Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]([NH2:17])[CH2:15][NH2:16].[BH4-].[Na+].Cl>CO.O1CCCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:16][CH2:15][CH2:14][NH2:17])[CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: NCCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(NCCN)c1ccc(S(C)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
4′-(Methylsulfonyl)acetophenone (1.0 g) and ethylenediamine (908 mg) were dissolved in methanol (10 ml), and the solution was heated at 50° C. for 3 hours. The reaction mixture was added with a suspension of sodium borohydride (286 mg) in tetrahydrofuran (50 ml), and then added with methanol (6 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was made acidic with 1 N hydrochloric acid, and then the solvent was evaporated under reduced pressure. The mixture was added with distilled water and potassium carbonate and thereby neutralized, then the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:0.1) to obtain the title compound (553 mg).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](O)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Na].S(Cl)([Cl:22])=O.CN(C)C=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([Cl:22])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 15.0 g (0.052 mol) of 4-(4-fluorophenoxy)benzenesulfonic acid□, sodium salt, in 150 mL of dry toluene was added 11.3 mL (0.155 mol, 3 equivalents) of thionyl chloride and 0.04 mL (0.5 mmol, 0.01 equivalents) of dimethylformamide. The resulting mixture was stirred at room temperature for 48 hours, filtered through diatomaceous earth, and concentrated under reduced pressure to 40 mL. This solution was used without further purification to prepare 1-[4-(4-fluorophenoxy)benzenesulfonylamino] cyclopentanecarboxylic acid benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=1.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C)C=O.O>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=1
Reactant: CCCCCCCCCBr
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1cc(C(=O)Nc2c(Cl)cncc2Cl)ccc1OC
Temperature: 25 °C

Procedure:
A stirred solution of N-(3,5-dichloropyrid-4-yl)-3-hydroxy-4-methoxybenzamide (2.0 g; that is prepared as described in Reference Example 12) in dimethylformamide (20 mL) at room temperature under nitrogen is treated portionwise with a suspension of sodium hydride (60% dispersion in oil; 0.26 g), and then it is stirred for a further hour at room temperature. It is then treated dropwise with 1-bromononane (1.2 mL) and stirred at 60° C. for 5 hours. The solution is then cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (2×100 mL). The combined organic extracts are dried over magnesium sulfate and evaporated, to give a white solid, which is subjected to flash chromatography on silica gel, eluting with t-butyl methyl ether, to give N-(3,5-dichloropyrid-4-yl)-3-nonyloxy-4-methoxybenzamide (0.56 g), m.p. 151-153° C. [Elemental analysis: C,60.3; H,6.45; N,6.3%; calculated: C,60.1; H,6.4; N,6.4%].
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[N+:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:30]3[CH2:31][CH2:32][N:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)=[CH:20][C:7]=2[C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1oc2ccc(CN3CCN(c4ccccc4)CC3)cc2c1-c1ccccc1

Procedure:
Using the method of Example 1, 5-bromomethyl-2-nitro-3-phenylbenzofuran is reacted with N-phenylpiperazine in ethanol to provide yellow needles of 4-(2-nitro-3-phenyl-5-benzofuranylmethyl)-1-phenylpiperazine, m.p. 155°-157° C., having the structure
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH3:10].[C:11](O)(=[O:15])[C:12](O)=[O:13]>Cl.O>[F:9][C:5]1[CH:6]=[C:7]2[C:2]([NH:1][C:11](=[O:15])[C:12](=[O:13])[NH:8]2)=[C:3]([CH3:10])[CH:4]=1
Reactant: O=C(O)C(=O)O
Reactant: Cc1cc(F)cc(N)c1N
Agent: Cl
Solvent: O
Product: Cc1cc(F)cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
20 g (0.118 mol) of 2,3-diamino-5-fluorotoluene and 15.8 g (0.176 mol) of oxalic acid are stirred at reflux for 16 hours in 4N hydrochloric acid. The reaction mixture is cooled, diluted with water, filtered off on a suction filter and washed with water. The title compound is obtained as beige crystals of m.p.>300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:33]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=2)=[O:34])=[CH:20][CH:21]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc([N+](=O)[O-])cc4)cc3)c2cc1OC
Yield: 88.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (103 mg) was dissolved in toluene (10 ml) with heat, 4-nitrophenyl isocyanate (366 mg) was added, and the admixture was refluxed with heat for 60 minutes. The separated crystals were filtered and washed with toluene to obtain 141 mg of the title compound (yield: 88%).
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(C(C)C)CC)(C)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C(Cl)Cl>[CH2:14]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:35](=[O:38])[CH:36]=[CH2:37])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C=CC(=O)Cl
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N(CCCCCCCCCCCC)CCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
To a solution of didodecylamine 66 (25 g, 70.7 mmol) and diisopropylethylamine (18 g, 141 mmol) in anhydrous CH2Cl2 (700 mL) at −10° C., a solution of acryloyl chloride (7.68 g, 85 mmol) in CH2Cl2 (100 mL) was added dropwise over a period of 20 min. After the completion of the addition the reaction mixture was stirred for 4 h at 0° C. after which the TLC of the reaction mixture showed the completion of the reaction. The reaction mixture was washed with satd. NaHCO3 solution (200 mL), water (200 mL), brine (100 mL) and dried over NaSO4. Concentration of the organic layer provided the product 71 (28.4 g, 100%) which was used as such in the next step. 1H NMR CDCl3 δ 0.94 (t, J=6.5 Hz, 6H), 1.05-1.69 (m, 40H), 3.15-3.60 (dt, 4H), 5.64 (d, 1H), 6.36 (d, 1H), 6.63 (m, 1H).
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:8]1([Mg]Cl)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[CH:8]1([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: ON1CCCCC1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCCCC1C1CCCCC1
Reaction time: 1 h
Yield: 26.6 %

