Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][NH:13][C:12]2=[O:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:17]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:21]([O:20][C:18]([CH:17]([N:13]1[CH2:14][CH:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:15])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cc1ccccc1)NC1CNC1=O
Reactant: O=C(OCc1ccccc1)C(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)NC1CN(C(C(=O)OCc2ccccc2)c2ccccc2)C1=O

Procedure:
3-(2-Phenylacetamido)-2-azetidinone (816 mg.) and benzyl 2-bromo-2-phenylacetate (1.22 g.) were dissolved in N,N-dimethylformamide (20 ml.), and to the solution was added sodium hydride (50% oily) (210 mg.) in nitrogen atmosphere under ice-cooling while stirring, and then the reaction mixture was stirred for an hour at the same temperature. Ethyl acetate (150 ml.) was added to the reaction mixture, and the solution was washed with water, a sodium bicarbonate-saturated-aqueous solution and water respectively, and then dried over anhydrous magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give the yellow oily material (1.7 g.). The material was subjected to column chromatography using silica.gel (developer: chloroform) to give two isomers of 1-(α-benzyloxycarbonylbenzyl)-3-(2-phenyl)acetamido-2-azetidinone. Yield of the isomer A is 26 mg. and it of the isomer B is 65 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(S(C)=O)nc21
Reactant: CN1CCN(CCCCN)CC1
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(NCCCCN3CCN(C)CC3)nc21
Yield: 41 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1253 g (0.732 mmol) of 4-(4-methyl-piperazin-1-yl)-butylamine were reacted. The residue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v), to give 0.0527 g (41%) of the title compound: HPLC=94% pure.
Reaction SMILES: N1C=CN=C1.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([Br:15])[CH:14]=1)[CH2:10][OH:11].[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([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>CN(C=O)C.C(OCC)(=O)C>[C:29]([Si:16]([O:11][CH2:10][C:9]1[CH:8]=[C:7]([Br:6])[CH:14]=[C:13]([Br:15])[CH:12]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: OCc1cc(Br)cc(Br)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1cc(Br)cc(Br)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
With stirring, imidazole (1.1 g, 16.0 mmol) is added to a solution of 3,5-dibromobenzyl alcohol (2.8 g, 10.5 mmol) in absolute DMF (20 ml), and the mixture is cooled to 0° C. tert-Butyldiphenylsilyl chloride (3.3 ml, 17.8 mmol) is added dropwise to the reaction solution, which is then stirred at 0° C. for 2 h. The mixture is then warmed to RT and stirred for another 2 h. The reaction mixture is diluted with ethyl acetate (20 ml) and extracted with a semisaturated aqueous NH4Cl solution (20 ml). The organic phase is dried over MgSO4, filtered off and concentrated under reduced pressure. Further purification is carried out by chromatography [PE/EA (99:1)] on a silica gel column. This gives the title compound (5.0 g) as a colorless solid. TLC, silica gel (glass plates), [petroleum ether/ethyl acetate (99:1)], Rf=0.8.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:13])[O:11][CH:12]=2)=[C:4]([F:14])[CH:3]=1.[C:15]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)(=[O:22])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[NH2:13][C:10]1[O:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[C:23]([S:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:21])=[O:22])=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:3][C:4]=2[F:14])[N:9]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: Nc1nc(-c2ccc(Br)cc2F)co1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2coc(N)n2)c(F)c1

Procedure:
The title compound was prepared using methods described in Example 427 using 4-(4-bromo-2-fluorophenyl)oxazol-2-amine and (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd. for C19H20FN3O3S, 389.12; m/z found, 390.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, J=7.9, 1.4, 1H), 7.98 (m, 1H), 7.66 (d, J=4.2, 1H), 7.57 (m, 1H), 7.54-7.48 (m, 1H), 7.38-7.30 (m, 3H), 4.63 (s, 2H), 3.64 (s, 1H), 1.03 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][C:15]#[N:16].[C:17](#[N:19])[CH3:18]>>[N:1]1([CH2:18][C:17]#[N:19])[CH2:6][CH2:5][N:4]([CH2:14][C:15]#[N:16])[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: N#CCBr
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#CCN1CCN(CC#N)CC1

Procedure:
To a solution of piperazine (6 g, 69.77 mmol, 1.00 equiv) in acetonitrile (150 mL) was added potassium carbonate (19.2 g, 139.13 mmol, 2.00 equiv) and the mixture was stirred. To this was added dropwise a solution of 2-bromoacetonitrile (16.7 g, 140.34 mmol, 2.00 equiv) in acetonitrile (100 mL) and the suspension was stirred for 4 h at room temperature. The solids were filtered out and the resulting solution was concentrated under vacuum. The crude product was purified by re-crystallization from methanol resulting in 7.75 g (68%) of Intermediate 50.1 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([CH3:14])[CH2:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:26][CH3:27])=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([CH3:14])[CH2:10][N:11]2[S:22]([C:20]2[CH:21]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:26][CH3:27])(=[O:23])=[O:24])=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)NCC2C
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CC2C

