Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][C:37]=1[S:44]([NH2:47])(=[O:46])=[O:45]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:47][S:44]([C:37]3[CH:38]=[C:39]([CH2:42][CH3:43])[CH:40]=[CH:41][C:36]=3[Cl:35])(=[O:46])=[O:45])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CCc1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CCc1ccc(Cl)c(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c1
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of 8-chloro-6-(trifluoromethyl)imidazo[1,2-c]pyridine-2-carboxylic acid (100 mg, 0.38 mmol, prepared as described in Example 1 Step C) in a 1:1 mixture of t-butanol (5 mL) and dichloromethane (5 mL) was added 4-(dimethylamino)pyridine (138 mg, 1.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (182 mg, 0.95 mmol). The reaction mixture was stirred for 15 min, 2-chloro-5-ethylbenzenesulfonamide (74 mg, 0.34 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (100 mL) was then added, the mixture was washed with 1 N hydrochloric acid (3×50 mL), and the organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford a solid. The solid was rinsed with diethyl ether to afford 84 mg of the title compound, a compound of the present invention, as a solid, m.p. 214-215° C. 1H NMR (CDCl3) δ 10.12 (br s, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.53 (s, 1H), 7.40 (s, 2H), 2.77 (q, 2H), 1.30 (t, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[CH:9][CH:8]=1.[H][H].F[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C)C=O.O>[CH3:3][CH:4]([O:22][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccccn1
Reactant: [H][H]
Reactant: CC(O)COc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(COc1ccc(Oc2cc(F)cc(F)c2)cc1)Oc1ccccn1
Yield: 72.2 %

Procedure:
To a suspension of sodium hydride (20 mg, 0.5 mmol; 60% in oil) in dimethylformamide (1 ml), a solution of 1-methyl-2-[4-(3,5-difluorophenoxy)phenoxy]ethanol (140 mg, 0.5 mmol) in dimethylformamide (1 ml) was dropwise added with stirring, and stirring was continued at room temperature until the generation of hydrogen gas ceased. 2-Fluoropyridine (97 mg, 1.0 mmol) was dropwise added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (40 ml) and extracted with toluene (20 ml) three times. The toluene layer was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography to give 2-{1-methyl-2-[4-(3,5-difluorophenoxy)phenoxy]ethoxy}pyridine (129 mg) as pale yellow liquid. nD19.0 1.5602.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[C:19]([OH:30])(=O)[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([NH:18][C:24](=[O:26])[C:23]4[CH:22]=[CH:21][C:20]([C:19]([NH:18][C:16]5[CH:15]=[CH:14][C:12]6[NH:13][C:9]([C:6]7[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=7)=[N:10][C:11]=6[CH:17]=5)=[O:30])=[CH:28][CH:27]=4)=[CH:17][C:11]=3[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3ccc(N)cc3[nH]2)cc1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: COc1ccc(-c2nc3cc(NC(=O)c4ccc(C(=O)Nc5ccc6[nH]c(-c7ccc(OC)cc7)nc6c5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 274 was prepared according to the procedure similar to that described in Scheme V from 2-(4-methoxyphenyl)-5-aminobenzimidazole and terephthalic acid. [M+H]+ calcd for C36H28N6O4: 609.22; found: 608.99.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][C:46]([CH3:49])=[CH:47][N:48]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:35]([NH:43][C:44]2[S:45][C:46]([CH3:49])=[CH:47][N:48]=2)=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: Cc1cnc(N)s1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ncc(C)s4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 134.9 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (84 mg) was dissolved in chloroform (2.5 ml) and triethylamine (0.25 ml) to prepare a solution. A solution of triphosgene (38 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 2-amino-5-methylthiazole (32 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated and was evaporated to dryness. Diethyl ether was then added to the solid, and the solid was collected by filtration. Further, the collected solid was washed with methyl alcohol to give the title compound (81.5 mg, yield 70%).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6][C:5]=1[CH3:14].O.[OH-].[Li+].C(OCC)(=O)C.Cl>CO.O>[CH3:14][C:5]1[N:6]=[C:7]([C:10]([F:13])([F:11])[F:12])[CH:8]=[CH:9][C:4]=1[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)O
Reaction time: 4 h
Yield: 90.9 %

