Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C:10]1[CH2:9][CH2:8][CH:7]([N:25]([CH3:27])[CH3:26])[CH2:6][C:5]2=1.C([Li])(C)(C)C.CN(OC)[C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[Na+]>O1CCCC1>[C:35]([C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([Si:15]([CH:19]([CH3:20])[CH3:21])([CH:16]([CH3:18])[CH3:17])[CH:22]([CH3:24])[CH3:23])[C:10]1[CH2:9][CH2:8][CH:7]([N:25]([CH3:26])[CH3:27])[CH2:6][C:5]2=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3cc(Br)ccc31)CC(N(C)C)CC2
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3cc(C(=O)c4ccccc4)ccc31)CC(N(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 0.50 gm (1.11 mMol) 6-bromo-3-(dimethyl)amino-9-triisopropylsilyl-1,2,3,4-tetrahydro-9H-carbazole in 50 mL tetrahydrofuran at -78° C. were added 1.96 mL (3.33 mMol) t-butyllithium (1.7 M in pentane) and the resulting dark solution was allowed to stir for 30 minutes. To this mixture were then added 0.20 gm (1.22 mMol) N-methyl-N-methoxybenzamide and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was then treated with 0.1 N sodium hydroxide and then extracted well with chloroform. The organic phases were combined, dried over potassium carbonate and concentrated under reduced pressure to give 0.48 gm (91%) of the desired compound as a red-orange oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([O-:12])([OH:11])=[O:10].[N:13]#[C:14][NH2:15]>CCO>[N+:9]([O-:12])([OH:11])=[O:10].[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]([NH2:15])=[NH:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: N#CN
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccc(F)cc1
Yield: 47 %

Procedure:
A solution of 4-fluoroaniline (25 mmol, 2.80 g) in EtOH (10 mL) was cooled on an ice bath. Nitric acid (69% aq. soln.; 1.8 mL) was added dropwise. Then cyanamide (50% aq. soln.; 4 mL) was added. The reaction mixture was refluxed under N2 for 21 h. The solvent was evaporated to dryness. The solid residue was washed with EtOH and dried under high vacuum overnight to afford the title compound as a purple powder (2.54 g, 47%). This material was used for subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[NH2:16][C@H:17]([CH3:20])[CH2:18][OH:19].C(N(CC)CC)C.CO>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:16]([C@H:17]([CH3:20])[CH2:18][OH:19])[CH:6]=[CH:5]2
Reactant: C[C@@H](N)CO
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H](CO)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 100 °C