Procedure:
3-Methyl-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester was reacted with 5-chloro-2-methoxybenzenesulfonyl chloride in analogy to example 34, step 2, yielding 1-(5-chloro-2-methoxy-benzenesulfonyl)-3-methyl-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester. Off-white solid, MS (ISP): m/e 395.9 (M+H).
Reaction SMILES: N[CH:2]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1=[O:20].C(O)(=[O:23])C.N(OC(C)(C)C)=O.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH2:18]([O:17][C:15]([CH2:14][N:4]1[C:5]2=[CH:13][CH:12]=[CH:11][CH2:10][CH:6]2[CH2:7][CH2:8][CH2:9][C:2](=[O:23])[C:3]1=[O:20])=[O:16])[CH3:19]
Reactant: CC(=O)O
Reactant: CCOC(=O)CN1C(=O)C(N)CCCc2ccccc21
Agent: CC(C)(C)ON=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN1C(=O)C(=O)CCCC2CC=CC=C21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-amino-1-ethoxycarbonylmethyl-3,4,5,6-tetrahydro-1-benzazocin-2-(1H)-one (8.0 g), acetic acid (0.4 ml), and t-butyl nitrite (4.2 ml) is dissolved in chloroform (150 ml) and the solution is refluxed for 2 hours then cooled to room temperature. m-Chloroperbenzoic acid (5.7 g) is added in portions, and the resulting solution stirred at room temperature for 30 minutes. The solution is washed with saturated aqueous sodium bicarbonate (120 ml), water (75 ml), 2N hydrochloric acid (50 ml), water (50 ml), 2N hydrochloric acid (50 ml), and water (50 ml). The solution is dried over magnesium sulfate and the solvent removed under reduced pressure to give 1-ethoxycarbonylmethyl-tetrahydro-1-benzazocin-2,3(1H)-dione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2Cl)=O)[NH:5][CH:6]=1.O.[NH2:20][NH2:21]>C1(C)C=CC=CC=1.CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[C:9]3[C:10](=[CH:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=3)[NH:21][N:20]=2)[NH:5][CH:6]=1
Reactant: NN
Reactant: O=C(c1cc(Br)c[nH]1)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2[nH]nc(-c3cc(Br)c[nH]3)c2c1
Temperature: 110 °C

Procedure:
A mixture of (4-bromo-1H-pyrrol-2-yl)-(2-chloro-5-nitro-phenyl)-methanone (400 mg) and hydrazine hydrate (0.4 mL) in toluene (6 mL) and 1-methyl-2-pyrrolidinone (1.5 mL) was heated at 110° C. for 1 hour. The reaction was concentrated, the residue was triturated with 10% ethyl acetate in DCM to give 210 mg of the titled compound as an orange solid.
Reaction SMILES: C([N:4]1[C:17]2[C:12]3=[C:13]([C:18](=[O:28])[C:19]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:20][N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=3)[CH:14]=[CH:15][CH:16]=2)(=O)C.N1CCCCC1>C(O)C>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][C:19]2[C:18](=[O:28])[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:12]=3[N:11]([CH:20]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4]4)[CH:23]=1
Reactant: CC(=O)N1c2ccccc2-n2cc(Cc3cccnc3)c(=O)c3cccc1c32
Solvent: CCO
Solvent: C1CCNCC1
Product: O=c1c(Cc2cccnc2)cn2c3c(cccc13)Nc1ccccc1-2
Yield: 26 %

Procedure:
The compound (500 mg) obtained in Example 9 was suspended in ethanol (20 mL) and to the suspension was added piperidine (2 mL). The mixture was heated under reflux for 30 hours under an argon atmosphere and allowed to cool. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate =1:1) to obtain the title compound (115 mg; 26%)
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)=[O:4].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[Si:18]([O:1][CH2:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)=[O:4])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=C(CO)c1ncn2ccsc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
7-Hydroxyacetylimidazo[5,1-b]thiazole (1.42 g) was dissolved in 10 ml of DMF. Imidazole (847 mg) and 1.77 g of t-butyldimethylsilyl chloride were added to the solution in an argon atmosphere. The mixture was stirred at room temperature for 24 hr. Brine was added to the reaction solution, followed by extraction twice with ethyl acetate. The organic layers were combined together, washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 2.19 g of 7-t-butyldimethylsilyloxyacetylimidazo[5,1-b]thiazole.
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][CH3:3].O.[NH2:9][NH2:10].C(S[C:14]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[N:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23])C>C(O)CCC>[CH3:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=1[N:15]1[C:14]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[N:10][N:9]=[C:1]1[CH2:2][CH3:3]
Reactant: CCOC(=O)CC
Reactant: CCSC(=Nc1c(C)cccc1C)c1ccc(F)cc1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CCc1nnc(-c2ccc(F)cc2)n1-c1c(C)cccc1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 11 %

