Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[OH-].[Na+].C(O)C[O:21][CH2:22][CH2:23]O.[CH3:26]O>>[OH:21][CH2:22][CH2:23][CH2:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CO
Reactant: O=C(O)CCCCCCCCCCCCO
Reactant: OCCOCCO
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCCCCCCCCCO
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A compound of General formula 4 (n=10) (2.72 g, 10 mmole) was mixed with 2.0 g of ground sodium hydroxide, 16 ml of diethylene glycol, 1.3 ml of 85% hydrated hydrazine, and 0.6 ml of methanol, and stirred at 110° C. for 30 min. The mixture was heated up to 195-200° C. and stirred for 15 hours. Distillable components were completely distilled off to ensure its removal out of the system. The residue was cooled, acidified and subjected to extraction with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off to provide a crystalline material. It was recrystallized from benzene to produce 2.1 g of 15-hydroxypentadecanoic acid 2 (n=10). The yield was 81%. The product had a melting point of 84-86° C. The structure of 15-hydroxypentadecanoic acid was confirmed from IR and NMR spectral observation.
Reaction SMILES: [Br:1]CCCCCCCCCCCO.C(N(CC)CC)C.C(Cl)(=O)C=C.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39](=[O:42])[CH:40]=[CH2:41].[CH3:43][N:44]1[CH:48]=[CH:47][N:46]=[CH:45]1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>O1CCCC1>[Br-:1].[C:39]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][N+:46]1[CH:47]=[CH:48][N:44]([CH3:43])[CH:45]=1)(=[O:42])[CH:40]=[CH2:41]
Reactant: Cn1ccnc1
Reactant: C=CC(=O)OCCCCCCCCCCCBr
Reactant: OCCCCCCCCCCCBr
Agent: C=CC(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCCCCCC[n+]1ccn(C)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
11-Bromoundecanol (10.00 g, 40 mmol) was dissolved in 40 ml of dry tetrahydrofuran (THF) in a two-necked round bottom flask. The flask was cooled in an ice-bath and triethylamine (5.13 mL, 40 mmol) in THF (40 mL) was added to the stirring solution. Acryloyl chloride (3.65 g, 40 mmol) dissolved in 40 ml of THF was added dropwise to the stirring solution over a period of 15 min under N2 atmosphere. The mixture was further stirred for 2 days at room temperature and was filtered. The filtrate was washed with 2% sodium bicarbonate solution to remove any unreacted acid chloride and dried over anhydrous MgSO4. The dried solution was filtered and the filtrate was passed through a short column of neutral alumina, using CH2Cl2 as the light yellow liquid (yield 10.58 g, 87%). Under N2 atmosphere, a mixture of 11-bromoundecylacrylate (6.08 g, 20 mmol) and 1-methylimidazole (1.64 g, 20 mmol) and a small amount of 2,6-di-tert-butyl-4-methylphenol (inhibitor) was stirred at 40° C. for 48 h, and yielded a viscous liquid. The viscous liquid was purified by the precipitation method with diethyl ether to obtain a yellow viscous liquid 1-(11-acryloyloxyundecyl)-3-methylimidazolium bromide. The viscous liquid was dried under vacuum at room temperature to obtain a white waxy solid (5.73 g, 74%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[O:11]1CCC[CH2:12]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(N(CC)CC)C>[C:4]([C:3]1([CH3:8])[CH2:9][O:10][C:12](=[O:11])[O:1][CH2:2]1)([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(CO)CO
Reactant: C1CCOC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1(C)COC(=O)OC1
Temperature: -78 °C

Procedure:
In a 500 mL three neck RB flask were added methyl 2,2-bis(hydroxymethyl)propionate (12.45 g) and tetrahydrofuran (THF) (100 mL). The resulting mixture was stirred under nitrogen via a mechanical stirrer until a homogeneous solution results. Triphosgene (8.78 g) was added and the solution cooled to −78° C. Triethylamine (18.3 g) was slowly added to the cooled solution. The resulting mixture was stirred at this temperature for one hour and then allowed to warm to room temperature. The triethylamine/HCl salt was filtered off and the resulting filtrate pass through a shallow bed of silica gel. The filtrate was concentrated at reduced pressure and then dried under vacuum affording 13.4 g of product which had a small amount of contamination. This contamination was removed via washing with warm diethyl ether. 1H NMR (CDCl3) ppm: 4.67 (ab doublet, 2H), 4.20 (ab doublet, 2H), 3.77 (S, 3H), 1.30 (S, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1([CH3:25])[O:22][CH:21]([CH2:23][NH2:24])[CH2:20][O:19]1.CO>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]([NH:24][CH2:23][CH:21]1[CH2:20][O:19][C:18]([CH3:25])([CH3:17])[O:22]1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OCC(CN)O1
Reactant: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(CNC(=O)OC(C)(C)C)NCC1COC(C)(C)O1
Yield: 32.6 %

