Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:14]2[C:10](=[CH:11][N:12]([C:17]3[CH:27]=[CH:26][C:20]([C:21](OCC)=[O:22])=[CH:19][C:18]=3[F:28])[N:13]=2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC2C(=CN(C3C=CC(C(OCC4C=CC=CC=4)=O)=CC=3F)N=2)C=1)C1C=CC=CC=1.CC(C[AlH]CC(C)C)C>ClCCl>[CH2:1]([C:8]1[CH:16]=[CH:15][C:14]2[C:10](=[CH:11][N:12]([C:17]3[CH:27]=[CH:26][C:20]([CH2:21][OH:22])=[CH:19][C:18]=3[F:28])[N:13]=2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(-n2cc3cc(Cc4ccccc4)ccc3n2)c(F)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(OCc1ccccc1)c1ccc(-n2cc3cc(Cc4ccccc4)ccc3n2)c(F)c1
Solvent: ClCCl
Product: OCc1ccc(-n2cc3cc(Cc4ccccc4)ccc3n2)c(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture (171 mg) of ethyl 4-(5-benzyl-2H-indazol-2-yl)-3-fluorobenzoate and benzyl 4-(5-benzyl-2H-indazol-2-yl)-3-fluorobenzoate in dichloromethane (10 mL) was added 1.0 M solution of DIBAL-H (1.37 mL, 1.37 mmol) in dichloromethane slowly at −78° C. The mixture stirred for 1 hour at −78° C. followed by quenching at −78° C. with 0.5 mL of a saturated solution of ammonium chloride. Hydrochloric acid (2N, 0.6 mL) was added, the cooling bath removed, and the mixture stirred for 1 hour. The mixture was subsequently extracted with dichloromethane and the extracts were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give (4-(5-benzyl-2H-indazol-2-yl)-3-fluorophenyl)methanol. MS (ESI) m/z: Calculated: 332.37; Observed: 333.3 (M++1).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[NH2:26][CH:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH2:28][OH:29]>O1CCCC1>[OH:29][CH2:28][CH:27]([NH:26][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[S:3])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: COc1ccc(C(N)CO)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(CO)NC(=S)Nc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole (1.09 g, 2.70 mmol) in tetrahydrofuran (7 mL) was added 2-amino-2-(4-methoxyphenyl)ethanol (0.506 g, 3.30 mmol) (Reggelin, M. et al., Synlett, 2012, 23, 1095-1098). The reaction was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was recrystallized with petroleum ether providing the title compound as a white solid (1.42 g, 81%): 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.72-7.57 (m, 2H), 7.27 (s, 1H), 7.23-7.14 (m, 2H), 6.87-6.72 (m, 4H), 6.64-6.56 (m, 2H), 6.38-6.22 (m, 3H), 5.05 (s, 1H), 3.47-3.28 (m, 2H), 3.20 (s, 3H); ESIMS m/z 530 ([M+H]+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1)=[O:2].O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>C1(C)C=CC=CC=1>[CH3:14][C:13]1([CH3:15])[C:16]([CH3:18])([CH3:17])[O:11][B:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=2)[O:10]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=Cc1ccc(B(O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OB(c2ccc(C=O)cc2)OC1(C)C
Yield: 93.1 %

Procedure:
A suspension of 5 g (33.3 mmol) of 4-formylphenylboronic acid and 3.93 g (33.3 mmol) of pinacol in 25 ml of toluene was refluxed on a water separator. When all the water of reaction had been removed, a clarifying filtration was carried out, and the solvent was removed by distillation until the product started to crystallize, giving 7.2 g (31 mmol) of product.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:19]4[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=4[N:13]([CH3:21])[CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH2:30][C:31]([N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:19]4[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=4[N:13]([CH3:21])[CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)=[O:32]
