Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[I:17]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1c1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)O[C@@H]1CCCC[C@H]1c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of trans-racemic-2-phenylcyclohexyl acetate (5.60 g, 25.7 mmol) under nitrogen in TFA (50 ml) at 0° C. was added N-iodosuccinimide (5.77 g, 25.7 mmol) portionwise over 5 minutes. The mixture was allowed to warm and stir at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The resultant oil was chromatographed using an 80 g silica gel cartridge eluted with 0-20% ethyl acetate in hexanes over 15 column volumes. The desired product fractions were combined and concentrated under reduced pressure to provide the desired product as a yellow oil. LC-MS: calculated for C14H17IO2 344.19 observed m/e: 345.33 (M+H)+ (Rt 2.60/4 min).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17](=[O:26])[N:18]([CH3:25])[C:19](=[O:24])[N:20]([CH3:23])[C:21]=1[CH3:22]>>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[C:17](=[O:26])[N:18]([CH3:25])[C:19](=[O:24])[N:20]([CH3:23])[C:21]=1[CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Cc1c(NCCN)c(=O)n(C)c(=O)n1C
Product: Cc1c(NCCNCC(O)COc2ccccc2)c(=O)n(C)c(=O)n1C
Reaction time: 24 h

Procedure:
2.43 g. Phenyl glycidyl ether and 5.15 g. 5-(2-aminoethylamino)-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione are left to stand for 24 hours at ambient temperature, whereupon the reaction mixture is separated with silica gel using, as elution agent, methylene chlorideammoniacal methanol (95:5 v/v). The yellowish oil obtained by evaporation of the pure fractions is triturated with ethyl acetate. After subsequent recrystallization from ethyl acetate, there are obtained 2.55 g. (43% of theory) of the desired product in the form of colorless crystals; m.p. 92°-94° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([N:13]([CH2:32][C:33]([NH:35][CH2:36][C:37]1[CH:48]=[CH:47][C:40]([C:41]([O:43][CH2:44][C:45]#[N:46])=[O:42])=[C:39]([OH:49])[CH:38]=1)=[O:34])[CH2:14][C:15](=[O:31])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH2:27][C:28]#[N:29])=[O:25])=[C:20]([OH:30])[CH:19]=1)=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClC(Cl)C>[NH2:8][CH2:9][CH2:10][C:11]([N:13]([CH2:14][C:15]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH2:27][C:28]#[N:29])=[O:25])=[C:20]([OH:30])[CH:19]=1)=[O:31])[CH2:32][C:33](=[O:34])[NH:35][CH2:36][C:37]1[CH:48]=[CH:47][C:40]([C:41]([O:43][CH2:44][C:45]#[N:46])=[O:42])=[C:39]([OH:49])[CH:38]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N(CC(=O)NCc1ccc(C(=O)OCC#N)c(O)c1)CC(=O)NCc1ccc(C(=O)OCC#N)c(O)c1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: N#CCOC(=O)c1ccc(CNC(=O)CN(CC(=O)NCc2ccc(C(=O)OCC#N)c(O)c2)C(=O)CCN)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude Cyanomethyl 4-{[2-(3-[(tert-Butoxy)carbonylamino]-N-{[N-({4-[(cyanomethyl)oxycarbonyl]-3-hydroxyphenyl}methyl)carbamoyl]methyl}propanoyl-amino)acetylamino]methyl}-2-hydroxybenzoate from above was dissolved in 20 mL of dichloroethane and 10 mL of trifluoroacetic acid (26.0 mmole) was added. The deprotection reaction was stirred for 2 hours at room temperature. Dichloroethane and trifluoroacetic acid were removed in vacuo. The resulting oil was dissolved in 10 mL of ethyl acetate, and the resulting solution was added dropwise to 150 mL of rapidly stirred methyl tert-butyl ether. The product precipitated over the course of one hour and was collected by filtration, washed with methyl tert-butyl ether and dried in vacuo under a high vacuum. Obtained 2.78 grams (65% for two steps) of product as a white solid.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[C:8]([F:12])[C:9]=1[CH2:10][OH:11].[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[C:8]([F:12])[C:9]=1[CH2:10][OH:11]
Reactant: OCc1c(F)cc(O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)c(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Methyl iodide (0.13 mL, 2.08 mmol) was added dropwise to a solution of 3-chloro-5-fluoro-4-(hydroxymethyl)phenol (334 mg, 1.89 mmol) and potassium carbonate (287 mg, 2.08 mmol) in DMF (5 mL) and the reaction mixture stirred for 4 h at rt. The reaction mixture was partitioned between DCM and H2O, the organic layer separated and the aqueous further extracted with DCM. The combined organic phases were concentrated in vacuo to yield the title compound as a yellow oil (360 mg, 1.89 mmol).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26]>>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1O
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1O
Yield: 58.5 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 278 mg of 2-aminophenol in place of the 2,4-difluoroaniline. 370 mg of N-(2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:20]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[CH:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:20]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[CH:27]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:6][CH:7]=1
Reactant: CNc1cc(-c2cccnc2Cl)ccn1
Reactant: Nc1ccc(O)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CNc1cc(-c2cccnc2Oc2ccc(N)cn2)ccn1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
In a microwave vial, 5-aminopyridin-2-ol (125 mg, 1.14 mmol) was dissolved in DMSO (0.910 mL, 0.228 mmol) and cesium carbonate (445 mg, 1.37 mmol) was added. The vial was capped with a septum and the reaction was stirred at RT for 25 minutes until a paste was formed. Then 4-(2-chloropyridin-3-yl)-N-methylpyridin-2-amine (50 mg, 0.23 mmol) was added and the vial was sealed and heated to 180° C. in Personal Chemistry Microwave for 15 min. The mixture was extracted with EtOAc, organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography on silica gel using 60:40 DCM:(90:10:1 DCM:MeOH:NH4OH to flush out top spots, then 50:50 DCM:(90:10:1 DCM:MeOH:NH4OH) to collect the product. Green solid, 4-(2-(5-aminopyridin-2-yloxy)pyridin-3-yl)-N-methylpyridin-2-amine was obtained. MS m/z 294 [M+1]+. Calcd for C16H15N5O: 293.13.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:26]=1[OH:33]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:26]4[C:25]([F:24])=[CH:30][C:29]([F:31])=[CH:28][C:27]=4[F:32])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1c(F)cc(F)cc1F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4c(F)cc(F)cc4F)ncnc32)CC1

