). MS(ESI) [M−H+]−=420.1, 422.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:19]3[CH2:26][CH:27]([NH2:30])[CH2:28][CH3:29])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:31][C:32]1[N:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](O)=[O:35].CCN=C=NCCCN(C)C>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[CH2:20][N:19]3[CH2:26][CH:27]([NH:30][C:34]([C:33]3[C:32]([CH3:31])=[N:40][CH:39]=[CH:38][CH:37]=3)=[O:35])[CH2:28][CH3:29])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: CCC(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCC(CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12)NC(=O)c1cccnc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of 4-(2-amino-butyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide (100 mg, 0.233 mmol) in pyridine (4 mL) was added 2-methyl-nicotinic acid (38.4 mg, 0.280 mmol) and EDCI (71.5 mg, 0.373 mmol). The solution was stirred overnight at room temperature, then diluted with water (5 mL). The mixture was poured into a separatory funnel and diluted further with water (20 mL). The mixture was extracted with EtOAc (2×20 mL), then the combined organic layers were washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield a yellow-brown oil which was purified via column chromatography. The resulting yellow solid was dissolved in methanol (2 mL) and HCl in Et2O (2M, 2 mL) was added. The mixture was stirred for 5 minutes, then concentrated to yield 103 mg of 6,6-dimethyl-4-{2-[(2-methyl-pyridine-3-carbonyl)-amino]-butyl}-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide (71% yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:13]#[N:14])=[CH:6][CH:5]=1.Br[C:23]1[CH:24]=[N:25][CH:26]=[N:27][CH:28]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])([C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)[C:13]#[N:14])=[CH:8][CH:9]=1
Reactant: N#CC(CCc1ccc(Cl)cc1)c1ccccc1F
Reactant: Brc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCc1ccc(Cl)cc1)(c1cncnc1)c1ccccc1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A 1 L 4-neck flask under a nitrogen atmosphere was charged with 4.4 g. of 60% sodium hydride (1.1 equiv., 0.11 moles), and washed with hexanes, in 75 ml. DMF. Then over 30 minutes, 27.3 g. of 4-(4-chlorophenyl)-2-(2-fluorophenyl) butanenitrile (1.0 equiv., 0.10 moles) in 110 ml. DMF was added dropwise to the base causing an exotherm to 30° C. After the addition was complete, the reaction mixture was stirred for 30 minutes. Over 5 minutes 17.5 g. of 5-bromopyrimidine (1.1 equiv., 0.11 moles) in 75 mi. DMF was added to the reaction mixture which was heated at 50° C. and monitored by GLC analysis. The reaction was quenched after 2 hours by the addition of 350 ml. water and extracted with 600 ml. ethyl acetate. The organic phase was washed with three 300 ml. portions of water, the organic phase dried over anhydrous magnesium sulfate, and then concentrated in vacuo at 50° C. to give 34.2 grams oil which solidified. The solid was with triturated with 75 ml. isopropanol, filtered, and dried to give 16.5 g. white solid (47.0% yield), m.p.=86° C.-88° C.
Reaction SMILES: [I:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[F:9][C:10]([F:24])([F:23])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[I:1][C:2]1[N:3]=[N:4][C:5]([N:20]2[CH2:19][CH2:18][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:23])([F:24])[F:9])[CH:12]=3)[CH2:22][CH2:21]2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(I)nn1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cccc(N2CCN(c3ccc(I)nn3)CC2)c1
Temperature: 70 °C
Yield: 48 %

Procedure:
A mixture of 5.2 parts of 3,6-diiodopyridazine, 3.5 parts of 1-[3-(trifluoromethyl)phenyl]piperazine, 3.2 parts of sodium carbonate and 90 parts of N,N-dimethylacetamide was stirred and heated overnight at 70° C. The reaction mixture was poured onto water. The precipitated product was filtered off and crystallized from 2-propanol, yielding 3.2 parts (48%) of 3-iodo-6-[4-[3-(trifluoromethyl)phenyl)-1-piperazinyl]-pyridazine; mp. 144.6° C. (compound 202).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH2:12][CH3:13].Cl>C(O)C.O1CCOCC1>[ClH:1].[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[C:12]2[CH3:13]
Reactant: CCC(=O)c1cccnc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1c(-c2cccnc2)[nH]c2ccc(Br)cc12

