Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([CH2:37][NH2:38])[OH:36].CO>C1(C)C=CC=CC=1>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][CH2:37][CH2:35][OH:36])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: NCCO
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Solvent: CO
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(NCCO)n2)c1F)c1ccoc1
Temperature: 140 °C
Yield: 46 %

Procedure:
To the solution of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol) in toluene (2 ml) was added ethanol amine (64.5 mg, 1.056 mmol) and the reaction mixture heated in MW for 30 min at 140° C. Methanol (1 ml) was added and solution was purified by chromatography (100% EtOAc to 20% MeOH:EtOAc). N-{2-fluoro-3-[5-{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (53 mg, 43.7%) was isolated as white powder. 1H NMR (400 MHz, DMSO-d6) ppm 1.74 (qd, J=12.19, 4.48 Hz, 2H), 2.01 (dd, J=12.66, 2.12 Hz, 2H), 3.21-3.34 (m, 4H), 3.42-3.57 (m, 4H), 3.93 (dt, J=9.58, 2.22 Hz, 2H), 4.67 (t, J=6.00 Hz, 1H), 6.66 (t, J=1.29 Hz, 1H), 7.17 (t, J=5.75 Hz, 1H), 7.24-7.40 (m, 2H), 7.46 (td, J=7.69, 1.99 Hz, 1H), 7.82 (t, J=1.80 Hz, 1H), 8.08 (d, J=5.18 Hz, 1H), 8.28 (t, J=1.20 Hz, 1H), 10.31 (s, 1H); MS (ESI): 546.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[CH:14]2.Cl>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([CH3:20])=[CH:14]3)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1cc2cc(N)ccc2[nH]1
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc2cc(Nc3nc(Cl)ncc3F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
2,4-Dichloro-5-fluoropyrimidine (1 mmol) and 5-amino-2-methylindole (1.5 mmol) were dissolved in 3 ml CH3OH and 9 ml H2O. After the reaction mixture was stirred at room temperature for 1 h, it was diluted with H2O, acidified with 2N HCl, and sonicated. The reaction mixture was then filtered, washed with H2O and dried to give N-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-1H-indol-5-amine in a yield of 78%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1[N-]C(NC(OC(C)(C)C)=O)CCCCCCCCCCC)(=O)C>CCCCCC.C(OCC)(=O)C>[OH:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCCCCCCCCCC([N-][C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCCCC(CO)NC(=O)OC(C)(C)C
Yield: 87 %

Procedure:
Procedure as for 44 (using 40 in place of 41). RF=0.50 hexane:ethyl acetate 4:1 (v/v); yield 87%; 1H NMR δ 3.65-3.48 (m, 3H, αCH, CH2), 1.43 (s, 9H, 3×Boc CH3), 1.24 (m, 18H, 9CH2), 0.86 (t, 3H, CH3); FAB MS C17H35NO3 (301.46) m/z (%) 302 [M+H]+ (15), 324 [M+Na]+ (5), 434 [M+Cs]+ (10), 202 [M−Boc+H]+ (95).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=2)[C:10]1=[O:19].[CH2:20]([O:22]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:21]>>[C:20]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=2)[C:10]1=[O:19])(=[O:22])[CH3:21]
Reactant: Cc1ccc2c(c1)CC(Cc1ccncc1Br)C2=O
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Product: CC(=O)c1cnccc1CC1Cc2cc(C)ccc2C1=O

Procedure:
The title compound 114 is prepared according to the procedure reported in Example 36.5 with compound 105 (750 mg, 2.38 mmol) and (1-ethoxyvinyl)tri(n-butyl)stannane (0.8 mL, 238 mmol) as reactants. White solid. (Yield 398.8 mg, 60%).
Reaction SMILES: N(OCCC(C)C)=O.CS[S:11][CH3:12].[Br:13][C:14]1[CH:20]=[CH:19][C:17](N)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([S:11][CH3:12])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CSSC
Agent: CC(C)CCON=O
Product: CSc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 97.1 %

Procedure:
A solution of isoamyl nitrite (10.05 mL, 75 mmol) in dimethyl disulfide (49.5 mL, 550 mmol) at 25° C. was slowly treated with 4-bromo-2-nitroaniline (10.85 g, 50 mmol). The reaction was exothermic with gas evolution. The resulting brown reaction mixture was heated to 80-90° C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (300 mL). The organic layer was washed successively with a 1N aqueous hydrochloric acid solution (1×300 mL) and a saturated aqueous sodium chloride solution (1×300 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 6/1 to 5/1 hexanes/ethyl acetate) afforded 4-bromo-1-methylsulfanyl-2-nitro-benzene (12.05 g, 97%) as a brown solid: EI-HRMS m/e calcd for C7H6BrNO2S (M+) 246.9372, found 246.9368.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[CH:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[Br:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C#CCCCCCC
Reactant: Brc1ccsc1Br
Product: CCCCCCC#Cc1sccc1Br
Yield: 87.5 %

