Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C@H:14]([C:22](O)=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C@@H:59]([CH2:80][C:81]1[N:82]=[CH:83][NH:84][CH:85]=1)[C:60]([NH:62][C@@H:63]([CH2:73][CH:74]1[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]1)[C@@H:64]([OH:72])[CH2:65][C@@H:66]([CH:69]([CH3:71])[CH3:70])[CH:67]=[CH2:68])=[O:61].CCN(C(C)C)C(C)C>C(#N)C>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C@H:14]([C:22](=[O:23])[NH:58][C@H:59]([C:60](=[O:61])[NH:62][C@@H:63]([CH2:73][CH:74]2[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79]2)[C@@H:64]([OH:72])[CH2:65][C@@H:66]([CH:69]([CH3:70])[CH3:71])[CH:67]=[CH2:68])[CH2:80][C:81]2[N:82]=[CH:83][NH:84][CH:85]=2)[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:12])=[CH:5][CH:6]=1
Reactant: O=C(NCCOc1ccc(-c2ccccc2)cc1)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)NCCOc1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
A solution of 103 mg of N-[[2-(4-biphenyloxy)ethyl ]carbamoyl]-3-phenyl-L-alanine and 113 mg of BOP in acetonitrile was added to 100 mg (0.256 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide 0.052 ml of Hunig base in 5 ml of acetonitrile, and the mixture was subsequently stirred at room temperature for 12 hours. Subsequently the reaction mixture was poured onto 1N hydrochloric acid/ice, extracted with ethyl acetate, the extracts were dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by chromatography on silica gel with a 10:1 mixture of methylene chloride and methanol, to obtain 90 mg (45%) of 1-[2-(4-biphenyloxy)ethyl]-3-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]- carbamoyl]phenethyl]urea as an amorphous powder. MS: 777 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH2:20][OH:21])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cccs2)s1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(Cl)s2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a solution of 5-chloro-[2,2′]bithiophenyl (3.00 g, 14.9 mmol) in 30 mL of THF at 0° C. is added n-BuLi (9.8 mL of a 1.6M solution in hexanes, 15.7 mmol) dropwise. DMF (2.30 mL, 30 mmol) is added dropwise and the resulting solution is heated at reflux for 1 hour. The solution is diluted with H2O and extracted with Et2O. The organic layer is washed with H2O and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude aldehyde is dissolved in 40 mL of anhydrous MeOH and sodium borohydride (0.85 g, 22.5 mmol) is added portionwise. The mixture is stirred at room temperature for 10 min, then quenched with water. The mixture is diluted with Et2O and the layers separated. The organic layer is washed with H2O, then dried over MgSO4, filtered and concentrated to yield the title compound (2.23 g, 9.66 mmol) which is used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ6.95 (d, 1H), 6.90 (m, 2H), 6.86 (d, 1H), 4.82 (s, 2H), 1.88 (bs, 1H).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.C[Zn]C.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:22]=[CH:21][C:16]([C:17](Cl)([CH3:19])[CH3:18])=[CH:15][CH:14]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:11][C:12]([F:24])([F:23])[C:13]1[CH:22]=[CH:21][C:16]([C:17]([CH3:1])([CH3:19])[CH3:18])=[CH:15][CH:14]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[Zn]C
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(F)(F)F)cc1
Temperature: -40 °C

Procedure:
To a toluene solution of dimethylzinc (150 mL, 2.0M, 0.30 mol) at -78° C. is added a CH2Cl2 solution of titanium tetrachloride (150 mL, 1.0 M, 0.15 mol) and after stirring for 30 min 4-trifluoromethyl-α,α-dimethylbenzyl chloride (83.3 g, 0.373 mol) in CH2Cl2 (100 mL) is added dropwise over 20 min. After the addition is complete the reaction is allowed to warm to -40° C. over 1.5 h. After an additional 2 h at -40° C. the brown reaction mixture is carefully poured onto crushed ice, extracted with CH2 Cl2 (2×500 mL), the combined extracts dried over MgSO4 and concentrated to give 4-trifluoromethyl-t-butylbenzene; yield: 60.3 g (80%). Anal. Calcd. for C11H13F3 : C, 65.32; H, 6.48. Found: C, 65.11; H, 6.38.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:18])([CH3:17])[CH2:10]/[C:11](/[CH3:16])=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:41][N:42]([C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:43](=[O:58])[CH:44]([NH:56][CH3:57])[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:18])([CH3:17])[CH2:10]/[C:11](/[CH3:16])=[CH:12]/[C:13](=[O:15])[N:56]([CH3:57])[C@@H:44]([C:43](=[O:58])[N:42]([CH3:41])[C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Reactant: C/C(=C\C(=O)O)CC(C)(C)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C(\C)CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.2 %

