Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@@H:5]4[CH2:6][C@H:7]([CH3:8])[C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@H](C)[C@@H](N)C1
Agent: Cl
Product: COCC(=O)N[C@H]1C[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from N-[(1R*,3S*,4S*)-3-amino-4-methylcyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f68) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:15])[CH:5]=1)(=[O:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1.C(N(CC)CC)C>CCCCCCC>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]([OH:29])([C:25]([F:26])([F:27])[F:28])[CH2:2][C:1]([C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:15])[CH:5]=2)=[O:3])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1C
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
0.63 g of ethyl 4-acetyl-2-methylbenzoate, 0.73 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 0.73 g of n-heptane and 0.30 g of triethylamine were fed and the mixture was stirred for 4 hours at 60° C. The mixture was left to cool, and further stirred for one night at room temperature. 0.53 g of n-heptane was added to the slurry-state reaction solution, and the mixture was filtered under reduced pressure. The solid was washed with a small amount of n-heptane, and dried under reduced pressure. 0.97 g of ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoate as a light yellow solid was obtained by drying under reduced pressure.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C@@H:5]([NH:23][C@H:24]1[C:33]2[C:28](=[C:29]([O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.O=S(Cl)Cl>C(Cl)Cl>[C:11]1([C:9]2[N:10]=[C:6]([C@H:5]3[CH2:4][CH2:3][CH2:2][N:23]3[C@H:24]3[C:33]4[C:28](=[C:29]([O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[O:7][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N1CCC[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a solution of (1R)-1-[[(1R)-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butyl]amino]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (2.6 g) in CH2Cl2 (50 ml) was added SOCl2 (3 ml). After being stirred for 12 hours, the solvent was removed. The residue was dissolved in N,N-dimethylformamide (DMF) (15 ml) and K2CO3 (2 g) was added to the solution. After being stirred for 4 hours at the room temperature, the solution was poured into the mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R)-1-[(2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-tert-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.22 g).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][CH2:16][CH2:15][C:2]2([OH:1])[CH2:14][CH2:13][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:4][CH2:3]2)[CH3:27])=[CH:22][CH:21]=1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: COc1ccc([C@H](C)N)cc1
Product: COc1ccc([C@H](C)NCCC2(O)CCC3(CC2)OCC(C)(C)CO3)cc1
Yield: 45 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-methoxy-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 45% of theory; LC (method 1): tR=1.44 min; Mass spectrum (ESI+): m/z=378 [M+H]+.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.[NH:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[OH:18][CH:16]1[CH2:17][N:14]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:15]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CC(O)C2)cc1
Temperature: 180 °C
Yield: 72.7 %

Procedure:
A mixture of ethyl 4-fluorobenzoate (0.841 g, 5.00 mmol, Aldrich: Cat. #102644), azetidin-3-ol hydrochloride (0.438 g, 4.00 mmol, Aldrich: Cat. #680079) and potassium carbonate (1.38 g, 9.98 mmol) in dimethyl sulfoxide (4 mL) was heated at 180° C. for 2 hours. After cooling, the mixture was diluted with ethyl acetate (50 mL), and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-50%) to afford the desired product (0.643 g, 72.6%). LCMS (M+H)+: m/z=222.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16](NC1C=C2OCOC2=CC=1C(=O)C)=[O:17])(=[O:10])=[O:9].[NH2:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:34]=1[C:35]#[N:36]>>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:34]=1[C:35]#[N:36])=[O:17])(=[O:9])=[O:10]
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Reactant: COc1cc(N)c(C#N)cc1OC
Product: COc1cc(C#N)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)cc1OC

