Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:46]=[CH:45][C:10](/[CH:11]=[CH:12]/[CH:13]([S:22]([CH:25](/[CH:34]=[CH:35]/[C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][CH:37]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)(=[O:24])=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)([O-])=O.O.NN>[Pd].C(Cl)(Cl)Cl>[NH2:4][C:7]1[CH:46]=[CH:45][C:10](/[CH:11]=[CH:12]/[CH:13]([S:22]([CH:25](/[CH:34]=[CH:35]/[C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)(=[O:23])=[O:24])[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C(/C=C/c2ccc([N+](=O)[O-])cc2)S(=O)(=O)C(/C=C/c2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(C(/C=C/c2ccc(N)cc2)S(=O)(=O)C(/C=C/c2ccc(N)cc2)c2ccc(OC)cc2)cc1
Yield: 52 %

Procedure:
In a 100 mL round-bottomed flask fitted with condenser, 5% Pd/C (0.073 g) was taken and 20 mL ethanol was added slowly. Compound 6d (0.5 g, 1.4 mmol) and hydrazine hydrate (1.24 g, 38.7 mmol) were added to the content of the flask and refluxed for 6 h. Completion of the reaction was monitored by TLC (CHCl3 on silica gel plate), filtered the reaction mixture through celite and concentrated the reaction mixture to 50% volume. The concentrated mixture was poured onto crushed ice, the solid formed was filtered, washed with cooled water, dried to get the desired product 6e. Yield: 52%; light yellow solid mp 164-168° C. 1H NMR: δ 3.80 (s, 3H, OCH3), 4.22 (s, 2H, CH2), 4.04 (br s, 2H, NH2), 6.42 (d, 1H, J=15.6 Hz, ═CH), 6.60-7.31 (m, 9H, Ar—H+ vinylic). Anal. (C16H17NO3S): C, H, N.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1([F:23])[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>CN(C)C=O.O>[F:15][C:16]1([F:23])[CH2:21][CH2:20][CH:19]([N:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][CH2:10]2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C1CCC(F)(F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(C2CCC(F)(F)CC2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (2.00 g, 10 mmol) and 4,4-difluorocyclohexanone (1.61 g, 12 mmol) in N,N-dimethylformamide (50 mL), kept at room temperature, acetic acid (3 mL, 50 mmol) and tetramethylammonium triacetoxyborohydride (5.24 g, 20 mmol) were subsequently added. The reaction mixture was allowed to stir overnight then diluted with water (150 mL), extracted with diethyl ether and the organic layer was discarded. The aqueous phase was made basic with ammonia and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate, evaporated to dryness and the residue was purified by column chromatography, using dichloromethane/ethanol/concentrated aqueous ammonia: 97.5/2.5/0.25 as the mobile phase. Tert-butyl [1-(4,4-difluorocyclohexyl)-piperidin-4-yl]-carbamate was obtained in fairly good yield as a white solid (2.5 g, 78%).
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.Br[C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][CH:27]=1>>[NH:32]1[C:33]2[C:29](=[CH:28][CH:27]=[C:26]([C:12]#[C:11][C:9]3[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=3)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:34]=2)[CH:30]=[CH:31]1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc3cc[nH]c3c2)c1)c1ccccc1
Yield: 17.9 %

Procedure:
In a manner similar to that described in Example 443, (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (150 mg, 0.42 mmol) and 6-bromoindole (90.7 mg, 0.46 mmol) were reacted to give the title compound (30 mg).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH:17]([OH:19])[CH2:16][C@H:12]1[C:13](O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].B.CSC.CO>C1COCC1>[CH2:4]([O:3][C:1]([N:11]1[CH:12]([CH2:13][OH:14])[CH2:16][CH:17]([OH:19])[CH2:18]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: O=C(OCc1ccccc1)N1CC(O)CC1CO
Temperature: 25 °C