Procedure:
A microwave vial was charged with 6-chloro-5-nitro-1H-isochromen-1-one (80.0 mg, 0.000355 mol), (2R)-2-aminopropan-1-ol (29 mg, 0.00039 mol), triethylamine (0.15 mL, 0.0011 mol) and methanol (4 mL, 0.1 mol), and heated under microwave irradiation at 100° C. for 30 minutes. the solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the desired product as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[N:32]1([CH2:37][CH2:38][NH2:39])[CH:36]=[CH:35][N:34]=[N:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:32]1([CH2:37][CH2:38][NH:39][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:30])[CH:36]=[CH:35][N:34]=[N:33]1
Reactant: NCCn1ccnn1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCn2ccnn2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 2-[1,2,3]triazol-1-yl ethylamine (200 mg, 1.78 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (15-95% of ACN/water) rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (83.7 mg, 34.7%) as an off-white powder. HRMS ES+) m/z Calcd for C27H28Cl2F2N6O+H [(M+H)+]: 561.1743. found: 561.1741.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[O:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Reactant: CC(=O)NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)NCCOC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
A mixture of 25.4 g (0.1 mole) of bis(p-fluorophenyl)methyl chloride, 10.3 g (0.1 mole) of N-(2-hydroxyethyl)acetamide (prepared according to F. J. McQuillin et al., J. Chem. Soc. 1955, 2966), 14 g of potassium carbonate and 100 ml of benzene is refluxed for 5 hours. After cooling, the reaction mixture is poured into water. The aqueous layer is extracted with dichloromethane and the combined organic layers are dried over potassium carbonate and concentrated by evaporation of solvent. The residue is crystallised from toluene. N-{2-[Bis(p-fluorophenyl)methoxy]ethyl}acetamide, m.p. 112°-113.5° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=O)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[NH2:30][OH:31]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[N:30][OH:31])[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2=O)C(=O)Nc2cnccn2)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2=NO)C(=O)Nc2cnccn2)cc1Cl
Temperature: 25 °C
Yield: 5.6 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (99.3 mg, 0.23 mmol) in pyridine (0.69 mL) and methanol (0.69 mL) at 25° C. was treated with hydroxylamine hydrochloride (24.5 mg, 0.35 mmol). The reaction mixture was heated under reflux for 12 h. At this time, the reaction was cooled to 25° C. and was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (75 mL) and was washed with a 1N aqueous sodium hydroxide solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-hydroxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (5.6 mg, 5.4%) as a white wax: (ES)−-HRMS m/e calcd for C19H21ClN4O4S (M−H)− 435.0899, found 435.0902.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][CH:16]3[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:27][CH2:28][CH2:29][NH:30]C(=O)OC(C)(C)C)=[CH:5][C:4]=2[N:3]=1.[ClH:38]>C(O)C>[ClH:38].[ClH:38].[NH2:30][CH2:29][CH2:28][O:27][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([CH2:15][CH:16]4[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]4)[C:13]([CH2:23][O:24][CH2:25][CH3:26])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC1COC(C)(C)O1
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC1COC(C)(C)O1
Temperature: 25 °C

Procedure:
A suspension of tert-butyl 2-{[4-amino-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate (prepared in Example 372, 1.5 g, 2.9 mmol) in ethanol (20 mL) and 4.3 M HCl in ethanol (2.70 mL, 17.5 mmol) was heated at reflux overnight. The reaction mixture was allowed to cool to room temperature and a white solid was collected by filtration, washed with ethanol, and dried under vacuum at 60° C. to yield 0.85 g of 7-(2-aminoethoxy)-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride as a white solid, mp 221-223° C.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][S:12][C:13](=N)N.BrC[CH2:18][CH2:19][CH2:20][Cl:21]>O>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:13][S:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1
Reactant: ClCCCCBr
Reactant: N=C(N)SCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCCSCc1ccccn1
Temperature: 73 °C
Reaction time: 15 h
Yield: 76.7 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (100 cc) is added dropwise, in the course of 20 minutes and whilst keeping the temperature below 15° C., to a solution of 2-(pyrid-2-ylmethyl)-isothiourea dihydrochloride (120 g) in distilled water (250 cc), cooled to 13° C. After heating for 20 minutes at 73° C. and then cooling to 13° C., a 10 N aqueous solution of sodium hydroxide (60 cc) and then 1-bromo-4-chlorobutane (85 g) are added, whilst stirring, and stirring is continued for 15 hours at a temperature of about 20° C. The reaction mixture is then extracted three times with methylene chloride (430 cc in total); the organic extracts are combined, washed with distilled water (300 cc); dried over anhydrous sodium sulphate and filtered. The solution is poured onto neutral silica gel (100 g) contained in a column of diameter 3 cm; the column is eluted with methylene chloride (3700 cc). The first fraction (700 cc) is discarded. The second (2000 cc) is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. Pyrid-2-ylmethyl 4-chlorobutyl sulphide (82 g) is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]=1[C:19](O)=[O:20].[NH2:22][CH2:23][CH:24]([OH:31])[CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([C:19]([NH:22][CH2:23][CH:24]([OH:31])[CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:20])=[C:3]2[O:2][CH3:1]
Reactant: COc1c(C(=O)O)n(-c2ccccc2)c2ccc(C)cc12
Reactant: CCN(CC)CC(O)CN
Product: CCN(CC)CC(O)CNC(=O)c1c(OC)c2cc(C)ccc2n1-c1ccccc1

