Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CN(C=O)C>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[CH:6][C:5]3[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=3)[C:1]#[N:2])=[N:19]2)=[CH:14][CH:13]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Yield: 82.9 %

Procedure:
Under the protection by nitrogen, meta-cyanobenzaldehyde (137.6 g, 1.05 mol), 7-chloroquinaldine (177 g, 1.0 mol) and sodium acetate (82 g) are added into 200 ml of acetic anhydride and 800 ml of dimethyl fomamide (DMF), and the resulted mixture solution is stirred and heated to reflux for 24 hours. After distilling the most solvent, 300 ml of water is added into the residue, and then extracted by ethyl acetate (500 ml×3), washed with saturated saline water, dried with anhydrous sodium sulfate and condensed in the vacuum. The resulted residue is then purified through Flash Column Chromatography to obtain 241 g of the title compound, with a yield of 83%.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH3:20][O:21][C:22]([CH3:28])([CH2:25][O:26][CH3:27])[C:23]#[CH:24]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:24]#[C:23][C:22]([O:21][CH3:20])([CH3:28])[CH2:25][O:26][CH3:27])[N:5]=2
Reactant: C#CC(C)(COC)OC
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(C)(COC)OC)nc21

Procedure:
A suspension of 1.5 g (5.34 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide in 30 ml of a DMF/Et3N (v/v; 2/1) mixture is placed in an 80 ml microwave tube. Argon is sparged into this suspension for 10 minutes and then 1.37 g of (±)-3,4-dimethoxy-3-methylbut-1-yne (10.69 mmol), 0.101 g of CuI (0.53 mmol) and 0.187 g of bis(triphenylphosphine)palladium(II)dichloride (0.27 mmol) are successively added.
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CCOCC>[CH2:1]([O:5][S:14]([CH3:13])(=[O:16])=[O:15])[C:2]#[C:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC#CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC#CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
2-Butyne-1-ol (1.4 g, 20 mmol) is dissolved in ether (50 mL) and cooled to 0° C. Triethylamine (3.3 mL, 24 mmol) is added to the solution. Methanesulfonyl chloride (1.6 mL, 22 mmol) is dissolved in ether (5 mL) and added dropwise to the reaction solution. The mixture is stirred for 30 minutes at 0° C., then filtered and concentrated to give crude methanesulfonic acid but-2-ynyl ester 20 (2.96 g, 20 mmol, quant.) as a colorless liquid: 1H-NMR (400 MHz, CDCl3) δ=4.79 (q, J=2.4 Hz, 2H), 3.08 (s, 3H), 1.87 (t, J=2.4 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].C(N(CC)CC)C.Cl.Cl[CH2:25][C:26]1[C:27]([NH2:33])=[N:28][C:29]([CH3:32])=[N:30][CH:31]=1>CN(C)C=O>[CH3:32][C:29]1[N:28]=[C:27]([NH2:33])[C:26]([CH2:25][N:13]2[CH2:12][CH2:11][N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14]2)=[CH:31][N:30]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCN(c3ccccc3[N+](=O)[O-])CC2)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
A solution of 1.25 g (0.0060 mol) of 1-(2-nitro-phenyl)-piperazine and 2.1 ml (0.015 mol) of triethylamine in 20 ml of dimethylformamide was treated with 0.97 g (0.0050 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride and the mixture was stirred at room temperature under argon for 3 hours. The mixture was completely freed from the solvents and the residue was triturated in 20 ml of water. The resulting crystals were filtered off under suction, dried and chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent. 1.25 g (76%) of 2-methyl-5- [4-(2-nitro-phenyl )-piperazin-1-ylmethyl]-pyrimidin-4-ylamine were obtained as a yellow solid.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](O)=[O:4].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.[NH2:28][C:29]1[N:34]2[N:35]=[CH:36][C:37]([C:38]3[CH:39]=[N:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:42][CH:43]=3)=[C:33]2[N:32]=[C:31]([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[C:30]=1[C:56](=[O:59])[CH2:57][OH:58].C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:28][C:29]1[N:34]2[N:35]=[CH:36][C:37]([C:38]3[CH:39]=[N:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:42][CH:43]=3)=[C:33]2[N:32]=[C:31]([CH:50]2[CH2:55][CH2:54][N:53]([C:3](=[O:4])[C@H:2]([OH:1])[CH3:6])[CH2:52][CH2:51]2)[C:30]=1[C:56](=[O:59])[CH2:57][OH:58]
Reactant: Nc1c(C(=O)CO)c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Reactant: C[C@@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)C(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2C(=O)CO)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (R)-2-hydroxypropanoic acid (13.8 mg, 0.16 mmol), EDCI (46 mg, 0.24 mmol), and 1-hydroxybenzotriazole (16.22 mg, 0.12 mmol) in DMF (2 ml) was stirred at room temperature for 10 min. To this 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyethanone (58.77 mg, 0.12 mmol) was added followed by N,N-diisopropylethylamine (0.1 ml, 0.6 mmol). It was stirred further for 20 min at room temperature at which time LC/MS analysis confirmed full consumption of starting material. This crude compound was submitted to the analytical group for purification to afford the desired (R)-1-(4-(7-amino-6-(2-hydroxyacetyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)-2-hydroxypropan-1-one. LCMS: 3.27 mins, m/z=501.0 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl[S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([OH:31])[CH:23]=1)(=[O:21])=[O:20]>C1COCC1>[OH:31][C:24]1[CH:23]=[C:22]([S:19]([O:1][C:2]2[CH:17]=[CH:16][C:5]([C:6](=[O:7])[C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)(=[O:21])=[O:20])[CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: COc1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)cc2)cc1
