Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21]([C:23]1[N:27]([CH3:28])[C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[N:27]([CH3:28])[C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)=[CH:3][C:4]=1[O:16][C:17]([F:20])([F:19])[F:18])(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NC(C)(C)C)c(OC(F)(F)F)c1
Reaction time: 16 h
Yield: 18.6 %

Procedure:
According to general procedure B, 4-bromo-N-tert-butyl-2-(trifluoromethoxy)benzenesulfonamide (225 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. N-tert-butyl-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)benzenesulfonamide (44 mg, 19%) was provided after purification. MS (ESI) m/z 401. HPLC purity 99.0% at 210-370 nm, 10.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: C([O:3][P:4]([CH2:24][C:25]([N:27]1[CH2:41][CH2:40][CH2:39][C@H:28]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:26])([CH:6]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.Br[Si](C)(C)C>ClCCl>[OH:5][P:4]([CH2:24][C:25]([N:27]1[CH2:41][CH2:40][CH2:39][C@H:28]1[C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])=[O:26])([CH:6]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][C:8](=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:3]
Reactant: CCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(CCc1ccccc1)CC(=O)c1ccccc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C(CC(CCc1ccccc1)P(=O)(O)CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of the product from part (e) (1.146 g., 1.99 mmole) in dry dichloromethane (6 ml.) is treated with bromotrimethylsilane (0.55 ml., 4.17 mmole) and stirred at room temperature under argon. After 3 hours, additional bromotrimethylsilane (0.2 ml.) is added and stirring continued for 1 hour. The excess bromotrimethylsilane and dichloromethane are removed in vacuo and the residue is treated with water and ethyl acetate and stirred for 15 minutes. The aqueous phase is separated and the ethyl acetate layer is washed with saturated sodium chloride, dried over Na2SO4 and evaporated to give (±)-1-[[hydroxy[3-oxo-3-phenyl-1-(2-phenylethyl)propyl]phosphinyl]acetyl]-L-proline, phenylmethyl ester (100%) as a white foam, Rf (acetic acid/methanol/dichloromethane 1:1:18) 0.42.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[C:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=2.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C1(O)C=CC=CC=1>[ClH:2].[CH2:27]([NH:34][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[C:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCCCCCCCCc1ccc2nc3c(c(Cl)c2c1)CCCC3
Reactant: NCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: CCCCCCCCCCc1ccc2nc3c(c(NCc4ccccc4)c2c1)CCCC3
Yield: 43.9 %

Procedure:
9-Chloro-7-decyl-1,2,3,4-tetrahydroacridine hydrochloride (5.0 g) was dissolved in 50 ml of phenol and heated at 150° C. with 3.50 g of benzylamine. After 2 hours at this temperature the reaction mixture was poured into 10% NaOH and extracted with Et2O. The organic phase was separated, washed with water and treated with 5% HCl. The insoluble hydrochloride was filtered off and recrystallized from MeOH/Et2O to give 2.59 g of product, m.p. 215° C.
Reaction SMILES: C(OC(N1C2C(=CC(C3C=CC=CC=3OC)=CC=2)C(C(O)C)=CC1(C)C)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([CH3:50])([CH3:49])[CH:43]=[C:42]2[CH:51]([O:53][CH2:54]/[CH:55]=[CH:56]/[C:57]1C=CC=CC=1)[CH3:52].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(Br)C=CC1C=CC=CC=1>C1COCC1>[CH2:54]([O:53][CH:51]([C:42]1[C:41]2[C:46](=[CH:47][CH:48]=[C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[O:32][CH3:31])[CH:40]=2)[NH:45][C:44]([CH3:50])([CH3:49])[CH:43]=1)[CH3:52])/[CH:55]=[CH:56]/[CH3:57]
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)OC/C=C/c1ccccc1)=CC(C)(C)N2
Agent: BrCC=Cc1ccccc1
Agent: COc1ccccc1-c1ccc2c(c1)C(C(C)O)=CC(C)(C)N2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: C/C=C/COC(C)C1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Yield: 19 %

