Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOC(C)=O.[F:7][C:8]([F:34])([C:23]1([OH:33])[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:20]=[C:19]([CH2:21][OH:22])[O:18][N:17]=1)=[O:10].CCN(CC)CC.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>O>[CH3:42][S:43]([O:22][CH2:21][C:19]1[O:18][N:17]=[C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9](=[O:10])[C:8]([F:7])([F:34])[C:23]2([OH:33])[CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[CH:20]=1)(=[O:45])=[O:44]
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(CO)on2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COS(C)(=O)=O)on2)C1
Reaction time: 0.5 h

Procedure:
To an AcOEt (3 mL) solution of the compound (45 mg) obtained in Example 3-(4) and Et3N (31 μL), MsCl (13 μL) was added at 0° C. and after stirring the mixture for 30 minutes, MsCl (13 μL) was added and the mixture was stirred at 0° C. for 30 minutes, followed by addition of Et3N (31 μL) and stirring at 0° C. for 2.5 hours. The reaction mixture was added to water (50 mL) and the organic layer extracted with AcOEt (50 mL) was dried (MgSO4), filtered and concentrated to give the titled compound (58 mg, colorless oil.)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH:20]=[C:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][CH:12]=3)[N:7]([CH3:8])[CH2:6]1)=[O:4].C[Si](C)(C)[Br:24]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH:20]=[C:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][C:12]=3[Br:24])[N:7]([CH3:8])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: C[Si](C)(C)Br
Product: COC(=O)[C@@H]1C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]2N(C)C1

Procedure:
Following the process of Example 25, 1 g of lysergic acid methyl ester is reacted with 2.7 ml of trimethylbromosilane and the product is purified by chromatography on a Kieselgel column by using a 7:3 mixture of benzene and acetone as eluant. After recrystallization from benzene, the title compound is obtained in a yield of 0.7 g (0.0019 mole, 55%), m.p.: 177°-178° C., [α]D20 =+41° (c=1, chloroform).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH:8]2[CH2:9][C:10](=[N:16]O)[CH2:11]3)=[CH:4][CH:3]=1.[Na].Cl>C(O)CCCC.CCOCC>[NH2:16][CH:10]1[CH2:9][CH:8]2[N:7]([CH2:6][C:5]3[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:12]([CH2:13][CH2:14][CH2:15]2)[CH2:11]1
Reactant: Cc1ccc(CN2C3CCCC2CC(=NO)C3)cc1
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CCCCCO
Product: Cc1ccc(CN2C3CCCC2CC(N)C3)cc1
Yield: 95.1 %

Procedure:
9-(4-Methylbenzyl)-9-aza-bicyclo-[3.3.1]-nonan-3-one oxime (4 g) was dissolved in amyl alcohol (100 ml) and heated to reflux. Sodium (2 g) was added portionwise whilst the solution was stirred. After all the sodium had dissolved, the solution was cooled, diluted with ether and acidified with dilute hydrochloric acid. The acid extract was washed with ether and then basified with excess potassium carbonate. Extraction with ethyl acetate followed by evaporation of solvent afforded crude 3-amino-9-(4-methylbenzyl)-9-azabicyclo[3.3.1]-nonane (3.6 g, 95%) used in the next procedure without purification.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][OH:6])#[N:2].C(N(CC)CC)C.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO>ClCCl>[C:14]([O:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CCCCO
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 3-cyano-1-n-propanol (16.85 g, 198 mmol, prepared by method of Blicke, et al., J. Org. Chem. 1961, 26, 3685) in dichloromethane (250 mL) were added triethylamine (80.1 g, 792 mmol) and trityl chloride (82.8 g, 297 mmol) at room temperature and the mixture was stirred for 16 h. To the reaction mixture was added methanol (25 mL) and stirred for 1 h. After concentration, the residue was purified on a column of silica gel using ethyl acetate and hexanes as eluent to give 40 g (61.7%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].N[C:12](N)=[O:13].Cl>>[CH2:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:10][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1)[CH3:9]
Reactant: NC(N)=O
Reactant: CCc1ccc(O)c(N)c1
Agent: Cl
Product: CCc1ccc2oc(=O)[nH]c2c1
Temperature: 180 °C
Yield: 60.5 %