Procedure:
Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxy-piperidine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of cyclohexylmagnesium chloride (2.0 M in diethyl ether, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 40% diethyl ether in hexanes to give the title compound (0.241 g, 27%) as a white crystalline solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([C@@H:17]([N:28]2[CH2:32][C@H:31]([CH2:33][OH:34])[C@@H:30]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)[CH2:29]2)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[CH:11]1([C@@H:17]([N:28]2[CH2:32][C@H:31]([CH:33]=[O:34])[C@@H:30]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)[CH2:29]2)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(OCc1ccccc1)[C@@H](C1CCCCC1)N1C[C@H](CO)[C@@H](c2cccc(F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of oxalyl chloride (1.03 mL, 11.8 mmol) in 60 mL CH2Cl2 was cooled in a dry ice/acetone bath. DMSO (1.67 mL, 23.6 mmol) was added dropwise. The mixture was stirred for 15 min then a solution of benzyl (2R)-cyclohexyl[(3S,4R)-3-(3-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]ethanoate (4.2 g, 9.8 mmol, from Step C) in 70 mL CH2Cl2 was added dropwise. After stirring for 15 min TEA (6.8 mL, 49 mmol) was added in 10 mL CH2Cl2. The mixture was warmed to rt and stirred for 2 h. The solution was poured into a speparatory funnel and diluted with 200 mL CH2Cl2 and washed with 1 N NaOH (2×), water and sat'd NaCl. The organic portion was dried over sodium sulfate and concentrated. Flash chromatography (150 g silica, 0→30% EtOAc/hexanes) gave the desired aldehyde. 1H NMR (500 MHz, CDCl3) δ0.95-1.05 (m, 2H), 1.14-1.29 (m, 3H), 1.6 (br d, 1H), 1.66-1.83 (m, 4H), 1.93 (br d, 1H), 2.65-2.69 (m, 1H), 2.88-2.93 m, 1H), 3.15 (dd, 1H), 3.20-3.24 (m, 2H), 3.27-3.30 (m, 1H), 3.55 (dd, 1H), 5.18 (d, 1H), 5.19 (d, 1H), 6.89-6.97 m, 3H), 7.23-7.27 (m, 1H), 7.33-7.4 (m, 5H).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][NH:8]C(=O)C)(=[O:4])=[O:3].[ClH:12]>O>[ClH:12].[CH3:1][S:2]([NH:5][CH2:6][CH2:7][NH2:8])(=[O:4])=[O:3]
Reactant: CC(=O)NCCNS(C)(=O)=O
Agent: Cl
Solvent: O
Product: CS(=O)(=O)NCCN

Procedure:
N-[2-(Methylsulphonamido)ethyl]acetamide (14.5 g, 88.3 mmol) and concentrated hydrochloric acid (100 ml) were dissolved in water (100 ml) and heated to reflux for a total of 3 hours. After cooling, the water was removed in vacuo, and the residue was left for several days at room temperature until crystallisation was underway. Trituration with a mixture of ethanol and ether gave the title compound as a white solid which was dried in vacuo at 60° C. (7.5 g, 42.9 mmol, 49%); δH [2H6]DMSO 8.22 (2H,br s), 7.42 (1H,t), 3.23 (2H,q), 2.87 (3H,s), 2.85-2.95 (2H,m).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH2:10][C@@H:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3ccon3)ccc3c2[C@H](CN3)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4ccon4)c(c23)C1
Reaction time: 4 h
Yield: 14.2 %