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine HCl (200 mg, 0.663 mmol), (2,5-difluorophenyl)acetic acid (120 mg, 0.696 mmol), HATU (265 mg, 0.696 mmol) in DMF (5 mL) was added Hunig's base (0.463 mL, 2.65 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The solid was filtered and dried to afford 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a white solid. NMR showed there is 1 eq. of DMF in the compound. LCMS (ES) m/z=420 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 3.27 (t, J=8.46 Hz, 2H), 3.74 (s, 3H), 3.95 (s, 2H), 4.29 (t, J=8.46 Hz, 2H), 6.05 (br. s., 2H), 7.21-7.27 (m, 5H), 7.34 (s, 1H), 8.09 (d, J=8.34 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[CH3:16][N:17]1[C:26]2[C:21](=[CH:22][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:25]=2)[CH2:20][CH2:19][C:18]1=[O:36]>>[CH3:16][N:17]1[C:26]2[C:21](=[CH:22][C:23]([C:2]3[C:3]4[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=4[CH:5]=[N:6][CH:7]=3)=[CH:24][CH:25]=2)[CH2:20][CH2:19][C:18]1=[O:36]
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CCC(=O)NC1CCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21
Yield: 87 %

Procedure:
In analogy to the procedure described for the preparation of intermediate A-2 [E], (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-3) was reacted with 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (intermediate A-1) to give the title compound as an off-white powder in 87% yield. MS: 350.2 (M+H+).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:23])[CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:18])=[C:14]([CH3:17])[CH:15]=2)[N:10]=[C:9]([C:19]([OH:21])=O)[C:8]1=[O:22].[NH2:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1>CN(C)C=O>[ClH:1].[CH3:23][N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:18])=[C:14]([CH3:17])[CH:15]=2)[N:10]=[C:9]([C:19]([NH:24][C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[O:21])[C:8]1=[O:22]
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc2nc(C(=O)O)c(=O)n(CCCN(C)C)c2cc1C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc2nc(C(=O)Nc3nnn[nH]3)c(=O)n(CCCN(C)C)c2cc1C
Reaction time: 1 h

Procedure:
4-(3-Dimethylaminopropyl)-3,4-dihydro-6,7-dimethyl-3-oxo-2-quinoxalinecarboxylic acid, hydrochloride (Example 18b) (0.26 g) and N,N'-carbonyldiimidazole (0.14 g) in dimethylformamide (5 ml) were heated at 100° for 5.5 hours. 5-Amino-1H-tetrazole (0.78 g) was added and heating at 100° was continued for 1 hour. The solid was collected and dissolved in hot aqueous dimethylaminoethanol (8 ml) (5%) and the solution was acidified with 2N hydrochloric acid. The solid that crystallised as the solution cooled was collected and dried. It had m.p. 280°-283° (d) (14%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]([CH2:10][CH2:11][CH:12]=O)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[NH2:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C1COCCN1
Reactant: N#Cc1cc(N)c(Cl)cc1CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cc(N)c(Cl)cc1CCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of 5-amino-4-chloro-2-(3-oxopropyl)benzonitrile (50 mg, 0.240 mmol, Example 566A) in THF (0.5 mL) at room temperature was added morpholine (37.6 mg, 0.431 mmol), sodium cyanoborohydride (30.1 mg, 0.479 mmol), and a drop of acetic acid. The reaction was stirred at room temperature for 1 h at which point LCMS indicated full conversion. The reaction was quenched with aq. Na2CO3 and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography (0-10% MeOH/DCM) to give 5-amino-4-chloro-2-(3-morpholinopropyl)benzonitrile (54 mg) as yellow oil.
Reaction SMILES: N[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][NH:16][CH3:17]>CO>[CH3:15][N:16]([CH3:17])[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:3])=[O:4]
Reactant: CNC
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
A suspension of 2.3 g of 5-chlorosulfonyl-2-oxindole (O-17) in 10 mL of 2 M dimethylamine in methanol was stirred at room temperature for 4 hours at which time a white solid was present. The precipitate was collected by vacuum filtration, washed with 5 mL of 1 N sodium hydroxide and 5 mL of 1 N hydrochloric acid and dried under vacuum at 40° C. overnight to give 1.9 g (79% yield) of 5-dimethylaminosulfonyl-2-oxindole.
