Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([Cl:19])[CH:13]=[CH:12]3)[C:4]1=[O:20].[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]([S:33](Cl)(=[O:35])=[O:34])=[CH:30]2)=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:19][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:33]([C:29]4[CH:28]=[CH:27][C:26]5[C:31](=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=5)[CH:30]=4)(=[O:35])=[O:34])[C:4]3=[O:20])[CH:10]=2)[N:15]=1
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Reactant: N[C@H]1CCN(Cc2ccc3nc(Cl)ccc3c2)C1=O
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5nc(Cl)ccc5c4)C3=O)cc2c1

Procedure:
The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using 6-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline hydrochloride as the starting material and 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is triturated in CH2Cl2 and filtered to provide the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:26]([OH:28])=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O)=[O:11].[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:26]([OH:28])=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[O:11]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)C=Cc1ccccc1F)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCCC[C@H](NC(=O)C=Cc1ccccc1F)C(=O)O
Yield: 92 %

Procedure:
The same procedures as in Example 29 were carried out from the compound obtained in Example 113 (3.8 g), 4 mol/L of hydrogen chloride-dioxane (7.0 mL), and methylene chloride (80 mL), to give the captioned compound (3.0 g, 92%) as crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)CCCCCBr
Reactant: c1ccsc1
Product: O=C(CCCCCBr)c1cccs1

Procedure:
Using thiophene (5 ml) and 6-bromohexanoyl chloride (10.5 ml) according to the same method as that of Reference Example 1, the title compound (12.8 g) was obtained as a pale red solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][NH2:20])=[S:18])[CH:12]=1.Cl.C([O:25][C:26](=N)[CH2:27][CH2:28]O)C>N1C=CC=CC=1.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[S:18][C:28]([CH2:27][CH2:26][OH:25])=[N:20][N:19]=2)[CH:12]=1
Reactant: CCOC(=N)CCO
Reactant: COC(=O)c1cccc(C(=S)NN)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nnc(CCO)s2)c1
Temperature: 100 °C
Yield: 100.9 %

Procedure:
A mixture of 3-hydrazinothiocarbonyl-benzoic acid methyl ester trifluoroacetate (0.45 g) and 3-hydroxy-propionimidic acid ethyl ester hydrochloride (0.35 g) in pyridine (5 mL) was heated to 100° C. for 1.5 h. The mixture was diluted with AcOEt and washed with IN HCl and with brine. The organic layer was dried and evaporated and the residual oil was chromatography on silica gel using AcOEt/hexane (1:1) as eluent to give 3-[5-(2-hydroxy-ethyl)-[1,3,4]thiadiazol-2-yl]-benzoic acid methyl ester (0.37 g) as a white solid, MS (ISP) 265.3 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=O)[CH2:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.Cl.Cl.Cl.[CH2:18]([NH:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C(O)C>[CH2:18]([N:25]1[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][C:3]([C:2]([F:14])([F:13])[F:1])=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: NNCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1cc(-c2ccco2)n(Cc2ccccc2)n1
Temperature: 25 °C
Yield: 105.1 %

Procedure:
To a solution of 50 g (0.240 mol) 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione in 24 ml (0.024 mol) 1M solution of hydrogen chloride in ethanol and further 520 ml EtOH was added. 50 g (0.248 mol) benzylhydrazine dihydrochloride in small portion at room temperature. The reaction mixture was then heated under reflux for 7 h. After cooling to room temperature the reaction mixture was neutralized with saturated NaHCO3, the EtOH was distilled off and the residual oil/water mixture was extracted with 300 ml dichloromethane. The organic phase was washed twice with 100 ml water and dried over Na2SO4 and concentrated in vacuo to give 73.7 g 1-benzyl-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole as a brown oil which was used crude for the next reaction.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.Cl.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[NH:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[N:23]=[C:4]([OH:14])[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:22]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: N=C(N)c1ccc(Cl)cc1
Agent: Cl
Product: Oc1cc(-c2ccccc2)nc(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was prepared from 3-oxo-3-phenyl-propionic acid ethyl ester and 4-chloro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 6.97 (s, 1H), 7.50-7.58 (m, 3H), 7.16 (d, J=8.5 Hz, 2H), 8.10-8.20 (m, 2 H), 8.30 (d, J=8.5 Hz, 2H), 12.50 (br s, 1H); MS: m/z (ESI) 283 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].S(=O)(=O)(O)O.[CH3:25]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:25])=[O:7])=[CH:4][C:3]=1[S:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1

