Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH3:15].S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>O>[OH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:27]([O-:29])=[O:28])[CH:17]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1C(=O)c2cccnc2C1(O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCN1C(=O)c2cccnc2C1(O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
7-Hydroxy-7-phenyl-6-(n-butyl)-6,7-dihydropyrrolo-[3,4-b]pyridin-5-one (47.15 g, 167 moles) was mixed with 250 mL of concentrated sulfuric acid (96%). The resulting mixture was placed in a cooling bath. Nitric acid (70%, 12 mL, 189 moles) was added at such a rate that the temperature remained below 45° C. The mixture was stirred for 30 minutes poured onto ice (500 g) and diluted with 1 L of water. The mixture was extracted twice with 700 mL of ethyl acetate. The organic solvent was removed yielding 7-hydroxy-7-(3-nitrophenyl)-6-(n-butyl)-6,7-dihydropyrrolo[3,4-b]-pyridin-5-one, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=[CH:10][CH:11]=1)=[CH:3][Cl:4].[H][H]>C(O)C.[Ni]>[Cl:1][C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[NH2:12])=[CH:3][Cl:4]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(OC(Cl)=CCl)c1
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc(OC(Cl)=CCl)c1

Procedure:
Yield: 115 grams of 3-(1',2'-dichlorovinyloxy)-nitrobenzene 1 mole of the nitro-product was dissolved in 1liter of ethanol and was reduced by means of hydrogen in an autoclave at 60°C, after 5 grams of a Raney-nickel catalyst (R/50) had been added. The catalyst was then filtered off with suction, the ethanol was distilled off, and the residue was distilled in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[NH2:23][C@@H:24]([CH3:27])[CH2:25][OH:26]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:23][C@@H:24]([CH3:27])[CH2:25][OH:26])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](CO)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 126.9 %

Procedure:
A 1-L, three-necked, round bottomed flask fitted with a nitrogen inlet, overhead stirrer, thermocouple, and condenser was charged with 4-bromo-1-fluoro-2-nitrobenzene (46 g, 209 mmol), DMF (230 mL), potassium carbonate (31.8 g, 230 mmol), and (S)-2-aminopropane-1-ol (17.9 mL, 230 mmol). The reaction mixture was heated to 60° C. for 6 h and then cooled to rt and stirred overnight. The mixture was slowly diluted with water (690 mL), and the resulting slurry stirred at rt for 3 h and was then filtered. The solids were washed with water (120 mL) and dried under house vacuum (ca 17 Torr) overnight to afford (S)-2-(4-bromo-2-nitrophenylamino)propane-1-ol (72.98 g) as a yellow-orange solid which contained excess water, and was used in next step without further drying or purification. MS (ESI, pos. ion) m/z 275 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:8]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:25](Cl)=[O:26])[CH:22]=2)[CH2:17]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl>O.O1CCOCC1>[CH2:8]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:25]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:26])[CH:22]=2)[CH2:17]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCC1Cc2ccc(C(=O)Cl)cc2C1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCC1Cc2ccc(C(=O)NCC(=O)O)cc2C1
Yield: 66.5 %

