Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[CH2:13]/[CH:14]=[CH:15]/[Sn:16]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:25]([Sn:16]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15]/[CH:14]=[CH:13]/[CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6])[CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)CC(=O)OC
Reactant: CCCC[Sn](/C=C/CBr)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC[Sn](C/C=C/C(C(=O)OC)C(=O)OC)(CCCC)CCCC
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Sodium hydride (75 mg) was added to a solution of dimethyl malonate (387 mg) in dry DMF (5 mL) at 0° C. [(1E)-3-bromoprop-1-enyl](tributyl)stannane (600 mg) was added to the reaction mixture after 10 min. The reaction mixture was stirred for 3 h at 20° C. and then quenched with saturated NH4Cl(aq.). Extraction with EtOAc and drying (MgSO4) of the organic phase gave, after concentration in vacuo, the crude product. Purification was done by chromatography eluting with petroleum ether/Et2O 12:1 to afford the title compound as a liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH2:11][CH2:12][Cl:13].[N:15]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl.O>[Cl:13][CH2:12][CH2:11][CH2:10][C:9]1[C:3]2[C:2](=[CH:7][C:6]([F:8])=[CH:5][CH:4]=2)[NH:1][N:15]=1
Reactant: Nc1cc(F)ccc1C(=O)CCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Fc1ccc2c(CCCCl)n[nH]c2c1
Temperature: -3 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a suspension of 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (500 mg, 2.3 mmol) in conc. HCl (3.2 mL) was added a solution of NaNO2 in H2O (0.7 mL) and stirred for 1 h at −6-0° C. A solution of SnCl2.2H2O (1.25 g, 5.51 mmol) in conc. HCl (1.7 mL) was added the reaction mixture and stirred for additional 1 h at 0° C. The reaction was quenched by addition of ice water and extracted with Et2O. The combined organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo to give a white solid. It was recrystalized to give pure 3-(3-chloropropyl)-6-fluoroindazole (420 mg, 86%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[I-].[K+].[Cl:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2[NH:21][C:20]([CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[N:19][C:18]=2[CH:33]([CH3:35])[CH3:34])[CH:12]=[C:13]([Cl:15])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:3]([CH2:2][N:21]1[C:17]([S:16][C:11]2[CH:12]=[C:13]([Cl:15])[CH:14]=[C:9]([Cl:8])[CH:10]=2)=[C:18]([CH:33]([CH3:34])[CH3:35])[N:19]=[C:20]1[CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:5])[CH3:4]
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
(1)In acetone (2 ml)was dissolved 111 mg (1.20 mmol)of chloroacetone, followed by addition of 200 mg (1.2 mmol)of potassium iodide, and the mixture was stirred at room temperature for 15 minutes. Then, 437 mg (1.00 mmol)of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (16b)and 170 mg (1.20 mmol)of potassium carbonate were added in order, and the mixture was stirred for 5 hours and was left overnight. This reaction mixture was concentrated under reduced pressure and the residue was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The residue was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:9). The oil was crystallized from ether to provide 270 mg (yield 62%)of 1-acetylmethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (17v). mp 87-90° C.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[S:4].N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:11][N:5]1[C:6](=[O:7])[CH:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[S:4]
Reactant: CCOC(=O)Cl
Reactant: CN1C(=O)CC(=O)N(C)C1=S
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)N(C)C(=S)N(C)C1=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
155 g (0.9 mol) of 1,3-dimethyl-2-thiobarbituric acid, 88,3 g (1.12 mol) of pyridine and 9 g of 4-dimethylaminopyridine are dissolved in 660 ml of dichloromethane and the solution is cooled to 0° C. Then 102 g (0.94 mol) of ethyl chloroformate are added dropwise over 1 hour. The mixture is subsequently stirred for 12 hours at 0° C., then allowed to warm to room temperature and worked up after a further 7 hours as follows. 600 ml of dichloromethane are added and the solution is washed with three 1000 ml portions of water, dried over Na2SO4 and the solvent is evaporated off. The crude product is recrystallised from ethanol. Melting point 90°-93° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[O:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][NH:14][CH2:13][CH2:12]1>C(OCC)(=O)C>[CH:1]([N:14]1[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:11][CH2:12][CH2:13]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CNCCO2
