Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N>O1CCOCC1.ClCCl.[Cu]I>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=2)[C:3]1=[O:14]
Reactant: Cn1ccnc1Br
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1C(=O)N(c2nccn2C)CC1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (0.200 g, 1.00 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-bromo-1-methyl-1H-imidazole (0.146 ml, 1.500 mmol) in 1,4-dioxane (8 ml) was added potassium phosphate (1.062 g, 5.00 mmol), copper(I) iodide (0.190 g, 1.000 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.155 ml, 1.000 mmol) and the mixture heated at reflux under argon overnight. The mixture was cooled to room temperature and diluted with dichloromethane. The solid was filtered off, washed with dichloromethane and the filtrate reduced under vacuum. The residue was re-dissolved in dichloromethane and washed with 0.880 ammonia solution (×2), water then brine and passed through a hydrophobic frit and the organic layer reduced under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-10% methanol in dichloromethane to give 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-2-yl)-2-oxo-4-imidazolidinecarboxylate (145 mg, 37.8% yield). LC/MS [M+H]+=281. (ii) Trifluoroacetic acid (0.059 ml, 0.517 mmol) was added to a solution of 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-2-yl)-2-oxo-4-imidazolidinecarboxylate (145 mg, 0.517 mmol) in DCM (2 ml) and the reaction stirred at room temperature overnight. The reaction mixture was co-evaporated with toluene and dried to give 3-methyl-1-(1-methyl-1H-imidazol-2-yl)-2-oxo-4-imidazolidinecarboxylic acid (assume ˜0.517 mmol) which was used which was used in the next step. LC/MS [M+H]+=225.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].O>Br(O)(=O)=O.C(O)(=O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: [O-][Br+2]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccccc1[N+](=O)[O-]

Procedure:
In the same manner as in Example 3, the operation was conducted, except that 0.61 g (4 mmols) of o-nitrobenzyl alcohol was used in place of m-methoxybenzyl alcohol and 2 ml of water and one drop of 47% bromic acid were used in place of 2 ml of acetic acid. With respect to the components in the reaction solution, the intended o-nitrobenzaldehyde was produced in an area ratio, as determined by gas chromatography, of 75.2% and 24.2% of o-nitrobenzyl alcohol as a raw material was remained.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.[CH2:9]([N:16]1[CH2:21][C@@H:20]([CH3:22])[NH:19][CH2:18][C@@H:17]1[CH3:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[CH2:9]([N:16]1[C@@H:17]([CH3:23])[CH2:18][N:19]([CH2:2][C:3]2([OH:1])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[C@H:20]([CH3:22])[CH2:21]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Reactant: C1CC2(CCO1)CO2
Solvent: CO
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1CC1(O)CCOCC1
Temperature: 150 °C

Procedure:
To a microwave vial was added 1,6-dioxaspiro[2.5]octane (259 mg, 2.3 mmol), (2S,5R)-1-benzyl-2,5-dimethylpiperazine (464 mg, 2.3 mmol) and 5 mL of MeOH. The vial was heated to 150° C. for 2 h in the microwave. The crude reaction was concentrated to provide intermediate H1(ii) (723 mg, 100%) 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.92 (d, J=6.22 Hz, 3H), 1.13 (d, J=5.84 Hz, 3H), 1.35-1.45 (m, 1H), 1.46-1.68 (m, 4H), 1.83 (dd, J=11.30, 9.80 Hz, 1H), 2.12 (d, J=13.94 Hz, 1H), 2.36-2.53 (m, 3H), 2.60-2.69 (m, 2H), 2.85 (d, J=9.04 Hz, 1H), 3.08 (d, J=13.38 Hz, 1H), 3.71-3.82 (m, 4H), 4.04 (d, J=13.38 Hz, 1H), 7.10-7.47 (m, 5H). Mass Spectrum: Calcd for C19H30N2O2 (M+H): 318. Found: 318.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[CH:32]=[CH:31][CH:30]=1.[OH2:38]>CN(C)C=O>[C:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[CH:32]=[CH:31][CH:30]=1)([OH:38])=[O:22]
Reactant: OCCCCCCc1cccc2cncn12
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: O=C(O)CCCCCc1cccc2cncn12
Reaction time: 6 h

