Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]=[CH:8]2.[CH3:19][S-:20].[Na+].O>CN(C)C=O>[C:15]([O:14][C:12]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][S:20][CH3:19])[CH:8]=[CH:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)n1ccc2cccc(CBr)c21
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCc1cccc2ccn(C(=O)OC(C)(C)C)c12

Procedure:
160 mg (516 μmmol) of the compound from Example 6A and 36.2 mg (516 μmol) of sodium methanethiolate were stirred in 5 ml of dimethylformamide at RT for three days. Water was then added, and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate gradient) to result in 64 mg (45% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9][CH3:10].[C:11](=[O:13])=[O:12]>CCCCCC.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[C:4]([F:8])[C:3]=1[S:9][CH3:10]
Reactant: O=C=O
Reactant: CSc1c(F)cccc1Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1c(Cl)ccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
n-Butylithium (2.5M in hexane, 140 ml) was added to a stirred, cooled solution of crude 2-chloro-6-fluorothioanisole (60.0 g) in dry tetrahydrofuran while maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 3.5 hours then poured onto solid carbon dioxide pellets. It was stirred and allowed to warm to room temperature. It was evaporated to dryness and the residue was dissolved in water and washed with ether. The aqueous layer was acidified to pH1 and extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with hexane and filtered to give 4-chloro-2-fluoro-3-(methylsulphenyl)benzoic acid as a white solid, m.p. 183°-185° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:4]=1.[C-:19]#[N:20].[Na+]>CN(C=O)C.O>[C:19]([CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:4]=1)#[N:20]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(CC#N)c2cccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (5.18 g, 16.59 mmol) in DMF (30 mL) was added sodium cyanide (1.626 g, 33.2 mmol) and stirred at 25° C. for 4 hours. After this time, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (3×300 mL). The extracts were combined and the resulting solid precipitate was filtered. The filtrate was dried over MgSO4, filtered and the solvent removed in vacuo. This residue was purified by chromatography using 120 g RediSep column and eluting with 0-100% EtOAc/CH2Cl2 gradient. The desired fractions were combined and evaporated in vacuo to provide the title compound. LRMS (M+1): 259.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:15])[C:13]=1[OH:14])[C:5]([NH:7][CH2:8][CH2:9][OH:10])=O.S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:10][CH2:9][CH2:8][N:7]=2)[CH:11]=[C:12]([Cl:15])[C:13]=1[OH:14]
Reactant: O=C(NCCO)c1cc(Cl)c(O)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: Oc1c(Cl)cc(C2=NCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
3,5-Dichloro-4-hydroxy-N-(2-hydroxyethyl)benzamide (400 gm, 1.61 moles) was ground and sifted through a No. 20 mesh screen prior to use. To a stirred suspension of the above in 2.8 L isopropyl acetate was added thionyl chloride (285 gm, 2.41 moles) in a steady stream. An exotherm to 45°-50° C. developed and the gray suspension appeared lighter after a short time. After stirring 2.5 hr, the suspension was cooled to room temperature and filtered. The cake was rinsed with isopropyl acetate and dried in a vacuum oven at room temperature overnight. There was obtained 371 gm (86% yield) of 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol in the form of its hydrochloride salt, m.p. 189°-191° C., acceptable for use in the next step. The purified free base had the m.p. 195° C. (decompn.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=O)[NH:11][CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)C(Cc2ccc(C(F)(F)F)cc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2)cc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a stirred solution of 1-benzyl-3-(4-trifluoromethyl-benzyl)-piperazine-2,5-dione (0.53 g, 1.46 mmol) in dry THF (15 mL), 1M LAH in THF (6.14 mL, Aldrich) was slowly added at 0° C. and then heated to reflux for 18 h under argon. The reaction was cooled to room temperature and carefully quenched with H2O (1 mL), 1N NaOH (1 mL) and H2O (1 mL). The reaction mixture was filtered through bed of celite and rinsed with THF (100 mL). The filtrate was conc in vacuo and then dissolved in EtOAc (100 mL), washed with brine (2×10 mL), dried over MgSO4, and conc in vacuo to yield 0.45 g (92%) of the product as a colorless oil. MS (ESI) 335 (M+H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[OH:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16].C(O)(=O)C>O>[Cl:20][C:19]1[CH:18]=[CH:17][C:15]([N:16]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[CH:14][C:13]=1[OH:12]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(Cl)c(O)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A mixture of 15.2 g. of 3,4,5,6-tetrahydrophthalic anhydride, 14.4 g. of 3-hydroxy-4-chloroaniline and 50 ml. of glacial acetic acid was refluxed with stirring for 2 hours and then, the reaction mixture was cooled to a room temperature and water was added to precipitate a crystal and the crystal was separated by a filtration and recrystallized from isopropanol to obtain N-(4-chloro-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (m.p.: 236.5°-238° C.; yellow crystal) (yield: 87.5%).
Reaction SMILES: O[CH:2]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:11]=[CH:10][C:9]=2[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:7]=1)[CH2:3][O:4]C.[H][H]>[C].[Pd].C(O)(=O)C>[OH:4][CH2:3][CH2:2][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[N:11]=[CH:10][C:9]=2[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:7]=1
Reactant: [H][H]
Reactant: COCC(O)c1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: [Pd]
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCn1ncc2c(c(CCO)cn2COCC[Si](C)(C)C)c1=O
Yield: 66.4 %

