Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]1[C:35]([CH3:36])=[C:34]([CH3:37])[C:33]([CH3:38])=[C:32]([CH3:39])[C:31]=1[CH3:40])(=[O:29])=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]3[C:31]([CH3:40])=[C:32]([CH3:39])[C:33]([CH3:38])=[C:34]([CH3:37])[C:35]=3[CH3:36])(=[O:28])=[O:29])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: Cc1c(C)c(C)c(S(=O)(=O)NCCN=[N+]=[N-])c(C)c1C
Product: Cc1c(C)c(C)c(S(=O)(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)c(C)c1C

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.120 g, 0.434 mmol) was reacted with N-(2-azidoethyl)-2,3,4,5,6-pentamethylbenzenesulfonamide (0.141 g, 0.434 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(2,3,4,5,6-pentamethylphenylsulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.30 (s, 1H), δ 7.01 (s, 1H), δ 6.44 (s, 1H), δ 6.17 (s, 2H), δ 4.35 (s, 2H), δ 3.34 (s, 2H0, δ2.47 (s, 2H), δ 2.48 (s, 6H), δ 2.20 (m, 11H), δ 1.43 (m, 15H) ppm; 13C NMR (75 MHz, CDCl3) δ 149.6, 148.1, 139.7, 136.2, 134.9, 134.3, 122.4, 84.9, 53.7, 50.2, 42.5, 31.1, 29.3, 28.9, 28.4, 28.2, 25.6, 19.1, 17.9, 17.2 ppm; HRMS (ESI) calcd for C28H43N7O4S (M+) 573.3097. found 573.3086, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2,3,4,5,6-pentamethylbenzenesulfonamide hydrochloride (0.143 g, 76% yield). 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), δ 6.42 (s, 1H), δ 4.48 (s, 2H), δ 3.34 (s, 2H), δ 2.65 (s, 2H), δ 2.40 (s, 8H), δ 2.12 (s, 9H), δ 1.58 (s, 4H), δ 1.19 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 159.9, 147.3, 139.6, 136.1, 134.8, 134.0, 127.8, 127.6, 108.6, 108.4, 54.1, 51.5, 41.8, 36.5, 28.2, 28.1, 27.7, 24.1, 23.7, 18.2, 16.8, 16.1 ppm; HRMS (ESI) calcd for C23H35N7O2S (M+) 473.2573. found 473.2565.
Reaction SMILES: OCCCCCC1CCCC1=O.OCCCCCC1CCCC1=O.C(OCCCCCC1CCCC1=O)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C)(=O)C.[CH3:59][C:60]([O:62][CH2:63][C:64]1[C:77]2[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=2)[C:71]([CH2:78][O:79][C:80]([CH3:82])=[O:81])=C2C=1C=CC=C2)=[O:61]>>[C:80]([O:79][C:78]1[CH2:71][CH2:72][CH2:73][C:74]=1[CH2:75][CH2:76][CH2:77][CH2:64][CH2:63][O:62][C:60](=[O:61])[CH3:59])(=[O:81])[CH3:82]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)OCCCCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCCC1CCCCCO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCCCCC1=C(OC(C)=O)CCC1