Procedure:
2,3-Dibromothiophene (3.78 g 15.6 mmole) was reacted with 1-octyne (2.57 g 23.4 mmole) using the method given in Example 20. The reaction product was purified by chromatography on silica eluting with hexane to yield 3.70 g (87.2%) of the title compound as a yellow oil bp 0.05 155°, νmax (mull) 3100, 2225, 870, 710; δ(CDCl3), 0.9(3H, t, J=6 Hz), 1.3(8H, m), 2.47(2H, t, J=6 Hz), 6.9(d, 1H, J=9 Hz), 7.13(1H, d, J=9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32](=[O:39])(=[O:38])[NH:33]C(C)(C)C)=[CH:22][C:21]=2[F:40])[C:15]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:14]1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32](=[O:39])(=[O:38])[NH2:33])=[CH:22][C:21]=2[F:40])[C:15]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:14]1
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Yield: 88 %

Procedure:
The title compound was prepared from 2-[2-bromo-5-(propionylamino)-phenyl]-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step E) by reaction with trifluoroacetic acid in the presence of anisole according to the procedure of Example 28, Step G, giving an 88% yield of the title compound as an off-white foam; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 630,632 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:9]=2[CH:10]=1)[CH3:2].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23]Br>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[O:7][C:8]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:9]=3[CH:10]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[CH3:2]
Reactant: BrCCCCBr
Reactant: CCOC(=O)Cc1cc2cc(C)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc3cc(C)ccc3o2)CCCC1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product of Step 3, above (57) (1.85 mmol), in 2 ml DMF was added 60% sodium hydride in oil (3.6 mmol) at ambient temperature. The reaction mixture was stirred for 15 minutes and then 1,4-dibromobutane (1.85 mmol) was added. The reaction mixture was heated to 80° C. for 2 hours, cooled to ambient temperature, diluted with EtOAc and washed with saturated sodium bicarbonate and brine. The combined organics were then dried over MgSO4, filtered and concentrated to dryness. The crude material was chromatographed on silica gel using 10% EtOAc in hexanes as the eluant to obtain the title compound (58).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[N:8]=1>O1CCCC1>[Cl:14][C:9]1[CH:10]=[C:11]([Cl:13])[N:12]=[C:7]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:8]=1
Reactant: C1CCNC1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: Clc1cc(Cl)nc(N2CCCC2)n1
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
After dropping 23.7 ml (286.6 mmoles) of pyrrolidine to a mixture containing 25.0 g (136.3 mmoles) of 2,4,6-trichloropyrimidine in 200 ml of tetrahydrofuran at -20° C. within about 30 minutes, the cooling is stopped and after stirring for an additional 30 minutes the reaction mixture is evaporated. After distributing the residue between 500 ml of chloroform and 50 ml of 10% sodium hydroxide solution, the organic phase is separated, washed 4 times with 150 ml of water each, then dried and evaporated. The residue is subjected to chromatography on a silica gel column. By using a 19:1 hexane/ethyl acetate mixture as eluent the eluate is evaporated and the evaporation residue is recrystallized from hexane to give 7.51 g (25.27%) of 4,6-dichloro-2-pyrrolidinopyrimidine, m.p. 95°-98° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[Br:18][C:19]1[O:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=1>>[Br:18][C:19]1[O:23][C:22]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Br)o4)cc23)CC1
Yield: 47.5 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 25.0 mg (0.131 mMol) 5-bromo-2-furoic acid, 8.4 mg (48%) of the title compound were recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[N:8]=[CH:7][N:6]=[C:5]2[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=1.[C:28](O)(=[O:31])[CH:29]=[CH2:30].CCN(CC)CC.Cl.CN(C)CCCN=C=NCC>CC(N(C)C)=O.C(Cl)Cl.CCOCC.CO.CCOC(C)=O.CCOC(C)=O.CCCCCC>[Br:27][C:23]1[CH:22]=[C:21]([NH:20][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])=[C:2]([NH:1][C:28](=[O:31])[CH:29]=[CH2:30])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: C=CC(=O)O
Reactant: CN(C)CCCCOc1cc2ncnc(Nc3cccc(Br)c3)c2cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: C=CC(=O)Nc1cc2c(Nc3cccc(Br)c3)ncnc2cc1OCCCCN(C)C
Yield: 32 %

