Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:10])([CH3:7])([CH3:6])[CH3:5]>N1C=CC=CC=1.[OH-].[K+]>[C:4]([O:8][C:9](=[O:10])[NH:11][C@H:12]([CH2:13][N:2]([CH3:3])[CH3:1])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:7])([CH3:6])[CH3:5]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CN(C)C[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.2 %

Procedure:
Dimethylamine (11.2 g, 249.3 mmol, 30.0 equiv) was added portionwise to a stirred solution of toluene-4-sulfonic acid(S)-2-tert-butoxycarbonylamino-4,4-dimethyl-pentyl ester (3.2 g, 8.31 mmol, 1.0 equiv.) in pyridine (9.6 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for an additional 20 hours at the same temperature. The reaction mixture was diluted with the addition of an aqueous solution of 10% potassium hydroxide (w/v; 30 mL) and was extracted with dichloromethane (3×150 mL). The collected organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude mass. This was purified by purified by silica gel column chromatography (100-200 mesh) using a gradient of 2-5% methanol/dichloromethane to give ((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (1.4 g, 65%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1.CN(C)C=O>[CH:33]1([NH:39][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)NC1CCCCC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
11.15 g (0.05 mol) of N-benzyloxycarbonyl-L-alanine were dissolved in 75 ml of dry tetrahydrofuran and the mixture was cooled to -10° C. 6.35 ml (0.05 mol) of N-ethylmorpholine were added followed by 6.5 ml of isobutyl chloroformate and the solution obtained was stirred at -10° C. for 20 minutes. A solution of 6.05 ml of cyclohexylamine in 75 ml of tetrahydrofuran was then added and the resulting solution was stirred at 0° C. After 30 minutes the mixture solidified and 30 ml of dimethylformamide were added. After stirring for a further 1 hour at 0° C., the solvent was removed by evaporation, water was added and the solid filtered off. The solid was washed with 150 ml of 1-N hydrochloric acid, 150 ml of water, 150 ml of 5% sodium bicarbonate solution and 150 ml of water and then dried in vacuo. Recrystallisation from ethyl acetate yielded 11.7 g (77%) of N-benzyloxycarbonyl-L-alanine cyclohexylamide of melting point 163°-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([Cl:10])[CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([Cl:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc(Br)cc1Cl

Procedure:
To a solution of (4-bromo-2-chlorophenyl)methanol (2.8 g, 12.8 mmol) that was obtained in Example 24 (24e) in dichloromethane (50 ml) was added pyridinium dichromate (7.2 g, 19.2 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, ether (250 ml) was added to the reaction mixture under stirring, and the resulting mixture was filtered with Celite. The filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:20) as the eluent to afford the title compound (2.0 g, yield: 70%) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([N+:18]([O-])=O)[CH:5]=1>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[C:6]([NH2:18])[CH:5]=1
Reactant: COC(=O)c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NCC2CCCCC2)c(N)c1
Reaction time: 4 h

Procedure:
12.00 g 4-(Cyclohexylmethyl-amino)-3-nitro-benzoic acid methyl ester were dissolved in 75 ml ethyl acetate and 75 ml methanol, 0.45 g of palladium on carbon (10%) were added and the mixture was hydrogenated at 5 bar for 4 h. The catalyst was removed by filtration over celite, the filtrate was concentrated and after precipitation with cyclohexane 12.00 g (93%) of 3-Amino-4-(cyclohexylmethyl-amino)-benzoic acid methyl ester were obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[CH:21]=O)[CH:14]=[CH:13][CH:12]=1>>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH:7][CH2:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[N:11]=[CH:12][CH:13]=[CH:14]2)[CH3:6])[CH3:2]
Reactant: O=Cc1cccc2cccnc12
Reactant: CCOC(OCC)[C@H](C)N
Product: CCOC(OCC)[C@H](C)NCc1cccc2cccnc12
Yield: 90 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2, (S)-1,1-diethoxypropan-2-amine (Compound XIX-1) 442 mg (3.00 mmol) was reacted with 8-Quinolinecarbaldehyde 393 mg (2.50 mmol) to obtain the title compound 649 mg (91%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)#[N:18].[OH-].[Na+].C(O)C>O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(SCc2ccc(C#N)cc2)cc(C(C)(C)C)c1O