Procedure:
A solution of 400 g. (2.04 moles) of a mixture of 2-(5-hydroxypentyl)cyclopentanone and 2-(5-acetoxypentyl)cyclopentanone (Example 55) and 4.0 g. of p-toluenesulfonic acid monohydrate in 11. l. of acetic anhydride is refluxed acetic a rate to maintain a steady distillation of accetic acid from the reaction through a helix -packed fractionation column. The reaction is continued with the addition of acetic anhydride to maintain a constant volume until complete conversion of starting materials to product is evident. The mixture is cooled and partitioned between 2 l. of hexane and 3 l. of cold water containing solid sodium bicarbonate to maintain a neutral pH. The organic phase is washed with saturated brine, dried (MgSO4), and evaporated to yield 452 g. of an oil.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH2:17][CH2:16]2.C([O:24][B:25](OCC)[O:26]CC)C.[Cl-].[NH4+]>O1CCCC1>[CH2:18]1[C:19]2[C:15](=[CH:14][C:13]([B:25]([OH:26])[OH:24])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: CCOB(OCC)OCC
Reactant: Brc1ccc2c(c1)CCC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2c(c1)CCC2
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium in hexane (13.2 mL of 1.6 M, 21 mmol) is added to a stirred solution of 5-bromo-indane (1.06 g, 4 mmol) in dry tetrahydrofuran (30 mL) at −75° C. under an argon atmosphere. The mixture is stirred for 30 min at −65° C., then treated with triethylborate (3.07 g, 21 mmol) and stirred for 60 min at −50° C. The resulting mixture is allowed to warm to 0° C. and then treated with a saturated aqueous solution of ammonium chloride (60 mL) and extracted with ethyl acetate (2×80 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 50% ethyl acetate in hexaen) and recrystallized from ethyl acetate-hexane to give indan-5-boronic acid as a colourless crystalline solid.
Reaction SMILES: [CH3:1]C1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Sn:23]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH:22]=1.CI>CCCCCC.O1CCCC1>[F:16][C:17]1[C:18]([CH3:1])=[N:19][CH:20]=[C:21]([Sn:23]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:24][CH2:25][CH2:26][CH3:27])[CH:22]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(F)c1
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a mixture of 2,2,6,6-tetramethyl-piperidine (0.30 mL, 1.8 mmol) and 10 mL tetrahydrofuran at −78° C. was dropwise added 2.5 M of n-butyllithium in hexane (0.80 mL). The reaction vessel was then placed into a 0° C. ice bath and stirred for 60 minutes. The reaction vessel was then cooled to −78° C., and 3-fluoro-5-tributylstannylpyridine (504.7 mg, 1.307 mmol) was added as a solution in tetrahydrofuran (2 mL). The reaction mixture was stirred at −78° C. for 90 minutes, and then methyl iodide (0.15 mL, 2.4 mmol) was added. After an additional 30 minutes, the reaction was quenched with saturated aqueous NH4Cl, and extracted with ethyl acetate. The organic extract was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (2 g silica, solvent gradient: 0-30% ethyl acetate in heptanes) to yield 381.8 mg (50% pure, 37% yield) of 3-fluoro-2-methyl-5-(tributylstannyl)pyridine. LCMS (ESI): M+H=402.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=O.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=C.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC>C(OCC)(=O)C(OCC)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH:5]=[CH:13][C:12]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C=Cc1ccc(Cl)c(Cl)c1
Yield: 11.4 %

Procedure:
0.152 g (0.5 millimol) of bis-(acetylacetonato)palladium(II), 10.53 g (50 millimols) of 3,4-dichlorobenzoyl chloride, 7.5 g (75 millimols) of ethyl acrylate and 17.65 g (50 millimols) of tri-n-octylamine in 100 ml of diethyl oxalate are stirred for 2.5 hours at 120° C. The crude product is distilled in vacuo and then recrystallised from methanol. 1.4 g (11% of theory) of ethyl 3,4-dichlorocinnamate are obtained; melting point 56.0° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O>CS(C)=O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Clc1ccc(Cn2ccc3ccccc32)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 5.86 g (0.05 mol) of indole in 25 ml of DMSO is added to a mixture of 1.32 g of sodium hydroxide (0.055 mol, suspension in mineral oil) in 50 ml of dimethyl sulfoxide. The mixture is heated at 60° C. for 1.3 hours and then allowed to cool, and 17.7 g (0.11 mol) of 4-chlorobenzyl chloride are added dropwise. The solution is heated at 60° C., allowed to stand overnight and then poured with stirring into 200 ml of water. The mixture is extracted repeatedly with a total of 75 ml of CH2Cl2, the organic phase is dried with anhydrous sodium sulfate and filtered and the filtrate is concentrated under reduced pressure.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br.C(S[CH:20]1[NH:24][CH2:23][CH2:22][NH:21]1)CCC>C(O)CCCC>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:11]=[C:20]3[NH:24][CH2:23][CH2:22][NH:21]3)=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCCSC1NCCN1
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: Br
Solvent: CCCCCO
Product: c1cc(C2CCCCC2)ccc1N=C1NCCN1