Procedure:
First, 1.80 g of ethyl propionate, 10 mL of 1-butanol, and 0.88 g of hydrazine monohydrate (NH2NH2.H2O) were put in a 100 mL three-neck flask, and heated and stirred at 80° C. for 5 hours to be reacted. Then, 5.0 g of N-[(ethylsulfanyl)(4-fluorophenyl)methylidene]-2,6-dimethylaniline was added to this mixed solution, and heated and stirred at 130° C. for 22 hours to be reacted. Further, a solution obtained by heating and stirring 0.90 g of ethyl propionate, 5 mL of 1-butanol, and 0.44 g of hydrazine monohydrate at 80° C. for 3 hours to be reacted was added to the above mixed solution, and the mixed solution was heated and stirred at 130° C. for 8 hours to be reacted. After the reaction, 1-butanol was distilled off under a reduced pressure. The resulting residue was purified by silica gel column chromatography. Ethyl acetate was used as a developing solvent. The resulting fraction was concentrated to give a solid. This solid was recrystallized from a mixed solvent of toluene and hexane, so that 4-(2,6-dimethylphenyl)-3-ethyl-5-(4-fluorophenyl)-4H-1,2,4-triazole (abbreviation: HEFptz-dmp) was prepared (a white solid, yield: 11%). The synthetic scheme of Step 1 is shown by (a-9).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]CC)[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]CC)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][P:94](=[O:101])([O:98][CH2:99][CH3:100])[O:95][CH2:96][CH3:97]>C(Cl)Cl>[CH2:99]([O:98][P:94]([CH2:93][CH2:92][O:91][CH2:90][CH2:89][O:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][NH:82][C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:101])[O:95][CH2:96][CH3:97])[CH3:100]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)NCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio) propanoic acid (1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq, from example 18, step 4). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford the title compound as an opaque oil.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[N:26]=2)[N:4]=1)[CH3:2].FC(F)(F)C(O)=O.[Cl:52]CCl>>[ClH:52].[ClH:52].[ClH:52].[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]3)[N:26]=2)[N:4]=1)[CH3:2]
Reactant: ClCCl
Reactant: CCc1nn(Cc2ccn(CCN3CCN(C(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Solvent: O=C(O)C(F)(F)F
Product: CCc1nn(Cc2ccn(CCN3CCNCC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Product: Cl
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(2-(3-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate (21.5 mg; 0.0360 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of methanol and dichloromethane. Ammonium hydroxide solution was added to neutralize. The material was purified by preparative thin layer chromatography on silica, eluting with 15% methanol in dichloromethane containing 0.5% ammonium hydroxide solution. The isolated product was dissolved in a mixture of methanol and ethyl acetate and treated with hydrogen chloride (1 mL; 2M in ether). Removal of solvent under reduced pressure followed by high vacuum gave N-(3-ethyl-1-((1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide trihydrochloride (9.5 mg). MS (APCI), positive scan, m/z=498.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([OH:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl>[Si:16]([O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:12]=[CH:11]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2ccc(C(F)(F)F)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C(F)(F)F)nc12
Yield: 101.3 %

Procedure:
A solution of 2-trifluoromethylquinolin-8-ol (11.5 g), tert-butyldimethylsilyl chloride (8.9 g) and triethylamine (6.5 g) in dichloromethane (60 ml) was stirred overnight at room temperature. The reaction mixture was washed with water (2×50 ml), dried over sodium sulfate, filtered and the solvent removed in vacuo to give the product (17.9 g) as a white solid
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([O:34][P:35]([O-:39])[O:36][CH2:37][CH3:38])[CH3:33]>C1C=CC=CC=1.CO>[C:1]([C:5]1[CH:6]=[C:7]([C:8]2[C:22]([CH2:23][NH:18][CH2:19][P:35](=[O:39])([O:36][CH2:37][CH3:38])[O:34][CH2:32][CH3:33])=[CH:21][CH:20]=[CH:24][N:25]=2)[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: NCc1cccnc1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CO
Product: CCOP(=O)(CNCc1cccnc1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)OCC
Yield: 66.7 %