Procedure:
4-[4-(2,4,6-Trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2,4,6-trifluorophenol (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.99-2.05 (m, 4H), 2.97-3.05 (m, 2H), 4.07-4.11 (m, 2H), 5.00-5.05 (m, 1H), 7.51-7.55 (m, 2H), 8.53 (s, 1H), 8.60 (s, 1H). Mass spectrum MH+=450.
Reaction SMILES: [C:1]([N:6]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[C:1]([N:6]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)N(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(=O)N(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a solution of ethyl [4-({butyryl[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)-2-methylphenoxy]acetate (40 mg, 0.078 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL), was added 2M sodium hydroxide (1 mL). After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue acidified with 2M HCl, before extraction into ethyl acetate (2×15 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a white solid (28 mg).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:20])[C:16]=1[O:17][CH2:18][CH3:19])[O:13][C:12]([CH3:22])([CH3:21])[CH2:11][C:10]2=O.CN1CCCN(C)C1=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:20])[C:16]=1[O:17][CH2:18][CH3:19])[O:13][C:12]([CH3:22])([CH3:21])[CH:11]=[C:10]2[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Cl
Reactant: CCOc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOc1c(Br)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Reaction time: 12 h

Procedure:
Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 111 mL, 22 mmol), 6-bromo-8-chloro-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 10, 1.5 g, 4.5 mmol), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU, 2.6 mL) in THF was reacted then quenched with 10% HCl, and stored at room temperature for 12 h.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCBr)cc1
Temperature: 70 °C
Yield: 89.3 %

Procedure:
A mixture of methyl 4-hydroxybenzoate (1.52 g, 10 mmol), 1,3-dibromo-propane (20.3 mL, 200 mmol) and potassium carbonate (4.2 g, 30 mmol) in 100 mL of dry CH3CN was heated at 70° C. for 5.0 hr. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite and rinsed with CH3CN. The combined filtrates were concentrated in vacuo and purified by ISCO (Hexane-ethyl acetate: 80:20 to 0:100) on silica gel to afford 107A (2.44 g, 89%) as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([O:18][C@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[N:13][N:12]=[CH:11]3)[CH:7]=1.[Cu](C#N)[C:27]#[N:28]>CN(C=O)C.C(Cl)Cl>[CH3:25][C:5]1[CH:4]=[CH:3][C:2]([C:27]#[N:28])=[CH:7][C:6]=1[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([O:18][C@H:19]([CH3:24])[C:20]([F:21])([F:22])[F:23])=[N:13][N:12]=[CH:11]2
Reactant: N#C[Cu]C#N
Reactant: Cc1ccc(I)cc1-c1ccc2c(O[C@H](C)C(F)(F)F)nncc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1-c1ccc2c(O[C@H](C)C(F)(F)F)nncc2c1
Temperature: 120 °C