Procedure:
Pyridinium dichromate (0.94 g) is added as a solid to a solution of 5-(6-hydroxyhexyl)-imidazo[1,5-a]pyridine (123 mg) in 10 ml of N,N-dimethylformamide at 25° under nitrogen. The solution is stirred for 6 hours, poured into 150 ml of water and extracted with methylene chloride (5×20 ml). The organic extracts are washed with 1 N sodium hydroxide. Acidification of the aqueous phase to pH=6, extraction with methylene chloride and drying over sodium sulfate/magnesium sulfate yields 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine of Example 2 melting at 145°-146°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[CH3:30].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.CCCCCC.[Cu]I.C(OC(=O)C)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]2=[O:14]
Reactant: Cc1ccncc1I
Reactant: COc1ccc(F)c2c1C(=O)NCC2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCCC
Product: COc1ccc(F)c2c1C(=O)N(c1cnccc1C)CC2
Temperature: 25 °C
Yield: 14.6 %

Procedure:
5-Fluoro-8-methoxy-3,4-dihydro-2H-isoquinolin-1-one (I-44d: 0.12 g, 0.6 mmol) was refluxed with K3PO4 (0.32 g, 1.5 mmol), 3-Iodo-4-methyl-pyridine (0.175 g, 0.79 mmol), trans-N,N′-dimethyl-cyclohexane-1,2-diamine (0.026 g, 0.18 mmol) and CuI (0.01 g, 0.06 mmol) in 1,4-dioxane (20 mL) at 120° C. overnight. The reaction was monitored by TLC (80% ethylacetate in hexane). The reaction mass was cooled to room temperature, filtered and partitioned between DCM and water. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated. Purification by column chromatography on silica gel (2% methanol in chloroform) followed by preparative HPLC afforded 25 mg of the product (14.75% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Mg].[Br-].CON(C)[C:16]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=1)=[O:17]>CCOCC>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][C:16]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=1)=[O:17]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CON(C)C(=O)c1ccc(I)cc1
Agent: [Br-]
Agent: [Mg]
Solvent: CCOCC
Product: O=C(Cc1ccc(F)cc1F)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4-Difluorobenzyl bromide (23.7 ml, 0.114 mol) was added dropwise to a stirred mixture of magnesium turnings (8.1 g, 0.183 mol) in dry ether (300 ml) under nitrogen. The mixture was warmed initially until reaction started, and thereafter the bromide was added at such a rate as to maintain a gentle reflux. After 1 hour, the resulting solution of the Grignard reagent was added dropwise at −78° C. to a solution of O,N-dimethyl-4-iodobenzenehydroxamic acid [see step (a)] (45.7 g, 0.157 mol) in dry ether (300 ml), and the mixture was allowed to warm slowly to room temperature overnight. The mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate, and the organic solution was separated, dried (MgSO4) and concentrated under reduced pressure, to give the title compound as a white solid, 38.71 g (69%), which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: C(=[N:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[O:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22]2)=[CH:17][CH:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C1COCC1>[CH2:27]([N:23]1[CH2:24][CH2:25][O:26][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([NH2:14])=[CH:20][CH:19]=2)[CH2:22]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(CN2CCOC(c3ccc(N=C(c4ccccc4)c4ccccc4)cc3)C2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of benzhydrylidene-[4-(4-benzyl-morpholin-2-yl)-phenyl]-amine (3.30 g; 7.63 mmol) in THF (50 mL) was added hydrochloric acid (30.5 mL; 1.00 mol/L in water; 30.5 mmol). The resulting mixture was stirred overnight at RT. The reaction mixture was partitioned between 1M aqueous HCl and EtOAc. The aqueous layer was made basic with 1M aqueous NaOH (pH>10) and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford 4-(4-benzyl-morpholin-2-yl)-phenylamine (1.85 g).
Reaction SMILES: FC1C(OC(=O)CCC[CH2:13][CH2:14][N:15]2C(=O)C=CC2=O)=C(F)C(F)=C(F)C=1F.[C:27](=O)([O:35][C:36]1[CH:41]=CC=CN=1)[O:28][C:29]1[CH:34]=CC=CN=1>C(Cl)Cl>[NH2:15][CH2:14][CH2:13][CH:27]([O:28][CH2:29][CH3:34])[O:35][CH2:36][CH3:41]
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: O=C(CCCCCN1C(=O)C=CC1=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Product: CCOC(CCN)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 924 mg (3 mmol) of 6-maleimidocaproic acid pentafluorophenyl ester 1 (see Example 11) dissolved in dry methylene chloride (30 ml) was added 10 g (1 mmol) of alpha-amino-omega-carboxy-PEG (2) (MW 10,000, n=226) and 4-dimethylpyridine (402 mg, 3 mmol) dissolved in 50 ml of dry methylene chloride. The reaction mixture was stirred at room temperature for 2 h and the product precipitated in ether (100 ml). After cooling to 4° C. the crude amide of formula 3 was collected by filtration and precipitated twice from methylene chloride by addition of ether to give 9 g of compound 3 as a white solid.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH:12]3[C:10]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=4)([CH2:11]3)[CH2:9]2)C=CC=CC=1>C(O)C.[Pd]>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([C:10]23[CH2:11][CH:12]2[CH2:13][NH:8][CH2:9]3)=[N:15][CH:16]=1
Reactant: FC(F)(F)c1ccc(C23CC2CN(Cc2ccccc2)C3)nc1
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1ccc(C23CNCC2C3)nc1
Yield: 81 %

