Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:30]1[N:29]=[C:28]([C:21]2[C:22]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:19][CH:20]=2)[CH:33]=[CH:32][N:31]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Nc1ccc(Cl)cc1Cl
Product: Clc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)c(Cl)c1
Yield: 48.9 %

Procedure:
Using the procedure of example 1, 2,4-dichloroaniline (131 mg) was reacted with compound 1f (100 mg) to provide compound 36 (47 mg, 49%). 1H NMR (400 MHz, CD3OD) δ 8.69 (d, J=8.0 Hz, 1H), 8.33 (d, J=4.8 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 8.23 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J=5.6 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.18 (dd, J=8.0 Hz, 4.8 Hz, 1H). MS (ESI) m/z: 356 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[BH4-].[Na+].C(Cl)(=O)C.O=C[C@@H]([C@@H]([C@H]([C@@H](CO)O)O)O)O.O=C[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[O:43]=[CH:44][C@H:45]([C@H:47]([C@@H:49]([C@@H:51]([C:53]([OH:55])=[O:54])[OH:52])[OH:50])[OH:48])[OH:46]>Cl.N=C=N.CO>[O:43]=[CH:44][C@@H:45]([C@@H:47]([C@H:49]([C@@H:51]([C:53]([OH:55])=[O:54])[OH:52])[OH:50])[OH:48])[OH:46]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N=C=N
Solvent: CO
Solvent: CC(=O)Cl
Product: O=C[C@H](O)[C@H](O)[C@@H](O)[C@H](O)C(=O)O
Reaction time: 0.05 h

Procedure:
Determination of the carbohydrate constituents of the mucoid antigens was performed by GLC analyses. Material to be analyzed was both the purified mucoid antigen and this same material reduced twice with water soluble carbodiimide and sodium borohydride by the method of Taylor and Conrad, Biochem., 11, 1383-1388 (1972). The use of EDTA in the extraction and purification steps of the preferred method of the invention markedly reduced the viscosity of the purified alginate, eliminating the need to perform a preliminary limited hydrolysis step previously described as necessary by others in order to reduce the exopolysaccharide with the carbodiimide reagent. Both intact and reduced exopolysaccharides were analyzed as the tri-methyl silyl (TMS) derivitized esters following hydrolyses for 24 hr in 12% methanolic HCl, prepared with acetyl chloride and methanol (2 ml acetyl chloride/10 ml methanol). The TMS procedure was chosen since both gulose and mannose in the carbodiimide reduced alginate could be measured, as well as gluluronic and mannuronic acid in the intact alginate. This procedure also allowed for measurement of the amount of reduction by the carbodiimide reagent. GLC was performed on a Packard model 421 using a 4 mm by 6 ft column packed with 3% SE-30 on Gaschrom Q. Nitrogen carrier gas flowed at 33 cc/min. The temperature program was 140° for 3 min followed by a rise of 5° C. per min to 245° C., which was held for 5 min. Injector temperature was 200° C., and the flame ionization detector was at 250° C. Data recording and analyses were performed with a Hewlett Packard model 3388A integrator. Quantitation was performed by comparisons of the areas obtained from analyzed samples with those obtained for authentic standards, except for guluronic acid, which was determined from authentic alginic acid (Sigma Chemical Co., St. Louis, Mo.) after subtraction of the mannuronic acid level.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=[O:15])[C:12](O)=[O:13])=[CH:2]1.OC1C2N=NNC=2C=CC=1.Cl.[CH3:27][NH:28][CH3:29]>O1CCCC1.CN1CCOCC1.[Au].C(Cl)Cl>[CH3:27][N:28]([CH3:29])[C:12](=[O:13])[C:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:15]
Reactant: CNC
Reactant: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Agent: [Au]
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN(C)C(=O)C(=O)Cc1c[nH]c2ccccc12