Reaction SMILES: [NH2:1][C:2](=[N:33]C(=O)[O-])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH2:32])=[N:30][OH:31])=[CH:25][CH:24]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl>C(O)C>[NH2:32][C:29](=[N:30][OH:31])[C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][O:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([NH2:33])=[NH:1])=[CH:8][CH:7]=3)[CH2:14][CH2:15]2)=[CH:24][CH:25]=1
Reactant: NC(=NO)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=NC(=O)[O-])cc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: N=C(N)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Reaction time: 15 h

Procedure:
To an ethanol (5 mL) suspension of 0.30 g of tert-butyl=[1-amino-1-(4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}phenyl)methylidene]carbamate was added 5 mL of hydrochloric acid at room temperature, which was then stirred at the same temperature for 15 hours. The solvent was distilled off under reduced pressure, and water was subsequently added to the resultant residue, which was then adjusted to pH 12.5 using a 1 mol/L sodium hydroxide aqueous solution. The precipitate was collected by filtration and washed with water to provide 0.22 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamidine as white solid form.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH3:27][O:28][C:29](=[O:32])[CH2:30][NH2:31]>CN(C)C=O>[CH3:27][O:28][C:29](=[O:32])[CH2:30][NH:31][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C(O)CN1CCCC1=O
Reactant: COC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)CN1CCCC1=O
Temperature: -8 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
55 g of (2-oxo-1-pyrrolidinyl)acetic acid was dissolved in 1 l of dimethylformamide and 39.3 g of triethylamine was added thereto. After the solution was cooled to -8° C., 55.1 g of isobutyl chloroformate was added at -8° to -1° C. Then the reaction liquid was stirred at 0° to -7° C. for 10 minutes, 50.7 g of glycine methyl ester hydrochloride was added at -7° to -4° C. and stirred at -4° to -8° C. for 6 minutes. Next, 40.8 g of triethylamine was added at -8° to -3° C. The reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours and triethylamine hydrochloride was filtered off. Dimethylformamide was distilled off under reduced pressure and the residue was purified through the chromatography on silica gel (silica gel 1200 g, chloroform-1 to 3% of methanol as the eluent) to obtain 70.5 g of N-[(2-oxo-1-pyrrolidinyl)acetyl]glycine methyl ester as the oily substance. This was dissolved in 120 ml of methanol and 21.7 g of potassium hydroxide dissolved in 150 ml of methanol was added thereto. After reacting at room temperature for 5 hours, 40 g of acetic acid was added. The solvent was distilled off under reduced pressure and the residue was purified through the chromatography on silica gel (silica gel 1 kg, chloroform-5 to 20% of methanol-1% of formic acid as the eluent) and crystallized from tetrahydrofuran to obtain the titled compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:25])=[O:24])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:24])=[O:25])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NCC1CCNCC1)c1ccccn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of N-{[1-(tert-butoxycarbonyl)-4-piperidyl]methyl}pyridine-2-sulphonamide (1.45 g) in dichloromethane (10 ml) and the mixture stirred at ambient temperature for 1.5 hours. The solvent was removed under reduced pressure to yield crude N-(4-piperidyl methyl)pyridine-2-sulphonamide trifluoroacetate.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:15]1([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:5][C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:20][CH2:19]2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Reaction time: 3 h

Procedure:
