Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:12]/[C:13](/[CH3:19])=[CH:14]\[C:15]([O:17][CH3:18])=[O:16].[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([O-:22])=[O:21]>CC(O)C>[CH3:5][C:3]1[NH:12][C:13]([CH3:19])=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:26]([C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)[C:2]=1[C:1]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)/C=C(/C)N
Reactant: CCCCOC(=O)CC(C)=O
Solvent: CC(C)O
Product: CCCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Yield: 49 %

Procedure:
A solution of n-butyl acetoacetate (0.10 mole), methyl 3-aminocrotonate (0.10 mole), 3-nitrobenzaldehyde (0.10 mole) and 150 mL of i-PrOH was refluxed overnight (18 h). The volatiles were removed in vacuo and the residue purified by flash chromatography (SiO2: EtOAc/Hex) to furnish the product in 49% yield as low melting, yellow solid: mp 69°-70° C.; 1H NMR (DMSO-d6) δ9.03 (s, 1H), 7.98 (m, 2H), 7.58 (m, 2H), 4.96 (s, 1H), 3.91 (m, 2H), 3,53 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H), 1.45 (p, 2H, J=6.6 Hz), 1.18 (m, 4H), and 0.83 (t, 3H, J=7.4 Hz); 13C NMR (DMSO-d6) δ167.0, 166.5, 150.1, 147.5, 146.5, 134.1, 129.7, 121.7, 121.1, 101.0, 100.9, 63.0, 50.8, 39.1, 30.2, 18.7, 18.3, and 13.5. Anal. Calcd for C20H24N2O6 : C, 61.85; H, 6.23; N, 7.21. Found: C, 62.02; H, 6.21; N, 6.95.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[N:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([CH3:20])=[CH:13][C:14]=1[C:15]([O:17]CC)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-].Cl>O>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[N:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([CH3:20])=[CH:13][C:14]=1[C:15]([OH:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C)n(CC(=O)OC(C)(C)C)c(=O)c1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)c(OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-benzyloxy-4-ethoxycarbonyl-6-methyl-1-tert-butyloxycarbonylmethyl-2-pyridinone from step 2 above (1.1 g, 2.8 mmol) in 1:1 THF:H2O (20 mL) was added aqueous LiOH (3.0 mL of a 1.1 N solution, 3.3 mmol) and the resulting solution was stirred at ambient temperature for 18 h. Aqueous HCl was added (3 mL of a 1 N solution, 3 mmol) and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc. The organic layer was separated and the aqueous layer was extracted four times with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and the solvent was removed in vacuo to give the title compound as an amorphous solid (0.91 g; HPLC RT=15.98 min, method B).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][C@H:7]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21]C)=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])=[CH:11][CH:10]=1)=[O:5].B(Br)(Br)Br>C(Cl)Cl>[CH2:28]([O:27][C:25](=[O:26])[C@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([O:23][CH3:24])=[CH:17][CH:18]=[CH:19][C:20]=2[OH:21])=[CH:11][CH:10]=1)[NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:34])[CH3:29]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(O)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine, ethyl ester (0.16 g, prepared in a fashion similar to that of the methyl ester described in Example 8) was dissolved in anhydrous CH2Cl2 (8 mL). The solution was cooled to −78° C. and BBr3 (0.56 mL, 1 M solution in CH2Cl2) was added. The mixture was allowed to warm to 0° C., and stirred at that temperature for 2 h. The mixture was subsequently warmed to room temperature and quenched with satd. NaHCO3 (5 mL). The mixture was stirred for 1 h, and diluted with CH2Cl2. The organic phase was dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexanes 1:2) to give 40 mg of N-(2,6-dichlorobenzoyl)-4-(2-hydroxy-6-methoxyphenyl)-L-phenylalanine ethyl ester ESMS: m/z 488 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][N:25]([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:26][N:25]([CH3:27])[CH2:24][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2
Reactant: CN(C)CC1CCCCN1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc(N2CCCCC2CN(C)C)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 34.2 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (88.3 mg, 0.36 mmol) and N-(2-piperidylmethyl)-dimethylamine (Salor Chemical Company) (0.25 g, 1.72 mmol) was added a solution of K2CO3 (0.25 g, 1.60 mmol) in H2O (2.5 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 2.5 h. After cooling, CH2Cl2 (10 mL) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution was washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3% MeOH:CHCl3 on silica gel) to give 43 mg (34%) of the title compound as a yellow oil. MS m/z: 350 (M+1), 305, 214. 1H NMR (DMSO-d6; 400 MHz): δ 1.63 (m, 6), 2.29 (s, 6), 2.40 (s, 3), 2.81 (m, 2), 3.03 (br t, 1, J=11.8), 4.53-4.63 (m, 2), 6.75 (s, 1), 7.37 (m, 1), 7.50 (t, 2, J=7.5), 7.81 (d, 2, J=7.8), 12.47 (s, 1).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]#[N:14])=[C:6](Cl)[C:5]=1[N+:16]([O-:18])=[O:17])[CH3:2].[NH3:21].C(COC)OC>C(O)C>[CH2:1]([N:3]([CH2:19][CH3:20])[C:4]1[C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH2:21])[C:7]([C:13]#[N:14])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCN(CC)c1c([N+](=O)[O-])cc(C#N)c(Cl)c1[N+](=O)[O-]
Reactant: N
Solvent: CCO
Solvent: COCCOC
Product: CCN(CC)c1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Reaction time: 72 h

