Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][CH3:28])=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>CN(C=O)C>[C:36]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][CH3:28])=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1)(=[O:38])[CH3:37]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4N)sc3c2)ccn1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4NC(C)=O)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.5 %

Procedure:
To the solution of 4-(2-((1R,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (9 mg, 22 μmole) and triethylamine (11 μL, 80 μmole) in 300 μL of DMF was added acetic anhydride (5 μL, 50 μmole). The reaction solution was stirred at room temperature for 1.5 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give 4-(2-((1R,2R)-2-acetamidocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (5.1 mg, 12 μmole) as white powder. ES/MS m/z 440.2 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][N+:25]=2[O-])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1>C(O)C.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[OH:1][CH:2]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][N:25]=2)(=[O:17])=[O:18])=[CH:12][CH:11]=1)[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CC(C)CN(c1ccc(C(C)C)c[n+]1[O-])S(=O)(=O)c1ccc(C(O)CN2CCOCC2)cc1
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: CCO
Product: CC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(C(O)CN2CCOCC2)cc1
Temperature: 150 °C

Procedure:
To a solution of 2-(4-(1-hydroxy-2-morpholinoethyl)-N-isobutylphenylsulfonamido)-5-isopropylpyridine 1-oxide (130 mg, 0.272 mmol) in ethanol (1 mL) at 20° C. was added molybdenum hexacarbonyl (71.9 mg, 0.272 mmol). The reaction vessel was sealed and heated by microwaves to 150° C. for 1 hour. After cooling, the reaction was filtered and evaporated in vacuo to give the crude product. The crude was purified by mass directed autoprep (ammonium carbonate modifier) but gave impure product. The sample was repurified by mass directed autoprep (formic acid modifier) to give the title product, 34.1 mg. LCMS (2 min, formic) Rt 0.85 min, m/z (ES+) 462 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:12]([C:17]1[CH:18]=[N:19][C:20](Cl)=[N:21][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH3:16]>>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[N:19]=[CH:18][C:17]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:22][N:21]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCCCCc1cnc(Cl)nc1
Product: CCCCCc1cnc(-c2cc(F)cc(F)c2)nc1