Procedure:
To a solution of N-CBz-4-hydroxy-L-proline (38.1 mmol) in 250 ml THF was added borane-methyl sulfide (78 mmol) dropwise at room temperature. After the evolution of H2 had ceased, the solution was heated to reflux with mechanical stirring. After 1 hour a white precipitate had formed. Methanol was carefully added, and the resulting solution refluxed for a further 15 minutes. The solution was cooled to room temperature, the solvents evaporated under reduced pressure, and the residual gum coevaporated with 2×100 ml MeOH. The product was obtained as a viscous oil in quantitative yield and identified by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:33].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:33].[ClH:33].[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])ccc1NCCc1ccccn1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COc1cc(N)ccc1NCCc1ccccn1

Procedure:
The N-(2-methoxy-4-nitrophenyl)-N-(2-pyrid-2-ylethyl)amine (9) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: NCCCCO
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: O=C(NCCCCO)c1ccc2c(c1)OCO2
Yield: 75 %

Procedure:
1,3-Benzodioxole-5-carboxylic acid (2.0 g, 12.0 mmol) and 4-amino-1-butanol (1.4 ml, 15.6 mmol) were coupled according to the procedure of Example 17 to 2.1 g (75% yield) of a pale yellow solid. MP 95-98° C.; 1H NMR (DMSO-d6): δ 1.38-1.65 (m, CH2, CH2), 3.31 (q, CH2), 3.39 (q, CH2), 4.39 (t, NH), 6.08 (s, CH2), 6.98 (d, 1 Ar H), 7.37 (d, 1 Ar H), 7.4 (d-d, 1 Ar H), 8.27 (t, NH) Electrospray Mass Spec: m/z 238.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Cl)=[CH:11][C:10]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][N:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:11][C:10]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CCl)ccc1OCc1ccccc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[2-Benzyloxy-5-(2-chloro-1-oxo-ethyl)-phenyl]-methanesulfonamide (Washburn, W. N., et al., EP 0 659 737) (17.0 g, 42.8 mmol) was dissolved in 200 mL of dimethylformamide and treated with dibenzylamine (22.0 g, 110 mmol). The mixture was stirred at room temperature overnight and then the solvent was removed. The residue was purified by silica gel chromatography using 20-50% ethyl acetate/hexanes as eluent to give the title compound as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.94 (s, 3 H), 3.77 (s, 2 H), 3.82 (s, 2 H), 5.16 (s, 2 H), 6.75 (brs, 1 H), 6.96 (d, J=8.7 Hz, 1 H), 7.20-7.50 (m, 15 H), 7.67 (dd, J=8.7, 2.1 Hz, 1 H), 8.10 (d, J=2.1 Hz, 1 H); MS (ES) m/z: 515.2 (MH+); HRMS Calcd. for C30H30N2O4S(M+): 514.1926. Found: 514.1927.
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].C[O-].[Na+].C([O:13][C:14](=O)[CH:15]([CH:27]=O)[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)C>CO>[N+:1]([NH:4][C:5]1[NH:7][C:14](=[O:13])[C:15]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[CH:27][N:6]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C=O)Cc1cccc2ccccc12
Reactant: N=C(N)N[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccc2ccccc12