Procedure:
8.2 g (0.06 M) 2-amino-4-ethylphenol and 5.4 g (0.09 M) urea were thoroughly mixed and heated in an oil bath to 180° C. for 2.0 hours. Thereafter the mixture was allowed to cool to 100° C. HCl solution (1.0 normal) was added to the mixture while stirring and the mixture was cooled to room temperature. The cooled mixture was extracted three times with methylene chloride. The combined organic phases were dried and stripped in vacuum. The sample yielded 5.9 g dark solid with a melting point of 75°-77° C. Spectroscopic data: nuclear magnetic resonance (NMR), C-13 NMR, infrared, and mass spectroscopy are consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([N:39]3[CH2:38][CH2:37][N:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])[CH2:41][CH2:40]3)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 76.6 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (562 mg, 1.41 mmol, 76%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]C#N)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.SC[C@H]([C@@H](CS)O)O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:18])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2
Reactant: COC(=O)COc1ccc(SC#N)c2c1CCC2
Agent: O[C@H](CS)[C@H](O)CS
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(S)c2c1CCC2
Reaction time: 1 h

Procedure:
(7-Thiocyanato-indan-4-yloxy)-acetic acid methyl ester (Example 1C) (3.09 g, 12.9 mmol) was dissolved in 30 ml methanol. Dithiothreitol (2.6 g) was added followed by sodium borohydride (200 mg). The reaction was stirred for 1 hour followed by concentration to an oil. The crude product was dissolved in 200 ml dichloromethane and filtered through silica gel and eluted with 200 ml dichloromethane. The product was then recrystallized from ethyl acetate/heaxanes to afford the title product. MS m/z 239 (M+1).
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:27])[CH2:8][N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15]C(=O)OCC2C=CC=CC=2)[C:10]1=[O:26])[CH2:2][CH:3]([CH3:5])[CH3:4]>C(O)C.[Pd]>[NH2:15][C:11]1[C:10](=[O:26])[N:9]([CH2:8][C:7]([NH:6][CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])=[O:27])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)CCNC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCNC(=O)Cn1cccc(N)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
573 mg of benzyl 1-(2-(isopentylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylcarbamate (ZED1020, 1.54 mmol) are dissolved under nitrogen atmosphere in 100 mL of ethanol. To this solution 50 mg of Pd/C (10%) is added and stirred under hydrogen atmosphere at atmosphere pressure for 1 h at RT. The catalysis is separated by filtration over silica gel, before the solvent is removed in vacuo. Green solid is obtained and it is suitable for further processing without purification.
Reaction SMILES: Cl[C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][S:5][N:6]=1.[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CS(C)=O>[CH2:13]([NH:19][C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][S:5][N:6]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCN
Reactant: Clc1nsnc1-c1cccnc1
Solvent: CS(C)=O
Product: CCCCCCNc1nsnc1-c1cccnc1

Procedure:
A solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3 mmol) and hexylamine (1.52 g, 15 mmol) in DMSO (5 ml) was heated at 100° C. for 48 h. After evaporation, water was added to the residue and extracted with ether. The combined organic extracts were dried and evaporated to give the title compound.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([C@@H:16]([C@H:18]([C:20]([O:22][CH3:23])=[O:21])[OH:19])O)([O:14][CH3:15])=[O:13]>CO>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:2]2[O:19][C@@H:18]([C:20]([O:22][CH3:23])=[O:21])[C@H:16]([C:12]([O:14][CH3:15])=[O:13])[O:1]2)[CH:11]=[CH:10][C:8]=1[OH:9]
Reactant: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Reactant: COc1cc(C=O)ccc1O
Solvent: CO
Product: COC(=O)[C@@H]1OC(c2ccc(O)c(OC)c2)O[C@H]1C(=O)OC

