Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2([CH3:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:14][C:15]([O:17]C)=[O:16].[OH-].[Na+].Cl>C(O)C.O>[NH:4]1[CH2:3][CH2:2][O:6][CH2:5][CH2:7]1.[CH3:1][C:2]1[O:6][C:5]([C:7]2([CH3:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: COC(=O)Cc1nc(C2(C)CCCCC2)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C1COCCN1
Product: Cc1oc(C2(C)CCCCC2)nc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-methyl-2-(1-methylcyclohexyl)-4-oxazoleacetate (64.3 g) in ethanol (100 ml) was added 2N sodium hydroxide (170 ml). The mixture was stirred at room temperature for 30 minutes, diluted with water, adjusted to pH 2 with hydrochloric acid and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off and morpholine (23 ml) was added. The resulting crystalline precipitate was collected by filtration to give 5-methyl-2-(1-methylcyclohexyl)-4-oxazoleacetic acid morpholine salt, yield 75.0 g. Recrystallization from acetone gave colorless needles melting at 109°-110° C. Yield 66.0 g.
Reaction SMILES: [CH3:1][CH:2]([OH:21])[CH2:3][C:4]1[N:5]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:24][O:21][CH:2]([CH3:1])[CH2:3][C:4]1[N:5]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1
Reactant: CI
Reactant: CC(C)Cn1c(CC(C)O)nc2cnc3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)Cc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
α-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-ethanol (6.5 g, 23 mmol, Example 74) was dissolved in N,N-dimethylformamide (50 mL) then cooled to 0° C. Sodium hydride (0.8 g, 25 mmol), 80% dispersion in mineral oil) was added and the resulting mixture was stirred at 0° C. for about 1 hour. Methyl iodide (2.2 mL, 34 mmol) was added and the resulting mixture was stirred at 0° C. for about 1 hour and then allowed to warm to room temperature. The reaction was quenched with water and then diluted with ethyl acetate. The organic layer was separated, washed several times with water, dried over magnesium sulfate then concentrated under vacuum. The resulting residue was purified by silica gel chromatography using 2-5% methanol in methylene chloride to give about 3 g of the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10](=[O:17])[N:9]3[CH2:18][CH2:19][NH:20][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:23]I.O>CN(C)C=O>[CH3:23][N:20]1[C:8]2[N:9]([C:10](=[O:17])[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:18][CH2:19]1
Reactant: O=c1c2cccnc2c(-c2ccccc2)c2n1CCN2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCn2c1c(-c1ccccc1)c1ncccc1c2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 2,3-dihydro-10-phenyl-imidazo-[1,2-g][1,6]naphthyridin-5(1H)-one (2.63 g) in N,N-dimethylformamide (100 ml), and add the solution to a stirred suspension of dimethylformamide (25 ml) and sodium hydride (as a 60% dispersion in mineral oil). Use 0.25 g of the dispersion, and stir the resulting mixture for 1 hour at 25° C. Add methyl iodide (8.5 g), and stir for 15 hours, again at 25° C. Pour the mixture over ice and water (500 g), and extract with dichloromethane. Combine extracts, wash them with water and brine, dry them over magnesium or sodium sulfate, and concentrate them. Crystallize the residue from chloroform-acetone to obtain 2,3-dihydro-1-methyl-10-phenylimidazo[1,2-g]-[1,6]naphthyridin-5(1H)-one, mp 237°-240° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][CH:3]=1.CN([CH:11]=[O:12])C.O=P(Cl)(Cl)Cl.[OH-].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH:11]([C:3]1[S:4][CH:5]=[C:6]([CH3:7])[C:2]=1[CH3:1])=[O:12]
Reactant: CN(C)C=O
