Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[N+:23]([O-])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCOCC1>[C:1]1([C:7]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[NH2:23])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccc2nc(-c3ccccc3)c(-c3ccccc3)nc12
Solvent: C1COCCO1
Product: Nc1cccc2nc(-c3ccccc3)c(-c3ccccc3)nc12

Procedure:
1.04 g of 2,3-diphenyl-5-nitroquinoxaline was dissolved in 30 g of dioxane, followed by purging with argon and further addition of 0.5 g of 5% Pd/C (hydrous). After sufficient purging with argon again, hydrogen was added and reacted at room temperature for 30 hours. After completion of the reaction, the reaction mixture was filtered and the solvent was removed, followed by isolation and purification with a silica gel column (ethyl acetate:hexane=1:3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C1([O:23][C:24]([O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=O)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:24]([O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:23])[CH2:15][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: Brc1ccc(OCCC2CCNCC2)cc1
Product: CCOC(=O)COC(=O)N1CCC(CCOc2ccc(Br)cc2)CC1
Yield: 54.6 %

Procedure:
The procedure described in Example 4.3. is repeated. Starting from 1.76 g (6.19 mmol) of 4-{2-[(4 bromophenyl)oxy]ethyl} prepared in Step 9.2., and 1.39 g (6.19 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}-acetate, prepared in accordance with Example 1.1., gives 1.4 g of product in oil form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:15][CH:14]3[N:16]([CH3:17])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:5][CH:4]=1.C(O)(=O)C.Cl.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:10][CH:11]3[N:16]([CH3:17])[CH:14]([CH2:13][CH2:12]3)[CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(O)CC3CCC(C2)N3C)cc1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C2=CC3CCC(C2)N3C)cc1

Procedure:
The title compound was prepared from 3-(4-methoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (2 g, 8 mmol), glacial acetic acid (6.4 mL) and concentrated hydrochloric acid (6.4 mL). The free base of the title compound was dissolved in ethanol (96%) and added fumaric acid (0.8 g, 6.9 mmol), no precipitate appeared, the solution was concentrated to dryness, the residue was crystallised from absolute ethanol. Yield 1.1 g (40%) as white crystals m.p. 167.3-168.7° C.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[CH:9][S:10][CH:11]=1.IC>O1CCCC1>[CH3:1][C:9]1[S:10][CH:11]=[C:7]([CH3:6])[C:8]=1[C:12]([OH:14])=[O:13]
Reactant: Cc1cscc1C(=O)O
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1csc(C)c1C(=O)O
Temperature: -78 °C
Yield: 82.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 18.6 mL, 46 mmol) was added to a pre-cooled solution of 4-methylthiophene-3-carboxylic acid (3.0 g, 21 mmol) in dry tetrahydrofuran (THF, 35 mL) at −62° C. The reaction mixture was stirred at −78° C. for an hour, allowed to warm to −40° C. and re-cooled to −78° C. before adding iodomethane (3.28 mL, 7.49 g, 53 mmol). After addition, the reactants were stirred at −78° C. for an hour and then allowed to warm to room temperature over 14 hours and quenched with water (20 mL). The organic phase was extracted with dilute sodium hydroxide (0.2 N, 3×30 mL). The combined aqueous extracts were washed with ether (2×30 mL), cooled in an ice bath and acidified to pH 3 using concentrated hydrochloric acid. The resultant precipitate was extracted with ether (3×50 mL). The combined ethereal extracts were washed with water (50 mL) and brine (50 mL), dried over magnesium sulphate, concentrated under reduced pressure and recrystallised from ethyl acetate/hexane to give product as an amorphous white solid (2.7 g, 82%): mp 164–165° C.; 1H NMR (CDCl3) δ 6.65 (q, 1H), 2.73 (s, 3H), 2.43 (d, 3H); EI/MS 156 m/e (M+); IR (liq film) 1664 cm−1; Calcd for C7H8O2S: C, 53.8; H, 5.16; Found: C, 53.8; H, 5.11.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCl>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([Cl:18])=[O:14])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(CC(=O)Cl)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Combine 3-isopropoxy-phenyl-acetic acid (0.5 g, 2.6 mmol) and dichloromethane (5 mL). Cool to -5° C. using a ice-salt bath. Add 2 drops of dimethylformamide followed by dropwise addition of oxalyl chloride (0.34 g, 2.7 mmol). after 1 hour, warm the reaction mixture to ambient temperature. After 2 hours, evaporate the reaction mixture in vacuo to give the title compound as a liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:15]3[CH2:21][C:20]4[CH:22]=[C:23]([C:26]5[N:31]=[C:30]([NH2:32])[C:29]([NH2:33])=[CH:28][CH:27]=5)[CH:24]=[CH:25][C:19]=4[O:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]([NH:38][C:39](=NC(OC)=O)SC)=[O:37]>C(O)(=O)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:15]3[CH2:21][C:20]4[CH:22]=[C:23]([C:26]5[N:31]=[C:30]6[NH:32][C:39]([NH:38][C:36](=[O:37])[O:35][CH3:34])=[N:33][C:29]6=[CH:28][CH:27]=5)[CH:24]=[CH:25][C:19]=4[O:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2ccc3c(c2)CN(c2ncncc2Cc2ccc(F)cc2)CCO3)nc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(c3ncncc3Cc3ccc(F)cc3)CCO4)nc2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 304.1 %