Procedure:
A solution of 4.33 g. (0.0144 mole) of N,N-diethyl-3-chloro-2,6-dinitro-4-cyanoaniline, 6.40 g. (0.0288 mole) of a 7.66% solution of ammonia in absolute ethanol, and 15 ml. of dimethoxyethane was sealed in a Pyrex reaction tube and alloed to stand at room temperature for 72 hours. The contents were distilled to dryness at reduced pressure and extracted with 100 ml. of boiling chloroform. The filtered chloroform extract was evaporated to dryness and the residual orange solid taken up in hot 95% ethanol. Upon cooling, the product crystallized and was isolated by filtration to give 1.51 g. (37.3%) or an orange, crystalline solid melting at 142°-145°C. Recrystallization from 95% ethanol gave the desired product, m.p. 145.5°-146.5°C.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.C(O)(=O)C.[O-:33][C:34]#[N:35].[K+]>C1COCC1.O>[CH3:17][C:15]1[CH:16]=[C:11]([C:8]2[S:7][C:6]([C:2]3([NH:1][C:34]([NH2:35])=[O:33])[CH2:3][CH2:4][CH2:5]3)=[N:10][CH:9]=2)[CH:12]=[C:13]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:14]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)CCC3)s2)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NC(N)=O)CCC3)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of N-{3-[2-(1-aminocyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 61B-1, 50 mg, 0.123 mmol) and acetic acid (7 μL, 0.123 mmol) in THF/water (1.6:1, 2.1 mL), potassium cyanate (10 mg, 0.123 mmol) was added. The reaction mixture was stirred overnight at room temperature and then concentrated. The residue was purified by column chromatography on silica (50-100% ethyl acetate in hexanes, 0-20% methanol in dichloromethane) and lyophilized to afford 1-{1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}urea (31.3 mg, 0.068 mmol, 54.9%) as a white powder. MS ESI: [M+H]+ m/z 449.1. 1H NMR (500 MHz, DMSO-d6 δ 10.23 (s, 1H), 8.82 (d, J=4.9, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.47 (s, 1H), 7.27 (d, J=4.9, 1H), 7.15-7.00 (m, 2H), 5.58 (s, 2H), 2.63-2.51 (m, 2H), 2.32 (m, 5H), 1.96 (m, 2H). rhSYK activity=+++
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([O:7][C:8]2[CH:23]=[CH:22][C:11]([O:12][CH:13]([CH3:21])[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH3:28]>C(O)C>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:23]=[CH:22][C:11]([O:12][CH:13]([CH3:21])[CH:14]([NH2:28])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:24][CH:25]=1
Reactant: N
Reactant: CCOC(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: CCO
Product: CCOC(=O)CC(N)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-2-pentenoate (0.8 g) in ethanol (25 ml), chilled in an ice bath and under nitrogen, ammonia is flowed over for about 10 minutes while stirring. Reaction is allowed to warm to R.T. The reaction is again chilled and additional ammonia added for about 15 minutes. Reaction is allowed to rise to R.T. and stirring continued over night. Reaction is concentrated under vacuum to an oil. The oily concentrate is purified by prep. thin layer chromatography using ethyl acetate/hexane (1:1) to give ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-aminopentanoate (purity 93.7%, structure confirmed by MS).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]1[NH:10][N:9]=[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[N:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][C:6]1[NH:10][N:9]=[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]=[C:1]=[S:2])[N:7]=1
Reactant: Cc1nc(Cc2ccccc2N)n[nH]1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(Cc2ccccc2N=C=S)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.41 g of thiophosgene in 30 ml of methylene chloride is added dropwise at 0° a solution of 7.5 g of 5-methyl-3-(o-aminobenzyl)-1,2,4-triazole and 8.07 g of triethylamine in 285 ml of methylene chloride over a period of 45 minutes. The mixture is stirred at room temperature overnight, washed first with 10% aqueous potassium bicarbonate, then with water, dried over magnesium sulfate, decolorized with charcoal and evaporated to dryness to give 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazole; IR 2080 cm-1.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 102 mg (1 mmole) of n-pentanoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 223 mg (Yield: 60%) of the title compound having the following structure as a red oil.
Reaction SMILES: [NH2:1][C:2]1[C:8]2=[CH:9][CH:10]=[CH:11][N:7]2[CH2:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.[Cl-].[NH4+].[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21]N>C1(C)C=CC=CC=1>[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH:1][C:2]1[C:8]2=[CH:9][CH:10]=[CH:11][N:7]2[CH2:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1
Reactant: COC(CN)OC
Reactant: NC1=Nc2ccccc2Cn2cccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COC(CNC1=Nc2ccccc2Cn2cccc21)OC
Temperature: 0 °C