Procedure:
3-(Phenylmethyl)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane was dissolved in ethanol (15 mL), hydrochloridic acid (3M, 0.76 mL) was added followed, in inert atmosphere, by Pd/C 10% w/w (120 mg). After 20 h under a hydrogen atmosphere (1 atm) the mixture was filtered. Solvent was removed under reduced pressure. A saturated solution of sodium bicarbonate was added (10 mL) and the mixture extracted with diethyl ether (2×10 mL) to provide the title compound (0.14 g, 81%) after evaporation of volatiles.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:19]=[C:12]2[C:13]([O:15]C(=O)[NH:17][C:11]2=[CH:10][CH:9]=1)=O)(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)Cl.C(OCC)C>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:13](=[O:15])[C:12]2[C:11](=[CH:10][CH:9]=[C:8]([S:5](=[O:6])(=[O:7])[NH:4][CH:1]([CH3:2])[CH3:3])[CH:19]=2)[NH2:17])[CH2:23][CH2:22]1
Reactant: CC(C)NS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: CN1CCNCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(N)c(C(=O)N2CCN(C)CC2)c1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-(N-isopropylsulfamoyl)-isatoic anhydride with 1-methylpiperazine yields 5-(N-isopropylsulfamoyl)-anthranilic acid (4-methyl)-piperazide with a melting point of 118°-122° (from methylene chloride/diethyl ether; melting point of the methanesulfonate: 232°-234°).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[C:20]3[C:21]4[CH:35]=[C:34]([C:36]5[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=5)[CH:33]=[N:32][C:22]=4[N:23](COCC[Si](C)(C)C)[C:19]=3[CH:18]=[N:17][C:16]=2[C:42]#[N:43])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:41][N:39]1[CH:40]=[C:36]([C:34]2[CH:33]=[N:32][C:22]3[NH:23][C:19]4[CH:18]=[N:17][C:16]([C:42]#[N:43])=[C:15]([S:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[C:20]=4[C:21]=3[CH:35]=2)[CH:37]=[N:38]1
Reactant: Cn1cc(-c2cnc3c(c2)c2c(SC4CCN(C(=O)OC(C)(C)C)CC4)c(C#N)ncc2n3COCC[Si](C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cnc3[nH]c4cnc(C#N)c(SC5CCNCC5)c4c3c2)cn1
Temperature: 25 °C
Reaction time: 22 h
Yield: 32.5 %

