Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH2:14][CH2:15][CH3:16].O1CCCC1.C([Li])CCC.C([O:30][B:31](OC(C)C)[O:32]C(C)C)(C)C>CCCCCC>[CH2:9]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([B:31]([OH:32])[OH:30])=[C:3]([CH2:14][CH2:15][CH3:16])[CH:4]=1)([OH:13])[CH2:11][CH3:12])[CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCc1cc(C(O)(CC)CC)ccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCc1cc(C(O)(CC)CC)ccc1B(O)O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
In a three-necked flask, introduce under nitrogen 5 g of 3-(4-bromo-3-propylphenyl)pentan-3-ol (17.5 mmol) and 50 cm3 of tetrahydrofuran. Cool the mixture to −70° C. and add dropwise 17.5 cm3 (43.7 mmol) of a 2.5M solution of n-butyllithium in hexane, over 30 minutes. Leave the reaction mixture for approximately 2 h with stirring at −70° C. and then add dropwise 10 cm3 of triisopropylborate (43.7 mmol), over 20 minutes. Leave the reaction mixture with stirring for 4 h, allowing the temperature to increase to −40° C. Hydrolyse the mixture with saturated NH4Cl solution and extract twice with ethyl acetate. Wash the combined organic phases with saturated sodium chloride solution and evaporate the solvents under vacuum. This gives 5.4 g of a colorless oil, which is chromatographed on silica gel (heptane/ethyl acetate=3/1). This gives 1.92 g of 4-(1-ethyl-1-hydroxypropyl)-2-propylphenylboronic acid in the form of a highly viscous oil. (Yield=44%)
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([Cl:19])[CH:14]=2)[C:9]1=[O:22])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([Cl:19])[CH:14]=2)[C:9]1=[O:22]
Reactant: CC=CCC1C(=O)c2cc(OC)c(Cl)cc2C1(C)C
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)C(C)(C)C(CC=O)C2=O
Reaction time: 0.83 h
Yield: 90 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 50 minutes while stirring through a solution, cooled to -70°, of 11.9 g of (RS)-2-(2-buten-1-yl)-5-chloro-6-methoxy-3,3-dimethyl-1-indanone in 160 ml of anhydrous dichloromethane and 40 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4.7 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 120 ml of dichoromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. The oil obtained was crystallized from hexane/ethyl acetate. 10.3 g (90%) of (RS)-2-(2-oxoethyl)-5-chloro-6-methoxy-3,3-dimethyl-1-indanone were obtained as a light yellow solid with m.p. 102°-103°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:7][CH:8]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:18])[CH3:19])[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(Cc1cccc(CO)c1)OC(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Product: CC(C)OC(Cc1cccc(COC(=O)Nc2ccc(Cl)cc2)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(hydroxymethyl)phenyl]-2-isopropoxypropanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([O:22][C:23](=O)[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]3[N:35]([CH3:36])[N:34]=[N:33][N:32]=3)[CH:26]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:23]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]3[N:35]([CH3:36])[N:34]=[N:33][N:32]=3)[CH:26]=2)=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 68 h
Yield: 90.6 %

Procedure:
A mixture of 3-aminomethylpiperidine-1-carboxylic acid tert-butyl ester (1.81 g, 8.47 mmol), [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (2.50 g, 8.47 mmol), triethylamine (2.4 mL, 16.9 mmol) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 68 hours. The mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate. The solution was washed with 1.0 N aqueous sodium hydroxide, then with water, then with saturated aqueous sodium chloride, and the organic phase was dried (sodium sulfate) and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 30% hexane in ethyl acetate, then with 25% hexane in ethyl acetate, to provide a white amorphous solid (3.19 g, 90%). 1H NMR (300 MHz, CDCl3) δ7.84 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.40 (t, J=8 Hz, 1H), 7.29 (d, J=7 Hz, 1H), 4.20 (s, 3H), 3.85 (m, 1H), 3.75 (m, 1H), 3.28 (dd, J=14, 5 Hz, 1H), 3.05 (m, 2H), 2.81 (dd, J=13, 9 Hz, 1H), 1.9-1.6 (m, 3H), 1.45 (s+m, 10H), 1.27 (m, 1H). Mass spec (AP+) m/z 416.2 (M+H+, 100%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[CH3:19][O:20][CH2:21][CH2:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C(O)(C)C>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:27][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][O:20][CH3:19])=[CH:29][CH:28]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COCCc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Solvent: CC(C)O