Procedure:
9.1 g of p-cyclohexylaniline and 11.9 g of 2-n-butylthioimidazolidine hydrobromide in 60 ml of amyl alcohol are refluxed for 6 hours. The solvent is then distilled off in vacuo. The residue is taken up in methylene chloride and successively washed with dilute sodium hydroxide solution and water. The methylene chloride is distilled off and the crude final product is recrystallised from acetonitrile. The resylting 2-(4-cyclohexylphenyl)imino-imidazolidine decomposes at 163° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH2:11]1[O:13][CH2:12]1.[H-].[Na+].O>O1CCOCC1>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH2:11][CH2:12][OH:13])[CH:7]=[CH:8]1
Reactant: C1CO1
Reactant: Oc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCCOc1cccc2cc[nH]c12
Temperature: 100 °C
Reaction time: 120 h
Yield: 33.9 %

Procedure:
A mixture of 7-hydroxyindole (1.00 g, 7.51 mmol) and ethylene oxide (0.33 g, 7.50 mmol) in dioxane (3 mL) was placed in a reaction tube. NaH (60% in oil; 0.100 g, 2.45 mmol) was added and the reaction mixture was stirred at 100° C. for 5 days. The reaction mixture was poured into water, extracted with EtOAc, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (1:1) as eluent to give 0.45 g (34%) of the title product. Pos-EI-MS shows M+ and 5 ions supporting the stated structure. HRMS m/z calcd for C10H11NO2 (M)+ 177.0790, found 177.0799.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:18]([NH2:21])(=[O:20])[CH3:19]>>[C:18]([NH:21][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(Br)cc(N2CCCC2=O)c1
Reactant: CC(N)=O
Product: COC(=O)c1cc(NC(C)=O)cc(N2CCCC2=O)c1

Procedure:
D12 was prepared as for E1, from methyl 3-bromo-5-(2-oxopyrrolidin-1-yl)benzoate and acetamide.
Reaction SMILES: Br[C@H:2]1[C:28](=[O:29])[C@@:27]2([CH3:30])[C@@H:13]([CH2:14][C@@H:15]3[O:20][C@@:19]4([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH2:21]4)[C@@H:17]([CH3:18])[C@@H:16]32)[C@H:12]2[C@H:3]1[C@:4]1([CH3:32])[C@@H:9]([CH2:10][CH2:11]2)[CH2:8][C@@H:7]([OH:31])[CH2:6][CH2:5]1.C([OH:37])(C)(C)C.[OH-].[Na+]>O>[CH3:18][C@@H:17]1[C@:19]2([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH2:21]2)[O:20][C@H:15]2[CH2:14][C@@H:13]3[C@@:27]([CH3:30])([C@@H:16]12)[C@H:28]([OH:29])[C:2](=[O:37])[C@H:3]1[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@:4]1([CH3:32])[CH2:5][CH2:6][C@H:7]([OH:31])[CH2:8]2
Reactant: CC(C)(C)O
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](Br)C(=O)[C@]3(C)[C@H]1[C@@H]2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Temperature: 83 °C

Procedure:
A glass lined reactor was charged with 12.4 Kg of (3β,5α,11β,25R)-11-bromospirostan-3-ol-12-one (24.34 mole), 33 gallons of t-butanol, 33 gallons of water and 7.5 Kg (189 mole, 7.75 eq) of sodium hydroxide pellets. The reaction was heated to reflux over 1.5 hours, maintained at -reflux for 4.5 hours (pot temperature was 83° C.), then cooled to room temperature. TLC at this point indicated complete reaction.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:11]1([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: ClCCCCCCCCOc1cccc2ccccc12
Product: c1ccc(NCCCCCCCCOc2cccc3ccccc23)cc1

