Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:6]2[CH2:7][N:8](CC3C=CC=CC=3)[CH2:9][C@@H:5]2[CH2:4][N:3]1[CH3:17].Cl>CO.[Pd]>[CH3:1][C:2]1([CH3:18])[C@@H:6]2[CH2:7][NH:8][CH2:9][C@@H:5]2[CH2:4][N:3]1[CH3:17]
Reactant: CN1C[C@H]2CN(Cc3ccccc3)C[C@H]2C1(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1C[C@H]2CNC[C@H]2C1(C)C
Reaction time: 8 h

Procedure:
To a degassed solution of (rac)-cis-1,1,2-trimethyl-5-(phenylmethyl)octahydropyrrolo[3,4-c]pyrrole (1.44 g, 6 mmol) in MeOH (30 mL) was added 1 M HCl (12.3 mL, 12 mmol) followed by 10% Pd/C (220 mg). The resulting mixture was stirred overnight under a hydrogen balloon. Filtration of the catalyst and evaporation of the solvents in vacuo yielded (rac)-cis-1,1,2-trimethyloctahydropyrrolo[3,4-c]pyrrole in quantitative yield as a hydrochloride salt. LCMS: (M+H)+: 155.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH2:34][CH3:35])=[C:16]([C:22]4[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[N:26][CH:27]=4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[Cu](C#N)[C:37]#[N:38]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH2:34][CH3:35])=[C:16]([C:22]4[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[N:26][CH:27]=4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([C:37]#[N:38])[C:3]=12
Reactant: N#C[Cu]C#N
Reactant: CCOc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2nc(C#N)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 120 °C

Procedure:
A mixture of 5-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (13 mg, 0.021 mmol, racemic intermediate from Example 15) and copper cyanide (12 mg, 0.13 mmol) in N,N-dimethylformamide (0.2 mL) was heated at 120° C. overnight. The mixture was filtered and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C25H26ClN8O2 (M+H)+: m/z=505.2; Found: 505.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: Cc1ncc(C(CN)N2CCCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2c(F)cccc2Cl)N2CCCOCC2)cn1

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][N:8]1[C:17]2[C:16](=[O:18])[NH:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=3[NH:12][C:11]=2[C:10]([CH3:23])=[CH:9]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:1][CH2:2][CH2:3][C:4]([N:12]1[C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[NH:15][C:16](=[O:18])[C:17]2[N:8]([CH3:7])[CH:9]=[C:10]([CH3:23])[C:11]1=2)=[O:5]
Reactant: Cc1cn(C)c2c1Nc1ccccc1NC2=O
Reactant: O=C(Cl)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cn(C)c2c1N(C(=O)CCBr)c1ccccc1NC2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
A solution of 3.42 g of 3-bromopropionyl chloride in 20 ml of dioxane is added dropwise to 4.54 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one, 5.0 g of powdered anhydrous potassium carbonate and 80 ml of dry dioxane in the course of 10 minutes at from 50° to 60° C., and the mixture is stirred at this temperature for a further 2 hours. The solvent is stripped off in vacuo, and the resulting solid residue is stirred with 300 ml of ice water and filtered off. 5.1 g of the title compound of m.p. 194° to 195° C. (D.) are obtained after recrystallization from isopropanol.
Reaction SMILES: [NH2:1][CH:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][S:4][C:3]1([CH3:10])[CH3:9].[NH2:11][C@H:12]([C:17]([NH:19][C@@H:20]([C:22](N)=[O:23])[CH3:21])=[O:18])[CH2:13][C:14](=[O:16])[OH:15].C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>>[CH3:9][C:3]1([CH3:10])[CH:2]([NH:1][C:22](=[O:23])[C@@H:20]([CH3:21])[NH:19][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH2:11])[C:6]([CH3:8])([CH3:7])[CH2:5][S:4]1
Reactant: C[C@@H](NC(=O)[C@@H](N)CC(=O)O)C(N)=O
Reactant: CC1(C)CSC(C)(C)C1N
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: C[C@@H](NC(=O)[C@@H](N)CC(=O)O)C(=O)NC1C(C)(C)CSC1(C)C