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=CN1CCOc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (30 ml),was added dropwise to formic acid (90 ml) at room temperature and after the mixture was stirred for 30 minutes, a solution of 2,3,4,5-tetrahydro-1,4-benzoxazepine (13.0 g) in ethyl acetate (50 ml) was added dropwise at:room temperature. The mixture was then stirred for 30 minutes, after which it was diluted with ice-water and extracted with ethyl acetate. The extract was washed successively with water, aqueous solution of sodium hydroxide (NaOH/H2O), and saturated aqueous solution of sodium chloride (NaCl/H2O) and dried over anhydrous magnesium sulfate (MgSO4). The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide the title compound (14.4 g) as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[C:51]([C:55]1[CH:60]=[CH:59][C:58]([S:61][CH2:62][CH2:63]CO)=[CH:57][CH:56]=1)([CH3:54])([CH3:53])[CH3:52]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][CH2:63][CH2:62][S:61][C:58]2[CH:59]=[CH:60][C:55]([C:51]([CH3:52])([CH3:54])[CH3:53])=[CH:56][CH:57]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(SCCCO)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCSc4ccc(C(C)(C)C)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 78.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (78 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (121 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-[4-(tert-butyl)phenyl]sulfanyl-1-propanol (80 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (109 mg, yield 74%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([N:12]2[CH2:13][C@@H:9]([CH3:8])[CH2:10][C@H:11]2[C:14]([OH:16])=[O:15])[CH:21]=[CH:22][CH:23]=1
Reactant: Brc1ccc(Br)cc1
Reactant: C[C@@H]1CN[C@H](C(=O)O)C1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C[C@@H](C(=O)O)N(c2cccc(Br)c2)C1
Temperature: 95 °C

Procedure:
To (4S)-4-methyl-L-proline trifluoroacetate (2.92 g, 8.17 mmol), 1,4-dibromobenzene (2.9 g, 12.27 mmol), potassium carbonate (3.95 g, 28.6 mmol), and copper iodide (315 mg, 1.64 mmol) was added dry DMF (30 mL) under dry nitrogen. The reaction flask was thoroughly degassed with dry nitrogen and heated at 95° C. for 3 days. Water and hexane were added and the organic phase was separated and discarded (to remove excess 1,4-dibromobenzene). The pH of the aqueous phase was adjusted to 3 with aqueous 10% HCl and the product extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (AcOH/EtOAc/Hex, 0.5/49.5/50) to afford (4S)-1-(3-bromophenyl)-4-methyl-L-proline.
Reaction SMILES: CC(C(OC)=O)=C.Br[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=CC=2)[CH:12]=[CH:11][CH:10]=1>>[CH2:18]=[CH:9][CH:10]=[CH2:11].[CH2:15]=[CH:14][C:13]1[CH:18]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Brc1cccc2ccccc12
Agent: C=C(C)C(=O)OC
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
In the above example, the matrix phase must have about the same R.I. as the grafted rubber phase. The 80 percent by weight of matrix phase must be a blend of SAN and PMMA that matches the graft rubber phase having an R.I. of about 1.5390. A blend of about 42 percent of PMMA and 58 percent of SAN (76/24) was found to have a R.I. about 1.5385 matching the graft copolymer closely, giving a low haze polyblend. The refractive index was determined by an Abbe Refractometer with bromonapthalene as the immersion fluid using ASTM D-2225 at 25° C. The haze values were determined by: ##EQU1##
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl.[CH2:19](Br)[CH:20]=[CH2:21].[C:23](=[S:25])=[S:24]>C(COC)OC>[C:11]([C:7]1[CH:8]=[C:9]([CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])[C:23]([S:25][CH2:19][CH:20]=[CH2:21])=[S:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: S=C=S