Procedure:
In a fashion similar to that described for Example 3, vanillin and dimethyl L-tartrate were condensed to provide (4R,5R)-2-(3-methoxy-4-hydroxy-phenyl)-4,5-dicarbomethoxy-1,3-dioxolane, mp 88°-90° C., [α]D25 -35.1° (c, 0.1, methanol). 1H-NMR (CDCl3) δ7.20 (1H, d, J=1.8 Hz), 7.06 (1H, dd, J=1.8 Hz and 8.2 Hz), 6.19 (1H, d, J=8.2 Hz), 6.08 (1H,s), 5.82 (1H, s), 4.96 (1H, d, J=3.8 Hz), 4.85 (1H, d, J=3.8 Hz), 3.91 (3H,s), 3.87 (3H,s), 3.84 (3H,s). IR (film) 3450, 1750, 1600, 1510, 1460, 1430 cm-1. Ms m/e (% abundance) 313(2), 312(12), 253(40), 168(84), 151(100), 124(22), 109(14), 59(18).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:33](=[O:34])[NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:36])[F:35])[CH:27]=3)[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)c1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.8 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 94 mg, 0.298 mmol) in methylene chloride (6.0 mL) was added trifluoro-m-tolyl isocyanate (82 μL, 0.596 mmol) at room temperature under nitrogen. The resulting light brown solution was stirred at room temperature for 40 minutes. The reaction mixture was diluted with water (˜25 mL) and the resulting mixture was extracted with methylene chloride (3×25 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to a yellow-orange film. Silica gel chromatography (20-25% ethyl acetate in hexanes) provided {6-fluoro-3-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (97 mg, 65%) as a colorless film. MS cald. for C27H27F4N2O3 [(M+H)+]: 503, obsd. 503.2.
Reaction SMILES: [CH2:1]([P:8](=[O:15])([O:12]CC)[O:9]CC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.Cl>[CH2:1]([P:8](=[O:9])([OH:15])[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: Cl
Solvent: CO
Product: O=P(O)(O)Cc1ccccc1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A solution of diethyl benzylphosphonate (25 g) in methanol (10 ml) and concentrated hydrochloric acid (500 ml) solution was refluxed for 4 days. The mixture was cooled to room temperature, and precipitated crystal was collected by filtration to give benzylphosphonic acid (11.17 g) as colorless crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23]([CH:28]=[CH:29][C:30](O)=[O:31])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CN1C(=O)CCC1>C1COCC1>[C:16]([C:20]1[N:25]=[C:24]([O:26][CH3:27])[C:23]([CH:28]=[CH:29][C:30]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:31])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: COc1nc(C(C)(C)C)ccc1C=CC(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COc1nc(C(C)(C)C)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Yield: 63 %

Procedure:
3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (17.8 mg, 0.052 mmol) was reacted with 3-(6-tert-butyl-2-methoxy-pyridin-3-yl)-acrylic acid (12 mg) DMTMM (1.1 eq, 16 mg) and NMP (1.2 eq, 90 μl) in THF to give the title compound (14 mg, 61.8%) after purification by column chromatography (Hex EtOAc=3/2).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[S:14][CH:15]=[C:16]([Br:18])[CH:17]=2)[C:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[F:28])([C:19]#[N:20])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Br:18][C:16]1[CH:17]=[C:13]([CH:12]2[C:11]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])([C:19]#[N:20])[CH:10]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[S:14][CH:15]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(Br)cs2)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cc(Br)cs2)C1(C#N)c1ccc(Cl)cc1F
Yield: 92 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 70b (0.9 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(4-bromo-thiophen-2-yl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light blue solid (0.9 g, 92%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].Br[C:17]1[CH:18]=[N:19][C:20]([O:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:21][CH:22]=1.CCN(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:24]1([O:23][C:20]2[N:19]=[CH:18][C:17]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=3)=[CH:22][N:21]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Reactant: Brc1cnc(OC2CCCC2)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(C)Cc1ccc(C#Cc2cnc(OC3CCCC3)nc2)cc1
Temperature: 25 °C