Procedure:
The above 3-methoxy-5-methyl-1-phenylindole-2-carboxylic acid is converted into its acid chloride analogously to Example 1H, and this is reacted with 1-amino-3-diethylamino-2-hydroxypropane. The title compound is obtained as an oily base. This base is dissolved in isopropanol, and citric acid is added to the solution. The citrate of the title compound which has precipitated is filtered off with suction and recrystallised from isopropanol. Melting point: 126°-128° C., yield: 7.7 g.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)(=[O:3])[CH3:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:18][CH:19]=2)=[O:12])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CC(=O)Nc1nc(C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(=O)Nc1nc(C(=O)Nc2ccc(NC(=O)OC(C)(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
A mixture of 2-(acetylamino)-1,3-thiazole-4-carboxylic acid (500 mg), tert-butyl 4-aminophenylcarbamate (615 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (566 mg), 1-hydroxybenzotriazole (399 mg) and dichloromethane (5 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen bicarbonate, and the organic layer was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 3% methanol/chloroform as an eluent. The crystalline residue was collected and washed with ethyl acetate to give tert-butyl 4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}amino)phenylcarbamate (580 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[O:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=O)Oc1ccccc1
Product: COc1ccccc1N1CCN(C(=O)Nc2cc(C(C)=O)c(C)nc2OC)CC1
Yield: 79 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[N:24]=[C:23]([O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:22]=[CH:21][N:20]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3([OH:17])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1.[C:39](Cl)(=[O:41])[CH3:40].C(N(CC)CC)C>C(Cl)Cl>[C:39]([NH:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[N:24]=[C:23]([O:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)[CH:22]=[CH:21][N:20]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3([OH:17])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Nc3cc(N)cc(-c4cnc(C5(O)CCC5)s4)c3)n2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Reaction time: 1 h
Yield: 65.2 %

Procedure:
At 0° C., the product from Step 3 (40 mg, 0.074 mmol) in DCM (0.4 mL) was added to acetyl chloride (6.34 μl, 0.089 mmol) and triethylamine (15.53 μL, 0.111 mmol) and the reaction was aged for 1 h. The mixture was then purified directly by column chromatography on silica gel (30-100%, ethyl acetate: 10:1 methanol in hexanes) to afford tert-butyl 4-{[2-({3-(acetylamino)-5-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (28 mg, 65% yield). Example 109(1). MS ESI: [M+H]+ m/z 581.3. 1H NMR (600 MHz, CDCl3): δ 8.10 (d, J=6.0 Hz, 1H); 7.90 (s, 1H); 7.76 (s, 1H); 7.65 (br s, 1H); 7.53 (s, 1H); 7.11 (s, 1H); 6.14 (d, J=6.0 Hz, 1H); 5.25 (m, 1H); 3.67 (m, 2H); 3.12 (br s, 2H); 2.64 (m, 2H); 2.43 (m, 2H); 2.13 (s, 3H); 1.92 (m, 4H); 1.66 (m, 2H); 1.43 (s, 9H). rhSYK activity=++
Reaction SMILES: [C:1]1([C:7](=[O:40])[CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)[N:16]=3)[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C[O:44]CC1.[OH-].[K+]>CO>[C:1]1([C:7](=[O:40])[C:8]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=4)[N:16]=3)[NH:11][CH:10]=2)=[O:44])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: COc1cc(-c2cnc3c(n2)c(CC(=O)c2ccccc2)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(=O)c4ccccc4)c3n2)cc(OC)c1OC
Temperature: 40 °C