Procedure:
The commercially available Tert-butyl-N-(2-hydroxypropyl)carbamate (10 g, 57.0 mmol)) and trietylamine (12 ml, 85.6 mmol) were dissolved in dichloromethane (60 mL) and cooled to 0° C. Methanesulfonyl chloride (4.9 ml, 62.7 mmol) was added dropwise to the ice-cold solution and the reaction was allowed to warm up to room temperature with stirring overnight. The reaction was then quenched with NaOH (1M, 5 ml). The organics were washed with water (2×100 ml) and then brine, collected, dried over MgSO4, filtered and evaporated under reduced pressure to give methanesulfonic acid 3-tert-butoxycarbonylamino-propyl ester (13.5 g). The crude methanesulfonic acid 3-tert-butoxycarbonylamino-propyl ester (13.5 g, 53 mmol) and 2,2-dimethyl-1,3-dioxolane-4-methanamine (12 g, 91.6 mmol) were stirred overnight at room temperature. The mixture was dissolved in ethyl acetate (100 ml) and washed with water (3×100 ml) and brine. The organics were collected, dried over MgSO4, filtered and evaporated under reduced pressure to give an oil. This was purified by silica column chromatography eluting with ethyl acetate: methanol to give the desired product {2-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-propyl}-carbamic acid tert-butyl ester (4.74 g, 17.3 mmol). Mass Spec (ESI) m/z: [M+H]+=289.12. 1H NMR (CDCl3; 300 MHz) δ=5.15 (s, br, 1H), 4.19 (quin, 1H), 4.02 (t, 1H), 3.66 (t, 1H), 3.18 (q, 2H), 2.70 (m, 4H), 1.63 (quin, 2H), 1.42 (s, 9H), 1.40 (s, 3H), 1.40 (s, 3H). 13C NMR (CDCl3; 300 MHz) δ=156.00, 109.05, 78.85, 75.23, 67.47, 52.30, 47.91, 39.20, 29.69, 28.35, 26.81, 25.37.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1)#[N:26]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:34](=[O:35])[CH2:33][C:30]4[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: N#Cc1ccc(CC(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)Cc2ccc(C#N)cc2)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. α-(4-Cyanophenyl)acetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[α-(4-cyanophenyl)acetyloxy]-2(1H)-pyrimidinone as the residue.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.O.[NH2:15][NH2:16]>O1CCOCC1>[NH:15]([C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1)[NH2:16]
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NN)c2cccc(O)c2n1

Procedure:
A mixture of 4-chloro-2-methyl-quinolin-8-ol (0.10 g, 0.51 mmol) and hydrazine monohydrate (0.75 mL, 15 mmol) in dioxane (10 mL) was heated to reflux for 4 d. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with DCM/methanol/conc. aqueous NH3 5:1:0.033) to give the title compound. MS (m/z): 190.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12](O)=[O:13])=[CH:7]2>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][OH:13])=[CH:7]2
Reactant: O=C(O)c1ccc2c(Br)cccc2c1
Solvent: C1CCOC1
Product: OCc1ccc2c(Br)cccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-bromonaphthalene-2-carboxylic acid (10.04 g, 40 mmol) in dry THF (400 mL) cooled to 0° C. was added BH3 ·THF (54 mL, 54 mmol; 1.0M solution in THF) dropwise over 45 minutes. The resulting solution was stirred overnight while warming to room temperature. The excess BH3 was quenched by the addition of H2O (200 mL) at 0° C. and the volatiles were removed in vacuo. The aqueous residue was extracted with Et2O (2×250 mL) and the combined organic layers were dried (MgSO4) and concentrated in vacuo to give the title compound as a colorless liquid which solidified to a white solid upon standing (9.48 g, 100%). This material was of adequate purity to be used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:16]=[CH:15][NH:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:16]=[CH:15][N:14]([CH3:17])[C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: Clc1nc(-c2cccnc2)nc2[nH]ccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)nc(-c3cccnc3)nc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.7 %