Reactant: Cc1cscc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1csc(C=O)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 3,4-dimethylthiophene trimer (3.7 g, 11 mmol) in 20 mL of a DMF: CHCl3 (1:1, v:v) solvent mixture, was added 20 mL of a solution of DMF and POCl3 (4:1, v:v). The DMF:POCl3 mixture was added cautiously, dropwise at 0° C. Following the addition, the reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was then poured into ice water and neutralized with 25% NaOH solution to pH˜8. The aqueous mixture was extracted with dichloromethane. Upon solvent removal the residue was subjected to purification by column chromatography using silica gel and a dichloromethane-petroleum ether (1:3) mixed solvent as the eluting solution to yield pure product 2-formyl-3,4-dimethylthiophen trimer 2.2 g (Yield: 55%) 1H NMR (CDCl3) δ 10.09 (1H, s, CHO), 7.00 (1H, s, aromatic H), 2.54 (3H, s, CH3), 2.23 (3H, s, CH3), 2.16 (3H, s, CH3), 2.13 (3H, s, CH3), 2.11 (6H, s, CH3), and the corresponding trimer dialdehyde 1.57 g (Yield: 37%) 1H NMR (CDCl3) δ 10.09 (2H, s, CHO), 2.54 (6H, s, CH3), 2.15 (12H, m, CH3).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2].[Cl:17][CH2:18][CH2:19][CH2:20][S:21][C:22]1[N:26]([CH3:27])[C:25]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[CH3:33])=[N:24][N:23]=1>>[ClH:17].[CH2:1]([C:3]1[S:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][N:11]([CH2:18][CH2:19][CH2:20][S:21][C:22]3[N:26]([CH3:27])[C:25]([C:28]4[O:32][CH:31]=[N:30][C:29]=4[CH3:33])=[N:24][N:23]=3)[CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2]
Reactant: CCc1nc2cc3c(cc2s1)CCNCC3
Reactant: Cc1ncoc1-c1nnc(SCCCCl)n1C
Product: CCc1nc2cc3c(cc2s1)CCN(CCCSc1nnc(-c2ocnc2C)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-ethyl-6,7,8,9-tetrahydro-5H-[1,3]thiazolo[4,5-h][3]benzazepine (0.14 mmol) and 3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (0.16 mmol) and was obtained as a colourless slightly hygroscopic solid (13 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[C:17]([S:18][CH2:19][CH2:20][CH3:21])=[CH:16][CH:15]=[CH:14][N:13]=1>O>[C:4]1([CH2:3][S:10][C:12]2[C:17]([S:18][CH2:19][CH2:20][CH3:21])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: SCc1ccccc1
Reactant: CCCSc1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCSc1cccnc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a stirred suspension of 0.62 g (0.013 mol) of 50% sodium hydride (in mineral oil), which had been washed with hexanes, in 20 mls dry dimethylformamide cooled to -5° under nitrogen was added dropwise 1.6 g (0.013 mol) benzyl mercaptan such that the temperature was maintained below 5°. The suspension was stirred at room temperature for 1 hour, cooled to 0°, and a solution of 2.0 g (0.012 mol) of the product from Example 1 was added dropwise while maintaining the temperature between 0° and 5°. After warming to room temperature, the solution was poured into water and extracted with ether. The combined organic layers were washed with water and with brine, dried over magnesium sulfate, and evaporated to an oil which was purified by flash chromatography to afford 0.9 g (27%) oil: NMR (CDCl3, 200 MHz), 1.02 (3H, t, J=7 Hz), 1.6 (2H, m), 2.9 (2H, t, J=7 Hz), 4.45 (2H, s), 6.9-7.6 (7H, m), 8.3 (1H, m); IR (neat) 1560, 1370 cm-1.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[CH3:5])[CH3:2].CC(C)([O-])C.[K+].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(OC(=O)C)C>C1COCC1.O>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:3]([CH2:1][CH3:2])[C:4](=[O:6])[CH3:5])=[CH:16][CH:15]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCNC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(Cc1ccc(Br)cc1)C(C)=O
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
0.568 mL N-ethylacetamide was dissolved in 20 mL THF. 0.67 g Potassium tert-butoxide was added and the mixture stirred for 20 min at 50° C. Then 1 g of 4-bromobenzylbromide dissolved in 5 mL THF was added and the suspension stirred for 2 h at 50° C. After cooling, ethylacetate and water were added and the organic phase extracted with water (1×), dried and the solvent distilled off. The product was purified via FCC (cyclohexane/ethylacetate: 90/10→50/50) to yield 830 mg N-(4-bromobenzyl)-N-ethylacetamide as an oil.
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].C(C1(C2C=CC(Cl)=C(Cl)C=2)CCC1)(=O)C.[CH3:30][NH2:31].[H][H]>C(O)C.[Pt]=O>[CH3:30][NH:31][CH:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: [H][H]
Reactant: CN
Agent: O=[Pt]
Agent: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: CCO
Product: CNC(C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 60 °C