Procedure:
When levorotatory 3-amino-2,2,4,4-tetramethyltetrahydrothiophene, resolved by standard methods, was employed in the above procedure in place of the racemic amine the resulting L-aspartyl-D-alanine amide was found to be 800 times as sweet as sucrose.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6]1[CH:10]=[C:9]([C:11]([CH2:13][CH2:14][CH2:15][Cl:16])=O)[S:8][CH:7]=1>CO.Cl.O>[Cl:16][CH2:15][CH2:14][CH2:13][C:11](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[C:9]1[S:8][CH:7]=[CH:6][CH:10]=1
Reactant: NNC(N)=S
Reactant: O=C(CCCCl)c1cccs1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CCCCl)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
Thiosemicarbazide (9.11 g, 0.1 mol) was added under nitrogen to a solution 4-chloro-2'-butyrothienone (16.2 mL, 0.1 mol) in 350 mL of methanol plus 27 mL 1N HCl plus 25 mL of water. After stirring at room temperature for approximately 2 hours, all of the solid had dissolved. The reaction was then stirred at room temperature for 24 hours (overnight). By TLC starting material remained. An additional 27 mL of 1N HCl was added and the reaction stirred at room temperature for 6 hours. The solid formed was removed by filtration and dried under high vacuum to give 14.87 g (57%) of the title compound as a brown solid, mp 120-122° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=O)=O)=CC=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.CCOCC>[N:25]([CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CN=[N+]=[N-]
Temperature: 70 °C
Yield: 90.6 %

Procedure:
(S)-2-[[[(4-Methylphenyl)sulfonyl]oxy]methyl]-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3.55 g, 10 mmol, see J. Das et al, J. Med Chem, 1992, Vol.35,2610 for preparation) was dissolved in dimethyl sulfoxide (DMSO) (40 mL) and treated with sodium azide (980 mg, 15 mmol). The mixture was heated at 70° C. for 5 hours, then cooled and diluted with ether. After washing with water (3×50 mL), the ether layer was dried (MgSO4) and freed of solvent in vacuo to give title compound as a colorless oil (2.05 g, 91%) which was used without further purification.
Reaction SMILES: C[Al](C)C.[C:5](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C.[CH3:22][C@:23]12[CH2:40][CH2:39][C@H:38]3[C@@H:28]([CH2:29][CH2:30][C:31]4[C@:36]3([CH3:37])[CH:35]=[CH:34][C:33](=[O:41])[CH:32]=4)[C@@H:27]1[CH2:26][CH2:25][C:24]2=[O:42]>CCCCCC.C(OC)(=O)C.[Ni+2].C/C(/[O-])=C/C(C)=O.O>[CH3:5][C:35]1[C@@:36]2([CH3:37])[C:31]([CH2:30][CH2:29][C@@H:28]3[C@@H:38]2[CH2:39][CH2:40][C@@:23]2([CH3:22])[C@H:27]3[CH2:26][CH2:25][C:24]2=[O:42])=[CH:32][C:33](=[O:41])[CH:34]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: O
Solvent: COC(C)=O
Product: CC1=CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]12C
Temperature: 50 °C
Yield: 183.1 %

Procedure:
86.4 ml (80 mmol) of a 10% solution of trimethylaluminum in hexane is introduced at room temperature under nitrogen atmosphere. With stirring, 17.4 g (80 mmol) of 2,6-di-tert-butyl-4-methylphenol is added in portions. The solution is stirred for 30 more minutes and subsequently stirred until the end of the methane generation. 28.4 g (100 mmol) of androsta-1,4-diene-3,17-dione (ADD) in 200 ml of methyl acetate is added at 25° C. The solution is heated to 50° C. 1.43 g (5 mmol) of nickel(II)-acetylacetonate is added at 50° C. The solution is stirred for 50 more minutes at a temperature of 50° C. For hydrolysis, 15 ml of water is added with cooling, for completion, it is stirred for 15 more minutes. The inorganic solid is filtered off and rewashed twice with 50 ml of methyl acetate. After concentration by evaporation Of the methyl acetate phases, 43.71 g of crude product is obtained, which is chromatographed on silica gel with hexane/ethyl acetate as eluent with increasing ethyl acetate portion. After concentration by evaporation of the fractions, 6.5 g of 1-methyl-androsta-1,4-diene-3,17-dione (23% of theory) of melting point 168° C. is obtained.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9]>N1C=CC=CC=1>[F:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[NH:2][C:11](=[O:12])[CH2:10][CH:5]([CH3:6])[CH3:4]
Reactant: COC(=O)Cc1ccc(F)c(N)c1
Agent: [Cl-]
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(F)c(NC(=O)CC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 166 %

