Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:21])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1>CN(C=O)C>[F:31][C:32]1[CH:33]=[CH:34][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH3:10])[CH2:8][CH2:9]3)=[O:21])[CH2:40][CH2:39]2)=[CH:36][CH:37]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(COC(=O)N2CCN(c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.8 %

Procedure:
(1-Methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 1; 4.99 g, 16.9 mmol) was dissolved in DMF (40 mL). DIPEA (5.90 mL, 33.9 mmol) and 4-(4-fluoro-phenyl)piperazine (3.21 g, 17.8 mmol) were added. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was dissolved in EtOAc (400 mL) and then washed sequentially with 1 M aq NaOH solution (6×150 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and methyl isocyanate resin (1.0 g) was added. The reaction mixture was shaken for 14 h, filtered and then concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (0.67 g, 11.8%) as a pale yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]1[CH2:24][C:23]2([CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[O:22][CH2:21][CH2:20]1)=[O:18]>C(Cl)Cl>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]1[CH2:24][C:23]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)c1nc3ccccc3s1)CCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1nc2ccccc2s1)N1CCOC2(CCNCC2)C1
Reaction time: 0.42 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 4-(benzo[d]thiazole-2-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 106, step a) (0.83 g) in DCM (15 mL) and the resulting mixture was stirred for 25 minutes. The solvent was evaporated in vacuo. The residue was dissolved in DCM:methanol (1:1) (5 mL) and applied to a SCX cartridge pre-wetted with DCM:methanol (1:1). The cartridge was washed with methanol (60 mL) and eluted with 2M ammonia in methanol solution (40 mL). The eluent was evaporated in vacuo to give the subtitled compound as a colourless oil. Yield 0.57 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].C1CCC(N=C=NC2CCCCC2)CC1>CC#N>[C:31]1(=[O:36])[N:30]([N:24]([C:22](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:25][C:26]([OH:28])=[O:27])[C:34](=[O:35])[CH2:33][CH2:32]1
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)O)N1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 67.6 %

Procedure:
To a solution of acid 58 (887 mg, 2.20 mmol) in dry MeCN (11 mL) at 0° C. was added N-hydroxysuccinimide (278 mg, 2.42 mmol) and DCC (499 mg, 2.42 mmol). After stirring for 4.5 h at 0° C., the reaction mixture was filtered, solids were washed with several small portions of MeCN and the combined filtrates were concentrated to dryness. The crude product was purified by flash chromatography on a Biotage™ flash chromatography system, using a gradient of 60-75% EtOAc in CH2Cl2 as eluent. Evaporation of pure fractions yielded compound 59 (744 mg, 68%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 1.35-1.53 (m, 3H), 1.44 (s, 18H), 1.61-1.71 (m, 2H), 1.83-1.92 (m, 1H), 2.85 (s, 4H), 3.07-3.13 (m, 2H), 4.10-4.15 (m, 1H), 4.40 (d, J=5.7 Hz, 2H), 4.62 (bs, 1H), 5.16 (bs, 1H), 6.86 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:13][C:14]([O:16]C)=O)[C:6]2=[N:11]O.[H][H]>CO.C(O)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]1[CH2:13][C:14](=[O:16])[NH:11][CH:6]12
Reactant: [H][H]
Reactant: COC(=O)CC1Cc2c(Cl)cccc2C1=NO
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CC2Cc3c(Cl)cccc3C2N1
Yield: 40.7 %

Procedure:
Methyl 4-chloro-1-hydroxyimino-2,3-dihydro-inden-2-acetate (15 g) is hydrogenated at 40 atm of hydrogen in 200 ml of methanol plus 50 ml of acetic acid in the presence of 1.5 g of platinum oxide catalyst at 30°-50° C. for 7 hours. The catalyst is then filtered off, and the filtrate is concentrated. The residual oil is extracted with chloroform. The extract is washed with aqueous potassium carbonate solution, then with water and dried over sodium sulfate, and the solvent is distilled off. The residue is heated on an oil bath at 110°-120° C. for 2 hours. After cooling, ether is added, and the precipitated crystals are collected by filtration and recrystallized from ether to give 5 g of 5-chloro-1,2,3,3a,4,8b-hexahydro-indeno[1,2-b]pyrrol-2-one, melting at 186°-187° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH2:11][F:12])[S:8][C:4]=2[CH:3]=1.[CH3:15][N:16]([C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][CH2:11][CH2:10][NH:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([C:27]3[CH:26]=[CH:25][C:24]([N:16]([CH3:15])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:29][CH:28]=3)[CH:14]=[CH:13][C:5]=2[N:6]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FCCNc1nc2ccc(Br)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2ccc3nc(NCCF)sc3c2)cc1
Temperature: 100 °C

