Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Cl)([O:3][CH3:4])=[O:2].[C:15]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:15]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])([O:17][CH3:18])=[O:16]
Reactant: COC(=O)COc1ccccc1CCl
Reactant: COC(=O)CCCOc1cc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1cc(OCc2ccccc2OCC(=O)OC)ccc1C=O

Procedure:
A mixture of 2-carbomethoxymethoxybenzyl chloride (0.1 mol) and 3-carbomethoxypropoxy-4-hydroxybenzaldehyde (0.08 mol) in 8:1-acetone: dimethylformamide (900 mL) is refluxed with anhydrous potassium carbonate (0.1 mol). When the reaction is complete, the cooled reaction mixture is filtered and evaporated. The resulting oil is diluted with ethyl acetate and washed with water (6X's). The dried ethyl acetate solution is absorbed on silica gel and eluted through a column of flash silica (500 g) with a mixture of ethyl acetate: petroleum ether. Condensation of the appropriate fraction gives 3-carbomethoxypropoxy-4-(2-(carbomethoxymethoxy)phenyl)methyloxybenzaldehyde which is used directly in the next step.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[O-2].[Mg+2].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18]>O.C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][S:13]([C:11]1[S:12][C:8]([Cl:7])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:15])=[O:14]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(S(=O)(=O)NCCO)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a stirred solution of ethanolamine (0.67 g, 11 mmol) in water (4 ml) was added at room temperature magnesium oxide (2.22 g, 55 mmol) and THF (12 ml). The suspension was stirred at room temperature for 30 min and a solution of 5-chloro-4-nitrothiophene-2-sulfonyl chloride (3.46 g, 13.2 mmol) in THF (4 ml) was added. The light yellow suspension was stirred at room temperature for 1 h and, after filtration on Dicalit, evaporated. Water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and subsequent crystallization from ethyl acetate/hexane to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-amide (1.39 g, 44%) as a yellow solid. MS (ISP) 284.8 [(M−H)−], mp 99° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7]CC)=O.O.Cl.[Cl:16][C:17]1[C:26]2[C:25](=O)[O:24][C:23](=O)[N:22](C)[C:21]=2[CH:20]=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[C:25]([OH:24])=[C:4]([C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:5](=[O:7])[N:22]2[CH3:23]
Reactant: Cn1c(=O)oc(=O)c2c(Cl)cccc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
Sodium hydride (1.9 g, 79.17 mmol, 1.60 equiv) was added in several portions to the mixture of 5-chloro-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione in N,N-dimethylformamide from Step 2. Diethyl malonate (7.7 g, 48.07 mmol, 1.00 equiv) was then added dropwise to the stirred mixture over a period of about 30 minutes. The resulting solution was stirred at about 85° C. for about 1 hour, water (800 ml) was added, and the pH of the solution was adjusted to 2 with a solution of hydrochloric acid (5 mol/L). The resulting crude product was collected by filtration and then re-crystallized in ethanol to give the title product as a light yellow solid (2.5 g, yield: 18% 2 steps).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[CH3:13][C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[N:16][N:15]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:19]([C:17]1[S:18][C:14]([CH3:13])=[N:15][N:16]=1)(=[O:21])=[O:20])[CH3:4]
Reactant: Cc1nnc(S(=O)(=O)Cl)s1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(C)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-methyl-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H HMR (500 MHz; DMSO-d6) δ 4.07 (q, 2H), 3.27 (s, 2H), 3.09 (t, 2H), 2.82 (s, 3H), 2.62 (t, 2H), 1.18 (t, 3H).
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:45]/[O:46][CH3:47])/[C:12]([NH:14][C:15]2([CH2:43][OH:44])[CH2:19][O:18][N:17]([C:20]3([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:24][CH2:23][C:22](=[O:25])[O:21]3)[C:16]2=[O:42])=[O:13])[N:10]=1)=O.CNC(=S)[S-].[Na+].O>CN(C)C=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:45]/[O:46][CH3:47])/[C:12]([NH:14][C:15]2([CH2:43][OH:44])[CH2:19][O:18][N:17]([C:20]3([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:24][CH2:23][C:22](=[O:25])[O:21]3)[C:16]2=[O:42])=[O:13])[N:10]=1
Reactant: CO/N=C(\C(=O)NC1(CO)CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)CCC(=O)O2)C1=O)c1csc(NC(=O)CCl)n1
Agent: CNC(=S)[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/N=C(\C(=O)NC1(CO)CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)CCC(=O)O2)C1=O)c1csc(N)n1
Yield: 76.1 %

