Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][CH:33]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[CH:33]=[N:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)F)nc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 5-bromo-2-(trifluoromethyl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[Br:16]Br>C1COCC1>[Br:16][C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:8]=1
Reactant: BrBr
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccnc2cc(Br)sc12
Reaction time: 0.5 h
Yield: 755.8 %

Procedure:
To a stirred solution of the chloride 2 (10.12 g, 5.59 mmol) in dry THF (200 ml) at −78° C. was added n-BuLi (24 ml, 76.7 mmol, 2.5 M solution in hexanes) and the resultant suspension was stirred for 15 minutes. Bromine (18.9 g, 120 mmol) was added slowly and the reaction mixture was stirred for additional 30 min, quenched with water and diluted with EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (9:1 EtOAc/hexane) afforded title compound 41 (10.5 g, 71% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.62 (d, J=5.09 Hz, 1H), 7.92 (s, 1H), 7.59 (d, J=5.09 Hz, 1H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10]O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].P(Br)(Br)[Br:13]>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][Br:13])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: BrP(Br)Br
Reactant: CCC[C@H]1CC[C@H](CO)CC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H](CBr)CC1
Temperature: 0 °C

Procedure:
Compound (31) obtained according to section (A) (15.6 g, 0.1 mole) was added at 0° C. to 150 ml of pyridine-benzene mixture (1:1), and while being stirred, the solution was added to 9.0 g (0.033 mole) of PBr3. The reaction mixture was stirred for 2 hours at 0° C. and then 2 hours at room temperature, poured over ice/2 N HCl and extracted with diethyl ether. The ether extract was washed once each with 2 N HCl, 2 N NaOH, and NaCl solution, dried with Na2SO4, and concentrated. The bromide of formula (32) was purified chromatographically with silica gel.
Reaction SMILES: COC1C=CC(C[O:8][C@H:9]([C@H:58]([CH3:71])[CH2:59][C@@H:60]([CH3:70])[CH2:61][O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[C@@H:10]([CH3:57])/[CH:11]=[CH:12]\[C@@H:13]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[CH2:14][C@H:15]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:16]([CH3:40])/[CH:17]=[CH:18]/[CH2:19][O:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=CC=1.C(Cl)Cl.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O>[Si:63]([O:62][CH2:61][C@H:60]([CH3:70])[CH2:59][C@@H:58]([CH3:71])[C@@H:9]([OH:8])[C@@H:10]([CH3:57])/[CH:11]=[CH:12]\[C@@H:13]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:51])[CH3:52])[CH2:14][C@H:15]([O:41][Si:42]([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:44])[CH3:43])[C@@H:16]([CH3:40])/[CH:17]=[CH:18]/[CH2:19][O:20][C:21]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:66]([CH3:69])([CH3:67])[CH3:68])([CH3:65])[CH3:64]
Reactant: COc1ccc(CO[C@H]([C@H](C)C[C@@H](C)CO[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C/COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](C)[C@@H](O)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
The above PMB alcohol 85 (2.90 g, 2.77 mmol) was added to CH2Cl2 (25 mL) and H2O (1 mL), and DDQ (0.94 g, 4.15 μmol) was added. After 1 h of stirring, the reaction mixture was quenched by adding sat'd NaHCO3 (200 mL). The organic phase was washed by sat'd NaHCO3 solution (3×100 mL) and brine, dried over MgSO4 and concentrated. Purification by flash column chromatography (EtOAc/hexane 5:95) furnished 86 (2.16 g, 84%) as a colorless oil: IR (CHCl3) 3477, 2956, 2928, 2856, 1471, 1386, 1254, 1088, 836, 774 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.55-7.52 (m, 6H), 7.38-7.25 (m, 9H), 5.92 (dd, J=15.7, 6.0 Hz, 1H), 5.62 (dt, J=15.7, 5.5 Hz, 1H), 5.52 (dd, J=11.1, 9.3 Hz, 1H), 5.35 (t, J=10.5 Hz, 1H), 4.63 (m, 1H), 3.97 (m, 1H), 3.63 (d, J=5.4 Hz, 2H), 3.51-3.36 (m, 2H), 3.18 (m, 1H), 2.68 (m, 1H), 2.47 (m, 1H), 1.71-1.59 (m, 3H), 1.42-1.27 (m, 2H), 1.17 (m, 1H), 1.08 (d, J=6.7 Hz, 3H), 1.04 (d, J=6.9 Hz, 3H), 0.99 (s, 9H), 0.97 (s, 9H), 0.96 (s, 9H), 0.91 (d, J=6.8 Hz, 3H), 0.84 (d, J=6.6 Hz, 3H), 0.18 (s, 3H), 0.16 (s, 3H), 0.15 (s, 3H), 0.13 (s, 3H), 0.12 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 144.4, 135.2, 134.1, 131.1, 128.7, 127.7, 126.8, 126.4, 86.7, 79.8, 72.8, 69.6, 66.2, 65.2, 43.0, 42.1, 35.5, 33.7, 32.8, 32.5, 26.1, 26.0, 25.9, 18.4, 18.1, 17.6, 16.8, 16.3, 14.7, −2.9, −4.0, −4.15, −4.22, −5.3; LRMS (ESI) 951.7 [M+Na]+, 823.7, 577.4, 413.3, 328.4, 243.1; HRMS (ESI) calcd for C56H92O5Si3Na 951.6150 [M+Na]+, found 951.6165; [α]20D30.0 (c 3.6, CHCl3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:15]=[C:16]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH:17]=[C:18]([CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.[OH-].C[N+](C)(C)C.[CH2:47](Br)[CH:48]=[CH:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C)C=O>[CH2:47]([O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][C:14]1[CH:15]=[C:16]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH:17]=[C:18]([CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=1)[CH:48]=[CH:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CCOP(=O)(Cc1cc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc(-c2ccc(Cl)cc2)c1)OCC
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1cc(CC(NC(=O)OC(C)(C)C)C(=O)OCC=Cc2ccccc2)cc(-c2ccc(Cl)cc2)c1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.05 g of the product of step b) in 5 ml dimethylformamide are added 362 mg tetramethyl ammonium hydroxide pentahydrate. The mixture is stirred at room temperature 11/2 hours and then treated with 394 mg cinnamyl bromide. The mixture is stirred at room temperature 17 hours. The mixture is diluted with ice/water (about 50 ml) and extracted with diethyl ether. The extracts are washed with 10 ml aqueous 1N KHCO3 solution, dried (Na2SO4) and evaporated to give the heading compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:17](=[O:27])[C:8]4[CH:9]=[C:10]([O:15]C)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:17](=[O:27])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: COc1cc2c(=O)c(Cc3ccccn3)cn3c4ccc(Br)cc4c(c1)c23
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cc2ccccn2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.1 %

Procedure:
10-bromo-2-methoxy-5-(2-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (0.54 g) obtained in Example 84 was suspended in anhydrous methylene chloride (30 ml), and boron tribromide (5 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water, and to this mixture was added saturated aqueous solution of sodium carbonate until the termination of foaming. The crystals precipitated were recovered by filtration, and the resulting crude crystals were washed with a mixed solution of methylene chloride and methanol to obtain the title compound (0.173 g, 33%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH:24][C:25](=[N:28][CH3:29])SC)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[Cl:20]>C(#N)C>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH:24][C:25]([NH:28][CH3:29])=[N:12][CH2:11][CH2:10][S:9][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CN=C(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)SC
Reactant: Cc1cccc(CSCCN)n1
Solvent: CC#N
Product: CNC(=NCCSCc1cccc(C)n1)NS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 6-methyl-2-((2-aminoethyl)thiomethyl) pyridine (3.7 g) and N-(3,4-dichlorobenzenesulphonyl)-N', S-dimethylisothiourea (6.2 g) in acetonitrile (250 ml) was heated under reflux for 48 hours. Concentration, followed by chromatographic purification on a column of alumina afforded N-(3,4-dichlorobenzenesulphonyl)-N'-methyl-N"-[2-((6-methyl-2-pyridyl)methylthio)ethyl]guanidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:12][CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=2)[CH2:11][CH2:10]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2cccc(F)c2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2cccc(F)c2)CC1)c1ccccc1
Yield: 66.8 %

Procedure:
0.2 g (0.000956 mol) of 1-(3-fluoro-benzyl)-piperidin-4-ol and 0.16 ml (0.00147 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.122 ml (0.00105 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.2 g (67%) of 1-(3-fluoro-benzyl)-piperidin-4-yl benzoate was obtained as yellow crystals.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C@:8]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)([C:10]1[CH:11]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)[C:13]([F:16])=[CH:14][CH:15]=1)O)(=[O:3])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1(C)C=CC=CC=1>[C:1]([NH:4][CH2:5][CH2:6][CH:7]=[C:8]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)[C:10]1[CH:11]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)[C:13]([F:16])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC[C@@](O)(c1ccc(F)c(-c2cccc(C)c2)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: Cc1ccccc1
Product: CC(=O)NCCC=C(c1ccc(F)c(-c2cccc(C)c2)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 30.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((S)-4-acetamido-1-(6-fluoro-3′-methylbiphenyl-3-yl)-1-hydroxybutyl)piperidine-1-carboxylate (380 mg, 0.76 mmol) in anhydrous toluene (8 mL) was added Burgess reagent (352 mg, 1.47 mmol). The reaction mixture was stirred under reflux overnight. The solvent was removed and the residue was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residual oil was purified by preparative tlc to afford (S)-tert-butyl 3-(4-acetamido-1-(6-fluoro-3′-methylbiphenyl-3-yl)but-1-enyl)piperidine-1-carboxylate (110 mg, 30% yield). 1H NMR (400 MHz, MeOH):7.33-7.39 (m, 2 H), 7.13-7.23 (m, 2 H), 6.95-7.03 (m, 3 H), 5.29-5.33 (m, 1 H), 3.93-4.15 (m, 1 H), 3.78-3.91 (m, 1 H), 3.00-3.04 (m, 2H), 2.40-2.53 (m, 1 H), 2.37 (d, 3 H), 1.89 (s, 3 H), 1.75 (m, 1H), 1.44-1.62 (m, 4 H), 1.41 (s, 9 H), 1.16-1.32 (m, 3H), 1.01 (m, 1 H). MS (E/Z): 481 (M+H+)
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10](=[O:11])[CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[NH2:19])[S:7]1(=[O:21])=[O:20].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29].C(Cl)Cl>>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[NH2:19][C:13]1[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:12]=1[N:8]1[S:7](=[O:21])(=[O:20])[NH:6][C:10](=[O:11])[CH2:9]1
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(N)cc3N)S2(=O)=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(N2CC(=O)NS2(=O)=O)c(N)c1
Reaction time: 0.33 h

Procedure:
A solution of the title D compound, 2-(2,4-dimethoxybenzyl)-5-(2,4-diaminophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (40 mg, 0.10 mmol) is stirred in 4 mL of TFA/CH2Cl2 (1:1) at RT for 16 h. The volatiles are evaporated and the residue is stirred in 4 mL of MeCN/water (1:1) for 20 min. The mixture is filtered through a 0.2 μM Acrodisc and the solvents are evaporated. The residue is triturated from diethylether (Et2O) to give 5-(2,4-diaminophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one TFA salt as a brown solid: [M+1]+=243.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([CH3:13])[O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N)(=[S:16])C>C(O)C>[SH:16][CH2:2][C:3]1[N:4]=[C:5]([CH3:13])[O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(N)=S
Reactant: CCOC(=O)c1oc(C)nc1CBr
Solvent: CCO
Product: CCOC(=O)c1oc(C)nc1CS
Temperature: 90 °C
Yield: 95 %

Procedure:
5 mmol of ethyl 4-(bromomethyl)-2-methyl-1,3-oxazole-5-carboxylate was dissolved in 50 ml of ethanol, then 5.5 mmol of thioacetoamide was added, then heated up to 90° C. to carry out the reaction for 4 hours. The reacted liquid was cooled down to a room temperature. Ethanol is evaporated out and then the product was purified using column separation with solvents of ethyl acetate and hexane, obtaining ethyl 4-(mercaptomethyl)-2-methyl-1,3-oxazole-5-carboxylate (yield 95%).
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH:7]2[NH:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1.C=O.[CH:14](O)=O.[OH-].[Na+]>O>[CH3:14][N:11]1[CH:7]([C:3]2[CH:2]=[CH:1][CH:6]=[N:5][CH:4]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: c1cncc(C2CCCN2)c1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCCC1c1cccnc1
Temperature: 85 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
To a solution of nornicotine (50 g 0.338 mol) in 100 ml water a mixture of 37% formaldehyde (49.7 g, 1.656 mol) and 85% formic acid (37.26 g 0.81 moles) was added and stirred at 85° C. for 20 hrs. The reaction was cooled and pH adjusted to >13 using NaOH, extracted with dichloromethane (100 ml×3) dried over Na2SO4 and solvent removed completely to get crude oil (52.5 g, 94.33% purity by GC). It was further purified by high vacuum distillation at 0.1 mm Hg to obtain colorless (R,S)-nicotine (44.54 g, 81.3% yield, 99.1% purity by GC). 1H NMR (CDCl3): δ 1.72-2.0 (3H, m), 2.1 (3H, s), 2.25 (1H, m), 2.3 (1H, m), 3.08 (1H, m), 3.23 (1h, t), 7.25 (1H, m), 7.69 (1H, dt), and 8.5 (2H, m). 13C-NMR (CDCl3): 149.71, 148.76, 139, 134.97, 123.7, 68.9, 57.1, 40.5, 35.5, and 22.83. IR: 3233, 1642, and 1402 Cm−1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:13])[F:1]
Reactant: OCCCc1ccccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1CCCBr
Yield: 80.2 %

Procedure:
Compound 24-1 (5.07 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (7.24 g) and N-bromosuccinimide (4.86 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 4.5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (5.32 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N+:12]([O-])([OH:14])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc2ncccc2c1
Product: O=[N+]([O-])c1cc(F)cc2cccnc12
Temperature: 25 °C

Procedure:
A mixture of 6-fluoroquinoline (2 g, 13.6 mmol) and fuming HNO3 (15 mL) in a round bottom flask equipped with a cooling condenser was refluxed for 100 hours, the resulting mixture was cooled to r.t., poured slowly into crushed ice/H2O, and then the mixture was extracted with DCM (200 mL×3). The combined organic layers were dried over Na2SO4, and concentrated. The residue was passed through a short pad of silica gel to give 1.6 g of title compound. 1H NMR (CHLOROFORM-d) δ: 9.08 (dd, J=4.1, 1.5 Hz, 1H), 8.25 (dd, J=8.5, 1.5 Hz, 1H), 7.89 (dd, J=7.5, 2.8 Hz, 1H), 7.72 (dd, J=8.1, 2.8 Hz, 1H), 7.62 (dd, J=8.4, 4.3 Hz, 1H). LC-MS: m/z 466.6 (M+H)+
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:11])[CH2:6][C:7]([F:10])([F:9])[F:8])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([OH:11])[CH2:6][C:7]([F:10])([F:9])[F:8]
Reactant: [N-]=[N+]=NC[C@@H](O)CC(F)(F)F
Agent: [Pd]
Solvent: CO
Product: NC[C@@H](O)CC(F)(F)F

Procedure:
The slurry of (S)-1-azido-4,4,4-trifluorobutan-2-ol (2.26 g, 13 mmol) and Pd/C (200 mg) in MeOH (20 mL) was subjected to balloon hydrogenation for 18 hr. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to give (S)-1-amino-4,4,4-trifluorobutan-2-ol as a crude product (1.02 g, 45%). NMR: 400 MHz 1H (CDCl3) 3.88 ppm, 1 H, m, J=7.85, 7.85, 3.84, 3.74 Hz; 2.93 ppm, 1 H, dd, J=12.74, 3.52 Hz; 2.61 ppm, 1H, dd, J=12.52, 8.13 Hz; 2.34 ppm, 1 H, m; 2.21 ppm, 1 H, m; 1.91 ppm, 3 H, s.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=2)[CH:34]=[CH:33]1.C(N(CC)CC)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:16])[CH3:17])[C:41]([C:38]2[CH:39]=[C:40]3[C:35]([CH:34]=[CH:33][N:32]3[CH2:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:36][CH:37]=2)=[O:42])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCn1ccc2ccc(C(=O)O)cc21
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCCn1ccc2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(C)(C)O[SiH2]C(C)(C)C)C(C)C)cc21

Procedure:
From (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 12.9 mmol), 1-(3-methoxy-propyl)-1H-indole-6-carboxylic acid (4.22 g, 18.1 mmol), BOPCI (4.6 g, 18.1 mmol) and triethylamine (7.2 mL, 51.7 mmol). TLC, Rf (AcOEt)=0.32.
Reaction SMILES: [CH2:1]1[O:20][C:4]2([CH2:9][CH2:8][N:7]([C:10](=O)[C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O1CCOCC1>[CH2:1]1[O:20][C:4]2([CH2:9][CH2:8][N:7]([C:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)=[S:30])[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(C(=S)N2CCC3(CC2)OCCO3)cc1
Yield: 42.2 %

Procedure:
A solution of 1-(4-cyanobenzoyl)-4-piperidone ethylene ketal (1.00 g, 3.68 mmol) and Lawesson's reagent (1.2 g, 2.9 mmol) in dioxane (20 ml) was heated to reflux for 1 h, cooled and evaporated. The residue was pre-absorbed on silica gel and purified by flash chromatography eluting with 25% ethyl acetate/hexane, increasing the gradient to 40% ethyl acetate/hexane, to afford the product as a yellow solid (353 mg), MS (+EI) 288 (M+), 1H NMR(CDCl3) 7.67 (2H, d, J 7 Hz), 7.36 (2H, d, J 7 Hz), 4.5-4.45 (2H, m), 4.06-3.98 (4H, m), 3.58 (2H, dd, J 6, 4.2 Hz), 1.94 (2H, t, J 6 Hz), 1.69 (2H, t, J 6 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:24])=[N:22][N:23]=3)=[CH:15][CH:14]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C:27]1=[O:32]>CN(C=O)C>[CH3:24][C:21]1[O:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:10]3[CH:9]=[C:4]([CH:3]=[C:2]([O:1][CH:26]4[CH2:30][CH2:29][N:28]([CH3:31])[C:27]4=[O:32])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=2)=[N:23][N:22]=1
Reactant: CN1CCC(Br)C1=O
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(OC2CCN(C)C2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a stirring solution of Methyl 3-hydroxy-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (4 g) (Intermediate 7) in dry DMF, 3-Bromo-1-methyl-pyrrolidine-2-one (4.12 g) (Intermediate 5) [J. Med. Chem., 1987, 30, 1995-98] was added under nitrogen atmosphere at room temperature in three portions at 4 h interval. The reaction mixture was stirred at room temperature for 16 h and then warmed to 45-50° C. for 3 h. The reaction was monitored by TLC. After completion, reaction mixture was diluted with ice cold water and extracted with EtOAc. All organic layers were combined and washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get crude thick liquid product. Crude residue was chromatographed to yield pure compound (5.2 g).