Procedure:
11-Amino-5H-pyrrolo[2,1-c][1,4]benzodiazepine (described by W. B. Wright et al., J. Med. Chem., 23,462 (1980), 2.00 g, 10.1 mmol) and ammonium chloride (200 mg, 19 mmol) were stirred in dry toluene (50 mL) in the presence of aminoacetaldehyde dimethylacetal (8.8 mL) under refluxing conditions for 3 hr. The precipitate which formed in the beginning redissolved to afford a brown solution. The reaction mixture was cooled in ice-water, washed with 10% (v/v) aqueous sodium hydroxide and then with brine, dried and evaporated to yield an oily residue. Crystallization of the residue from cyclohexane-hexane gave [(5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)amino]acetaldehyde dimethylacetal (2.41 g), mp 132°-132.5° C.; Anal. Calcd for C16H19N3O2 : C, 67.34% H, 6.71% N, 14.73%, Found: C, 67.11% H, 6.69% N, 14.40%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21].C([BH3-])#N.[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:22][CH2:19][CH2:20][CH3:21])[CH:12]=2)[CH:3]=1
Reactant: CCCN
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 76.9 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.20 g, 0.78 mmol), n-propylamine (140 μL, 101 mg, 1.7 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 5 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[3-(propylaminomethyl)phenoxy]benzonitrile fumarate (250 mg, 78%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.C1C2C(=CC=CC=2)C=C(N)N=1>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH:6]=[C:7]([NH:12][C:13]([CH:15]2[CH2:16][CH2:17]2)=[O:14])[N:8]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: Nc1cc2ccccc2cn1
Product: O=C(Nc1cc2ccccc2cn1)C1CC1

Procedure:
The title compound was synthesized following the same method as described for the synthesis of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide, using commercially available isoquinolin-3-amine instead of 7-bromo-isoquinolin-3-amine. LCMS (ESI): RT (min)=3.537, M+H=213.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.14 (s, 1H), 8.45 (s, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.69 (t, J=7.5 Hz, 1H), 7.51 (t, J=7.5 Hz, 1H), 2.06 (d, J=4.4 Hz, 1H), 0.89-0.77 (m, 4H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].O.C(O[CH2:23][CH3:24])C>C1COCC1.CCCCCC>[C:1]1([CH2:17][CH:16]([CH:24]2[CH:23]=[CH:11][CH:6]=[CH:7]2)[CH2:15][CH2:14][CH2:5][CH2:13][CH2:1][CH2:2][CH2:3][CH3:4])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCC(Cc1cccc2c1Cc1ccccc1-2)C1C=CC=C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
19.0 g (114 mmol) of fluorene was introduced into a flask under a high purity argon atmosphere and dissolved in 200 ml of THF. 50.2 ml of 2.5 N n-butyl lithium (n-BuLi) in hexane was slowly added thereto at −78° C. The mixture was slowly warmed to room temperature and then stirred for another 2 hours. 11.7 of spiro (2-octylcyclopropane)-1,1′-cyclopentadiene diluted in 200 ml of THF was added dropwise thereto at 0° C., and then stirred for 24 hours at room temperature. 200 ml of water and 500 ml of diethyl ether were added to the reaction mixture, agitated and the organic layer was separated and dried on anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was evaporated under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: hexane) to obtain 8.1 g of pure 1-fluorenyl-2-cyclopentadienyldecane (Yield: 38%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:20]2[S:42][C:23]3=[N:24][C:25]([N:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)=[CH:26][C:27](=[O:28])[N:22]3[N:21]=2)[CH:5]=[C:6]([NH:8][C:9](=[O:19])[CH2:10][NH:11]C(OC(C)(C)C)=O)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][CH2:10][C:9]([NH:8][C:6]1[CH:5]=[C:4]([C:20]2[S:42][C:23]3=[N:24][C:25]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:26][C:27](=[O:28])[N:22]3[N:21]=2)[CH:3]=[C:2]([Br:1])[CH:7]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cc(Br)cc(-c2nn3c(=O)cc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3s2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)Nc1cc(Br)cc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)c1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(2-(3-bromo-5-(2-(tert-butoxycarbonylamino)-acetamido)phenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (30 mg, 0.045 mmol) in DCM (2 ml) is added TFA (0.5 ml) and the mixture is stirred for 1 h. After the removal of DCM in vacuo, the crude residue is directly purified by preparative HPLC to give the desired product, 2-amino-N-(3-bromo-5-(5-oxo-7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)phenyl)acetamide: 1H NMR (400 MHz, DMSO-d6) δ 8.70-8.20 (br.s., 3H), 8.19 (t, J=1.8 Hz, 1H), 8.11 (t, J=1.8 Hz, 1H), 7.83 (t, J=1.8 Hz, 1H), 5.61 (s, 1H), 3.84 (s, 2H), 3.79 (t, J=5.2 Hz, 4H), 3.18 (t, J=5.2 Hz, 4H); LC/MS: tR=2.743 min; HRMS: m/z (M+H+)=464.0495 and 466.0479 (Calculated for C17H19BrN7O2S=464.0499 and 466.0479).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])[CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[F:22]>>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]3[CH:13]=[CH:12][N:11]=[C:10]3[CH3:14])[CH:7]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Cc1nccn1Cc1cncc(Br)c1
Product: Cc1nccn1Cc1cncc(-c2ccc(F)c(Cl)c2)c1
Product: Cl