Procedure:
Isovaleryll chloride (2.93 ml, 2.90 g, 0.024 mol) was added, dropwise, to a chilled (ice-bath) solution of methyl 3-amino-4-fluorophenylacetate (4.00 g, 0.022 mol) in pyridine (16 ml) and, once the addition was complete, the cooling bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. Trituration with dichloromethane/hexane gave methyl 4-fluoro-3-(3-methylbutyramido)phenylacetate (4.88 g) as a pale brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[O:19]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[CH3:35][CH2:36][CH2:37]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[O:19]2)[CH:10]=[C:11]([O:17][CH2:35][CH2:36][CH3:37])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(S(=O)(=O)CCO)c1OCCC
Temperature: 75 °C

Procedure:
A mixture of trans-2-[3-(2-hydroxyethylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (366 mg, 0.74 mmol), n-propyl bromide (0.12 mL, 1.33 mmol) and potassium carbonate (255 mg, 1.85 mmol) in DMF (3 mL) was heated at 75° C. for 1 h. The reaction mixture was cooled and partitioned between ethyl ether and water, and the aqueous layer was re-extracted with ether (2 ×). The organic extracts were combined, dried, and evaporated to dryness. The residue was purified by chromatography to give the title compound: Rf 0.43 (hexane-ethyl acetate; 1:2, v/v); NMR (CDCl3) δ1.05 & 1.09 (2 t, J=7.5 Hz, 2 CH2CH2CH3), 2.85 (t, J=6.5 Hz, OH), 3.65 (m, SO2CH2), 3.95 (m, SO2CH2CH2), 4.03 & 4.15 (2 t, J=6.5 Hz, 2 CH2CH2CH3), 6.63 (s, 2 H, C5ArH), 7.27 & 7.49 (2 d, J=1.5 Hz, C2ArH).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[F:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.CN(C)[CH:30]=[O:31]>O1CCCC1.O>[F:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: Fc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=Cc1ccncc1F
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Form a solution of lithium diisopropylamide by the addition of n-butyl lithium (37.5 mL, 0.06 mol, 1.6 M in hexanes) to diisopropylamine (8.40 mL, 0.06 mol) in tetrahydrofuran (200 mL) at 0 to −10° C. under a nitrogen atmosphere. Stir for 30 min. Cool to −70° C. and add 3-fluoropyridine (4.29 mL, 0.05 mol) dropwise via syringe. Stir for 1 hour at this temperature. Add N,N-dimethylformamide (7.75 mL, 0.10 mol) dropwise via syringe and stir for 2 hours near −70° C. Add water (200 mL) when the mixture warms to −20° C. and extract with ethyl acetate. Dry the combined extracts over sodium sulfate and concentrate in vacuo. Elute the resulting residue over silica gel, allowing for isolation of the desired aldehyde (4.28 g, 68%) as an oil. MSEI): M+ 125.0 m/z.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:23])[CH2:17][CH:18]1[CH2:22][CH2:21][O:20][CH2:19]1)[CH3:14].CI>O1CCCC1>[CH2:13]([O:15][C:16](=[O:23])[CH:17]([CH:18]1[CH2:22][CH2:21][O:20][CH2:19]1)[CH3:1])[CH3:14]
Reactant: CCOC(=O)CC1CCOC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)C1CCOC1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
A stirred solution of N,N-diisopropylamine (2.38 mL, 17.0 mmol) in anhydrous tetrahydrofuran (40 mL) was cooled to −20° C. before adding n-butyllithium (6.3 mL, 15.8 mmol, 2.5 M in hexanes). The reaction was allowed to warm to −10° C. for 10 minutes then cooled to −78° C. A solution of (tetrahydro-furan-3-yl)-acetic acid ethyl ester (1.23 g, 7.77 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction was stirred for 2.5 h at −78° C. and then methyl iodide (3.92 mL, 63.2 mmol) was added. The reaction was stirred for 15 h gradually warming to room temperature. The reaction was quenched with a saturated aqueous ammonium chloride solution (60 mL) and then extracted with ethyl acetate (3×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 4:1 to yield the title product (0.87 g, 65%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.13-1.30 (m, 6H), 1.51-1.69 (m, 1H), 1.96-2.11 (m, 1H), 2.29-2.51 (m, 2H), 3.39-3.48 (m, 1H), 3.67-3.80 (m, 1H), 3.81-3.95 (m, 2H), 4.08-4.20 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:8]2[C:14]([CH2:15][CH:16]=[CH2:17])=[C:13]([CH2:18][CH:19]=[CH2:20])[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])=[C:8]2[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([CH2:18][CH2:19][CH3:20])[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: C=CCc1c(CC=C)n(Cc2ccccc2)c2cnc(C(=O)OCC)c(OC(=O)C(C)(C)C)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(CCC)n(Cc2ccccc2)c2cnc(C(=O)OCC)c(OC(=O)C(C)(C)C)c12

