Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([F:12])[C:4]=1[F:13].[CH:14]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[CH2:15].Cl>C1COCC1.C1(C)C=CC=CC=1>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:19]2([OH:22])[CH2:20][CH2:21][CH:16]([CH:14]=[CH2:15])[CH2:17][CH2:18]2)=[C:4]([F:13])[C:5]=1[F:12])[CH3:11]
Reactant: C=CC1CCC(=O)CC1
Reactant: CCOc1ccc(Br)c(F)c1F
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC1CCC(O)(c2ccc(OCC)c(F)c2F)CC1
Temperature: 53 °C
Reaction time: 0.5 h
Yield: 135.6 %

Procedure:
Seventh Step: 1.76 g of well dried magnesium and 10 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 53° C. 17.2 g of the compound (1) dissolved in 30 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 56° C., followed by stirring for 30 minutes. Thereafter, 6.0 g of the compound (16) dissolved in 10 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 55° C., followed by stirring for 30 minutes. After cooling the resulting reaction mixture to 25° C., the reaction mixture was poured into and mixed with a mixture of 100 mL of 1N hydrochloric acid and 100 mL of toluene. The mixture was then separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, a 2N sodium hydroxide aqueous solution, a saturated sodium bicarbonate aqueous solution, and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 18.5 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-vinylcyclohexanol (17) as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([N:35]=[C:36]=[S:37])=[O:34].[ClH:38]>C1COCC1.CO>[ClH:38].[ClH:38].[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[F:25])=[S:37])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(Cc1ccccc1F)N=C=S
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4F)cc3F)c2s1
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of aniline 219 (100 mg, 0.29 mmol, scheme 47) and 2-(2-fluorophenyl)acetyl isothiocyanate (115 mg, 0.58 mmol) in THF (3 mL) was stirred for 1 hour, loaded directly onto a column containing silica gel and eluted sequentially with EtOAc and EtOAc/MeOH (100:1), to produce a white solid. This material was suspended in MeOH (5 mL) and HCl (1.0M in ether, 1 mL) was added to form a clear solution that was evaporated to dryness. The residue was washed with ether, suspended in H2O, and lyophilized to afford the title compound (80 mg, 45% yield) as a yellowish solid. 1H-NMR (DMSO-d6) δ (ppm): 12.42(s, 1H), 11.88(s, 1H), 8.65(d. 1H, J=5.5 Hz), 8.20(s, 1H), 8.05(d, 1H, J=1.7 Hz), 7.74(s, 1H), 7.58-7.55(m, 3H) 7.39-7.32(m, 2H), 7.21-7.16(m, 2H), 6.82(d, 1H, J=5.5 Hz), 4.02(s, 3H), 3.93(s, 2H), MS (m/z): 536.2(M+H) (found).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:12][CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(Cc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCNC3)c(F)c2)C(=O)O1
Reaction time: 18 h

Procedure:
A mixture of (5S)-N-[3-[3-fluoro-4-[1-(phenylmethyl)-3-pyrrolidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 41, 1.09 g) and 20% palladium hydroxide on carbon (545 mg) in methanol (30 mL) is shaken on the Parr apparatus under a hydrogen atmosphere at 40 psi for 1.5 hours and at 10 psi for 18 hours. The catalyst is then removed by filtration through Celite, and the filtrate is concentrated under reduced pressure to give the title compound, NMR (CDCl3, 400 MHz) 7.39, 7.24, 7.11, 6.35, 4.78, 4.04, 3.77, 3.67, 3.44, 3.37, 3.18, 3.11, 2.88, 2.21, 2.02, 1.86 δ.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[C:4]([NH2:8])=[C:3]([NH2:9])[CH:2]=1.[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>C(O)(C)C.[Pd]>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:18]2[NH:8][C:4]3[C:5]([NH2:7])=[CH:6][N:1]=[CH:2][C:3]=3[N:9]=2)=[CH:20][CH:21]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: Nc1cncc(N)c1N