Procedure:
A solution of 500 mg 3-indolepyruvic acid in 25 ml anhydrous tetrahydrofuran on an ice-salt bath, under argon atmosphere and under stirring was additioned in swift succession with: 400 mg hydroxybenzotriazole (HOBt) and 570 mg 1-(3-dimethylaminopropyl)-3-ethylcarbimdie.HCl (EDC.HCl). After dissolving and still maintaining the ice-salt bath, 240 mg dimethylamine.HCl were added dissolved in 10 ml anhydrous tetrahydrofuran and 325 microliters 4-methylmorpholine (NMM). The yellowish gold solution was maintained under stirring for one night, leaving the bath temperature to rise up to room temperature. The volume was then tripled adding CH2Cl2 and the organic solution was washed in sequence with 5% NaHCO3 (10×25 ml), saturated NaCl solution (3×25 ml), 5% KHSO4 (10×25 ml) and saturated NaCl solution up to neutrality. After standing for one night on anhydrous Na2SO4, this was filtered off, the mixture was purified by flash chromatography (silica gel, eluent CH2Cl2 25/n-propanol 1,5).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[NH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.CS(O)(=O)=O>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCc1cccnc1
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCc3cccnc3)c3ccccc3nc21
Temperature: 90 °C
Yield: 76.7 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]-quinoline (1.0 g, 0.0043 mol), DMSO (1 mL) and 3-aminomethylpyridine (0.97 mL, 0.0093 mol) was heated at 90° C. for 4 hours. The reaction mixture was poured into water and the solid which formed was collected by filtration and recrystallized from ether/CH2Cl2 /hexane to afford the product as the free base. The free base was dissolved in methanol (100 mL) and then was treated with methanesulfonic acid (1 mL). The methanol was evaporated and then the residue was crystallized from 2-propanol/ether. The product was collected by filtration, washed with ether and dried in vacuo to afford 1.0 g of 1-ethyl-N-(3-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine .2CH3SO3H, m.p. 282°-284° C.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][C:7]1(O)[C:12](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][CH2:9][C:8]1=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[C:21]1([CH:20]2[N:3]3[CH2:4][CH2:5][S:1][C:2]3=[N:6][C:7]3[C:12](=[CH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:11][O:10][CH2:9][C:8]2=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC1(NC2=NCCS2)C(=Cc2ccccc2)COCC1=Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C(=C1COCC2=C1N=C1SCCN1C2c1ccccc1)c1ccccc1

Procedure:
To a stirred suspension of 4-[(4,5-dihydro-2-thiazolyl)amino]tetrahydro-3,5-bis(phenylmethylene)-2H-pyran-4-ol (2.5 g, 6.6 mmole) in toluene (100 ml) is added slowly a solution of titanium tetrachloride (0.63 g, 3.3 mmole) in toluene (6.1 ml). The yellow mixture is heated at reflux temperature for 45 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[C:15]=1[C:24]([O:26][CH3:27])=[O:25])(=[O:12])=[O:11])([O-])=O.CO>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[C:15]=1[C:24]([O:26][CH3:27])=[O:25])(=[O:12])=[O:11]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2[N+](=O)[O-])ccc2c1CCCC2
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2N)ccc2c1CCCC2
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A solution of Example 418B (2.0873 g, 5.35 mmol) in 4:1 methanol:ethyl acetate (120 mL) was treated with Raney nickel (4.00 g), pressurized to 60 psi with H2 and shaken for 2 hours. The reaction was then filtered and the filtrate was concentrated to yield the desired product (1.8750 g, 97%). MS (ESI(+)) m/e 361 (M+H)+, 383 (M+Na)+; MS (ESI(−)) m/e 359 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.32 (dd, 1H), 7.23 (td, 1H), 7.02 (d, 1H), 6.80 (m, 2H), 6.52 (td, 1H), 3.74 (s, 3H), 2.65 (m, 2H), 2.53 (m, 2H), 1.65 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.BrCC1CCCCO1>>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: mp 208-209° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ8.58 (d, J=4.8 Hz, 1H), 7.65 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.28-7.15 (m, 4H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 5.21 (d, J=16.0 Hz, 1H), 4.97 (d, J=16.0 Hz, 1H), 4.96 (d, J=8.7 Hz, 1H), 4.68 (d, J=8.7 Hz, 1H), 4.22-4.17 (m, 2H), 4.15-4.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.6, 155.6, 155.3, 149.6, 144.6, 142.2, 138.3, 137.1, 132.2, 128.9, 123.8, 123.5, 122.8, 121.6, 121.1, 111.8, 109.6, 99.4, 80.2, 64.5, 63.9, 58.2, 46.1; MS (ES+) m/z 387.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([SH:13])[CH3:12]>>[Cl:1][C:2]1[CH:9]=[C:8]([S:13][CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCS
Reactant: N#Cc1ccc(F)cc1Cl
Product: CCSc1ccc(C#N)c(Cl)c1