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148) except that 2-amino-4,5-dimethoxybenzonitrile was used instead of 2'-amino-4',5'-(methylenedioxy)acetophenone. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[{2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide was obtained via HPLC purification as a light brown powder (36% yield, m.p. 53°-56° C.).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=[O:12])=[CH:6][CH:5]=1.B.C1COCC1>C1COCC1>[F:1][C:2]([F:14])([F:15])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: B
Solvent: C1CCOC1
Product: OCCc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
To a stirred solution of 1.0 g (4.54 mmol) of 4-(trifluoromethoxy)-phenylacetic acid in 15 mL of anhydrous THF at 0° C. was added dropwise 9 mL (9.08 mmol) of 1 M BH3THF and the reaction allowed to warm to RT over 16 h. The mixture was cooled back down to 0° C. and the reaction quenched with 15 mL of water/acetic acid/THF (1:1:3). After warming to RT, the solvent was removed in vacuo, the residue diluted with water, and the solution extracted with EtOAc. The layers were separated, the organics washed with NaHCO3, the layers separated, the organics dried (MgSO4), and the solvent removed in vacuo. The residue was purified by silica gel chromatography using EtOAc/hexane (1:1) as eluent to give 540 mg (57% yield) of the title compound: TLC (EtOAc/hexane (1:1)): Rf=0.43.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8](O)[CH3:9])[CH:5]=[N:6][CH:7]=1.C1(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C.O>[N:25]([C@H:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:9])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](O)c1cncc(Br)c1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C[C@H](N=[N+]=[N-])c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of (1R)-1-(5-bromopyridin-3-yl)ethanol (10 mmol) in tetrahydrofuran (40 mL), cooled to 0° C., was added diphenylphosphoryl azide (4.3 mL, 20 mmol) in one portion followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (3 mL, 20 mmol) dropwise over 30 minutes. After this time the reaction mixture was allowed to warm slowly to room temperature and was stirred overnight. The mixture was diluted with ethyl acetate (50 mL) and water (50 mL), the two phases separated and the aqueous phase extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to give a black liquid which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give 3-[(1S)-1-azidoethyl]-5-bromopyridine (1.7 g, 75%) as a colourless liquid. A mixture of m-toluamide (164 mg, 1.21 mmol), 3-[(1S)-1-azidoethyl]-5-bromopyridine (227 mg, 1 mmol), copper (I) iodide (9.6 mg, 0.05 mmol), N,N-dimethylethylene diamine (0.011 mL, 0.1 mmol) and potassium carbonate (276 mg, 2 mmol) in dioxane (1 mL) was heated in a microwave reactor at 110° C. for 30 minutes then at 160° C. for a further 30 minutes. After this time the mixture was allowed to cool to room temperature, was diluted with ethyl acetate (5 mL) and was filtered through Celite. The filtrate was concentrated under reduced pressure to give a brown oil which was purified by flash chromatography (silica, ethyl acetate/dichloromethane) to give N-{5-[(1S)-1-azidoethyl]pyridin-3-yl}-3-methylbenzamide (80 mg, 28%) as a colourless oil.
Reaction SMILES: [N:1]([C:4]1[C:5]2[N:6]([C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:21][N:22]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]=1[C:10]#[N:11])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CO.O>[NH2:1][C:4]1[C:5]2[N:6]([C:20]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:21][N:22]=2)[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]=1[C:10]#[N:11]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1N=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CO
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1N
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A mixture of crude 8-azido-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-carbonitrile (144 mg, 0.33 mmol) and triphenylphosphine (133 mg, 0.51 mmol) in MeOH (4 mL) was stirred and refluxed for 1 h. 2M HCl in water (1 mL) was added and the reaction mixture was further refluxed for 1 h. The reaction mixture was cooled to RT, concentrated under vacuum and the remaining residue was dissolved in water. The aqueous solution was basified to pH 12 by the addition of a 2M NaOH solution in water. The resulting slurry was extracted with DCM (3×) and the combined organic fractions were dried over Na2SO4, filtered and evaporated. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/MeOH 99:1→92:8) to yield the title compound (112 mg, 0.29 mmol, 87%). MS: 388 [M+1]+; HPLC: AtRet=1.91; TLC: RF 0.56 (DCM/MeOH 95:5).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.N([O-])=O.[Na+].[NH4+].[OH-].[BrH:26]>O>[Br:26][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2
Reactant: Br
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ncccc2[C@]12Cc1ccc(Br)cc1C2
Temperature: 100 °C

Procedure:
To a solution of (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (500 mg, 1.99 mmol, described in Intermediate 3) in 48% HBr (4 mL) at 0° C. was added slowly over 10 min a solution of sodium nitrite (137 mg, 1.99 mmol) in water (0.8 mL). After 5 minutes CuBr (285 mg, 1.99 mmol) was added and the reaction mixture was placed into a 100° C. oil bath and heated at 100° C. for 20 min. The reaction mixture was then diluted with water followed by 2.5 mL of 30% NH4OH (2.5 mL) and the resulting solid was collected by filtration and washed with water. The solid was air dried and chromatographed by first mixing with silica and dry loading on a silica gel column. The product was eluted. with (10% MeOH/CH2Cl2). Concentration of the product containing fractions gave the title compound. to 740 mg and ˜2 g of silica gel was added. The mixture was dry-loaded on to a silica gel column and the product was eluted with a gradient of EtOAc:hexanes:CH2Cl2—10:80:10 to 70:20:10. The product containing fractions were combined and concentrated at reduced pressure to give the title compound. MS: m/z=315 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: BrC1CCOC1
Reactant: Oc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(OC2CCOC2)c(Br)c1
Temperature: 85 °C
Yield: 143.7 %

