Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.CO.[Cl-].[NH4+]>O1CCCC1.O>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(OCc2cccs2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(OCc2cccs2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
In addition, to a solution of lithium aluminum hydride (220 mg, 5.80 mmol) in tetrahydrofuran (2.5 mL) was added a solution of the resulting 4-(thiophene-2-ylmethoxy)-benzonitrile (500 mg, 2.32 mmol) in tetrahydrofuran (1 mL) on an ice bath, and the solution was stirred at room temperature for 4 hours. A mixture solvent of methanol and water (9:1) was added to the reaction solution, an aqueous solution of saturated ammonium chloride was further added, the solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, then, the solvent was evaporated to obtain the title compound (415 mg, 82%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(O)(=O)C.CN.[C:19]([BH3-])#[N:20].[Na+]>CO.O1CCCC1>[CH3:19][NH:20][CH2:11][C:6]1[C:5]2[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: [BH3-]C#N
Reactant: Cc1ccc2c(C=O)c[nH]c2c1
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1c[nH]c2cc(C)ccc12
Reaction time: 1 h

Procedure:
To a suspension of 6-methyl-1H-indole-3-carbaldehyde (0.96 g, Lit. 5) in methanol (15 ml) was added at 22° C. acetic acid (1.7 ml) and a solution of methylamine in tetrahydrofurane (2 M, 12.0 ml). After stirring for 1 h, sodium cyanoborohydride (0.76 g) was added in 5 portions and stirring was continued for 2 h. The mixture was evaporated and the residue partitioned between aqueous hydrochloric acid (1 N) and dichloromethane. The pH of the aqueous layer was adjusted to 14 using sodium hydroxide followed by extraction with dichloromethane. The organic layer was dried and evaporated to give crude methyl-(6-methyl-1H-indol-3-ylmethyl)-amine.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.S1C2C(=NC(C(OC)=O)=CC=2)C=[CH:15]1.BrBr.CCOC(C)=O>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([O:13][CH3:15])=[O:12])=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1
Reactant: COC(=O)c1ccc2sccc2n1
Reactant: O=C(O)c1ccc2scc(Br)c2n1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2scc(Br)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21 %

Procedure:
3-Bromo-thieno[3,2-b]pyridine-5-carboxylic acid (Gronowitz, S.; Westerlund, C.; Hornfeldt, A. -B.; Acta Chem Scand. 29, 233, 1975) was esterified to the corresponding methyl ester. To a solution of the resulting methyl thieno[3,2-b]pyridine-5-carboxylate 9.7 g, 50.2 mmol) in CHCl3 at 0° C. was added a solution of bromine (16 g, 100.4 mmol) in CCl4 (150 mL) dropwise. The mixture was warmed to r.t. and stirred for 72 h. EtOAc (750 mL) was added. The mixture was washed with NaHSO3, dried (anhyd. MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel to give 2.84 g (21%) of the title compound and 5.5 g of starting material.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH3:14])[C:11]([O-:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:41][CH2:42][C@@H:43]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH3:14])[C:11]([NH:41][CH2:42][C@@H:43]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CNC(=O)OC(C)(C)C)C(=O)[O-]
Reactant: CC(C)C[C@H](CN)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)C[C@H](CNC(=O)[C@H](C)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
A solution of (2R)-3-(tert-butoxy)carbonylamino-2-methylpropanoate (0.81 g, 4.0 mmol) in THF (20 ml) was cooled under Ar to −15° and successively treated with NMM (0.46 ml, 4.2 mmol), isobutyl chloroformate (0.55 ml, 4.2 mmol) and, after stirring for 5 min, a precooled solution of benzyl (2R)-2-aminomethyl4methylpentanoate toluenesulfonate ((2),1.79 g, 4.4 mmol) and NMM (0.48 ml, 4.4 mmol) in DMF (10 ml). The mixture was allowed to warm to r.t. over a period of 2 h and stirring was continued for further 2 h. The solvent was removed under reduced pressure, the residue dissolved in AcOEt and washed with 10% aq. citric acid (3×), sat. aq. K2CO3 (3×), H2and sat. aq. NaCl soln. The org. phase was dried (MgSO4) and evaporated. Purification by FC (hexane/AcOEt 2:1) yielded The title compound (1.46 g, 87%): White solid.1H-NMR (200 MHz, CDCl3): 0.92 (d, J=5.5, 6H, CH(CH3)2); 1.05 (d, J=6.5, 3H, CHRCH3); 1.23-1.40 (m,1H, CH(CH3)2); 1.44 (s, 9H, C(CH3)3); 1.52-1.77 (m, 2H, CH2CH(CH3)2); 2.30-2.50 (m, 1H, COCHR); 2.68-2.85 (m, 1H, COCHR); 3.08-3.42 (m, 3H, 3 NCH); 3.45-3.60 (m, 1H, NCH); 5.04 (br.,1H, NHCOCHR); 5.16 (s, 2H, CH2Ph); 5.90 (br.,1H, NHCOOtBu); 7.10-7.28 (m, 5H, H-arom.).
Reaction SMILES: [Na+].[I-:2].Cl[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:7]1>CC(=O)CC>[I:2][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:7]1
Reactant: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCI
Yield: 95.8 %