Procedure:
1-Phenyl-2-[5-(toluene-4-sulfonyl)-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-ethanone (100 mg, 0.18 mmol) was suspended in 4 ml of a 1:1 mixture of THF and methanol and 5N potassium hydroxide (0.180 ml, 0.9 mmol) was added dropwise. The reaction was heated at 40° C. for 2 hours. The solvents were evaporated using a rotary evaporator. Ethyl acetate and 1M hydrochloric acid were added to the residue and the layers were separated. The organic layer was washed with water, dried and concentrated. The crude reaction mixture was purified by preparative thin layer chromatography (50% ethyl acetate in hexanes) and flash chromatography to yield 4 mg of 1-phenyl-2-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-ethane-1,2-dione. MS: (M+H)+=418.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11].[Br:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.CO>C1(C)C=CC=CC=1>[Br:17][C:18]1[CH:26]=[C:25]2[NH:24][C:23](=[O:27])[C:22]3([CH:28]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=4)[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:21]2=[CH:20][CH:19]=1
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Reactant: C=C(N=Cc1ccccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Temperature: 135 °C

Procedure:
To a solution of 1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 17a in toluene (20 mL) was added E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole prepared in example 157a (0.3 g, 0.83 mmol). The reaction mixture was stirred and heated under microwave irradiation in a sealed tube at 135° C. for 0.5 h. After the solution was cooled to room temperature, methanol (50 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:3) to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid. (Yield 0.22 g, 53%).
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[C:7]([Cl:9])[C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1>CO>[Cl:9][C:7]1[C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=[C:3]([NH2:1])[N:8]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: N
Solvent: CO
Product: Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ammonia in methanol (7N solution, 15 mL) is added dropwise to the stirred neat 2,4-dichloro-5-(trifluoromethyl)pyrimidine (H-1) (5.0 g, 23.04 mmol) under argon, and the resulting mixture is stirred at RT for 2 h. The reaction mixture is quenched with water and then extracted with ethyl acetate (200 mL×2). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography on silica gel (0-20% ethyl acetate-hexanes) to afford the product, 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (H-2) as a white solid. The regional-isomer, 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine (H-3) can also be isolated as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: BrCCCCCBr
Reactant: N#CCc1ccc(Br)cn1
Product: N#CC1(c2ccc(Br)cn2)CCCCC1
Yield: 60 %

Procedure:
The title compound was prepared from (5-bromo-pyridin-2-yl)-acetonitrile and 1,5-dibromopentane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 60% of theory; Mass spectrum (ESI+): m/z=265/267 (Br) [M+H]+.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=O)([O:41][CH3:42])=[O:40].O>O1CCCC1>[CH3:42][O:41][C:39](=[O:40])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:28][CH:27]=1
Reactant: COC(=O)CCCCCCCC=O
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCC=Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 12.8 %

Procedure:
To a solution of 18.2 g (43 mmol) of 4-chlorobenzyltriphenylphosphonium chloride in 200 mL of dry tetrahydrofuran at -78° C. is added dropwise, 30.7 mL (43 mmol) of a 1.4M solution of potassium hexamethyldisilazide in tetrahydrofuran. This is allowed to stir for 1 hour when 8.0 g (43 mmol) of 8-carbomethoxyoctanal is added dropwise. The solution is stirred at -78° C. for 2 hours, allowed to warm to room temperature, and stirred for 2 days. The reaction is worked up by adding water and extracting three times with diethyl ether. The ether extracts are combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow solid. Pad filtration through flash silica gel eluting with 10% ethyl acetate/hexane, gives a yellow oil after concentration in vacuo. Flash chromatography on a 60 mm×150 mm silica column eluting with 5% ethyl acetate/hexane gives 1.62 g (13%) of 10-(4-chlorophenyl)-dec-9-enoic acid methyl ester as a mixture of E and Z isomers.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[CH2:26][C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cccnc1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(Cc1cccnc1)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Yield: 71 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine was reacted with pyridine-3-carbaldehyde using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-pyridin-3-ylmethyl-amine as a solid (71% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 427 as a solid (99% yield). NMR (CDCl3, 400 MHz), 2.34 (3H, s), 3.67 (2H, s), 3.88 (2H, s), 3.92 (4H, t, J=5.2), 4.06 (4H, t, J=5.2), 5.25 (2H, s), 7.30-7.33 (2H, m), 7.73-7.75 (2H, m), 8.55-8.57 (1H, m), 8.66-8.67 (1H, m), 9.30 (2H, s). MS: (ESI+): MH+=449