Procedure:
A mixture of afford 6-bromo-N-(2-fluoroethyl)benzo[d]thiazol-2-amine (55 mg, 0.2 mmol), tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (66 mg, 0.2 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in 2 mL dioxane and 0.5 mL of a 1 M Na2CO3 aqueous solution was heated at 100° C. in a microwave reactor for 10 min. After cooling to rt, it was diluted with EtOAc (30 mL) and washed with brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified with silica chromatography (5% to 30% EtOAc in hexane) to afford tert-butyl 4-(2-(2-fluoroethylamino)benzo[d]thiazol-6-yl)phenyl(methyl)carbamate as a clear wax (25 mg, 31%). MS (ESI) m/z 402 (M+H+).
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH:8]=[N:9]O)[CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1
Reactant: ON=Cc1cc(O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: N#Cc1cc(Cl)ncn1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-Hydroxy-pyrimidine-4-carbaldehyde oxime (9.3 g, 67 mmol) was stirred in 37 ml POCl3 under N2 at 40° C. for 30 min, 60° C. for 30 min, and 80° C. for one h. N,N,-Dimethylaniline was added very slowly by syringe, and stirred for one h at 80° C. After cooling to 0° C., the mixture was poured into a separatory funnel containing 300 g of ice. The mixture was carefully swirled, then extracted with 500 ml t-BuOMe. The organic layer was washed with 1 N HCl (4×100 ml), then several times with NaHCO3, then brine. Acidic and basic aqueous layers were separately back-extracted with t-BuOMe, and the organics again washed with 1 N HCl, saturated aqueous NaHCO3, and brine. The combined organic layers were dried with Na2SO4 and concentrated by rotary evaporator. The residue was filtered through a pad of silica gel, applying in CH2Cl2 and eluting with 10:1 hexanes/t-BuOMe. Fractions were carefully concentrated to obtain 6-chloro-pyrimidine-4-carbonitrile as a (volatile) pale yellow, semi-crystalline solid.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]3[CH:40]=[CH:39][C:35]4[O:36][CH2:37][O:38][C:34]=4[CH:33]=3)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].FC(F)(F)C(O)=O>O.C(#N)C>[C:1]1([CH2:7][NH:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]3[CH:40]=[CH:39][C:35]4[O:36][CH2:37][O:38][C:34]=4[CH:33]=3)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NCc2ccccc2)c1)c1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NCc2ccccc2)c1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 410.3 %

Procedure:
The compound of Example 121 (400 mg, 0.094 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to result in a white solid (200 mg). MS and 1H-NMR were consistent with the proposed structure.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([NH2:13])=[CH:5][CH:4]=[C:3]3[CH2:2]1.C(N(CC)CC)C.[C:21]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([NH:13][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=2)=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: Nc1ccc2c3c(cccc13)CC2
Reactant: CC(C)(C)c1ccc(CBr)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(CNc2ccc3c4c(cccc24)CC3)cc1
Temperature: 4 °C

Procedure:
A mixture of 5-acenaphthylamine (1.0 g, 6 mmol) and triethylamine (0.76 g, 7.5 mmol) in toluene (50 mL) was stirred at 4° C., and 4-tert-butylbenzyl-bromide (1.36 g, 6 mmol) was added in slowly. The reaction mixture was stirred at 23° C. for 15 hours and precipitates formed. The precipitates (triethylamine.HBr) were filtered out; the filtrate was concentrated to dryness. Then the crude reaction mixture was purified by column chromatography (SiO2, hexane/CH2Cl2=5/1). N-(5-acenaphthyl)-4-tert-butylbenzylamine (1.67 g, an oil) was obtained.
Reaction SMILES: [CH3:1][C:2]([NH2:16])([CH3:15])[CH2:3][NH:4][C:5](=[O:14])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[NH2:18][C:19]1[C:24]([Cl:25])=[CH:23][C:22]([C:26]([CH:28]=O)=[O:27])=[CH:21][C:20]=1[Cl:30]>>[NH2:18][C:19]1[C:20]([Cl:30])=[CH:21][C:22]([CH:26]([OH:27])[CH2:28][NH:16][C:2]([CH3:1])([CH3:15])[CH2:3][NH:4][C:5](=[O:14])[CH2:6][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:23][C:24]=1[Cl:25].[ClH:25]
Reactant: CC(C)(N)CNC(=O)COc1ccccc1
Reactant: Nc1c(Cl)cc(C(=O)C=O)cc1Cl
Solvent: O
Product: CC(C)(CNC(=O)COc1ccccc1)NCC(O)c1cc(Cl)c(N)c(Cl)c1
Product: Cl

