Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[C:17]([O:24][CH3:25])[C:16]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.Cl.[O:34]=[C:35]1[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:50]3[CH:51]=[C:52]([C:56]([OH:58])=[O:57])[CH:53]=[N:54][CH:55]=3)[CH:48]=2)[O:43][C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36]1.Cl>O.C(N(CC)CC)C.CN(C=O)C>[CH3:25][O:24][C:17]1[CH:18]=[C:19]([C:21]([N:40]2[CH2:41][CH2:42][C:37]3([CH2:36][C:35](=[O:34])[C:49]4[C:44](=[CH:45][CH:46]=[C:47]([C:50]5[CH:51]=[C:52]([C:56]([OH:58])=[O:57])[CH:53]=[N:54][CH:55]=5)[CH:48]=4)[O:43]3)[CH2:38][CH2:39]2)=[O:23])[CH:20]=[C:15]([O:14][CH3:13])[C:16]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1-c1ccccc1
Reactant: O=C(O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc(OC)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
Carbonyldiimidazole (81 mg) was added to a DMF solution (2 mL) of 2,6-dimethoxybiphenyl-4-carboxylic acid (129 mg), and stirred at 60° C. for 2.5 hours. To the reaction liquid, added were 5-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)pyridine-3-carboxylic acid dihydrochloride (246 mg) and triethylamine (209 ml), and stirred at that temperature for 17 hours. 1 N hydrochloric acid and water were added to the reaction liquid, and the resulting solid was purified through high-performance preparative liquid chromatography (0.1% TFA, water/acetonitrile). Then, this was further purified through silica gel thin-layer chromatography (chloroform/methanol) to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 9.06 (1.0H, d, J=2.4 Hz), 9.02 (1.0H, d, J=2.0 Hz), 8.41 (1.0H, dd, J=2.4, 2.0 Hz), 8.12-8.01 (2.0H, m), 7.38-7.32 (2.0H, m), 7.29-7.24 (2.0H, m), 7.23-7.19 (2.0H, m), 6.75 (2.0H, s), 4.36-4.22 (1.0H, br m), 3.69-3.12 (3.0H, m), 3.68 (6.0H, s), 2.95 (2.0H, s), 2.15-1.93 (2.0H, m), 1.91-1.75 (2.0H, m). MS [M+H]+=579.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].F[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[N:12][CH:13]=1
Reactant: N#Cc1cccc(O)c1
Reactant: Cc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2cccc(C#N)c2)nc1
Temperature: 150 °C
Yield: 35.9 %

Procedure:
A mixture of 3-hydroxy-benzonitrile (500 mg, 4.17 mmol), 2-fluoro-5-methylpyridine (467 mg, 4.17 mmol) and K2CO3 (150 mg) in N,N-dimethylformamide (5 mL) was heated at 150° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using hexane/ethyl acetate (2:1) to give the title compound (315 mg, 36%). MS (DCI/NH3) m/z 211 (M+1)+. 1HNMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 7.02 (d, J=8.59 Hz, 1H) 7.45 (ddd, J=8.29, 1.53, 0.92 Hz, 1H) 7.61 (m, 3H) 7.71 (ddd, J=8.29, 2.46, 0.61 Hz, 1H) 7.99 (dt, J=2.45, 0.61 Hz, 1H).