Procedure:
To 40 ml of acetic acid solution containing 2.30 g (4.90 mmol) of 3-(1-hydroxy-2-methoxyethyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 57-(d) was added 1.0 g of 10% palladium-carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at 80° C. for 2.5 hours. After completion of the reaction, insoluble material was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure. Water was added to the residue, the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=3:7 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.43 g of the title compound as a colorless oil. (Yield: 66%)
Reaction SMILES: C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].[Cl-].[Ce+3].[Cl-].[Cl-].[C:17]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:24][C:23]2=[O:34])(=[O:19])[CH3:18].[Cl-].[NH4+].[CH3:37][N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43]>O1CCCC1>[CH2:30]([C:25]1[NH:26][C:27]2[C:22]([C:23](=[O:34])[N:24]=1)=[CH:21][C:20]([C:17]([OH:19])([CH:40]1[CH2:41][CH2:42][N:38]([CH3:37])[C:39]1=[O:43])[CH3:18])=[CH:29][CH:28]=2)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Reactant: CN1CCCC1=O
Agent: C[Si](C)(C)[NH-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(C)(O)C3CCN(C)C3=O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3.14 ml of 1-methyl-2-pyrrolidinone in 120 ml of dry tetrahydrofuran at -78° C. is added dropwise 32 8 ml of lithium bis(trimethylsilylamide)(1.0M in tetrahydrofuran followed by stirring for 1.5 hours. To the reaction mixture is added portionwise 8.07 g of cerium chloride and the mixture stirred for 1 hour at -70° C. To the mixture is added portionwise 2.0 g of 6-acetyl-2-butyl-4(1H)quinazolinone and the mixture stirred 5 hours at -70° C. The mixture is allowed to warm to 0° -hydroxy-1(1methyl-C. and stand overnight (0° C.). After addition of 60 ml of saturated ammonium chloride, the mixture is allowed to warm to room temperature and is filtered through diatomaceous earth which is washed with ethyl acetate. The filtrate is concentrated, the residue dissolved in ethyl acetate and the solution washed with 80 ml each of water, and brine and dried (Na2SO 4). The solvent is removed and the solid purified by high pressure liquid chromatography (HPLC) on silica with 2% methanol in ethyl acetate as solvent to give 2.21 g of product as a white glass. Anal. Calcd. for C19H25N3O3 1/2H2O:C,64.8;H,7.4; N,11.9. Found:C,64.1;H,7.6;N,11.9. Mass Spec MSFABL 344 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23][C:24]#[C:25][Si](C)(C)C)[CH:22]=2)[O:19][C:18]([CH3:31])([CH3:30])[CH2:17][C:16]3([CH3:33])[CH3:32])=[CH:7][CH:6]=1.CO.O1CCCC1.O.[OH-].[Li+]>O>[CH3:30][C:18]1([CH3:31])[CH2:17][C:16]([CH3:32])([CH3:33])[C:15]2[C:20](=[C:21]([CH2:23][C:24]#[CH:25])[CH:22]=[C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:34])=[O:2])=[CH:10][CH:9]=3)[CH:14]=2)[O:19]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(CC#C[Si](C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C#CCc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C

Procedure:
Following general procedure K and using {4-[2,2,4,4-tetramethyl-8-(3-trimethylsilanyl-prop-2-ynyl)-chroman-6-ylethynyl]-phenyl}-acetic acid methyl ester (Compound 48, 0.105 g, 0.21 mmol), methanol (3 mL), tetrahydrofuran (3 mL), water (1.5 mL) and lithium hydroxide monohydrate (0.128 g, 3.07 mmol), the title compound was obtained as a pale yellow solid (0.077 g, 95%). 1H NMR (300 MHz, CDCl3): δ7.51 (d, 1H, J=2.2 Hz), 7.49 (d, 2H, J=8.2 Hz), 7.39 (d, 1H, J=2.2 Hz), 7.25 (d, 2H, J=8.2 Hz), 3.66 (s, 2H), 3.52 (d, 2H, J=2.6 Hz), 2.61 (t, 1H, J=2.6 Hz), 1.83 (s, 2H), 1.36 (s, 6H), 1.35 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=O)[N:13]=[N:12]1.[NH2:20][C:21]1[C:22](=[O:34])[N:23]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:24]([CH3:27])[C:25]=1[CH3:26].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[C:14]([C:17]([NH:20][C:21]2[C:22](=[O:34])[N:23]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[N:24]([CH3:27])[C:25]=2[CH3:26])=[O:19])[N:13]=[N:12]1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(C2CC2)cc1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)nnn1-c1ccc(C2CC2)cc1Cl
Temperature: 10 °C
Reaction time: 2.5 h