Procedure:
To a solution of 6-(4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridine-2,3-diamine (0.200 g, 0.438 mmol) in glacial acetic acid (3 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.117 g, 0.570 mmol). The reaction mixture was stirred at 80° C. for 2 h and then concentrated. Ethyl acetate (100 mL) was added to the residue, and the solution was washed with saturated sodium bicarbonate (50 mL) then dried over anhydrous sodium sulfate. Filtration and concentration afforded a brown residue that was taken up in diethyl ether (10 mL) and the resulting precipitate was collected by filtration to give methyl [5-(4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3H-imidazo[4,5-b]pyridine-2-yl]carbamate (0.70 g, 30% yield) as a brown solid. MS (EI) for C26H25FN6O: 457 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13](Cl)(=[O:15])=[O:14].[OH-].[Na+]>N1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
2-Fluoro-5-nitroaniline (15.7 g) solution in pyridine (100 ml) was added drop-wise with methanesulfonylchloride (17.2 g) in an ice bathing. After being stirred for 2 hours at room temperature, the reaction mixture was added with 2N sodium hydroxide (200 ml) and washed with hexane (200 ml) two times. 2N HCl (300 ml) was added into the resultant aqueous layer and solids separated were collected by filtration, washed with water and dried under vacuum to obtain 2′-fluoro-5′-nitromethanesulfonanilide (21.8 g) as brownish solid.
Reaction SMILES: ClC(Cl)([O:4][C:5](=[O:11])[O:6]C(Cl)(Cl)Cl)Cl.[CH3:13][C:14]1[N:18]([CH2:19][CH2:20][OH:21])[C:17]([N+:22]([O-:24])=[O:23])=[CH:16][N:15]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][C:14]1[N:18]([CH2:19][CH2:20][OH:21])[C:17]([N+:22]([O-:24])=[O:23])=[CH:16][N:15]=1.[C:5](=[O:4])([O-:11])[O-:6]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: Cc1ncc([N+](=O)[O-])n1CCO
Solvent: ClCCl
Product: O=C([O-])[O-]
Temperature: 25 °C

Procedure:
mPEG11OH (0.39 mmol, 200 mg) and DMAP (0.93 mmol) were dissolved in anhydrous DCM (10 ml). Triphosgene (0.13 mmol, 38.5 mg) was added at room temperature. The solution was stirred at room temperature for ten minutes. Metronidazole (0.43 mind, 73.5 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was evaporated at reduced pressure. The residue was subjected to flash chromatography (methanol/DCM=2˜5%) to obtain compound 2c (107 mg, yield 38%). 1H NMR (CDCl3) δ 7.92 (s, 1H), 4.55 (t, 2H), 4.45 (t, 2H), 4.21 (t, 2H), 3.66-3.49 (m, 42H), 3.33 (s, 3H), 2.47 (s, 3H). LC/MS 714 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[C:18]([O-])([O-])=O.[Na+].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:18])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cccc(F)c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C=C/c1cccc(F)c1
Yield: 339.2 %