Procedure:
The title compound, MS: m/e=301.1 (M+) was obtained as a yellow solid (53% yield) by the reaction of 3-bromo-5-(2-methyl-imidazol-1-yl-methyl)-pyridine with 3-chloro-4-fluoro-phenyl boronic acid.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13]C(O)=O.C([O-])(=O)C.[NH4+:25]>C(O)C>[CH2:19]([O:18][C:12](=[O:17])[CH2:13][CH:10]([NH2:25])[C:6]1[N:5]=[C:4]2[CH:3]=[CH:2][O:1][C:9]2=[CH:8][CH:7]=1)[CH3:20]
Reactant: O=Cc1ccc2occc2n1
Reactant: CCOC(=O)CC(=O)O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)CC(N)c1ccc2occc2n1
Temperature: 25 °C

Procedure:
A solution containing aldehyde 23-2 (1.5 g, 10 mmol), ethyl hydrogen malonate (1.6 g, 20 mmol), and ammonium acetate (3.8 g, 50 mmol) in anhydrous ethanol (125 mL) was heated at reflux for 8 h After cooling to room temperature, the solvent was evaporated and the residue partitioned between sat. sodium bicarbonate and EtOAc, the organic layer removed, dried, and concentrated. Chromatography of the residue afforded the amino ester 23-3 as a waxy solid.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[Cl:13][CH2:14][CH2:15]O>>[OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH2:15][CH2:14][Cl:13])=[O:4]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: OCCCl
Product: O=C(OCCCl)C(O)Cc1ccccc1

Procedure:
2-Chloroethyl 2-hydroxy-3-phenylpropionate was prepared from (S)-2-hydroxy-3-phenylpropionic acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1; however, the distillate solidified after standing at 4° C.: b.p. 120° C./0.35 mm Hg; 1H NMR δ 2.86 (bs, 1H), δ 2.98 (dd, 1H, J=6.7 Hz and 14.0 Hz) δ 3.13 (dd, 1H, J=4.6 Hz and 14.0 Hz), δ 3.63 (t, 2H, J=5.6 Hz), δ 4.35 (m, 2H), δ 4.48 (dd, 1H, J=4.7 Hz and 6.6 Hz), δ 7.2-7.3 (5H) 13C NMR 40.5, 41.0, 64.8, 71.3, 126.8, 128.3, 129.4, 136.2, 173.6 ppm; HRMS calcd for C10H9ClO3Tms (M--CH3) 285.0714, obsd 285.0756.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=2[F:18])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[N:23]#[C:24][NH2:25].[F:26][C:27]([F:33])([F:32])[S:28]([OH:31])(=[O:30])=[O:29]>C1COCC1>[OH:31][S:28]([C:27]([F:33])([F:32])[F:26])(=[O:30])=[O:29].[C:24](=[NH:23])([O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:19]([F:22])([F:20])[F:21])[CH:4]=2)=[C:10]([F:18])[CH:11]=1)[NH2:25]
Reactant: N#CN
Reactant: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 23.8 %

Procedure:
To the solution of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3-fluorophenyl)ethanol (4.0 g, 11.95 mmol) and cyanamide (0.603 g, 14.34 mmol) in anhydrous THF (25 mL) was added trifluoromethanesulfonic acid (2.55 mL, 28.7 mmol) at 0° C. The reaction mixture was stirred at 60° C. for 4 h. Purification via a reverse phase Biotage then afforded the title compound as a white solid (1.5 g, 23.82% yield). LCMS: rt=3.68 min, [M+H+]=377