Procedure:
A mixture of 4-[6-cyano-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester (106 mg, 0.17 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (9 mL) was stirred at ambient temperature for 22 h. The reaction mixture was concentrated in vacuo and the resultant residue partitioned between dichloromethane (10 mL) and a saturated aqueous solution of sodium hydrogen carbonate (10 mL). The organic phase was concentrated in vacuo and the residue was adsorbed onto HM-N then purified by flash chromatography (silica, 25 g column, Si-SPE, 0-13% (2M ammonia in MeOH) in DCM) to afford the title compound as a pale yellow solid (21.5 mg, 25%). NMR (DMSO-D6, 300 MHz): 9.04 (d, J=2.2 Hz, 1H), 9.02-8.97 (m, 2H), 8.29 (s, 1H), 7.98 (s, 1H), 3.93 (s, 3H), 3.54-3.21 (m, 1H), 2.97-2.86 (m, 2H), 2.49-2.36 (m, 2H), 1.89-1.77 (m, 2H), 1.65-1.47 (m, 2H). LCMS (Method F): RT=7.08 min, M+H+=390.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH3:14])([CH3:13])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[OH:16].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:7]2[C:8]([CH3:13])([CH3:14])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[O:16][CH2:28][CH2:27][CH2:26][CH2:25][S:24][C:21]1[CH:20]=[CH:19][C:18]([CH3:17])=[CH:23][CH:22]=1
Reactant: Cc1ccc(SCCCCCl)cc1
Reactant: CC1(C)OC(=O)Nc2cc(Cl)c(O)c(Cl)c21
Product: Cc1ccc(SCCCCOc2c(Cl)cc3c(c2Cl)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 4 from 5,7-dichloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]([CH3:36])[C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.ClCCl>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([N:33]4[CH2:34][CH2:35][C@H:31]([N:30]([CH3:36])[CH3:29])[CH2:32]4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(Cn2nc(N3CC[C@H](N(C)C)C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 90 °C
Yield: 19.9 %

Procedure:
To a stirred solution of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (49 mg, 0.1 mmol) (prepared in Example 7, step B) in 300 μL DMSO at ambient temperature in a capped reaction vial was added (S)—N,N-dimethylpyrrolidin-3-amine (19 uL, 0.15 mmol) followed by K2CO3 (27 mg, 0.2 mmol), Cu(I)I (19 mg, 0.01 mmol) and L-proline (2.3 mg, 0.02 mmol). The mixture was heated 90° C. overnight, then the mixture was cooled to room temperature, diluted to 30 mL with dichloromethane and washed with H2O. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12S column with dichloromethane and eluted with 5/95 MeOH/dichloromethane to provide the product as a tan oil (9.5 mg, 20% yield).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1>CO>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:17][CH:16]=1
Reactant: COC(=O)C(Br)c1ccc(I)cc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CO
Product: COC(=O)C(Sc1ccc(Cl)cc1)c1ccc(I)cc1

Procedure:
In a similar manner as in Example 29, 12.7 g of methyl α-bromo-α-(p-iodophenyl)acetate is reacted with 6.47 g of 4-chlorothiophenol in methanol to yield a white solid, mp 44°-46° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:31]=1[NH:30][CH:29]=[CH:28]2)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[CH:38][C:39](/[CH:43]=[CH:44]/[C:45]3[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=3)[CH2:48]Cl)=[N:40]2)=[CH:35][CH:34]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[CH:38][C:39](/[CH:43]=[CH:44]/[C:45]3[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=3)[CH2:48][N:30]3[C:31]4[C:27](=[CH:26][CH:25]=[CH:24][C:23]=4[O:22][C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:28]=[CH:29]3)=[N:40]2)=[CH:35][CH:34]=1
Reactant: c1ccc(C(Oc2cccc3cc[nH]c23)(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Clc1ccc2ccc(/C=C/c3cccc(Cn4ccc5cccc(OC(c6ccccc6)(c6ccccc6)c6ccccc6)c54)c3)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
60% Sodium hydride dispersion in mineral oil (44 mg 1.1 mmol) was added to a stirred solution of 7-trityloxyindole (Example 12a) (375 mg, 1.0 mmol) in dimethylformamide (4 ml). The mixture was stirred for 10 minutes at room temperature then a suspension of 3-[2(E)-(7-chloroquinolin-2-yl)ethenyl]benzyl chloride (Example 6a) (251 mg, 0.80 mmol) in dimethylformamide (4 ml) was added and the mixture was stirred for a further 3 hours. The dark solution was poured onto saturated ammonium chloride solution and extracted with dichloromethane. The extract was dried and evaporated under high vacuum and the residue was chromatographed on silica in ethyl acetate-hexane (1:5).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.N>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[NH:17][CH:18]=[CH:19]4)=[CH:7][N:6]=1)[CH2:10]2
Reactant: Brc1cnc(O[C@H]2CN3CCC2CC3)nc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: N
Product: c1cc2cc(-c3cnc(O[C@H]4CN5CCC4CC5)nc3)ccc2[nH]1