Procedure:
A mixture of 6-(5-iodo-2-methylphenyl)-1-((R)-1,1,1-trifluoropropan-2-yloxy)phthalazine (100 mg, 0.22 mmol) and copper cyanide (98 mg, 1.09 mmol) in 1.0 mL of DMF in a sealed glass tube was heated at 120° C. in a microwave synthesizer for 20 min. The cooled reaction was diluted with CH2Cl2 and washed with water and brine. The organic layer was dried (MgSO4), filtered, and concentrated. Purification on a silica gel column (20-50% of EtOAc in Hexanes) afforded 4-methyl-3-(1-((R)-1,1,1-trifluoropropan-2-yloxy)phthalazin-6-yl)benzonitrile as a white solid. MS (ESI, pos. ion) m/z: 358.4 (M+1).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C@:9]1([NH2:31])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([O:27]CC)=[O:26])=[O:8])C.Cl>O1CCCC1.O>[NH2:31][C@@:9]1([C:7]([OH:8])=[O:6])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.7 %

Procedure:
5.53 g of lithium hydroxide hydrate was added to 22.9 g of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 480 mL of tetrahydrofuran and 240 mL of water, and the mixture was stirred for three days at room temperature. 443 mg of lithium hydroxide hydrate was further added thereto, and the mixture was stirred for 1 day at room temperature. 169 mL of 1N hydrochloric acid was added dropwise thereto at ice-cooling, and the mixture was stirred for 14 hours at room temperature. The precipitated solids were filtered, and then washed with 200 mL of tetrahydrofuran and 100 mL of water, thereby yielding 12.3 g of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH3:21])[C:18]([NH2:20])=[NH:19])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[CH:26]([CH:28]([CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=1)[C:29](OC)=O)=[O:27]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH3:21])[C:18]3[NH:20][CH:29]=[C:28]([CH2:33][C:34]4[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=4)[C:26](=[O:27])[N:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:22]([F:23])([F:24])[F:25]
Reactant: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=N)N
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(N(C)CCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 200 °C
Yield: 18.6 %

Procedure:
To the solution of N-[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]-N-methylguanidine (100 mg, 0.269 mmol), methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (78 mg, 0.350 mmol) in NMP (5 mL) was added neat N-[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]-N-methylguanidine (100 mg, 0.269 mmol). The reaction mixture was heated with a microwave reactor at 200° C. for 2 h. Purification via MDAP then afforded the title compound as a white solid (33 mg, 0.050 mmol, 18.5% yield). LCMS: rt=3.14 min, [M+H+]=545.9
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:30])[CH:28]=[O:29].[CH:31]([Mg]Br)=[CH2:32]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:30])[CH:28]([OH:29])[CH:31]=[CH2:32]
Reactant: C=C[Mg]Br
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC=C(C)C=O)C(=O)OC2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(O)C(C)=CCc1c(OC)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranyl)2-methylbut-2-enaldehyde (0.90 g) in tetrahydrofuran (40 mL) was added vinylmagnesium bromide (4.5 mL of a 1M solution in tetrahydrofuran). After stirring for 0.5 hours, the reaction was diluted with ethyl acetate and washed successively with aqueous ammonium chloride and brine. Drying over magnesium sulfate was followed by filtration and solvent removal to leave a residual oil, 6-(1,3-dihydro -6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranyl)-3-hydroxy-4-methylhexa-1,4-diene, which was carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5](Br)=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1.[CH3:16][N:17](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([C:16]#[N:17])=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cc1cc(N)c(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Cc1cc(N)c(F)cc1C#N
Temperature: 100 °C
Yield: 25 %