Procedure:
To a solution of (E)-3-(3-fluorophenyl)acrylic acid (5, 6.0 g, 32.7 mmol) in MeOH (150 mL) at 0° C. was added concentrated H2SO4 (3.0 mL) slowly. The reaction was heated under reflux for 24 h then cooled to room temperature and neutralized with Na2CO3 (1.0 g). The solvent was removed by rotary evaporation and the resulting yellow oil partitioned between EtOAc (300 mL) and saturated NaHCO3 (300 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (200 mL) and dried over Na2SO4. The solvent was removed by rotary evaporation to yield 6 as a low melting (<25° C.) white solid (32.0 mmol, 99%): 1H NMR (500 MHz, CDCl3) δ 3.79 (s, 3H), 6.39-6.43 (d, J=16.0 Hz, 1H), 7.04-7.07 (dt, J=2.0, 8.0 Hz, 1H), 7.18-7.20 (d, J=9.0 Hz, 1H), 7.25-7.26 (d, J=8.0 Hz, 1H), 7.30-7.35 (m, 1H), 7.60-7.64 (d, J=16.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 52.0, 114.4, 114.6, 117.3, 117.4, 119.4, 124.29, 124.32, 130.6, 130.7, 136.8, 136.9, 143.6, 143.7, 162.2, 164.2, 167.2; LCQ-MS (M+H+) calcd for C10H10FO2 181. found 181.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1.C(O)(=O)C>COCCOC>[CH3:27][C:25]1[NH:24][N:23]=[C:22]([NH:21][C:13]2[N:12]=[C:11]([S:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=1
Reactant: Sc1ccccc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3ccccc3c(Sc3ccccc3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
NaH (155 mg) was added to a solution of benzenethiol (500 mg) in DME (2 ml) and the mixture was stirred for 1 hour at room temperature. (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was then added, and the resulting mixture was heated at 150° C. for 30 minutes under microwave irradiation. The reaction mixture was acidified to pH=7 with acetic acid and purified by preparative LC-MS to give 20 mg of (5-methyl-1H-pyrazol-3-yl)-(1-phenylsulfanyl-isoquinolin-3-yl)-amine as a yellow solid. LC-MS: m/e 333(MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([C:16]2[NH:20][N:19]=[N:18][N:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36]>ClCCCl>[C:2]1([CH2:1][NH:8][C:9]2[N:14]=[C:13]([NH:15][C:35]([C:31]3[S:30][CH:34]=[CH:33][CH:32]=3)=[O:36])[C:12]([C:16]3[NH:17][N:18]=[N:19][N:20]=3)=[CH:11][N:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(NCc2ccccc2)ncc1-c1nnn[nH]1
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(Nc1nc(NCc2ccccc2)ncc1-c1nnn[nH]1)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
To a solution of N2-Benzyl-5-(1H-tetrazol-5-yl)pyrimidine-2,4-diamine (27 mg, 0.1 mmol) in 1 mL of DCE, DIPEA (0.3 mmol, 3.0 eq.) was added followed by thiophene-2-carbonyl chloride (0.15 mmol, 1.5 eq.). The reaction was stirred at room temperature for 2 hours. The crude reaction mixture was concentrated down in vacuo, and the residue redissolved in ethylacetate. This organic solution was extracted several times with water, dried with magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to give 4.8 mg of the desired compound. 1H-NMR (400 MHz, d6-DMSO): δ 9.07 (t, 1H), 7.81 (dd, 1H), 7.77 (dd, 1H), 7.36-7.29 (m, 4H), 7.28-7.23 (m, 1H), 7.16 (t, 1H), 4.45 (d, 2H). MS (EI) for C17H14N8OS: 379 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[C:25]([NH2:27])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][CH:22]=1>>[N+:28]([C:24]1[C:25]([NH2:27])=[N:26][C:21]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)=[CH:22][CH:23]=1)([O-:30])=[O:29]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: Nc1nc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)ccc1[N+](=O)[O-]