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCSC(=S)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 0.1 mol sample of 2,6-di-t-butylphenol was added dropwise to a solution of 0.2 mol sodium hydride (57% in mineral oil) in 150 ml dimethoxyethane under an atmosphere of nitrogen at about 25° C. After the addition was completed, the reaction mixture was stirred for one hour at 25° C. A 0.1 mol sample of carbon disulfide was then added and the resulting reaction mixture stirred at about 25° C. for 10 minutes. Concentrated hydrochloric acid (0.1 mol) was added slowly, followed by 0.1 mol allyl bromide in 50 ml dimethoxyethane. The reaction mixture was then heated at reflux overnight (about 16 hours). The reaction mixture was poured into ice water and the crystalline product recovered by filtration. Recrystallization from ether/hexane gave the product, which melted at 93°-95° C. Elemental analysis of the product is tabulated in Table I.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([C@H:31]1[O:33][CH2:32]1)[Cl:30].[O-]S([O-])(=O)=O.[Mg+2]>CO>[CH2:21]([N:20]([CH2:32][C@H:31]([OH:33])[CH2:29][Cl:30])[CH2:19][CH2:18][CH2:17][CH2:16][C@H:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNCc1ccccc1)C(=O)OC(C)(C)C
Reactant: ClC[C@@H]1CO1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN(Cc1ccccc1)C[C@H](O)CCl)C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 66.9 %

Procedure:
A mixture of Nε-benzyl-Nα-BOC-L-lysine t-butyl ester (24) (16.0 g, 40.76 mmol), CH3OH (40 ml), (S)-(+)-epichlorohydrin (4.17 g, 45.0 mmol) and anhydrous MgSO4 (5.33 g. 44.28 mmol) was stirred under N2 for three days. The solids were filtered off and washed with CH3OH. The filtrate was concentrated at room temperature to give a yellow oil. The resulting oil was purified by flash chromatography on silica gel (66% hexane/ethyl acetate) to give 13.23 g of (25) (77%) as a colorless oil. 1H NMR (C6D6) δ7.18 (m, 5H), 5.00 (br d, 1H), 4.40 (m, 1H), 3.62 (m, 1H), 3.40-3.10 (m, 4H), 2.20-2.00 (m, 4H), 1.63 (m, 1H), 1.40 (s, 9H), 1.31 (s, 9H), 1.20 (m, 2H). 13C NMR (C6D6) δ171.7, 155.2, 138.8, 128.8, 127.9, 127.0, 80.8, 78.8, 67.7, 58.8, 57.2, 53.9, 53.7, 47.3, 32.5, 28.0, 27.5, 26.3, 22.8. HRMS m/z calcd. for C25H42ClN2O5 485.2782, found 485.2775. [α]25D+5.3° (c=1.00, CHCl3).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:50][C:51]1[CH:62]=[CH:61][CH:60]=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>CN(C=O)C.O>[Cl:50][C:51]1[CH:62]=[CH:61][CH:60]=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][N:56]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:55]1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Reactant: Clc1ccccc1OC1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)C1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 34.7 %

Procedure:
DIPEA (167.9 mg, 1.3 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (80 mg, 0.32 mmol) in DMF (2 mL) followed by HOBt (48.3 mg, 0.35 mmol) and EDCI (124 mg, 0.65 mmol). After 2 minutes of stirring, 3-(2-chloro-phenoxy)-pyrrolidine hydrochloride (prepared by the method used for the synthesis of Intermediate 72) (76 mg, 0.32 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. Purification by recrystallisation from a mixture of DCM in hexane afforded 48 mg (34.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[3-(2-chloro-phenoxy)-pyrrolidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 425, 93.15%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.3 (s, 1H), 8.1-8.0 (t, 1H), 7.8-7.7 (t, 2H), 7.5-7.4 (m, 2H), 7.4-7.2 (m, 2H), 7.06-7.0 (m, 1H), 5.3-5.1 (d, 1H), 4.2-4.0 (m, 2H), 4.0-3.5 (m, 4H), 2.3-2.2 (m, 1H), 2.2-2.0 (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)/C=C\C(O)=O.[Cl:18][C:19]1[N:24]=[N:23][C:22]2[CH2:25][CH2:26][NH:27][CH2:28][C:21]=2[CH:20]=1.C(N(CC)CC)C.O>C(Cl)CCl>[C:1]([N:27]1[CH2:26][CH2:25][C:22]2[N:23]=[N:24][C:19]([Cl:18])=[CH:20][C:21]=2[CH2:28]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCc2nnc(Cl)cc2C1

Procedure:
A mixture of 12.6 g of benzoyl chloride in 100 cc of ethylene chloride is added dropwise to a suspension of 25.6 g of 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate in 250 cc of ethylene chloride and 21.8 g of triethylamine within 18 minutes at room temperature while stirring. The mixture is stirred at room temperature for a further 14 hours, 200 cc of water are added, the organic phase is separated and concentrated to an oil in a vacuum. Upon adding ether/dimethoxyethane to this oil, crude 6-benzoyl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine is obtained. After recrystallization from absolute ethanol with the addition of a small amount of coal, the compound has a M.P. of 125°-127° (decomp.).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[CH3:11][C:12]([O-:15])([CH3:14])[CH3:13].[K+]>C1COCC1.CCOCC>[C:12]([O:15][C:7](=[O:9])[CH2:8][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(CC(=O)O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
