Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.Cl[CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8].[CH3:10][C:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=O)[C:15]=2[CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[CH3:10][C:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[CH:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc2c1CCc1ccccc1C2=O
Reactant: CN(C)CCCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: Cc1cccc2c1CCc1ccccc1C2=CCCN(C)C
Temperature: 45 °C
Reaction time: 10 h

Procedure:
10 g. of Gilman alloy are covered with 30 ml. of dry ether and treated with 0.5 ml. of methyl iodide. After the vigorous reaction has subsided somewhat, 40 ml. of 1-chloro-3-dimethylaminopropane in 120 ml. of dry ether are added dropwise in such a way that the reaction mixture is maintained at boiling. The mixture is heated at 45° C. under reflux conditions for an additional 3 hours, then cooled with ice water and treated dropwise over a period of one hour with a solution of 21.8 g. of 1-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (J. Med. Pharm. Chem. 4, 335-49, 1961) in 400 ml. of dry ether. Subsequently, the mixture is stirred at 45° C. under reflux conditions for an additional 10 hours, then cooled with ice water and decomposed with a cold saturated ammonium chloride solution. The organic layer is removed by separation. The aqueous phase is shaken twice with 100 ml. portions of ether and the combined ether extracts are dried over sodium sulfate and evaporated. The residual 1-methyl-10,11-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene has a melting point of 154°-155° C. after recrystallization from high-boiling petroleum ether.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[N:11]=2)=[CH:3][CH:2]=1.C([Li])CCC.[CH3:25][S:26]SC.CCOCC>O1CCCC1.O>[CH3:25][S:26][C:3]1[CH:2]=[C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][C:4]=1[C:7]1[O:8][CH2:9][C:10]([CH3:12])([CH3:13])[N:11]=1
Reactant: CC1(C)COC(c2ccc(-c3ccccc3)cc2)=N1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CSc1cc(-c2ccccc2)ccc1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A stirred solution of 13.3 g of the biphenyl oxazoline of Example 1 in 210 mL tetrahydrofuran (THF) was treated with 36 mL of 1.6M n-butyllithium in hexanes at <-70° under nitrogen atmosphere. The mixture was kept at ca. -40° for 50 min., then 5.2 mL methyl disulfide was added and the mixture slowly warmed to room temperature. After 2 days the solution was poured into ether and water, the organic phase was washed successively with saturated sodium bicarbonate solution, brine, then dried and evaporated. Trituration of the residue with n-chlorobutane plus hexanes gave 10.9 g of the title compound, mp 93°-95°.
Reaction SMILES: C(NC(C)(C)C1C=CC(C#CC2C=CC=CC=2)=CC=1)=O.C([NH:23][C:24]([CH2:41][CH3:42])([CH2:39][CH3:40])[C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=O.C([NH:45][C:46]([CH2:64][CH2:65][CH3:66])([CH2:61][CH2:62][CH3:63])[C:47]1[CH:52]=[CH:51][C:50]([C:53]#[C:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:49][CH:48]=1)=O>>[CH2:39]([C:24]([NH2:23])([CH2:41][CH3:42])[C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)[CH3:40].[CH2:61]([C:46]([NH2:45])([CH2:64][CH2:65][CH3:66])[C:47]1[CH:52]=[CH:51][C:50]([C:53]#[C:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[CH:49][CH:48]=1)[CH2:62][CH3:63]
Reactant: CCC(CC)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Reactant: CCCC(CCC)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Agent: CC(C)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Product: CCC(N)(CC)c1ccc(C#Cc2ccccc2)cc1
Product: CCCC(N)(CCC)c1ccc(C#Cc2ccccc2)cc1