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([OH:11])[C@H:3]1[O:8][C:6](=[O:7])[C@@H:5]([OH:9])[C@H:4]1[OH:10].CO[C:15](OC)([CH3:17])[CH3:16].[C:20]1(C)[CH:25]=CC(S(O)(=O)=O)=C[CH:21]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CC(C)=O>[CH3:16][C:15]1([CH3:17])[O:11][CH:2]([CH:3]2[O:8][C:6](=[O:7])[CH:5]3[O:9][C:20]([CH3:25])([CH3:21])[O:10][CH:4]23)[CH2:1][O:12]1
Reactant: O=C1O[C@H]([C@@H](O)CO)[C@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(C)(C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)OCC(C2OC(=O)C3OC(C)(C)OC32)O1
Yield: 79 %

Procedure:
L-Gulonolactone (20.00 g, 112.3 mmol) was stirred with acetone (160 ml), 2,2-dimethoxypropane (40 ml) and a catalytic amount of p-toluenesulphonic acid under dry nitrogen for 36 h when t.l.c. (ethyl acetate) revealed no starting material (Rf 0.0) and one product (Rf 0.9). The reaction mixture was stirred with an excess of sodium bicarbonate and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane (200 ml) and washed with water (3×200 ml). The organic extracts were dried (magnesium sulphate) and the solvent removed under reduced pressure to give a solid which was recrystallized from ethyl acetate to yield 2,3:5,6-di-O-isopropylidene-L-gulonolactone, (22.89 g, 79%), m.p. 151°-153° C. [α]D20 +68.4° (c, 1 in acetone) [lit. m.p. 153°-154° C. [α]D20 +91.5°]. δC (CDCl3), 173.3 (s, C-1), 114.7 (s), 110.5 (s), 80.9, 76.0, 75.7 and 75.2 (4×d, C-2, C-3, C-4 and C-5), 65.1 (d, C-6), 26.5 (q), 25.7 (q), 25.0 (q).
Reaction SMILES: Cl.Cl.C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)C=CC=CC=1.CC(C)([O-])C.[K+].C[O:36][C:37]1[C:42]([CH2:43][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]2[CH2:50][CH:51]=O)=[CH:41][CH:40]=[CH:39][N:38]=1.O>CN(C=O)C>[O:36]=[C:37]1[C:42]([CH2:43][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]2[CH2:50][CH2:51][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:41][CH:40]=[CH:39][NH:38]1
Reactant: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ncccc1CN1CCCCC1CC=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cccc1CN1CCCCC1CCCc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
In DMF was dissolved 2.1 g of triphenyl(2-pyridylmethyl)phosphonium dihydrochloride, followed by adding 1.4 g of potassium tert-butoxide thereto at room temperature under stirring. After 15 minutes, a solution of 1.25 g of 2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]acetaldehyde dissolved in DMF was added dropwise into the above-mentioned solution at room temperature under stirring, and the mixture was left overnight. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1, subsequently ethyl acetate, and subsequently ethyl acetate:methanol=4:1). 760 mg of the resulting brown oil, 0.56 ml of thionyl chloride and 10 ml of ethanol were stirred under reflux for 30 minutes. The reaction solution was cooled to room temperature, a 2N aqueous sodium hydroxide was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1, subsequently ethyl acetate, and subsequently ethyl acetate:methanol=4:1). The resulting yellow oil (350 mg) was dissolved in 10 ml of ethanol, 100 mg of 10% palladium-carbon (water-containing product) was added thereto, and the mixture was catalytically hydrogenated at normal pressure under stirring for 1.5 hours. The catalyst was filtered off and the solvent was evaporated. The residue was purified by NH-silica gel chromatography (ethyl acetate, subsequently ethyl acetate:methanol=4:1), to give 310 mg of an oil.