Procedure:
80 mmol of 3,5-difluorophenylboronic acid are coupled to 80 mmol of 5-pentyl-2-chloropyrimidine analogously to Example IB
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Cl:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[C:13]([Cl:18])[CH:12]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc(Br)cc2Cl)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A solution of 50 mg (0.40 mmol) of 4-fluorobenzaldehyde and 83.6 mg (0.40 mmol) of 4-bromo-2-chlorophenol in 2 mL DMSO was combined with 80 mg (0.58 mmol) of potassium carbonate and stirred overnight at 120° C. The reaction mixture was filtered through Alox B, washed with dichloromethane and evaporated down. The residue was purified by chromatography (reversed phase).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([CH3:28])=[CH:25][CH:26]=3)[N:21]=[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[OH:35])[N:19]=2)[CH2:13]1)C1C=CC=CC=1.N#N>[Pd].CCO.CCOC(C)=O>[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([CH3:28])=[CH:25][CH:26]=3)[N:21]=[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[OH:35])[N:19]=2)[CH2:13]1
Reactant: Cc1ccc2c(N3CCCC(CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc2c(N3CCCC(CN)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of benzyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (1.75 g, 3.63 mmol) and EtOH/EtOAc (50 mL/20 mL) was heated to obtain a homogeneous solution. After cooling to room temperature, Pd/C (175 mg, 10% wt Pd on carbon) was added and the flask was sealed with a septum. The same flask was 3 times charged with N2 and evacuated under vacuum. The mixture was then stirred under an H2 atmosphere at ambient pressure for 1 h. The product was collected by filtration through a plug of Celite, eluting with MeOH. The filtrate was concentrated to a yellow solid (1.26 g) to give 2-(4-(3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol. LC/MS: m/z 349.3 (M+H)+ at 1.80 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][O:12][CH2:11][C@@H:10]1[N:14]1[C:18]([C:19](OCC)=[O:20])=[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]([I:29])=[N:15]1)=O)(C)(C)C.Cl>O1CCOCC1>[I:29][C:16]1[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]2[C:19](=[O:20])[NH:8][C@@H:9]3[CH2:13][O:12][CH2:11][C@@H:10]3[N:14]2[N:15]=1
Reactant: CCOC(=O)c1c(I)nn([C@H]2COC[C@H]2NC(=O)OC(C)(C)C)c1C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(I)nn2c1C(=O)N[C@@H]1COC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
To an ice cold solution of Intermediate 352A (6.0 g, 11.5 mmol) in dioxane (20 mL) was added a 4 M solution of HCl in dioxane (100 mL, 11.47 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated; the pH of the residue was adjusted to 8 with a 10% aqueous solution of NaHCO3 and the mixture was stirred at RT for 30 min. then was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water, dried over Na2SO4, concentrated and kept under vacuum at 60° C. for 6 h to obtain Intermediate 352B as an off-white solid (2.1 g, 48%). MS(ES): −m/z=378 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (d, J=3.5 Hz, 1H), 5.11-5.04 (m, 1H), 4.45 (dq, J=4.0, 6.5 Hz, 1H), 4.31-4.12 (m, 4H), 4.04-3.94 (m, 1H), 3.57 (dd, J=6.0, 9.0 Hz, 1H), 1.32-1.22 (m, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[NH:9][C:8]1=[O:18])(O)=[O:2].N1C2C(=CC=CC=2)C(=O)NC1=O.BrCC1C=CC=CC=1C(OC)=O.COC(C1C=C(C=CC=1)CN1C2C(=CC=CC=2)C(=O)NC1=O)=O.[N:70]1([C:76]2[N:81]=[CH:80][CH:79]=[CH:78][N:77]=2)[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1>>[N:77]1[CH:78]=[CH:79][CH:80]=[N:81][C:76]=1[N:70]1[CH2:75][CH2:74][N:73]([C:1]([C:4]2[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=2[CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][C:8]2=[O:18])=[O:2])[CH2:72][CH2:71]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)c1ccccc1Cn1c(=O)[nH]c(=O)c2ccccc21
Agent: COC(=O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Agent: COC(=O)c1ccccc1CBr
Agent: O=c1[nH]c(=O)c2ccccc2[nH]1
Product: O=C(c1ccccc1Cn1c(=O)[nH]c(=O)c2ccccc21)N1CCN(c2ncccn2)CC1

Procedure:
The title compound was prepared from 1-(2-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (prepared from quinazoline-2,4(1H,3H)-dione and methyl 2-(bromomethyl)benzoate using a procedure similar to those used for compounds of Example 1 and 2), and 2-(piperazin-1-yl)pyrimidine using a procedure similar to that described for the synthesis of compound of Example 3. 1H NMR (DMSO-d6): 11.76 (s, 1H), 8.40 (d, J=4.8 Hz, 2H), 8.03-8.00 (m, 1H), 7.70-7.50 (m, 1H), 7.35-7.00 (m, 6H), 6.68 (t, J=4.8 Hz, 1H), 5.25 (s, 2H), 4.10-3.60 (m, 8H). MS: m/z 443.2 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].O1CCOC[CH2:12]1.CO>Cl>[CH3:12][O:9][C:8](=[O:10])[C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[NH:2][CH3:1]
Reactant: CN[C@@H](CC(C)C)C(=O)O
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: CN[C@@H](CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
N-methyl-L-leucine (1.3 g, 8.95 mmol) was dissolved in 4M HCl, 1,4-dioxane (10 mL) and methanol (10 mL). The solution was stirred overnight at room temperature, then concentrated to afford the title compound as a white solid (100%). MS (ESI): 160.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([N:14]1[CH2:15][CH2:16][C:8]2[C:9](=[N:10][C:11]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C:7]=2[CH3:17])[CH2:12][CH2:13]1)=[O:20])[CH3:23]
Reactant: Cc1c2c(nc3c(Cl)cccc13)CCNCC2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCc2nc3c(Cl)cccc3c(C)c2CC1
Yield: 70 %