Procedure:
1-(2-Chloro-4-cyclopropylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (15 g, 54.0 mmol) and 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate A)(11.30 g, 54.0 mmol) were slurried in EtOAc (150 mL). The reaction mixture was cooled to 10° C. and triethylamine (18.82 mL, 135 mmol) was added dropwise, followed by dropwise addition of T3P (50% w/w in EtOAc) (47.7 mL, 81 mmol) over 15 mins, maintaining a temperature <10° C. The reaction mixture was allowed to warm to RT and stirred for 2.5 hrs. The resulting mixture was quenched with sat. sodium bicarbonate (aq) (150 ml). The layers were separated and the organic layer was washed with sat. sodium bicarbonate (aq) (50 ml), water (150 ml) and brine (150 ml). The organic extracts were dried over MgSO4 and charcoal. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The crude material was slurried in ethyl acetate (335 ml) and heated to reflux with stirring. The hot mixture was filtered and the filtrate was seeded and at left to stand at room temperature overnight. The resulting crystalline solid was collected by filtration and dried under reduced pressure at 40° C. over 2 days to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]3[N:16]([CH3:26])[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[N:18][N:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]3[N:16]([CH3:26])[C:17]([C:20]4[CH:25]=[CH:24][N+:23]([O-:35])=[CH:22][CH:21]=4)=[N:18][N:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1c(SCc2noc(-c3cccc(Cl)c3)n2)nnc1-c1ccncc1
Solvent: ClCCl
Product: Cn1c(SCc2noc(-c3cccc(Cl)c3)n2)nnc1-c1cc[n+]([O-])cc1
Reaction time: 16 h
Yield: 8 %

Procedure:
4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine and wet 57%-86% MCPBA (52.4 mg, 0.20-0.30 mmol) were dissolved in dichloromethane (4 ml) and stirred for 16 h. The reaction mixture was purified via reversed phase preparative LC to give the title compound (7.5 mg, 8%). 1H NMR (CDCl3), δ (ppm): 8.33 (d, 2 H), 8.06 (m, 1 H), 7.96 (m, 1 H), 7.67 (d, 2 H), 7.57 (m, 1 H), 7.46 (apparent t, 1 H), 4.60 (s, 2 H), 3.71 (s, 3 H).
Reaction SMILES: CI.[C:3](=[O:6])([O-])[O-].[K+].[K+].[Cl:9][C:10]1[C:15]2[N:16]=[C:17]([O:19][CH2:20][CH2:21][CH3:22])[S:18][C:14]=2[C:13]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[NH:25][C:24]2=O)=[C:12]([F:35])[CH:11]=1>CC(CC)=O>[Cl:9][C:10]1[C:15]2[N:16]=[C:17]([O:19][CH2:20][CH2:21][CH3:22])[S:18][C:14]=2[C:13]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:24])[C:3]2=[O:6])=[C:12]([F:35])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCCOc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2s1
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CCCOc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2s1
Reaction time: 12 h

Procedure:
1.7 g of methyl iodide were added dropwise at about 20° C. to a mixture of 200 ml of absolute ethyl methyl ketone, 1.7 g of potassium carbonate and 5.0 g of 3-[4-chloro-6-fluoro-2-propoxybenzothiazol-7-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (compound I.8). Stirring was carried out for 12 hours at room temperature, after which the insoluble components were filtered off. The clear solution obtained was evaporated down. The residue was then taken up in water, after which the solution was neutralized with dilute hydrochloric acid. The product was then extracted with ethyl acetate. The ester phase was finally dried over sodium sulfate and then evaporated down. The purification of the crude product thus obtained was carried out by chromatography over silica gel (eluent: 9:1 cyclohexane/methyl tert-butyl ether). Yield: 1.0 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCCCC1CC(N)=O
Yield: 46.2 %