Product: COCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 64.7 %

Procedure:
Following general procedure A2 except using iso-propanol as a solvent, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.107 g, 0.35 mmol) was reacted with 4-(2-methoxyethyl)aniline (0.108 g, 0.71 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.094 g, 64%) as a white solid. MW=415.36. 1H NMR (DMSO-d6, 500 MHz) δ 14.03 (s, 1H), 9.75 (s, 1H), 7.89 (t, J=1.9 Hz, 1H), 7.71-7.67 (m, 2H), 7.59 (t, J=7.9 Hz, 1H), 7.36-7.32 (m, 4H), 6.99 (s, 1H), 3.57 (t, J=6.8 Hz, 2H), 3.25 (s, 3H), 3.15 (t, J=7.5 Hz, 2H), 2.91 (t, J=7.2 Hz, 2H), 2.85 (t, J=6.8 Hz, 2H), 2.24 (quin, J=7.5 Hz, 2H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[CH:27]=[C:28]([CH2:29][N:1]3[CH:2]([C:11]4[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=4[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]3=[O:7])[CH:31]=[CH:32][N:33]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: O=Cc1ccnc(-n2cccn2)c1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccnc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with 2-(1H-pyrazol-1-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 394.85 g/mol.
Reaction SMILES: [C:1]1([CH:7]([C:11](O)=[O:12])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.C1COCC1>[OH:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][OH:12]
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5.11 g of phenylmalonic acid in 50 mL of ether cooled to 0° C. was added 60 mL of a 1M solution of lithium aluminum hydride in THF. After stirring the mixture at room temperature overnight, the excess lithium aluminum hydride was quenched with ethyl acetate and dilute hydrochloric acid. The 1,3-dihydroxy-2-phenylpropane was isolated by ether extraction, and subsequent purification by flash chromatography gave 1.34 g of product characterized by NMR. This is treated with one equivalent of tosyl chloride in pyridine to afford the monotosylate. The purified monotosylate is heated in acetone with excess sodium iodide (as described in Example 23) to produce the 1-iodo-2-phenyl-3-propanol. Subsequent silylation with trimethylsilyltriflate (as in Example 16) and treatment of the iodosilylether with triphenylphosphine in toluene at 100 ° C. gives the title compound, which is characterized by its NMR and mass spectra.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O[CH:15]=[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:25]>O1CCCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][CH:15]=[C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:25])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C1Nc2ccccc2C1=CO
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1ccc(N2CCOCC2)cc1
Temperature: 40 °C
Yield: 101.7 %

Procedure:
A solution of 4-morpholinoaniline (8.3 g, 51.5 mmol) in 100 mL of tetrahydrofuran was treated with 3-hydroxymethylene-1,3-dihydro-indol-2-one (5.5 g, 30.9 mmol) in one portion. The reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated. The residue was treated with 125 mL of ethyl acetate and the resulting suspension was heated at 40° C. for 2 h. The suspension was cooled to room temperature and the solid collected by suction filtration and washed with ethyl acetate. The solid obtained was dried under vacuum to give the title compound (10.1 g, 92%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]1.[H-].[Na+].CS(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O.O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([S:19]([CH2:22][CH3:23])(=[O:20])=[O:21])[CH2:17][CH2:18]3)=[O:12])[N:8]2[CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:4][C:3]=1[O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]1
Reactant: CCS(=O)(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)c(Br)cc3[nH]2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)c(Br)cc3n2CC(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of 144 mg (0.26 mmol) [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4-ethanesulfonyl-piperazin-1-yl)-methanone (example 10) in 3 mL N,N-dimethylformamide, were added 13 mg (0.29 mmol; 55% dispersion in mineral oil) sodium hydride. The reaction mixture was stirred 15 min at 70° C. 68 mg (0.29 mmol) 2,2,2-Trifluoroethyl methanesulfonate were added and the solution was stirred another 2 h at 70° C. After cooling to room temperature, the reaction was poured into water and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant, to afford 86 mg (52%) of the title compound as a light-yellow oil.
