Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:14]=[CH:15][C:16]([F:20])=[C:17]([CH:19]=3)[NH2:18])[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=1.[CH:21]1([C:24]([NH2:26])=[O:25])[CH2:23][CH2:22]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.CCOC(C)=O>[NH2:18][C:17]1[CH:19]=[C:13]([C:7]2[C:8]([CH3:12])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([NH:26][C:24]([CH:21]2[CH2:23][CH2:22]2)=[O:25])[CH:11]=3)[CH:14]=[CH:15][C:16]=1[F:20]
Reactant: Cc1nc2cc(Cl)ncc2cc1-c1ccc(F)c(N)c1
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc2cc(NC(=O)C3CC3)ncc2cc1-c1ccc(F)c(N)c1
Temperature: 80 °C
Yield: 34.2 %

Procedure:
Sparge a solution of 5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoroaniline (0.5 g, 1.738 mmol) in dioxane (15 mL) with argon, add cyclopropanecarboxamide (0.739 g, 8.69 mmol), XantPhos (0.101 g, 0.174 mmol), Cs2CO3 (1.699 g, 5.21 mmol) and Pd2(dba)3 (0.080 g, 0.087 mmol) and heat at 80° C. overnight. Cool to RT, add EtOAc and MeOH, remove the solids via filtration through diatomaceous earth, rinse well with EtOAc and H2O and separate the layers of the filtrate. Wash the organic layer with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (200 mg, 34%) as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 9.13 (d, J=0.9 Hz, 1H), 8.44 (m, 1H), 8.17 (s, 1H), 7.08 (m, 1H), 6.82 (dd, J=8.7, 2.2 Hz, 1H), 6.59 (m, 1H), 5.28 (s, 2H), 2.56 (s, 3H), 2.02 (m, 1H), 0.88-0.81 (m, 4H); MS(ESI) m/z: 337.1 (M+H+).
Reaction SMILES: [CH2:1]([CH:4]1[C:9](=[O:10])[CH:8]([CH2:11][CH:12]=[CH2:13])[C:7](=[O:14])[C:6]([NH:15][C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)=[C:5]1[NH2:29])[CH:2]=[CH2:3].[OH-].[K+]>C(O)C.O>[CH2:11]([CH:8]1[C:9](=[O:10])[CH:4]([CH2:1][CH:2]=[CH2:3])[C:5]2[NH:29][C:16]([CH:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:15][C:6]=2[C:7]1=[O:14])[CH:12]=[CH2:13]
Reactant: C=CCC1C(=O)C(NC(=O)[C@@H]2CCC[C@H]2c2ccccc2)=C(N)C(CC=C)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCC1C(=O)c2nc(C3CCCC3c3ccccc3)[nH]c2C(CC=C)C1=O
Yield: 52.4 %

Procedure:
Dissolve trans-2-phenylcyclopentanecarboxylic acid (3,5-diallyl-2-amino-4,6-dioxo-cyclohex-1-enyl)amide (300 mg, 0.76 mmol) in ethanol (100 ml), add 10% potassium hydroxide (100 ml) and heat the reaction to 60° C. for 4 hours. Cool the reaction and dilute with water (200 ml). Acidify with concentrated hydrochloric acid and extract with diethyl ether (400 ml). Rinse the organic extract with water (200 ml), saturated sodium chloride (200 ml), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by radial chromatography (40% to 50% ethyl acetate/hexane, 2 mm plate) to provide 5,7-diallyl-2-(2-phenylcyclopentyl)-1,7-dihydrobenzoimidazole-4,6-dione (149 mg).
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:18][C:19]1[O:23][C:22]([CH:24]([C:26]2([CH3:31])[CH2:30][CH2:29][CH2:28][O:27]2)O)=[CH:21][CH:20]=1.N12CCCN=C1CCCCC2.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:15]([CH:24]([C:26]1([CH3:31])[CH2:30][CH2:29][CH2:28][O:27]1)[C:22]1[O:23][C:19]([CH3:18])=[CH:20][CH:21]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(O)C2(C)CCCO2)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(N=[N+]=[N-])C2(C)CCCO2)o1
Temperature: 0 °C
Reaction time: 41 h
Yield: 36.7 %