Procedure:
In a similar manner but using 1,1-dimethyl-2-(2-phenoxyacetamido)ethylamine and 4-amino-3,5-dichlorophenylglyoxal hydrate as starting materials there was obtained 1-(4-amino-3,5-dichlorophenyl)-2-[1,1-dimethyl-2-(2-phenoxyacetamido)ethylamino]ethanol (Example 2) in 35% yield, m.p. 107°-9° C. (hydrochloride, monohydrate).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH2:4][CH:5]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH:6]2[CH:20]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.N>>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:3]2[CH2:4][CH:5]3[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[O:11])[CH:6]3[CH:20]=2)[CH:25]=1
Reactant: Brc1cccnc1
Reactant: C[Sn](C)(C)C1=CC2C(CCN2C(=O)OCc2ccccc2)C1
Agent: N
Product: O=C(OCc1ccccc1)N1CCC2CC(c3cccnc3)=CC21

Procedure:
The mixture of Example 38C (140 mg, 0.332 mmol) and 3-bromopyridine (0.042 mL, 0.43 mmol) were processed as described in Example 4C. Purification by chromatography (SiO2, 30% EtOAc/hexane) provided 90 mg (85%) of a 4:1 mixture of the title compounds. MS (DCI/NH3) m/z 321 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[C:17]1([C:23]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[NH:7][C:8]([N:31]1[CH2:32][CH2:33][N:28]([C:26]2[S:25][N:24]=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:27]=2)[CH2:29][CH2:30]1)=[O:15]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cn1ncc(Br)c1NC(=O)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cn1ncc(Br)c1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 15.5 h
Yield: 69.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl (4-bromo-1-methyl-1H-pyrazol-5-yl)carbamate (289 mg, 0.822 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (184 mg, 0.747 mmol) and diisopropylethylamine (0.143 ml, 0.822 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 15.5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 233 mg (69.7%) of the desired product as a solid.
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1.N1C=C[CH:12]=[CH:11][CH:10]=1.C([O-])(=[O:17])C.[Na+]>C(OC(=O)CC)(=O)CC>[Br:8][C:5]1[S:6][CH:7]=[C:3]([NH:2][C:10](=[O:17])[CH2:11][CH3:12])[N:4]=1
Reactant: c1ccncc1
Reactant: CC(=O)[O-]
Reactant: Nc1csc(Br)n1
Agent: Br
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Product: CCC(=O)Nc1csc(Br)n1
Yield: 11.9 %

Procedure:
4-Amino-2-bromothiazole hydrobromide (6.5g.) was suspended in propionic anhydride (25 ml.) with stirring; then treated with pyridine (12.5 ml.) over 15 minutes, maintaining reaction temperature at 0° C. with an ice bath. After the addition was complete, the reaction mixture was stirred for 2 hours at room temperature, then poured onto 20% aqueous sodium acetate (250 ml.) and stirred for 30 minutes. The precipitate was removed by filtration and washed with water. The solid was air dried and extracted with hexane, in a Sexhlet apparatus. The hexane was cooled and the crystals collected and recrystallised to give the title compound (2.8 g.) m.p. 122°-5° C. (Found: C, 31.1; H, 3.1; N, 11.9. C6H7BrN2OS requires C, 30.7; H, 3.0; N, 11.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][N:6]=[CH:5]2.C[Si](C)(C)N[Si](C)(C)C.[Li].Br[CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CN(C=O)C>[C:31]([Si:28]([CH3:30])([CH3:29])[O:27][CH2:26][CH2:25][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH:5]=[N:6]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1cc2cn[nH]c2cc1[N+](=O)[O-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CN(C)C=O
Product: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 50.7 %

Procedure:
5-Methyl-6-nitro-1H-indazole (354 mg, 2.0 mmol) was dissolved in DMF (10 ml) and the mixture was cooled to 0° C. with stirring. Lithium hexamethyldisilazane (2.2 ml of 1.0 M toluene solution) was added dropwise. The mixture was allowed to stir for five minutes, and then (2-bromoethoxy)-tert-butyldimethylsilane (0.52 ml, 2.4 mmol) was added. The mixture was stirred for 30 minutes at 0° C., then allowed to warm to room temperature with stirring for four hours. The reaction was quenched with pH2 buffer solution, and the mixture was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 4:1 hexanes/ethyl acetate) to give 340 mg (50.7%) of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-1H-indazole as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:27](O)[CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6][C:3]=1[CH:4]1[O:29][CH2:28][CH2:27][O:5]1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C=O)c(F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C2OCCO2)c(F)c1
Temperature: 25 °C