Procedure:
When the preceding experiment is repeated using in place of N-formyl-α,α-dimethyl-4-(phenylethynyl)-benzylamine the corresponding N-formyl-α,α-diethyl-4-(phenylethynyl)-benzylamine or N-formyl-α,α-di(n-propyl)-4-(phenylethynyl)-benzylamine there is obtained respectively α,α-diethyl-4-(phenylethynyl)-benzylamine and α,α-di(n-propyl)-4-(phenylethynyl)-benzylamine.
Reaction SMILES: [CH2:1](O)[CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17]CC[CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH-].[K+].[C:31](#[N:34])[CH:32]=[CH2:33].C1[O:52][CH2:51][CH2:50]OCCOCCOCCOCCOC1>C(Cl)Cl>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][CH:51]([O:52][CH2:33][CH2:32][C:31]#[N:34])[CH2:50][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: C=CC#N
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CC(CO)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(OCCC#N)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Cholestanol (1.554 g, 3.998 mmol) was dissolved in DCM (6 mL). To this solution was added KOH (40% w/w in water, 1.2 mL) and acrylonitrile (0.8 mL), followed by 18-crown-6 (104 mg). The mixture was stirred at room temperature overnight. The organic layer was washed with brine and dried (Na2SO4) before the solvent was evaporated. The residue was recrystallized from hot MeOH to yield the pure product as a colourless crystalline solid (1.42 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ: 3.68 (t, 2H, CH2O), 3.29 (m, 1H, CHO), 2.57 (t, 2H, CH2CN), 1.98-0.58 (m, 31H), 0.89 (d, 3H, J=6.6, CH3), 0.87 (d, 3H, J=1.8, CH3), 0.85 (d, 3H, J=2.0, CH3), 0.79 (s, 3H, CH3), 0.64 (s, 3H, CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:19]([C:18]3[C:17]([Cl:16])=[N:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: O=C(Nc1cccc(F)c1)c1ccc[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.3 %

Procedure:
To a solution of 1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (1.56 g, 7.6 mmol) and 2-chloronicotinoyl chloride (1.925 g, 10.9 mmol) in benzene (15 mL) at 0° C. was added dropwise a solution of tin (IV) chloride (3.5 g) in dry benzene (5 mL). The mixture was allowed to warm up slowly to room temperature and stirred for 4 hours. The reaction was added with NaOH (100 mL) and extracted with ethyl acetate, washed with brine (2×), dried and concentrated. The residue was purified on a silica gel column to give 477 mg (18%) of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2OC)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2OC)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(2-methoxyphenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 17, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=3)=[CH:14][CH:15]=2)[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])[N:7]=1)=[O:5])C.[OH-].[Na+].CO>CCOC(C)=O>[CH3:25][S:22]([C:18]1[CH:17]=[C:16]([C:13]2[S:12][C:11]([C:9]3[N:8]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:33])([F:34])[F:35])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=3)=[CH:15][CH:14]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2C(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(=O)O)nn3-c3ccccc3C(F)(F)F)s2)c1
Reaction time: 1.5 h
Yield: 55 %

Procedure:
To a 100 mL round bottom flask attached with condenser was added 5-[5-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-1-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (2.52 g, 4.98 mmol), 1N aq NaOH (30 mL), and MeOH (25 mL). The reaction solution was stared at 55° C. for 1.5 hr prior to TLC analysis. The reaction solution was diluted with EtOAc (200 mL), poured into a separately funnel and the organic phase was partitioned. The aqueous phase was neutralized by the addition of aq 1 N HCl and extracted with EtOAc (70 mL×2). The combined organic phase was dried over Na2SO4, filtered into a round bottom flask and concentrated on the Rotavapor. The crude residue was chromatographed thru a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 85% EtOAc to afford 1.35 g (55% yield) title compound. MS (ES) 493.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([OH:12])=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].CO.[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([O:12][C:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][NH:9][C:10]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Oc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Reactant: ClCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(COc2c(-c3ccccc3)n[nH]c2-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 3,5-diphenyl-4-pyrazolol (10 g, 0.042 mole), sodium methoxide (2.27 g, 0.042 mole) and methanol (60 ml) is heated at 60° C for 2 hours. Then benzyl chloride is added slowly at 60° C. A white solid forms. Heating is continued overnight at 60° C. The reaction mixture is examined by glc and the reaction is found to be complete. The mixture is poured into water and the solid isolated by filtration. The solid is washed well with water, dried and recrystallized from acetonitrile to give pale yellow crystals, melting point 152°-152.5° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C([O-])(O)=O.[Na+].[CH2:19]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1.O.C(OCC)(=O)C>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2.05 g 3-amino-1-N-Boc-pyrrolidine, 1.85 g NaHCO3 and 3.17 g N-(Benzyloxycarbonyloxy)succinimide in 10 ml dioxane/water 1:1 was stirred for 12 h at RT. The reaction mixture was diluted with ethyl acetate, the phases separated and the organic phase washed with saturated NaHCO3 and brine. The crude product obtained after evaporation of the solvent was used in the next reaction step without further purification.
Reaction SMILES: Cl.C([O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:21][CH:22]3[CH2:27][CH2:26][CH:25]([CH:28]([NH2:37])[C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)=[C:17]([Cl:20])[CH:18]=2)[CH:13]=[CH:12][N:11]=1)C1C=CC=CC=1.C(#N)C.O>C(O)(C)C>[NH2:37][CH:28]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH:25]1[CH2:24][CH2:23][CH:22]([O:21][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][C:17]=2[Cl:20])[C:10](=[O:9])[NH:11][CH:12]=[CH:13]3)[CH2:27][CH2:26]1
Reactant: COc1ccc(C(N)C2CCC(Oc3cc4ccnc(OCc5ccccc5)c4cc3Cl)CC2)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CC#N
Product: COc1ccc(C(N)C2CCC(Oc3cc4cc[nH]c(=O)c4cc3Cl)CC2)cc1
Reaction time: 8 h

