Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([C:10]1[S:14][C:13]([NH2:15])=[N:12][N:11]=1)[CH2:6][CH2:7][CH2:8][CH3:9]>C(OCC)(=O)C>[CH2:5]([C:10]1[S:14][C:13]([N:15]=[C:1]=[O:2])=[N:12][N:11]=1)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCc1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-pentyl-2-amino-1,3,4-thiadiazole (40 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-pentyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=O)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[CH:4][CH:3]=1.[OH-:30].[Na+].S([O:37][CH3:38])(OC)(=O)=O>>[OH:30][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([C:8]3[CH:21]=[CH:20][C:38]([OH:37])=[CH:14][CH:9]=3)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C1c2ccccc2C(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Reactant: [OH-]
Agent: [Na+]
Product: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3C(c3ccc(O)cc3)(c3ccc(O)cc3)c3ccccc32)cc1

Procedure:
A mixture of 7.6 g 10,10-bis (p-hydroxyphenyl) anthrone, 10 ml alcohol, and 100 ml 10% sodium hydroxide solution was refluxed and 30 ml dimethyl sulfate was added gradually. It was heated for 1 h and the crystalline precipitate was recrystallized from acetic acid to give a white product. MP=208°-209° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[NH:23]=[C:22]1[N:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]2=[N:1][CH:15]=[C:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Nc1nccc2ccccc12
Solvent: CCO
Product: CCOC(=O)c1cnc2c3ccccc3ccn2c1=N
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
A mixture of 1-aminoisoquinoline (14.4 g., 0.10 mole) and ethyl ethoxymethylenecyanoacetate (16.9 g., 0.10 mole) was plunged into an oil bath at 105°-110° and lept there for 10 minutes under a nitrogen atmosphere. During this time the mixture melted, evolved ethanol and set solid. The solid was crystallized from toluene to give bright yellow crystals (18 g., 67% yield) of ethyl 4-imino-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate, m.p. 197°-199°. Another recrystallization from toluene provided an analytical sample, m.p. 199°-201°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][CH2:19][CH2:20][N:21]1[C@H:26]([CH3:27])[CH2:25][NH:24][CH2:23][C@@H:22]1[CH3:28])=[O:17].C=O.[C:31]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C.C(OCC)C>[NH3:3].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][CH2:19][CH2:20][N:21]1[C@H:26]([CH3:27])[CH2:25][N:24]([CH3:31])[CH2:23][C@@H:22]1[CH3:28])=[O:17]
Reactant: C[C@@H]1CNC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CC#N
Product: C[C@@H]1CN(C)C[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Product: N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
A solution of (2S)-1-(1,3-benzoxazol-2-yl)-N2-2-[(cis)-2,6-dimethyl-1-piperazinyl]ethyl-2-piperidinecarboxamide (108 mg) [see Example 8] and 37% aqueous formaldehyde (0.21 ml) in acetonitrile (3 ml) was added to sodium cyanoborohydride (86.5 mg), followed by glacial acetic acid (0.1 ml). The reaction mixture was stirred at room temperature for 1.5 hours, after which time glacial acetic acid (0.1 ml) was added, and the mixture was stirred for a further 30 minutes. Diethyl ether was added to the mixture and the organic layer was washed several times with 2N aqueous sodium hydroxide solution. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 97:3.5:0.5 changing to 97:3:1, by volume, dichloromethane:methanol:0.88 aqueous ammonia solution, to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-2-[(cis)-2,4,6-trimethyl-1-piperazinyl]ethyl-2-piperidinecarboxamide (53.1 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:19][NH:20][C@H:21]([C:23]([OH:25])=[O:24])[CH3:22].O.ON1C2C=CC=NC=2C=N1.CN1CCOCC1>O1CCCC1>[CH3:19][N:20]([C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1])[C@H:21]([C:23]([OH:25])=[O:24])[CH3:22]
Reactant: CN[C@@H](C)C(=O)O
Reactant: Nc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: On1ncc2ncccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: C[C@@H](C(=O)O)N(C)C(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1N
Reaction time: 8 h
Yield: 71.2 %