Procedure:
Nitroguanidine (9.10 g) was added to a solution of sodium methoxide (from 2.22 g sodium) in methanol (100 ml) and the mixture was heated under reflux for 45 minutes, ethyl-2-formyl-3-(1-naphthyl)propionate (16.05 g) was added and the mixture was heated under reflux for 20 hours and evaporated to dryness. The residue was poured into water and the mixture was extracted with chloroform and the pH of the residual aqueous phase was adjusted to 4 with acetic acid. The solid which precipitated was recrystallised from acetic acid to give 2-nitroamino-5-(1-naphthylmethyl)-4-pyrimidone, m.p. 226°-7°.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].O.[CH3:18][CH2:19][CH2:20]CCC>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:20][C:19]#[CH:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCCC
Reactant: CC(C)(C)[Si](C)(C)OCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOCCOCCO[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of 5-(t-butyldimethylsilyloxy)-3-oxa-1-pentanol (2.16 g, 9.8 mmol) in dry tetrahydrofuran (20 ml) was added sodium hydride (432 mg, 60% in oil, 10.8 mmol) at room temperature. The mixture was stirred for 30 minutes, and propalgyl bromide (2.9 g, 19.6 mmol) was added thereto. The mixture was stirred at room temperature for 12 hours. After the reaction was completed, water was added thereto. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=8:1) to give the title compound (950 mg, yield: 38%).
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5](O)=[O:6])([CH3:3])[CH3:2].S(Cl)(Cl)=O.C(N(CC)CC)C.Cl.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]=[O:6])=[CH:13][CH:12]=1
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=C=O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 60.4 %

Procedure:
A sample of 53.2 g of isopropyl(4-chlorophenyl)acetic acid was treated with 21.5 ml of thionyl chloride in a 500 ml flask and heated slowly to 80° C. and maintained at 80° C. for 20 minutes. The reaction mixture was allowed to stand at room temperature for 2 days. The volatiles were stripped to 75° C. at 0.5 mm Hg. The resulting yellow liquid was diluted with 250 ml of methylene chloride followed by addition of 38.0 g of triethylamine. The mixture was stirred until triethylamine hydrochloride began to precipitate after 30 minutes. After 16 hours, the reaction mixture was filtered and solid triethylamine hydrochloride was washed with heptane. Most of the solvent was stripped from the filtrate by rotary evaporation at 50° C. The residue was diluted with 75 ml of heptane and additional triethylamine hydrochloride was removed by filtration as above. The filtrate was restripped and rediluted with 75 ml heptane and refiltered with the aid of 25 ml of heptane. The filtrate was cooled in dry ice, seeded and crystallized. The resulting crystals were filtered with a filter stick and washed with chilled heptane. The filtered solids were melted, diluted with one-half volume heptane, crystallized at -80° C. and the collected solid was melted and stored at -80° C. The filtrate solution was warmed, stripped of most solvent, then distilled through a Bantam were short path head at 0.05 to 0.06 mm Hg from an oil bath at 90°-120° C. Total distillate was 14.5 g collected as a bright yellow-orange liquid at a head temperature of 60°-85° C. The distillate was crystallized from an equal volume of pentane at -80° C., filtered and washed twice with heptane as above to give, on warming, a second melt. The stripped filtrates totalling 5.79 g were crystallized as above in a 6-inch test tube and the melt was recrystallized immediately as described above to give a third melt. The three melts were combined and stripped to 50° C. at 5 mm Hg to give 29.4 g of the desired ketene as a yellow liquid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16].[H-].[Na+].Br[C:20]1[CH:21]=[C:22]([O:26][CH3:27])[CH:23]=[CH:24][CH:25]=1.[NH4+].[OH-]>C(OCC)(=O)C.CN(C)C=O>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=[C:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])[C:8]2=[O:16])[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(Br)c1
Reactant: CN1CCCC1=C1C(=O)Nc2ccccc21
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(N2C(=O)C(=C3CCCN3C)c3ccccc32)c1