Procedure:
In 3 ml of dimethylformamide was dissolved 170 mg of the Compound (9a) obtained as above. To the solution was added, under ice-cooling, 48 mg of sodium N-methyldithiocarbamate, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The concentrate was subjected to a silica-gel column chromatography, eluting with ethyl acetate - n-hexane (2:1) to give 115 mg of the above-titled Compound (9b).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[O:13][CH3:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[O:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)N1CCC(N)C(OC)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC(N(Cc2ccccc2)Cc2ccccc2)C(OC)C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of racemic ethyl 4-amino-3-methoxypiperidine-1-carboxylate (1 part by mole) in DMF were added benzyl bromide (about 2.2 part by mole), potassium carbonate (about 2.4 part by mole) and potassium iodide (about 0.2 part by mole) respectively. The reaction was heated to about 80° C. After about 6 hours, the reaction was slowly diluted with water (about 12 parts by volume) and extracted with, for example, ethyl acetate. The organic layer was washed with brine and then dried over anhyh Na2SO4. Subsequent filtration and concentration of the solvent provided the 1 as the yellow-orange oil (1 part by mole).
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12](O)=[O:13])[O:3]1)=[O:2].CSC.B>C1COCC1>[C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH2:12][OH:13])[O:3]1)=[O:2]
Reactant: O=C(O)CC1OC(=O)c2ccccc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: O=C1OC(CCO)c2ccccc21
Reaction time: 24 h

Procedure:
A solution of phthalide-3-acetic acid (1 mmol) in THF was treated with borane dimethylsulfide (1.5 mmol) at 0° C. for 1 h, and 25° C. for 24 h. Extraction and chromatography gave 2-(3-phthalidyl)ethanol as a light yellow oil. TLC: Rf=0.25, 50% EtOAc-hexane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.NC1C=CC([I:29])=CC=1NC1C=CN=C(N)N=1>>[I:29][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1
Reactant: Nc1nccc(Nc2cc(I)ccc2N)n1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Product: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(I)cc32)n1

Procedure:
The title compound was prepared by procedure described for 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine, by replacing 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine with 4-N-(2-amino-5-iodophenyl)pyrimidine-2,4-diamine: 1H NMR (500 MHz, DMSO) delta 1.91 (3H, s), 7.01 (1H, d, J=5.1 Hz), 7.22 (2H, s), 7.77-7.69 (3H, m), 8.58 (1H, d, J=5.0 Hz), 11.97 (1H, s); LC-MS: m/z=+454/456/458 (M+H)+.
Reaction SMILES: N#N.[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[CH:15])[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4].I[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>CCN(CC)CC.C1COCC1.[Cu]I>[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Fc1ccc(I)cc1
Reactant: C#Cc1ccnc(NC(C)(C)C)n1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
To a mixture of Pd(PPh3)Cl2 (0.4 g) in Et3N (150 mL) and THF (150 mL) under a stream of N2, was added tert-butylamino-4-ethynylpyrimidine (18.6 g, 0.11 mol). After bubbling N2 into the solution for 15 min, 4-iodo-fluorobenzene (23.6 g, 0.11 mol) and CuI (0.22 g) were added sequentially. The mixture was stirred at rt for 2.5 h. The precipitate was filtered and washed with EtOAc. The filtrate was concentrated and the residue was diluted with EtOAc and loaded directly onto a short pad of silica gel. The product was eluted with 10% EtOAc in hexanes to afford the crude product, which was recrystallized from EtOAc/hexanes to give the title compound as a light yellow solid (25 g, 84%). TLC: Rf=0.30. mp 97-99° C. IR: 3287 (w), 2964 (w), 2222 (w), 1566 (s). 1H NMR: 8.26 (d, J=4.2 Hz, 1H), 7.60-7.55 (m, 2H), 7.10-7.00 (m, 2H), 6.65 (d, J=4.9 Hz, 1H), 5.22 (s, 1H), 1.45 (s, 9H). 13C NMR: 164.19, (162.19, 162.03), 157.77, 150.83, (134.35, 134.29), (117.84, 117.81), (115.94, 115.76), 112.37, 89.91, 87.24, 51.07, 28.86. Anal. Calcd for C16H16FN3: C, 71.36; H, 5.99; N, 15.60. Found: C, 71.25; H, 5.95; N, 15.66.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)=[C:2]=[S:3].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[C:11]1([C:8]2[CH2:7][CH:6]([CH2:5][CH2:4][NH:1][C:2]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[S:3])[O:10][N:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1COCCN1
Reactant: S=C=NCCC1CC(c2ccccc2)=NO1
Product: S=C(NCCC1CC(c2ccccc2)=NO1)N1CCOCC1