Yield: 54.3 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using commercial 4-hydroxy-4'methoxybenzophenone (0.206 g, 0.903 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.427 g, 1.81 mmol) in THF (5 mL). Purification by preparative HPLC (C18, eluting with 60% CH3CN/H2O containing 0.1% TFA) and crystallization from EtOAc/hexane gave 0.21 g (54%) of the title compound as an off white solid, mp 73-75° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.07 (d, 2H), 7.24 (d, 2H), 7.36-7.38 (m, 2H), 7.68-7.73 (m, 4H), 7.99 (s, 1 H). IR (KBr) 3400, 1700, 1650, 1000 and 1260 cm-1. mass spectrum (-ESI) m/z 427 (M-H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14](Cl)=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:3])=[O:2].[F-:21].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([F:21])=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:3])=[O:2]
Reactant: CCOC(=O)COc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 122 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
A suspension of ethyl 2,4-dinitro-5-chlorophenoxyacetate (2.0 g) and potassium fluoride (0.76 g) in N,N-dimethylformamide (10 g) was stirred at a temperature of 122° C. for 1.5 hours. After cooling, the reaction mixture was diluted with ice water (200 ml) and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution in order, dried over anhydrous magnesium sulfate and concentrated to give ethyl 2,4-dinitro-5-fluorophenoxyacetate (1.4 g; yield, 74.0%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10](=[CH2:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9].[CH2:17]([N:24]([CH2:28][Si](C)(C)C)[CH2:25]OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([N:24]1[CH2:25][CH2:16][C:10]([C:8]#[N:9])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:28]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=C(C#N)C(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C#N)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
TFA (4.31 mmol, 0.49 g) was added to a solution of ethyl 2-cyanoacrylate (17.58 mmol, 2.20 g) in DCM (100 mL) under nitrogen atmosphere. Subsequently, a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (21.49 mmol, 5.10 g) in DCM (50 mL) was added dropwise while cooling with an ice-bath in order to keep the reaction temperature at room temperature (exothermic reaction). The reaction mixture was stirred overnight at room temperature. Then the mixture was washed with saturated aqueous NaHCO3 (100 mL). The aqueous phase was extracted with DCM (100 mL). The combined organic phase was dried over MgSO4 and evaporated in vacuo. The crude product was purified by flash silicagel chromatography (100% heptane to 50% EtOAc) yielding 4.27 g of a colorless oil (94%). 1H-NMR (400 MHz, CDCl3, 300K): δ=1.32 (3H, t, J=7.1 Hz), 2.44 (1H, m), 2.59 (1H, m), 2.69 (1H, m), 2.89 (1H, m), 2.99 (1H, d, J=9.8 Hz), 3.17 (1H, d, J=9.8 Hz), 3.69 (2H, s), 4.27 (2H, q, J=7.1 Hz), 7.29 (5H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](C(F)(F)F)=[CH:18][C:17]([CH2:24][OH:25])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH3:26])=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:34]CCl>C1(C)C=CC=CC=1>[Cl:34][C:19]1[CH:18]=[C:17]([CH2:24][OH:25])[CH:16]=[N:15][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][C@H:9]([CH3:26])[CH2:10]1
Reactant: ClCCl
Reactant: C[C@@H]1CN(c2ncc(CO)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-(5-hydroxymethyl-3-trifluoromethyl-pyridin-2-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester from step (f) above (3.75 g, 10 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL, Aldrich) dropwise at 0° C. over a period of 10 min. The mixture was stirred at room temperature for 16 h and diluted with toluene (20 mL). The solvents were removed in vacuo and the residue was dissolved in EtOAc (100 mL), washed with saturated aqueous solution of NaHCO3 (2×30 mL) and brine (20 mL), dried over Na2SO4, and filtered. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 90:10:1 mixture of MeOH/CH2Cl2/ammonium hydroxide to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 276 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][C:52](O)=[O:53].Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:52](=[O:53])[CH2:51][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[F:44])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccccc1F)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2-fluorophenylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The reaction mixture was stirred at room temperature overnight and was then concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), and the solution was washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (eluent: EtOAc: CH2Cl2=4:6) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(2-fluoro-phenyl)-acetamide (0.7 g, 79%) as a white solid: mp 172-174° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.87 min. (98%); 1H NMR (DMSO-d6) δ 2.04-2.09 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.94 (m, 1H), 3.61 (s, 2H), 4.75 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.12-7.38 (m, 4H), 7.68-7.86 (m, 3H), 8.70 (t, J=6.0 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 35.20, 37.87, 48.83, 114.83 (115.12), 121.88, 122.95 (123.17), 124.14 (124.19), 127.10, 128.60 (128.71), 131.51, 131.85 (131.91), 133.11, 134.68, 139.15, 158.96 (162.20), 166.90, 167.44, 169.59, 169.78, 172.73; Anal. Calcd. for C22H18N3O5F: C, 62.41; H, 4.29; N, 9.92; F, 4.49. Found: C, 62.65; H, 4.25; N, 9.95; F, 4.62.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:24][CH3:25])=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16](=[O:21])(=[O:20])[C:17]=2[C:18]=1[Br:19])=[CH:14][C:13]([O:22][CH3:23])=[CH:12][CH:11]=3)(=O)C.[OH-].[Na+].C(O)(=O)C>CO>[Br:19][C:18]1[C:17]2[S:16](=[O:20])(=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH3:23])[CH:14]=3)[NH:9][C:8]=2[CH:7]=[C:6]([O:24][CH3:25])[C:5]=1[OH:4]
Reactant: COc1ccc2c(c1)S(=O)(=O)c1c(cc(OC)c(OC(C)=O)c1Br)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)S(=O)(=O)c1c(cc(OC)c(O)c1Br)N2
Reaction time: 0.33 h