Reaction SMILES: Br[CH2:2][CH:3]([OH:6])[CH2:4]Br.C(=O)([O-])[O-].[Na+].[Na+].[C:13]([O:17][C:18](=[O:27])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1.[C:33]([Si:37]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)Cl)([CH3:36])([CH3:35])[CH3:34]>C(OCC)(=O)C.C(O)C>[Si:37]([O:6][CH:3]1[CH2:4][N:26]([C@H:23]2[CH2:22][CH2:21][C@H:20]([NH:19][C:18](=[O:27])[O:17][C:13]([CH3:16])([CH3:14])[CH3:15])[CH2:25][CH2:24]2)[CH2:2]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: OC(CBr)CBr
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)CC1

Procedure:
1,3-Dibromo-2-propanol (1.70 ml, 16.5 mmol) and sodium carbonate (15.9 g, 150 mmol) were added to an ethanol (300 ml) solution of tert-butyl(trans-4-aminocyclohexyl)carbamate (3.21 g, 15.0 mmol) and the resulting mixture was stirred under heating to reflux overnight. After cooling, insoluble matter was removed by filtration through celite and then the filtrate was concentrated under reduced pressure. The residue was diluted with water, followed by extraction with ethyl acetate. Then the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (15 ml) and imidazole (2.45 g, 36.0 mmol) and tert-butyldiphenylchlorosilane (4.29 ml, 16.5 mmol) were added under ice cooling. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate and washed with water and brine in that order. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [chloroform:methanol=10:0→10:1 (v/v)] to give 2.45 g (32%) of the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([CH:32]([CH3:34])[CH3:33])=[C:29]([SH:31])[CH:30]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:31][C:29]1[CH:30]=[C:25]([CH3:24])[CH:26]=[CH:27][C:28]=1[CH:32]([CH3:34])[CH3:33]
Reactant: Cc1ccc(C(C)C)c(S)c1
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(C(C)C)c(SC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.1 mmol of 5-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 66°-67° C.). 1H NMR (DMSO-d6) δ1.16 (m, 6H), 1.87 (s, 3H), 2.26 (m, 3H), 2.57 (m, 1H), 3.23 (m, 1H), 3.43 (q, 2H), 6.01 (bs, 1H), 6.78 (d, 1H), 7.03-7.27 (m, 6H), 7.37-7.47 (m, 5H).
Reaction SMILES: [C:1]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:50][C@@H:51]([CH2:55][OH:56])[C@H:52]([CH3:54])[OH:53]>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:50][C@@H:51]([CH2:55][OH:56])[C@H:52]([CH3:54])[OH:53])=[O:26])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: O=C(O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](O)[C@H](CO)NC(=O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 23 °C
Reaction time: 8 h

Procedure:
N-Fmoc-6-aminocaproic acid (10 g, 28.30 mmol) was dissolved in DMF (50 ml) and N-hydroxysuccinimide (3.26 g, 28.30 mmol) and 1,3-dicyclohexylcarbodiimide (5.84 g, 28.3 mmol) were added to the solution. The reaction mixture was stirred at RT (about 23° C.) overnight and the precipitated 1,3-dicyclohexylurea filtered off. To the filtrate D-threoninol (2.98 g, 28.30 mmol) was added and the reaction mixture stirred at RT overnight. The solution was reduced to ca half the volume in vacuo, the residue diluted with about m ml of ethyl acetate and extracted with about x ml of 5% NaHCO3, followed by washing with brine. The organic layer was dried (Na2SO4), evaporated to a syrup and chromatographed by silica gel column chromatography using 1-10% gradient of methanol in ethyl acetate. Fractions containing the product were pooled and evaporated to a white solid (9.94 g, 80%). 1H-NMR (DMSO-d6-D2O) δ7.97-7.30 (m, 8H, aromatic), 4.34 (d, J=6.80, 2H, Fm), 4.26 (t, J=6.80, 1H, Fm), 3.9 (m, 1H, H3 Thr), 3.69 (m, 1H, H2 Thr), 3.49 (dd, J=10.6, J=7.0, 1H, H1 Thr), 3.35 (dd, J=10.6, J=6.2, 1H, H1′ Thr), 3.01 (m, 2H, CH2CO Acp), 2.17 (m, 2H, CH2NH Acp), 1.54 (m, 2H, CH2 Acp), 1.45 (m, 2H, CH2 Acp), 1.27 (m, 2H, CH2 Acp), 1.04 (d, J=6.4, 3H, CH3). MS/ESI+ m/z 441.0 (M+H)+.