Procedure:
8.77 g (31.8 mmol, 1.2 eq) of diphenylphosphoryl azide were added dropwise to a solution of 5.21 g (26.5 mmol, 1 eq) of (5-methylfuran-2-yl)-(2-methyltetrahydrofuran-2-yl)methanol in 90 ml of toluene. The reaction medium was cooled to 0° C. and then 4.75 ml (31.8 mmol, 1.2 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added dropwise. The reaction medium was stirred at ambient temperature for 41 hours. The (heterogeneous) reaction medium was treated with water and with ethyl acetate and then separated by settling out. The organic phase was washed with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on HP silica gel (column puriFlash IR50SI-200G, Spot II) eluted with heptane/ethyl acetate (95/5). 2.15 g of 2-[azido-(2-methyltetrahydrofuran-2-yl)methyl]-5-methylfuran were obtained. Yield=37%. TLC/SiO2: heptane/EtOAc (80/20), developing with KMnO4.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]([F:41])([F:40])[C:12]1[CH:13]=[C:14]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:16].O>ClCCl>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:14]([CH:13]=[C:12]([C:11]([F:10])([F:40])[F:41])[CH:35]=1)[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:8](=[O:9])[NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:19][C@H:18]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:16]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: O=C(NC1CCCCC1)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 4 h

Procedure:
Cyclohexyl isocyanate (0.06 ml) was added to a stirred solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.2 g) in dichloromethane (10 ml) at room temperature. After stirring for 4 hours, dichloromethane (10 ml) and water (5 ml) were added. The organic layer was separated, washed with brine and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (98:2) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-cyclohexylcarbamoyl-2-(1H-indol-3-yl-methyl)piperazine (0.18 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:20])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.CN(C)C=O.[H-].[Na+].Br[CH:29]([CH3:31])[CH3:30]>O>[CH3:30][CH:29]([S:20][C:11]1[NH:12][C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[CH3:31]
Reactant: CC(C)Br
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccncc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(SC(C)C)[nH]c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Methoxyphenyl)-5-(4-pyridyl)-2-mercaptoimidazole (2.2 g, 8 mm) was covered with 25 ml of dimethylformamide and sodium hydride (13 mm) was added. 2-Bromopropane (1.10 g, 9.5 mm) was added in a dimethylformamide solution (20 ml) and the reaction was allowed to stir at room temperature overnight. Pouring the solution into water precipitated the product which was taken up in chloroform, dried and evaporated to an oil which crystallized by the addition of ether. Yield of the title product was 1.5 g, m.p. 206°-210°.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[S:11])[CH3:2].[CH:12]([NH:15][CH2:16][C:17](O)=[O:18])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[CH2:16][N:15]([CH:12]([CH3:14])[CH3:13])[C:10]1=[S:11])[CH3:2]
Reactant: CC(C)NCC(=O)O
Reactant: CCc1ccccc1N=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1ccccc1N1C(=O)CN(C(C)C)C1=S
Yield: 26 %

Procedure:
The title compound was prepared by the procedure described in Example 18 using 16.3 g of 2-ethylphenyl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the title compound (6.8 g) as a white solid, m.p. 103°-105° C. Anal. Calcd. for. C14H18N2OS: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.08; H, 6.92; N, 10.62. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH2:18]([S:34](Cl)(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O1CCCC1>[CH2:18]([S:34]([NH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)(=[O:36])=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc(C(C)=O)c1
Reaction time: 2 h

Procedure:
To a mechanically stirred solution of 31.2 g (0.23 M) of m-aminoacetophenone and 35.4 ml (0.254 M) of triethylamine in 1 liter of tetrahydrofuran was added 75 g (0.23 M) of 1-hexadecanesulfonyl chloride at room temperature. The mixture was stirred for 2 hours and the suspended salt was removed. The filtrate was treated on a rotary evaporator to give a solid which was recrystallized from hexane: mp 95.5°-100° C.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33])=[CH:27][CH:26]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:33][CH2:32][C:31]([C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=3)([CH3:35])[CH3:34])=[O:18])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CC(C)(CN)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: CC(C)(CNC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)c1ccc(Cl)cc1