Procedure:
A mixture of 2,3-diallyl-1-benzyl-4-(2,2-dimethyl-propionyloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (710 mg, 1.54 mmol), 10% Pd—C (100 mg) in EtOAc (20 mL) was stirred at 1 atm hydrogen atmosphere for two days at room temperature. Then the catalysts were filtered off through celite, the filtrate was concentrated to give an oil, the crude product (628 mg), which is pure and used directly in the next step. The title compound: ESI MS (m/z): 465 (M+H+).
Reaction SMILES: C(N)C1C=CC=CC=1.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:27][O:28][C:29]1[C:34]([O:35][CH2:36][CH2:37][N:38]([CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]2[C:55]3[C:56]4[C:61]([NH:62][C:54]=3[CH:53]=[CH:52][CH:51]=2)=[CH:60][CH:59]=[CH:58][CH:57]=4)CC2C=CC=CC=2)=[CH:33][CH:32]=[CH:31][CH:30]=1>[Cl-].[Cl-].[Zn+2].C(OC(=O)C)C>[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][NH:38][CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]2[NH:62][C:61]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:55]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: [Cl-]
Agent: [Zn+2]
Agent: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Solvent: CCOC(C)=O
Solvent: NCc1ccccc1
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 400 ml ethylacetate, 70 g (0.27 moles) of anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 10.25 g (0.075 moles) of anhydrous ZnCl2 and 50 g (0.21 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to 70-75° C. for 3 hrs (TLC control for checking conversion to N-benzylcarvedilol). The reaction mixture is cooled to ambient temperature and quenched into 100 ml of ˜12-15% aqueous ammonia. The aqueous layer separated, and the product enriched organic layer is washed with water till neutral pH. The organic layer is charcoalised, filtered. To this solution of N-benzyl carvedilol in ethylacetate, (7 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 3.5-4.5 Kg/cm2 at temperature of 60-70° C. for a period of about 10 hours. The reaction mixture is filtered and filtrate concentrated to remove ethylacetate. To the resultant syrupy mass n-butanol (100 ml) is added and the solution is stirred for about 10 hours, the crystals separated by filtration, washed successively with n-butanol (50 ml) and toluene (50 ml) to obtain carvedilol (47 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (42 g).
Reaction SMILES: [Cl:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32](OC)=[O:33])[CH:27]=2)[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:9](=[O:11])[NH2:10])=[C:4]([NH:22][C:23]([OH:25])=[O:24])[CH2:3]1.[CH3:36][NH2:37]>>[Cl:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32](=[O:33])[NH:37][CH3:36])[CH:27]=2)[CH:7]=[CH:6][C:5]([N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:21])[F:20])[C:9](=[O:11])[NH2:10])=[C:4]([NH:22][C:23]([OH:25])=[O:24])[CH2:3]1
Reactant: CN
Reactant: COC(=O)c1cccc(C2(Cl)C=CC(N(C(N)=O)c3ccccc3C(F)(F)F)=C(NC(=O)O)C2)c1
Product: CNC(=O)c1cccc(C2(Cl)C=CC(N(C(N)=O)c3ccccc3C(F)(F)F)=C(NC(=O)O)C2)c1
Reaction time: 8 h