Procedure:
7-Chloro-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared from 7-chloro-1,2,4,5-tetrahydro-11methyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]=2[N+:20]([O-:22])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[N+:20]([O-:22])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(OCC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 21-2 (1.38 g, 4.50 mmol) in THF (22.5 ml) cooled in an ice-bath was added 1N lithium hydroxide solution (22.5 ml). The resulting solution was stirred 18 h while warming to ambient temperature. The solution was partially evaporated at reduced pressure, and the remaining aqueous solution was washed with ethyl acetate (20 ml). The aqueous layer was cooled in an ice-bath, stirred rapidly, and concentrated hydrochloric acid (2 ml) was added dropwise, resulting in formation of a precipitate. The mixture was stirred 1 h, the precipitate was collected and dried in vacuo to give product 21-3 as a white solid, mp: 200°-202° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([CH3:17])=[CH:19][CH:20]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: C=Cc1ccc(C)cc1
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3cc(C)ccc3n2CCc2ccc(C)cc2)C1
Yield: 9.8 %

Procedure:
The title compound was prepared according to General Method 2. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (100 mg, 0.4 mmol), 4-methylstyrene (1 mL, 7.6 mmol) and NaH (100 mg, 60% dispersion in oil, 2.5 mmol) in DMF (2 ml) at 180° C. for 24 h to obtain 13 mg of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:2][C:1]1([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[O:12][CH2:11][CH2:10][O:3]1
Reactant: CC(=O)c1cccnc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2cccnc2)OCCO1

Procedure:
3-Acetylpyridine (10 g), ethylene glycol (50 ml) and p-toluenesulfonic acid (0.5 g) were dissolved in toluene and the solution was refluxed at 150° C. for 1 day with the by-product water being constantly removed. After cooling, saturated aqueous sodium hydrogen carbonate and toluene were added and the mixture was stirred and allowed to stand. The aqueous layer was separated and extracted with 2 portions of toluene. The toluene layers were combined, washed sequentially with saturated aqueous sodium hydrogen carbonate, water and aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give 2-methyl-2-(pyridin-3-yl)-1,3-dioxolane (13.6 g).
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:26][CH2:27][CH:28]3[CH2:30][CH2:29]3)=[O:25])=[CH:20][CH:19]=2)[CH:17]=1)=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O>[CH:28]1([CH2:27][NH:26][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C:16]3[CH:17]=[C:12]([C:10]([NH:9][NH2:8])=[O:11])[CH:13]=[CH:14][C:15]=3[CH3:31])=[CH:23][CH:22]=2)=[O:25])[CH2:30][CH2:29]1
Reactant: Cc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NN)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.3 %

Procedure:
5′-[2-t-Butoxycarbonyl(hydrazinocarbonyl)]-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (450 mg, 1.06 mmol) was dissolved in trifluoroacetic acid (4 ml) and stirred at room temperature for 3.5 h. The trifluoroacetic acid was evaporated under vacuum and the residue was partitioned between DCM and aqueous sodium bicarbonate. The organic phase and any precipitate produced were separated, washed with brine and concentrated under vacuum to give N-(cyclopropylmethyl)-5′-(hydrazinocarbonyl)-2′-methyl-1,1′-biphenyl-4-carboxamide as a white solid (210 mg, 61%).
Reaction SMILES: [OH:1][CH:2]=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:15][CH3:16])[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]1=[O:17].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH2:19]1[O:20][CH:2]([CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[C:6]([O:15][CH3:16])[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=3)[C:4]2=[O:17])[O:1][CH2:18]1
Reactant: OCCO
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=CO)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc2c(c(OC)c1)C(=O)C(C1OCCO1)CC2