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(-c2nc3cncc(N)c3[nH]2)cc1
Yield: 37 %

Procedure:
Pyridine-3,4,5-triamine 3 (100 mg, 0.81 mmol) was dissolved in isopropanol (4 ml) with Pd/C (20 mg of 10% powder). 4-t-butyl benzaldehyde (150 mg, 0.92 mmol) was added, and this mixture was refluxed for 48 hours. The reaction mixture was filtered through CELITE to remove the palladium, and the crude was purified by HPLC (Method E) to yield the title compound 4 (81 mg (37%), 0.3 mmol). 1H NMR (DMSO-d6): δ 8.64 (bs, 1H), 8.18 (d, J=8.6 Hz, 2H), 7.75 (s,1H), 7.69 (d, J=8.6 Hz, 2H), 6.30-6.61 (bs, 2H), 1.35 (s, 9H). MS (ESI-POS): [M+H]+=266.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:5]2.[Li]CCCC.CON(C)[C:29](=[O:32])[CH2:30][CH3:31]>C1COCC1>[Si:14]([O:13][CH2:12][C:6]1[N:7]([CH3:11])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:29](=[O:32])[CH2:30][CH3:31])=[CH:10][CH:9]=2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CCC(=O)N(C)OC
Reactant: Cn1c(CO[Si](C)(C)C(C)(C)C)cc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)c1ccc2c(c1)cc(CO[Si](C)(C)C(C)(C)C)n2C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
To a stirred solution of 5-bromo-2-((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-indole (3.76 g, 10.6 mmol), prepared according to procedure described in Example 39 Step 3, in THF (15 mL) was added n-BuLi (2.5 M solution in hexanes, 5.1 mL, 12.7 mmol, 1.2 eq) at −78° C. dropwise. The mixture was stirred for 30 min at −78° C. before a solution of N-methoxy-N-methylpropionamide (1.49 g, 12.7 mmol, 1.2 eq) in THF (5 mL) was added. After stirred at −78° C. for 10 min, the reaction was quenched with saturated aqueous NH4Cl solution. The resulting mixture was extracted by ether (3×30 mL) and combined organic layers were dried over Na2SO4. The crude product was purified by flash chromatography (0-10% EtOAc in hexanes) to give the title compound (2.70 g, 77%).
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([C:10]3[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:19]1[C:28]2[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH3:17][O:16][C:11]1[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:29][C:25]4[CH:24]=[C:23]5[C:28](=[CH:27][CH:26]=4)[N:19]=[CH:20][CH:21]=[CH:22]5)[N:18]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1ncccc1-c1cccn2nc(Cl)nc12
Reactant: Nc1ccc2ncccc2c1
Product: COc1ncccc1-c1cccn2nc(Nc3ccc4ncccc4c3)nc12

Procedure:
[8-(2-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-quinolin-6-yl-amine was prepared from 2-chloro-8-(2-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine and quinolin-6-ylamine in a manner analogous to Example 2d (0.12 g, 65%). MP=247-249° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.18 (s, 1H), 8.88 (d, J=6.58 Hz, 1H), 8.75 (d, 1H), 8.45 (d, 1H), 8.25 (d, 1H), 8.15 (t, 1H), 7.85-7.90 (m, 2H), 7.55 (m, 1H), 7.42 (m, 1H), 7.10 (m, 1H), 3.90 (s, 3H). MS=369 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[CH2:23][OH:24])[CH:16]=[CH:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][CH2:29]Cl.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[CH2:23][O:24][CH2:27][O:28][CH3:29])[CH:16]=[CH:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc3cccc(CO)c32)CC1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOCc1cccc2ccn(C3CCN(C(=O)OC(C)(C)C)CC3)c12
Reaction time: 0.67 h
Yield: 80.8 %

Procedure:
Dissolve 4-(7-hydroxymethylindol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.76 mmol) in 5 mL of tetrahydrofuran and add sodium hydride (36 mg, 1.5 mmol) at room temperature. After 40 minutes, add methoxymethyl chloride (0.11 mL, 1.5 mmol) and stir the mixture for 4 hours. Concentrate the reaction and subject it to flash chromatography using 5:1 hexanes:ethyl acetate to give 0.23 g product. FAB MS 374.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:53][O:54][C:55](=[O:74])[C@@H:56]([NH2:73])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65]2[CH:70]=[CH:69][N:68]=[C:67]([CH3:71])[C:66]=2[CH3:72])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:73][C@H:56]([C:55]([O:54][CH3:53])=[O:74])[CH2:57][C:58]2[CH:59]=[CH:60][C:61]([O:64][C:65]3[CH:70]=[CH:69][N:68]=[C:67]([CH3:71])[C:66]=3[CH3:72])=[CH:62][CH:63]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccc(Oc2ccnc(C)c2C)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (80 mg) was taken up in 2 mL of anhydrous DCM and EDCl (34 mg), HOBT (25 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride (50 mg) were added and stirred for 5 minutes. The reaction mixture was cooled to 0° C. and DIEA (85 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction was complete, it was purified by column chromatography (silica gel; 1:3 ethyl acetate/hexanes to 4% MeOH in 1:1 ethyl acetate/hexanes) (70 mg). LCMS (m/z): 869.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1H-indole-5-carboxylic acid (323 mg, 2.0 mmol) in 10 mL of DCM was added DIPEA (1.03 g, 8.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (400 mg, 2.1 mmol). HBTU (1.14 g, 3.0 mmol) was added at 0° C. The resulting mixture was stirred at r.t. for 18 h. TLC indicated that the starting material was gone. The mixture was diluted with DCM (100 mL) and washed with water (30 mL). The organic layer was separated and dried over anhydrous Na2SO4. The solution was concentrated to give a crude product, which was then purified with silica gel column (Hexane/EtOAc=1/1) to give HJC-2-13 (605 mg, 92%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 8.44 (s, 1H), 7.73 (s, 1H), 7.40 (d, 1H, J=8.4 Hz), 7.26-7.27 (m, 2H), 6.59 (s, 1H), 3.56-3.63 (m, 4H), 3.42-3.47 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [Mg].[CH2:2](I)[CH3:3].[CH3:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]2[CH:18]=[N:19][C:20]([CH:21]=[O:22])=[C:8]2[CH2:7]1>C(I)C.C(OCC)C.O1CCCC1>[OH:22][CH:21]([C:20]1[N:19]=[CH:18][N:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[N:6]([CH3:5])[CH2:7][C:8]=12)[CH2:2][CH3:3]
Reactant: CCI
Reactant: CN1Cc2c(C=O)ncn2-c2ccccc2C1=O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C

Procedure:
1.22 g (50.2 mmol) of magnesium shavings are covered with 60 ml of absolute diethyl ether under an argon atmosphere and treated with 2-3 drops of ethyl iodide. When the Grignard reaction starts, a solution of 4.3 ml (51 mmol) of ethyl iodide in 10 ml of absolute diethyl ether is added dropwise at the boiling point. After the magnesium has dissolved completely, the mixture is treated dropwise with a solution, warmed to 30° C., of 0.65 g (40 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehye in 200 ml of absolute tetrahydrofuran. The yellow coloured suspension is heated to boiling under reflux for ca 5.5 hours, cooled to room temperature and poured into 600 ml of ice/water. The mixture is filtered over Dicalit while rinsing with tetrahydrofuran. After concentration of the filtrate in vacuo, the residue is taken up in 250 ml of chloroform. The chloroform phase is washed twice with 60 ml of water each time, dried over magnesium sulphate and concentrated. The crude product is chromatographed on silica gel using chloroform/methanol (19:1, vol/vol) for the elution. After recrystallisation from ca 40 ml of ethyl acetate, there is obtained 4,5-dihydro-3-(1-hydroxypropyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 145°-147° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][NH:5][S:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:19])[CH:15]=2)[CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C.O1CCCC1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:20][CH3:21])[S:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:19])[CH:15]=2)[CH:10]=1)(=[O:8])=[O:7])[CH3:30]