Procedure:
4-Fluoro-3-(morpholinosulfonyl)benzoic acid (50 mg, 0.173 mmol) was refluxed overnight in the presence of concentrated sulfuric acid (1.117 mg, 8.64 μmol) in methanol (8 mL) at 70° C. The reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and compound was purified by column chromatography affording the title compound (20 mg). 1H NMR (400 MHz, CD3OD): δ 8.42 (dd, 1H, J=2.0 & 6.4 Hz), 8.33 (m, 1H), 7.49 (t, 1H, J=8.8 Hz), 3.94 (s, 3H), 3.71 (m, 4H), 3.16 (m, 4H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:23]2[CH2:27][S:26]C(=S)[S:24]2)[CH:17]=[C:18]([O:21][CH3:22])[C:19]=1[OH:20]>C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:23]([SH:24])[CH2:27][SH:26])[CH:17]=[C:18]([O:21][CH3:22])[C:19]=1[OH:20]
Reactant: COc1cc(C2CSC(=S)S2)cc(OC)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(S)CS)cc(OC)c1O
Temperature: 0 °C

Procedure:
Lithium aluminum hydride (0.553 g, 14.58 mmole) is added to 10 ml dry diethyl ether and 10 ml dry THF. To this slurry is added dropwise 4-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-dithiolane-2-thione (34) (2.00 g, 6.94 mmole) predissolved in 40 ml dry THF. The reaction is stirred under a nitrogen (N2) atmosphere until the solution becomes colorless (1 hour). The reaction is cooled to 0° C. and the excess hydride destroyed with H2O. The reaction mixture is acidified with 10% HCl and immediately extracted with diethyl ether. The organic layer was washed with H2O, dried over MgSO4, filtered and evaporated to a white solid (1.64 g, 96%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14].S(=O)(=O)(O)O>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH2:14][CH2:13][C:12]([OH:16])=[O:15]
Reactant: C=CC(=O)O
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CN(CCC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 90.6 %

Procedure:
Methyl-(4-nitro-phenyl)-amine (3.0 g, 19.7 mmol) and acrylic acid (4.06 mL, 59.2 mmol) were added at 0° C. to a solution of concentrated sulfuric acid (2.15 mL, 39.5 mmol) in water (28 mL). The reaction mixture was heated at 80° C. for 30 min, cooled to room temperature and diluted with water. The precipitated solid was filtered and dried to give a crude product which was purified by washing with diethyl ether and pentane, affording 3-[methyl-(4-nitro-phenyl)-amino]-propionic acid (4.0 g, 91%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]3[C:13]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:16][O:17][C:18]=4[CH3:19])=[N:12][N:11]=[C:8]32)=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](OB=O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]=1[C:13]1[N:7]2[CH2:6][C:5]3[C:9]([C:8]2=[N:11][N:12]=1)=[CH:10][C:2]([C:29]1[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=1)=[CH:3][CH:4]=3
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Reactant: O=BOc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(-c3ccncc3)cc1-2
Temperature: 100 °C
Yield: 22.8 %