Procedure:
One hundred mg. of the product of Example 2 was reacted with excess morpholine to produce 100 mg. of product, m.p. 128°-130° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:11](=[O:12])[CH2:10][NH:9][C:8](=[O:13])[C:5]21[CH2:7][CH2:6]2.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH3:3][N:4]1[C:11](=[O:12])[CH2:10][N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](=[O:13])[C:5]21[CH2:7][CH2:6]2
Reactant: BrCc1ccccc1
Reactant: CN1C(=O)CNC(=O)C12CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CN(Cc2ccccc2)C(=O)C12CC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.8 %

Procedure:
Sodium hydride (302 mg, 12.62 mmol) was taken up in DMF (10 mL) and cooled to 0° C. for 30 min. Then a mixture 4-methyl-4,7-diazaspiro[2.5]octane-5,8-dione (1.769 g, 11.47 mmol) in DMF (5 mL) was slowly added over 10 min. This mixture was allowed to stir for 45 min, and then benzyl bromide (4.08 mL, 34.41 mmol) was added, and the reaction was stirred for 45 min further. The mixture was carefully diluted with water (10 mL) and concentrated in vacuo. The resulting crude product was purified via reverse phase HPLC to provide 4-methyl-7-(phenylmethyl)-4,7-diazaspiro[2.5]octane-5,8-dione (1.535 g, 54%). LCMS: (M+H)+: 245.1.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:38]5C(=O)C6=CC=CC=C6C5=O)=[CH:30][CH:29]=4)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.O.NN>C(O)C>[ClH:1].[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][NH2:38])=[CH:32][CH:33]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cl
Product: NCCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1

Procedure:
To 500 ml of ethanol containing 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-[2-[4-(3-phthalimidopropyloxy)phenoxy]ethyl]piperazine (10.5 g) was added 85% hydrazine hydrate (2.95 g). The solution was stirred and refluxed for 24 hours. The insoluble phthalazinedione was then removed by filtration and the filtrate concentrated in vacuo. Water (200 ml) and concentrated ammonium hydroxide (50 ml) was added to the residue. The oil was extracted with dichloromethane and the solution dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue dissolved in ethyl acetate. Hydrogen chloride was bubbled into the solution to precipitate the product as its trihydrochloride salt which was recovered by filtration and crystallized from acetonitrile-methanol. The yield of 3-[[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-1-piperazinyl]ethoxy]phenyl]oxy]propanamine trihydrochloride, mp 237°-240°, was 6.0 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[O:13]=[C:14]1[N:20]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C@@H:30]([C:44](O)=[O:45])[CH2:31][C:32]3[CH:42]=[C:41]([CH3:43])[C:35]4[NH:36][C:37]([O:39][CH3:40])=[N:38][C:34]=4[CH:33]=3)=[O:28])[CH2:23][CH2:22]2)[CH2:19][CH2:18][C:17]2[CH:47]=[CH:48][CH:49]=[CH:50][C:16]=2[NH:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:13]=[C:14]1[N:20]([CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C@H:30]([CH2:31][C:32]3[CH:42]=[C:41]([CH3:43])[C:35]4[NH:36][C:37]([O:39][CH3:40])=[N:38][C:34]=4[CH:33]=3)[C:44]([N:1]3[CH2:6][CH2:5][CH:4]([N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)[CH2:3][CH2:2]3)=[O:45])=[O:28])[CH2:25][CH2:26]2)[CH2:19][CH2:18][C:17]2[CH:47]=[CH:48][CH:49]=[CH:50][C:16]=2[NH:15]1
Reactant: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)O)cc(C)c2[nH]1
Reactant: C1CC(N2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCOCC4)CC3)cc(C)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 mg (0.24 mmol) 4-piperidin-4-yl-morpholine were added to a solution of 90 mg (0.16 mmol) (R)-1-carboxy-2-(2-methoxy-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 60 mg (0.19 mmol) TBTU and 30 μL (0.22 mmol) triethylamine in 1 mL DMF and the reaction mixture was stirred overnight at RT. The reaction mixture was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][O:12][C:13](=[O:25])[CH2:14][C@H:15]([OH:24])[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17].[CH2:26](Br)[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OCC)(=O)C>C1COCC1.C(Cl)Cl>[CH3:11][O:12][C:13](=[O:25])[C@@H:14]([C@H:15]([OH:24])[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCC=Cc1ccccc1
Reactant: COC(=O)C[C@H](O)C(=O)N1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@H](C/C=C/c1ccccc1)[C@H](O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Lithium hexamethyldisilazide (1M in THF, 14.5 ml, 14.5 mmol) was added to a solution of (S)-3-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methyl ester (1.5 g, 6.9 mmol) in dry THF (15 ml) at −78° C. under N2 and stirred for 30 min. Cinnamyl bromide (1.6 g, 7.32 mmol) was then added, the reaction mixture stirred at −78° C. for 2 hrs, warmed up to room temperature and stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, adjusted the pH to 6 with 1N HCl and extracted with ethyl acetate. Combined ethyl acetate extracts were dried over MgSO4 and concentrated under reduced pressure to give yellow solid. Column chromatography on silica eluting with a mixture of ethyl acetate and methylene chloride gave the title compound as pale yellow solid (1.15 g).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[N:9]([N:14]=[C:15]([NH2:17])[N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[CH:20]=1.C(Cl)Cl>C(Cl)Cl.CO>[C:1]1([C:7]2[C:8]3[N:9]([N:14]=[C:15]([NH:17][CH:28]4[CH2:29][CH2:30][N:25]([C:21]5[CH:20]=[C:19]([CH3:18])[N:24]=[CH:23][N:22]=5)[CH2:26][CH2:27]4)[N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Cc1cc(C2=CCCCC2)c2nc(N)nn2c1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C2=CCCCC2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1