Procedure:
2-Fluoro-4-(hexadecylamino)benzaldehyde (1.7 g.) is dissolved in toluene (20 ml), and ethylene glycol (2.5 ml.) and p-toluenesulfonic acid (10 mg.) are added. The reaction mixture is heated under reflux for 16 hours while water is removed using a Dean-Stark trap. The reaction mixture is then cooled to room temperature, diluted with toluene (70 ml.), washed with aqueous sodium bicarbonate and then with water. The organic layer is separated dried over mangnesium sulfate, decolorized with charcoal and filtered through anhydrous magnesium silicate. Removal of the solvent in vacuo gives a light yellow solid which is recrystallized from hexane to yield 2-[2-fluoro-4-(hexadecylamino)phenyl]-1,3-dioxolane.
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][NH:3]1.CI.[CH3:11]COC(C)=O.CC(O)=O>[OH-].[Na+]>[CH3:11][S:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]=1
Reactant: O=c1cc[nH]c(=S)[nH]1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CC(=O)O
Product: CSc1nccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
2-thioxo-2,3-dihydropyrimidin-4(1H)-one (66.7 g, 0.497 mol) was dissolved in aq. NaOH (41.6 g of solid in 365 mL of H2O). The mixture was then treated with CH3I (100.1 g, 0.704 mol) and was stirred at room temperature for 18 h. TLC (petroleum ether: EtOAc=4:1) indicated that the reaction was complete. The resulting mixture was adjusted to pH=5˜6 with HOAc (30 mL). The solid formed was collected and dried on vacuum to give title compound (40 g, 54%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[N:43]1[CH:48]=[CH:47][C:46]([CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:45][CH:44]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:53]2[CH2:54][CH2:55][N:50]([CH2:49][C:46]3[CH:45]=[CH:44][N:43]=[CH:48][CH:47]=3)[CH2:51][CH2:52]2)=[O:17])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1cccc(OCCc2ccc(Cl)cc2Cl)c1
Reactant: c1cc(CN2CCNCC2)ccn1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cccc(OCCc2ccc(Cl)cc2Cl)c1)N1CCN(Cc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.100 g (0.321 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-benzoic acid was dissolved in 2 ml of DMF and treated with 0.148 g (1.28 mmol) of N-NEM and 0.105 g (0.321 mmol) of TOTU and 0.0569 g (0.32 mmol) of 1-Pyridin-4-ylmethyl-piperazine. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with a gradient of 0-17% MeOH in DCM.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:42])[C@H:10]([CH3:41])[NH:11][C:12](=[O:40])[C@H:13]([CH3:39])[N:14]([C:16](=[O:38])[C@H:17]([CH:35]([CH3:37])[CH3:36])[NH:18][C:19](=[O:34])[C@H:20]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:21](C(OC(C)(C)C)=O)[CH3:22])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9](=[O:42])[C@H:10]([CH3:41])[NH:11][C:12](=[O:40])[C@H:13]([CH3:39])[N:14]([C:16](=[O:38])[C@H:17]([CH:35]([CH3:36])[CH3:37])[NH:18][C:19](=[O:34])[C@H:20]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:21][CH3:22])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](C(=O)N[C@H](C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)C)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)C
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A solution of 15.7 g (0.0266 mole) of Boc-N-methyl-L-leucyl-L-valyl-N-methyl-L-alanyl-L-alanine benzyl ester in 125 ml of dry dichloromethane was stirred and cooled to -10° C. while 70 ml trifluoroacetic acid, previously cooled at -15° C., was added. After 2 hours, the reaction was carefully added with good stirring to a mixture of 105 g of sodium bicarbonate, ice, and 200 ml of dichloromethane. The organic layer was separated and the aqueous layer was extracted with another 50 ml of dichloromethane. The combined organic layers were washed with 3×80 ml of saturated sodium bicarbonate solution, dried over magnesium fulfate, and evaporated leaving 11.85 g (91% of theory) of product. The FAB m.s. showed a molecular ion peak at 491.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[CH:11]=2)=[N:4][S:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:18]([O-])=O.[Na+]>C(O)(=O)C.Cl.CN1CCCC1=O.O>[CH2:16]([C:12]1[CH:11]=[C:10]([C:3]2[C:2]3[N:1]=[N:18][NH:9][C:7](=[O:8])[C:6]=3[S:5][N:4]=2)[CH:15]=[CH:14][CH:13]=1)[CH3:17]
Reactant: CCc1cccc(-c2nsc(C(N)=O)c2N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: O
Product: CCc1cccc(-c2nsc3c(=O)[nH]nnc23)c1
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
496 mg of 4-amino-3-(3-ethylphenyl)-5-isothiazolecarboxamide in 7 ml of glacial acetic acid, 4 ml of concentrated hydrochloric acid and 4 ml of N-methyl-pyrrolidone was stirred at 0° C. during the addition of 165 mg of sodium nitrite in 1 ml of water. The mixture was held at 0° C. for 1.5 hours then filtered and the solid residue was recrystallized from ethanol to give 400 mg of 7-(3-ethylphenyl)isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one, m.p. 156°-157° C. (dec.).