Procedure:
A mixture of 8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (220 mg) (prepared as in Example 4), 4-pyridylboranic acid (295 mg), Cs2CO3 (1.26 g/l ml H2O), and DME (3 ml) was degassed with a stream of N2 for 0.5 h. Bis(triphenylphosphine)palladium(II) chloride (42 mg) was added and the reaction heated to 100° C. for 5 h. The reaction mixture was cooled, poured into H2O and extracted into CH2Cl2, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica, eluting with 3% MeOH/CH2Cl2, and recrystallised from CH2Cl2/hexane to give the title compound (50 mg, 21%). 1H NMR (360 MHz, CDCl3) δ 8.72 (2H, d, J=4.5 Hz), 8.29 (1H, d, J=1.3 Hz), 7.67 (1H, dd, J=8.0, 1.7 Hz), 7.57–7.53 (4H, m), 7.48–7.39 (4H, m), 4.07 (2H, s), 2.73 (3H, s), m/z (ES+) 392 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([NH2:11])[CH2:9][CH3:10]>C(Cl)Cl>[CH2:8]([NH:11][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:9][CH3:10]
Reactant: CCCN
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Product: CCCNCC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.53 ml (50 mM) of ethyl bromoacetate were added dropwise to a solution of 20.5 ml (250 mM) of n-propylamine in 50 ml of CH2Cl2 at 0°. The reaction mixture was then warmed to room temperature and stirred for 1 hour, then concentrated to remove volatiles through a short path distillation head at atmospheric pressure. The residual liquid was taken up in ether and washed with saturated aqueous NaHCO3. The layers were separated and the ether layer was washed once with brine then dried over anhydrous MgSO4. The ether was removed to yield 7.16 g of ethyl N-(n-propyl)-glycinate as a pale yellow liquid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].S(O)(O)(=O)=O.CO[C:18](=[NH:20])[NH2:19].[Na]>CO.O>[NH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:18]([NH2:20])=[NH:19]
Reactant: NCCCCCCC(=O)O
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Solvent: CO
Product: N=C(N)NCCCCCCC(=O)O
Yield: 66.1 %

Procedure:
50.0 g (0.344 mols) of 7-aminoheptanoic acid and 63.5 g (0.514 mol) of O-methylisourea sulfate were dissolved in 250 ml of 50% aqueous methanol (v/v). To the solution was added dropwise a solution of 34.3 g (0.858 mol) of sodium hdyroxide in 400 ml of water. Then, the mixture was heated overnight under reflux. The reaction mixture was concentrated to about a half volume under reduced pressure followed by cooling the concentrate to precipitate white crystals. The crystals were collected by filtration, and dried to give 42.6 g (yield: 66.1%) of 7-guanidinoheptanoic acid.
Reaction SMILES: NCCN[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[NH2:22][C@@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][OH:25]>>[OH:25][CH2:24][C@@H:23]([NH:22][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)C[C@H](N)CO
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Product: CC(C)C[C@@H](CO)NC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using (2S)-2-amino-4-methylpentan-1-ol instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 359 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.23 (1H, s) 8.00 (1H, d, J=5.37 Hz) 7.78 (1H, d, J=5.37 Hz) 7.62 (1H, d, J=8.59 Hz) 7.45 (1H, d, J=5.37 Hz) 7.30 (1H, dd, J=3.12, 1.85 Hz) 6.75 (1H, d, J=5.47 Hz) 6.42 (1H, d, J=2.73 Hz) 4.68 (1H, t, J=5.66 Hz) 4.05 (1H, td, J=9.42, 4.39 Hz) 3.36-3.47 (1H, m) 1.46-1.63 (1H, m, J=13.76, 6.82, 6.82, 6.65, 6.65 Hz) 1.23-1.45 (2H, m, J=13.36, 9.07, 9.07, 8.92, 4.59 Hz) 0.83 (6H, dd, J=6.54, 4.30 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24](B5OC(C)(C)C(C)(C)O5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.C(=O)([O-])O.[K+].[NH2:41][C:42]1[C:47]([N+:48]([O-:50])=[O:49])=[CH:46][C:45](Br)=[CH:44][N:43]=1.CCN(C(C)C)C(C)C>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:45]5[CH:46]=[C:47]([N+:48]([O-:50])=[O:49])[C:42]([NH2:41])=[N:43][CH:44]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1ncnc(N2CCOc3ccc(B4OC(C)(C)C(C)(C)O4)cc3C2)c1Cc1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1ncnc(N2CCOc3ccc(-c4cnc(N)c([N+](=O)[O-])c4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 90 °C
Yield: 37.3 %