Procedure:
A 2M aqueous solution of hydrochloric acid (3.8 mL) was added to a solution of C-[4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-C-(4-methoxy-phenyl)-methylamine (36, 40 mg, 0.08 mmol) in isopropanol (4 mL). The reaction mixture was stirred overnight. Isopropanol was removed under reduced pressure and the remaining aqueous solution freeze dried to give crude product as an amorphous powder. This was treated twice with acetonitrile/water and freeze dried to give the desired product as a colourless hydrochloride salt. The relative stereochemistry was not assigned.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])C1C=CC=CC=1.[OH-]>C(O)C.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Temperature: 40 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
A mixture of (R)-5-dibenzylamino-3-(N-methylpyrrolidin-2-ylmethyl) indole (1.08 g, 2.64 mmol) and palladium [II] hydroxide on carbon (0.6 g) in absolute ethanol (25 mL) was shaken under a hydrogen atmosphere (3 atm) at 40° C. for 4 hours. The resulting mixture was filtered through diatomaceous earth, and the filtrate was evaporated under pressure to afford the title compound (0.60 g, 2.62 mmol, 99%) as a white foam: 1H NMR (DMSO-d6) δ10.65 (br s, NH), 7.14 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 6.60 (dd, J=2.0 and 8.6 Hz, 1H), 3.63-2.83 (m, 7H), 2.78 (s, 3H), 2.05-1.67 (m, 4H); [α]25D =+9° (MeOH, c=1.0); HRMS: calculated for C14H19N3 : 229.1575; found 229.1593.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([OH:22])[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Si:30](Cl)([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)OC(C)(C)C)cc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CNCCN2C(=O)OC(C)(C)C)cc1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
To a solution of (2R)-1-tert-butoxycarbonyl-2-(3-hydroxy-4-methylbenzyl)piperazine (7.73 g) and 4-dimethylaminopyridine (620 mg) in dichloromethane (90 ml) was added successively triethylamine (15.82 ml) and tert-butyldiphenylsilyl chloride (26.24 ml) at room temperature. After stirring under reflux for 27.5 hours, water (200 ml) was added to the mixture, and the mixture was extracted with dichloromethane (100 ml, 50 ml×2). The combined organic extracts were washed successively with water and brine, dried over magnesium sulfate, and evaporated under reduced pressure to give crude oil. The oil was purified with column chromatography (silica gel, 500 ml, methanol:dichloromethane 5:95) to give (2R)-1-tert-butoxycarbonyl-2-(3-tert-butyldiphenylsilyloxy-4-methylbenzyl)piperazine (12.07 g) as a solid.
Reaction SMILES: C(O)(=O)C.O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[NH:19]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[OH:24][C@H:21]1[CH2:22][CH2:23][N:19]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](O)C2)CC1
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
Acetic acid (90 mg, 1.2 mmol) was added to solution of tert-butyl 4-oxopiperidine-1-carboxylate (300 mg, 1.5 mmol) and (S)-pyrrolidin-3-ol (140 mg, 1.7 mmol) in DCE (3 mL) at 10-15° C. and stirring was continued at the same temperature for 10 minutes. Sodium triacetoxyborohydride (957 mg, 4.5 mmol) was added portionwise to the reaction mixture and stirring was continued at 20-35° C. for 16 h. The reaction mixture was diluted with DCM, washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 200 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)c(Cl)c(OC)c1OC
Reaction time: 6 h