Procedure:
To 33.1 mg (0.17 mmol) N-[2-(4-ethynyl-phenyl)-1-methyl-ethyl]-acetamide (I58.3) and 40.0 mg (0.17 mmol) 5-bromo-2-cyclopentyloxypyrimidine (I14.1) in 2.0 mL THF are added 11.6 mg (0.02 mmol) bis(triphenylphosphin)palladiumdichlorid, 1.57 mg (8.00 μmol) CuI and 56.0 μL (0.33 mmol) DIPEA. The reaction mixture is stirred at r.t. over night. The solvent is removed in vacuo and the residue is purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9](=[O:10])[NH:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(CN)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCc1ccc(CNC(=O)OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of benzylchloroformate (10.48 ml, 74 mmol) in dichloromethane (250 ml) was added to an ice-cooled solution of 4-aminomethyl benzylamine (10 g, 74 mmol) and triethylamine (9.77 ml, 74 mmol), in dichloromethane (480 ml) over 90 minutes. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (450 ml) and 1M sodium hydroxide solution (300 ml). The resulting mixture was filtered, the layers separated and the organic phase dried over magnesium sulphate and evaporated under reduced pressure. The residue was dissolved in hot ethyl acetate, the solution cooled in an ice-bath, the resulting solid filtered off, and the filtrate evaporated under reduced pressure to afford the title compound as a white solid, 7.44 g.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4](C2CCNCC2)[N:3]=1.CN1CCC(=O)CC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[NH:4]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]2[CH:2]=[N:3]1
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CN1CCC(=O)CC1
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Nc1ncnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 304.4 %

Procedure:
3-Iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.00 g, 5.81 mmol), 1-methyl-4-piperidone (2.14 mL, 17.42 mmol), sodium triacetoxyborohydride (2.45 g, 11.62 mmol) and glacial acetic acid (1.05 g, 17.42 mmol) were mixed with 1,2-dichloroethane (75 mL). The reaction mixture was stirred at room temperature for 6 hours and saturated sodium bicarbonate solution was added to adjust the pH to about 9. The solid was collected by filtration to give 3-Iodo-1-[1-(1-methylpiperidin-4-yl)]-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.39 g, 93%). 1H NMR (DMSO-d6) δ 1.52 (m, 2H), 1.75 (m, 2H), 1.87 (m, 2H), 2.05 (m, 4H), 2.24 (s, 3H), 2.28 (m, 3H), 2.91 (m, 2H), 3.00 (m, 2H), 4.55 (m, 1H), 8.18 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1[N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([O:26]CC)=[O:25])[CH2:19]1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1[N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=[O:25])[CH2:19]1
Reactant: CCOC(=O)C1CCCN(c2nc3c(c(=O)n(C)c(=O)n3C)n2Cc2c(F)cccc2Cl)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(nc(N3CCCC(C(=O)O)C3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Yield: 103.7 %