Procedure:
A solution of 2.00 g (8.39 mmole) of the known compound 2,6-di-t-butyl-4-mercaptophenol, 1.65 g (8.39 mmole) of p-cyanobenzyl bromide, 5 ml of 1.68N sodium hydroxide and 75 ml of ethanol was heated at reflux for 48 hours. The reaction mixture was poured into water, and was then extracted with diethyl ether. The ether extract was washed with water, dried with magnesium sulfate and evaporated to give the crude product. This material was purified by silica gel chromatography, eluting with 1% ethyl acetate in hexane, followed by recrystallizations from a mixture of ethyl acetate and hexane and from ethanol to give 1.1 g of 2,6-di-t-butyl-4-[(4-cyanophenyl)methylthio]phenol as white needles, m.p. 143°-145° C. Analysis: Calculated for C22H27NOS: %C, 74.7; %H, 7 7; %N, 4.0; Found: %C, 75.1; %H, 8.1; %N, 4.1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 120 °C

Procedure:
2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole (11.93 g, 1.0 eq), sodium azide (3 eq), and ammonium chloride (3 eq) were mixed and stirred in DMF (150 mL) in a round bottom connected to a reflux condenser under N2. An oil bath with a temperature controller was then used to heat the reaction at 100° C. for 2 days, after which the temperature was raised to 120° C., for 6 days. The reation was cooled and 3 more equivalents of ammounium chloride and sodium azide were added. The reaction was again heated for 5 more days at 120° C. The reaction was cooled, the inorganic salts filtered, and the filtrate solvent removed in vacuo. Water (200 mL) and ethyl acetate (200 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with ehtyl acetate (2×200 mL), the organic layers were collected, dried. (MgSO4) and the solvent removed in vacuo, to yield a dark yellow oil. The product was purified by flash chromatography in 100% ethyl acetate to 100% ethanol over silica gel to yield 5.60 g of a light yellow solid. Recrystallization from acetonitrile yielded 4.36 g of light yellow crystals which still melted broadly. The crystals were taken up in 100 mL of hot acetonitrile. The solid that did not dissolve was filtered off to yield 1.04 g of product as a light yellow solid; m.p. 183.5°-184.5°. Upon cooling, the mother liquor yielded an additional 1.03 g of product as a light yellow solid; m.p. 179.0°-180.0°. NMR (200 MHz, DMSO-d6) δ 7.75-7.48 (m, 4H); 7.07 (d, 2H, J=9 Hz); 7.04 (d, 2H, J=9 Hz); 5.24 (s, 2H); 5.24 (bs, 1H); 4.34 (s, 2H); 2.48 (t, 2H, J=7 Hz); 1.48 (t of t, 2H, J=7,7Hz); 1.27 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz). Anal. Calcd. for C22H23ClN6O: C, 62.48; H, 5.48; Cl, 8.38. Found for the solids which did not dissolve in 100 mL of acetonitrile: C, 62.73; H, 5.50; Cl, 8.26. Found for the solids obtained from the mother liquor: C, 62.40; H, 5.23; Cl, 8.35.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: CCOC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(CCC(=O)OCC)cc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Allyl bromide (2.30 g) was added to a stirred suspension of ethyl 3-(4-hydroxyphenyl)propionate (3.49 g) and anhydrous potassium carbonate (2.76 g) in butan-2-one (30 ml). The reaction mixture was heated at reflux for 18 hours. The reaction mixture was allowed to cool to ambient temperature and the mixture was filtered. The filtrate was evaporated to give an oil which was purified by column chromatography on silica gel (Merck.Art. No. 9385) using a 4:1 (v/v) mixture of n-hexane and ethyl acetate as eluent to give ethyl 3-(4-allyloxyphenyl)propionate (4.09 g) as a colourless oil; NMR (CDCl3): 1.22 (3H, t), 2.48 (2H, t), 2.88 (2H, t), 4.13 (2H, q), 4.51 (2H, m), 5.25-5.42 (2H, m), 5.95-6.15 (1H, m), 6.83 (2H, d) and 7.03 (2H, d); m/z 235 (M+H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:10]([N:27]2[CH2:31][CH2:30][CH:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28]2)=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:13][N:14]=1>C(Cl)Cl>[NH2:32][CH:29]1[CH2:30][CH2:31][N:27]([C:10]2[C:9]([NH2:8])=[N:14][CH:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH:24]([CH3:25])[CH3:26])(=[O:23])=[O:22])=[CH:19][CH:20]=3)[N:11]=2)[CH2:28]1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(N3CCC(NC(=O)OC(C)(C)C)C3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(N3CCC(N)C3)n2)cc1
Reaction time: 17 h
Yield: 47.7 %