Procedure:
To a stirred solution of the above 6-aminoquinazoline (276 mg, 0.64 mmol), acrylic acid (6 mol eq., 3.85 mmol, 264 mL), and Et3N (excess, 1.0 mL) in DMA (10 mL) under N2 was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl) (3 mol eq., 1.92 mmol, 369 mg). The standard procedure above was followed to give after chromatography on grade III alumina eluting with EtOAc/hexane (1:1) to MeOH/EtOAc (3:97), N-[4-[(3-bromophenyl)amino]-7-[4-(N,N-dimethylamino)butyloxy]-quinazolin-6-yl]acrylamide (98 mg, 32%) as a cream powder, mp (CH2Cl2/Et2O) 112-115° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=2)[N:5]=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][N:3]12.Cl.[NH2:21][OH:22].C(NC(C)C)(C)C.C(O)(=O)C>CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:21][OH:22])=[O:13])[CH:10]=2)[N:5]=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][N:3]12
Reactant: COC(=O)c1ccc2nc3ccccn3c(=O)c2c1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=C(NO)c1ccc2nc3ccccn3c(=O)c2c1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
5.9 gm of 11-oxo-11-H-pyrido[2,1-b]quinazoline-2-carboxylic acid chloride (see Example 12) were introduced into a solution of 2.08 gm of hydroxylamine hydrochloride and 9.8 ml of diisopropylamine in 100 ml of dimethylformamide, and the mixture was stirred at 20° C for 5 hours. Thereafter, the reaction mixture was acidified with dilute acetic acid and suction-filtered, yielding as the filter cake the semihyrate of the formula ##STR25##
Reaction SMILES: [C:1]1([CH:11](O)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[C:1]1([CH:11]([Cl:16])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)c1cccc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(Cl)c1cccc2ccccc12

Procedure:
A solution of 1-(1-naphthalyl)ethanol (6.34 g, 38.8 mmol) and thionyl chloride (5.37 ml, 73.6 mmol) in 65 ml of toluene was refluxed for 4 hours. The reaction mixture was evaporated to give the residue as an oil. The residue was dissolved in 150 ml of ethyl acetate, washed successively with 50 ml of water, 50 ml of saturated sodium bicarbonate and 50 ml of brine, and dried over sodium sulfate. The solvent was removed in vacuo to give 3(6.83 g, 97%) as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.O[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:32][C:33](=[O:34])[N:35]([CH3:37])[CH3:36])=[O:13])(=[O:6])=[O:7]
Reactant: CN(C)C(=O)CO
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C(=O)COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 14.9 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (1.1 g, 2.90 mmol) dissolved in 40 mL of anhydrous dichloromethane (DCM) was reacted with 1.74 mL (3.48 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, an aliquot (ca. 1.45 mmol) of the acid chloride was reacted with 455 mg (4.41 mmol) of 2-hydroxy-N,N-dimethylacetamide (36b) and 352 μL mL of pyridine (344 mg, 4.35 mmol) in 10 mL of anhydrous dichloromethane (DCM). After work-up, the crude material was purified by silica gel column chromatography using mixtures of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=2:3→EtOAc/Hxn=1:1) to provide 200 mg (30% yield) of the title compound (36c) as an opaque, viscous oil. Rf=0.28 (EtOAc/Hxn=1:1). MS (ESI) m/z 464.2 (M+H)+, 486.1 (M+Na)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][CH2:13][CH:14]1[O:18][C:17](=[O:19])[N:16](C(OC(C)(C)C)=O)[CH2:15]1>O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][CH2:13][CH:14]1[O:18][C:17](=[O:19])[NH:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(COc2cccc(Cl)c2)OC1=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC(COc2cccc(Cl)c2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
4 ml of trifluoroacetic acid were added, whilst ice-cooling, to a solution of 1.97 g of 5-(3-chlorophenoxymethyl)-3-t-butoxycarbonyloxazolidin-2-one (prepared as described in Preparation 2) in 4 ml of anhydrous tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. At the end of this time, the tetrahydrofuran and trifluoroacetic acid were removed from the reaction mixture by evaporation under reduced pressure, to give 1.23 g of the title compound having an Rf value of 0.43 (on silica gel thin layer chromatography, using ethyl acetate as the developing solvent).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.S(OC(CC#C)C(=O)C)([C:19]1[CH:25]=[CH:24][C:22](C)=[CH:21][CH:20]=1)(=O)=O>C(O)C>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([C:19]([CH2:20][C:21]#[CH:22])=[C:25]([CH3:24])[N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: C#CCC(OS(=O)(=O)c1ccc(C)cc1)C(C)=O
Solvent: CCO
Product: C#CCc1c(C)nc2c(OCc3ccccc3)cccn12
Yield: 31 %