Procedure:
To a suspension of 4-bromophenylhydrazine hydrochloride (10.00 g, 42.95 mmol) in anhydrous ethanol (200 mL) is added 3-propionylpyridine (7.51 g, 42.95 mmol) and the mixture is stirred at reflux for 30 min. 4M HCl in 1,4-dioxane (42.9 mL) is added to the yellow solution and stirring is continued at reflux overnight. The reaction mixture is cooled with an ice-water bath and the yellow precipitate is filtered through a sintered funnel to give 5-bromo-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride as a yellow solid. The product is dissolved in methanol (100 mL) and treated with sodium methoxide to give the free base, which is used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][CH2:8][N:9]1[CH2:29][CH2:28][C:12]2([O:17][CH2:16][CH2:15][N:14]([C:18]([C:20]3[N:21]=[C:22]([CH:25]([CH3:27])[CH3:26])[S:23][CH:24]=3)=[O:19])[CH2:13]2)[CH2:11][CH2:10]1.[C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:36])[CH:34]=[CH2:35].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(#N)C>[CH:25]([C:22]1[S:23][CH:24]=[C:20]([C:18]([N:14]2[CH2:13][C:12]3([CH2:28][CH2:29][N:9]([CH2:8][CH2:7][C:6]4[CH:5]=[C:4]([CH:32]=[CH:31][CH:30]=4)[CH2:3][CH2:2][O:1][CH2:35][CH2:34][C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][CH2:11]3)[O:17][CH2:16][CH2:15]2)=[O:19])[N:21]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCO)c4)CC3)C2)cs1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC#N
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCOCCC(=O)OC(C)(C)C)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(9-(3-(2-Hydroxyethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone [Example 34a, step a] (13.2 g) was dissolved in acetonitrile (20 mL) and tert-butyl acrylate (8.13 g) added, followed by benzyltrimethylammonium hydroxide (40% in water, 3.93 mL). The mixture was stirred at ambient temperature for 3 hours. The volatiles were removed under reduced pressure and the residue purified by flash silica chromatography eluting with 5% methanol and 1% triethylamine in ethyl acetate to afford the subtitled compound Yield 13.2 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH2:19][CH:20]4[CH2:22][CH2:21]4)[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([NH2:33])=[CH:28][CH:27]=2>>[CH:20]1([CH2:19][O:18][C@@H:15]2[CH2:16][CH2:17][N:13]([C:11]([C:9]3[S:10][C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[NH:33][C:29]4[CH:30]=[C:31]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24]([CH3:23])=[CH:32]5)[CH:8]=3)=[O:12])[CH2:14]2)[CH2:22][CH2:21]1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](OCC2CC2)C1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CC[C@@H](OCC6CC6)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (3R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-cyclopropylmethoxy-pyrrolidin-1-yl)-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 447.2 (MH+); HPLC Rf: 5.341 min.; HPLC purity: 100%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:43]1[CH2:44][CH2:45][N:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([Br:33])[CH:35]=2)[CH2:41][CH2:42]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: Brc1cccc(N2CCNCC2)c1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2cccc(Br)c2)CC1
Yield: 16 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3-bromo-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (12.6 mg, 16%) as light yellow oil. MS m/e=569.3 [M+H]+.
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:5]=[C:6](Cl)[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1.II.[O:15]1[CH2:19][CH2:18][CH:17]([CH:20]=[O:21])[CH2:16]1>O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:20]([CH:17]2[CH2:18][CH2:19][O:15][CH2:16]2)[OH:21])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: O=CC1CCOC1
Reactant: COc1cc(Cl)cc(OC)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)C2CCOC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Magnesium turnings (8.5 g, 0.35 mol) are activated by stirring at room temperature overnight under argon and suspended in anhydrous tetrahydrofuran (60 ml). 10 ml of a solution of 3,5-dimethoxychlorobenzene (60.4 g, 0.35 mol) in anhydrous tetrahydrofuran (75 mL) is added, followed by a crystal of iodine, and the mixture is placed in an ultrasonic bath for 10 minutes. A further 10 mL of the solution of 3,5-dimethoxychlorobenzene in tetrahydrofuran is added and reaction is heated at 80° C. for 1 h. The remainder of the starting material is added dropwise to the reaction mixture at 80° C. over 50 minutes, then heating is continued at 80° C. for a further 30 minutes. The reaction mixture is cooled to below room temperature in an ice/water bath and a solution of tetrahydrofuran-3-carbaldehyde (35 g, 0.35 mol) in anhydrous tetrahydrofuran (35 mL) is added dropwise over 30 minutes. Once the addition is complete, the reaction mixture is stirred at room temperature overnight. The reaction mixture is decanted and 2M aqueous hydrochloric acid is carefully added to the decanted solution, until the pH of the reaction mixture reaches pH 1. The reaction mixture is extracted with ethyl acetate (4×100 mL) and the organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue is purified by column chromatography on silica gel to give (3,5-dimethoxyphenyl)(tetrahydrofuran-3-yl)methanol as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([NH:20][C:21](=O)[CH2:22][O:23][CH3:24])[CH2:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].B.CSC>O1CCCC1>[CH3:24][O:23][CH2:22][CH2:21][NH:20][CH:13]([C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11][CH2:12]1)[CH2:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17]
Reactant: CCC(CC)CC(NC(=O)COC)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCC(CC)CC(NCCOC)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 168 h

Procedure:
Borane-methyl sulphide complex (2 ml) was added dropwise to a solution of the methoxyacetamide (5 g) prepared as described above in dry tetrahydrofuran (20 ml) at 0°-5° C. This mixture was left at ambient temperature for 7 days, then poured onto ice-water basified and extracted into ether, washed with water, dried and evaporated to dryness to give an oil. This oil was treated as above with more borane-methyl sulphide to give N-(2-methoxyethyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-ethyl pentylamine (b.p. 189°-190° C./1.5 mm Hg) as an oil.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][N:16]=1>COCCOC.C(=O)(O)[O-].[Na+]>[N:10]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][N:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=12
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cnccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1cn2ccncc2n1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
Ethyl bromopyruvate (2.153 g, 11.04 mmol) was added to a solution of 3-aminopyrazine (1 g, 10.51 mmol) in DME (10 mL) and the mixture was stirred continuously at 20-35° C. for 2 h. The reaction mixture was filtered and the solid which precipitated out was dried well, dissolved in EtOH (10 mL) and stirred under reflux for 2 h. This reaction mixture was then concentrated under reduced pressure to obtain a crude residue. The residue was diluted with aqueous sodium bicarbonate solution, and extracted with chloroform. The organic layer separated was washed with water and then with brine solution; dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. The crude product was further purified by column chromatography (using Silica gel 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 450 mg of the title compound the as a yellow solid.