Procedure:
To a cooled (-5° C.) mixture of 20.0 parts of 2-amino-3-nitro-5-(trifluoromethyl)benzoic acid, 11.17 parts of methyl (S)-alanine monohydrochloride, 21.62 parts of 1-hydroxy-1H-1,2,4-benzotriazole monohydrate and 356 parts of tetrahydrofuran under argon there were added 8.1 parts of N-methylmorpholine and, after stirring for 10 min 16.5 parts of N,N-methanetetraylbis[cyclohexanamine]. Stirring was continued for 1 hour at -5° C. and overnight at room temperature. After cooling on ice, the reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane and this solution was washed with NaHCO3 (aq.), dried, filtered and evaporated. The residue was recrystallized from methylcyclohexane (2×), yielding 19.1 parts (71.2%) of methyl (S)-N-[2-amino-3-nitro-5-(trifluoromethyl)benzoyl]alanine; mp. 136.4° C. (interm. 33).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][OH:25])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][O:25][C:27](=[O:29])[CH3:28])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 60 °C
Yield: 91 %

Procedure:
0.50 g of N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) was added to a mixture of 0.47 ml of acetic anhydride and 0.39 g of pyridine, and the resulting mixture was heated at 60° C. for 2 hours. At the end of this time, the reaction mixture was poured into ice-water, after which a saturated aqueous solution of sodium hydrogencarbonate was added. The aqueous mixture was then extracted with chloroform. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and methylene chloride as the eluent, to give 0.51 g (yield 91%) of the title compound as an oil.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:23])[CH:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:23])[CH:15]([NH:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3]
Reactant: NCc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)C(Br)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C(NCc1ccccc1)c1ccccc1
Yield: 69.7 %

Procedure:
A solution of (±)-N-[2,6-bis(1-Methylethyl)phenyl]-α-bromobenzeneacetamide (4.3 g, 12 mmol), benzylamine (1.8 g, 18 mmol), and triethylamine (8.0 mL, 57 mmol) in toluene was refluxed (96 hours) then cooled and concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL), washed with water (2×100 mL), with saturated aqueous sodium bicarbonate (1×100 mL), with brine (1×100 mL), then dried (MgSO4) and concentrated to a solid. The solid was recrystallized from ethyl acetate/hexane to yield 3.35 g (72.8%) of the title compound as a white solid, mp 134°-137° C.
Reaction SMILES: C(Cl)(=[O:3])C.[C:5]1([CH:11]2[NH:15][CH2:14][CH:13]([CH2:16][Cl:17])[O:12]2)C=CC=CC=1.Cl>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:11]([NH:15][CH2:14][CH:13]([OH:12])[CH2:16][Cl:17])(=[O:3])[CH3:5]
Reactant: CC(=O)Cl
Reactant: ClCC1CNC(c2ccccc2)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)NCC(O)CCl
Temperature: 25 °C
Yield: 65 %

Procedure:
15.7 g of acetylchloride are added dropwise to a solution of 39.5 g of 2-phenyl-5-chloromethyloxazolidine in a mixture of 150 ml of chloroform and 16 ml of pyridine at a temperature of -40° C. under agitation. The solution is allowed to warm up to room temperature. After a reaction period of 14 hours, 100 ml of concentrated hydrochloric acid are added. After thoroughly mixing, the aqueous phase is separated and diluted with water to twice its volume and then is saturated with sodium chloride. By extracting the aqueous phase with methylene chloride, drying the methylene-chloride-extract and evaporating the solvent, 19.7 g of N-acetyl-3-chloro-1-aminopropan-2-ol is obtained as an oil which can be used in the following reaction without any purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[NH:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: OCCNCCO
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Product: OCCN(CCO)CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and diethanolamine were converted to yield 2-[{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-hydroxy-ethyl)-amino]-ethanol as colorless oil, MS: 390 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50]Br)=[CH:48][CH:47]=1>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1([CH2:50][C:49]2[CH:52]=[CH:53][C:46]([F:45])=[CH:47][CH:48]=2)[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccc(F)cc2)CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (10.5 g, 27.8 mmol), prepared as described by Bigge et al. (Tetrahedron Let. 1989, 30, 5193), in tetrahydrofuran (200 mL) under a nitrogen atmosphere was added N,N-dimethylformamide (30 mL). The reaction was cooled to about −78° C., and a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (83 mL, 42 mmol) was added. The reaction was stirred at about −78° C. for about 1 hour, and then 4-fluorobenzyl bromide (5.2 mL, 42 mmol) was added. The reaction was stirred for about 1 hour more at about −78° C., then warmed to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were extracted twice with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product as a yellow oil. Purification by silica gel chromatography using 0-20% ethyl acetate/hexanes as eluent afforded the title compound of part 1-A (8.54 g, 63%) as a colorless oil: +APcI MS (M−Boc+H)+ 387; 1H NMR=400 MHz (CDCL3) δ: 7.45-7.30 (arom, br s, 5H), 7.00-6.80 (arom, br m, 4H), 5.35-5.05 (br m, 2H), 2.53 (br t, 1H), 1.40 (Boc, s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].CCCCCC.C([Li])CCC.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>C(OCC)C>[CH3:23][Si:22]([CH3:25])([CH3:24])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccc(C)c(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc(C)c([Si](C)(C)C)c1
Reaction time: 5 h