Procedure:
(2E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid (0.30 g; 1.17 mmol.) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazol (0.16 g; 1.17 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g; 1.28 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.47 g; 1.67 mmol) was dissolved in methylene chloride (10 mL) and added. Diisopropylethylamine (0.20 mL; 1.66 mmol ) was added and the reaction was stirred for 12 hours at room temperature. Methylene chloride (10 mL) was added and the reaction was washed with water (10 mL), an aqueous solution of sodium hydrogen sulfate (10%; 10 mL) and an aqueous solution of sodium hydrogen carbonate (pH 8; 10 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3×30 cm) using ethyl acetate/methylene chloride (1:1) as eluent to afford 0.37 g of ((3E)-1,1,3-trimethyl-4-(methyl-((1R)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert butylester.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].[Na].Br[CH2:7][C:8](=[O:30])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C:24](=[O:28])[CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@H:18]([OH:29])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1>CC(O)C.C1(C)C=CC=CC=1>[OH:29][C@@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[C:24](=[O:28])[CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C:8](=[O:30])[CH2:7][S:4][CH:2]([CH3:3])[CH3:1])[CH2:17]1
Reactant: CC(C)S
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)SCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
Propane-2-thiol (1.3 ml.) was added to a warm solution of sodium (0.6 g.) in a mixture of propan-2-ol (25 ml.) and toluene (30 ml.). 21-Bromo-3α-hydroxy-5α-pregnane-11,20 -dione (0.7 g.) was then added and the mixture was gently refluxed for 2 hr. The mixture was then partitioned between water and ether and the organic layer was washed with water, dried (Na2SO4) and evaporated. The residual foam was purified by preparative t.l.c. (CHCl3) to give title compound (0.2 g.) as a white foam, [α]D + 67° (c 1.3).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](CCO)=[CH:26][CH:25]=1>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH2:7][C:27]1[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=1)=[O:4]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Reactant: OCCc1ccc(Cl)cc1
Agent: [Ti+4]
Agent: CC[O-]
Product: CN1CCC2(C)c3cc(C(=O)C(=O)OCCc4ccc(Cl)cc4)ccc3N(C)C12

Procedure:
To a chilled (0° C.) solution of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester (1.18 g) in 4-chlorophenylethyl alcohol (31 ml) was added titanium (IV) ethoxide (0.30 ml) under a nitrogen atmosphere with stirring. The mixture was gently heated without refluxing for 4 hours. The 4-chlorophenylethyl alcohol was removed by distillation under high vacuum and the crude residue was dissolved in dichloromethane (20 ml) and washed successively with two 100 ml portions of saturated ammonium chloride solution, two 100 ml portions of saturated sodium bicarbonate solution and 100 ml of brine. The organic phase was dried (Na2SO4) filtered, and purified using preparative HPLC (silica gel, 3% methanol in dichloromethane as the loading solvent and eluent). The appropriate fractions were combined and the solvent removed under vacuum. Concentration of the appropriate fractions yielded 0.87 g of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, 4 -chlorophenylethyl ester as an oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:13])[CH2:8]2
Reactant: C1CCNC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1N1CCCC1

Procedure:
Phenyl-5-pyrrolidin-1-y1-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and pyrrolidine. Mass spectrum (ES) MH+=391.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][C@H:16]([CH2:21][N:22]([CH2:30][C@H:31]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:46][O:47][CH2:48][C:49](O)=[O:50].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:39]([O:38][C@H:31]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[CH2:30][N:22]([CH2:21][C@@H:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([NH:1][C:49](=[O:50])[CH2:48][O:47][CH3:46])(=[O:4])=[O:3])[CH:6]=3)[CH:12]=2)[O:17]1)[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41]
Reactant: COCC(=O)O
Reactant: CC(C)(C)OC(=O)N(C[C@@H]1CCc2cc(-c3cccc(S(N)(=O)=O)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCC(=O)NS(=O)(=O)c1cccc(-c2ccc3c(c2)CC[C@@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)c1