Procedure:
6.68 g (0.0305 mol) of 2-methyl-6-trifluoromethyl-nicotinic acid methyl ester (prepared in the manner described in Heterocycles, 46, 129 (1997)) are dissolved in 250 ml of methanol/water (3:1 mixture) and 1.92 g (0.046 mol) of lithium hydroxide hydrate are added in portions at a temperature of 22° C. After 4 hours at 22° C., the reaction mixture is added to ethyl acetate and 2N hydrochloric acid; the organic phase is washed three times with water, dried over sodium sulfate and concentrated by evaporation, and the residue is triturated with a small amount of hexane. After filtering, 5.69 g (90% of theory) of the expected 2-methyl-6-trifluoromethyl-nicotinic acid having a melting point of 147-149° C. are obtained.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:32][CH3:33])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:21].C(O)C.C(OC(C)C)(C)C>>[ClH:1].[CH2:32]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:27]1)[CH3:33]
Reactant: CCN(CC)CCCC1CCCNC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CCN(CC)CCCC1CCCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Product: Cl
Yield: 84 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[3-(diethylamino)propyl]piperidine in a yield of 84% of theory. Colourless crystals, m.p. 257°-258° C. (ethanol/diisopropylether)
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8]C)=[O:7].[C:16]([C:18]1[CH:23]=[C:22]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[F:30])#[CH:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CCOC(C)=O.O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:3]([O:4][CH:5]([CH3:10])[C:6]([OH:8])=[O:7])=[C:2]([C:17]#[C:16][C:18]2[CH:23]=[C:22]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[F:30])[CH:14]=1
Reactant: COC(=O)C(C)Oc1ccc(Cl)cc1Br
Reactant: C#Cc1cc(S(=O)(=O)CCC)ccc1F
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCCS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OC(C)C(=O)O)c1
Temperature: 80 °C

Procedure:
A solution of methyl 2-(2-bromo-4-chlorophenoxy)propanoate (Intermediate 263 ; 130 mg; 0.44 mmol), 2-ethynyl-1-fluoro-4-(propane-1-sulfonyl)-benzene (Intermediate 109 ; 110 mg; 0.49 mmol), bis(triphenylphosphine)palladium (II) chloride (9.3 mg; 0.01 mmol), triphenylphosphine (23.2 mg; 0.09 mmol) and cuprous iodide (2.5 mg; 0.01 mmol) in TEA (985 μl) was degassed with nitrogen. The reaction mixture was heated overnight at 80° C., diluted with EtOAc and washed with sat. ammonium chloride solution and brine. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording a dark brown sticky solid, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The intermediate thus obtained was dissolved in a mixture of dioxane (2.6 ml) and water (2.6 ml) and treated with a 4 N solution of HCl in dioxane (1.33 ml). After heating at 100° C. for 16 hours, water was added and the reaction mixture was extracted 3 times with EtOAC. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording a yellow sticky solid, which was triturated in diethylether/pentane to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[CH:60][C:59]=2[F:68])=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:51]=[CH:52][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:65])[F:66])[CH:61]=[CH:60][C:59]=2[F:68])[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:69][CH:70]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2cc(C(F)(F)F)ccc2F)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cc(C(F)(F)F)ccc2F)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29.8 %

Procedure:
To a solution of 100 mg (0.47 mmol) of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 150 mg of TBTU (0.47 mmol) in 10 ml DMF, were added 0.4 ml (2.34 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 184 mg (0.47 mmol) of (4-tert-butyl-benzyl)-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-amine were added. After stirring for 22 h at rt, the reaction mixture was diluted with 10 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by two successive column chromatographies (8 g silica gel; EtOAc/heptane 1:3; then again 8 g silicagel and DCM/heptane 70:30 to 90:10) to give 77 mg white solid (30%). MS(ISP) 548.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:24][C:23]([O:20][C@@H:14]1[C@@H:13]2[O:12][C:11]3=[C:10]([O:21][CH3:22])[CH:9]=[CH:8][C:7]4=[C:6]3[C@:5]32[CH2:4][CH2:3][N:2]([CH3:1])[C@H:18]([CH2:19]4)[C@@H:17]3[CH:16]=[CH:15]1)=[O:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2c3c1O[C@H]1[C@@H](OC(C)=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reaction time: 12 h
Yield: 99.4 %