Procedure:
7.0 Gm of 1-chloro-8-(1-naphthyloxy)octane was refluxed for 1 hour in 100 ml of aniline. The excess aniline was then removed under vacuum and the residue was distributed between methylene chloride and dilute aqueous potassium hydroxide. The organic solution was dried and evaporated, and the residue was chromatographed on silica gel, eluting with methylene chloride, so as to produce the title compound as an oil.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:18]1([NH2:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[C:18]1([NH:24][C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][CH:9]=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc3ccc4cccc5ccc2c3c45)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
1-Bromopyrene (10 mmol), C6H5NH2 (12 mmol), Pd(dba)2 (0.20 mmol), P(t-Bu)3 (0.20-0.30 mmol) and sodium t-butoxide (1.44 g, 15 mmol) were charged in a two-necked flask under a nitrogen atmosphere. Toluene (25 ml) was added and the resulting violet solution was stirred at room temperature for 8 hours. During this period the contents of the flask became a pale yellow fluorescent solution. The reaction was quenched with water (30 ml) and the organic layer was taken into 100 ml diethyl ether, washed with brine solution, and dried over MgSO4. Evaporation of the solvent under vacuum resulted in a yellow solid that was adsorbed in silica gel and purified by column chromatography using dichloromethane/hexane (1:1) as eluant to produce phenyl-pyren-1-yl-amine (89%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC(C(F)(F)F)=O.[NH2:21][C@@H:22]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([NH:21][C@@H:22]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](Cc1ccccn1)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccn1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
To (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (495 mg, 2.62 mmol) was added (S)-benzyl 2-amino-3-(pyridin-2-yl)propanoate TFA salt (0.82 g, 2.22 mmol), HOBt (482 mg, 3.57 mmol), HBTU (1.35 g, 3.57 mmol), and ACN (10 mL). The mixture was cooled to 0° C. and DIEA (1.46 mL, 8.88 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated to provided crude (S)-benzyl 2-((S)-2-((tert-butoxycarbonyl)amino)propanamido)-3-(pyridin-2-yl)propanoate as a colorless solid (0.46 g) that was carried forward without further purification. MS (EI) for C23H29N3O5, found 428.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].F[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:39]#[N:40]>CS(C)=O.O>[Cl:1][C:2]1[C:7]([O:8][C:36]2[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:45])([F:47])[F:46])[CH:43]=2)[C:39]#[N:40])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)(F)F)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methylphenol (8.49 g, 52.9 mmol) and 18-crown-6 (13.98 g, 52.9 mmol) in dimethyl sulfoxide (80 ml) was added potassium t-butoxide (20% wt solution in THF) (31.2 g, 55.5 mmol) (31.2 mL) and the mixture was stirred at rt for 30 minutes. Next, 3-fluoro-5-(trifluoromethyl)benzonitrile (10.00 g, 52.9 mmol) was added and the mixture was heated with stirring for 5 hours at 135° C. The reaction mixture was cooled to 0° C., poured into 700 mL water, and the precipitate was filtered off to give the title compound (12.6 g, 38.2 mmol, 72% yield) as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.39-7.49 (m, 1H), 7.34 (t, 1H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][CH:15]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]OS(C)(=O)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH3:31]>>[CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][CH:15]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17][NH2:31])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: N
Reactant: Cc1ccc2c(c1)c1c(n2CC(CCOS(C)(=O)=O)c2ccncc2)CCN(C)C1
Product: Cc1ccc2c(c1)c1c(n2CC(CCN)c2ccncc2)CCN(C)C1