Combined 1-boc-4-piperidone (10.0 g, 50.2 mmol), benzyl 1-piperazine-carboxylate (19.3 mL, 100.4 mmol), HOAc (4.3 mL, 75.3 mmol) and TEA (7.0 mL, 50.2 mmol) in DCE (150 mL) were stirred at rt. Sodium triacetoxyborohydride was added (16.0 g, 75.3 mmol). The reaction was stirred for 3 h at which point TLC shows starting material is consumed. The reaction was quenched with NaHCO3 and extracted with DCM (3×). Combined organics were dried over MgSO4, filtered and concentrated in vacuo. Diluted crude material with DCM and adsorbed onto a prepacked silica gel solid loading cartridge and purified by column chromatography to give title compound of step A (yield not obtained). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.04-7.52 (m, 5H), 5.02 (s, 2H), 3.74-4.05 (m, 2H), 3.06-3.49 (m, 4H), 2.63 (br. s., 2H), 2.22-2.50 (m, 5H), 1.64 (d, J=12.1 Hz, 2H), 1.07-1.27 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]1[C:11]#[N:12])[CH:2]=[CH2:3].[C:13]([Si](C)(C)C)([F:16])([F:15])[F:14].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([N:4]1[CH:8]=[C:7]([CH:9]([OH:10])[C:13]([F:16])([F:15])[F:14])[CH:6]=[C:5]1[C:11]#[N:12])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=CCn1cc(C=O)cc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCn1cc(C(O)C(F)(F)F)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a chilled (0° C.) solution of 1-allyl-4-formyl-1H-pyrrole-2-carbonitrile (1.25 g, 7.8 mmol, 1 equiv.) in 10 mL of THF was added CF3TMS (1.5 ml, 9.5 mmol, 1.2 equiv.) dropwise followed by TBAF (1M in THF, 9.4 ml, 9.4 mmol, 1.2 equiv.) slowly dropwise. The cold bath was then removed and the mixture was stirred at room temperature. After 2 hours, the reaction was quenched with water and extracted with EtOAc. The organic was dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc-hexanes (5-40% gradient) to afford 1-allyl-4-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrrole-2-carbonitrile which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11]C(=O)C3C=CC(Cl)=CC=3)[CH:9]=2)[C:4]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:3]1[CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33].C[O-].[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[C:4]([C:21](=[O:29])[C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:3]1[CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(OC(=O)c3ccc(Cl)cc3)cc2n1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(O)cc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 270 mg of the p-chlorobenzoate from Step D in 3 mL of MeOH was added 1.2 mL of a solution of 1.3M NaOMe in MeOH and the mixture was stirred at R.T. for 2 hr. The reaction mixture was poured onto 25% aq. NH4OAc and extracted with ethyl acetate. The organic extract was dried over Na2SO4, evaporated to dryness and the residue chromatographed on flash silica gel using ethyl acetate:hexane (40:60) as eluant to afford the title compound as a yellow foam.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[CH2:22]([OH:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C1(C)C=CC=CC=1>[CH2:22]([O:30][C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Reactant: CCCCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc2c(c1)C(=O)c1cc3ccccc3cc1C2=O

Procedure:
20 g (72.4 mmol) of 2-fluorotetracene-5,12-dione, 94.3 g of 1-octanol, 30.01 g (217.2 mmol) of anhydrous potassium carbonate and 200 ml of DMSO are stirred at 100° for 20 hours. The reaction mixture is cooled, toluene/dilute hydrochloric acid are added, and the organic phase is separated off, washed twice with water, dried using sodium sulfate and evaporated. The residue is washed with pentane and recrystallized from cyclohexane.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2.N1C=CC=CC=1.O.[OH-].