Procedure:
To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-carbomethoxyphenyl)carboxyaminophenyl)urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL, 1.7 mmol) and the resulting mixture was stirred at room temp. overnight, then concentrated under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl)urea as a white solid: mp 247; TLC (100% EtOAc) Rf 0.35.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]([CH3:10])[N:8]=[N:9][C:5]=2[CH:4]=1.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C.CCOCC>C(O)C.ClCCl>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:2][C:3]2[CH:12]=[CH:11][C:6]3[N:7]([CH3:10])[N:8]=[N:9][C:5]=3[CH:4]=2)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1nnc2cc(CBr)ccc21
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(O)nc(SCc2ccc3c(c2)nnn3C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.6 %

Procedure:
To a mixture of 5-(bromomethyl)-1-methyl-1H-1,2,3-benzotriazole (1.0 g, 4.22 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (0.404 g, 2.87 mmol) in anhydrous ethanol (50 mL) at 0° C. was added triethylamine (0.894 g, 8.84 mmol). Then, the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated to provide a crude residue. Ether was added to precipitate the triethylamine hydrochloride salt. The solid was filtered and washed with ether several times. The solvent was evaporated to provide a crude residue, which was purified by Combiflash using 0-10% methanol:dichloromethane to provide 6-methyl-2-{[(1-methyl-1H-1,2,3-benzotriazol-5-yl)methyl]sulfanyl}pyrimidin-4-ol as a white solid (953 mg, 75% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.28 (s, 2H), 4.55 (s, 3H), 6.04 (bs, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 8.07 (s, 1H); M+287.5.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:41]1[CH2:43][CH2:42]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+].O>O1CCCC1>[CH:41]1([N:11]([CH2:10][CH2:9][OH:8])[C:12]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]3([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:15]=2)=[O:13])[CH2:42][CH2:43]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amide (284) (430 mg, 0.69 mmol) in tetrahydrofuran (20 mL) was added 1N HCl (3.5 mL. 3.48 mmol) at room temperature and the reaction mixture was stirred for 30 min. After completion of the reaction, solid NaHCO3 was added, basified up to pH 8. Water (10 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The organic part was dried and concentrated to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (285) (300 mg, 88.4%) as a light yellow sticky mass.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2C(OC(C)(C)C)=O)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]4[C@H:25]([CH3:26])[CH2:24][C@@H:23]([OH:27])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:18]4[C@H:25]([CH3:26])[CH2:24][C@@H:23]([OH:27])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:4][CH:3]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4)CC3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-butyl 2-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (0.74 g, 1.331 mmol) was dissolved in dioxane (3 mL) and treated with 4M hydrogen chloride in dioxane (8.317 mL, 33.27 mmol). The mixture was stirred at ambient temperature for 8 hours. The reaction was concentrated in vacuo, re-dissolved and re-concentrated from MeOH three times. Then the residue was re-dissolved in MeOH (3 mL) and added dropwise to stirred Et2O (100 mL). After stirring for 30 minutes, the solid was collected, washed with Et2O, and then air-dried under a blanket of nitrogen. (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone was recovered as a white solid, (0.47 g, 79%). MS (ESI+) [M+H] 456.1/458.1