Procedure:
To a suspension of 3-acetoxy-4-bromo-2,7-dimethoxy-10H-phenothiazine-5,5-dioxide (10.0 g) in methanol (105 ml) was added a solution of 2N aqueous sodium hydroxide (74 ml) under a nitrogen atmosphere. After 20 minutes, the mixture was acidified with 10% v/v aqueous acetic acid (250 ml), causing a large amount of compound to precipitate. The mixture was then diluted with water (105 ml) and the solid filtered, washed with water and ether and dried in a dessicator to afford quantitatively the title compound, m.p. 252°-260° C. (dec).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([NH:12][C:13]3([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:11])=[CH:4][C:3]=2[O:2]1.[OH-].[Na+]>C(O)C.O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([NH:12][C:13]3([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:11])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1(NC(=O)c2ccc3c(c2)OCO3)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccc2c(c1)OCO2
Yield: 66.9 %

Procedure:
Subsequently, 5.21 g of ethyl 1-[N-(3,4-methylenedioxyphenylcarbonyl) amino]cyclohexanecarboxylate synthesized in the above was dissolved in ethanol, and then, 16 ml of aqueous solution of 1N-sodium hydroxide was added dropwise thereto. After making heat reflux for 18 hours, the reaction solution was concentrated under reduced pressure. The residue thus obtained was dissolved in water and was washed with ether. After the resulting water layer was made acid (pH=2) by addition of 4-hydrochloric acid thereto, said layer was extracted with ethylacetate and was washed with 1N-hydrochloric acid and saturated brine. The resultant organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, whereby 3.18 g of the captioned 1-[N-(3,4-methylenedioxyphenylcarbonyl)amino]cyclohexanecarboxylic acid was obtained in a yield of 68%.
Reaction SMILES: O=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.Cl.[NH2:25][OH:26].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[OH:26][N:25]=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)c3ccccc32)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=NO)c3ccccc32)CC1