Reaction SMILES: C(O)(=O)C.Br.C(OP([N:14]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:24][CH2:23][CH2:22][C:21]([F:41])([F:40])[CH2:20][CH2:19][CH2:18][N:17]([S:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N+:51]([O-:53])=[O:52])(=[O:44])=[O:43])[CH2:16][CH2:15]1)(=O)OCC)C>C(OCC)C>[F:41][C:21]1([F:40])[CH2:22][CH2:23][CH2:24][N:25]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:26][CH2:27][NH:14][CH2:15][CH2:16][N:17]([S:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N+:51]([O-:53])=[O:52])(=[O:43])=[O:44])[CH2:18][CH2:19][CH2:20]1
Reactant: CCOP(=O)(OCC)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCCC(F)(F)CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCC(F)(F)CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
Acetic acid (10 ml), saturated with anhydrous hydrogen bromide (gas) was added to [11,11-difluoro-1,7-bis(2-nitro-benzenesulfonyl)-1,4,7-triaza-cyclotetradec-4-yl]-phosphonic acid diethyl ester (311 mg, 0.41 mmol) contained in round-bottomed flask closed by glass stopper. The resulting mixture was allowed to stir for 18 hours at room temperature and then diethyl ether (50 ml) was added. The white precipitate which formed was allowed to settle to the bottom of the flask and the diethyl ether solution was decanted off. This white solid was re-dissolved in methanol, stirred with K2CO3 (solid) for 30 mins and the mixture was diluted with 100-ml ethyl acetate. The solids were removed by filtration and the filtrates were evaporated to give the title compound (239 mg, 94%) as white form.
Reaction SMILES: [CH2:1]([P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])[P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C=O.[CH2:16](NCC)C>CO>[C:1]([P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])([P:8](=[O:13])([O:9][CH3:10])[O:11][CH3:12])=[CH2:16]
Reactant: CCNCC
Reactant: COP(=O)(CP(=O)(OC)OC)OC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OC)OC)P(=O)(OC)OC
Yield: 71.8 %

Procedure:
Tetramethyl ethenylidenebisphosphonate was synthesized via following general synthetic procedure. ##STR11## Specifically, 4.03 g (17.4 mmol) of tetramethyl methylenebisphosphonate, 2.60 g (86.7 mmol) of paraformaldehyde and 1.27 g (17.4 mmol) diethylamine were combined with the same reactants and at the same conditions as described above in Example I and refluxed for 2 hours. After the methanol was eliminated as described in Example I, 3.05 g of tetramethyl ethenylidenebisphosphonate was produced as a clear liquid with the following spectral characteristics: 1H NMR (CDCl3) 6.99 (distorted dd, 2H H2C=, J=33.9 and 37.7), (distorted dd, 12H, --OCH3, J=5.1 and 6.1); 13C NMR (CDCl3) 150.2 (s, H2C=), 130.2 (t, PCP, J=168), 53.2 (s, --OCH3); 31P NMR (CDCl3) +15.5. Anal. Calcd for C5H14O6P2 : C, 29.52; H, 5.78; P, 25.38. Found: C, 29.26 ; H, 6.01; P, 25.19.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16](C)[C:15](=O)[N:14]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[C:13]=2[N:12]=[C:11]1[CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[OH-].[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:18]([C:17]([NH:16][CH3:15])=[O:19])=[C:13]([NH:14][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:12]=[C:11]1[CH2:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nc2c(c(=O)n(C)c(=O)n2-c2ccc(Cl)cc2Cl)n1COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: CCc1nc(Nc2ccc(Cl)cc2Cl)c(C(=O)NC)n1COCc1ccccc1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
7-benzyloxymethyl-3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione (5.20 g, 11.32 mmol) was dissolved in dioxane (25 mL) and the mixture was treated with EtOH (25 mL) and aqueous NaOH (50 mL, 3 N). The reaction mixture was heated at 60° C. for 2 h. The mixture was then cooled to rt and was transferred to a separatory funnel containing saturated aqueous NaHCO3 (100 mL). The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (40% ethyl acetate in hexanes→40% ethyl acetate in hexanes with 0.2% MeOH) to afford 1-benzyloxymethyl-4-[(2,4-dichlorophenyl)amino]-2-ethyl-N-methyl-1H-imidazole-5-carboxamide (2.90 g, 59% yield) as a light yellow amorphous solid: 1H NMR (300 MHz, CDCl3) δ 9.35 (s, 1H), 8.41 (d, J=8.8 Hz, 1H), 7.44-7.29 (m, 7H), 7.16 (dd, J=9.1, 2.5 Hz, 1H), 5.45 (s, 2H), 4.63 (s, 2H), 2.89 (d, J=4.8 Hz, 3H); 2.65 (q, J=7.7 Hz, 2H), 1.35 (t, J=7.7 Hz, 3H); LRMS (APCI) m/e 433.1 [(M+H)+, calcd for C21H23N4O2Cl2 433.1].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].CCO[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[C:19](=[CH:18][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)CNCc1ccccc1