Procedure:
To a solution of 4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (1.3 g, 2.7 mmol), potassium hydrogen carbonate (1.4 g, 14 mmol), 2-amino-5-bromo-3-nitropyridine (0.98 g, 4.5 mmol) and DIPEA (1.4 mL, 8.2 mmol) in dioxane (8 mL) and water (1 mL) was added dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.20 g, 0.27 mmol). The biphasic mixture was then heated (90° C.) for 2 h and the organic layer was separated and purified by column chromatography on silica (0-10% methanol/dichloromethane) to provide 5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3-nitropyridin-2-amine (0.49 g, 37% yield) as a orange-red solid. MS (EI) for C26H23FN6O3: 487 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](OC2C=CC=CC=2)=[O:29])[CH:4]=[N:3]1.C(N(CC)CC)C.[NH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51].O>CN(C)C=O>[C:50]([O:49][C:48]([NH:47][CH2:46][CH2:45][NH:44][C:28]([NH:27][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[NH:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:29])=[O:54])([CH3:53])([CH3:52])[CH3:51]
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc(NC(=O)NCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
To a suspension of 1-methyl-4-phenoxycarbonylamino-5-triphenylmethylaminopyrazole (253.6 g) in N,N-dimethylformamide (1.5 L) were added triethylamine (59.5 g) and tert-butyl N-(2-aminoethyl)carbamate (94.2 g) in N,N-dimethylformamide (254 ml). The mixture was stirred for 5 hours and poured into water (10.6 L). The slurry was stirred for 1 hour. The precipitated solid was collected by filtration and dried to give a crude product. The crude product was suspended in N,N-dimethylformamide, and the suspension was heated under reflux for 20 minutes. The suspension was cooled to ambient temperature over 4 hours. The solid was collected by filtration, washed with acetonitrile and dried to give 4-[N-(2-tert-butoxycarbonylaminoethyl)carbamoylamino]-1-methyl-5-triphenylmethylaminopyrazole (261.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][O:11][C:10](=O)[C:9]=2[C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[N:22](C(OC(C)(C)C)=O)=[N:23]C(OC(C)(C)C)=O.Cl.CC([O-])=O.[Na+]>C(Cl)Cl.O1CCOCC1.CC#N.CO.C1CCN2C(=NCCC2)CC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[N:23][NH:22][C:10](=[O:11])[C:9]=2[C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(C2=C(c3ccc(Cl)cc3)COC2=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2c(-c3ccc(Cl)cc3)cn[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.1 %