Procedure:
The product of Example 11A (283 mg, 1 mmol) was coupled with 5-indolylboronic acid (Aldrich, 193 mg, 1.2 mmol) according to the procedure of Example 3A. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min. flow rate, 75 mL/min., uv, 250 nm) as solid (40 mg, yield, 12%). 1H NMR (300 MHz, CD3OD) δ 1.50-1.63 (m, 1H), 1.67-1.93 (m, 2H), 2.04-2.17 (m, 1H), 2.24-2.31 (m, 1H), 2.75-3.05 (m, 5H), 3.38-3.48 (m, 1H), 5.14-5.21 (m, 1H), 6.53 (dd, J=3.1, 0.7 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 7.35 (dd, J=8.5, 1.7 Hz, 1H), 7.51 (dt, J=8.5, 0.7 Hz, 1H), 7.80 (dd, J=1.7, 0.7 Hz, 1H), 8.82 (s, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19]>>[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:19]
Reactant: NCC(=O)CCC(=O)O
Reactant: OCCCCc1ccccc1
Agent: Cl
Product: NCC(=O)CCC(=O)OCCCCc1ccccc1
Reaction time: 29 h

Procedure:
From 4-phenyl-1-butanol (5.0 g; 33 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 29 h. The yield was 1.22 g (68%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][CH:13]([CH2:22][CH3:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.S(=O)(=O)(O)O.B(O)(O)O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:13]([CH3:12])[CH2:22][CH3:23])=[CH:20][CH:19]=1)=[O:5]
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: CCC(C)Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: CCC(C)Cc1ccc(OC(=O)c2ccc(O)cc2Cl)cc1

Procedure:
This esterification may be carried out by the method described by Lowrance (Tet. Lett. 1971, 3453). The reactants (2-chloro-4-hydroxybenzoic acid and (+)4-(2'-methylbutyl)phenol in equimolar amounts) are dissolved in toluene and heated in a Dean and Stark apparatus together with catalytic amounts of sulphuric acid and boric acid. After crystallisation from ethanol/water, the product has the m.p. 142° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]4)=[N:13][C:14]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:16]=3[O:17]C)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[C:10]2[S:9][C:8]([C:11]3[C:16](=[O:17])[NH:15][C:14]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[N:13][C:12]=3[NH:25][C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cccc(Cl)c2s1
Agent: Cl
Product: O=c1[nH]c(N2CCOCC2)nc(N[C@@H]2CCCNC2)c1-c1nc2cccc(Cl)c2s1

Procedure:
Following the same procedure as in step 4 of Example 337 using tert-butyl (3R)-3-[[5-(7-chloro-1,3-benzothiazol-2-yl)-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (40.0 mg, 0.07 mmol, 1.00 equiv) and 12 N hydrochloric acid (3.0 ml). The solid was collected by filtration and dried in vacuo to give the title compound as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): ppm 1.611-1.736(m, 3H), 1.935(m, 1H), 2.621-2.819(m, 3H), 3.079-3.114(m, 1H), 3.687-3.698(m, 8H), 4.157-4.167(m, 1H), 7.306-7.325(d, J=7.6 Hz, 1H), 7.399-7.419(d, J=8.0 Hz, 1H), 7.686-7.706(d, J=8.0 Hz, 1H), 10.667-10.685(m, 1H). MS m/z [M+H]+ (ESI): 447. IRAK4 IC50=180 nM