3,3-Dimethylglutaric anhydride (6.5 g, 45.7 mmol) was dissolved in THF (75 mL) and the t-BuOK, 1M in THF (52.5 mL, 52.5 mmol) was added and the mixture was stirred at room temperature for one hour. The reaction mixture was then diluted with ether, washed with 1N HCl, brine (3×), dried (MgSO4), and concentrated to give 6.8 g (69%) of the desired product as a colorless oil. 1H NMR (DMSO-d6) 12.0 (br s, 1H), 2.22 (s, 4H), 1.39 (s, 9H), 1.03 (s, 6H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+:22]=[N-:23])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:37]([OH:40])[C:38]#[CH:39].CCN(C(C)C)C(C)C>C1COCC1.CCOCC.[Cu]I>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:39]=[C:38]([CH2:37][OH:40])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C#CCO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(CO)nn4)nn23)CC1
Reaction time: 22 h

Procedure:
To a stirred colorless clear solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.049 g, 0.098 mmol), propargyl alcohol (0.029 ml, 0.490 mmol) and DIEA (0.086 ml, 0.490 mmol) in THF (2 mL) was added CuI (0.037 g, 0.196 mmol) at rt. The resulting turbid yellow reaction mixture stirred for 22 h and diluted with Et2O (50 mL), washed with 1% aq NH4OH (2×10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as pale yellow paste which was used in the next step without purification.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:23])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:8][CH:7]=1)=O.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C.FC(F)(F)C(O)=O>CC(C)=O>[CH:24]1([N:30]2[C:4]([C:6]3[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:8][CH:7]=3)=[C:3]([CH3:23])[NH:2][C:31]2=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCCC1
Reactant: CCCCCCCCCCOc1ccc(C(=O)C(C)N)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCOc1ccc(-c2c(C)[nH]c(=O)n2C2CCCCC2)cc1
Reaction time: 1 h

Procedure:
2-Amino-4'-decyloxypropiophenone hydrochloride (500 mg, 1.46 mmol) was suspended in acetone (180 ml) under ice-cooling, and cyclohexyl isocyanate (201 mg, 1.61 mmol) was added thereto. Triethylamine (590 mg, 5.84 mmol) was added, and the mixture was stirred for one hour under ice-cooling. After addition of trifluoroacetic acid (2 ml), the mixture was stirred overnight at room temperature. The solvent was removed by evaporation in vacuo, and the residue was extracted with ethyl ether. The extract was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. Evaporation of the solvent provided a crude product, which was then purified by column chromatography (chloroform/ethanol=50/1 (v/v)) to give the title compound. Yield: 235 mg (39%), m.p. 137°-138° C.
Reaction SMILES: [CH:1]([C:5]1[C:6]([OH:15])=[C:7]([CH:13]=[O:14])[CH:8]=[C:9]([CH:12]=1)[CH:10]=O)([CH2:3][CH3:4])[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1.Cl>O1CCOCC1>[CH:1]([C:5]1[C:6]([OH:15])=[C:7]([CH:8]=[C:9](/[CH:10]=[CH:24]/[C:23](=[O:25])[C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)[CH:12]=1)[CH:13]=[O:14])([CH2:3][CH3:4])[CH3:2]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CCC(C)c1cc(C=O)cc(C=O)c1O
Agent: Cl
Solvent: C1COCCO1
Product: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc(C=O)c1O
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A solution of 5-sec-butyl-4-hydroxyisophthalaldehyde of formula I (0.50 g, 3.05 mmol) and p-methyl acetophenone (0.41 g, 3.05 mmol) in dioxane (25 mL) was treated with conc.HCl (0.5 mL). The solution was heated at 80° C. for 2.5 h. Further, 0.5 mL of conc.HCl was added and reaction was continued for 2.5 h more. Most of the excess reagent was evaporated under reduced pressure, and the residue was suspended in water (50 mL) and extracted 3-fold with CHCl3 (50 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 4% ethyl acetate in hexane, which upon concentration provides (E)-3-sec-butyl-2-hydroxy-5-(3-oxo-3-p-tolylprop-1-enyl)benzaldehyde (General Formula III).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OC(C)C)(C)C>O1CCCC1>[C:25]1([NH:31][C:32]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccccc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 80.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (1.00 g, 4.06 mmol) and triethylamine (0.565 ml, 4.06 mmol) in tetrahydrofuran (20 ml) was added, under ice-cooling, phenyl isocyanate (0.529 ml, 4.87 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added diisopropyl ether (40 ml), and the solid was separated by filtration. The resulting solid was recrystallized from a mixed solvent of hexane and ethyl acetate to give 1.19 g (80.4%) of the desired product as a solid.