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-((E)-3-phenylallyloxy)ethyl]-1,2-dihydroquinoline 4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester (70 mg) was treated with 255 μL of 1 M solution of sodium bis(trimethylsilyl)amide in THF and 50 mg of cinnamyl bromide to give the alkylated product, which was deprotected to yield 5.8 mg of the title compound as a foam.
Reaction SMILES: Cl.[CH:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1>[Zn].C(O)(=O)C>[CH:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([C:14]=2[C:7]2[C:8]4[C:13]([CH:14]=[C:15]5[C:6]=2[CH:5]=[CH:4][CH:3]=[CH:2]5)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2Cc2ccccc21
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: c1ccc2c(-c3c4ccccc4cc4ccccc34)c3ccccc3cc2c1

Procedure:
After hydrochloric acid was added to an acetic acid solution of anthrone, it was refluxed upon addition of zinc. Thereafter it was refined in accordance with an ordinary method to obtain 9,9′-bianthryl. After it was added little by little to a melt of aluminum chloride and sodium chloride, the reaction mixture was poured into diluted hydrochloric acid and a solids constituent was collected. The solids constituent thus obtained was refined in accordance with an ordinary method to obtain target dibenzo[a,o]perylene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].NC(N)=O.[N-:21]=[N+:22]=[N-].[Na+].C(=O)(O)[O-].[Na+]>O>[N:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccnc1
Agent: NC(N)=O
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: [N-]=[N+]=Nc1cccnc1
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
3-Aminopyridine (18.89 g, 0.20 mol) was added to a warm (55° C.) solution of 36 ml of concentrated sulfuric acid in 210 ml of water. The mixture was stirred for five minutes and was then cooled to 5° C. and a solution of 16.66 g (0.24 mol) of sodium nitrite in 140 ml of water was added dropwise, keeping the temperature below 6° C. The mixture was left to stir for 20 minutes. Urea (2.4 g, 0.04 mol) was added and the mixture was again left to stir at 5° C. for 20 minutes. A solution of 15.60 g (0.24 mol) of sodium azide in 150 ml of water was added, keeping the temperature below 10° C. Nitrogen was immediately evolved. The mixture was stirred at ambient temperature for 1.5 hours after the addition was complete and was then neutralized to pH 6-7 with sodium bicarbonate and extracted with ether. The ether extract was dried over magnesium sulfate and stripped of solvent to yield 21.5 g (89 percent of theory) of dark oil. NMR (CDCl3): δ8.58 (m, 2H) δ7.47 (m, 2H).
Reaction SMILES: C([O:8][C:9](=[O:37])[C@@H:10]([O:34][CH2:35][CH3:36])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:33])[CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[CH2:35]([O:34][C@@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19](=[O:33])[CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:16][CH:17]=1)[C:9]([OH:37])=[O:8])[CH3:36]
Reactant: [H][H]
Reactant: CCO[C@@H](Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCO[C@@H](Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Reaction time: 3 h
Yield: 96.5 %

Procedure:
(S)-2-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxy]-phenyl}-propionic acid benzyl ester (0.1 g, 0.2 mmol) was dissolved in EtOAc (4 mL) and 10% Pd/C (0.04 g, 0.037 mmol) was added. After evacuation the reaction vessel was connected to a hydrogen line and the hydrogeneation was performed at atmospheric pressure at room temperature for 3 h. The catalyst was filtered off, washed with EtOAc and the combined organic filtrates were evaporated under reduced pressure to afford the product as a solid (0.079 g, 96.4%). 1H NMR (400 MHz, CDCl3): δ 7.98-7.99 (d, 2H), 7.42 (m, 3H), 7.23-7.25 (d, 2H), 7.02-7.04 (m, 2H), 6.71 (br s, 1H), 4.01-4.02 (m, 1H), 3.80 (s, 2H), 3.57-3.60 (m, 1H), 3.36-3.39 (m, 1H), 3.07-3.10 (m, 1H), 2.94-2.99 (m, 1H), 2.40 (s, 3H), 1.11-1.14 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C(C(/N=N/C(C)(C)C#N)(C)C)#N.[Br:21]N1C(=O)CCC1=O.FC1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Br:21])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccn1
Agent: CC(C)(C#N)/N=N/C(C)(C)C#N
Solvent: Fc1ccccc1
Product: BrCc1cc(Br)ccn1
Temperature: 90 °C
Yield: 100 %