Procedure:
Methanesulfonic acid-4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyl ester (200 mg, 0.468 mmol) in 10 mL of aqueous ammonia was heated at 100° C. for 1 h. The progress of reaction was monitored by TLC. After consumption of starting material, the reaction mixture was dried and the crude product was purified by reverse phase chromatography to obtain 33 mg of 4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butylamine as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.5 (d, 2H), 7.5 (m, 2H), 7.25 (d, 1H), 7.24 (s, 1H), 7.05 (t, 1H), 4.6 (d, 1H), 4.5 (d, 1H), 4.3 (m, 1H), 4.23 (t, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.08 (d, 3H), 2.8 (m, 2H), 2.7 (m, 2H), 2.4 (s, 3H), 2.25 (m, 1H), 2.2 (m, 1H). Separation by chiral HPLC provides enantiomers II-231a-b.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: Nc1ccc(C(=O)c2ccccn2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)c2ccccn2)cc1N

Procedure:
A suspension of 20 g. (0.082 mol) of 2-(3-nitro-4-aminobenzoyl)pyridine in 1 liter of tetrahydrofuran containing 5 g. of 5% palladium on carbon was reduced with hydrogen under a pressure of 3 atmospheres. The resulting mixture was filtered and concentrated in vacuo to a reddish oil which was dissolved in a minimum amount of methylene chloride and diluted with petroleum ether to yield 2-(3,4-diaminobenzoyl)pyridine as a slightly unstable yellow solid, mp. 137° -138° C. (water).
Reaction SMILES: [CH2:1]=O.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][NH:17][CH3:18])([O-:5])=[O:4].O.[OH-].[Na+]>C(O)(=O)C.CCOC(C)=O>[CH3:18][N:17]1[CH2:16][CH2:15][C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=3)[NH:11][C:10]=2[CH2:1]1
Reactant: CNCCc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN1CCc2c([nH]c3ccc([N+](=O)[O-])cc23)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under N2, formaldehyde (0.56 ml of a 36.5% aqueous solution, 7.3 mmol) was added to a solution of 5-nitro-3-(2-methylaminoethyl)-1H-indole (1.6 g, 7.3 mmol) in glacial acetic acid (10 mL). After 20 h of stirring at room temperature, the mixture was refluxed for 2 h and taken to dryness in vacuo. The residue was treated with H2O (150 mL) and EtOAc (150 mL) and then basified by the addition of 2M NaOH. The organic phase was separated and the aqueous layer was reextracted with three portions of EtOAc. The combined organic solution was extracted with 10% aqueous H2SO4 (3×160 mL). The acidic aqueous phase was cooled in an ice bath, basified with concentrated aqueous NaOH and extracted with tert-butyl methyl ether (4×175 mL). The dried (Na2SO4) extract was evaporated to dryness to afford 1.40 g of 2-methyl-6-nitro-2,3,4,9-tetrahydro-1H-β-carboline that were used directly in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(COC)OC>[NH:1]1[C:9]2=[N+:8]([O-:18])[CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: COCCOC
Product: [O-][n+]1cccc2cc[nH]c21
Reaction time: 2 h

Procedure:
1H-Pyrrolo[2,3-b]pyridine 7-oxide 658 was synthesized by reacting 7-azaindole 94 with an oxidizing agent (e.g. m-CPBA) in a non-reactive solvent (e.g. dimethoxyethane) as described by Schneller, S. W.; Luo, Jiann-Kuan. J. Org. Chem. 1980, 45:4045-4048. The compound was isolated by filtration of the resulting solid that forms upon standing at 5° C. for typically 1-3 h.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:30]=[CH:29][C:17]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CCOC(C)=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18](=[O:19])[C:17]2[CH:29]=[CH:30][C:14]([S:11]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:3]3)(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[CH:23][CH:24]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2nc(Cl)c3ccccc32)cc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2nc(N3CCOCC3)c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Dissolve 4-(3-chloro-indazole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide (91 mg, 0.20 mmol) in morpholine (1.0 mL) and stir at 100° C. overnight. Dilute the solution with EtOAc (30 mL) and wash with 1N HCl (11 mL), water (10 mL), and satd NaHCO3 (10 mL). Dry, filter and concentrate the organic solution and purify the residue by flash chromatography, using a linear gradient of 20% to 80% EtOAc/hexanes, to give the title compound as a white foam (17 mg, 34%). MS (ES) 495.0 (M+1)+, 493.1 (M−1)−.