Procedure:
To a stirred solution of 4-(4-(4-chlorophenyl)-2-oxo-2,5-dihydrofuran-3-yl)benzonitrile (58.2 g, 196.81 mmol) in CH2Cl2(300 mL) was added DBU (1.55 mL, 10.36 mmol) at room temperature under argon followed by the slow addition of a solution of di-tert-butyl azo-dicarboxylate (98%, 46.24 g, 196.8 mmol) in CH2Cl2 (100 mL) over 20 min. The reaction mixture was stirred at room temperature for 20 min. After this time, CH3CN (200 mL) was added to the reaction mixture followed by the addition of 4.0 M solution of HCl in dioxane (200 mL) at room temperature. The reaction mixture was stirred at 60° C. for 2.5 hr and a thick precipitate formed as the reaction proceeded. The reaction mixture was cooled to room temperature and diluted with CH3CN (200 mL). The solid was collected by filtration, washed with CH3CN (2×100 mL) and air dried to obtain a tan solid which was used directly in the next step. To the tan solid in MeOH (440 mL) at room temperature under argon was added NaOAc (64.6 g, 787.5 mmol). The reaction mixture was stirred at 65° C. for 2.5 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove most of the MeOH. Water (440 mL) was added and the resulting suspension was stirred at room temperature for 10 min. The solid was filtered, washed thoroughly with water followed by hexanes and dried in a vacuum oven at 50° C. overnight to furnish 4-(5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (44.9 g, 74% yield) as a light yellow solid.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:9][C:10]([S:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[C:10]([S:13]([N:15]=[CH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:14])([CH3:12])([CH3:11])[CH3:9]
Reactant: COC(=O)CCC=O
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COC(=O)CCC=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of commercially available methyl 4-oxobutanoate (4.454 g; 38.36 mmol) in DCM (90 ml) was treated with 2-methylpropane-2-sulfinamide (4.650 g; 38.36 mmol) and with anh. CuSO4 (12.246 g; 76.73 mmol). The resulting heterogeneous mixture was further stirred at rt, under nitrogen, for 12 h. The resulting grey mixture was then filtered over a short pad of celite, and the separated solids were further washed with DCM. The obtained orange filtrate was concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded methyl 4-((tert-butylsulfinyl)imino)-butanoate as a yellow oil. LC-MS (conditions A): tR=0.56 min.; [M+H]+: 220.40 g/mol.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:34]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O)#[N:35].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:39][C:38]5[CH:37]=[C:36]([CH:43]=[CH:42][CH:41]=5)[C:34]#[N:35])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3cccc(C#N)c3)CC2)cc1

Procedure:
3-{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-ylmethyl}-benzonitrile was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 25) with 3-cyanobenzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.95-1.99 (m, 2H), 2.23-2.29 (m, 4H), 2.94-2.97 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.62 (s, 2H), 4.78-4.85 (m, 1H), 7.55-7.80 (m, 6H), 8.04-8.07 (m, 2H), 8.38 (s, 1H), 8.56 (s, 1H). Mass spectrum MH+=489.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C)C=O>[CH2:10]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCCCO
Reactant: CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOCCCCO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7.1 ml of 1,4-butanediol in 40 ml of dimethylformamide, 1.8 gms of sodium hydride are added; and the reaction mixture is stirred at room temperature for 15 minutes. To this solution is added 7.6 ml of bromononane and the reaction mixture is stirred at room temperature for 44 hours. The reaction mixture is then partitioned between ethyl acetate and water and the organic layer is washed with brine, dried over sodum sulfate, filtered, and concentrated under vacuum. The residue is flash chromatographed with an 8/1 ratio of ethyl acetate and hexane to give 4-nonyloxybutanol as a clear colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:10][C:9](C(OC)=O)=[C:8]([O-:15])[C:4]=2[CH:5]=[N:6][CH:7]=1.[Na+].CCOCC.[OH-].[K+]>Cl>[Br:1][C:2]1[C:3]2[CH2:10][CH2:9][C:8](=[O:15])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)C1=C([O-])c2cncc(Br)c2C1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Product: O=C1CCc2c(Br)cncc21
Yield: 16.3 %

Procedure:
The crude sodium 4-bromo-6-(methoxycarbonyl)-5H-cyclopenta[c]pyridin-7-olate (20.0 mmol) was dissolved in aq. 6 M HCl, (54 mL) and heated at reflux for 1.5 h. The acidic solution was cooled in ice, poured into Et2O, basified with aq. 6 M KOH (to give a pH of −9) and extracted with Et2O (2×). The Et2O phases were collected, dried over Na2SO4, concentrated and purified by flash chromatography (20 g SiO2, i-PrOH (1%)/CH2Cl2) to afford after trituration with a small amount of Et2O the title compound (0.69 g, 16% over 2 steps) as pink solid. MS: 212.0 (M+H−, 1 Br).