Procedure:
4-bromo-2-methyl-pyridine (5 g, 29.07 mmol), 2-[(E)-(1-cyano-1-methyl-ethyl)azo]-2-methyl-propanenitrile (954.7 mg, 5.814 mmol) and N-bromosuccinimide (7.244 g, 40.70 mmol) were added to fluorobenzene (8 mL) and the mixture heated to 90° C. for 1 hour. Reaction mixture was purified by filtering through a silica gel pad and eluting with 50% diethylether/petroleum ether. Product fractions were combined and concentrated in vacuo to give the crude sub-title product (7.294 g, assumed 100% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 4.52 (s, 2H), 7.42 (d, 1H), 7.65 (s, 1H) and 8.42 (d, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](F)[CH:6]=1)[CH3:2].[CH3:16][NH2:17]>C1COCC1.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([NH:17][CH3:16])[CH:6]=1)[CH3:2]
Reactant: CN
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NC)c1

Procedure:
3-Methylamino-4-nitro-benzoic acid ethyl ester (2.8 g) was prepared by following General Procedure A starting from 3-fluoro-4-nitro-benzoic acid ethyl ester (3 g) and 2 M methylamine in THF (15 mL) in DMF (15 mL).
Reaction SMILES: [CH2:1]([C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[C:5]([NH:15]S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=1)[CH3:2].ClC1C=C2C(C(CC(O)=O)=[C:32]([C:36]([C:38]3[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][N:39]=3)=[O:37])N2)=CC=1>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[CH:14][CH:13]=2)[NH:15][C:32]=1[C:36]([C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][N:39]=1)=[O:37]
Reactant: CCc1ccc(/C=C/C(=O)OC)c(NS(=O)(=O)c2ccc(C)cc2)c1
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Product: CCc1ccc2c(CC(=O)OC)c(C(=O)c3cc(C)ccn3)[nH]c2c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-ethyl-2-(p-toluenesulfonylamino)cinnamate (step 5) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described in step 2 of Example 31).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:32])[C:18]=3[NH:22][C:23](=[O:31])[CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:13]=2)[CH2:8]1)C.[OH-].[Na+].Cl>CO>[Cl:32][C:17]1[C:18]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:9]1[CH2:10][CH2:11][C@H:7]([NH:6][CH2:5][C:4]([OH:33])=[O:3])[CH2:8]1)[CH:21]=[CH:20]2
Reactant: CCOC(=O)CN[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Yield: 29.8 %

Procedure:
N-[(3S)-1-[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]-3-pyrrolidinyl]-glycine ethyl ester (Example 85(a)) (100 mg), 1M sodium hydroxide (0.422 mL) and methanol (5 mL) were stirred for 12 hours before reaction was acidified with 1M hydrochloric acid and volatiles removed under vacuum. Purification (SiO2, 7M ammonia in methanol:methanol:dichloromethane 1:4:95) gave the title compound (0.028 g)
Reaction SMILES: [CH2:1]([C:5]1[NH:14][C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]2[C:32]#[N:33])=[CH:21][CH:20]=1>CS(C)=O>[CH2:1]([C:5]1[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]3[C:32]#[N:33])=[CH:23][CH:24]=2)[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)ccnc2[nH]1
Reactant: N#Cc1c(Cl)c(Cl)cn1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)c(Cl)c2C#N)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 41.5 %