Procedure:
A solution of Example C5 (3 g, 10.9 mmol) in DMF (50 mL) was treated with ZnCN2 (1.7 g, 16.4 mmol) and Pd(PPh3)4 (1.26 g, 1.09 mmol), sparged with N2 and heated at 100° C. for 12 h. The mixture was cooled to RT, treated with water and extracted with EtOAc (3×). The combined organics were washed with brine (3×), dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/pet ether) to afford ethyl 2-(5-amino-2-cyano-4-fluorophenyl)acetate (600 mg, 25% yield). 1H NMR (400 MHz, CDCl3): δ 7.19 (d, J=2.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 4.13-4.11 (q, J=6.8 Hz, 2H), 3.66 (s, 2H), 1.23-1.19 (t, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH:18]([C:22](=O)[CH3:23])[C:19](=O)[CH3:20]>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[C:22]([CH3:23])=[C:18]([CH3:17])[C:19]([CH3:20])=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: CC(=O)C(C)C(C)=O
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2c(C)c1C)CN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (2.4 g; 10.7 mmol; 1 eq.) and 3-methyl-2,4-pentanedione (1.75 mL; 15 mmol; 1.4 eq.) in AcOH (25 mL) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and sat. aq. NaHCO3. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ACN and the precipitate filtered off to afford the title compound (1.7 g, 52%) as a white solid. The mother liquor was concentrated in vacuo and the residue purified by column chromatography (DCM/EtOH, 95/5) to afford the title compound (1.5 g, 46%) as a white solid. 1H NMR (DMSO-d6) δ 4.59-4.53 (m, 4H), 3.34 (s, 6H), 2.27 (s, 3H), 1.47 (s, 9H). HPLC (max plot) 96.1%; Rt 3.92 min. UPLC/MS: (MS+) 303.1 ([M+H]+).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Br:6][CH:7]([CH2:11][CH2:12][Br:13])[C:8](Cl)=[O:9].[OH-].[Na+]>O.ClCCl>[Br:6][CH:7]([CH2:11][CH2:12][Br:13])[C:8]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:9]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: CC(C)CN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)CNC(=O)C(Br)CCBr
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.52 g (20.8 mmol) Isobutylamine were dissolved in 3 ml of water, and 13 ml dichloromethane were added. The mixture was cooled to 0° C. and vigorously stirred. A solution of 5.0 g (18.9 mmol) of 2,4-dibromobutanoic acid chloride (J. Med. Chem., 1987, 30, 1995) in 3 ml dichloromethane was added within 5 min. Thereafter a solution of 0.83 g (20.8 mmol) NaOH in 1.5 ml water was added a a rate resulting in the temperature remaining between 7 and 10° C. After complete addition, stirring was continued for 3 h at this temperature. Finally the phases were separated and the aqueous phase was extracted thrice with 15 ml dichloromethane. The combined organic phases were washed once with 17 ml 0.5M HCl, once with 14 ml 5% sodium bicarbonate solution and once with 10 ml brine and dried over magnesium sulfate. After evaporation of the solvent a colourless solid was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6](=[O:16])[C:5]12[O:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][O:17]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:22][C:19]1([CH3:23])[CH2:20][O:21][C:5]2([C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[CH:3]=3)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6]2=[O:16])[O:17][CH2:18]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc(N)ccc21
Solvent: c1ccncc1
Product: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 92 %

Procedure:
A solution of methyl 2-(5′-amino-5,5-dimethyl-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (307 mg, 0.958 mmol) in pyridine (15 ml) was cooled to 0° C. and methanesulfonyl chloride (0.090 ml, 1.150 mmol) was added; the reaction was warmed to room temperature and stirred for 25 minutes. The solvent was evaporated, and the residue was partitioned between ethyl acetate and 1N HCl; the organic phase was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (DCM:MeOH from 99.5:0.5 to 98.75:1.25) affording methyl 2-(5,5-dimethyl-5′-(methylsulfonamido)-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (351 mg, 0.881 mmol, 92% yield). MS/ESI+ 398.9 [MH]+.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl.[CH3:8][NH:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12]Cl>C(O)C>[CH3:8][NH:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][S:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1
Reactant: CNc1ccccc1CCl
Reactant: Sc1ncc[nH]1
Agent: Cl
Solvent: CCO
Product: CNc1ccccc1CSc1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To a solution of 693 mg (6.9 mmol) of 2-mercapto-imidazole in 26 ml of ethanol was added 1.33 g (6.9 mmol) of 2-methylaminobenzyl chloride hydrochloride, and the mixture was stirred for 15 min. at room temperature. Ethanol was distilled off under reduced pressure. The residue was made alkaline by addition of saturated aqueous sodium hydrogencarbonate and then to the alkaline solution was added 20 ml of water to precipitate a crystalline product. The product was collected by filtration and washed successively with two portions of water and each one portion of chilled ethanol and ether to give 990 mg of the desired compound as a white crystalline powder, yield 65.5%.