Procedure:
A solution of ethyl 1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylate (5.0 g, 10.5 mmol) in 75 mL THF and 25 mL H2O at room temperature was treated with solid LiOH (1.8 g, 43.9 mmol). After stirring overnight the THF was removed under reduced pressure, and the residue was diluted with H2O. The aqueous layer was acidified to pH 4, and the aqueous layer was extracted with CH2Cl2. The combined extracts were concentrated under reduced pressure to give 4.9 g (>99% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) δ7.18 (dt, 2H, J=8.1, 5.7), 7.14 (t, 1H, J=7.6), 6.98-6.90 (m, 1H), 5.57 (AB quartet, 2H, J=15.7, 5.7), 3.51 (s, 3H), 3.42 (dd, 1H, J=12.6, 4.0), 3.30 (s, 3H), 3.20-3.05 (m, 2 H), 2.94-2.83 (m, 1H), 2.59-2.47 (m, 1H), 2.03-1.93 (m, 1H), 1.75-1.40 (m, 3H); LRMS (ESI) m/z 450 (M+H+); TLC (hexanes:EtOAc/1:1) Rf=0.10.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:18]([C:23]2[C:42]([CH:43]3[CH2:45][CH2:44]3)=[CH:41][C:26]3[C:27]([C:37]([NH:39][CH3:40])=[O:38])=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[O:29][C:25]=3[CH:24]=2)[S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=[CH:7][C:8]=1[B:9]1[O:13]C(C)(C)C(C)(C)[O:10]1)#[N:2].Cl.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([N:18]([C:23]2[C:42]([CH:43]3[CH2:44][CH2:45]3)=[CH:41][C:26]3[C:27]([C:37](=[O:38])[NH:39][CH3:40])=[C:28]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[O:29][C:25]=3[CH:24]=2)[S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=[CH:7][C:8]=1[B:9]([OH:10])[OH:13])#[N:2]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B4OC(C)(C)C(C)(C)O4)c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B(O)O)c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
The crude 6-(N-(3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (108 mg, 0.172 mmol) was dissolved in tetrahydrofuran (4.0 mL). 1M HCl (2.059 mL, 1.029 mmol) was added followed by sodium periodate (294 mg, 1.373 mmol). The mixture was stirred at room temperature overnight. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×). The organic phase was washed with 10% aq. Na2S2O3, brine, and dried over Na2SO4. After concentration, the crude residue was purified by reverse phase HPLC (10-100% MeCN/H2O with 0.1% TFA) to give the title compound as a white solid (58 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (br. s., 1H) 8.48 (q, 1H) 8.12 (s, 1H) 7.94-8.02 (m, 2H) 7.73-7.80 (m, 2H) 7.58-7.65 (m, 1H) 7.41 (t, 2H) 7.21 (s, 1H) 3.46 (s, 3H) 2.84 (d, 3H) 2.03-2.14 (m, 1H) 0.99 (br. s., 1H) 0.85 (br. s., 2H) 0.45 (br. s., 1H). LCMS (m/z, ES+)=548 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[CH2:9][CH2:10][O:11][C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: Cc1ccc(CCO)cc1F
Product: Cc1ccc(CCOc2cc3n(c(=O)n2)CCCN3C)cc1F

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from of 2-(3-fluoro-4-methylphenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14]1[N:15]=[C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[S:17][C:18]=1[C:19]([NH2:21])=[O:20].[O:28]([CH2:35][C:36](Cl)=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:14]2[N:15]=[C:16]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[S:17][C:18]=2[C:19](=[O:20])[N:21]=[C:36]1[CH2:35][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Cc1c(CNc2nc(N3CCOCC3)sc2C(N)=O)cccc1C(F)(F)F
Solvent: C1CCOC1
Product: Cc1c(Cn2c(COc3ccccc3)nc(=O)c3sc(N4CCOCC4)nc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-({[2-methyl-3-(trifluoromethyl)phenyl]methyl}amino)-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.250 mmol) in Tetrahydrofuran (THF) (1249 μl) at 0° C. was added phenoxyacetyl chloride (69.0 μl, 0.499 mmol). The mixture was stirred at room temperature overnight, then quenched with methanol and concentrated. The residue was purified by reversed-phase HPLC to provide 4-{([2-methyl-3-(trifluoromethyl)phenyl]methyl}-2-(4-morpholinyl)-5-[(phenyloxy)methyl][1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (14 mg, 11%); LC/MS: MS (ES+) m/e 517 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3H), 3.48-3.54 (m, 4H), 3.62-3.71 (m, 4H), 5.12 (s, 2H), 5.57 (s, 2H), 6.61 (d, J=7.8 Hz, 2H), 6.85-6.97 (m, 2H), 7.19 (dd, J=8.7, 7.5 Hz, 2H), 7.25-7.33 (m, 1H), 7.60 (d, J=7.8 Hz, 1H).