Procedure:
A solution containing 5.73 g. of 2-hydroxymethylene-6,8-dimethoxy-1-tetralone, 2.23 g. of ethylene glycol and 100 mg. of p-toluenesulfonic acid in 25 ml. of benzene was heated at reflux two hours under a Dean-Stark water separator. The mixture was filtered, the filtrate was washed with saturated aqueous solutions of sodium bicarbonate and sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo to give 1,2,3,4-tetrahydro-6,8-dimethoxy-1-oxo-2-naphthaldehyde ethylene acetal which was converted directly to 1,2,3,4-tetrahydro-1-hydroxy-6,8-dimethoxy-2-naphthaldehyde ethylene acetal as described hereinabove in Example 155.
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][C:7]([Cl:11])=[C:6]([Cl:12])[C:5]=1[CH2:13]C(OC(C)(C)C)=O)([O-:3])=[O:2].[NH3:21]>COCCO.O.C(OCC)(=O)C>[NH2:21][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH3:13])[C:6]([Cl:12])=[C:7]([Cl:11])[CH:8]=1
Reactant: CC(C)(C)OC(=O)Cc1c(Cl)c(Cl)cc(Cl)c1[N+](=O)[O-]
Reactant: N
Solvent: COCCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(Cl)c(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
A mixture of t-butyl (2-nitro-3,5,6-trichlorophenyl)acetate (123 g, 0.361 mol) and saturated aqueous ammonia (300 mL) in 2-methoxy ethanol (360 mL) was heated in an autoclave at 150° C. for 72 hours. The resulting viscous, black mixture was diluted with water (1 L) and ethyl acetate (1 L) and filtered through Arbocel filter aid. The dark red filtrate was separated, and the aqueous layer extracted with ethyl acetate (2×1 L). The combined organic solutions were washed with brine (1 L), dried (MgSO4) and evaporated onto silica gel (70-200μ, 200 g). The silica gel was applied to the top of a chromatography column containing silica gel (40-60 μ, 800 g). Elution with hexane/ethyl acetate (98:2-92:8) gave 3-amino-5,6-dichloro-2-nitrotoluene (EP-A-0385850) as a bright orange solid (39.7 g), which was contaminated with 5-amino-3,6-dichloro-2-nitrotoluene (14%). This mixture was carried onto the next step without further purification. 1H NMR (300 MD, CDCl3) 2.48 (3H, s), 4.80 (2H, s), 6.82 (1H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[S:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.FC(F)(F)C(O)=O>[N+](C)([O-])=O>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)c1cccs1
Reactant: c1ccsc1
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: O=C(c1cccs1)c1cccs1
Reaction time: 14 h
Yield: 41.6 %

Procedure:
To a mixture of 12.7 g (0.099 mol) of 2-thienylcarboxylic acid, 8.33 g (0.099 mol) of thiophene, and 34.9 mL of Ambedyst-15 in 250 mL of nitromethane was added 34.9 mL (0.247 mol) of trifluoroacetic acid at room temperature and stirred for 14 h. The reaction mixture was filtered, the filtrate was concentrated in vacuo, and a green oil residue was chromatographed on silica (hexane/methylene chloride 1:1) to afford 8 g (41.6%) of di-(2-thienyl)ketone, as white needles.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH:13]([CH2:20][CH:21]=O)[C:14]2=O>C(Cl)Cl>[Cl:8][C:9]1[C:10]2[CH2:11][CH2:12][C:13]3[CH:20]=[CH:21][N:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:14]=3[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=CCC1CCc2c(Cl)cccc2C1=O
Reactant: CC(=O)NCCN
Solvent: ClCCl
Product: CC(=O)NCCn1ccc2c1-c1cccc(Cl)c1CC2
Yield: 73.6 %