Procedure:
Add NaI (1.10 equiv., 30 mg, 0.20 mmol) to bisazaindole 17 (93 mg, 0.182 mmol) in 2-butanone (10 mL). After 16 h of reflux, the reaction mixture is concentrated under vacuum and the residue is dissolved in EtOAc (100 mL), washed with brine, dried (MgSO4) and concentrated, to give 18 (105 mg, 91%) as an ivory-colored solid: TLC (EtOAc at 40%/heptane) Rf=0.08, m/z obs.=604 (M+1).
Reaction SMILES: Cl[O-].[Na+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])[S:15][CH:16]=2)=[CH:8][CH:7]=1.P([O-])(O)(O)=[O:26].[K+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:26])=[O:24])[S:15][CH:16]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(-c2csc(CCCCCCC=O)n2)cc1
Reactant: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2csc(CCCCCCC(=O)O)n2)cc1
Reaction time: 0.67 h
Yield: 92.4 %

Procedure:
Add 2-methyl-27-butene (7.0 mL) and sodium hypochlorite (2.51 g, 27.75 mmol) to a solution of 7-[4-(4-methoxyphenyl)thiazol-2-yl]heptanal (4.02 g, 13.25 mmol) and potassium dihydrogen phosphate (3.10 g, 22.78 mmol) in tert-butanol (60 mL) and water (12 mL) at room temperature. Stir the mixture for 40 minutes, dilute with ethyl acetate (500 mL) and wash with brine (3×200 mL). Dry the combined organic extracts over sodium sulfate and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1:19), and triturate the residue with hexanes/methylene chloride to afford 7-[4-(4-methoxyphenyl)thiazol-2-yl]heptanoic acid (3.91 g, 88%): APCI MS m/z 320 [C17H21NO3S+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC=O
Yield: 91.7 %

Procedure:
A solution of (3-hydroxypropyl)-carbamic acid tert-butyl ester (0.60 g, 3.4 mmol) in anhydrous CH2Cl2 (17 mL) was treated with Dess-Martin reagent (1.74 g, 4.1 mmol) for 3 hours at room temperature. The reaction mixture was diluted with Et2O (30 mL) and washed with a 20% aqueous solution of sodium thiosulfate (15 mL) followed by a saturated aqueous solution of sodium bicarbonate (15 mL). The combined aqueous phase was then extracted with Et2O (2×35 mL) and re-washed with 20% sodium thiosulfate solution (30 mL), saturated NaHCO3 solution (25 mL), and brine (25 mL). The organic component was then dried (MgSO4), filtered, and concentrated under reduced pressure to provide (3-oxopropyl)-carbamic acid tert-butyl ester as a colorless oil (0.54 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].N#N.ClCCl>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C)cc2)cc1
Temperature: 85 °C