Procedure:
Combine methyl 2-chloro-3,4,5-trimethoxybenzoate (2.0 g, 7.8 mmol) and a 1 M aqueous solution of sodium hydroxide (100 mL, 100 mmol) in methanol (50 mL). After 6 hours, adjust the pH to about 2 using a 1 M aqueous hydrochloric acid solution and extract with dichloromethane. Dry the combined organic layers over MgSO4, filter, and concentrate in vacuo to give the title compound; Rf=0.81 (silica gel, 10% ethanol/85% chloroform/5% acetic acid).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]C(C2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=O)=[CH:3][CH:2]=1.[F:28][C:29]1[C:40]([F:41])=[C:39]([O:42][CH2:43][C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]=2)[CH:38]=[CH:37][C:30]=1[C:31](N(OC)C)=[O:32]>>[F:28][C:29]1[C:40]([F:41])=[C:39]([O:42][CH2:43][C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]=2)[CH:38]=[CH:37][C:30]=1[C:31](=[O:32])[CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)c(F)c1F
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(F)c1F

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 2,3-Difluoro-N-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide provided the title compound. MS: (M+H m/z=391.1).
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)CN(CCCC)[C@@H:10]1COCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C@H:43]1[C@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:46][NH:45][C@@H:44]1[CH2:56][O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O=CC(CO)O.C([BH3-])#N.[Na+]>CO>[CH2:35]([O:42][C@H:43]1[C@H:47]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:46][N:45]([CH2:10][CH:9]([OH:8])[CH2:13][OH:14])[C@@H:44]1[CH2:56][O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCCCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: O=CC(O)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: OCC(O)CN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Yield: 72 %

Procedure:
The title compound was synthesized as described for compound 10 using (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.5 g, 1.2 mmol), methanol (30 ml), glyceraldehyde (0.134 g, 1.5 mmol) and sodium cyanoborohydride (0.094 g, 1.5 mmol). Purification of the crude product on silica gel (Eluent: Ethyl acetate) afforded (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-(2,3-dihydroxyprop-1-yl)pyrrolidine (0.424 g, yield: 72%) as an oil.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[N:10]=[C:9]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[CH3:13])[C:8]([C:21]([O:23]CC)=[O:22])=[CH:7][N:6]=1>O.CO.O1CCCC1>[Cl:4][C:5]1[N:10]=[C:9]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[CH3:13])[C:8]([C:21]([OH:23])=[O:22])=[CH:7][N:6]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1N[C@@H](C)c1ccc(F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H](Nc1nc(Cl)ncc1C(=O)O)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A solution of lithium hydroxide monohydrate (633 mg, 15.09 mmol) in water (6 mL) was added to a solution of (S)-ethyl 2-chloro-4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidine-5-carboxylate (Preparation 5a, 490 mg, 1.51 mmol) in a mixture of methanol (6 mL) and tetrahydrofuran (2 mL) and the reaction mixture was stirred at ambient temperature for 3 hours. The solvents were evaporated under reduced pressure and water was added to the resulting residue. The pH was then adjusted to ca. 6 with 2M aqueous hydrochloric acid and the aqueous suspension was extracted with diethyl ether (×3). The organic phase was washed with water and brine, dried (MgSO4), filtered and the solvent evaporated under reduced pressure to give the title compound (0.21 g, 41%) as a semi-solid.
Reaction SMILES: C([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+]([O-])=O)[CH:8]=[CH:7][CH:6]=2)C.[H-].[Na+].CCCCCC.C(Br)C1C=CC=CC=1>CN(C=O)C.O>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:3]1
Reactant: CCc1cc2c([N+](=O)[O-])cccc2[nH]1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-Ethyl -4-nitro-1H-indole (4.75 g, 25 mmol) was added to a mixture of 1.0 g (25 mmol) of 60% NaH/mineral oil (washed with hexane before adding DMF) in 40 ml DMF. After 45 minutes, 3.0 ml (25 mmol) of benzyl bromide was added. The mixture was stirred at room temperature for four hours, diluted with water, and extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 20% EtOAc/Hexane to give 6.36 g (91%) of 1-Phenylmethyl-2-ethyl-4-nitro]1H-indole as an oil.