Procedure:
1.10 g (14.7 mM) of glycine, 0.29 (7.25 mM) of NaOH, 5.8 ml of distilled water were placed in a 100 ml-three necked flask and dissolved to prepare a solution. To the solution, 5.8 ml of dioxane was added, followed by stirring or a ice-common salt bath. To the mixture, a solution of 0.29 g (7.25 mM) of NaOH in 2.5 ml of distilled water and a solution of 2.14 g (7.29 mM) of 2-octylindan-5-carbonyl chloride in 10 ml of dioxane were gradually added dropwise at the same time at -1° to 3° C. by means of a dropping funnel, respectively, followed by stirring for 30 minutes at 1°-2° C. After the reaction, 0.87 ml of concentrated HCl was added to the reaction mixture to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by drying and recrystallization from methanol to obtain 1.61 g of N-(2-octylindan-5-carbonyl)glycin (Yield: 66.6%).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]([F:22])[F:21])[N:5]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[F:22][CH:20]([F:21])[O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:6]1[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1](=[O:3])[CH:2]=[CH:25][N:26]([CH3:28])[CH3:27])=[N:5]1
Reactant: COc1cn(-c2ccccc2OC(F)F)nc(C(C)=O)c1=O
Reactant: COC(OC)N(C)C
Product: COc1cn(-c2ccccc2OC(F)F)nc(C(=O)C=CN(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of 3-acetyl-1-[2-(difluoromethoxy)phenyl]-5-methoxypyridazin-4(1H)-one (3.70 g, 11.93 mmol) and N,N-dimethylformamide dimethyl acetal (50 mL) was refluxed for 5 h and stirred overnight at room temperature. The precipitate was collected by filtration and washed with AcOEt to give the title compound (4.07 g, 93% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.90 (3H, s), 3.12 (3H, br s), 3.87 (3H, s), 5.87 (1H, br s), 6.31-6.82 (2H, m), 7.30-7.41 (2H, m), 7.43-7.50 (1H, m), 7.63 (1H, dd, J=7.8, 1.8 Hz), 7.74 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH:37][C:38]2[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:40][CH:39]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:37]([CH2:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:31][CH:32]=1)[C:38]1[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:40][CH:39]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(OCc3ccccc3)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 71 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.59 g) and [(4-benzyloxyphenyl)methyl](4-isopropylphenyl)amine (0.58 g) as starting materials, 5-benzyloxy-N-[(4-benzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.74 g) was obtained. By the reaction and treatment in the same manner as in Example 17 using this compound, 5-hydroxy-N-[(4-hydroxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) was obtained. melting point: 241-243° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:6]([O:8][CH3:9])=[O:7]>C(OCC)(=O)C.[Pd]>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:12]([NH2:13])=[C:3]([NH:2][CH3:1])[CH:4]=1
Reactant: CNc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNc1cc(C(=O)OC)ccc1N
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
A suspension of methyl 3-(methylamino)-4-nitrobenzoate (Bionet) (0.5 g, 2.4 mmol) and Pd/C (Aldrich, 10%, 0.1 g) in ethyl acetate (7 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 4-amino-3-methylamino-benzoic acid methyl ester as a dark brown foam (0.4 g, 93%).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:3]=1[CH3:15].Br.[C:17](O)(=[O:19])[CH3:18]>>[C:17]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:15])(=[O:19])[CH3:18]
Reactant: Cc1c(O)c(=O)ccn1CCCCCO
Reactant: CC(=O)O
Agent: Br
Product: CC(=O)OCCCCCn1ccc(=O)c(O)c1C
Yield: 65 %

Procedure:
3-Hydroxy-1-(5'-hydroxypentyl)-2-methylpyrid-4-one, prepared as described under (N), (2 g) is dissolved in glacial acetic acid containing about 1% w/v of hydrogen bromide and the solution is refluxed for 2 hours. The resultant mixture is subjected to rotary evaporation and the residue crystallised from aqueous ethonal to give 1-(5'-acetoxypentyl)-3-hydroxy-2-methylpyrid-4one in 65% yield, m.p. 132°-133° C., δmax (nujol) 1520, 1540, 1580, 1635, 1735 cm-1 and δ(d6DMSO), 1.6 (m, 6H), 2.1 (s, 3H), 2.4 (s, 3H), 4.05 (m, 4H), 6.4 (d, 1H), 7.3 (d, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH2:13](O)[CH3:14].N1C=CC=CC=1>O1CCCC1>[CH3:12][Si:2]([CH3:1])([CH3:11])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:13][CH3:14])=[O:9]
Reactant: C[Si](C)(C)C#CCCCC(=O)O
Reactant: CCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCC#C[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 5.3 gm of 1,1-carbonyldiimidazole in 80 ml of dry tetrahydrofuran under argon, was added a solution of 5.03 gm of 6-trimethylsilyl-5-hexynoic acid in 15 ml of dry tetrahydrofuran. The mixture was stirred for 1 hour. Absolute ethanol (80 ml) and pyridine (1 ml) were then added, and the resulting mixture was stirred at room temperature for 48 hours. The solvent was evaporated and the residual oil was extracted with ether and 1.5% hydrochloric acid. The ethereal layer, which was washed with water and then dried, was evaporated to an oil. This material was purified by distillation, b.p. 70°-75° C. (0.6 mm Hg); IR: 2170, 1735 cm-1.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(C)(C)C.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[NH2:7][CH2:8][C:9]([N:10]([CH3:17])[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)=[O:18]
Reactant: CN(C(=O)CNC(=O)OC(C)(C)C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CN)c1ccncc1
Reaction time: 1 h