Procedure:
A solution of codeine (30 g, 100.2 mmol), acetic anhydride (18.4 g, 180.2 mmol), triethylamine (18.25 g, 180.2 mmol) and 4-dimethylaminopyridine (0.5 g) in dry ethyl acetate (620 ml) was stirred at rt. under nitrogen for 12 hr, added saturated aqueous sodium bicarbonate solution until no acetic anhydride detected. The organic portion was separated, washed with water (3×120 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give 6-acetylcodeine as white solids (34.0 g, 99% yield). IR (KBr)(v, cm-1): 1725 (st, sharp, 3-AcO); NMR (δH)(CDCl3): 6.66 (1, d, J, 8.2, 2-H), 6.53 (1, d, J, 8.2, 1-H), 5.63 (1, ddd, J, 10.0, 2.4 & 1.0, 7-H), 5.42 (1, dt, J, 9.9 & 2.3, 8-H), 5.22-5.51 (1, m, 6-H), 5.06 (dd, J, 6.7 & 1.0, 5-H), 3.85 (3, s, 3-OCH3), 3.39 (1, dd, J, 6.0 & 3.3, 9-H), 3.03 (1, d, Jjem, 18.6, 10-Hβ), 2.78 (1, dd, J, 5.2 & 2.6, 14-H), 2.63 (1, dd, J, 11.9 & 4.6, 16-Ha), 2.45 (3, s, N--CH3), 2.40 (1, td, J, 12.0 & 3.8, 16-He), 2.33 (1, dd, J, 18.5 & 6.0, 10-Hα), 2.15 (3, s, 6-OAc), 2.06 (1, td, J, 12.0 & 5.0, 15-Ha) and 1.85 (1, dm, J, 12.0, 15-He).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH:6]([OH:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[Cl:17][C:18]1[C:19](=[O:25])[NH:20][N:21]=[CH:22][C:23]=1Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH:6]([OH:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:23]1[CH:22]=[N:21][NH:20][C:19](=[O:25])[C:18]=1[Cl:17]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: NCCNCC(O)COc1ccccc1Cl
Solvent: CCO
Product: Cl
Product: O=c1[nH]ncc(NCCNCC(O)COc2ccccc2Cl)c1Cl
Yield: 78 %

Procedure:
4.9 g of N-[3-(o-chlorophenoxy)-2-hydroxy-propyl]-ethylenediamine ##STR15## are dissolved in 50 ml of ethanol. A solution of 3.3 g of 4,5-dichloropyridazin-3-one ##STR16## in 50 ml of ethanol is added to the above solution, and the mixture is then heated under reflux for 12 hours. The mixture is then concentrated in vacuo, the residue is digested with a little ethyl acetate and decanted off from the ethyl acetate, and the residue is finally recrystallised from ethanol. The N-[3-(o-chlorophenoxy)-2-hydroxypropyl]-N'-[4-chloro-3-oxopyridaz-5-yl]-ethylenediamine hydrochloride ##STR17## is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].C(OCC=C)C=C>C1(C)C=C(C)C=C(C)C=1>[CH2:21]([C:6]1[C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=[C:4]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:9])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: Cc1cc(O)c(C(C)C)cc1Cl
Agent: C=CCOCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1cc(C)cc(C)c1
Product: C=CCc1c(C)c(Cl)cc(C(C)C)c1O
Yield: 73.5 %

Procedure:
Treatment of 4-chloro-2-isopropyl-5-methylphenol (10.00 g, 0.054 mol) with potassium carbonate (29.94 g, 0.217 mol) and allyl bromide (7.86 g, 0.065 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 8.92 g (73%) of 2-allyl-4-chloro-6-isopropyl-3-methylphenol as a colorless oil. Rf=0.85 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C13H17ClO: C, 69.48; H, 7.62. Found: C, 69.87; H, 7.43.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].Cl.[NH2:9][C@@H:10]([CH2:13][CH:14]1[CH2:19][CH2:18]CCC1)[CH2:11][OH:12]>C(Cl)Cl>[N:9]1[CH:18]=[CH:19][CH:14]=[CH:13][C:10]=1[C:11]1[O:12][CH2:2][CH2:1][N:3]=1
Reactant: N[C@H](CO)CC1CCCCC1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: c1ccc(C2=NCCO2)nc1
Temperature: 50 °C

Procedure:
Methyl-6-phenylpyridyl-2-imidate (0.160 g, 0.754 mmol) was dissolved in CH2Cl2 (3 mL). Triethylamine (0.12 mL, 0.83 mmol) was added followed by 2-(S)-amino-3-cyclohexylpropanol hydrochloride (0.161 g, 0.829 mmol). The reaction vessel was sealed and heated on a heating block (50° C.) for 16 hours and the resultant solution was then filtered to remove the insoluble salts. The filtrate was loaded onto the top of a Biotage cartridge (silica gel, 40S) and the product was eluted using a stepped gradient of 0 to 30% ethyl acetate in hexanes as the eluent. The product was obtained after evaporation of the eluent as a slightly yellow solid (0.181 g, 75%).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=O)[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH3:32][NH:33][CH3:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([N:33]([CH3:34])[CH3:32])=[O:26])[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@@H](C(=O)O)C3)n3nccc3n2)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Yield: 66.8 %