Procedure:
To a solution of 2-bromo-4-fluorophenol (500 mg, 2.62 mmol) in acetonitrile (5 ml) was added potassium carbonate (1090 mg, 7.85 mmol) followed by 3-bromotetrahydrofuran (1000 mg, 6.62 mmol) and the resulting solution was heated to 85° C. in a Reacti-vial™ for 72 hours. The reaction mixture was cooled then the solvents removed in vacuo. tert-Butyl-dimethyl ether (20 ml) and sodium hydroxide (10% aqueous solution) (10 ml) were added and the layers were separated. The organic layer was washed with further sodium hydroxide (10% aqueous solution) (10 ml) then saturated brine solution (10 ml). The organic layer was then dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo to afford crude title compound as a yellow oil (983 mg, >100%). Material was taken on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[F:33][C:34]1[CH:56]=[CH:55][C:37]([CH2:38][N:39]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N:41]=[C:40]2[NH:48][CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(#N)C.CO.C(OCC)(=O)C>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH:49]([NH:48][C:40]3[N:39]([CH2:38][C:37]4[CH:55]=[CH:56][C:34]([F:33])=[CH:35][CH:36]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:50][CH2:51]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.42 g, 0.9 mmol) and (1(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.49 g, 1.5 mmol), and N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) in acetonitrile (12 mL). Heat to reflux. After 18 hours, pour the reaction mixture into ethyl acetate. Extract twice with water, saturated aqueous sodium bicarbonate solution, and aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on a short column of silica gel eluting sequentially with ethyl acetate and then 25% methanol/ethyl acetate. Evaporate the product containing fractions and partition between dichloromethane and 1/1 brine/water. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give the title compound: Rf=0.38 silica gel, 25% methanol/ethyl acetate).
Reaction SMILES: CS(C)=O.[C:5]1([C:11]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:14])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C(OCC)(=O)C>[C:15]1([C:13]([C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:12])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(C(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 78 %

Procedure:
While the temperature is maintained at from 2° C. to 25° C., 16 g of the composition prepared as in Example 8 are added in small fractions over a period of 15 minutes to 35 ml of dimethyl sulfoxide containing 4.8 g of benzoin. After 2 hours, agitation at ambient temperature, the medium is poured into 200 ml of water and 60 ml of ethyl acetate. The precipitate formed is eliminated and the organic phase is concentrated under vacuum. The solid residue is recrystallised from 20 ml of ethanol. Benzil is obtained with a yield of 78%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:21])[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[O:15]1.[N:22]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.CCCCCC.C(N(CC)CC)C.CN(C)P(N(C)C)(N(C)C)=O>[CH3:13][C:14]1([CH3:21])[C:18](=[O:19])[CH:17]=[C:16]([CH:20]=[CH:28][C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)[O:15]1
Reactant: O=Cc1ccncc1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(C=Cc2ccncc2)=CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.6 %

Procedure:
To a solution of dry diisopropylamine (2.6 mL, 19.1 mM) in dry tetrahydrofuran (350 mL) at -78° C., was added dropwise a 2.5M solution of n-butyllithium in hexane (7.6 mL, 19.1 mM). After the reaction solution was stirred for 15 minutes, a solution of 2,2,5-trimethyl-3(2H)-furanone (20 g, 15.9 mM) in tetrahydrofuran (25 mL) was added dropwise. Hexamethylphosphoramide (6.4 mL, 35.7 mM) was then added after 30 minutes. Finally, 4-pyridinecarboxaldehyde (2.5 g, 23.5 mM) in tetrahydrofuran (25 mL) was added in one portion. The reaction solution was stirred 15 minutes when trifluoroacetic anhydride (6.7 mL, 47.7 mM) was added in one portion. Again, the reaction solution was stirred 15 minutes before triethylamine (11 mL, 80 mM) was added and was allowed to warm to room temperature. The reaction mixture was concentrated to 100 mL then diluted with diethyl ether (300 mL). The organic layer was extracted with 1N aqueous hydrochloric acid (100 mL). The acid layer was neutralized with solid sodium bicarbonate and washed with diethyl ether (2×100 mL). The combined etheral layers were washed with saturated aqueous sodium chloride (2×50 mL), dried over MgSO 4, filtered and concentrated under reduced pressure to give a brown crystalline solid. The crude product was purified by chromatography (silica gel, pet. ether/ethyl acetate) to afford a yellow crystalline solid (935 mg, 32% yield), m.p. 94°-96° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[N:21][C:22]([N+:25]([O-])=O)=[CH:23][CH:24]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]>CO.[C].[Pd]>[NH2:25][C:22]1[N:21]=[CH:20][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:28]=[CH:29][CH:30]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])nc3)c2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.7 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-{3-[(6-nitropyridin-3-yl)oxy]phenyl}benzamide (6.00 g, 14.9 mmol) in methanol (150 mL) was added 10% palladium-carbon (790 mg), and the mixture was stirred at room temperature for 20 hr under a hydrogen atmosphere (3.0 atm). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (4.42 g, 79%) as colorless crystals.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1cccc(Cl)c1
Reactant: CN(C)CCNc1ncc2c(-c3ccnc(S(C)(=O)=O)n3)n[nH]c2n1
Product: CN(C)CCNc1ncc2c(-c3ccnc(NCc4cccc(Cl)c4)n3)n[nH]c2n1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
The mixture of N′-[3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N,N-dimethyl-ethane-1,2-diamine (from Example 23 supra) (160 mg, crude) and 3-chlorobenzylamine (236 mg, 1.67 mmol) was heated at 130° C. with stirring for 3 hours. The resulting oil was purified by chromatography (silica gel, 7 g, 200-300 mesh, eluting with dichloromethane:methanol, 10:1) and further purified by prep-HPLC. Concentrated HCl was added to the fractions with product and concentrated under reduced pressure to give N-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-N′,N′-dimethyl-ethane-1,2-diamine; hydrochloride. (Yield 26 mg).