Procedure:
A solution of 2-amino-3-benzyloxypyridine (2 g) and 3-tosyloxy-5-hexyn-2-one (2.66 g) in ethanol (15 ml) was stirred and refluxed for 24 hours and then evaporated in vacuo. To the residue was added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (50 g) using chloroform as an eluent to give a solid, which was recrystallized from a mixture of methylene chloride and diethyl ether to give 8-benzyloxy-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (0.855 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)[N:20]=[C:19]([CH3:31])[N:18]=2>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:32][CH2:33][NH2:34])[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1)[N:20]=[C:19]([CH3:31])[N:18]=2
Reactant: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(CCNC(=O)OC(C)(C)C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(CCN)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Add trifluoroacetic acid (5 mL) to a solution of tert-butyl N-[2-[8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)purin-9-yl]ethyl]carbamate (0.51 g, 0.001 mol) in dichloromethane (5 mL) at 0° C. Allow the reaction to warm to room temperature and stir for 2 h. Quench the reaction mixture with saturated aqueous sodium bicarbonate solution and then extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give 2-[8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)purin-9-yl]ethanamine (0.39 g). ES/MS m/z 386 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:20]([Si:24]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)Cl)([CH3:23])([CH3:22])[CH3:21].C(Cl)(Cl)Cl>ClCCl>[O:1]([CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][OH:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCCC1(CCO)CCCCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[1-(2-hydroxyethyl)cyclohexyl]ethanol (6.41 g) in dichloromethane (170 mL) were added triethylamine (6.74 mL) and tert-butyldiphenylchlorosilane (11.1 mL) at room temperature. After stirring the solution at room temperature for 18 hours, chloroform was added to the solution, and it was washed in turn with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=85:15) to give the title compound (10.97 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[NH:28]1[CH2:31][CH2:30][CH2:29]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:28]1([C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:27])[CH2:31][CH2:30][CH2:29]1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
A mixture of 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 223 μmol), azetidine (60.2 μl, 893 μmol), propylphosphonic anhydride (50% in ethyl acetate, 329 μl, 558 μmol) and N,N-diisopropylethylamine (114 μl, 669 μmol) in tetrahydrofurane (7 ml) is stirred for 18 hours at room temperature. The solvent is evaporated and the residue triturated with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water and dried affording 4-(azetidine-1-carbonyl)-1-methyl-N-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (28 mg, 31.2%) as a light brown solid. mp.: 253-4° C. MS: m/z=403.4 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[O:19][N:18]=[C:17]([CH2:20][CH2:21][CH2:22][OH:23])[CH:16]=2)[CH:12]=[N:13][CH:14]=1.[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([C:15]2[O:19][N:18]=[C:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]=2)[CH:10]=1
Reactant: Oc1ccccc1
Reactant: CN1CCC[C@H]1COc1cncc(-c2cc(CCCO)no2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1cncc(-c2cc(CCCOc3ccccc3)no2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 154 %

Procedure:
To a solution of 3-[5-[5-[(1-methyl-2(S)-pyrrolidinyl)methoxy]-3-pyridyl]-3-isoxazolyl]-1-propanol (10 mg, 33 μmol), phenol (5 mg, 50 μmol, 1.5 equiv.) and PPh3 (13 mg, 50 μmol, 1.5 equiv.) in anhydrous THF (0.2 mL) was added diethyl azodicarboxylate (DEAD; 8 μL, 50 μmol, 1.5 equiv.) at 0° C. The mixture was stirred for 1 h at 0° C. and then warmed to room temperature. Stirring was continued for 11 h, then the mixture was concentrated in vacuo. The residue was purified by CC on SiO2 with CH2Cl2/MeOH 9:1 to give 3-[(1-methyl-2(S)-pyrrolidinyl)methoxy]-5-[3-(3-phenoxypropyl)-5-isoxazolyl]pyridine (20 mg, 51%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16]C=CC=3)N=2)=[CH:7][CH:6]=1.C(OC1C=CC(C(O)=O)=CC=1)C1C=CC=CC=1>>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([N:3]([O:2][CH3:1])[CH3:24])=[O:23])=[CH:10][CH:9]=1)[C:13]1[CH:22]=[CH:21][CH:20]=[CH:15][CH:16]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C(O)c1ccc(OCc2ccccc2)cc1
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Following the procedure for the preparation of N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide but substituting 4-benzyloxy benzoic acid provided the title compound as a waxy solid. MS: (M+H m/z=272.3).