Procedure:
1-Acetyl-1-(4-chlorophenyl)cyclobutane (61 g prepared in a similar manner to that described in Example 1 for 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane, platinum oxide (0.75g), 33% solution of methylamine in ethanol (60 g) and ethanol (30 ml) were charged into an autoclave. The autoclave was filled with hydrogen and maintained at about 60° C. and 20 bar pressure for ten hours. The reaction mixture was filtered through charcoal and the solids washed with absolute alcohol. The solvents were removed by evaporation and a sample of the residue (10 g) was shaken with 2M hydrochloric acid (50 ml) and ether (50 ml). The aqueous layer was basified and extracted with ether. The ether extract yielded a liquid on evaporation which was distilled (109° C./0.3 mm Hg) to give N-methyl-1-[1-(4-chlorophenyl) cyclobutyl]ethylamine (Formula I R1 =Me; R2 =H; R3 =Me; R4 =H; R5 =4--Cl and R 6 =H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([OH:24])=[O:23])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([O:24][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:23])[CH2:13][O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](COCc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 199.6 %

Procedure:
Into a solution of 25 g (0.076 mol) of N-(benzyloxycarbonyl)-O-benzylserine in 600 ml of CH2Cl2 cooled to -6° C. in an ice-salt bath was bubbled isobutylene, while 4.1 ml of concentrated sulfuric acid was added dropwise thereto. The mixture was stirred for 4 hours and worked up as described in Synthetic Commun., 26:2723 (1996) to give 29.24 g of product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH:8]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH2:7][C:6]=2[NH:5][C:4](=[O:18])[CH:3]=1.[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH3:21][N:5]1[C:6]2[CH2:7][CH:8]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH2:9][C:10](=[O:12])[C:11]=2[C:2]([CH3:1])=[CH:3][C:4]1=[O:18]
Reactant: Cc1cc(=O)[nH]c2c1C(=O)CC(c1ccsc1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(C)c2c1C(=O)CC(c1ccsc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-methyl-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.518 g) in dimethylformamide (5 ml) was added at room temperature 60% sodium hydride (0.08 g) and then was added methyl iodide (0.3 ml), and the mixture was stirred at room temperature for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The resulting crystals were washed with ethyl acetate to give 1,4-dimethyl-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.405 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]=[C:8]([N:10]=[N:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[S:9][C:5]=2[CH:4]=1.[S:23]([O:28]C)([O:26][CH3:27])(=[O:25])=[O:24]>ClC1C=CC=CC=1>[CH3:27][O:26][S:23]([O-:28])(=[O:25])=[O:24].[CH3:20][N:18]([CH3:19])[C:15]1[CH:14]=[CH:13][C:12]([N:11]=[N:10][C:8]2[S:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:22]=[CH:21][C:6]=3[N+:7]=2[CH3:27])=[CH:17][CH:16]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc2nc(N=Nc3ccc(N(C)C)cc3)sc2c1
Solvent: Clc1ccccc1
Product: COS(=O)(=O)[O-]
Product: COc1ccc2c(c1)sc(N=Nc1ccc(N(C)C)cc1)[n+]2C

Procedure:
A solution of [4-(6-methoxy-benzothiazol-2-ylazo)phenyl]-dimethyl-amine (Example 4b, 0.75 g, 2.40 mmol) and dimethyl sulfate (0.50 mL, 5.28 mmol) in 15 mL of chlorobenzene was heated under nitrogen at 70° C. for 3 hours. The solution was cooled and solid formed. The mixture was filtered, the solid was washed with diethyl ether and recrystallized from ethanol to give the title compound as a dark blue-black solid, mp 206-207° C., dec.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(F)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 29.7 %

Procedure:
In a similar fashion compound to CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 4-Fluorobenzaldehyde (23.2 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to yield 20.09 mg (30%) of the title compound. (300 MHz, DMSO-d6) 13.31 (s, 1H), 8.18 (s, 2H), 7.96 (m, 1H), 7.77 (s, 1H), 7.41 (m, 2H), 7.23 (s, 2H), 6.40 (m, 2H), 5.18 (t, J=17 Hz, 8.5 Hz, 1H), 2.90 (s, 1H), 2.78 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=398 (M+H), HPLC: 2.54 min. (G Method)
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]([O:17][CH:18]([CH3:20])[CH3:19])(=[O:16])[CH2:9][C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11].Br[CH2:22][C:23]([O:28][CH3:29])([O:26][CH3:27])[CH2:24]Br>O>[CH:18]([O:17][C:8]([C:9]1([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])[CH2:24][C:23]([O:28][CH3:29])([O:26][CH3:27])[CH2:22]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Reactant: COC(CBr)(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Temperature: 145 °C