Procedure:
[(Methyl-pyridin-4-yl-carbamoyl)-methyl]carbamic acid tert-butyl ester (181) (7 g, 28.1 mmol) was dissolved in TFA (35 mL) at rt. The reaction had to be cooled to prevent excessive heat being released. Once the reaction had settled, it was left for 1 hr. TFA was evaporated and the residue co-evaporated with toluene (3×100 mL) and dried under vacuum to afford compound (182).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[C:4]1=[O:14])[CH3:2].[CH3:15][O:16][C:17]1[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=1.FC(F)(F)C(O)=O>O1CCOCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([OH:13])([CH2:23][C:18]2[C:17]([O:16][CH3:15])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:4]1=[O:14])[CH3:2]
Reactant: CCN1C(=O)C(=O)c2cc(C)ccc21
Reactant: COc1cccnc1C
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)C(O)(Cc2ncccc2OC)c2cc(C)ccc21
Temperature: 110 °C

Procedure:
To a flame dried sealed tube cooled under argon was added the 1-ethyl-5-methylindoline-2,3-dione (0.03 grams, 0.15 mmol) and 3-methoxy-2-methyl-pyridine (0.072 grams, 0.59 mmol, purchased from Fisher Scientific) and 0.5 mL of 1,4 dioxane. After the addition of trifluoro acetic acid (2 μL) the vessel was sealed and heated to 110° C. for 48 hours. The reaction was then concentrated. 1H-NMR δ 8.21 (s, 1H), 7.35 (bs, OH), 7.26 (m, 1H), 7.20 (d, 1H), 7.09 (d, 1H), 6.90 (s, 1H), 6.75 (d, 1H), 3.78 (s, 3H), 3.77 (m, 2H), 3.34 (d, 1H), 3.18 (d, 1H), 2.27 (s, 3H), 1.28 (t, 3H). Calculated mass for C18H20N2O3, 312.15. Observed 313.1 (M+1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.C([O:15][C:16](F)(F)[CH:17]([F:19])[F:18])C>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:16](=[O:15])[CH:17]([F:18])[F:19])[CH3:2]
Reactant: CCNCC
Reactant: CCOC(F)(F)C(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)C(F)F
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
The crude reaction gas was bubbled at 10° C. in a 2 l plastic bottle charged with 219 g (3.0 mols) of diethylamine, 303 g (3.0 mols) of triethylamine and 300 g of methylene chloride. Then, 365 g (2.5 mols) of 1-ethoxy-1,1,2,2-tetrafluoroethane was fed over a period of about 75 minutes. Then, nitrogen was supplied to the gas phase reactor at a rate of 200 cc/min for 20 minutes. The crude reaction solution was washed with 2 l of water, and the aqueous phase was extracted with 300 g of methylene chloride. The organic layers were put together and distilled to obtain 353 g (yield: 93.5%) of N,N-diethyl difluoroacetic acid amide (boiling point: 64° C./11 torr) having a purity of at least 99.5%.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:18]=2I)=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:28]([O-])([O-])=[O:29].[K+].[K+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:28](=[O:29])[C:18]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(S(C)(=O)=O)cc2I)CC1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nc3ccc(S(C)(=O)=O)cc3c(=O)o2)CC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a stirring solution of 2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-methylsulfonyliodobenzene (1.89 g, 3.72 mmol) in acetonitrile (50 mL) was added K2CO3 (2.53 g, 18.6 mmol) followed by Pd(PPh3)4 (0.22 g, 0.19 mmol) and CuI (0.036 g, 0.19 mmol). The mixture was placed under an atmosphere of CO and heated to 75° C. After 2 h, the heat was removed and the mixture was diluted with ethyl acetate and washed with water, then brine The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a gradient of 10% to 20% ethyl acetate in dichloromethane The product containing fractions were combined and concentrated in vacuo to give 0.485 g (32%) of a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N-:13]=[N+:14]=[N-:15].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[N:13]([CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCCCl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
4-Chlorobutyrophenone (300.0 mg, 1.64 mmol) was dissolved in N,N-dimethylformamide (20 ml) at room tempaerature and then added to sodium azide (1.07 g, 16.42 mmol) at the same temperature, and thereafter stirred at 100° C. for 24 hours. The reaction solution was added to a saturated aqueous sodium hydrogencarbonate solution and then extracted by ethyl acetate, to obtain an organic layer. The extracted organic layer was washed with water and brine sequentially, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant saubstance was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1), whereby the target compound was obtained as a colorless oil (285.5 mg, 91.9%)
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:30]=[CH:29][C:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:27][CH3:28])[CH2:23][CH2:24][C:18]=3[CH:17]=2)[N:9]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:14][C:13]1[C:8]([NH:7][C@H:3]2[CH2:4][CH2:5][CH2:6][C@H:2]2[NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[N:9][C:10]([NH:15][C:16]2[CH:30]=[CH:29][C:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:27][CH3:28])[CH2:23][CH2:24][C:18]=3[CH:17]=2)=[N:11][CH:12]=1
Reactant: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CCC[C@H]4N)n3)cc2CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CCC[C@H]4NS(C)(=O)=O)n3)cc2CC1

Procedure:
To a solution of N*4*-((1S,2R)-2-Amino-cyclopentyl)-5-chloro-N*2*-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-pyrimidine-2,4-diamine (132 mg, 0.298 mmol) in DCM (2 mL) was added Et3N (62.0 μL, 0.447 mmol) at 0° C. under argon. Stirred reaction for 10 min. before adding methanesulfonyl chloride (34.6 μL, 0.447 mmol) dropwise via syringe. Reaction stirred for 20 minutes at 0° C. The reaction mixture was diluted with DCM and washed with 1N NaOH (2×). Dried organic layer over MgSO4, filtered and concentrated. The residue was purified by column chromatography to yield (58 mg, 38%). mp: 73-74° C., MS (ESI+): 509 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.14 (s, 1H), 7.97 (s, 1H), 7.51 (s, 1H), 1.33 (d, J=7.5 Hz, 1H), 7.32 (s, 1H), 6.96 (d, J=8 Hz, 1H), 6.40 (d, J=7 Hz, 1H), 4.34 (m, 1H), 3.89 (br s, 1H), 3.44 (t, J=6 Hz, 2H), 3.23 (s, 3H), 2.75 (br s, 8H), 2.62 (m, 8H), 2.50 (m, 5H), 2.02 (m, 2H), 1.76 (m, 2H), 1.66 (m, 1H), 1.54 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([NH:28][CH2:29][CH3:30])=[O:27])[C:20]([Cl:36])=[CH:19][N:18]=1>>[Cl:36][C:20]1[C:21]([NH:23][C:24]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl
Yield: 12 %