Procedure:
Prepared in analogy to example 1h, starting from 8-cyclohexenyl-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b). The title compound was obtained as a yellow viscous oil (yield: 17%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 404.6 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6](N)[CH:7]=1.N([O-])=O.[Na+].[BrH:14]>O>[Br:14][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:9]
Reactant: Br
Reactant: Cc1ccc(Cl)cc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Cl)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-chloro-2-methylbenzenamine (50 g, 0.355 mol) was dissolved in HBr solution (1.5 M, 100 mL) and cooled to 0° C., a solution of NaNO2 (27.6 g, 0.4 mol) in water (200 mL) was added dropwise. After addition, the mixture was stirred for 1 hr. In another flask CuBr (30 g, 0.21 mol) was added to HBr solution (1.5 M, 30 mL) and heated to 60° C., then the mixture was added to the above solution. The mixture was heated to reflux for 1 hr then cooled to rt. The reaction was quenched with water (500 mL), the aqueous layer was extracted 3 times with CH2Cl2, dried over Na2SO4, solvent removal and purification by column chromatography afforded 2-bromo-4-chloro-1-methylbenzene (53 g, 0.26 mol). 1H NMR (CDCl3, 400 MHz) δ 7.53 (s, 1H), 7.20-7.10 (m, 2H), 2.36 (s, 3H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:30])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24]OS(C)(=O)=O)[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:22]=2)=[O:30])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CNCCN1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCOS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CCN3CCNCC3)cs2)c(C(=O)C2CCCC2)c1
Yield: 61 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[4-(2-piperazin-1-yl-ethyl)-thiazol-2-yl]-urea (35 mg, 70%) was prepared from methanesulfonic acid 2-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl ester (0.06 g, 0.13 mmol) and piperazine (0.50 g, 5.82 mmol) following the general procedure Z.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[F:8][C:9]([F:24])([F:23])[C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[C:13](Cl)=[O:14].[OH2:25]>ClCCl>[F:8][C:9]([F:24])([F:23])[C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[C:13]([N:3]1[CH2:4][CH2:5][C:7]2([C:6](=[O:25])[NH:3][CH2:4][CH:5]2[C:10]2[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:6]1)=[O:14]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(CC)CC
Reactant: O
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
The residue was dissolved in dichloromethane (100 ml), triethyl amine (8.1 mL, 58 mmol) and 3,5-bistrifluoromethyl benzoylchloride (2.65 mL, 15 mmol) were added and the mixture was stirred at room temperature overnight. Water was added, the organic layer was separated and dried. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (methylene chloride/methanol 98:2) to yield the desired product (4.65 g, 85%), MS: m/e=471.2 (M+H+).
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH:8]2[C:26](O)=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1([CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([N:51](CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:35]([N:36]1[CH2:37][CH2:38][N:39]([NH:51][C:26]([CH:8]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][CH2:10][N:9]2[C:12](=[O:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:27])[CH2:40][CH2:41]1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1cc(C(=O)N2COC(c3ccccc3)C2C(=O)O)cc(OC)c1OC
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: COc1cc(C(=O)N2COC(c3ccccc3)C2C(=O)NN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Phenyl-3-(3,4,5-trimethoxybenzoyl)-oxazolidine-4-carboxylic acid (12) (120 mg; 0.310 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. 1-(Diphenylmethyl)piperazine (94 mg; 0.372 mmol), N,N-diisopropylethylamine (128 mg; 0.99 mmol) and PyBOP (193 mg; 0.372 mmol) are added sequentially. The reaction is stirred for 1 hour at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (30%→60% ethyl acetate in hexanes) affording the desired product as a white solid. CIMS: MH+ 622