Procedure:
4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with ethanethiol to afford 2-chloro-4-(ethylthio)benzonitrile. 2 g of 2-chloro-4-(ethylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(ethylthio)benzoic acid. 1.5 g of 2-chloro-4-(ethylthio)benzoic acid was reacted via Procedure R to yield 2-chloro-4-(ethylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide. MS (Q1) 435.1 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[N:15](CC3C=CC(C4C=CC=CC=4)=CC=3)[C:14]3[CH:29]=[C:30]([F:44])[C:31]([C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[N:39]([CH3:43])[CH:38]=[CH:37]5)=[C:32]([F:33])[C:13]=3[N:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:45].C1CCC=CC=1>[OH-].[OH-].[Pd+2].CCOC(C)=O.CCO>[CH3:1][O:2][C:3](=[O:46])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[NH:15][C:14]3[CH:29]=[C:30]([F:44])[C:31]([C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[N:39]([CH3:43])[CH:38]=[CH:37]5)=[C:32]([F:33])[C:13]=3[N:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:45]
Reactant: COC(=O)c1cc(Oc2nc3c(F)c(-c4ccc5c(ccn5C)c4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)ccc1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1=CCCC=C1
Product: COC(=O)c1cc(Oc2nc3c(F)c(-c4ccc5c(ccn5C)c4)c(F)cc3[nH]2)ccc1C
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-[1-biphenyl-4-ylmethyl-4,6-difluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzoimidazol-2-yloxy]-2-methyl-benzoic acid methyl ester (900 mg, 1.467 mmol) and Pearlman's catalyst (20% Pd(OH)2 on carbon) (180 mg) in EtOAc-EtOH (2:1, 7 mL) was treated with cyclohexadiene (2351 mg), and the resulting reaction mixture was heated under microwave at 130° C. for 10 min, and then at 130° C. for another 10 min. The cooled reaction mixture was filtered through a Celite pad (washed with 10% MeOH—CH2Cl2), and the filtrate was absorbed onto silica gel and purified by ISCO flash chromatography to give desired product as a white foam.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[I:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(I)cc1
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1nccc(-c2cccnc2Oc2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(2-Chloropyridin-3-yl)-N-methylpyrimidin-2-amine (3.30 g, 15.0 mmol), 4-iodophenol (3.96 g, 18.0 mmol), cesium carbonate (10.6 g, 30.0 mmol), and 15 mL of DMSO were added into a 50-mL round bottom flask. The flask was sealed with a septum and placed in a preheated oil bath at 130° C. After 3 h, the reaction was completed according to TLC and LC-MS analysis. The reaction was cooled to room temperature. Water was added into the reaction mixture until all product precipitated out of the solution. The solid was filtered, ground, and washed with water. The product was collected and dried in a vacuum oven overnight. The product, 4-(2-(4-iodophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine was obtained as a light brown solid. 1H NMR (Varian, 300 MHz, CDCl3): 8.40 (br s, 1H), 8.34 (d, J=4.1 Hz, 1H), 8.19 (dd, J=4.8, 2.2 Hz, 1H), 7.73 (m, 2H), 7.30 (dd, J=7.4, 4.8 Hz, 1H), 7.19 (m, 2H), 7.00 (m, 2H), 2.84 (d, J=4.8 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][O:14][CH3:15]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:13]([O:14][CH3:15])[CH3:12])=[O:10])=[N:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(O)cn1
Agent: Cl
Product: CON(C)C(=O)c1ccc(O)cn1
Yield: 52 %