Procedure:
The compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide to yield a yellow solid (12%). LCMS: m/z=497.15 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.05 (s, 1H), 7.77 (m, 2H), 7.31 (m, 5H), 6.88 (d, 1H, J=8.6 Hz), 6.51 (m, 1H), 3.41 (m, 2H), 2.37 (m, 2H), 2.06 (m, 2H), 1.35 (s, 6H), 1.14 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[CH:4]=[CH:5][C:6](=[O:9])[C:7]=1[CH3:8].C(O[C:17]([CH3:26])([CH:23]([CH3:25])[CH3:24])[CH2:18][C:19]([O:21][CH3:22])=[O:20])(C(O)=O)=O>>[CH3:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([C:17]([CH3:26])([CH:23]([CH3:25])[CH3:24])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CC1=C(C)C(=O)C=CC1=O
Reactant: COC(=O)CC(C)(OC(=O)C(=O)O)C(C)C
Product: COC(=O)CC(C)(C1=CC(=O)C(C)=C(C)C1=O)C(C)C
Yield: 36 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 21 which is concerned with the preparation of starting materials, 2,3-dimethyl-1,4-benzoquinone was reacted with methyl 3-oxalooxy-3,4-dimethylpentanoate to give methyl 3-(2,3-dimethyl-1,4-benzoquinonyl)-3,4-dimethylpentanoate in 36% yield; NMR Spectrum: (CDCl3) 0.6 (d, 3H), 0.86 (d, 3H), 1.02 (s, 3H), 1.93 (s, 3H), 1.94 (s, 3H), 2.32 (, 1H), 2.45 (d, 1H), 3.31 (d, 1H), 3.45 (s, 3H), 6.38 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([CH:18]3[CH2:20][CH2:19]3)[C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:29]=[C:30]([Cl:36])[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1>CO.C(Cl)Cl>[Cl:36][C:30]1[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=[C:28]([NH:27][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([CH:18]3[CH2:20][CH2:19]3)[C:13]=2[C:14]([F:17])([F:16])[F:15])[CH:29]=1
Reactant: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)cc(Cl)c1=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (Step 40.2) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2) at RT for 3 days. tR: 1.24 min (LC-MS 2); ESI-MS: 529 [M+H]+ (LC-MS 2); Rf=0.52 (5% MeOH/CH2Cl2).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:16][CH2:17][C:18](=O)[C:19]3[CH:28]=[CH:27][C:22]4[NH:23][C:24](=[O:26])[S:25][C:21]=4[CH:20]=3)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:41]2)=CC=1>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[S:41][C:18]([C:19]4[CH:28]=[CH:27][C:22]5[NH:23][C:24](=[O:26])[S:25][C:21]=5[CH:20]=4)=[CH:17][N:16]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)NCC(=O)c1ccc2[nH]c(=O)sc2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(-c3cnc(CN4CCC(Cc5ccc(F)cc5)CC4)s3)cc2s1
Yield: 18 %

Procedure:
To a stirred solution of 2-[4-(4-fluorobenzyl)piperidin-1-yl]-N-[2-oxo-2-(2-oxo-2,3-dihydrobenzothiazol-6-yl)ethyl]acetamide (0.50 g, 1.13 mmol) in 1,4-dioxan (30 mL) was added [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (Lawesson's reagent) (0.69 g, 1.70 mmol). The resulting suspension was heated at reflux for 24 hours. The reaction mixture was condensed to dryness in vacuo, redissolved in EtOAc, and washed with saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic phase was dried (MgSO4) and condensed to dryness in vacuo. The material was then subject to column chromatography [silica gel, EtOAc/Heptanes (0-50% EtOAc over 60 min)] gave 6-{2-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]thiazol-5-yl}-3H-benzothiazol-2-one (0.087 g, 18%) as an off-white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5]([Cl:23])=[O:6]
Reactant: COc1c(F)cc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(F)cc(C(=O)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-chloro-5-fluoro-4-methoxybenzoic acid (295 mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.15 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (b).