Procedure:
Under N2, 3-(1-methyl-2-pyrrolidinylidene)-2(1H,3H)-indolone (1.0 g, 5 mmoles) was added portionwise to a slurry of NaH (50% oil dispersion>265 mg., 5.5 mmoles) slurried in 50 ml. dimethylformamide and the mixture stirred at 25° for 2 hours. Cu2Br2 (1 43 g, 5 mmoles) and then m-bromoanisole (1.9 ml, 15 mmole) were added. The mixture was heated at 130° for 3.5 days, cooled, poured over ice and ethyl acetate, basified with NH4OH and filtered over a pad of diatomaceous earth. The aqueous layer was separated from the filtrate and extracted with fresh ethyl acetate. The combined organic layers were back-washed with H2O, dried over MgSO4, treated with activated carbon, evaporated to dryness and the residue triturated with ether, and filtered to yield starting material (110 mg). The ether filtrate was evaporated to an oil and chromatographed on 75 ml. silica gel, eluting with CHCl 3. Clean product fractions were combined, evaporated to an oil and crystallized from CHCl3 /ether, 320 mg, m.p. 127°-129° (dec).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[NH:4][C:5](=O)[CH2:6][CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.[Cl-].[NH4+]>O1CCCC1>[CH2:5]([NH:4][C:3]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:2]=1[F:1])[CH2:6][CH3:7]
Reactant: CCC(=O)Nc1ccc(F)cc1F
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCNc1ccc(F)cc1F
Temperature: 70 °C
Reaction time: 7 h
Yield: 86 %

Procedure:
2′,4′-Difluoropropionanilide (7.17 g, 38.7 mmol) was dissolved in tetrahydrofuran (30 ml), followed by the addition of lithium aluminum hydride (7 g, 184 mmol). The resulting mixture was stirred at 70° C. for 7 hours. Under ice-water cooling, methanol (10 ml) was added to decompose excess lithium aluminum hydride. A saturated aqueous solution of ammonium chloride (100 ml) was then added to the reaction mixture, and a precipitate was filtered off. The filtrate was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was separated and purified by chromatography on a silica gel column (silica gel 5 g, chloroform), whereby the title compound was obtained as a pale liver-brown oil (5.7 g, 86.0%).
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][C:11]2([O:16][C:15]([F:18])([F:17])[CH2:14][N:13]([C:19]([C:21]3[N:22]=[C:23]([CH:26]([CH3:28])[CH3:27])[S:24][CH:25]=3)=[O:20])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].C1(C)C=CC=CC=1>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[F:18][C:15]1([F:17])[CH2:14][N:13]([C:19]([C:21]2[N:22]=[C:23]([CH:26]([CH3:28])[CH3:27])[S:24][CH:25]=2)=[O:20])[CH2:12][C:11]2([CH2:29][CH2:30][NH:8][CH2:9][CH2:10]2)[O:16]1
Reactant: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCNCC3)C2)cs1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl-2,2-difluoro-4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 44, step a) (0.78 g) in DCM (20 mL) was treated with trifluoroacetic acid (5 mL) and the reaction mixture allowed to stand at 20° C. for 30 minutes. Toluene (40 mL) was added and the solvents evaporated under reduced pressure. The residue was azeotroped twice with acetonitrile to afford the subtitled compound. Yield 0.8 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]3/[C:32](/[NH:44]C(=O)OCC3C=CC=CC=3)=[N:33]/C(=O)OCC3C=CC=CC=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:55]([OH:58])(=[O:57])[CH3:56].[H][H]>CO.[Pd]>[C:55]([OH:58])(=[O:57])[CH3:56].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]3[C:32](=[NH:33])[NH2:44])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(C(=N)N)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dibenzyl [(E)-{1-[1-(4-fluorophenyl)cyclobutyl]-7-{2-[(propylsulfonyl)amino]ethoxy}-3,4-dihydroisoquinolin-2(1H)-yl}methylylidene]biscarbamate (95 mg, 0.126 mmol) was dissolved in methanol (8 mL) under an atmosphere of nitrogen. Acetic acid (0.4 mL) was added followed by 10% palladium on charcoal (40 mg, 0.038 mmol). The nitrogen was replaced by one atmosphere of hydrogen and the reaction mixture was stirred at room temperature for 3 h. The catalyst was removed by filtration and the solution of the product was concentrated in vacuo. The product was dissolved in ethanol (0.5 mL) and water (15 mL) and was lyophilized. Yield: 61 mg (0.125 mmol, 99%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=[O:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.O.ClCCl>[Si:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=[O:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: O=Cc1ccc2c(c1)c1ccccc1n2CCCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCCn1c2ccccc2c2cc(C=O)ccc21
Yield: 64.9 %

