Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[NH:9][S@](C(C)(C)C)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.CCO.[ClH:29].CCOC(C)=O>C(Cl)Cl.O1CCOCC1>[ClH:29].[F:1][C:2]1[C:3]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)[NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) stirring solution of (S)—N—((S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide (108 g, 288.8 mmol) in DCM:EtOH (1:1,1080 mL), was added saturated HCl in 1,4-dioxane (216 mL). Stirring was continued for 2 h at 0° C. The progress of reaction was monitored by TLC (100% EtOAc). After completion of the reaction, the reaction mixture was concentrated and triturated with Et2O to give a white solid which was filtered and dried to give (S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl) methanamine hydrochloride as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 9.23 (s, 3H), 8.60 (d, J=4.8 Hz, 1H), 7.87 (d, J=1.2 Hz, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.59-7.63 (m, 1H), 6.09 (s, 1H). MS (ESI pos. ion) m/z: 270.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][C:22]1[N:26]([CH3:27])[N:25]=[N:24][N:23]=1.[CH2:28]([S:30][C:31]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)/[C:33](=[N:42]/[S:43]([C:46]2[S:47][CH:48]=[CH:49][CH:50]=2)(=[O:45])=[O:44])/[CH:32]=1)[CH3:29]>>[CH2:28]([S:30][C:31]1[CH:32]=[C:33]([NH:42][S:43]([C:46]2[S:47][CH:48]=[CH:49][CH:50]=2)(=[O:44])=[O:45])[C:34]2[C:39]([C:40]=1[OH:41])=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:29].[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][C:22]1[N:26]([CH3:27])[N:25]=[N:24][N:23]=1
Reactant: CCSC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Agent: Cn1nnnc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: CCSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O

Procedure:
N-(3-(ethylthio)-4-hydroxynaphthalen-1-yl)thiophene-2-sulfonamide (14j) was prepared according to the procedure for 14d except using (E)-N-(3-ethylthio-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (13j), which afforded the title compound 14 mg (100%) as a grey solid, m.p.: ° C.
Reaction SMILES: [I:1]I.[CH2:3]([S:10]/[C:11](/[Sn](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[CH:12]\[CH:13]=[C:14](\[S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)/[C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[CH2:3]([S:10]/[C:11](/[I:1])=[CH:12]\[CH:13]=[C:14](/[S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)\[C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: II
Reactant: C[Si](C)(C)C#C/C(=C\C=C(/SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1)SCc1ccccc1
Solvent: ClCCl
Product: C[Si](C)(C)C#C/C(=C/C=C(/I)SCc1ccccc1)SCc1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
Iodine (36 mg, 0.14 mmol) in CH2Cl2 (8 mL) was added over a period of 2 h at 0° C. to 7 (85 mg, 0.114 mmol) in CH2Cl2 (12 mL) under argon. Analysis by TLC (1:6CH2Cl2 :hexanes) indicated the disappearance of 7. The solution was warmed to room temperature, washed with NaHSO3 (2×20 mL) and KF (10 mL) solutions, dried (MgSO4), concentrated in vacuo, and the residue purified by flash column chromatography (1:4 CH2Cl2 :hexanes) to give 8 as a yellow solid (56.4 mg, 95% yield): 1H NMR δ 7.52 (d, J=10.5 Hz, 1 H), 7.2-7.4 (m, 10 H), 6.74 (d, J=10.5 Hz, 1 H), 4.11 (s, 2 H), 3.97 (s, 2 H), 0.27 (s, 9 H); 13C NMR δ 143.93, 136.42, 132.89, 129.20, 128.60, 127.62, 127.34, 120.75, 101.91, 95.48, 43.28, 37.36, -0.08; Anal., Calcd for C23H25IS2Si, C, 53.07; H, 4.84. Found C, 53.27; H, 5.00.
Reaction SMILES: C1COCC1.[Na].[F:7][C:8]([F:12])([F:11])[CH2:9][OH:10].Cl[C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([C:24]([Cl:27])([F:26])[F:25])[N:17]=[C:16]([C:28]([F:31])([F:30])[F:29])[C:15]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O>[Cl:27][C:24]([F:25])([F:26])[C:18]1[N:17]=[C:16]([C:28]([F:31])([F:29])[F:30])[C:15]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:14]([O:10][CH2:9][C:8]([F:12])([F:11])[F:7])[C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: OCC(F)(F)F
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
To 100 ml of dry THF was added 0.29 g (0.013 mol) of sodium metal. To this mixture 1.28 g (0.013 mol) of 2,2,2-trifluoroethanol was added dropwise. The solution was stirred under N2 until all of the sodium metal had been consumed. Then 5.0 g (0.0126 mol) of product of Example 28 was added to the sodium salt solution and the reaction mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was poured into 100 ml of H2O, and extracted with diethyl ether. The ether phase was dried (MgSO4) and concentrated in vacuo to yield 5.48 g of a gold crystalline solid. This solid was recrystallized in hexane to yield 4.2 g (72.4%) of product as a tan solid; mp 62°-63° C.
Reaction SMILES: [C:1]1([CH:7]([Ge:12](Cl)(Cl)Cl)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S>CC(C)=O>[C:1]1([CH:7]([GeH3:12])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(c1ccccc1)[Ge](Cl)(Cl)Cl
Agent: S
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(O)CC([GeH3])c1ccccc1

Procedure:
16.4 g (0.05 mol) of 3-phenyl-3-(trichlorogermyl) propionic acid was dissolved in 200 ml of anhydrous acetone. 12.6 g (0.16 mol) of anhydrous pyridine was added to the solution under cooling with an ice bath, followed by stirring. Dry hydrogen sulfide was introduced into the mixture for one hour. The acetone was removed and the residue was dissolved in 50 ml of ethanol. The solution was added to 400 ml of water to precipitate the crystal. The crystal was recrystallized from a mixture of methyl acetate and benzene (1:3) to obtain 12.7 g of crystalline sesquisulfide of 3-phenyl-3-germylpropionic acid. ##STR14##
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH:13]=O)[C:10]2[N:9]=[C:8]([C:15]#[N:16])[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[C:15]([C:8]1[N:9]=[C:10]2[C:5]([CH:4]=[CH:3][C:2](=[O:1])[N:11]2[CH2:12][CH2:13][N:39]2[CH2:38][CH2:37][CH:36]([N:28]([CH2:27][C:24]3[N:23]=[CH:22][C:21]4[O:20][CH2:19][CH2:18][O:17][C:26]=4[CH:25]=3)[C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[CH2:41][CH2:40]2)=[CH:6][CH:7]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: N#Cc1ccc2ccc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ccc(C#N)nc32)CC1
Yield: 73 %

Procedure:
A mixture of 7-oxo-8-(2-oxoethyl)-7,8-dihydro-1,8-naphthyridine-2-carbonitrile (329 mg, 1.545 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (539 mg, 1.545 mmol) in chloroform (15 ml) and MeOH (1 ml) was stirred for 2 h before addition of NaBH(OAc)3 (982 mg, 4.635 mmol). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the desired compound (620 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][C:25]([NH:27][CH3:28])=[O:26])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][C:25]([NH:27][CH3:28])=[O:26])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)CCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
(R)-tert-butyl 3-((R)-(3-chlorophenyl)(3-(methylamino)-3-oxopropoxy)methyl)piperidine-1-carboxylate (0.80 g, 1.95 mmol) was dissolved in a 20% solution of TFA in CH2Cl2 (20.6 mL) and stirred for about 1 h at rt until the reaction was complete. The solvent was removed by evaporation and the crude product was purified with preparative HPLC to afford 3-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)-N-methylpropanamide (542 mg, 1.75 mmol, 90% yield). MS (E/Z): 311 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:9][CH2:8][C:7]2=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=[C:6]2[CH2:5][CH2:4]1.[NH2:15]CC1CCC2C=C(N)C=CC=2CC1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:72]([C:74]1[CH:75]=[C:76]([CH:92]([CH3:94])[CH3:93])[C:77]2[O:81][C:80]([C:82]3[CH:90]=[CH:89][C:85]([C:86](O)=[O:87])=[CH:84][CH:83]=3)=[N:79][C:78]=2[CH:91]=1)#[N:73].ClCCl>>[NH2:14][C:10]1[C:7]2[CH2:8][CH2:9][CH:3]([CH2:2][NH:1][C:86](=[O:87])[C:85]3[CH:84]=[CH:83][C:82]([C:80]4[O:81][C:77]5[C:76]([CH:92]([CH3:94])[CH3:93])=[CH:75][C:74]([C:72]#[N:73])=[CH:91][C:78]=5[N:79]=4)=[CH:90][CH:89]=3)[CH2:4][CH2:5][C:6]=2[CH:13]=[CH:12][CH:11]=1.[NH2:15][C:12]1[CH:11]=[CH:10][C:7]2[CH2:8][CH2:9][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5][C:6]=2[CH:13]=1
Reactant: NCC1CCc2cccc(N)c2CC1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CCc2ccc(N)cc2CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCc5cccc(N)c5CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.93 %

Procedure:
To a suspension of a mixture of 7-(aminomethyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-1-amine and 7-(aminomethyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-amine (300 mg, 1.577 mmol) in dichloromethane (5 ml) were added o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (1315 mg, 3.47 mmol), 1-hydroxybenzotriazole (320 mg, 2.365 mmol), diisopropylethylamine (0.67 ml, 3.84 mmol), and 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (435 mg, 1.419 mmol, INTERMEDIATE 2), and the mixture was stirred overnight at 25° C. The residue was purified by flash chromatography on a Biotage Horizon, 40M column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes. The resulting mixture was repurified under the same conditions to provide the two diastereomers N-[(1-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methyl]-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (90 mg, 0.188 mmol, 11.93% yield) and 1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methanamine (56 mg, 0.117 mmol, 7.42% yield). Mass spectrum for N-[(1-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methanamine (ESI) 479.2 (M+1). Mass spectrum for 1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methanamine (ESI) 479.0 (M+1). 1H NMR data for the mixture (500 MHz, CDCl3): δ 8.32 (d, J=8.5 Hz, 2H), 7.90-8.96 (m, 4H), 7.51 (s, 1H), 7.49 (d, J=11 Hz, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.32 (d, J=7.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 1H), 7.20 (t, J=7.5 Hz, 1H), 6.42 (br s, 1H), 3.30-3.52 (m, 4H), 3.14 (dd, J=8.0, 14.0 Hz, 1H), 2.86-3.02 (m, 4H), 2.67 (dd, J=11.5, 14.5 Hz, 1H), 2.06-2.20 (m, 4H), 1.45 (d, J=7.5 Hz, 6H), 1.40-1.50 (m, 2H), 1.14-1.36 (m, 5H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1)=[CH2:2]>C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1ccc2c(C=O)c[nH]c2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1ccc2c(C=O)c[nH]c2c1
Reaction time: 4 h

Procedure:
6-Vinyl-1H-indole-3-carbaldehyde (1.5 g, 8.76 mmol) was dissolved in THF (45 mL), Pd/C 10% (300 mg) was added and the solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere 4 h and the catalyst was removed through a pad of Celite and washed with THF. The solvent was concentrated under and the crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1) to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.40; MS (LC/MS): 174.1 [M+H]+, 196.1 [M+Na]+, 172.1 [M−H]−; tR (HPLC conditions a): 3.05 min.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[O:16])[CH:10]=[CH:11]2)=[N:6]1.CC(O)=O.[NH:35]1[CH2:40][CH2:39][CH2:38][CH:37]([CH2:41][OH:42])[CH2:36]1>CO>[OH:42][CH2:41][CH:37]1[CH2:38][CH2:39][CH2:40][N:35]([CH2:2][CH2:3][CH2:4][N:5]2[CH:13]=[C:12]3[C:7]([CH:8]=[C:9]([NH:14][C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:20][CH:19]=4)=[O:16])[CH:10]=[CH:11]3)=[N:6]2)[CH2:36]1
Reactant: OCC1CCCNC1
Reactant: O=CCCn1cc2ccc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)cc2n1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Nc1ccc2cn(CCCN3CCCC(CO)C3)nc2c1
Reaction time: 18 h

Procedure:
To a solution of 1-[2-(3-oxopropyl)-2H-indazol-6-yl]-3-(4-phenoxyphenyl)urea (20 mg, 0.05 mmol) in Methanol containing 2% v/v AcOH (1 mL) was added 3-piperidinemethanol (10 mg, 0.10 mmol) and MS-CNBH3 (52 mg, 0.065 mmol). The reaction was shaken vigorously at 40 C for 18h. The reaction was filtered, eluting with additional Methanol (3×0.5 mL). The sample was directly purified by RP-HPLC to afford the titled product. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.15 (m, 1 H), 1.65 (m, 2 H), 1.83 (m, 2 H), 2.30 (m, 2 H), 2.63 (m, 1 H), 2.77 (m, 1 H), 3.10 (m, 2 H), 3.24 (dd, J=10.68, 6.61 Hz, 1 H), 3.36 (m, 1 H), 3.44 (m, 2 H), 4.47 (t, J=6.27 Hz, 2 H), 6.97 (m, 5 H), 7.09 (m, 1 H), 7.36 (m, 2 H), 7.49 (m, 2 H), 7.62 (m, 1 H), 7.90 (s, 1 H), 8.29 (s, 1 H), 8.76 (m, 2 H) and 9.16 (s, 1 H); MS (ESI) 500 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[CH2:10][C:11](=[O:17])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[N-:23]=[N+]=[N-].[Na+].C([O-])([O-])=O.[K+].[K+].[OH-].[K+]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[CH2:10][NH:23][C:11](=[O:17])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1)N2Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C1CC2CCCC(CN1)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
To a solution of 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one (0.5 g) in chloroform (4.4 ml), cooled down to −5° C., 1 ml of conc. H2SO4 is dropwise added while maintaining the temperature below 15° C. Then NaN3 (0.28 g) is slowly added, at small portions so to avoid temperatures in the reaction mixture higher than 35° C. The mixture is then heated at reflux for 2 hours. The reaction mixture is poured into a vessel containing about 200 ml of ice. Solid K2CO3 is added up to a strongly alkaline pH. An emulsion is formed, that is added of 25 ml of a 60% KOH aqueous solution. Stirring is effected for 10 minutes. At the end the formed inorganic salts are filtered and the reaction mixture extracted with chloroform. The organic phase is dehydrated with sodium sulphate and the solvent evaporated. 0.50 g of 10-benzyl-3,10-diazabicyclo[4.3.1]decan-4-one (1py1) are obtained as a light solid.
Reaction SMILES: N[C@H](C=O)CCSC.[Na].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br-].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC(O)C>[Br:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: BrCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CSCC[C@H](N)C=O
Agent: [Br-]
Agent: [Na]
Solvent: CC(C)O
Product: BrCCC/C=C/c1ccccc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Metal sodium (303 mg) was added to dry 2-propanol (30 mL), and the mixture was stirred at 70° C. After the sodium was dissolved, benzaldehyde (1.0 g) was added to the solution at 0° C., 4-bromobutyltriphenylphosphonium bromide (5.4 g) was then added, and the mixture was gradually warmed to room temperature. After 5 hours, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the resultant mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (hexane) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=1)[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2ccc(F)c(Cl)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(F)c(Cl)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a stirred mixture solution of 4-[(3-chloro-4-fluoro-benzylidene)-amino]-benzoic acid ethyl ester (3.1 g, 10.2 mmol) and ytterbium(III) triflate hydrate (944 mg, 1.5 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.93 mL, 10.2 mmol) and water (0.2 mL, 10.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-chloro-4-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid ethyl ester (3.8 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C20H21ClFNO3 (M+H)+: 378.85, observed: 360.1 & 378.1.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH2:11][OH:12])=[CH:8][CH:7]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:20]([O:12][CH2:11][C:9]1[S:10][C:6]([CH2:5][O:4][CH3:3])=[CH:7][CH:8]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COCc1ccc(CO)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1ccc(COS(C)(=O)=O)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-(methoxymethyl)thiophen-2-yl)methanol (900 mg, 5.69 mmol) in dry CH2Cl2 (20.0 mL) was treated at 0° C. with Et3N (1.19 mL, 8.53 mmol) followed by DMAP (70 mg, 0.57 mmol) and Ms-Cl (0.57 mL, 7.39 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (5 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 1.38 of crude (5-(methoxymethyl)thiophen-2-yl)methyl methanesulfonate as an orange oil. LC-MS-conditions 07: tR=0.51 min. A solution of this crude material in DMF (10.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (7.05 g of a 9.6% solution in DMF, 5.93 mmol) in DMF (15.0 mL) pre-treated for 30 min with DIPEA (1.96 mL, 11.9 mmol) and the reaction mixture was stirred overnight at 50° C. Water (10 mL), followed by EA (10 mL) was added. The aq. layer was extracted with EA (2×15 mL) and the combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (gradient from 95:5 hept-EA to 80:20 hept-EA) gave the title compound as a yellow oil. TLC: rf (8:2 hept-EA)=0.36. LC-MS-conditions 07: tR=0.80 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:4][N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=1.C1CCN2C(=NCCC2)CC1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([O:27][CH2:26][C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[N:3][N:4]=2)=[CH:14][CH:15]=1
Reactant: OCc1cccnc1
Reactant: Clc1ccc(Nc2nnc(Cl)c3ccccc23)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: Clc1ccc(Nc2nnc(OCc3cccnc3)c3ccccc23)cc1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
A dry 50-mL round-bottomed flask was equipped with a stir bar and an argon inlet. The flask was charged with 1-chloro-4-(4-chlorophenylamino)-phthalazine (R. D. Haworth and S. Robinson, J. Chem. Soc. 1948, pp.777-782) (2.00 g; ˜6.12 mmol), 3-pyridyl-carbinol (Aldrich) (10.02 g, 91.85 mmol), and DBU (18.3 mL, ˜18.7 g, ˜123 mmol). The reaction was heated at 125 C for 28 h. The mixture was cooled to room temperature and distilled water (400 mL) was added with stirring. The aqueous phase was extracted with ethyl acetate (3×300 mL). The combined organics were dried (MgSO4) and concentrated to yield a tan solid, which was purified by silica gel chromatography (100% dichloromethane→50% acetone/dichloromethane) to give the clean desired compound as a white solid (1.24 g, 3.42 mmol; 56% yield). TLC (20% acetone/dichloromethane): Rf=0.48.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl.C(OCC)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Diisopropylethylamine (DIEA, 0.7 mL, 2 mmol) was added to a solution of 4-(aminomethyl)-1-tert-butoxycarbonylpiperidine (200 mg, 0.93 mmol) in 5 mL of CH2Cl2 under nitrogen. (4-fluorophenyl)sulfonyl chloride (195 mg, 1 mmol) was then added, and the reaction mixture was stirred at room temperature for 30 min. The solution was diluted with diethyl ether, washed with 1N HCl, 1N NaOH, and brine, and then dried over MgSO4. The solution was then concentrated to afford 284 mg (82% yield) of the title compound, which could be purified by recrystallization from diethyl ether. 1H NMR (300 MHz, CDCl3). δ 1.00-1.13 (m, 1H), 1.42 (s, 9H), 1.61-1.70 (m, 3H), 2.58-2.70 (m, 2H), 2.80-2.84 (m, 2H), 4.02-4.16 (m, 2H), 4.46-4.52 (m, 1H), 7.17-7.22 (m, 2H), 7.82-7.90 (m, 2H).