Procedure:
To a stirred solution of 1.0M of 2-bromo-p-xylene in diethyl ether at 0° C. was added n-butyllithium hexane solution solwly, and the mixture was stirrd for 5 hr. To the above reaction mixture was added 1.0M of chlorotrimethylsilane as dropwise and it was stirred for 24 hr. The solvent was removed under reduced pressure, and the residne was redistilled in vacuo to afford titled compound(TSTX) in colorloss state. The structure of product was identified by infrared and nuclear magnetic resonance spectrum, and the result is summarized in Table 1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]([NH:30][CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)[C:9]2[C:4](=[C:5]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1cc(C)c(-c2cccc3c(Cl)cc(C)nc23)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(-c2cccc3c(NCCN4CCOCC4)cc(C)nc23)c(C)c1
Temperature: 100 °C
Yield: 39.8 %

Procedure:
Part C: To a solution of 5.1 g (17.1 mmol) of 2-methyl-4-chloro-8-(2,4,6-trimethylphenyl)-quinoline and 2.68 g (20.6 mmol) of 2-morpholinoethylamine in 150 ml of toluene, after bubbling through nitrogen gas for 30 minutes, a quantity of 2.29 g (23.9 mmol) sodium tertiary butoxide, 0.16 g (0.26 mmol) of 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (BINAP) and 0.082 g (0.09 mmol) Pd2(dibenzylideneacetone)3 were subsequently added. After heating to 100° C. for 16 hours and subsequent cooling, the reaction mixture was filtered and concentrated in vacuo. The product was purified on a silicagel column using CH2Cl2/MeOH/NH4OH 93:7:0.5 as the eluent. A total of 2.65 g of 2-methyl-4-(N-2-morpholinoethyl)amino-8-(2,4,6-tri-methylphenyl)-quinoline was obtained (40% yield).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]([NH:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[C:8]([NH:10][CH:11]([C:13]1[N:18]=[N:17][C:16]([NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[N:15][CH:14]=1)[CH3:12])=O)=[O:4].P(Cl)(Cl)(Cl)=O>ClCCCl>[F:1][C:2]([F:37])([F:36])[C:3]([NH:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[C:8]1[N:18]2[C:13]([CH:14]=[N:15][C:16]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)=[N:17]2)=[C:11]([CH3:12])[N:10]=1)=[O:4]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3NC(=O)C(F)(F)F)nn2)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4NC(=O)C(F)(F)F)n3n2)cc(OC)c1OC
Yield: 10.4 %