Procedure:
TFA (200 μL, 2.596 mmol) was added to a stirred solution of tert-butyl 1-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)pyrrolidin-3-ylcarbamate (46 mg, 0.09966 mmol) in DCM (5 mL) at ambient temperature. The reaction was stirred at this temperature for 17 hours. A further portion of TFA (200 μL, 2.596 mmol) was added and the reaction stirred at ambient temperature for a further 2 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM/ether (×3). The residue was passed through a 2 g SCX-2 cartridge and washed with MeOH. The product was eluted by washing the cartridge with 2M NH3 in MeOH. The residue was purified by column chromatography (ISCO Companion™, 12 g column, elueting with 0 to 10% MeOH+10% NH4OH/DCM) to give the title product as a yellow solid (17.2 mg, 45% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.17 (d, 6H), 1.61-1.70 (m, 1H), 1.97-2.06 (m, 1H), 3.01 (br s, 2H), 3.22 (dd, 1H), 3.38 (quin, 1H), 3.48-3.57 (m, 2H), 3.65-3.74 (m, 2H), 6.12 (br s, 2H), 7.84 (d, 2H), 8.13 (s, 1H) and 8.17 (d, 2H) ppm; (ES+) 362.3.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[N:9]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1.CI>C1COCC1>[CH3:1][C:11]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][N:9]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:10]1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -50 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a cold (−78° C.) solution of lithium diisopropylamide (LDA) (23.3 mmol) in THF (10 mL) under an argon atmosphere was added dropwise a solution of 1-tert-butyl 3-ethyl 1,3-piperidinedicarboxylate (3.0 g, 11.6 mmol) in THF (5 mL), then stirred at −50° C. for 2 hrs. To the resulting mixture was added a solution of MeI (1.98 g, 14 mmol) in THF at −50° C. The reaction mixture was allowed to warm to room temperature, and quenched with saturated aqueous NH4Cl solution. The mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate, 9:1) to give 1-tert-butyl 3-ethyl 3-methyl-1,3-piperidinedicarboxylate as a pale yellow oil (2.27 g, yield; 72%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].Br[C:25]1[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:27]([F:40])[CH:26]=1>>[CH2:1]([N:3]([C:25]1[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[C:27]([F:40])[CH:26]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: CCN(c1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Yield: 23.7 %

Procedure:
Synthesized from ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (200 mg) and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine (238 mg) according to an analogous synthetic method to Example 116, the title compound (81 mg) was obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][CH2:13][C@H:14]([C@H:16]1[O:20][C:19](=[O:21])[C@H:18]([CH:22]([CH3:24])[CH3:23])[CH2:17]1)Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN1C(=O)N(C)CCC1>[N:1]([C@H:14]([C@H:16]1[O:20][C:19](=[O:21])[C@H:18]([CH:22]([CH3:24])[CH3:23])[CH2:17]1)[CH2:13][O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](Br)COCc2ccccc2)OC1=O
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: CC(C)[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Temperature: 40 °C
Reaction time: 72 h
Yield: 51.4 %

Procedure:
5.10 g of sodium azide (78.5 mmol) was added to a solution of 22.33 g of (3S,5S)-5-[(1R)-2-benzyloxy-1-bromoethyl]-3-isopropyldihydrofuran-2-one obtained in Example (1d) (65.4 mmol) in N,N′-dimethylpropyleneurea (130 ml) at room temperature, and the mixture was stirred at 40° C. for three days. The reaction mixture was cooled and then poured into ice water, followed by extraction with diethyl ether. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=6/1) to obtain 10.19 g of the title compound (yield: 51%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[F:38][C:39]([F:49])([F:48])[C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43]>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:43][CH2:42][C:41]4[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=4[C:39]([F:48])([F:49])[F:38])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCc1ccccc1C(F)(F)F
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccccc4C(F)(F)F)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2-trifluoromethylbenzylamine, m.p. 165-167° C. MS [(+)ESI, m/z]: 610 [M+H]+ Anal. Calcd for C36H30F3N3O3: C, 70.93; H, 4.96; N, 6.89. Found: C, 70.70; H, 4.89; N, 6.81.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[C:16]([CH3:18])[S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][C:16]([CH3:18])=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:31]1[CH:32]=[CH:33][C:28]([CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: COc1ccc2[nH]c(=O)c3sc(C)cc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sc(C)cc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 57.3 %