Procedure:
To a solution of 2-butyl-7-methyl-3H-imidazo[4,5-b]pyridine (568 mg) in dimethyl sulfoxide (7 ml) was added sodium hydride (132 mg, 60% oil dispersion) at ambient temperature. The mixture was stirred for 40 minutes at the same temperature. To the mixture was added dropwise a solution of 1-(4-bromomethylphenyl)-3,4-dichloropyrrole-2-carbonitrile (990 mg) in dimethyl sulfoxide (3 ml). The mixture was stirred for 2 hours at ambient temperature and ice water (30 ml) was added therein. The separated oil was extracted twice with ethyl acetate. The extracts were washed with water, dried, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted by 50% ethyl acetate in n-hexane to give 2-butyl-3-[4-(2-cyano-3,4-dichloro-1-pyrrolyl)benzyl]-7-methyl-3H-imidazo[4,5-b]pyridine (546 mg) as an oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]2[N:25]=[C:24]([NH:26][C@@H:27]3[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]3)[CH:23]=[N:22][CH:21]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].Cl>CCOC(C)=O>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]2[N:25]=[C:24]([NH:26][C@@H:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)[CH:23]=[N:22][CH:21]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4cncc(N[C@@H]5CCCN(C(=O)OC(C)(C)C)C5)n4)c3c2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4cncc(N[C@@H]5CCCNC5)n4)c3c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-tert-butyl 3-(6-(5-(6-isopropoxy-pyrazin-2-yl)-1-tosyl-1H-indol-3-yl)pyrazin-2-ylamino)piperidine-1-carboxylate (0.250 g, 0.365 mmol) in 1-4-dioxane (3.6 mL), 1N NaOH (3.6 mL) was added and heated at 100° C. for 2 h. The reaction mixture was quenched with ice cold water and precipitate was formed. The precipitate was collected by filtration, washed with ice cold water and dried to give pure (R)-tert-butyl 3-(6-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)pyrazin-2-ylamino)piperidine-1-carboxylate (180 mg, 93%). MS (ESI, pos. ion) m/z: 530.0 (M+1). To a solution of (R)-tert-butyl 3-(6-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)pyrazin-2-ylamino)piperidine-1-carboxylate (180 mg, 1.25 mmol) in EtOAc (5.0 mL) was treated with HCl in EtOAc (5.0 mL) and stirred at RT for 3 h. The reaction mixture was quenched with water, neutralized with NaHCO3, extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and evaporated to dryness. The crude solid was re-crystallized in acetone to obtain (R)-6-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrazin-2-amine. MS (ESI, pos. ion) m/z: 430.0 (M+1).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][N:9]([CH:11](OC)OC)[CH3:10]>CN(C=O)C>[CH3:8][N:9]([CH3:11])/[CH:10]=[CH:1]/[C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C)=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCCCC(=O)/C=C/N(C)C
Yield: 19.3 %

Procedure:
A solution of 2-hexanone (2.0 g, 20 mmol) and DMF-DMA (2.4 g, 20 mmol) in DMF (10 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (PE/EtOAc=4:1˜2:1) to give the title compound (0.6 g, 19%) as yellow oil.
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]C(=O)C2C=CC=CC=2)=[CH:12][C:11]=1[N+:25]([O-:27])=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O[Li].O.Cl>CO.O.[OH-].[Na+]>[CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[N+:25]([O-:27])=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@H](C)Oc1ccc(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li]O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCC[C@H](C)Oc1ccc(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5.3 mmol of ester 10 in 40 ml of methanol and 15 ml of water, 22 mmol of LiOH.H2O was added. The reaction mixture was stirred vigorously at room temperature for 14-22 h until no starting material was detected by TLC. The solution was diluted with 65 ml of 3.5% (wt/wt) NaOH solution, acidified by adding concentrated HCl with ice and extracted several times with ethyl ether. The combined organic layers were dried over anhydrous MgSO4 and the solvent removed. The phenol were purified by flash chromatography with hexanes/ethyl acetate [90:10] to give (S)-4-(1-methyl-heptyloxy)-3-nitro-phenol (Compound 11, Scheme I, R2 =(S)--OCH(CH3)C6H13) in 89-98% yield as an orange liquid: Rf [hexanes/ethyl acetate 85/15]: 0.24; 1H NMR (300 MHz, CDCl3): δ 0.84(t, 3 H, J=6.8 Hz), 1.16-1.48(m, 8 H), 1.27(d, 3 H, J=6.1 Hz), 1.56(m, 1 H), 1.72(m, 1 H), 4.35(m, 1 H), 5.44(broad s, 1 H), 6.94(d, 1 H, J=9 Hz), 7.01(dd, 1 H, J=2.8 Hz, J=9 Hz), 7.28(d, 1 H, J=2.8 Hz); 13C NMR (300 MHz, CDCl3): δ 13.98, 19.49, 22.50, 25.19, 29.15, 31.66, 36.19, 77.57, 112.03, 118.50, 121.44, 140.98, 145.81, 148.84; Mass spectrum, m/z(rel.intensity): 267(M+ 0.3), 156(8), 155(100), 71(9) 57(20), 55(16), 43(29).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C@@H:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1cccc(O)c1
Solvent: ClC(Cl)Cl
Product: C[C@@H]1c2ccccc2-c2ccc(F)cc2N1C(=O)c1cccc(O)c1