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid was coupled with 2-(4-chloro-phenyl)-2-methyl-propylamine as in EXAMPLE 1, Part C. HPLC: RT=11.08 min. MS (ESI−): mass calcd. for C23H20Cl2N4O3S2, 534.04; m/z found, 533/535 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.53 (s, 1H), 8.35 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.71 (dd, J=8.8, 7.0, 1H), 7.70 (d, J=1.8, 1H), 7.35-7.31 (m, 2H), 7.30-7.26 (m, 2H), 6.89 (d, J=8.3, 1H), 6.86 (dd, J=8.4, 1.8, 1H), 5.58-5.52 (m, 1H), 3.56 (d, J=6.1, 2H), 1.36 (s, 6H).
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>O1CCCC1>[N:10]1([CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: COC(=O)CC(=O)CCl
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
To a solution (300 mL) of methyl 4-chloro-3-oxobutanoate (27.1 g) in tetrahydrofuran was added morpholine (34.5 g) under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, 1N hydrochloric acid (100 mL) was added, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10, volume ratio) to give the title object compound (12.8 g, 35%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]([C:12]#[N:13])[C:9]([OH:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:15]1([CH2:21][C:22]([NH:24][NH2:25])=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:21]([C:22]1[NH:13][C:12]([C:10]2[C:9]([OH:14])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([Br:1])[N:11]=2)=[N:25][N:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1nc(Br)c2cccnc2c1O
Reactant: NNC(=O)Cc1ccccc1
Product: Oc1c(-c2nnc(Cc3ccccc3)[nH]2)nc(Br)c2cccnc12

Procedure:
The title compound was prepared in a similar manner to that described in example 1 from 5-bromo-8-hydroxy-1,6-naphthyridine-7-carbonitrile (100 mg, 0.40 mmol) and phenylacetic hydrazide (120 mg, 0.80 mmol) to give a yellow solid (102 mg, 67%). 1H NMR (CDCl3/CD3OD): δ 9.03 (d, J=2.8 Hz, 1 H), 8.46 (d, J=8.0 Hz, 1 H), 7.62 (dd, J=8.4, 4.0 Hz, 1 H), 7.28-7.16 (m, 5 H), 4.12 (s, 2 H); MS m/z 382 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[C:9](OCC)(=[O:13])[C:10]([NH2:12])=[O:11].O.Cl>O1CCCC1.C(O)C>[Cl:1][C:2]1[C:3]([Cl:8])=[CH:4][CH:5]=[CH:6][C:7]=1[C:9](=[O:13])[C:10]([NH2:12])=[O:11]
Reactant: CCOC(=O)C(N)=O
Reactant: Clc1ccccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: NC(=O)C(=O)c1cccc(Cl)c1Cl
Temperature: -60 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
n-Butyl chloride (55.5 g, 0.6 mol) was added dropwise to a stirred suspension of lithium slices (8.30 g, 1.2 mol) in dried ether (300 ml) under N2 so as to maintain gentle reflux. After heating under reflux for a further 33/4 hours the mixture was cooled to room temperature and stirred overnight. (Previous analyses indicate that this procedure affords a 66% yield of butyl lithium (≡0.4 mol). The mixture was then cooled to -60° C. and held at this temperature during the following operations. Dried tetrahydrofuran (400 ml) was added, then a solution of 1,2-dichlorobenzene (58.8 g, 0.4 mol) in dried tetrahydrofuran (300 ml) was added dropwise over 40 mins. After stirring the mixture for 1 hour a solution of ethyl oxamate 23.4 g, 0.2 mol) in warm tetrahydrofuran (300 ml) was added dropwise over 1 hour and the mixture stirred for a further 1 hour at -60° C. After allowing to warm to 0° C., water (300 ml) was added cautiously and the mixture acidified to pH 6 within hydrochloric acid. The yellow organic phase was separated, washed with brine (2×300 ml), dried (magnesium sulphate) and evaporated to give a pale yellow solid. This was slurried with ethanol (250 ml), filtered and dried to give crude 2,3-dichlorophenylglyoxylamide (22.5 g, 52%) m.p. 214-215° C. (ref. 215-218° C.).
Reaction SMILES: O.[SH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.O.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN(C=O)C>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][S:2][C:3]2[N:11]=[CH:10][N:9]=[C:8]3[C:4]=2[NH:5][CH:6]=[N:7]3)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Sc1ncnc2nc[nH]c12
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CSc2ncnc3nc[nH]c23)cc1
Yield: 91 %