Procedure:
A mixture of 4-methylbenzeneboronic acid (10 g, 73.5 mmol), 4-bromoanisole (25 g, 134 mmol) and 2M aqueous Na2CO3 (75 mL, 150 mmol) in DMF (350 mL) was passed N2 for 15 min. [1,1′Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (200mg, 0.24 mmol) was added and the mixture was heated at 85° C. for 4 h. After cooling to r.t., the mixture was diluted with H2O and extracted with EtOAc. The EtOAc extract was washed with brine (2×), dried (anhydrous MgSO4) and concentrated. The residue was dissolved in small amount of CH2Cl2, filtered through a short pack (˜2.5”) of silica gel in a 600 mL sintered glass funnel and washed the silica with hexanes:EtOAc (4:1). The filtrate was evaporated. The residue was swished with hexanes to give a white flake. The mother liquor was concentrated and swished again with hexanes. After 4 cycles, the combined yield of title product was 10.5 g (72% based on the boronic acid used.).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.C(N(CC)CC)C.Cl.Cl.[N:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:27]CC(N)[CH2:24][CH2:23]1>C(Cl)Cl>[N:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:27][CH2:10][CH:9]([NH:8][C:6]([N:3]2[CH:2]=[CH:1][N:5]=[CH:4]2)=[O:7])[CH2:24][CH2:23]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A suspension comprising CDI (2.29 g, 14 mmol) and triethylamine (3.8 ml, 27 mmol) in dry DCM (20 ml) is treated portionwise over 5 minutes with 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylamine dihydrochloride (prepared using the procedure described in international patent application WO 01/94368) (2.88 g, 13 mmol). The reaction mixture is stirred at room temperature for 4.5 hours to yield the title compound as a 0.43 M solution in DCM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C@@H:13]1[CH2:15][O:14]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:15][C@H:13]([OH:14])[C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1ccc2nccc([C@@H]3CO3)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: COc1ccc2nccc([C@@H](O)CN3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 92.4 %

Procedure:
(R)-2-(6-Methoxyquinolin-4-yl)oxirane (Example 3a) (4.30 g, 21.37 mmol) was dissolved in acetonitrile (30 mL). To the solution was added piperazine-1-carboxylic acid tert-butyl ester (7.17 g, 38.47 mmol) and lithium perchlorate (2.27 g, 106.4 mmol). The resulting slurry was stirred at room temperature for 10 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organic phase dried over magnesium sulfate. Concentration in vacuo afforded a colourless oil which was subjected to purification by column chromatography on silica gel using a dichloromethane/methanol gradient. This provided the desired compound as a colourless oil (7.65 g, 92%).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:21])[N:11]([CH2:19][CH3:20])[C:12](=[O:18])[N:13]([CH2:16][CH3:17])[C:14]=1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22]Br>C(Cl)(Cl)Cl>[C:1]([C:9]1[C:10](=[O:21])[N:11]([CH2:19][CH3:20])[C:12](=[O:18])[N:13]([CH2:16][CH3:17])[C:14]=1[CH2:15][Br:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CCn1c(C)c(C(=O)c2ccccc2)c(=O)n(CC)c1=O
Solvent: ClC(Cl)Cl
Product: CCn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(CC)c1=O
Temperature: 60 °C

Procedure:
5-Benzoyl-1,3-diethyl-6-methylpyrimidine-2,4(1H,3H)-dione (step 2)(800 mg, 2.79 mmol) was dissolved in chloroform (Volume: 60 mL) and bromine (0.288 mL, 5.59 mmol) was added. The mixture was heated at 60° C. for 1 h. A further portion of bromine (0.288 mL, 5.59 mmol) was added. The mixture was heated for 30 mins and further bromine (0.288 mL, 5.59 mmol) was added. The reaction mixture was cooled to RT and washed with aqueous sodium metabisulfite. The organic phase was separated, passed through a hydrophobic frit and evaporated under vacuum. The residue was dissolved in DCM and evaporated onto silica. The silica was deposited onto a 10 g silica cartridge and the system eluted with 20% EtOAc/hexane, 30% EtOAc/hexane, and 40% EtOAc/hexane.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:5][CH:4]=1.[CH2:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:31][CH3:32]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[CH2:13][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:33]([CH2:30][CH2:31][CH3:32])(=[O:35])=[O:34])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(NC(=O)OC(C)(C)C)CC2