Procedure:
A mixture of 5.0 g (21.4 mmol) of 3,5-di-t-butyl-4-hydroxy benzaldehyde, 2.34 g (21.6 mmol) of 3-picolylamine and 6.0 g (42.8 mmol) anhydrous potassium carbonate in 50 ml benzene was refluxed for one day. The potassium carbonate was filtered and the solvent was evaporated. The residue was heated at 140° C. with 3.0 g (21.6 mmol) of diethylphosphite for 3 h. An amount of 6.6 g of compound was isolated by column chromatography (95/5 CHCl13 /MeOH), which gave 5.9 g (60%) after recrystallization in petroleum ether; mp=100°-101 ° C. IR (film): 3650 cm-1 :OH, 3300 (large): NH, 1430: tert-Bu, 1230: P=O, 1030: P--O--C, NMR (CDCl3): δ=8.50, 7.65 and 7.25 (3 m, 4H): aromatic H, 3-picolyl 7.20 (d, JP-H =2 Hz, 2H): aromatic H, 3,5-di-butyl-4-hydroxyphenyl 5.25 (s, 1H): OH 4.08, 3.94 and 3.80 (3m, 4H): P--O--CH2CH3 3.91 (d, JP-H =19 Hz, 1H): CH--PO3Et2 3.81 and 3.61 (2d, J=13 Hz, 2H): NH--CH2 --Py 2.20 (broad): NH-, 1.45 (s, 18H): tert-Bu 1.30 and 1.10 (2t, J=7 Hz, 6H): P--O--CH2CH3MS: m/e=462: M+, 324:M+ --HPO3Et2 (base peak) Elemental analysis C25H39N2O4P % Calc C 64.91 H 8.50 N 6.06 P 6.70 % Found C 64.83 H 8.70 N 5.88 P 6.45
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7]([OH:9])=O.[CH3:14][N:15]([CH3:31])[CH:16]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7]([NH:30][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([N:18]3[CH2:19][CH2:20][CH:16]([N:15]([CH3:31])[CH3:14])[CH2:17]3)[S:22][C:23]=2[CH:29]=1)=[O:9]
Reactant: O=C(O)COc1ccc(Cl)c(Cl)c1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)COc4ccc(Cl)c(Cl)c4)cc3s2)C1

Procedure:
Prepare according to the procedures described in Example 1, step 4, Method B, using 3,4-dichlorophenoxyacetic acid (135 mg, 0.611 mmol) and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (162 mg, 0.618 mmol) to afford the title compound, mass spectrum (m/e): 465 [M+H], 463 [M−H].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]2[CH2:17][C:18]([CH2:20][CH:13]1[CH2:14][CH2:15]2)=O.P(=O)(O)(O)O.[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH2:17][CH:16]4[N:12]([CH3:11])[CH:13]([CH2:14][CH2:15]4)[CH:20]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: Fc1ccc2cc[nH]c2c1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1C2C=C(c3c[nH]c4cc(F)ccc34)CC1CC2
Temperature: 62.5 °C
Yield: 9.4 %

Procedure:
A solution of 2.0 gm (14.8 mMol) 6-fluoroindole in 50 mL acetic acid was heated to 55° C. and vigorously deoxygen-ated with nitrogen. To this reaction mixture were then added 4.12 gm (29.6 mMol) tropinone and 12.3 mL 2N phosphor-ic acid. The resulting mixture was heated at 60-65° C. for 24 hours. The reaction mixture was cooled to room temperature and then poured into ice containing about 300 mL acetic acid. The pH of this mixture was then adjusted to about 8 by the addition of 50% aqueous NaOH. The resulting mixture was extracted well with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of dichlorometh-ane containing 30% dichloromethane saturated with ammonia and from 1-15% methanol. Fractions containing product were combined and concentrated under reduced pressure. The solid residue was crystallized from ethanol to provide 0.358 gm (9.44%) of the title compound as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:7][NH:6][C:5]1=[S:14].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:29])=[C:20]([C:22]2[O:26][N:25]=[C:24]([CH2:27]Cl)[N:23]=2)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CC#N>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:29])=[C:20]([C:22]2[O:26][N:25]=[C:24]([CH2:27][S:14][C:5]3[N:4]([CH2:3][CH2:2][OH:1])[C:8]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[N:7][N:6]=3)[N:23]=2)[CH:21]=1
Reactant: Fc1ccc(Cl)cc1-c1nc(CCl)no1
Reactant: OCCn1c(-c2cccs2)n[nH]c1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: OCCn1c(SCc2noc(-c3cc(Cl)ccc3F)n2)nnc1-c1cccs1
Yield: 62.7 %

Procedure:
4-(2-Hydroxyethyl)-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (101 mg), 5-(5-chloro-2-fluorophenyl)-3-(chloromethyl)-1,2,4-oxadiazole (116 mg), and potassium carbonate (86 mg) was stirred in a mixture of DMF (2 ml) and MeCN (15 ml) at r.t. for 3 h before concentration to dryness and washing of the residue with water, and then with EtOAc, to provide 122 mg of the title compound as a white solid.