Procedure:
A solution of the compound of Example 281 (60 mg, 0.091 mmol), methoxyacetic acid (13 mg, 0.13 mmol), EDCl (26 mg, 0.14 mmol), and DMAP (11 mg, 0.091 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated down and the crude product was purified by preparative TLC plate with CH2Cl2:MeOH:NH4OH (90:15:2) to obtain (60 mg). ESLC-MS: m/z=725 (MH+); 1H NMR (MeOH-d4): 8.566˜8.439 (m, 2H), 8.077 (s, 1H), 7.889˜7.780 (m, 1H), 7.675 (m, 1H), 7.453 (m, 2H), 7.313(m, 2H), 6.767 (d, 1H), 5.180˜5.035 (m, 1H), 4.220 (s, b, 1H), 3.907 (s, 2H), 3.760˜3.333 (m, 4H), 2.835 (m, 2H), 2.041 (m, 1H), 1.711 (m, 1H), 1.445 (d, 9H), 0.892 (s, 9H), 0.076 (s, 3H), −0.109 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[CH2:28]([CH:30]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([CH2:45][NH2:46])[CH:38]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:29]>ClCCl>[CH2:28]([CH:30]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([CH2:45][NH:46][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=2)[CH:38]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:29]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CN)c1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of 4-(trifluoromethyl)benzoic acid (114 mg, 0.600 mmol) and triethylamine (0.21 mL, 1.51 mmol) in dichloromethane (3 mL), ethyl chlorocarbonate (0.063 mL, 0.659 mmol) was added under stirring and cooling with ice, and the mixture was stirred for 20 minutes. Next, after ethyl 2-ethyl-3-[3-(aminomethyl)-4-methoxyphenyl]propanoate hydrochloride (200 mg, 0.663 mmol) was added, the mixture was stirred for 1 hour under cooling with ice and for 3 hours at room temperature. Dichloromethane (20 mL) was added to the reaction mixture, which was washed with 1 mol/L hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:1 v/v) to afford 245 mg (93%) of the title compound as colorless crystals.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][CH:3]3[O:8][C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[O:5][CH2:4]3)[CH2:21]2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(C2CCCNC2)cc1
Reactant: BrCC1COc2ccccc2O1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1ccc(C2CCCN(CC3COc4ccccc4O3)C2)cc1
Temperature: 130 °C
Yield: 69.8 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (34 mg, 0.15 mmol), 3-(4-chloro-phenyl)piperidine (38 mg, 0.165 mmol) and triethylamine (38 mg, 0.38 mmol) in acetonitrile (2 ml) was heated in a microwave reactor at 110-150° C. for 290 min. After evaporation to dryness, the crude product was purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 36 mg of the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([Sn](CCCC)(CCCC)[C:21]1[S:22][CH:23]=[CH:24][N:25]=1)CCC>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2nc(-c3nccs3)sc2c1
Temperature: 130 °C
Yield: 84.5 %

Procedure:
A mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 1w (150 mg, 0.53 mmol), 2-tributylstannylthiazole 9p (0.25 mL, 0.79 mmol), and Pd(PPh3)4 (30 mg, 0.03 mmol) in dioxane (2 mL) was heated at 130° C. for 30 min under microwave. The reaction mixture was diluted with CH2Cl2, washed with aq. NaHCO3, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 10% EtOAc/heptane) gave 9q (130 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:14][CH2:15][Cl:16])[P:5]1(=[O:13])[NH:10][CH:9](O)[CH2:8][CH:7]([CH3:12])[O:6]1.[CH:17]1([NH3+:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[SH:24][CH2:25][CH2:26][S:27]([O-:30])(=[O:29])=[O:28].ClC(Cl)(Cl)C(O)=O>O.CC(C)=O>[CH:17]1([NH3+:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl:1][CH2:2][CH2:3][N:4]([CH2:14][CH2:15][Cl:16])[P:5]1(=[O:13])[NH:10][CH:9]([S:24][CH2:25][CH2:26][S:27]([O-:30])(=[O:29])=[O:28])[CH2:8][CH:7]([CH3:12])[O:6]1
Reactant: O=S(=O)([O-])CCS
Reactant: CC1CC(O)NP(=O)(N(CCCl)CCCl)O1
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: O
Solvent: CC(C)=O
Product: CC1CC(SCCS(=O)(=O)[O-])NP(=O)(N(CCCl)CCCl)O1
Reaction time: 20 h

Procedure:
1.45 g (5 mmol) of 2-(bis-(2-chloroethyl)-amino)-4-hydroxy-6-methyl-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide and 1.2 g (5 mmol) of cyclohexylammonium-2-mercaptoethanesulphonate were dissolved in 5 ml of water and in 5 ml of acetone, acidified with trichloroacetic acid and left to stand for 20 hours at 0° C. The mixture was then filtered, the filtrate was carefully concentrated under vacuum, the residue was taken up twice in acetone and was concentrated. The residue was then dissolved in acetone, precipitated with ether, washed with ether and dried.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1COCC1.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Nc3ccc(F)cc3)CC2)c1
Yield: 10.9 %