Procedure:
A mixture of tert-butyl 4-oxo-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate A (1.24 g, 3.93 mmol), hydroxylamine hydrochloride (1.37 g, 19.7 mmol) and sodium acetate trihydrate (3.20 g, 23.5 mmol) in ethanol (50 ml) was heated under reflux for 20 h. The reaction was concentrated and the residue was suspended in water, extracted with dichloromethane (3×). The combined extracts were dried over Na2SO4 and concentrated to give tert-butyl 4-(hydroxyimino)-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate B (1.32 g). LC-MS: m/e=331.1 (M+H, 100%), 275.0 (M+H−C(CH3)3). Rt=3.35 min. 1H-NMR (500 MHz, CDCl3): 8.01 (d, 0.25H), 7.93 (d, 0.75H), 7.41-7.34 (m, 2H), 7.23-7.19 (m, 1H), 3.95-3.92 (m, 2H), 3.04-2.96 (m, 2H), 2.87 (t, 0.5H), 2.82 (t, 1.5H), 2.3 (br. s, 1H), 1.93-1.84 (m, 4H), 1.54-1.52 (d, 2H), 1.43 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)c2ccc(F)cc2Cl)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-piperazinone (4.00 g, 40 mmol, commercially available e.g. from Sigma-Aldrich) was dissolved in Dichloromethane (DCM) (125 mL) and to this was added triethylamine (6.69 mL, 48.0 mmol). This solution was then cooled with ice water. 2-Chloro-4-fluorobenzoyl chloride (8.49 g, 44.0 mmol, commercially available e.g. from Maybridge, Alfa Aesar or ABCR) was then diluted down with Dichloromethane (DCM) (25 mL), before being added via a pressure-equalizing dropping funnel. The solution was allowed to stir at room temperature overnight, and was then washed with sodium bicarbonate (100 ml), the solid was removed, and the remaining solution was washed again with sodium bicarbonate (100 ml) and brine (100 ml), before being dried over magnesium sulphate. The solvent was then removed in vacuo to afford crude product which was triturated with hexane then stirred in ethyl acetate at 80° C., before being filtered and air-dried to give 4-[(2-chloro-4-fluorophenyl)carbonyl]-2-piperazinone (5.179 g).
Reaction SMILES: BrC1C=CC(C[O:7][C:8]2[N:12]([C:13]3[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:11]=[CH:10][CH:9]=2)=CC=1.B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:7][C:8]1[N:12]([C:13]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2ccc(Br)cc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccnc(-n2nccc2O)c1
Temperature: -78 °C
Yield: 60.2 %

Procedure:
A solution of methyl 2-{5-[(4-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate (765 mg, 1.97 mmol, EXAMPLE 68) in DCM (8 mL) was purged with nitrogen and cooled to −78° C. BBr3 (6 mL, 5.93 mmol, 1M in DCM) was added at this temperature. Thereto, the mixture was stirred at the same temperature for an hour, methanol was added until no gas released, and then the above mixture was basified with NaHCO3 aq (pH=3). Extracted with ethylacetate three times, and the organic phase was washed with brine and dried with Na2SO4, concentrated and the residue was washed with ethylacetate to give 260 mg of the title compound (60%). 1H NMR (400 MHz, CD3OD): δ 4.02 (3H, s), 7.91-7.97 (2H, m), 8.69-8.70 (2H, m). [M+H] Calc'd for C10H9N3O3, 220. Found, 220.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[Cl:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>C1(C)C(C)=CC=CC=1>[Cl:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:15]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1ccc(Cl)cc1Cl
Yield: 69.5 %

Procedure:
A solution of 10.9 g (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 20.9 g (0.10 mole) 2,4-dichlorobenzoyl chloride was refluxed in 200 ml xylene for 20 hours. The reaction mixture was concentrated in vacuo and the resulting residue extracted with benzene. Addition of hexane resulted in precipitation of 13.6 g (69% yield) pure product; m.p. 136° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH:16][CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[CH:14]=[CH2:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Reactant: C=CCNC(C=O)COC
Solvent: c1ccccc1
Product: C=CCN(C(=O)Nc1nnc(C(C)(C)C)s1)C(C=O)COC

Procedure:
5-t-Butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-allylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-allyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]-3-methoxypropionaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=[O:21])[C:11](=[C:22]3[N:26]([CH3:27])[C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[S:23]3)[S:10]2)[CH:5]=[CH:6][CH:7]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[CH2:14]([N:13]1[C:12](=[O:21])[C:11](=[C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23]2)[S:10][C:9]1=[N:8][C:4]1[CH:3]=[C:2]([NH:1][S:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:40])=[O:39])[CH:7]=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1C(=C2SC(=Nc3cccc(N)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CN1C(=C2SC(=Nc3cccc(NS(=O)(=O)c4ccccc4)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Temperature: 50 °C
Reaction time: 20 h
Yield: 20.9 %

Procedure:
To a 25 mL flask was added 2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one (0.18 g, 0.40 mmol), anhydrous CHCl3 (7 mL), benzenesulfonyl chloride (56 μL, 0.44 mmol), and TEA (0.10 mL, 0.80 mmol). The solution was stirred at 50° C. for 20 h. The yellow precipitates were collected by filtration under reduced pressure, washed with hexanes (30 mL), and dried under vacuum to give the title compound (49 mg, 21%) as a yellow solid. 1H-NMR (DMSO-d6): δ 7.97 (1H, s), 7.76 (2H, d), 7.53 (2H, m), 7.45 (2H, t), 7.37 (2H, d), 7.09-7.31 (8H, m), 6.81 (1H, d), 6.74 (1H, s), 6.57 (1H, d), 4.99 (2H, s), 3.72 (3H, s); MS(ESI): 585 (MH+).