Procedure:
tert-Butyl [7-(aminomethyl)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (120 mg, 0.276 mmol, cf. Example 38) was dissolved in dichloromethane (5 mL). 4-Dimethylaminopyridine (35 mg, 0.289 mmol) was added. After stirring at room temperature for 5 min propane-1-sulfonyl chloride (39 mg, 0.031 mmol) was added and stirring was continued over night. The reaction mixture was diluted with dichloromethane and washed successively with 0.5 N hydrochloric acid (2×2 mL) and saturated NaHCO3 (1×2 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The crude product was used for the next step without further purification. Yield: 125 mg (0.231 mmol, 84%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[NH:5][CH:4]=1.[H][H]>CO.CCOC(C)=O.[Pd]>[CH3:1][N:2]([CH3:15])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][CH:4]=1
Reactant: CN(C)c1c[nH]c2ncc([N+](=O)[O-])cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)c1c[nH]c2ncc(N)cc12
Yield: 39.8 %

Procedure:
N,N-Dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-amine (50 mg) was taken up in methanol (3 mL) and EtOAc (3 mL). 10% Pd/C (50 mg) was added, and the mixture was hydrogenated under a balloon of hydrogen for one hour. The mixture was then filtered through GF/F filter paper, and the filtrate was concentrated to a solid. This material was purified by preparative TLC (0.5 mm plate, 10% MeOH/DCM/0.5% NH4OH) to give N3,N3-dimethyl-1H-pyrrolo[2,3-b]pyridine-3,5-diamine (17 mg, 40%). (APCI-pos) M+1=177.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].[OH-].[Na+].[N:22]1([CH2:28][CH2:29]Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1C=CC=CC=1.C(#N)C>[N:22]1([CH2:28][CH2:29][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9]([C:11]2[C:12]3[CH:13]=[CH:14][NH:15][C:16]=3[CH:17]=[CH:18][CH:19]=2)=[O:10])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCCCC1
Reactant: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccccc1OCCN1CCCCC1)c1cccc2[nH]ccc12
Yield: 83.3 %

Procedure:
3 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide in 50 ml of benzene, 25 ml of acetonitrile and 50 ml of a 5N aqueous solution of sodium hydroxide were heated to 60° C. for 3 hours with stirring under an inert atmosphere with 0.4 g of 2-tetrabutylammonium hydrogenosulfate and 2.2 g of 2-piperidino-1-chloroethane. After cooling, decanting, extracting with ethyl acetate and purifying by chromatography over silica (eluent: ethyl acetate-triethylamine, 9-1), 3.6 g of N-[2-[2-(1-piperidinyl)ethoxy]phenyl]-1H-indol-4-carboxamide were obtained.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8]2)[CH2:4][CH2:3]1.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[CH2:19].C([O-])(O)=O.[Na+].O>C(O)C.C(O)(=O)C>[ClH:1].[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:18][CH2:19][N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8]2)[CH2:4][CH2:3]1
Reactant: C=Cc1ccccn1
Reactant: O=C1CC2(CCNCC2)Sc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: O=C1CC2(CCN(CCc3ccccn3)CC2)Sc2ccccc21
Reaction time: 24 h
Yield: 82.7 %