Procedure:
In a similar manner as described for Example 1, 2-[(trifluoroacetyl)amino]-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 16) (0.118 g, 0.23 mmol) in 1,2-dichloroethane (30 mL) and phosphorus oxychloride (1.0 mL, 11 mmol) gave 2,2,2-trifluoro-N-(2-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)acetamide (0.012 g) as a yellow solid. 1H NMR (CDCl3): δ13.87 (s, 1H), 8.91 (dd, J=8.0, 1.4 Hz, 1H), 8.88 (s, 1H), 8.63 (dd, J=8.4, 1.1 Hz, 1H), 7.47-7.41 (m, 1H), 7.28-7.22 (m, 1H), 7.08 (s, 1H), 6.86 (s, 2H), 3.85 (s, 3H), 3.80 (s, 6H), 2.60 (s, 3H). MS m/z 503 (M+1).
Reaction SMILES: [CH2:1](O)[CH3:2].[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[SH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:8]([S:4][C:5]1[S:13][C:2]2[CH:1]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH3:9]
Reactant: CCO
Reactant: Sc1nc2ccccc2s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCSc1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
Ethyl alcohol (0.63 mL, 10.8 mmol), 2-benzothiazolethiol (2.0 g, 11.9 mmol) and triphenylphosphine (3.1 g, 11.9 mmol) were dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. Then added diisopropylazadicarboxylate (2.3 mL, 11.9 mmol) and continued stirring for 1 hr. Upon completion, the reaction mixture was dried in vacuo, filtered through a plug of silica with 5% ethyl acetate in hexane and dried in vacuo again to yield 2-(ethylthio)-1,3-benzothiazole (2.2 g, HPLC RT=3.05 min.). LC-MS m/z=196.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:40])[CH3:39])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][C:19]4([CH:32]([CH3:34])[CH3:33])[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].ClC1[N:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:58]=[CH:57][N:56]=1>ClCCl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:39])[CH3:40])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][C:19]4([CH:32]([CH3:33])[CH3:34])[CH2:24][CH2:23][N:22]([C:25]5[N:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:58]=[CH:57][N:56]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C(C)C)CCN(C(=O)OC(C)(C)C)CC4)cc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C(C)C)CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of tert-butyl 4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)-4-isopropylpiperidine-1-carboxylate (35 mg, 0.064 mmol) in dichloromethane was added trifluoroacetic acid. The mixture was stirred overnight at room temperature and then concentrated in vacuo. To the residue were added of methanol (2 ml), potassium carbonate (45 mg, 0.326 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (16 μl, 0.133 mmol). The mixture was heated to 50° C. and stirred at this temperature for 4 h, at which point LC/MS analysis showed a peak at the desired molecular weight. The reaction mixture was concentrated and then purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (33 mg, 0.056 mmol, 87% yield). Mass spectrum (ESI) 591.1 (M+1). 1H NMR (500 MHz, CDCl3): 8.47 (d, J=4.5 Hz, 1H), 8.33 (d, J=8.5 Hz, 1H), 7.93 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.51 (s, 1H), 6.71 (d, J=5.0 Hz, 1H), 6.18 (br t, J=6.0 Hz, 1H), 4.18 (m, 2H), 3.65-3.75 (m, 4H), 3.47 (septet, J=7.0 Hz, 1H), 1.89 (septet, J=6.5 Hz, 1H), 1.70 (m, 2H), 1.50-1.60 (m, 2H), 1.46 (d, J=6.5 Hz, 6H), 1.02 (d, J=7.0 Hz, 6H).
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[C:18]([Cl:25])[CH:17]=1.Cl.Cl.[NH2:28][OH:29]>O>[Cl:25][C:18]1[CH:17]=[C:16]([NH:15][C:3](=[O:5])[CH:2]=[N:28][OH:29])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: NO
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
To a solution of chloral hydrate (1.0 g, 6.00 mmol; Spectrum Quality Products, Inc., New Brunswick, N.J.) and water (80 mL) was added sodium sulfate (5 g), 4-amino-2-chloro-benzoic acid (855 mg, 4.98 mmol; Acros), concentrated aq. HCl (5 mL) and hydroxylamine hydrochloride (1.15 g, 16.5 mmol; Aldrich). It was refluxed for 20 minutes. The mixture was cooled to rt, the precipitate was filtered and washed with water. The title compound (1.08 g, 90%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Br)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:18]([C:25]1([OH:31])[CH2:30][CH2:29][N:28]([CH2:15][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)=[O:17])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CBr)Nc1ccc(C2CCCCC2)cc1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(CN1CCC(O)(Cc2ccccc2)CC1)Nc1ccc(C2CCCCC2)cc1
Reaction time: 1 h

Procedure:
A mixture of N-(4-cyclohexyl-phenyl)-2-bromoacetamide (29.6 mg, 0.10 mmol), 4-benzyl-4-hydroxypiperidine (19.1 mg, 0.10 mmol), and potassium carbonate (13.8 mg, 0.1 mmol) in dimethyl sulfoxide (1.0 mL) was stirred 1 hour. The mixture was filtered through a short pad of Celite in a pasteur pipet TLC Rf 0.21 (silica gel, 50:50 hexane/ethyl acetate), 0.14 (reverse phase, 80:20 methanol/water); HPLC: 5.89 min (C18 Cartridge column (Perkin Elmer/PE Xpress #0258-0164) 20:80 Acetonitrile/water to 95:5 acetonitrile/water); LC-MS: 407 (M+H+). The filtrate was tested directly in the in vitro biological assays.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][CH:31]=[CH:30][C:6]=1[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)=O.[O-:34][C:35]#[N:36].[Na+]>C(O)(=O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][CH:31]=[CH:30][C:6]=1[CH2:7][N:8]1[C:9]2[C:10](=[CH:11][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:13][CH:14]=2)[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[N:36][C:35]1=[O:34]
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCc2ccccc2OCCO)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1OCCO
Reaction time: 2 h

Procedure:
To a solution of 85 mg (0.192 mmol) {2-[2-(2-Hydroxy-ethoxy)-benzylamino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanone in 2 ml acetic acid is added 25 mg (0.383 mmol) sodium cyanate. After stirring for 2 h the solvent is removed in vacuo and the residue is partitioned between CH2Cl2 and water. The organic layer is extracted with 2 M sodium hydroxide solution. After evaporation of the organic phase the product is obtained as a yellow oil.