Procedure:
EXAMPLE 103 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 6-chloro-3-nitro-pyridin-2-ylamine: MS (m+1)=420.5.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[CH2:6][CH:7]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=2)[CH2:8][C:9]=1O)(=O)[CH3:2].N1CCCC1.Cl.[NH2:31][C:32]([NH2:34])=[NH:33]>CCO>[NH2:34][C:32]1[N:33]=[C:1]([CH3:2])[C:4]2[C:5](=[O:24])[CH2:6][CH:7]([C:11]3[S:12][CH:13]=[CH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=3)[CH2:8][C:9]=2[N:31]=1
Reactant: N=C(N)N
Reactant: COc1cccc(-c2ccsc2C2CC(=O)C(C(C)=O)=C(O)C2)n1
Agent: Cl
Solvent: C1CCNC1
Solvent: CCO
Product: COc1cccc(-c2ccsc2C2CC(=O)c3c(C)nc(N)nc3C2)n1
Temperature: 100 °C
Yield: 14.7 %

Procedure:
To a 150 mL pressure vessel was added 2-acetyl-3-hydroxy-5-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)cyclohex-2-enone (30G, 1.72 g, 5.01 mmol, 1.0 eq.), EtOH (50 mL), pyrrolidine (2.13 g, 30.1 mmol, 6.0 eq.), guanidine hydrochloride (1.44 g, 15 mmol, 3.0 eq.). The vessel was sealed and heated overnight at 100° C. LC/MS analysis showed the reaction to be complete whereupon the reaction mixture was concentrated and the residue was taken up in 20% EtOAc/CH2Cl2. An insoluble solid proving not to be product was filtered off. The remaining filtrate was purified via column chromatography (20% EtOAc/CH2Cl2 to 70% EtOAc/CH2Cl2) to yield the product 30H as a light gray solid (270 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.55 (s, 3H) 2.76-2.95 (m, 2H) 3.02-3.22 (m, 2H) 3.70 (s, 3H) 4.62-4.77 (m, 1H) 6.72 (d, J=8.34 Hz, 1H) 7.31 (d, J=7.58 Hz, 1H) 7.41-7.54 (m, 4H) 7.75 (t, J=7.83 Hz, 1H). ESI-MS: m/z 367.3 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:37])C(=O)C1>CN(C=O)C>[Br:37][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:10])[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)CCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)CCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of 7-methyl-octan-1-ol (1.20 g, 8.33 mmol) in DMF (20 mL) was added triphenylphosphine (2.43 g, 9.26 mmol). The solution was cooled to 0° C. and NBS (1.60 g, 8.99 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (100 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 1-bromo-7-methyl-octane (1.28 g, 74%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.41 (2H, t, J=6.6 Hz), 1.85 (2H, m), 1.52 (1H, m), 1.42 (2H, m), 1.28 (4H, m), 1.17 (2H, m), 0.87 (3H, s), 0.85 (3H, s); 13C NMR (75 MHz, CDCl3) δ 39.16, 34.34, 33.14, 29.34, 28.52, 28.24, 27.51, 22.94.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][C:19]=3[F:25])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:26](C#N)#[N:27].N1C=CC=CC=1.CN1CCCC1=O>Cl>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:26]#[N:27])=[CH:20][C:19]=3[F:25])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: N#CC#N
Reactant: CCC[C@H]1CC[C@H](CCc2ccc(-c3ccc(Br)cc3F)cc2)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H](CCc2ccc(-c3ccc(C#N)cc3F)cc2)CC1