Procedure:
To a solution of 4-chloro-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.34 mmol, 1.0 eq.) in dry DMF (20 mL) was added Cs2CO3 (221 mg, 0.68 mmol, 2.0 eq.) and iodomethane (54.3 mg, 0.38 mmol, 1.1 eq.) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2.5 h. The reaction mixture was poured into ice water and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 8:1) to give 65 mg of xlvi-a as brown solid (56.7%).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].I[CH3:38].O>CN(C)C=O>[CH3:38][O:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)[N:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (462 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 40.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Iodomethane (0.187 ml) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-methoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate was obtained (382 mg, yield: 80%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=O)[CH:8]=1)=[O:5].[NH:32]1[CH:36]=[C:35]([CH2:37][NH2:38])[N:34]=[N:33]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[NH:32]1[CH:36]=[C:35]([CH2:37][NH:38][C:18]([C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:21]=[C:22]([C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:23]=[CH:24][C:2]=3[Cl:1])[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[O:20])[N:34]=[N:33]1
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Reactant: NCc1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1c[nH]nn1)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
To a solution of 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105, 200 mg, 0.458 mmol), (1H-1,2,3-triazol-4-yl)methanamine (74 mg, 0.549 mmol) and N,N-diisopropylethylamine (406 μL, 2.29 mmol) in dichloromethane (3 mL) and N,N-dimethylformamide (1 mL) was added HATU (261 mg, 0.687 mmol). The reaction was stirred at room temperature for 2 hours. Further HATU (87 mg, 0.229 mmol) was added and the reaction continued for 3 hours. The reaction solution was partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous layer was further extracted with ethyl acetate (2×10 mL), and the combined organic layers were washed with brine (20 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by elution through an SCX-2 column using MeOH followed by 7N NH3 in MeOH followed by silica gel column chromatography eluting with 1% NH3(aq) and 8% MeOH in DCM to afford the title compound as white solid (51 mg, 21%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>CN(C=O)C.O.[Cu-]=O>[CH3:8][C:6]1[CH:7]=[C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=[C:4]([CH3:12])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: Sc1ccccc1
Reactant: CC(=O)c1c(C)cc(I)cc1C
Agent: O=[Cu-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(C)cc(Sc2ccccc2)cc1C
Yield: 65.5 %

Procedure:
A mixture of 1-(4-iodo-2,6-dimethylphenyl)ethanone (1.5 g, 5.5 mmol, 1.0 equiv), benzenethiol (0.60 mL, 8.2 mmol, 1.5 equiv), copper(I) oxide (39.2 mg, 0.3 mmol, 0.05 equiv), and potassium hydroxide (614.1 mg, 11.0 mmol, 2.0 equiv) in DMF (4.4 mL) and H2O (1.1 mL) was heated at reflux for 20 h. The mixture was quenched with H2O (10 mL) and extracted with ether (2×20 mL). The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to provide 1-(2,6-dimethyl-4-(phenylthio)phenyl)ethanone (931 mg, 3.6 mmol) as yellow oil in 66% yield: 1H NMR (CD3OD, 500 MHz) δ 7.34-7.35 (m, 5H), 6.97 (s, 2H), 2.46 (s, 3H), 2.17 (s, 6H); ESI-MS: m/z 257.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[N:10][C:9]=2[N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][CH2:35][C:36]([CH:39]1[CH2:41][CH2:40]1)([OH:38])[CH3:37]>CN(C)C=O>[CH:39]1([C:36]([OH:38])([CH3:37])[CH2:35][NH:34][C:14]([C:12]2[CH:11]=[N:10][C:9]([N:17]3[CH2:18][CH2:19][CH2:22][CH2:20][CH2:21]3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:13]=2)=[O:15])[CH2:41][CH2:40]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(O)(CN)C1CC1
Reactant: O=C(O)c1cnc(N2CCCC2)c(-c2ccc(Cl)cc2)n1
Solvent: CN(C)C=O
Product: CC(O)(CNC(=O)c1cnc(N2CCCCC2)c(-c2ccc(Cl)cc2)n1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of 0.050 g (0.00016 mol) 6-(4-chloro-phenyl)-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid in 2 ml dimethylformamide was added at room temperature 0.055 g (0.00032 mol) 1,1′-carbonyl-diimidazole and the mixture was stirred at room temperature for 30 min. To the resulting mixture was added 0.072 g (0.00063 mol) 1-amino-2-cyclopropyl-propan-2-ol, and the mixture was stirred at room temperature for 17 hours. The resulting mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel using a gradient of heptane to ethyl acetate to yield 0.043 g (66% yield) of the title compound as slightly yellow oil. MS (ISP) (M+H+)=415.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=[O:10])[O:6][CH:7]([CH3:9])[CH3:8].[CH3:11][C:12]([CH3:23])=[CH:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[CH3:11][C:12]([CH3:23])=[CH:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:2][CH2:3][NH:4][C:5](=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])=[CH:20][CH:21]=1
Reactant: CC(C)=CCOc1ccc(O)cc1
Reactant: CC(C)OC(=O)NCCCl
Product: CC(C)=CCOc1ccc(OCCNC(=O)OC(C)C)cc1

Procedure:
Following the procedures of Example 1, isopropyl 2-chloroethylcarbamate is prepared and is then reacted with 4-(3-methyl-2-butenoxy)phenol to give isopropyl N-{2-[4-(3-methyl-2-butenoxy) phenoxy]ethyl}carbamate, MS m/e 307 (M+).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)CBr)cc1
Yield: 97.6 %