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13](C(O)=O)=[C:12]2[NH:22][C@H:23]1[CH2:26][C@@H:25]([O:27][CH3:28])[CH2:24]1.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)[O:30]C1C=CC=CC=1.O>CN(C=O)C>[Br:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[NH:3][C:6](=[O:30])[N:22]([C@H:23]4[CH2:24][C@@H:25]([O:27][CH3:28])[CH2:26]4)[C:12]=3[C:11]=2[CH:10]=1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CO[C@H]1C[C@@H](Nc2c(C(=O)O)cnc3ccc(Br)cc23)C1
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1C[C@@H](n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Triethylamine (39.3 mL, 281.89 mmol) was added to 6-bromo-4-[(cis-3-methoxycyclobutyl)amino]quinoline-3-carboxylic acid (33 g, 93.96 mmol) in DMF (200 mL) at r.t. After stirring for 30 minutes diphenyl phosphorazidate (28.4 g, 103.36 mmol) was added and the resulting mixture stirred at 60° C. for 2 h. The reaction mixture was poured into water (500 mL), the precipitate collected by filtration, washed with water (200 mL) and dried under vacuum to afford the desired material (32.0 g, 98%) as a yellow solid, which was used without further purification. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.75-2.82 (2H, m), 2.9-3.05 (2H, m), 3.22 (3H, s), 3.80-3.90 (1H, m), 4.85-4.99 (1H, m), 7.71 (1H, dd), 7.94 (1H, d), 8.48 (1H, d), 8.69 (1H, s), 10.42 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=348, 350.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3]1.[CH3:19][I:20]>C1C=CC=CC=1>[I-:20].[CH3:1][N+:2]1[N:3]([CH3:19])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CI
Reactant: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Solvent: c1ccccc1
Product: Cn1c(-c2ccccc2)cc(-c2ccccc2)[n+]1C
Product: [I-]
Yield: 15 %

Procedure:
5.0 Grams of 1-methyl-3,5-diphenylpyrazole is dissolved in 30 ml. of dry benzene with heating and constant stirring. 30.4 Grams of methyl iodide is added to the mixture, and the mixture heated to reflux. After refluxing for 12 hours, the mixture is cooled and filtered. The filtrate is again refluxed and as product forms, it is separated from the mixture by filtration. The total amount of solid recovered is 1.21 grams, 15% yield, having a melting point of 167° C. to 169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[Li]CCCC.CCCCCC.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50]Cl)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][N:12]([CH2:11][C:7]2[N:6]([CH2:5][C:4]3[CH:21]=[C:22]([Cl:24])[CH:23]=[C:2]([Cl:1])[CH:3]=3)[CH:10]=[CH:9][N:8]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCl)CC1
Reactant: Fc1cccc(CNCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCN(CCN(Cc2cccc(F)c2)Cc2nccn2Cc2cc(Cl)cc(Cl)c2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of [1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amine (146 mg, 0.4 mmol) in THF (1 mL) at −78° C. was added dropwise a solution of n-BuLi in hexane (0.19 mL, 0.44 mmol) and the mixture stirred at −78° C. for 30 min. A solution of 4-(2-Chloro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (116 mg, 0.46 mmol) in THF (1 mL) was then added dropwise and the mixture allowed to warm to ambient temperature before stirring for an additional 24 h. The reaction was quenched with water (10 mL) and extracted with CH2Cl2 (2×40 mL). The combined CH2Cl2 extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20:1 CH2Cl2/MeOH) to provide 4-{2-[[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amino]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (102 mg, 44%) as a colorless viscous oil: ESI MS m/z 576 [C29H36Cl2FN5O2+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH2:11][CH2:10]1.Br[CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:23][CH2:24][C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:17]2)[CH2:13][CH2:14]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: COc1ccccc1N1CCN(CC2CCCNC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1N1CCN(CC2CCCN(CCc3c[nH]c4ccccc34)C2)CC1

Procedure:
A mixture of 1-(2-methoxy-phenyl)-4-piperidin-3-ylmethyl-piperazine (0.5 g, 1.72 mmol) from example 6, 3-(2-bromoethyl)indole (0.38 g, 1 equivalent) and potassium carbonate (0.48 g, 2 equivalents) in acetonitrile (25 mL) were refluxed for 24 hours under a nitrogen atmosphere. Water (100 mL)) was added and the product extracted into ethyl acetate (3×50 mL). The combined organics were washed with water (25 mL), brine (25 mL) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuum afforded the required product. Treatment with excess ethereal HCl gave the hydrochloride salt of the above titled compound as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[CH2:18]([N:36]1[C:40](=[O:41])[CH:39]=[CH:38][C:37]1=[O:42])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(O)(C)(C)C>[C:13]([C:9]1[CH:10]=[C:11]([CH:39]2[CH2:38][C:37](=[O:42])[N:36]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:40]2=[O:41])[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]=1[OH:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCCCCCCCN1C(=O)C=CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCCCCCN1C(=O)CC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 36.9 %

Procedure:
This compound is prepared by the procedure of Example 1 from 2.40 g (0.1 mol) of sodium hydride, 20.63 g (0.1 mol) of 2,6-di-tert-butylphenol, and 34.96 g (0.1 mole) of N-n-octadecylmaleimide in tert-butyl alcohol. The residue is purified by dry-column chromatography (3:1 heptane:ethyl acetate eluent) followed by recrystallization from petroleum ether to give 20.5 g (37%) of a white solid: mp 70°-73° C.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([CH2:6][CH2:7][S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.[BH4-].[Na+]>C(O)C>[OH:20][CH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:5][CH2:6][CH2:7][S:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCSc1ccncc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
of 4- (2-phthalimidoethylthio)pyridine in 150 ml of ethanol, 3.78 g (100 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10) to give 2.24 g of the desired compound (77.8% yield, colorless crystals), mp. 132°-133° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([CH3:9])[CH:8]=1.[CH3:10][NH2:11]>>[CH3:10][NH:11][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([CH3:9])[CH:8]=1
Reactant: CN
Reactant: Cn1cc(CCCl)cn1
Product: CNCCc1cnn(C)c1
Reaction time: 15 h

Procedure:
To neat 4-(2-chloroethyl)-1-methyl-1H-pyrazole (50 g, 0.24 mol) was added a 25% aqueous solution of methylamine (1.15 L, 7.21 mol). The mixture was placed into an autoclave at 60° C. for 15 h. The resulting mixture was concentrated in vacuo, treated with aqueous solution of NaOH and extracted with DCM. The combined organic layers were concentrated in vacuo and purified by vacuum distillation to afford the title compound. b.p. 89-90° C./2 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:7][CH2:6][C:5]([CH2:22][OH:23])([CH2:8][N:9]2[CH:13]=[C:12]([CH2:14][O:15][CH2:16][O:17][CH3:18])[N:11]=[C:10]2[N+:19]([O-:21])=[O:20])[CH2:4][O:3]1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.[Cl-].[NH4+]>C(N(CC)CC)C>[CH3:1][C:2]1([CH3:24])[O:3][CH2:4][C:5]([CH2:8][N:9]2[CH:13]=[C:12]([CH2:14][O:15][CH2:16][O:17][CH3:18])[N:11]=[C:10]2[N+:19]([O-:21])=[O:20])([CH2:22][O:23][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:6][O:7]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCOCc1cn(CC2(CO)COC(C)(C)OC2)c([N+](=O)[O-])n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: COCOCc1cn(CC2(COS(=O)(=O)c3ccc(C)cc3)COC(C)(C)OC2)c([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
23 mg (0.11 mmol equivalents) of 2,2-dimethyl-5-hydroxymethyl-5-[(4-methoxymethoxymethyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane was dissolved in 1.0 mL of triethylamine, 1 mg (0.01 mmol equivalents) of N,N-dimethylaminopyridine and 23 mg (0.12 mmol equivalents) of p-toluenesulfonyl chloride were added thereto, and the mixture was stirred at room temperature (25° C.) for 16 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were dried with anhydrous magnesium sulfate, and then concentrated under vacuum. The obtained crude product was purified by flash silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=1/3) to give 16 mg (0.03 mmol equivalents) of 2,2-dimethyl-5-[(4-methoxymethoxymethyl-2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane.