Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Br:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Br:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)c1ccc(F)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)c2ccc(F)cc2Br)CCN1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.601 g, 6 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (30 mL), and to this was added triethylamine (1.004 mL, 7.20 mmol). The solution was then cooled to 0° C. before 2-bromo-4-fluorobenzoyl chloride (1.567 g, 6.60 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Fluorochem) in dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then re-dissolved in DCM (40 mL) and washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL), before being dried over anhydrous sodium sulphate. The sodium sulphate was then removed by filtration and the solvent was evaporated in vacuo. The remaining solid was then stirred in hexane (40 mL) at 55° C. for 30 minutes. The solid was then removed by filtration to yield the product in 1.625 g.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:40][C:41](=[NH:43])[CH3:42]>CN(C=O)C.O>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:20]([C:21]4[O:23][N:43]=[C:41]([CH3:42])[N:40]=4)[CH:19]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:6])[CH3:7])(=[O:4])=[O:3]
Reactant: CC(=N)NO
Reactant: CC(C)(c1cc(-c2cccc(C(=O)O)c2)c2ncccc2c1)S(C)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzoic acid from Step 2 (1.0 eq.) in DMF (0.1M) was added CDI (2.0 eq.) and N-hydroxy-acetamidine (2.0 eq.). The mixture was stirred for 1 h at rt then 12 h at 120° C. The mixture was cooled, poured in water and extracted with EtOAc. The organic extract was washed with water (2×), brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1 to 1:9 in 20 min) afforded the title compound as a white solid. 1H NMR (500 MHz, acetone-d6): δ 8.91 (dd, 1H), 8.52 (m, 3H), 8.38 (d, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.78 (t, 1H), 7.64 (dd, 1H), 2.77 (s, 3H), 2.43 (s, 3H), 2.05 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:34][CH:33]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(=O)OC(C)(C)C)cc3)c(F)cn2c1=O
Yield: 108.9 %

Procedure:
Ethyl 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.31 mmol) and (4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-boronic acid (101 mg, 0.40 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (167 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].S(=O)(=O)(O)[OH:12]>>[F:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[C:7]([NH2:8])=[O:12]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(Br)ccc1F
Product: NC(=O)c1cc(Br)ccc1F

Procedure:
5-Bromo-2-fluorobenzonitrile (0.370 g) was heated at 110° C. for 1 hour in concentrated sulfuric acid (10 ml). After cooling, the reaction was diluted with ice-cold water and the slurry was extracted into ethyl acetate, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the sub-title compound as a solid (0.328 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([S:19][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:18]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1cccc(I)c1
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(C)(C)c1ccc(Sc2cccc(O)c2)cc1
Yield: 89.8 %

Procedure:
The general procedure in example 39 was followed. 3-Iodophenol (220 mg, 1.0 mmol), 4-tert-butylthiophenol (168 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 3-(4-tert-butylphenyl)sulfanylphenol (232 mg, 90% yield) as the colorless oil. Workup procedure: ethyl acetate (approx. 5 mL) and dodecane (227 μL, GC standard) were added to the reaction mixture after the reaction was completed. The organic layer was neutralized by dilute HCl to pH 8. The aqueous layer was extracted by ethyl acetate (4×10 mL). The combined organic layers were concentrated and purified by column chromatography on silica gel using hexane/ethyl acetate=10/1 as the eluent to afford the titled product. Rf=0.2 (hexane/ethyl acetate=10/1) (Note: same Rƒvalue as the starting material). 1H NMR (CDCl3, 300 MHz) δ 7.21-7.34 (m, 2 H), 7.14 (t, 1 H, J=8.1 Hz), 6.95 (t, 1 H, J=8.1 Hz), 6.84-6.88 (m, 1 H), 6.78-6.81 (m, 1 H), 6.64-6.71 (m, 2 H). 13C NMR (CDCl3, 75 MHz) δ 156.0, 132.5, 131.2, 130.3, 130.1, 124.8, 122.1, 116.3, 115.2, 113.8, 35.0, 31.7. IR (neat, cm−1) 3375 (broad), 2962, 2904, 2867. MS (EI) m/z (relative intensity) 258 (100). HRMS (EI), Cald. for C16H18OS, 258.1073; Found 258.1068.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[C:15]2[C:6]([C:7](=[O:17])[O:8][C:9]32[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[CH:5][CH:4]=1.[C:18]1([C:24]2[N:25]=[CH:26][C:27]([NH:30][C:31](=O)[O:32]C3C=CC=CC=3)=[N:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:16]=[C:15]2[C:6]([C:7](=[O:17])[O:8][C:9]32[CH2:14][CH2:13][N:12]([C:31]([NH:30][C:27]2[CH:26]=[N:25][C:24]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:29][N:28]=2)=[O:32])[CH2:11][CH2:10]3)=[CH:5][CH:4]=1
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2cc(F)ccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1OC2(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC2)c2cc(F)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 6-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (64 mg), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (73 mg) and triethylamine (174 μL) in chloroform (5 mL) was stirred at 80° C. for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20 mL). The organic layer was washed with saturated saline solution (20 mL), then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) and recrystallized from ethyl ether-hexane to give the subject compound (101 mg) as colorless crystals (melting point 222-224° C.).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[CH:22][CH:21]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: COc1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (30.0 mg, 0.133 mmol) using the same procedure employed for Example 2 (2), but with 4-methoxyphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (13.2 mg, 27%) having the following characteristics.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[O:15][N:14]=[C:13]([CH2:16][OH:17])[CH:12]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N12CCN(CC1)CC2.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>COC(C)(C)C>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:17][CH2:16][C:13]2[CH:12]=[C:11]([CH:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH3:10])[O:15][N:14]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1cc(CO)no1
Agent: C1CN2CCN1CC2
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCc2cc(C(C)O[Si](C)(C)C(C)(C)C)on2)cc1
Reaction time: 10 h
Yield: 30.6 %

Procedure:
7.35 g of {5-[1-(t-butyldimethylsilanyloxy)ethyl]isoxazol-3-yl}methanol was dissolved in 50 ml of methyl-t-butyl ether, and 3.36 g of 1,4-diazabicyclo[2.2.2]octane and 5.72 g of 4-toluenesulfonyl chloride were then added under ice-cooling. The mixture was stirred for 10 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.60 g of {5-[1-(t-butyldimethylsilanyloxy)ethyl]isoxazol-3-yl}methyl 4-methylbenzenesulfonate.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[C:4](=[CH2:11])/[C:3]/1=[C:12](/[O:15][Si](C)(C)C)\[CH:13]=[CH2:14].C(O)(=O)C(O)=O>C1(C)C=CC=CC=1.C1COCC1.O>[CH3:9][C:5]1([CH3:10])[C:6]([CH3:8])=[CH:7][C:2]([CH3:20])([CH3:1])[C:3]2[C:12](=[O:15])[CH2:13][CH2:14][CH2:11][C:4]1=2
Reactant: C=C/C(O[Si](C)(C)C)=C1\C(=C)C(C)(C)C(C)=CC1(C)C
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC1=CC(C)(C)C2=C(CCCC2=O)C1(C)C
Temperature: 410 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution containing (5a) (2.5 mmol) in toluene (15 ml) was injected over 1 hour through a 20 cm column packed with quartz tubes heated at 410° C. using argon as carrier. The column was washed with 5 ml of pure toluene and the collected mixture was evaporated to dryness. The concentrate was added to a solution of oxalic acid (1.12 mmol) in THF (10 ml) and water (1 ml) and the mixture was stirred at room temperature for 1 hour then quenched with a saturated bicarbonate solution and extracted with diethylether. The organic layer was washed with water and brine, then dried with MgSO4, and evaporated to dryness. The crude was purified by bulb-to-bulb distillation and column chromatography (Silicagel, Cyclohexane/EtOAc 99/1). Yield: 62%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])[CH2:2]1.[CH:23]([C:25]1[CH:26]=[C:27](OB(O)O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])=[O:24]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([C:8]([NH:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:27]4[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([CH:26]=4)[CH:23]=[O:24])[CH2:2]3)=[O:9])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(OB(O)O)cc1C=O
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NC1CCCNC1
Product: COc1ccc(N2CCCC(NC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)cc1C=O
Yield: 14 %

Procedure:
Using N-(piperidin-3-yl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (254 mg, 0.756 mmol) and 3-formyl-4-methoxyphenylboric acid (273 mg, 1.52 mmol), the same procedure was followed as in Example 2 to give 49.8 mg (14%) of the desired compound as a yellow powder.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:2].[NH3:11].[H][H]>CO>[NH2:11][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[C:1]1(=[O:2])[NH:11][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: N
Reactant: COC(=O)CCCCC=O
Solvent: CO
Product: COC(=O)CCCCCN
Product: O=C1CCCCCN1

Procedure:
Such a process is described in U.S. Pat. No. 4,731,445. This publication describes a process in which first methyl 5-formylvalerate is contacted with ammonia and hydrogen in the presence of methanol as solvent and a hydrogenation catalyst. In this step methyl 6-aminocaproate and a small amount of ε-caprolactam is obtained. In a second step, the excess ammonia and hydrogen are removed from the reaction mixture. In a third step, the methyl 6-aminocaproate is reacted with water in the presence of a small amount (0.1 to 2 wt. %) of ammonia at a temperature of 50 to 250 ° C. The released methanol is simultaneously removed. Example 1 of U.S. Pat. No. 4,731,445 discloses the reaction of methyl 6-aminocaproate with water in the presence of an almost negligible amount of ammonia at a temperature of about 100° C. The resulting aqueous mixture, which mixture contains 6-aminocaproic acid and small amounts of 6-minocaproamide and ε-caprolactam, is heated to a emperature of 330° C. In this step the 6-aminocaproic acid and 6-aminocaproamide reacts by cyclization to ε-caprolactam.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClS([N:17]=[C:18]=O)(=O)=O>CN(C=O)C>[C:18]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)#[N:17]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of 6-nitroindole (16.2 g, 100 mmol) in DMF (60 mL) at 0° C. was added chlorosulfonylisocyanate (10.9 mL, 125.0 mmol). The mixture was then stirred at room temperature overnight, poured into ice-water (1.0 L) and stirred for 3 h. The precipitate was filtered, washed with water and dried in air to provide 3-cyano-6-nitroindole (17.63 g, 94%).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@H:11]([OH:23])[C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[CH:14]=[C:15]([OH:22])[CH:16]=[CH:17]4)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36]>CC(C)=O.CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:35]([C:34]1[CH:33]=[C:32]([CH:39]=[CH:38][CH:37]=1)[CH2:31][O:22][C:15]1[CH:14]=[C:13]2[C:18]([N:19]=[CH:20][CH:21]=[C:12]2[C@H:11]([OH:23])[C@@H:10]2[N:5]3[CH2:6][CH2:7][C@H:8]([C@@H:3]([CH:2]=[CH2:1])[CH2:4]3)[CH2:9]2)=[CH:17][CH:16]=1)#[N:36]
Reactant: C=CC1CN2CCC1CC2[C@H](O)c1ccnc2ccc(O)cc12
Reactant: N#Cc1cccc(CBr)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OCc3cccc(C#N)c3)cc12
Yield: 79.1 %

Procedure:
To a solution of 0.6 g (1.91 mmol) of 6-hydroxycinchonine in 25 ml of anhydrous acetone (dried and distilled over potassium carbonate) and 8 ml of anhydrous dimethylformamide is added 0.516 g (2.87 mmol) of anhydrous potassium carbonate followed by 0.329 g (1.91 mmol) of 3-(bromomethyl)benzonitrile (Lancaster) and 4 mg of 18-crown-6. The reaction mixture is heated to reflux for 18 h, cooled and filtered. The filtrate is concentrated under reduced pressure and redissolved in 200 ml of chloroform. The organic layer is washed with 2×50 ml of 5% aqueous sodium hydroxide, washed with brine, dried with anhydrous magnesium sulphate to yield 0.647 g (1.51 mmol, 79%) of (9S)-6'-(3-cyanobenzyloxy) cinchonane-9-ol as pale off-white solids.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3](=O)[CH2:4][N:5]1[N:9]=C[O:7][C:6]1=O.O.[NH2:15][NH2:16].[C:17]([OH:22])(=O)[C:18](O)=O>CC(O)C.O>[C:2]([C:3]1[CH2:4][N:5]([NH:9][C:17](=[O:22])[CH3:18])[C:6](=[O:7])[NH:15][N:16]=1)([CH3:13])([CH3:12])[CH3:1]
Reactant: CC(C)(C)C(=O)Cn1ncoc1=O
Reactant: O=C(O)C(=O)O
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CC(=O)NN1CC(C(C)(C)C)=NNC1=O
Yield: 186.4 %

Procedure:
To a solution of 3-(3,3-dimethyl-2-oxo-butyl)-3H-1,3,4-oxadiazol-2-one (0.91 g, 4.59 mmol) in a mixture of 2-propanol (4 mL) and water (0.11 mL) is added hydrazine monohydrate (0.34 mL, 6.89 mmol). The reaction mixture is heated to reflux under nitrogen for 5 h, then a solution of oxalic acid (0.13 g, 1.38 mmol) in 2-propanol (5 mL) is added to the hot solution. The resulting precipitate is removed hot by filtration. The filtrate is concentrated in vacuo and the residue is purified on a pad of silica gel, eluting with heptane:EtOAc gradient to afford N-(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide (0.546 g, 56%) as a solid. MS: 213 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.64 (s, 1H), 4.22 (s, 2H), 2.04 (s, 3H), 1.15 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].O.[CH3:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:10]=1[NH:11][CH2:12][C:13]([NH2:15])=O.C(=O)=O.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(C(C)=O)C>[Cl:24][CH2:25][C:26]([N:11]([C:10]1[C:9]([CH3:8])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:20])[C:12](=[O:2])[CH2:13][NH2:15])=[O:27]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(C)c1NCC(N)=O
Reactant: O=C(Cl)CCl
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1cccc(C)c1N(C(=O)CN)C(=O)CCl

Procedure:
12.4 g of potassium carbonate and 0.5 ml of water are added to a solution of 14,5 g of 2,6-dimethylanilinoacetic acid amide in 150 ml of methyl ethyl ketone and 7.15 ml of chloroacetyl chloride are added dropwise thereto with stirring. The temperature rises in the process to 39° C and CO2 is evolved. The reaction mixture is stirred for 3 hours at room temperature, filtered and concentrated in vacuo to dryness. The crystalline residue is recrystallised from ethyl acetate to yield 6.3 g of N-chloroacetyl-N-(2,6-dimethylphenyl)-amino-acetamide (m.p. 135°-137° C).
Reaction SMILES: P(OCC)(OCC)(O[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[CH:18]([C:20]1[C:21](B(O)O)=[CH:22][S:23][CH:24]=1)=[O:19].ClC1C=CC(CC2SC(C=O)=CC=2)=CC=1>>[Cl:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:21]2[C:20]([CH:18]=[O:19])=[CH:24][S:23][CH:22]=2)=[CH:10][CH:9]=1
Reactant: CCOP(=O)(OCC)OCc1ccc(Cl)cc1
Reactant: O=Cc1cscc1B(O)O
Agent: O=Cc1ccc(Cc2ccc(Cl)cc2)s1
Product: O=Cc1cscc1Cc1ccc(Cl)cc1
Yield: 58 %

Procedure:
The title compound was synthesized from 4-chlorobenzyl diethyl phosphate and 4-formylthiophen-3-ylboronic acid using the conditions to synthesize 5-(4-chlorobenzyl)thiophene-2-carbaldehyde (Example 1.1.a). Purification by prep-TLC (50% heptane/DCM, double elution) yielded 266 mg of 4-(4-chlorobenzyl)thiophene-3-carbaldehyde (58%). 1H NMR (400 MHz, CDCl3) δ ppm 4.25 (s, 2H), 6.84-6.88 (m, 1H), 7.14-7.19 (m, 2H), 7.25-7.30 (m, 2H), 8.12 (d, J=3.17 Hz, 1H), 9.96 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 185.52, 140.84, 140.28, 140.02, 138.06, 132.10, 130.31, 128.58, 124.75, 34.70; LCMS-MS (ESI+) 236.68 (M+H).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][N:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[C:32]([O:31][C:29]([C:28]1[CH:27]=[CH:26][C:25]([C:12]2[C:13]([CH3:24])([CH3:23])[C@H:14]3[C@:9]([CH3:38])([CH2:10][CH:11]=2)[C@@H:8]2[C@:17]([CH3:22])([C@@:18]4([CH3:21])[C@H:5]([CH2:6][CH2:7]2)[C@H:4]2[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:3]2([CH2:1][NH:49][CH2:50][CH2:51][N:52]2[CH2:57][CH2:56][N:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:54][CH2:53]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:37][CH:36]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (0.019 ml, 0.334 mmol) and 4-N-(2-Aminoethyl)-1-N-Boc-piperazine (0.077 g, 0.334 mmol). The mixture was stirred at rt for 2 h then to the mixture was added sodium triacetoxyborohydride (0.177 g, 0.835 mmol). The mixture was stirred for 3 days at rt then was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was used in the next step without further purification. LCMS: m/e 812.3 (M+H)+, 3.30 min (method 6).
Reaction SMILES: [Si]([O:18][C:19]1[CH:57]=[CH:56][C:22]([O:23][CH2:24][C@@H:25]([OH:55])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:54]=[CH:53][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=4[F:52])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:52][C:46]1[CH:47]=[CH:48][CH:49]=[C:50]([F:51])[C:45]=1[CH2:44][NH:43][C:41]([N:38]1[CH2:39][CH2:40][CH:35]([NH:34][C:33]2[CH:53]=[CH:54][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:55])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:57][CH:56]=3)=[CH:31][CH:32]=2)[CH2:36][CH2:37]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4c(F)cccc4F)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1c(F)cccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 62.5 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-(2,6-difluorobenzyl)-1-piperidinecarboxamide (0.192 g, 0.24 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.085 g, 0.15 mmol).