Procedure:
The enantiomers of 3-[(3-fluoro-6-methylphenanthridin-5(6H)-yl)carbonyl]phenol (660 mg, 1.98 mmol) were separated by automated, preparative, normal phase, chiral chromatography on a Chiralpak AD (20 mm×250 mm) column eluting with 100% acetonitrile at a flow rate of 20 mL/min with. The fractions containing the first peak were combined and concentrated in vacuo, to provide one peak (99.9%) with a retention time of 2.708 minutes was isolated as a white solid (270 mg, 82% based upon a 1:1 ratio of enantiomers with a theoretical maximum amount of 330 mg). [α]D25 =−545° (c=0.0105 g/mL, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.98 Hz, 3 H) 5.66 (q, J=6.38 Hz, 1 H) 6.69 (d, J=7.24 Hz, 2 H) 6.72 (s, 1 H) 6.83 (ddd, J=8.15, 2.46, 0.78 Hz, 1 H) 7.09 (td, J=8.67, 2.59 Hz, 1 H) 7.16 (t, J=7.89 Hz, 1 H) 7.37 (m, 2 H) 7.44 (td, 1 H) 7.96 (d, J=7.76 Hz, 1 H) 8.00 (dd, J=8.79, 6.47 Hz, 1 H) 9.66 (s, 1 H) MS (ESI) m/z 334 ([M+H]+); MS (ESI) m/z 332 ([M−H]−); HRMS: calcd for C21H16FNO2, 333.1165 (M), 334.12379 ([M+H]+); found (ESI+), 334.12345.
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:18][N:19](C)CC1C=CC=CC=1.C#N.[C-]#N.[K+]>C(Cl)Cl.O>[Cl:1][C:2]([Cl:17])([Cl:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:11]=1)[C:6]([C:18]#[N:19])=[O:7]
Reactant: O=C(Cl)c1cc(C(Cl)(Cl)Cl)cc(C(Cl)(Cl)Cl)c1
Reactant: CN(C)Cc1ccccc1
Agent: C#N
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: N#CC(=O)c1cc(C(Cl)(Cl)Cl)cc(C(Cl)(Cl)Cl)c1

Procedure:
78 g of 3,5-bis-(trichloromethyl)-benzoyl chloride and 0.4 g of dimethylbenzylamine are dissolved in 500 ml of methylene chloride and, at -15° C., first a solution of 10 ml of hydrogen cyanide in 50 ml of methylene chloride and then a solution of 12.4 g of potassium cyanide in 20 ml of water are added dropwise. After 11/2 hours, the mixture is dried by means of sodium sulfate stirred in, the inorganic salts are filtered off with suction and the solvent is stripped off in vacuo. On addition of ether, 14 g (18% of theoretical) of dimeric 3,5-bis-(trichloromethyl)-benzoyl cyanide crystallize out from the remaining viscous residue. The remaining monomeric product is purified by double distillation in a bulb tube.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[Li+].[Cl-].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][Zn+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N1C=CN(C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C.O.C1COCC1.CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[F:23])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1C[Zn+]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Cc3ccccc3F)cc21
Temperature: 20 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a nitrogen-degassed mixture of 6-bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (4.09 g, 12.5 mmol), lithium bromide (3.22 g, 37.5 mmol), (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) dichloride (0.17 g, 0.25 mmol), 1-methyl-2-pyrrolidinone (30 mL) and THF (30 mL) was added a solution of 2-fluoro- benzylzinc chloride in THF (0.5 M, 40 mL, 20 mmol) and resulting mixture was stirred at 20° C. for 3 h. The mixture was poured into water (150 mL) and 5% aqueous citric acid (30 mL) and the resulting mixture extracted with Et2O (3×70 mL). The organic phase was washed with water (100 mL), brine (3×100 mL), dried (MgSO4) and evaporated in vacuo to give an oil. Chromatography (SiO2, eluted with petrol-EtOAc 0-30%) gave the title compound (4.29 g 96%) as an oil. MS: [M+H]+=357.