Reactant: COC(CNS(=O)(=O)c1ccc2cc(Cl)ccc2c1)OC
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(OC)OC)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
N-(2,2-Dimethoxyethyl)-6-chloro-2-naphthalenesulfonamide was dissolved in DMF (100 ml) and combined with sodium hydride (1.16 g, in oil), cooled to 0° C., treated dropwise with a solution of ethyl bromoacetate (4.843 g) in tetrahydrofuran (15 ml) and then stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, aqueous sodium bicarbonate and brine, dried and concentrated to obtain N-(2,2-dimethoxyethyl)-N-(6-chloro-2-naphthalenesulfonyl)glycine ethyl ester as a colorless oil.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:20]([N:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCCCNCCCCCC
Product: CCCCCCC/C=C/C(=O)N(CCCCCC)CCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and dihexylamine as starting materials to give the aimed compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C@@H:5]([NH:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[C:6]([O:8][CH3:9])=[O:7].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:14]([O:13][C:11]([NH:10][C@H:5]([CH2:4][CH2:3][NH:2][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])[C:6]([O:8][CH3:9])=[O:7])=[O:12])[CH2:15][CH2:16][CH3:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCOC(=O)N[C@H](CCN)C(=O)OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)N[C@H](CCNS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of methyl 4-amino-2(R)-(N-butyloxycarbonylamino)butyrate hydrochloride (2.28 g, 8.5 mmol) and p-toluenesulfonyl chloride (1.62 g, 8.5 mmol) in 10 mL CHCl3 cooled in an ice bath was added diisopropylethylamine (4.5 mL, 26 mmol). The mixture was stirred at room temperature overnight and concentrated. Ethyl acetate was added and the solution was washed with citric acid, brine, NaHCO3 and brine, dried (MgSO4) and concentrated. Purification on a silica gel column using 40% ethyl acetate/hexane gave 2.16 g (66%) product. 1H-NMR: d (CDCl3) 7.75 (d, 2H ); 7.26 (d, 2H); 5.72 (t, 1H); 5.22 (d, 1H); 4.32 (m, 1H); 3.72 (s, 3H); 3.18 (m, 1H); 2.82 (m, 1H); 2.41 (s, 3H); 2.10 (m, 1H); 1.60 (m, 1H); 1.40 (s, 9H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)=[N:3][CH:2]=1.[ClH:24]>O1CCOCC1>[ClH:24].[NH:13]1[CH2:14][CH2:15][CH2:16][C@H:11]([O:10][C:4]2[C:5]3[CH:9]=[CH:8][NH:7][C:6]=3[N:1]=[CH:2][N:3]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ncnc3[nH]ccc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1nc(O[C@H]2CCCNC2)c2cc[nH]c2n1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of (S)-tert-butyl 3-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (60 mg, 0.18 mmol) in 1,4-dioxane (2 mL) was added 4 N HCl in 1,4-dioxane (2 mL) and the reaction mixture was stirred for 30 min. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated in vacuo to give a residue which was triturated with ether to give (31 mg, 74%) the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cl)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(CBr)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a suspension of methyl 4-chloro-3-methylbenzoate I (19.9 g, 108 mmol) and N-bromosuccinimide (NBS, 20.2 g, 114 mmol) in carbon tetrachloride (500 mL) was added benzoyl peroxide (1.30 g, 5.4 mmol), and the mixture was stirred at 90° C. overnight. The mixture was then cooled and the white precipitate was removed by filtration. The filtrate was concentrated and the