Procedure:
Following General Procedure B A, 9-bromo-8-methoxy-2-methylthieno[2,3-c]quinolin-4(5H)-one (100 mg, 0.31 mmol) was reacted with 4-[(tert-butoxycarbonylamino)methyl]phenylboronic acid (120 mg, 0.40 mmol) to afford desired product (80 mg, 55%) as a brown solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][NH:43]C(=O)OC(C)(C)C)[CH2:38][CH2:37]2)=[CH:4][N:3]=1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][N:36]2[CH2:37][CH2:38][CH:39]([CH2:42][NH2:43])[CH2:40][CH2:41]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CCN4CCC(CNC(=O)OC(C)(C)C)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1cc(-c2csc3c(/C=C/CCN4CCC(CN)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 8 h
Yield: 30 %

Procedure:
Tert-butyl (1-{(3E)-4-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridin-7-yl]but-3-enyl}piperidin-4-yl)methylcarbamate (0.08 g, 0.112 mmol) was reacted according to General Procedure H. Dichloromethane and MP-carbonate resin were added and shaken overnight. The resin was filtered and the solvent evaporated under reduced pressure to give 0.02 g (29%) of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 8.01-7.99 (d, 1H), 7.92 (s, 1H), 7.71-7.69 (d, 1H), 7.60-7.57 (m, 2H), 7.35-7.31 (m, 2H), 7.19 (m, 1H), 7.15 (m, 1H), 7.13-7.07 (m, 1H), 6.59-6.55 (d, 1H), 6.27-6.23 (m, 1H), 5.58 (brs, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 2.94-2.91 (m, 3H), 2.44 (m, 6H), 1.92-1.87 (t, 2H), 1.69-1.66 (d, 1H), 1.23 (m, 1H), 1.16-1.11 (m, 2H); LCMS (conditions a) Rt 2.37 min (100%), M+ 595.4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17]>>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH3:17]
Reactant: CCOCCCCCCCl
Reactant: O=C1CCNCC1
Product: CCOCCCCCCN1CCC(=O)CC1

Procedure:
1-(6-Ethoxyhexyl)4-piperidone is prepared from 4-piperidone and 1-chloro-6-ethoxyhexane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-].[Na+].B(F)(F)F.CCOCC>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1ccc(Cl)nc1Cl
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 2,6-dichloronicotinic acid (1 g, 5.2 mmol) in THF (10 mL) was added NaBH4 (591 mg, 15.6 mmol) at 0° C. The mixture was stirred for 30 min and then BF3.OEt2 (2.2 g, 15.6 mmol) was added drop wise at 0° C. After addition was complete, the mixture was stirred at room temperature for 10 hr, until the reaction was completed. The reaction mixture was quenched by the addition of saturated NH4Cl solution (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the desired product as a white solid which was used in next step without further purification. (820 mg, Yield 80%).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20](SC)[N:19]=3)=[CH:16][C:15]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:30][CH2:29]3)=[CH:14][N:13]=2)=[CH:7][CH:6]=1.CC(O)C>>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:2][CH3:1])[N:19]=3)=[CH:16][C:15]([CH2:27][N:28]3[CH2:29][CH2:30][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:32][CH2:33]3)=[CH:14][N:13]=2)=[CH:7][CH:6]=1
Reactant: CN
Reactant: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(SC)n2)cn1
Solvent: CC(C)O
Product: CNc1nc(C)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2Nc2ccc(OC)nc2)n1
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Methylamine was bubbled through a mixture of N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amine (33 mg, 0.064 mmol) in IPA (1.50 mL, 19.47 mmol) for 15 min and then allowed to stand overnight. The resulting precipitate was collected by filtration and washed with a minimal amount of IPA to give 4-(2-(6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,6-dimethyl-1,3,5-triazin-2-amine (17.1 mg, 1.761 mmol, 54.7% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) mixture of rotamers δ 11.26-12.03 (m, 1H); 8.73 (d, J=13.69 Hz, 1H); 8.38-8.63 (m, 1H); 7.96-8.38 (m, 3H); 6.83 (d, J=8.41 Hz, 1H); 3.84 (br. s., 3H); 3.50 (d, J=12.72 Hz, 2H); 3.11 (br. s., 4H); 2.90-3.03 (m, 3H); 2.86 (br. s., 3H); 2.47-2.50 (m, 4H); 2.44 (br. s., 3H). m/z (ESI, +ve ion) 500.1 (M+H)+.