Procedure:
After stirring a mixture of 30 mmol of 6-mercaptopurine monohydrate (5.12 g) and 30 mmol of water-free K2CO3 (4.12 g) in 25 mL of dry DMF for 5 minutes, 30 mmol of 4-nitrobenzylbromide (6.48 g) was added. After stirring for 4 h, 200 mL of H2O was added. The obtained solid was filtered and washed with EtOAc and CH2Cl2, followed by drying under vacuum. Yield: 91%.—White powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7](=O)[CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:28]=[C:24]([C:25]([OH:27])=[O:26])[C:23]([OH:29])=[CH:22][CH:21]=1>C(O)(=O)C>[C:25]([C:24]1[CH:28]=[C:20]([N:19]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[CH:8]=[C:7]2[C:6]2[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:21]=[CH:22][C:23]=1[OH:29])([OH:27])=[O:26]
Reactant: COc1ccc(C(=O)CC2CCCCC2=O)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3c(n2-c2ccc(O)c(C(=O)O)c2)CCCC3)cc1

Procedure:
A mixture of 24.6 g. (0.1 mole) of 2-(p-methoxyphenacyl)cyclohexanone, 15.3 g. (0.1 mole) of 5-aminosalicylic acid, and 100 ml. of glacial acetic acid was heated under reflux for 3 hours, cooled and filtered. The filter cake was washed with water, dried and recrystallized from ethanol to provide 14.4 g. (40%) of crystals, m.p. 219°-221°.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:39])[C@H:10]([C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])=[CH:29][CH:28]=2)=[N:24][N:23]=1)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([Cl:20])[C:13]=1[CH3:21])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:20][C:14]1[C:13]([CH3:21])=[C:12]([NH:11][C@@H:10]([C:22]2[O:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])=[CH:31][CH:32]=3)=[N:24][N:23]=2)[C@H:9]([OH:8])[CH3:39])[CH:17]=[CH:16][C:15]=1[C:18]#[N:19]
Reactant: CCCC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)O)o2)cc1
Temperature: 10 °C
Yield: 97.4 %

Procedure:
To a pre-cooled (−55° C.) solution of N-(4-(5-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-cyano-2-methylphenylamino)propyl)-1,3,4-oxadiazol-2-yl)phenyl)butyramide (352 mg, 0.62 mmol) in THF (25 mL) was added TBAF (0.74 mL, 0.74 mmol, 1 M solution in THF) over 5 minutes. Upon complete addition the reaction mixture was allowed to warm to 10° C. over 2.5 h and quenched with sat. aq. NH4Cl (30 mL). The resulting mixture was partitioned between H2O (30 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (35 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide a colourless oil, which was purified by flash chromatography over silica gel (50-100% EtOAc in hexanes) to provided the title compound as a colourless solid (274 mg, 97%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.41 (s 1H), 7.91 (dm, J=9.0 Hz, 2H), 7.87 (dm, J=9.0 Hz, 2H), 7.49 (d, J=8.6 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 5.86 (d, J=8.8 Hz, 1H), 5.04 (dd, J=5.5, 8.6 Hz, 1H), 4.69 (br s, 1H), 4.52 (pentet, J=5.9 Hz, 1H), 2.38 (t, J=7.2 Hz, 2H), 2.36 (s, 3H), 1.69 (sextet, J=7.2 Hz, 2H), 1.42 (d, J=6.5 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:16][C:17]2([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:20][CH2:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.C[Sn](C)C.C[Sn](C)C.[Li+].[Cl-].Br[C:39]1[S:40][C:41]([CH2:44][C:45]#[N:46])=[CH:42][N:43]=1>C(OCC)(=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.[Cu]I.O1CCOCC1>[Cl:27][C:26]1[C:21]([C:17]2([CH2:16][N:8]([C:5]3[N:4]=[CH:3][C:2]([C:39]4[S:40][C:41]([CH2:44][C:45]#[N:46])=[CH:42][N:43]=4)=[CH:7][N:6]=3)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:20][CH2:19][CH2:18]2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2Cl)CCC1)c1ncc(Br)cn1
Reactant: N#CCc1cnc(Br)s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2Cl)CCC1)c1ncc(-c2ncc(CC#N)s2)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 20.3 %