[Li+].CO.Cl>O1CCCC1>[CH2:5]([O:4][C:2]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1ccc2[nH]ncc2c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzyl chloroformate (9.9 ml, ca. 66 mmol) in tetrahydrofuran (66 ml) was added dropwise with stirring to 5-aminoindazole (4.44 g, 33 mmol) in tetrahydrofuran (150 ml) and pyridine (12.0 ml, 150 mmol) at −5° C. The mixture was allowed to warm to room temperature, stirred for 4 h, and concentrated under vacuum. Ethyl acetate (100 ml) and water (150 ml) were added, and the aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic laters were washed with 0.3 N aq. HCI (2×100 ml), water, brine, and dried (MgSO4). Solvent was removed under vacuum to afford the crude product as a mixture of two regioisomers. MS (m/z): 402.1 [M+H]+. 0.3 M lithium hydroxide monohydrate in methanol (250 ml, ca. 75 mmol) was added. The mixture was stirred at room temperature for 45 min and then carefully acidified with 6 N aq. HCl until the pH of the solution was 2. The resulting product was filtered off, washed with water and dried under vacuum to afford the desired compound. Rt 4.2 min. MS (m/z): 268.1 [M+H]+. 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([CH2:41][NH2:42])[CH2:40][CH2:39]1>>[CH:38]1([CH2:41][NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40][CH2:39]1
Reactant: NCC1CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3CC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and cyclopropylmethylamine according to conditions described in general procedure C. Mp: 117-119° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.10-0.30 (m, 4 H), 0.90 (bs, 1 H), 1.58-1.60 (m, 6H), 3.00 (bs, 2H), 3.27-3.28 (m, 4 H), 6.29 (bs, 1 H), 6.96 (d, 1 H), 7.15 (d, 1 H), 7.20 (s, 1 H), 7.38 (d, J=8.0 Hz, 1 H), 7.45 (s, 1 H), 7.54-7.58 (m, 3 H), 7.80 (d, 1 H), 7.96 (d, 1 H), 8.20 (s, 1 H), 10.41 (s, 1 H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.CC1(C)C(C)(C)[O:36][B:35]([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[O:34]1.[CH3:48][N:49]([CH3:53])[CH2:50][CH2:51]O>C(Cl)Cl>[CH3:48][N:49]([CH2:50][CH2:51][O:46][C:43]1[CH:42]=[CH:41][C:40]([B:35]([OH:34])[OH:36])=[CH:45][CH:44]=1)[CH3:53]
Reactant: CN(C)CCO
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc(B(O)O)cc1
Reaction time: 1 h

Procedure:
To a suspension of solid-supported triphenylphosphine (30.0 g, 30.0 mmol) in DCM (150 mL) was added DEAD (3.93 mL, 25.0 mmol) dropwise via a syringe at room temperature. The reaction mixture was stirred for 1 hr, and then a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (4.40 g, 20.0 mmol) and 2-(dimethylamino) ethanol (2.01 mL, 20.0 mmol) in DCM (30 mL) was introduced. The reaction mixture was stirred at room temperature for 2 days. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluting with 95:5, DCM/MeOH) to afford 4-dimethylaminoethoxyphenyl boronic acid, pinacol ester (2.25 g) as an yellow oil. MS (MH+) 292.4; Calculated 29 for C16H26BNO3
Reaction SMILES: O[C:2]1[CH:10]=C[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](Cl)(=[O:13])[CH3:12]>CO>[OH:13][C:11]1[CH:10]=[CH:2][C:3]([C:4]([OH:6])=[O:5])=[C:7]([CH3:8])[CH:12]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccccc1O
Solvent: CO
Product: Cc1cc(O)ccc1C(=O)O
Temperature: 5 °C
Yield: 67.6 %

Procedure:
50 g (0.36 mole) of hydroxy-benzoic acid are dissolved in methanol in a 1 liter capacity Erlenmeyer. The mixture is cooled to a temperature of about 5° C. Thereafter, 70 ml (1 mole) of acetyl chlorine are added drop by drop and the mixture is left to return to ambient temperature. A magnetic stirring is carried out over a period of about ten hours. The methanol is then flushed out under vacuum, in the same way as the hydrochloric acid that is formed and the remaining acetyl chloride. 55 g of a solid brown product are recovered. At this step, the yield of the reaction is 99%. A recrystallization in ethanol produces 37 g of pure product, the melting point of which is 123° C. The overall yield of the reaction is 67%.