Product: CCOC(=O)CN(C=C(C(=O)OCC)C(=O)OCC)Cc1ccccc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
N-benzylglycine ethyl ester (5.79 g, 30 mmol) was combined with diethyl ethoxymethylene malonate (6.48 g, 30 mmol) and stirred at 120° C. for 1 hr. The crude material was used directly for the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][N:11]=[N:10]1.[C:14]([Cu])#[N:15]>CN1C(=O)CCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[N:15])=[C:3]([N:9]2[CH:13]=[CH:12][N:11]=[N:10]2)[CH:4]=1
Reactant: N#C[Cu]
Reactant: Fc1ccc(Br)c(-n2ccnn2)c1
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(F)cc1-n1ccnn1
Yield: 60.8 %

Procedure:
A mixture of 1-(2-bromo-5-fluorophenyl)-1H-1,2,3-triazole (0.603 g, 2.49 mmol), CuCN (0.245 g, 2.74 mmol), in 15 mL of NMP was subjected to microwave irradiation at 150° C. for 0.5 h. The brown mixture was filtered over Celite® and washed with DMF. This solution was treated with 10% aqueous NH4OH (28-30% solution) and extracted with EtOAc. The organic fractions were combined and successively washed with 10% aqueous NH4OH (28-30% solution), saturated aqueous NH4Cl, water, brine and dried over Na2SO4. The resulting mixture was concentrated in vacuo and the residue was purified with a Biotage column chromatography system on silica gel with hexanes:ethyl acetate (7:3 to 6:4) gradient as the eluent to afford the title compound as a light yellow solid (0.285 g, 61% yield): 1H NMR (400 MHz, CDCl3) δ: 8.40 (1 H, d, J=1.0 Hz), 7.96 (1H, s), 7.91 (1H, dd, J=8.6, 5.6 Hz), 7.77 (1H, dd, J=8.7, 2.4 Hz), 7.31-7.39 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:50])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.34 mmol) prepared in Example 5 and Lawesson's Reagent (270 mg, 0.61 mmol) in THF (5 mL) was stirred at room temperature for 1 h, then purified by flash column chromatography to give the title compound as white solid (130 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of bromobenzene (0.079 g, 0.5 mmol), phenyl boronic acid (0.073 g, 0.60 mmol) and potassium carbonate (0.138 g, 1 mmol) in 1,4-dioxane solvent (2.0 mL) was added the solid catalyst (0.01 mmol, 2 mol %) under argon gas. The reaction was then stirred at 80° C. for 16 hours. The mixture was then cooled to room temperature, filtered and concentrated in vacuo. The residue was subsequently purified by silica gel chromatography (hexanes/EtOAc or hexanes/ether). The isolated product was characterized by 1H NMR spectroscopy. Characterization Data (Biphenyl): Isolated as colorless solid; 1H NMR (CDCl3, 300 MHz): δ 7.71 (4H, d, J=7.8 Hz), 7.55 (4H, t, J=7.5 Hz), 7.45 (2H, t, J=7.2 Hz). Results are shown in Table 4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21]Br)=[O:5])[CH3:2].[CH2:23]([O:25][C:26](=[O:36])[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:24].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][N:28]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
A mixture of 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.05 g, 2.67 mmol), tert-butoxycarbonylamino-acetic acid ethyl ester (540 mg, 2.66 mmol) and sodium hydride (60% in mineral oil, 128 mg, 3.2 mmol) in anhydrous dimethylformamide (10 mL) was stirred at 0° C. for two hours and room temperature for half an hour before it was quenched with brine. The mixture was filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (319 mg): MS: (+) m/z 538.9 (M+Na+).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[C@@H:34]([OH:35])[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:31]1[CH2:32][CH2:33][C@H:34]([OH:35])[C@@H:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:30]1)(=[O:38])[CH3:37]
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CNCC[C@@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CN(C(C)=O)CC[C@@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*)-4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f39) and commercially available acetyl chloride the title compound is obtained as colorless solid.