Procedure:
N-Acetylethylenediamine (15.5 g) was dissolved in 300 ml of methylene chloride under argon, treated in succession with 260 g of molecular sieve 4 Å and a solution of 30.8 g of 5-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde in 150 ml of methylene chloride and refluxed for 23 hours while stirring. The reaction mixture was cooled, filtered over a Celite® pad and the filtrate was freed from solvent. The crude product, 37.5 g of brown, amorphous material, was dissolved in a 6-fold amount of hot ethyl acetate and, after the addition of an 8-fold amount of hexane boiled briefly. There were obtained 29.4 g (74%) of N-[2-(6-chloro-4,5-dihydro-1H-benz[g]indol-1-yl)-ethyl]acetamide; m.pt.: 124°-126° C.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][C:8]1[NH:9][C:10](=[O:18])[C:11]2[CH2:17][O:16][CH2:15][CH2:14][C:12]=2[N:13]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].[F:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:6]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:7][C:8]3[NH:9][C:10](=[O:18])[C:11]4[CH2:17][O:16][CH2:15][CH2:14][C:12]=4[N:13]=3)=[O:34])[CH2:30][CH2:31]2)=[O:25])=[CH:36][CH:37]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CC(C)(C)CNCc1nc2c(c(=O)[nH]1)COCC2
Product: CC(C)(C)CN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 17 %

Procedure:
The title compound (17 mg) was prepared following the general procedure of Example 1 from 2-((neopentylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (50 mg, 0.20 mmol) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (62 mg, 0.20 mmol). 1H NMR (400 MHz, CDC3) δ 7.98 (dd, J=9.0, 5.5 Hz, 2H), 7.07-7.21 (m, 2H), 4.61 (s, 2H), 4.49 (br. s., 2H), 3.86-4.05 (m, 2H), 3.30-3.50 (m, 3H), 3.13-3.29 (m, 2H), 2.90-3.13 (m, 2H), 2.52-2.76 (m, 4H), 2.01-2.27 (m, 3H), 1.88 (d, J=3.0 Hz, 1H), 1.02 (s, 3H), 0.96 (s, 7H). HRMS calculated for C27H35FN4O4 499.2721. found (ESI, [M+H]+), 499.2738. MS m/z 499.3 (M+1), retention time=3.32 min.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[C:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: CNC
Reactant: CCc1cc(-c2ccc(C(=O)O)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(=O)N(C)C)s2)c(C)[nH]c1=O
Yield: 77 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-carboxylic acid and dimethylamine to afford the title compound (77% yield). LC/MS: RT 2.44 min; m/e 291 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[CH:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[NH:8][CH2:7][CH2:6]2.[CH2:25]=O.[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:15])[C:12]=1[O:13][CH3:14])[CH:9]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[N:8]([CH3:25])[CH2:7][CH2:6]2
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(O)c32)cc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3O)CCN2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
6,7-Dimethoxy-1-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-8-ol (2.55 g, 7.74 mmol) obtained in Example 1-2 was dissolved in 100 ml of chloroform-methanol (1:1), 35% formalin (3.6 ml, 45.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. Sodium borohydride (3.40 g, 89.8 mmol) was added under ice cooling and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, 200 ml of water was added to the resultantresidue, and the mixture was neutralized with 1N hydrochloric acid and thenextracted with chloroform (100 ml×3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol) to give 2.09 g (yield: 79%) of the captioned compound as pale yellow powder. Melting point: 112°-114° C. FAB-MS (m/z, (C20H25NO4 +H)+ ): 344 1H-NMR (300MHz, CDCl3, δ ppm): 2.35 (3H, s), 2.35-2.45 (1H, m), 2.73-2.87 (2H, m), 2.98 (1H, dd, J=3.2Hz, 14.2Hz), 3.20-3.32 (1H, m), 3.78(3H, s), 3.83 (3H, s), 3.88 (3H, s), 3.95 (1H, d, J=3.2Hz, 8.8Hz), 6.20 (1H, s), 6.80 (1H, d, J=8.8Hz), 7.18 (1H, d, J=8.8Hz)