Procedure:
To a 50 mL round bottom flask was added t-butyl 5-bromopyrimidin-2-yl((1-(3-chloropyridin-2-yl)cyclobutyl)methyl)carbamate (1.0 g, 2.2 mmol), Pd(PPh3)4 (0.25 g, 0.22 mmol), hexamethylditin (0.92 mL, 2.2 mmol), LiCl (0.25 g, 5.9 mmol), and dioxane (10 mL). The mixture was heated to 90° C. for 1 h. To the resultant dark brown solution was added 2-(2-bromothiazol-5-yl)acetonitrile (0.89 g, 4.4 mmol), Pd(PPh3)4 (0.076 g, 0.066 mmol), and CuI (4.2 g, 22.2 mmol). The reaction mixture was stirred at 90° C. for 1 h. The reaction was then cooled to rt, diluted with ethyl acetate (50 mL), and filtered through Celite. The filtrate was washed with water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated, and purified by silica gel chromatography (EtOAc/hex) to afford 222 mg of t-butyl (1-(3-chloropyridin-2-yl)cyclobutyl)methyl(5-(5-(cyanomethyl)thiazol-2-yl)pyrimidin-2-yl)carbamate as a viscous brown oil. To this compound was added potassium carbonate (185 mg, 1.3 mmol) and DMSO (3 mL). The mixture was cooled to 0° C. and hydrogen peroxide (0.5 mL) was slowly added. The reaction was warmed to rt and stirred for 1 h. The reaction was diluted with EtOAc (75 mL) and washed three times with brine (50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by reverse phase chromatography to afford 48 mg of t-butyl 5-(5-(2-amino-2-oxoethyl)thiazol-2-yl)pyrimidin-2-yl((1-(3-chloropyridin-2-yl)cyclobutyl)methyl)carbamate as a white solid. This compound was dissolved in 25% TFA/CH2Cl2 and stirred for 10 min. The reaction was then concentrated, dissolved in ethyl acetate (75 mL), and washed three times with saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4, filtered, and concentrated to give 39 mg of 2-(2-(2-((1-(3-chloropyridin-2-yl)cyclobutyl)methylamino)pyrimidin-5-yl)thiazol-5-yl)acetamide as a white solid (M+H=415.1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:32][C@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][C@H:3]([CH3:31])[CH2:2][NH:1][C:34](=[O:35])[C@@H:33]([OH:32])[CH2:38][CH2:37][OH:36])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C1OCC[C@@H]1O
Reactant: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@H](CNC(=O)[C@@H](O)CCO)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 78 %

Procedure:
The procedure described in Example 63 was repeated using 5-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 65, preparation of starting materials) and (S)-(−)-α-hydroxy-γ-butyrolactone to give the title compound in 78% yield; NMR spectrum (DMSO-d6) 1.31-1.47 (m, 4H), 1.64-1.77 (m, 1H), 3.33-3.50 (m, 3H), 3.71-3.84 (m, 1H), 3.90-4.00 (m, 1H), 4.32 (t, 1H), 4.87-4.98 (m, 1H), 5.29 (s, 2H), 5.48 (d, 1H), 7.18-7.27 (m, 2H), 7.28-7.40 (m, 2H), 7.54-7.64 (m, 2H), 7.87 (dt, 1H), 8.10-8.21 (m, 2H), 8.47 (s, 1H), 8.59 (d, 1H), 9.95 (s, 1H); Mass spectrum MH+ 537.9.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl.Cl[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:3]=1
Reactant: CN(C)CCCl
Reactant: Cc1ccc2c(I)n[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(I)nn(CCN(C)C)c2c1
Temperature: 25 °C
Yield: 151.9 %

Procedure:
A mixture of 3-iodo-6-methyl-1H-indazole (516 mg, 2 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (346 mg, 2.4 mmol) and potassium carbonate (828 mg, 6 mmol) in 20 mL of DMF was heated to 80 degree overnight. After cooling to room temperature, water (50 mL) was added, product extracted with dichloromethane (3×50 mL), combined organics were dried with sodium sulfate, and concentrated to give 2-(3-iodo-6-methyl-1H-indazol-1-yl)-N,N-dimethylethanamine (1 g, 100%). 1H NMR (300 MHz, CDCl3): δ 7.33 (d, 1H, J=8.1 Hz), 7.15 (s, 1H), 7.03 (d, 1H, J=0.6 Hz), 4.47 (t, 2H, J=7.2 Hz), 2.81 (t, 2H, J=7.2 Hz), 2.51 (s, 3H), 2.34 (m, 6H).