Procedure:
Following the same procedure as described in example 41, step A, 5-hydroxypicolinic acid (6.2 g, 1.0 eq) was reacted with N,O-dimethylhydroxylamine hydrochloride (5.2 g, 1.2 eq) to get the desired product with column chromatography (4.25 g, 52% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccccc1Br
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In DMF (120 ml) was dissolved 2-bromophenol (12 g). To the mixture was added potassium carbonate (12.5 g) and then was added bromopropane (7.2 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-2-propoxybenzene (10.5 g).
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C>[C:1]([NH:4][C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH:25]=[CH2:24])=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(C)=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C[C@@H](NC(C)=O)C(=O)OC)cc1
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a solution of 51 (989 mg, 4.17 mmol), and anhydrous K2CO3 (1.15 g, 8.34 mmol) in DMF (10 mL) was added allyl bromide (1.01 g, 8.34 mmol) and the resulting mixture was allowed to stir for 16 h under a nitrogen atmosphere. The reaction was quenched with water (30 mL), extracted with ethyl acetate (3×30 mL), and the combined organics were washed with water (5×20 mL) before drying. The solvent was evaporated to yield the title compound (985 mg, 3.56 mmol, 85%) as a pale yellow solid. [α]D25-24.2 (c. 0.1, EtOH). Mp 90° C. 1H NMR (CDCl3, 300 MHz): δ 6.97 (d, J=8.7 Hz, 2H, ArH2′ and ArH6′); 6.80 (d, J=8.7 Hz, 2H, ArH3′ and ArH5′); 6.09 (d, J=7.8 Hz, 1H, NH); 6.01 (m, 1H, H2″); 5.37 (dd, J=1.8, 17.4 Hz, 1H, H3a″); 5.25 (dd, J=1.8, 10.5 Hz, 1H, H3b″); 4.80 (m, 1H, H2); 4.47 (d, J=5.5 Hz, 2H, H1″); 3.68 (s, 3H, OCH3); 3.04 (m, 2H, H3); 1.99 (s, 311, NCOCH3). Mass Spectrum (CI, +ve) m/z 278 (100%) [MH+]. HRMS (EI) calcd for C15H19NO4 277.131408, found 277.130309.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C>>[NH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=2[CH:17]=[CH:18][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: NCCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 34 %

Procedure:
Use a method similar to the Preparation 20, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (600 mg, 1.41 mmol) and tert-butyl N-(3-aminopropyl)-carbamate (1.11 g, 6.34 mmol) to give the title compound (34% overall).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)=[O:7])([O-])=O.[H][H]>[C].[Pt].ClCCl>[NH2:1][C:4]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)=[O:7]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: [Pt]
Solvent: ClCCl
Product: COc1ccc(N)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 28 °C
Reaction time: 16.5 h
Yield: 89.5 %