Procedure:
The title compound (0.92 g) was prepared from 2-(RS)-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and ammonium chloride (0.86 g) according to the method of Example 97.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([N:20]([CH2:31][CH:32]([CH3:34])[CH3:33])C(=O)OCC3C=CC=CC=3)[N:19]=[C:6]2[N:5]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[C:4]=1[CH3:45])#[N:2]>CO.[Pd]>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@H:8]2[N:7]3[N:17]=[C:18]([NH:20][CH2:31][CH:32]([CH3:34])[CH3:33])[N:19]=[C:6]3[N:5]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:44])[F:42])[CH:36]=3)[C:4]([CH3:45])=[C:3]2[C:1]#[N:2])=[CH:10][CH:11]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC(C)C)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC(C)C)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}(2-methylpropyl)-carbamate (25.0 mg, 41 μmol) was dissolved in degassed methanol (5 ml). After addition of palladium on activated carbon (10%; 5 mg), the mixture was hydrogenated under a hydrogen atmosphere (˜1 atm) at RT for 0.75 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (13.6 mg, 70% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.I[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][N:18]([CH:20]3[CH2:26][CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:21]3=[O:36])[CH:19]=2)=[CH:11][C:10]=1[O:37][CH3:38].CC(C)([O-])C.[K+].C1COCC1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:37][C:10]1[CH:11]=[C:12]([C:15]2[N:16]=[N:17][N:18]([CH:20]3[CH2:26][CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:21]3=[O:36])[CH:19]=2)[CH:13]=[CH:14][C:9]=1[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccnc1
Reactant: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1Nc1cccnc1

Procedure:
A suspension of pyridin-3-amine (3.48 mg, 0.037 mmol 3-[4-(4-iodo-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (20 mg, 0.037 mmol), potassium tert-butoxide 1M in THF (36.9 μL, 0.037 mmol), BINAP (4.59 mg, 0.008 mmol), and palladium acetate (1.66 mg, 0.008 mmol) were combined in a μwave vial and dissolved in DMF (738 μl). The reaction was microwaved at 180° C. for 10 min. The reaction mixture was filtered, and the solvent was removed in vacuo. Analytically pure material was obtained by purification by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% Formic Acid. Lyophilisation afforded 3-{4-[3-methoxy-4-(pyridin-3-ylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]([NH2:27])([CH3:26])[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][NH:27][CH:24]([CH3:26])[CH3:25])=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)N
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)NCc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 41.4 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg, 0.30 mmol), isopropylamine (30 μL, 0.36 mmol) and sodium triacetoxyborohydride (101 mg, 0.48 mmol) to afford 47 mg (42%) of the desired product after purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].C(N(C(C)C)CC)(C)C.Cl>O1CCCC1.O>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cccc(Nc2nc(Cl)nc3c2SCC3)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 38.4 %

Procedure:
0.200 g (0.93 mmol) of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine, 0.127 g (0.93 mmol) of 3-aminobenzoic acid, and 0.323 mL (1.85 mmol) of diisopropylethylamine are placed in 4 mL of tetrahydrofuran, stirred for 48 hours at ambient temperature and 48 hours at 70° C. Then the reaction mixture is combined with water and acidified with 1N hydrochloric acid. The precipitate formed is suction filtered and dried. 0.110 g of product I (39%) is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH:23]=[O:24])=[C:21]([C:25]3[CH:26]=[C:27]([C:31]([NH2:33])=[O:32])[N:28]([CH3:30])[CH:29]=3)[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.CO.[BH4-].[Na+]>CCOC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH2:23][OH:24])=[C:21]([C:25]3[CH:26]=[C:27]([C:31]([NH2:33])=[O:32])[N:28]([CH3:30])[CH:29]=3)[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc1C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc1C(N)=O
Reaction time: 1 h
Yield: 49.8 %

Procedure:
In a 25 mL pear-shaped flask, 4-(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-3-formylpyridin-4-yl)-1-methyl-1H-pyrrole-2-carboxamide (28 mg, 62.6 μmol, Eq: 1.00) was combined with CH2Cl2 (3 ml) and MeOH (1 ml) to give a colorless solution. Sodium borohydride (4.73 mg, 125 μmol, Eq: 2.00) was added. The reaction mixture was stirred for 1 h. The reaction mixture was poured into EtOAc (25 mL) and extracted with sat NH4Cl (3×10 mL). The organic layers were dried over MgSO4 and concentrated in vacuo followed by lyophilization to give 4-[2-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-3-hydroxymethyl-pyridin-4-yl]-1-methyl-1H-pyrrole-2-carboxylic acid amide (14 mg, 50%) as a white solid. 1H NMR (DMSO-d6) δ ppm 8.52 (d, J=2.8 Hz, 1H), 8.46 (d, J=5.0 Hz, 1H), 7.90 (d, J=1.8 Hz, 1H), 7.77 (dd, J=13.3, 1.8 Hz, 1H), 7.55-7.72 (m, 1H), 7.52 (d, J=5.0 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.04 (br. s., 1H), 4.88 (br. s., 1H), 4.29-4.57 (m, 2H), 3.91 (s, 3H), 1.39 (s, 9H); MS m/e 450.5 (M+H+).