resulting solid was re-crystallized from ethyl acetate to give methyl 3-bromomethy-4-chlorobenzoate II (15.0 g, 57 mmol, 53%) as a white solid: 1H NMR (CDCl3) δ 3.95 (s, 3H), 4.63 (s, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.94 (dd, J=2.1, 8.3 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:12])[CH3:11])=[C:4]([CH3:13])[CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.O>C(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:24])[F:25])=[CH:23][CH:22]=2)[CH:3]=[C:4]([CH3:13])[C:5]=1[NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Nc1c(C)cc(N)cc1C
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)cc2)cc1C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
N-(4-Amino-2,6-dimethyl-phenyl)-acetamide (1.2 g) and 4-trifluoromethyl-benzaldehyde (1.3 g) were dissolved in ethanol (100 mL) and refluxed for 16 h. The reaction mixture was poured into water (3 L) and the precipitate collected by filtration. Sodium cyanoborohydride (2 g) and acetic acid (2 mL) were added to the precipitate dispersed in methanol (50 mL) and stirred for 15 minutes. The reaction mixture was filtered, water (100 mL) was added and the organic solvent was removed in vacuo. The product was allowed to precipitate at 25° C. and collected by filtration and washed with water (200 mL) to furnish 0.68 g (30% yield) of the title compound as a pale yellow solid. LC-MS (m/z) 337 (MH+); tR=2.39, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.95 (s, 3H), 1.96 (s, 6H), 4.34 (d, 2H), 6.18 (t, 1H), 6.25 (s, 2H), 7.55 (d, 2H), 7.69 (d, 2H), 8.81 (s, 1H).
Reaction SMILES: [O:1]1[C@H:7]2[C@@H:2]1[CH2:3][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:6]2.[Cl-].[NH4+].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O>[N:15]([C@H:2]1[C@H:7]([OH:1])[CH2:6][CH2:5][C@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1)=[N+:16]=[N-:17]
Reactant: CCOC(=O)[C@H]1CC[C@H]2O[C@H]2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@@H](O)[C@H](N=[N+]=[N-])C1
Temperature: 75 °C
Reaction time: 13 h
Yield: 100.3 %

Procedure:
Ethyl (1S,3S,4R)-3,4-epoxycyclohexane-1-carboxylate (41 g) was dissolved in N,N-dimethyl-formamide (300 ml), ammonium chloride (19.3 g) and sodium azide (23.5 g) were successively added at room temperature, and the mixture was then stirred at 75° C. for 13 hours. The reaction mixture was filtered, the filtrate was concentrated to distill off 400 ml of the solvent, the product captured by the filter was put in the residue, and water was added to dissolve the collected product. The solution was extracted with ethyl acetate. The resultant organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (51.5 g) as an oil.
Reaction SMILES: [C:1]([C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:7]=1)#[N:2].[H-].[Na+].[CH3:18][N:19]([CH3:26])[P:20](Cl)([N:22]([CH3:24])[CH3:23])=[O:21].O>O1CCCC1>[CH3:18][N:19]([P:20]([N:22]([CH3:24])[CH3:23])([N:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:7]=[C:3]1[C:1]#[N:2])=[O:21])[CH3:26]
Reactant: CN(C)P(=O)(Cl)N(C)C
Reactant: N#Cc1nc(-c2ccc(Cl)cc2Cl)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)P(=O)(N(C)C)n1cc(-c2ccc(Cl)cc2Cl)nc1C#N
Reaction time: 2 h

Procedure:
A solution of 2-cyano-4-(2,4-dichlorophenyl)imidazole (1.0 g) in tetrahydrofuran (30 ml) was treated with sodium hydride (0.16 g of 80% dispersion in oil) at 0°. A solution of tetramethylphosphorodiamidic chloride (0.89 g) in tetrahydrofuran (10 ml) was added dropwise and the mixture stirred for 11/2 hours under nitrogen. It was then poured into water, stirred, and the precipitate filtered, dried and recrystalllsed from toluene/hexane to give 1-[bis(dimethylamino)phosphinyl]-2-cyano-4-(2,4-dichlorophenyl)imidazole, m.p. 140.5°-1°. (Compound 6).