Procedure:
A mixture of (-) (2aR,4S)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz [cd]indole (400 mg, 1.2 mmol) and 1 g of MnO2 in 100 ml of CH2Cl2 was sonicated at 50-55 KHz for four hours. The reaction mixture was warmed to reflux during the time period. After four hours, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness in vacuo. The resulting residue was chromatographed (flash column, silica gel, EtOAc) to provide 55 mg of title product as an oil. MS m/e 323(FD)
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(OCC)(=O)C>[CH3:23][S:24]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:26])=[O:25]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzyl 1-piperazinecarboxylate (2.03 g, 9.22 mmol) was dissolved in pyridine (23.0 mL, 9.22 mmol) and cooled to 0° C. before methanesulfonyl chloride (2.85 mL, 36.9 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and warmed to RT for 2 h. The reaction mixture was diluted with 75 mL of ethyl acetate, added to a separation funnel, partitioned with 3 N HCl (aqueous), washed 3× with 50 mL of 3 N HCl (aqueous), and separated, before the aqueous layer was extracted 3× with chloroform/isopropanol, then dried over sodium sulfate, and concentrated in vacuo to give the title compound. Benzyl 4-(methylsulfonyl)piperazine-1-carboxylate (2.80 g, 9.4 mmol) was dissolved in ethanol (0.43 g, 9.4 mmol) before palladium, 10 wt. % on activated carbon (2.0 g) was added and a hydrogen balloon attached. The reaction mixture was stirred at RT for 2 h before it was filtered through a pad of Celite®, washed with methanol, and concentrated in vacuo to give the title compound. MS (ES+): 165 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:14]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([CH3:25])=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([OH:13])[CH3:12])=[N:8][C:7]=2[CH:33]=1)#[N:2].[CH3:34]I.[H-].[Na+]>CN(C=O)C>[C:29]([O:28][C:26]([N:18]1[C:19]2[C:15](=[C:14]([C:11]([C:9]3[O:10][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][C:7]=4[N:8]=3)([O:13][CH3:34])[CH3:12])[C:22]([O:23][CH3:24])=[CH:21][C:20]=2[CH3:25])[CH:16]=[CH:17]1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CI
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(O)c1nc2cc(C#N)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(OC)c1nc2cc(C#N)ccc2o1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(1-(5-cyanobenzo[d]oxazol-2-yl)-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (250 mg, 0.559 mmol) in DMF (5.7 mL) at 0° C. was added successively MeI (0.105 mL, 1.676 mmol) and NaH (60% in mineral, 33.5 mg, 0.838 mmol). The reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was quenched with 4 mL of saturated aq. solution of ammonium chloride and diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-30% EtOAc:heptanes) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (dd, J=1.52, 0.63 Hz, 1H) 7.79-7.97 (m, 2H) 7.63 (d, J=3.79 Hz, 1H) 7.05 (d, J=3.79 Hz, 1H) 6.83 (s, 1H) 3.23 (s, 3H) 3.17 (s, 3H) 1.81-2.08 (m, 3H) 1.60 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH2:10])[CH:6]=[CH:7][CH:8]=1)[CH3:2].B#B.[Br:13]Br.C[O-].[Na+]>O1CCCC1.CO>[Br:13][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: BrBr
Reactant: C=Cc1cccc(CC)c1
Agent: B#B
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cccc(CCBr)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of 3-ethyl-1-vinylbenzene (Preparation 20, 1.45 g, 10.9 mmol) in anhydrous tetrahydrofuran (50 ml) under nitrogen at 0° C. was added diborane (1.0M solution in tetrahydrofuran, 4 ml, 4 mmol) dropwise over 30 min. After 30 min at room temperature, methanol (0.1 ml) was added to destroy excess diborane. The reaction mixture was cooled to 0° C., and bromine (0.59 ml, 11 mmol) and a solution of sodium methoxide in methanol (12.1 mmol) were added via separate syringes at such a rate that a pale yellow coloration was always maintained. The reaction mixture was partitioned between aqueous saturated potassium carbonate solution and hexane. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the crude product. The residue was purified by silica column chromatography eluting with hexane to afford the title compound (640 mg, 28%).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH3:19])[CH2:12][CH2:11]1.[ClH:21]>>[ClH:21].[CH3:19][O:18][CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:20])=[O:2])[CH2:11][CH2:12]1
Reactant: COCCN1CCN(c2ccccc2C(=O)OC)CC1
Agent: Cl
Product: COCCN1CCN(c2ccccc2C(=O)O)CC1

Procedure:
[4-(2-methoxy-ethyl)-piperazin-1-yl]-benzoic acid methyl ester (17 mmol) is dissolved in 4N HCl (70 ml) and heated under reflux for 5 hours. After cooling the solvent is evaporated and the residue is suspended in ethanol and the solid filtered of, washed with diethylether and dried (vacuum). A powder with mp. >270° C., Rf=0.35 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]=[N+]=[N-])[CH:18]=2)([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cccc(N=[N+]=[N-])c2)(C(F)F)COC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=NC(c2cccc(N)c2)(C(F)F)COC1