Procedure:
To a 780 L Hastelloy reactor, compound C (33 kg, 1.0 eq.), 5% platinum carbon (sulfided, 0.33 kg, 0.010 parts) and dichloromethane (578 kg, 17.5 parts) were charged. Agitation was started and reactor contents were adjusted to 22° C. (19-25° C.). The reactor was pressurized with ca. 30 psi hydrogen and the reaction mixture gently heated to 28° C. (25-31° C.). Hydrogenation of the reactor contents was performed under ca. 30 psi at 28° C. (25 to 31° C.; maximum 31° C.) until the reaction was complete by HPLC. After 16.5 hrs, the reaction was deemed complete after confirming the disappearance of starting material (0.472 A %). The contents of the reactor were circulated through a conditioned celite pad (0.2-0.5 kg celite conditioned with 20-55 kg dichloromethane) prepared in a 8″ sparkler filter to remove the platinum catalyst. The reactor and celite bed were rinsed forward with two portions of dichloromethane (83 kg, 2.5 parts each). The filtrate was transferred to and concentrated in a 570 L GLMS reactor under a atmospheric pressure to ca. 132 L (4 parts volume). Ethanol (69 kg, 2.1 parts) was charged and concentration continued under atmospheric pressure to ca. 99 L (3 parts volume). In-process NMR indicated that the dichloromethane content was 39%. Ethanol (69 kg, 2.1 parts) was charged again and concentration continued again to ca. 99 L (3 parts volume). In-process NMR indicated that the dichloromethane content was 5%. The reaction mixture was then adjusted to 3° C. (0 to 6° C.), agitated for ca. 1 hr, and the resulting slurry filtered onto a jacketed pressure nutsche fitted with a filter cloth. The reactor, pump, and lines were rinsed forward with cold [3° C. (0-6° C.)]ethanol (26 kg, 0.8 parts). The wet filter cake (36.6 kg) was dried under vacuum at 40-50° C. with a maximum temperature of water bath (to heat dryer jacket) of 50° C. LOD analysis after 12.5 hrs indicated solvent content was at 0.1%. The dry product (D) was discharged (26.4 kg) in 89.5% yield. HPLC showed 98.4 A % purity, with dechlorinated impurity at 0.083%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1.O.[OH-].[Na+]>O1CCCC1>[CH2:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH:11]1[CH2:10][CH2:9][OH:8]
Reactant: COC(=O)CC1Cc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCC1Cc2ccccc2C1
Yield: 100 %

Procedure:
1.02 g (26.8 mmol) of lithium aluminum hydride was suspended in 100 ml of tetrahydrofuran, to which was added dropwise a solution of 10 ml tetrafuran containing 5.06 g (26.6 mmol) of methyl(indan-2-yl)acetate under ice-cooling. After completion of the addition, stirring was continued for 1 hour, during which 1 ml water, 1 ml of 15% sodium hydroxide and 3 ml water were added dropwise in this order for decomposing the excessive reducing agent. The solid matter was removed by filtration, the filtrate was condensed and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 4.30 g of a colorless oil. Yield: 100%
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH2:3]1.[H-].[Na+].[CH3:18]I.CO>CN(C=O)C>[CH3:1][C:2]1([CH3:15])[N:7]([CH3:18])[CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH2:3]1
Reactant: CC1(C)CN(c2ccncc2N)CCN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(c2ccncc2N)CC1(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To 4-(3,3-dimethylpiperazin-1-yl)pyridin-3-amine (prepared according to methods similar to the one depicted in Preparation N-1) (120 mg, 0.5817 mmol) in DMF (2 mL) at 0° C. was added NaH (20.94 mg, 0.5235 mmol). The reaction mixture was stirred for 10 mins at 0° C. then MeI (276.3 uL, 0.5526 mmol, 2M in TBDME) was added. The reaction mixture was allowed to warm to RT and was stirred for 2 hours at RT. The crude was loaded onto a MeOH pre-washed SCX column, rinsed with MeOH and the product was released with methanolic ammonia. The ammonia extracts were concentrated under reduced pressure to yield 4-(3,3,4-trimethylpiperazin-1-yl)pyridin-3-amine (128 mg, 73%). MS (ES+) 221.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[CH3:24]>>[CH2:23]([N:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)=[CH:11]1)[CH3:24]
Reactant: CC(C)(C)c1cc(C(=O)c2cc[nH]c2)cc(C(C)(C)C)c1O
Reactant: CCBr
Product: CCn1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1

Procedure:
For example, using 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole as compound "E" in this general reaction together with ethyl bromide as "R--X" yields N-ethyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (a compound according to Formula X wherein: m is 0; n is 1; R is ethyl; and X, Y and Z are each H).