Procedure:
Following the procedure of Pigou and Scheisser (J. Org. Chem. 1988, 53, 3841), a 500 mL, 3-neck flask, fitted with a reflux condenser and thermocouple, was charged with NaH (60% in mineral oil, 4 g, 0.210 mol). DMF (100 mL) was added via syringe and the slurry was stirred under N2. Diisopropyl malonate was added at a rate so that the internal temperature did not rise above 70° C. After the H2 evolution had ceased, the flask was briefly opened and 1,3-dibromo-2,2-dimethoxypropane was added. The bath temperature was raised to 145° C. The reaction mixture was maintained at this temperature for 48 h. After this time the dark brown mixture was allowed to cool to rt. Water (50 mL) was added and the solvents were removed in vacuo. The residue was partitioned between ether (200 mL) and sat'd aq NH4Cl (200 mL) and the mixture filtered through a pad of Celite to remove solid impurities. The aqueous layer was extracted with ether (2×100 mL). The combined ether extracts were washed with brine, dried over Na2SO4, filtered and evaporated. Flash chromatography (SiO2, 0-25% EtOAc in hexanes) gave semi-pure diisopropyl-3,3-dimethoxycyclobutane-1,1-dicarboxylate (28.5 g), which was used in the next step.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH:14]([OH:16])[CH3:15].CN(C)C=O>>[C:1]1(=[O:11])[N:5]([CH2:15][CH2:14][OH:16])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: CC(O)Br
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCO
Temperature: 70 °C
Reaction time: 12 h
Yield: 44.12 %

Procedure:
Potassium phthalimide 2 (2.7 g, 14.6 mmol) was added to a solution of bromoethanol 1 in N,N-dimethylformamide (12 mL, 14.1 mmol). After stirring for 12 h at 70° C., the mixture was concentrated and then diluted with dichloromethane (100 mL). After removal of solids by filtration, the organic layer was washed with water, dried, and concentrated. The concentrate was purified by flash column chromatography (3:2 to 2:3 hexane-ethyl acetate) to give compound 3 as a white solid (1.19 g, 44.12%) having an RF of 0.22 (3:2 hexane-ethyl acetate). See FIG. 5.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:17][CH3:18]>C(#N)C>[I-:17].[CH3:18][N+:9]1[C:10]([CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: C[Si](C)(C)Cc1cn(-c2ccccc2)nn1
Reactant: CI
Solvent: CC#N
Product: C[n+]1nn(-c2ccccc2)cc1C[Si](C)(C)C
Product: [I-]

Procedure:
1-phenyl-4-((trimethylsilyl)methyl)-1H-1,2,3-triazole and excess iodomethane were added to a vial. The reaction was heated for 19.5 hours. and 5 mL ACN was added. The reaction was heated for another 2 hours. The precipitate was filtered, rinsed with ether and dried in vacuo overnight. The following 3-methyl-1-phenyl-4-((trimethylsilyl)methyl)-1H-1,2,3-triazol-3-ium iodide structure was confirmed:
Reaction SMILES: [C:1](=[O:4])([O-:3])[NH2:2].[CH3:5][N:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:8]([N+:21]([O-])=O)[CH2:7]1.C(O)(=O)C>CO.[Zn]>[C:1](=[O:3])([O-:4])[NH2:2].[CH3:5][N:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:8]([NH2:21])[CH2:7]1
Reactant: CN1CC(c2ccccc2C(F)(F)F)C([N+](=O)[O-])C1
Agent: NC(=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CC(N)C(c2ccccc2C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3S and R,4R and S)-1-Methyl-3-nitro-4-(2-(trifluoromethyl)phenyl) pyrrolidine (296.8 mg, 1.082 mmol) was dissolved in MeOH (5 mL) and the reaction mixture was cooled to 0° C. Acetic acid (5 mL) and zinc (354 mg, 5.41 mmol) were added and the reaction mixture was warmed to room temperature and stirred under N2 for 16 h. The suspension was filtered over Celite and washed with MeOH. The filtrate was concentrated in vacuo, the residue suspended in EtOAc, cooled in an ice bath, and basified with conc. NH4OH. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford (3S and R,4R and S)-1-methyl-4-(2-(trifluoromethyl)phenyl)pyrrolidin-3-amine, which was carried onto the next step without further purification. MS ESI calc'd. For C12H15F3N2 [M+1]+ 245. found 245.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:11][CH:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:27][C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:38])[CH:36]=[CH2:37])[CH:31]=[CH:32][CH:33]=1>>[C:12]1([CH:10]2[CH2:11][CH:9]2[NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:27][C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:38])[CH:36]=[CH2:37])[CH:31]=[CH:32][CH:33]=3)[N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ncnc(NC2CC2c2ccccc2)n1
Reactant: C=CC(=O)Nc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Nc2ncnc(NC3CC3c3ccccc3)n2)c1
Temperature: 100 °C