Procedure:
A solution of [5-(3-azido-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (1.71 g, 4.65 mmol) in 22 ml ethanol and 12 ml THF was hydrogenated with Pd/C (10%) (3 hrs, r.t.) The mixture was filtered through Celite, and the filtrate was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate) to yield the title compound as colorless solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].Cl[SiH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([F:32])[CH:23]=3)[CH2:18][CH2:17]2)[CH2:8][CH2:7]1>C1COCC1>[F:32][C:24]1[CH:23]=[C:22]([C@H:19]2[CH2:20][CH2:21][C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][C@H:9]3[CH2:8][CH2:7][Si@H:6]([CH2:1][CH3:2])[CH2:11][CH2:10]3)[CH2:17][CH2:18]2)[CH:27]=[CH:26][C:25]=1[O:28][CH:29]([F:30])[F:31]
Reactant: CC[Mg]Br
Reactant: Fc1cc([C@H]2CC[C@H](CCCCC3CC[SiH](Cl)CC3)CC2)ccc1OC(F)F
Solvent: C1CCOC1
Product: CC[Si@H]1CC[C@H](CCCC[C@H]2CC[C@H](c3ccc(OC(F)F)c(F)c3)CC2)CC1

Procedure:
130 ml (0.13 moles) of a THF solution of 1M of ethylmagnesium bromide was dropped in a mixed solution of 43.3 g (10 mmols) of 1-chloro-4-(4-(trans-4-(3-fluoro-4-difluoromethoxyphenyl)cyclohexyl)butyl)-1-silacyclohexane and 30 ml of THF. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments, followed by isolation through chromatography to obtain 42.7 g (yield: 87%) of the intended trans isomer product.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].Cl[CH2:12][CH:13]=[C:14]([Cl:16])[CH3:15]>C(O)C>[C:2]([CH:3]([CH2:12][CH:13]=[C:14]([Cl:16])[CH3:15])[C:4](=[O:5])[CH3:6])([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(Cl)=CCCl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC=C(C)Cl)C(C)=O

Procedure:
To a solution of 46 g sodium (2 g atom) in 500 ml ethanol at reflux, in a 2-liter flask equipped with mechanical stirrer, and addition funnel, was added 325 g ethyl acetoacetate (2.5 mole) over 30 minutes. The resulting solution of enolate was refluxed for 15 minutes, and then 250 g (2.0 mole) 1,3-dichlorobut-2-ene (nD20 1.4675) was added dropwise at such a rate as to maintain reflux with gentle heating towards the end of the addition. After addition, refluxing and stirring were maintained for 4 hours, the condenser converted for distillation, and ethanol removed as 500 ml distillate. The residual product was cooled, water and 1.2 N hydrochloric acid were added and the organic layer separated. The aqueous portion was extracted with ether, the organic layers combined, washed with water and brine, filtered through sodium sulfate and evaporated in vacuo to give 485 g. dark yellow oil (96%, based on dichlorobutene). Vpc showed 73% of trans plus cis product, together with 20% ethyl acetoacetate and other volatiles, and 7% dialkylated product at long retention time. A small sample was purified by TLC on silica gel (1:3 ethyl acetate:pentane) Rf 0.27, followed by distillation at 100° C./0.1 mm. 3-Carboethoxy-6-chlorohept-5-en-2-one was obtained as a colorless oil, nD20 1.4640.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: Cc1cccc(I)c1
Product: Cc1cccc(-n2ccc3ccc(Cl)cc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-3-methylbenzene: ESMS m/e: 241.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[C:5]([C:14]#[N:15])=[C:4]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:3]=1[C:25]#[N:26].[H-].[Na+].C(#N)C.O.[CH:33]1(O)[CH2:36]C[CH2:34]1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH:12]2[CH2:36][CH2:33][CH2:34]2)=[O:10])[C:5]([C:14]#[N:15])=[C:4]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:3]=1[C:25]#[N:26]
Reactant: OC1CCC1
Reactant: COC(=O)C(C)c1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C(=O)OC1CCC1)c1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
Methyl 2-[6-amino-4-(1,3-benzodioxol-5-yl)-3,5-dicyano-2-pyridinyl]propionate (from Example 6) (100 mg, 0.29 mmol) in cyclobutanol (5 ml) is heated under reflux with a catalytic amount of sodium hydride for 2.5 hours. The product is isolated by RP-HPLC (Kromasil column 250 * 20 mm, C18, 10 μm; acetonitrile/water gradient: 3 minutes 10%, then within 30 minutes to 80%, flow rate: 25 ml*min−1).