Procedure:
9-(6-hydroxyhexyl)-9H-carbazole-3-carbaldehyde (12.0 g, 0.0406 mol) and dichloromethane (100 ml) were loaded into a three-neck flask, stirred, added with tert-butyldimethylsilyl chloride (7.35 g, 0.0487 mol) and imidazole (3.04 g, 0.0447 mol), and allowed to react at room temperature for 24 hours with stirring. The reaction product was transferred into a separate funnel, and was then added with water and ethyl acetate, after which the organic layer was isolated therefrom, dehydrated using sodium sulfate, and then distilled under reduced pressure. Then, the obtained viscous liquid was separated through silica column chromatography, thus obtaining 10.8 g of a liquid as the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.O>CN(C)C=O>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:1][CH:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)=[CH:13][CH:12]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(COC2CCOCC2)cc1
Reaction time: 24 h

Procedure:
A mixture of 2.90 mL of 4-hydroxy-tetrahydropyran in 30 mL of dry N,N-dimethylformamide was added dropwise to a stirred suspension of 0.84 g of sodium hydride (95%, dispersion in mineral oil) in 30 mL of dry N,N-dimethylformamide at 5° C. The resulting clear solution was allowed to come to room temperature and stirring was continued for 24 hours, followed by dropwise addition of 9.40 g of 4-bromo-benzylbromide in 50 mL of dry N,N-dimethylformamide at 5° C. and stirring at room temperature for 24 hours. The mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (sodium sulfate), and concentrated. The residue was purified by silica chromatography (isohexane/ethyl acetate=9/1, 8/2, 7/3, 6/4 v/v) yielding 5.40 g of 4-(4-bromo-benzyloxy)-tetrahydropyran as an oil. EI-MS: 270 (M+).
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)=[C:3]([CH3:9])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1cc(N)ncc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N)ncc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C

Procedure:
To a mixture of 5-bromo-4-methylpyridin-2-amine (200 mg, 1.07 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (370 mg, 1.2 mmol) and sodium carbonate (400 mg, 1.28 mmol) in DMF/H2O (8/2 mL) was added tetrakis(triphenylphosphine) palladium (0) (62 mg, 5% mmol). The reaction tube is sealed, the mixture was purged with N2 for 3 min and then heated at 100° C. under N2 for overnight. The reaction was cooled to room temperature and poured into saturated aqueous ammonia chloride solution. The crude reaction mixture was extracted with ethyl acetate (3×15 mL). The organic extracts were combined, washed with brine and concentrated. The crude product was purified with silica gel column chromatography (80% ethyl acetate in hexanes) to afford tert-butyl 4-(6-amino-4-methylpyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a yellow oil. The obtained oil was dissolved in methanol (20 mL). To the solution was added Pd/C (10% w/w). The reaction mixture was degassed and purged with H2 for several times and then stirred under 1 atm. H2 overnight. The mixture was filtered and concentrated to afford tert-butyl 4-(6-amino-4-methylpyridin-3-yl)piperidine-1-carboxylate as a yellow solid; ESMS m/z 236 (M−56+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9]C(C#N)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:2].CC[O:16][C:17]([CH3:19])=[O:18]>S(=O)(=O)(O)O.O>[CH:1]([C:3]1[CH:10]=[CH:9][C:19]([C:17]([OH:16])=[O:18])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:2]
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc(C=O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
A mixture of 4-formyl-2-nitrobenzonitrile (150 mg, 0.85 mmol) in conc. sulfuric acid (2 mL) and water (4 mL) was heated at 100° C. for 13 hours. Followed standard aqueous/EtOAc workup to give Intermediate 73.