Procedure:
A solution of (R)-1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-3-carboxylic acid (Compound 84, 100 mg, 0.236 mmol), dimethylamine (236 μL, 0.472 mmol), EDCI (90 mg, 0.472 mmol), and HOBT (16 mg, 0.118 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 20-40% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a white solid (71 mg, 69%). 1H NMR (DMSO-d6) δ: 10.91 (s, 1H), 8.08 (d, J=2.3 Hz, 1H), 7.95-8.03 (m, J=8.6 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.37 (s, 1H), 6.36 (d, J=2.0 Hz, 1H), 4.55 (br. s., 1H), 4.35 (br. s., 1H), 2.97-3.18 (m, 6H), 2.83 (s, 3H), 1.57-2.01 (m, 4H), 1.45 (s, 6H). ESI-MS: m/z 451.0 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C.CN(C1C=CC=CN=1)C>[Cl:9][CH2:8][C:6]1[N:7]=[C:3]([NH:2][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[S:4][CH:5]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1nc(CCl)cs1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: ClCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 41.5 %

Procedure:
A solution of 2-amino-4-chloromethylthiazole hydrochloride (3.701 g), trityl chloride (11.15 g), triethylamine (10.5 ml) and dimethylaminopyridine (10 mg) in chloroform (150 ml) was stirred at room temperature. After 23 h the reaction mixture was diluted with chloroform (150 ml) and then washed with 5% aqueous sodium hydrogen carbonate solution (2×50 ml) and brine (50 ml), dried (MgSO4) and evaporated to an orange gum. The gum was triturated with diethyl ether to give a pale brown solid. The liquors from the trituration were diluted with ethyl acetate (250 ml) and washed with M-hydrochloric acid (3×60 ml), water (60 ml), and brine (30 ml) dried (MgSO4) and evaporated to a pale brown foam. The triturated solid was treated in the same manner as the liquors to give a pale brown foam. The two foams were combined and subjected to column chromatography on silica developing and eluting with ethyl acetate-petrol, 1:9 and gave an off white solid (3.241 g). A portion (240 mg) of the solid was crystallised twice from ethyl acetate-petrol to give off white crystals of the title thiazole (206 mg), m.p. 139°-140° C., λmax (EtOH) 267.5 nm (ε 8,050).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=[O:5].[CH3:16][NH:17][CH3:18]>C1COCC1>[CH3:16][N:17]([CH3:18])[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=[O:5]
Reactant: CNC
Reactant: O=C(CCCl)Nc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CN(C)CCC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-chloro-N-(3-nitrophenyl)propanamide (4.6 g, 20 mmol) in THF (50 mL) was added dropwise N,N-dimethyl amine (2M solution in THF) (1.8 g, 20 mL, 40 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was triturated with 5% NH3 (aqueous, 50 mL) and the solid product was collected by filtration, washed with water followed by hexane, and dried to give 3-(dimethylamino)-N-(3-nitrophenyl)propanamide, 4.1 g (87%), mp 80-81° C. 1H NMR (DMSO-d6) δ: 2.17 (6H, s, CH3), 2.47-2.50 (2H, t, J=6.4 Hz, CH), 2.56-2.59 (2H, t, J=6.8 Hz, CH), 7.57-7.62 (1H, t, J=8.2 Hz, Ar—H), 7.88-7.91 (2H, dd, J=8.1 and 2.2 Hz, Ar—H), 8.63-8.64 (1H, t, J=2.0 Hz, Ar—H), 10.49 (1H, brs, NH).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH:12]1[O:17][CH2:16][CH2:15][CH2:14][O:13]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH:12]1[O:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH3:2]
Reactant: BrCC1OCCCO1
Reactant: CCOC(CN)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CNCC1OCCCO1)OCC

Procedure:
2,2-Diethoxyethylamine (23.3 grams), 2-bromomethyl-1,3-dioxane (29.2 grams), triethylamine (25 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux overnight. After this time the mixture is cooled and filtered. The filtrate is then distilled under reduced pressure to yield the desired product N-(2,2-diethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)amine.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23]CCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCC1CC[N:68]([C:71]([O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:72])[CH2:67][CH2:66]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:68]([C:71]([O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:72])[CH2:67][CH2:66]1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCBr)CC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 4-(3-bromopropyl)-1-piperidinecarboxylate.