Procedure:
A mixture of 38.4 g of 1-(trans-4-n-propylcyclohexyl)-2-(4'-bromo-2'-fluorobiphenyl-4-yl)-ethane (M.p. 61.1°, C.p. 114.7°), 10 g of Cu2 (CN)2, 120 ml of pyridine and 60 ml of N-methylpyrrolidone is heated at 160° for 2 hours. The mixture is cooled, a solution of 120 g of FeCl3.6H2O in 600 ml of 20% hydrochloric acid is added and the mixture is warmed at 70° for 1.5 hours, with stirring, and worked up in the customary manner to give 1-(trans-4-n-propylcyclohexyl)-2-(4'-cyano-2'-fluorobiphenyl-4-yl)-ethane, M.p. 89.4°, C.p. 168.4°.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:19])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:7]=1.[CH3:20][O:21][C:22]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:23]=1[NH2:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:19][C:5]1[N:4]=[N:3][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)=[CH:28][C:22]=2[O:21][CH3:20])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)nnc2Cl)cc1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1nnc(Cl)c(Nc2ccc(P(C)(C)=O)cc2)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,2,4-triazin-5-amine (0.7 mmol), 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C[O-].[Na+].[CH2:8](Br)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>CO.O>[CH2:21]([CH2:2][C:1]([OH:4])=[S:3])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CC(O)=S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCC(O)=S
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
Thioacetic acid (3.32 g, 36.0 mmol) in MeOH (150 ml) was treated successively with NaOMe (25% in MeOH, 12 g, 0.08 mol) and tetradecyl bromide (10.0 g, 0.036 mol) and stirred vigorously at room temperature for 48 h. The mixture was poured into H2O, acidified to pH 2 (conc. HCl) and extracted with diethyl ether. Drying (MgSO4) and concentration in vacuo afforded a crude solid which was purified by flash column chromatography (FCC) (25% EtOAc in hexanes to 35% EtOAc in hexanes) to yield 3 as a colourless solid (8.6 g, 82%); m.p. 64-66° C. (lit. 65-67° C.); δH(300 M, CDCl3) 0.89 (t, 3H, J=6.7 Hz), 1.27 (m, 22H), 1.32 (m, 2H), 1.61 (m, 2H), 2.67 (t, 2H, J 7.4) and 3.28 (s, 2H); MS (FAB+) 289 (M+H)+, 288 M+; HRMS: Found M+0288.211823. Calc. for C16H32O2S: M+0288.212302.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]([C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)[OH:20])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Fc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 37.6 %

Procedure:
4-Fluorobromobenzene (19.26 g) in tetrahydrofuran (280 ml) was cooled to −78° C. and n-butyllithium (2.66 M n-hexane solution; 42 ml) was added thereto dropwise over 10 minutes or more while agitating. The reaction mixture was agitated for 1 hour while keeping the temperature. Then, 4-fluorobenzaldehyde (12.42 g) was added thereto dropwise over 10 minutes or more while agitating. The reaction mixture was agitated for 2 hours while keeping the temperature. Subsequently, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then brought to room temperature. The tetrahydrofuran was removed under reduced pressure, and the resultant residue was extracted with ethyl acetate. The organic layer washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography to thereby obtain the subject compound (8.28 g).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:2]=1.C(O[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:34]([N:28]1[CH2:29][CH:11]2[CH:12]([C:7]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)([C:3]3[CH:2]=[C:1]([CH3:21])[CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9][C:10]2=[O:13])[CH2:27]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cccc(C2(c3cccc(C)c3)C=CC(=O)CC2)c1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C2(c3cccc(C)c3)CCC(=O)C3CN(Cc4ccccc4)CC32)c1
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (12 drops) is added to a solution of 4,4-bis(3-tolyl)cyclohexenone (16.7 g) and N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine (18.7 cc) in dry dichloromethane (150 cc). The reaction mixture is brought to reflux, then stirred for 3 hours while allowing the temperature the return to 25° C. and for a further 10 minutes after the addition of potassium carbonate (12 g). After filtration and concentration to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 5 cm, height 50 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (85:15) and collecting 25-cc fractions. Fractions 14 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-bis(3-tolyl)perhydro-4-isoindolone (13.9 g) in the form of a colorless oil.