Procedure:
A solution of N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (26.4 mg, 0.0870 mol), 1-fluoro-4-isocyanatobenzene (11.9 mg, 0.0870 mmol), in THF (1.00 mL) was stirred for 12 h at 25° C. The resulting crude mixture was diluted with water (10 mL), the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 2.5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product N-{3-[1-(3-{[(4-fluoroanilino)carbonyl]amino}propyl)-4-piperidinyl]phenyl}-2-methylpropanamide (4.18 mg, 10.9%): 1H NMR (400 MHz, CDCl3) 7.45 (q, 2H, J=4.7 Hz), 7.23–7.21 (m, 4H), 7.05 (t, 4H, J=7.8 Hz), 6.75 (m, 1H), 4.05 (m, 1H), 3.19 (s, 1H), 2.71 (m, 1H), 2.53 (m, 1H), 2.26–2.21 (m, 3H), 1.80–1.60 (m, 9H), 1.25 (d, 6H, J=6.4 Hz); ESMS m/e: 439.4 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[C:11]2=[O:21])[CH2:3][CH2:2]1.OS(O)(=O)=O.[N+:27]([O-])([O-:29])=[O:28].[K+]>>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([N+:27]([O-:29])=[O:28])=[C:15]([F:20])[CH:16]=3)[C:11]2=[O:21])[CH2:3][CH2:2]1
Reactant: O=C1c2ccc(F)cc2CCN1c1cnccc1C1CC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1c2cc([N+](=O)[O-])c(F)cc2CCN1c1cnccc1C1CC1
Yield: 49.2 %

Procedure:
2-(4-Cyclopropylpyridin-3-yl)-6-fluoro-3,4-dihydroisoquinolin-1(2H)-one (81A: 700 mg, 2.482 mmol) was reacted with conc. H2SO4 (5 mL) and KNO3 (276 mg, 2.73 mmol) for 4 hours to afford 400 mg of the product (49.14% yield).
Reaction SMILES: F[C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH3:19][O-:20].[Na+].CO>CN(C)C=O>[CH3:19][O:20][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C[O-]
Reactant: Fc1c(OC(F)(F)F)cccc1C1CCNCC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1c(OC(F)(F)F)cccc1C1CCNCC1

Procedure:
Preparation according to preparation 34: 4-[2-fluoro-3-(trifluoromethoxy)phenyl]piperidine (1.23 g, 4.7 mmol), N,N-dimethylformamide (20 ml), sodium methoxide in methanol (30%, 2.35 ml, 13.2 mmol). Yield: 1.32 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(CCN(CCN(C)C)C)C.CN(C)[CH:28]=[O:29]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][C:7]=1[CH:28]=[O:29]
Reactant: Cc1cccc(F)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C=O)c(F)c1
Reaction time: 2 h
Yield: 22.6 %

Procedure:
The solution of 3-fluorotoluene (2.91 g, 0.0266 mol) in anhydrous tetrahydrofuran was cooled to −78° C. and a 1.4M solution of n-butyllithium in hexanes (19 mL, 0.0266 mol) was added dropwise keeping the reaction mixture temperature below −75° C. Upon the completion of the addition, N,N,N′,N′,N″-pentamethyldiethylenetriamine was added dropwise and the stirring at −78° C. was continued under an atmosphere of nitrogen for an additional 2 hours. N,N-dimethylformamide (3.89 g, 0.0532 mol) was added dropwise and the reaction mixture was slowly warmed up while stirring for 0.5 hours. It was quenched by dropwise addition of 1N hydrochloric acid and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2×150 mL) and the combined organic extracts were dried with magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield 2-fluoro-4-methylbenzaldehyde (0.83 g, 0.006 mol) as a white solid.
Reaction SMILES: ClC([O:4][CH3:5])Cl.[CH3:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH3:13]>>[CH3:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH:5]=[O:4]
Reactant: Cc1ccccc1C
Reactant: COC(Cl)Cl
Product: Cc1ccc(C=O)cc1C

Procedure:
The above reaction of Example 21A is repeated except that o-xylene and dichloromethyl methylether are the starting materials. Using the same reaction conditions and techniques, there is obtained 3,4-dimethylbenzaldehyde.