Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[C:3]1([NH:9][C:10]2([CH:23]=[O:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO.O>[C:3]1([NH:9][C:10]2([CH2:23][OH:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=CC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Sodium borohydride (2 g) was added portionwise to a stirred solution of 4-(N-phenylamino)-1-phenylmethyl-piperidine-4-carboxaldehyde (2 g) in methanol at room temperature. After stirring at room temperature for 2 hours the mixture was diluted with water, extracted with chloroform and the combined extracts washed and dried. After removal of the solvent, the crude product was purified by chromatography on silica gel, using chloroform/methanol (38:1) as eluant, to give the title compound (1.53 g) 4-(N-phenylamino)--1-phenylmethyl-4-piperidinylmethanol is then converted to sufentanil following the method described in U.S. Pat. No. 4,179,469 and as illustrated by FIG. 2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[NH:10]2)[N:4]=1>C1COCC1.[O-2].[O-2].[Mn+4].O=[Mn]=O>[CH:2]([C:3]1[CH:7]=[N:6][N:5]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[NH:10]2)[N:4]=1)=[O:1]
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1ncc(CO)n1)OCc1ccccc1
Agent: O=[Mn]=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (385 mg, 1.16 mmol) in THF (10 mL) was added manganese dioxide (2.0 g, 23 mmol). After stirring at rt for 12 h, another 1 g of MnO2 was added and stirred for another 1 h. The reaction mixture was filtered over celite with MeOH wash. The filtrate was concentrated in vacuo to give the title compound (340 mg, 89%). The crude residue was used as such in the following step. LCMS: Rt=0.61 min, m/z=330.0 (M+1) Method 2m_acidic.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[N:20]=[N:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH:22]=3)=[N:17]2)=[CH:11][CH:10]=1)(C)(C)C>FC(F)(F)C(O)=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:28]#[C:27][C:23]2[CH:22]=[C:21]([C:18]3[N:19]=[N:20][N:16]([CH2:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:37])=[O:5])=[CH:14][CH:13]=4)[N:17]=3)[CH:26]=[CH:25][CH:24]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cn2nnc(-c3cccc(C#CCc4ccc(F)cc4)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(Cn2nnc(-c3cccc(C#CCc4ccc(F)cc4)c3)n2)cc1
Yield: 62.3 %

Procedure:
A solution of [4-(5-{3-[3-(4-fluorophenyl)prop-1-ynyl]phenyl}tetrazol-2-ylmethyl) phenoxy]-acetic acid tert-butyl ester (0.19 g. 0.38 mmol) in trifluoroacetic acid (“TFA”) (6 mL) was stirred at room temperature for 75 minutes, then evaporated to dryness. The residue was triturated with ether, evaporated, triturated again with ether/hexanes, evaporated, then triturated with hexanes/ethyl acetate 3:1. The solid was collected by filtration, washed with hexanes/ethyl acetate 3:1 and dried to give 0.1047 g of orange solid (59.11% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[CH:36]1([C:39](O)=O)[CH2:38][CH2:37]1>>[CH:36]1([C:39]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([CH2:19][N:20]5[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]5)[N:15]4[CH3:18])=[C:11]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[N:10]=3)[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:38][CH2:37]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Reactant: O=C(O)C1CC1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21

Procedure:
Following the procedures for 178, 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and cyclopropanecarboxylic acid were reacted to give 159. LCMS: M+H+=531.3. 1H-NMR (400 MHz, DMSO-d6): δ 7.93 (m, 1H), 7.53 (m, 1H), 7.22 (m, 2H), 4.26 (s, br, 4H), 4.08 (m, 2H), 4.03 (s, 1H), 3.82 (s, 3H), 3.77 (m, 4H), 3.74 (s, 2H), 3.17 (d, 2H), 2.84-2.96 (m, 3H), 1.99 (m, 2H), 1.67 (m, 2H), 1.04-1.29 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: Cl[CH2:2][C@@:3]([CH3:7])([OH:6])[CH2:4][OH:5].[H-].[Na+].[CH3:10][CH:11]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:12][CH2:13][Mg]Br>O>[CH3:7][C@@:3]([OH:6])([CH2:2][CH2:13][CH2:12][CH:11]([CH3:10])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:4][OH:5]
Reactant: C[C@](O)(CO)CCl
Reactant: CC(C)CCCC(C)CCCC(C)CC[Mg]Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)CCCC(C)CCCC(C)CCC[C@@](C)(O)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
367 mg (3 mmol) of (2S)-3-chloro-2-methyl-1,2-propanediol were dissolved in 5 ml of dry tetrayhydrofuran and left to react at room temperature with 100 mg (7.2 mmol) of sodium hydride (55-60%) until the evolution of gas had finished. 350 mg of potassium tert.-butylate were added to the resulting thick suspension. Thereupon, 2.9 mmol of (3RS,7RS)-3,7,11-trimethyldodecylmagnesium bromide were added and the mixture was stirred at room temperature for 16 hours. 50 ml of water were subsequently added and the mixture was extracted with ether. The organic phases were dried over sodium sulphate and concentrated. There was obtained 0.81 g (96%) of (2R,6RS,10RS)-2,6,10,14-tetramethyl-1,2-pentadecanediol with [α]D20 =+1.35° (c=1.5% in CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(Cl)CCl.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CC1(C)C(C2C=NC(C)=C([N+]([O-])=O)C=2)=CCNC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: Cc1ncc(C2=CCNCC2(C)C)cc1[N+](=O)[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cc1cncc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 95 %

Procedure:
To a solution of (5-bromopyridin-3-yl)acetic acid (1.00 g, 4.63 mmol) and morpholine (0.50 mL, 5.73 mmol) in DCM (50 mL) was added EDC (1.78 g, 9.30 mmol) and 1-hydroxybenzotriazole (1.25 g, 9.26 mmol). The reaction mixture was allowed to stir at rt for 50 min and then diluted with DCM (50 mL) and 1N HCl (100 mL). The organic solution was separated and discarded. The aqueous solution was neutralized with sat. aq. NaHCO3 (100 mL) and was extracted with DCM (3×50 mL). The organic solutions were combined, dried over MgSO4, filtered and concentrated to give 4-[(5-bromopyridin-3-yl)acetyl]morpholine (1.26 g, 4.40 mmol, 95%) as a light brown solid. LCMS (FA): Rt=1.11 min, m/z=287.0 (M+H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26](=[O:28])[CH3:27].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38]>>[C:26]([C:20]1[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=1[O:18][CH:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=1)[C:37]([O:39][CH3:40])=[O:38])(=[O:28])[CH3:27]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: CC(=O)c1cc(C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: COC(=O)C(Oc1ccc(C)cc1C(C)=O)c1ccccc1
Yield: 62.8 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.67 mmol) of 2'-hydroxy-5'-methylacetophenone was alkylated with 1.68 g (7.34 mmol) of methyl 2-bromophenylacetate to afford 1.25 g (63%) of the title compound.
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][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.Br[CH2:37][CH2:38][N:39]1[C:43](=[O:44])[C:42]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]2[C:40]1=[O:49]>>[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][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:37][CH2:38][N:39]3[C:43](=[O:44])[C:42]4=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]4[C:40]3=[O:49])[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(CCN5C(=O)c6ccccc6C5=O)c4=O)CC3)c2cc1OC
Yield: 31 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 478.0 mg (1.00 mol) of Compound 24 was used and N-(2-bromoethyl)phthalimide was used in place of methyl iodide. As a result, 200 mg (yield: 31%) of Compound 33 was obtained as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6](COCC[Si](C)(C)C)[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[C:3]=1[N:25]1[CH2:29][CH2:28][C@H:27]([N:30]([CH2:38][CH3:39])C(=O)OC(C)(C)C)[CH2:26]1.Br.[OH-].[Na+].Cl>O1CCOCC1>[Br:1][C:2]1[CH:24]=[N:23][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[C:3]=1[N:25]1[CH2:29][CH2:28][C@H:27]([NH:30][CH2:38][CH3:39])[CH2:26]1
Reactant: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(Br)cnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN[C@H]1CCN(c2c(Br)cnc3[nH]c4cnc(C#N)cc4c23)C1
Temperature: 55 °C
Yield: 59.7 %

Procedure:
(S)-tert-butyl 1-(3-bromo-6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)pyrrolidin-3-yl(ethyl)carbamate (65 mg, 0.1 mmol) was dissolved in 1,4-dioxane (0.3 mL) and then treated with 48% HBr(aq) (0.3 mL) and heated at 55° C. for 20 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a pale yellow solid (23 mg, 26% over two steps). 1H NMR (500 MHz, d6-DMSO) δ 8.97 (s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 3.79-3.73 (m, 2H), 3.62-3.51 (m, 3H), 3.43 (m, 1H), 2.72-2.59 (m, 2H), 2.26 (m, 1H), 1.97 (m, 1H), 1.14 (t, J=7.1, 3H), NH signal not observed. LCMS (Method D): RT=7.535 min, M+H+=385.0/387.0.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27]([CH3:32])=[CH:26]3)[CH:14]=1)=[O:12].[CH2:33](I)[CH3:34]>CN(C=O)C>[CH2:33]([N:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:11]([N:7]5[CH2:8][CH2:9][CH2:10][C@@H:6]5[CH2:5][O:4][CH3:3])=[O:12])[S:21][C:20]=34)=[CH:31][CH:30]=2)[CH:26]=[C:27]1[CH3:32])[CH3:34]
Reactant: COC[C@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4[nH]c(C)cc4c3)c2s1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(C)cc2cc(Oc3ccnc4cc(C(=O)N5CCC[C@@H]5COC)sc34)ccc21
Reaction time: 0.33 h
Yield: 51.2 %

Procedure:
NaH (16 mg, 0.4 mmol) was added to a solution of (2R)-(2-methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone (85 mg, 0.2 mmol) in DMF (5 mL), at 0° C. The reaction mixture was allowed to stir for 20 min, and EtI (57 mg, 0.40 mmol) was added dropwise. After 3 h the reaction was quenched with saturated aqueous KCN (10 mL). The aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 94:6) afforded the title compound as a white solid (46 mg, 51%). MS: 450 (MH+); HPLC Rf: 6.83 min; HPLC purity: 95%.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[H-].[Na+].I[CH2:32][CH2:33][CH3:34].CO>CN(C=O)C.O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][O:23][CH2:32][CH2:33][CH3:34])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCCI
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCCOCC(CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 100 mg (0.26 mmol) of 8-[(2,6-difluorobenzyl)oxy]-N-(1,3-dihydroxypropan-2-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide were initially charged in 2.4 ml of DMF, 7.1 mg (0.28 mmol) of sodium hydride (95%) were added and the mixture was stirred at 0° C. for 30 min. At 0° C., a solution of 35 mg (0.20 mmol) of iodopropane in 0.4 ml of DMF was then slowly added dropwise, and the mixture was stirred at RT overnight. Another 1.6 mg (0.064 mmol) of sodium hydride (95%) were added at room temperature, the mixture was stirred for 30 min, another 10.6 mg (0.064 mmol) of iodopropane were then added dropwise and the mixture was stirred at room temperature overnight. At RT, another 1.6 mg (0.064 mmol) of sodium hydride (95%) were then added, the mixture was stirred for 30 min and 10.6 mg (0.064 mmol) of iodopropane were then added dropwise, and the mixture was stirred at room temperature overnight. A little methanol was added, and the reaction mixture was poured into 20 ml of water and extracted twice with ethyl acetate. The combined organic phases were washed with aqueous saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by silica gel chromatography (mobile phase: cyclohexane:ethyl acetate=7:3, then dichloro-methane:methanol=40:1). The crude product obtained was re-purified by preparative thick-layer chromatography (dichloromethane:methanol=20:1). This gave 44 mg of the target compound (38% of theory, purity 95%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1C=[CH:15][CH2:14][CH2:13]1.C([Mg]Cl)(C)C.P(=O)(O)(O)O>ClCCl.CS(O)(=O)=O.O1CCCC1>[CH3:13][CH:14]([CH3:15])[C:9](=[O:11])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: C1=COCC1
Agent: CC(C)[Mg]Cl
Agent: CS(=O)(=O)O
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)CCc1ccccc1
Temperature: -60 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
A mixture of 3-phenylpropionic acid (13.0 g, 86.6 mmol), 2,3-dihydrofuran (6.67 g, 95.2 mmol) and dichloromethane (90 ml) was cooled to −60° C., followed by adding thereto a solution of methanesulfonic acid (0.012 g, 0.13 mmol) in dichloromethane (1 ml). The reaction mixture was heated to −5° C. and stirred at this temperature for 4 hours. The reaction mixture was re-cooled to −60° C., followed by adding dropwise thereto isopropylmagnesium chloride (a 2M tetrahydrofuran solution; 48 ml, 95.2 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a cooled aqueous phosphoric acid solution and extracted with chloroform. The extract solution was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography to obtain 5.97 g of 4-methyl-1-phenylpentan-3-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:8][C:7]([C:14]2[N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[N:16][N:15]=2)([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:6]1.[Br:25]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:25][C:11]1[S:10][C:9]([C:7]2([C:14]3[N:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:17]4=[N:16][N:15]=3)[CH2:8][CH:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6]2)=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOC1CC(c2cccs2)(c2nnc3n2CCCCCC3)C1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COCOC1CC(c2ccc(Br)s2)(c2nnc3n2CCCCCC3)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.1 %

Procedure:
3-[3-(Methoxymethoxy)-1-(2-thienyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (343 mg) was dissolved in acetic acid (3 ml) and then N-bromosuccinimide (193 mg) was added, followed by stirring at room temperature for 7 hours under light-shielding. The reaction solution was diluted with chloroform (40 ml) and then washed with water (10 ml), a 1M aqueous sodium hydroxide solution (10 ml), and brine (10 ml). The organic layer was dried and then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (methanol:chloroform=2:98) to obtain 392 mg of 3-[1-(5-bromo-2-thienyl)-3-(methoxymethoxy)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (reddish purple syrup).
Reaction SMILES: S([CH2:5][CH2:6][OH:7])([O-])(=O)=O.[Na+:8].N1CCNCC1.S(CCO)(O)(=O)=O.[N:22]1([CH2:28][CH2:29][S:30]([O-:33])(=[O:32])=[O:31])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[Na+].C1OC1>O>[OH:7][CH2:6][CH2:5][N:25]1[CH2:26][CH2:27][N:22]([CH2:28][CH2:29][S:30]([O-:33])(=[O:31])=[O:32])[CH2:23][CH2:24]1.[Na+:8]
Reactant: O=S(=O)([O-])CCO
Reactant: O=S(=O)([O-])CCN1CCNCC1
Agent: C1CNCCN1
Agent: O=S(=O)(O)CCO
Agent: [Na+]
Solvent: O
Solvent: C1CO1
Product: O=S(=O)([O-])CCN1CCN(CCO)CC1
Temperature: 93.33333333333333 °C
Reaction time: 4 h

Procedure:
Forty-four grams of ethylene oxide (1 mole) is bled into a reaction vessel containing 104 grams of sodium bisulfite in water (45 percent by weight). The mixture is agitated at ambient temperature and 100 psi pressure during the addition of the bisulfite. The reactants interact to form an aqueous isethionic acid salt comprising 54 percent by weight sodium isethionate. A quantity of 86 grams of piperazine (1 mole) is admixed with the solution and the admixture is heated to a temperature of about 200° F. at atmospheric pressure. The reaction vessel has a cold finger trap attached thereto in communication with the contents of the reaction vessel. As the reaction progresses, water is produced as a by-product of the reaction which vaporizes as it is formed together with the other water present and which is collected as ice crystals upon the cold finger trap. The heating is continued for approximately 4 hours after which approximately 38 percent by weight of the reactants (about 127 grams) in the reaction vessel have collected upon the cold finger trap as ice crystals. The remaining liquid reaction product is analyzed and found to comprise sodium N-piperazineethanesulfonate. Further reaction with 44 grams of ethylene oxide (1 mole) at ambient conditions results in the formation of sodium N'-hydroxyethyl-N-piperazineethanesulfonate.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].Br[C:11]1[CH:12]=[C:13]([NH:21][C:22](=[O:24])[CH3:23])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.N1(CCCC2C=C(NC(=O)C)C=C(C(F)(F)F)C=2)CCCCC1>>[N:4]1([CH2:1][CH2:2][CH2:3][C:11]2[CH:12]=[C:13]([NH:21][C:22](=[O:24])[CH3:23])[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: C=CCN1CCOCC1
Reactant: CC(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Agent: CC(=O)Nc1cc(CCCN2CCCCC2)cc(C(F)(F)F)c1
Product: CC(=O)Nc1cc(CCCN2CCOCC2)cc(C(F)(F)F)c1

Procedure:
N-[3-(3-Morpholin-4-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide was prepared from allyl morpholine and N-(3-bromo-5-trifluoromethyl-phenyl)-acetamide similar to that described in the preparation of N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide.
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([C:23]([CH:26]=[CH2:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[Al](I)(I)I.[ClH:32]>>[C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([C:23]([CH2:26][CH2:27][Cl:32])([F:24])[F:25])([F:21])[F:22])([F:18])[F:19])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: C=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cl
Agent: I[Al](I)I
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCl

Procedure:
The same process as in Example 1 was conducted except that 41 g of CF3(CF2)7CH═CH2, 12 g of CaSO4/C (25/75 mass %) instead of AlI3, and 3.4 g of hydrogen chloride gas instead of 11 g of hydrogen iodide gas were used. CF3(CF2)7CH2CH2Cl was produced at a conversion rate of 1.7% and at a selectivity of 100%.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([CH2:9][OH:10])[N:6]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:12])[CH2:5]1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[OH-].[Na+]>ClCCl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:18][C:13]([C:11]([N:6]2[CH2:5][C:4](=[N:3][O:2][CH3:1])[CH2:8][C@H:7]2[CH2:9][O:10][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:12])=[CH:14][CH:15]=1
Reactant: CON=C1C[C@@H](CO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CON=C1C[C@@H](COCC(=O)OC(C)(C)C)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reaction time: 1 h

Procedure:
To a stirred solution of alcohol (2) (EZ mixture, 58 mg, 0.18 mmol) and tert-butyl bromoacetate (530 μl, 3.6 mmol) in dichloromethane (0.2 ml) were added 50% aqueous NaOH (0.8 ml) and tetrabutylammonium chloride (50 mg, 0.18 mmol) at room temperature, and the whole reaction mixture was stirred for 1 hour. After dilution with water, the mixture was extracted with ethyl acetate, organic phase was washed with brine, dried (MgSO4) and concentrated. The product (compound 5) was purified by silica gel column chromatography using DCM:MeOH, 95:5 as eluant.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]([C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)#[N:16].[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:20]3[CH2:21][CH2:22][C:17]([C:15]#[N:16])([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CC1(c2ccccc2)CCN(C[C@H](O)COc2cccc3[nH]ccc23)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-cyano-4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 57% overall yield. FDMS m/e=375 (M+ of free base). α[D]589 =-12.76 (c=0.48, methanol).