Procedure:
To a slurry of (4-chloro-[1,3,5]triazin-2-yl)-(2-phenyl-cyclopropyl)amine (Step 1)(45.6 mg, 0.185 mmol) in IpOH (2.5 ml) was added DIEA (0.048 mL, 0.277 mmol) and N-(3-aminophenyl)acrylamide (53. mg, 0.203 mmol). The mix was heated at 100° C. for 18 h. The solution was then cooled to RT. A precipitate fell out of solution, was filtered off and dried under reduced pressure to give N-{3-[4-(2-phenyl-cyclopropylamino)-[1,3,5]triazin-2-ylamino]phenyl}-acrylamide: MS m/z=373 [M+H]. Calc'd for C21H20N6O: 372.17.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:6][C:7]=1[C:8](Cl)=[O:9].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:6][C:7]=1[C:8]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]=1[Cl:17])=[O:9]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1cc(-c2ccncc2)nnc1Cl
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)nnc1Cl

Procedure:
The title compound was prepared by treating the dichloride (6) with 2,4-dichlorobenzylamine according to Scheme I. DCI-MS m/z 392 (m+H+). 1H NMR (CDCl3) δ 8.83 (d, J=6 Hz, 2H), 8.33 (a, 1H), 8.00 (d, J=6 Hz, 2H), 7.5 (m, 2H), 7.3 (m, 3H), 4.76 (d, J=6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23]S(C)(=O)=O.[CH2:28](O)[CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36]
Reactant: OCCOCCOCCO
Reactant: COCCOCCOCCOCCOCCOCCOCCOS(C)(=O)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO

Procedure:
Monodispersed compound 32 was prepared from compound 31 and monodispersed triethylene glycol using the procedure described herein. Oil; Rf 0.41 (methanol:chloroform=6:10); MS m/z calc′d for C21H44O11 472.29 (M++1), found 472.29.
Reaction SMILES: Br[C:2]1[C:3]([CH:9]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[Cl:7].CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[O:34][CH2:33][CH2:32][CH2:31]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([O:15][CH:9]([C:3]1[C:2]([C:28]2[CH:37]=[CH:36][C:35]3[O:34][CH2:33][CH2:32][CH2:31][C:30]=3[CH:29]=2)=[C:6]([Cl:7])[S:5][C:4]=1[CH3:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(Cl)c1Br
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(Cl)c1-c1ccc2c(c1)CCCO2
Temperature: 85 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
Under argon atmosphere, ethyl 2-(4-bromo-5-chloro-2-methylthiophen-3-yl)-2-(tert-butoxy)acetate (44d) (500 mg, 1.35 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (351.8 mg, 1.35 mmol), sodium carbonate (429 mg, 4.05 mmol) were dissolved in dioxane (28 mL) and water (4 mL). The solution was degassed under argon for 10 minutes and bis(triphenylphosphine)palladium (II) dichloride (142 mg, 0.20 mmol) was added. The reaction was heated and shaken at 85° C. for 8 hours. After cooling at room temperature, the mixture was filtered through celite, rinsed with methanol. The filtrate was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 97/3) to give the desired product (44e) (308 mg, 0.73 mmol, 54%).