Procedure:
Under N2, a mixture of product from Step D (0.54 g, 0.002 mol), 2-vinylpyridine (0.62 g, 0.0059 mol), NaHCO3 (0.6 g, 0.0071 mol) in absolute ethanol (20 ml) was heated at reflux. After 24 hours, acetic acid (4 drops) was added and refluxing was continued. After 24 hours, H2O (20 ml), and 2-vinylpyridine (2 ml) were added. After another 72 hours at reflux, the reaction was concentrated to dryness. The residue was chromatographed on silica gel (Still column, 50 mm) and the product eluted with 5% CH3OH--CHCl3. The compound was crystallized as the hydrochloride salt from ethanol to yield 0.62 g (80%) of product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:31]([CH3:33])([CH3:32])[CH2:30][CH2:29][C:28](=[O:34])[NH:27][C:26]=2[CH:35]=1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[C:31]([CH3:32])([CH3:33])[CH2:30][CH2:29][C:28](=[O:34])[NH:27][C:26]=3[CH:35]=2)=[N:3][CH:4]=1
Reactant: N#CCCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Product: CC1(C)CCC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4ccccc4OCCC#N)n3)ccc21

Procedure:
Title compound was prepared from 3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-propionitrile and 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in a manner analogous to Example 1221d. Product was isolated as an off-white foam (96 mg, 56%). 95% HPLC purity, LCMS 477.24 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.37 (d, J=8.0 Hz, 1H), 8.25 (s, 1H), 8.07-8.05 (m, 2H), 7.75 (s, 1H), 7.55 (s, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.14-7.08 (m, 2H), 7.01 (t, J=7.7 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 4.24 (t, J=7.9 Hz, 2H), 2.88 (t, J=6.2 Hz, 2H), 2.46 (t, J=6.8 Hz, 2H), 2.12 (t, J=6.6 Hz, 2H), 1.42 (s, 6H).
Reaction SMILES: [C:1](O)(=[O:13])[C@:2]1([CH2:12][CH2:11][C@@H:7]([C:8](O)=[O:9])[C:4]1([CH3:6])[CH3:5])[CH3:3]>C1COCC1.CCOCC>[OH:13][CH2:1][C:2]1([CH3:3])[CH2:12][CH2:11][CH:7]([CH2:8][OH:9])[C:4]1([CH3:6])[CH3:5]
Reactant: CC1(C)[C@H](C(=O)O)CC[C@]1(C)C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(CO)CCC(CO)C1(C)C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of (1S,3R)-camphoric acid (1) (3.0 g, 14.8 mmol) in dry THF (40 mL) and dry Et2O (30 mL) was added LiALH4 (2.0 g, 52.6 mmol) and the reaction mixture was refluxed for 5 hours. The reaction was then quenched by the addition of Na2SO4.10H2O (8.5 g) and the mixture stirred for 0.5 hour. H2O (100 mL) was added and the aqueous layer extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over anhydrous MgSO4 and the solvents concentrated in vacuo to a residue which was purified over silica (n-hexane/EtOAc, 6:4) to afford 2.39 g (95% yield) of the desired intermediate (2) as crystals which were characterized as follows:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])=[CH:4][C:3]=1[F:9]
Reactant: CCCCCCCCCCCCCCCBr
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCOc1ccc(Br)c(F)c1

Procedure:
This was prepared using a similar method to that described for compound 3. Quantities: compound 1 (2.31 g, 12.1 mmol), 1-bromopentadecane (3.97 g, 13.6 mmol), potassium carbonate (2.97 g, 21.5 mmol) and butanone (80 ml).
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:5]=1[CH:6]=NC(C(C)C)C(C)C)([CH3:3])[CH3:2].Cl.C1C[O:27]CC1>>[CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:5]=1[CH:6]=[O:27])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: COc1cc(C=NC(C(C)C)C(C)C)c(C(C)C)cc1OC
Agent: Cl
Product: COc1cc(C=O)c(C(C)C)cc1OC
Yield: 43 %

Procedure:
(2-Isopropyl-4,5-dimethoxy-benzylidene)-(1-isopropyl-2-methyl-propyl)-amine was dissolved in 30 ml of THF. HCl (4.1 mL, 4 M) was added and the mixture was warmed to reflux. After 3 hours the mixture was cooled concentrated in vacuo. 100 mL of H2O was added and the mixture was extracted with ethyl acetate, washed with H2O and then with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give an orange oil. Purification via flash chromatography (85:15 hexane/ethyl acetate) gave 2-isopropyl-4,5-dimethoxy-benzaldehyde (0.331 g, 43%) as a clear oil