Procedure:
A solution of bromine (0.31 mL, 5.9 mmol) in carbon tetrachloride (10 mL) was added to a suspension of N-(4-acetylphenyl)acetamide (1 g, 5.6 mmol) (Lancaster Synthesis) in carbon tetrachloride (20 mL). The reaction mixture was stirred for several hours but TLC indicated only starting material. Acetic acid (10 mL) was added, and the reaction mixture was stirred overnight. Filtration gave N-[4-(bromoacetyl)phenyl]acetamide (1.4 g) as a solid. HPLC indicated that the purity was approximately 80%. This material was used directly in subsequent steps without purification.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:8]([OH:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25].[Na]>O1CCOCC1>[CH2:25]([O:13][CH:8]([C:9]([CH3:11])([CH3:12])[CH3:10])[CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:20][CH:19]=1)[N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[CH:24]=[CH2:23]
Reactant: CC(C)(C)C(O)C(Oc1ccc(Br)cc1)n1cncn1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1COCCO1
Product: C=CCOC(C(Oc1ccc(Br)cc1)n1cncn1)C(C)(C)C
Yield: 78.9 %

Procedure:
34 g (0.1 mol) of 1-(4-bromophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol were suspended in 175 ml of dioxane and the suspension was added dropwise to a mixture of 3.5 g of 80% strength sodium hydride and 125 ml of dioxane while stirring. Thereafter, the mixture was heated under reflux for one hour. After cooling, 14.5 g (0.12 mol) of allyl bromide were added dropwise at room temperature to the sodium salt thus obtained. The mixture was then heated under reflux for 15 hours, allowed to cool and concentrated by distilling off the solvent. The oily residue was taken up in 600 ml of methylene chloride and the methylene chloride solution was washed twice with 1,000 ml of water each time, dried over sodium sulphate and concentrated. The residue was distilled under a high vacuum. 30 g (79% of theory) of 2-allyloxy-1-(4-bromophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butane of boiling point 152°-154° C./0.2 mm Hg were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]([CH3:28])([CH3:27])[NH2:26].[ClH:29]>C(#N)C>[ClH:29].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]([NH:26][CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[CH3:1])([CH3:27])[CH3:28]
Reactant: Cc1ccccc1OCC1CO1
Reactant: COc1ccc2[nH]cc(CC(C)(C)N)c2c1
Agent: Cl
Solvent: CC#N
Product: COc1ccc2[nH]cc(CC(C)(C)NCC(O)COc3ccccc3C)c2c1

Procedure:
(2-Methylphenoxymethyl)oxirane, 4.1 g., (0.025 mole) and 5.4 g. (0.025 mole) of 5-methoxy-α,α-dimethyl-1H-indol-3-yl-ethaneamine were mixed and heated at 130° for 2 hrs. The mixture was allowed to cool, but while still warm was dissolved in 60 ml. of acetonitrile and acidified with ethanolic 5 N HCl to pH 2. Th product crystallized as the hydrochloride salt, yield 8.3 g.; recrystallized from isopropanol/methanol, yield 7.4 g., m.p. 201.0°-203.0°.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH:9]=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11]1.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24].O>C(Cl)Cl>[C:22]([N:9]=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:12]=[CH:11]1)(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)C(=O)Cl
Reactant: N=c1ccn(-c2ccccc2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)C(=O)N=c1ccn(-c2ccccc2)nc1
Reaction time: 4 h
Yield: 47.2 %

Procedure:
11.5 g (114 millimoles) of triethylamine were added dropwise to 9.3 g (44.8 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride and 5.3 g (49.7 millimoles) of isobutyryl chloride in 50 ml of methylene chloride at room temperature, while stirring. After the addition was complete, stirring was continued for 4 hours at room temperature, after which water was added to the reaction mixture. The organic phase was separated off and mixed thoroughly with dilute hydrochloric acid (100 ml of water and 20 ml of concentrated hydrochloric acid). The methylene chloride phase was discarded, and the aqueous layer was brought to pH 10 with sodium hydroxide solution. The resulting solid substance was filtered off under suction, washed with water, dried and recrystallized from toluene/hexane. 5.1 g (47% of theory) of 1,4-dihydro-4-isobutyrylimino-1-phenylpyridazine were isolated as yellowish beige crystals of melting point 138° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:17](=[O:19])[CH3:18])[C:6]1=[O:16]
Reactant: COCCn1cc(-c2ccccc2)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Product: COCCn1cc(-c2ccccc2)n(C(C)=O)c1=O

Procedure:
Approximately 21.8 g of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one and 120 ml. of acetic anhydride is refluxed together for four hours. The acetic anhydride is distilled out at reduced pressure. The residual semisolid is recrystallized from ethyl acetate to yield the title compound Formula (2) in Sequence 2 as a white solid; m.p. 81°-82° C.