Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)COc1cc(Br)ccc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 4-bromo-2-isobutoxybenzoic acid (14.0 g) in N,N-dimethylformamide (70 ml) were added dipotassium carbonate (14.2 g) and iodomethane (4.79 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate-hexane (1/1, 600 ml) and washed with water (500 ml). The water layer was extracted with ethyl acetate-hexane (1/1, 200 ml) and the extract was washed with water (200 ml). The combined organic layer was washed with brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave methyl 4-bromo-2-isobutoxybenzoate (12.0 g) as a pale yellow oil.
Reaction SMILES: C[O-].[Na+].[Cl-].[F:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([NH2:20])=[NH2+:19])=[N:10]1.[CH:25]1([C:28](=[CH:31]N(C)C)[C:29]#[N:30])[CH2:27][CH2:26]1>CO>[NH2:30][C:29]1[C:28]([CH:25]2[CH2:27][CH2:26]2)=[CH:31][N:20]=[C:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:8][C:7]3[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=3[F:5])[N:10]=2)[N:19]=1
Reactant: NC(=[NH2+])c1nn(Cc2ccccc2F)c2ccccc12
Reactant: CN(C)C=C(C#N)C1CC1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ccccc23)ncc1C1CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under argon 1.08 g (6.00 mmol) of a solution of sodium methoxide (30 per cent in methanol) were admixed with 15 ml of abs. methanol and 1.83 g (6.00 mmol) of 1-(2-fluorobenzyl)indazol-3-amidinium chloride from Example X. The mixture was stirred at room temperature for 5 minutes, after which 816 mg (6.00 mmol) of 2-cyclopropyl-3-dimethylaminoacrylonitrile from Example II were added, and the mixture was heated under reflux overnight. After cooling to room temperature, the precipitate was filtered off with suction and stirred in pentane. Once more, the precipitate was filtered off with suction and dried under high vacuum, giving the product in the form of a virtually white solid.
Reaction SMILES: ClC1C=CC(OC)=C(C=1)CC1CNC(=O)CN(S(C2C=CC(Cl)=CC=2)(=O)=O)C1=O.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:42])[O:39][CH2:40][CH3:41])=[C:33](/[CH:43]=[C:44]2\[CH2:45][NH:46][C:47](=[O:62])[CH2:48][N:49]([S:52]([C:55]3[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=3)(=[O:54])=[O:53])[C:50]\2=[O:51])[CH:32]=1>>[CH2:40]([O:39][C:38](=[O:42])[NH:37][C:34]1[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][C:33]=1[CH2:43][CH:44]1[C:50](=[O:51])[N:49]([S:52]([C:55]2[CH:56]=[CH:57][C:58]([Cl:61])=[CH:59][CH:60]=2)(=[O:53])=[O:54])[CH2:48][C:47](=[O:62])[NH:46][CH2:45]1)[CH3:41]
Reactant: CCOC(=O)Nc1ccc(Cl)cc1/C=C1\CNC(=O)CN(S(=O)(=O)c2ccc(Cl)cc2)C1=O
Agent: COc1ccc(Cl)cc1CC1CNC(=O)CN(S(=O)(=O)c2ccc(Cl)cc2)C1=O
Product: CCOC(=O)Nc1ccc(Cl)cc1CC1CNC(=O)CN(S(=O)(=O)c2ccc(Cl)cc2)C1=O

Procedure:
Instead of the starting material of Example 29, that is, the compound 1, the compound of Example 278 was used for the similar procedure as in Example 29 to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([C@@H:18]([C:26]1[CH:31]=[CH:30][C:29]([O:32]CC2C=CC=CC=2)=[CH:28][CH:27]=1)[CH2:19][N:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1)[C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]([C@@H:18]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:19][N:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1)[C:3](=[O:17])[CH:4]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(C(=O)C(c1ccccc1)c1ccccc1)[C@H](CN1CC[C@H](O)C1)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C(=O)C(c1ccccc1)c1ccccc1)[C@H](CN1CC[C@H](O)C1)c1ccc(O)cc1

Procedure:
A solution of 1 g of N-methyl-N-[(1S)-1-(p-benzyloxyphenyl)-2-((3S)-3-hydroxypyrrolidino)ethyl]-2,2-diphenylacetamide in 25 ml of ethyl acetate is hydrogenated on 0.5 g of 5% Pd-C at 20° and under 1 bar until hydrogen uptake ceases, the mixture is filtered, the filtrate is evaporated, and N-methyl-N-[(1S)-1-(p-hydroxyphenyl)-2-((3S)-3-hydroxypyrrolidino)ethyl]-2,2-diphenylacetamide is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]=[C:6]2[CH2:19][C:20]([NH:22]N)=[O:21]>[Ni].CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]=[C:6]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: COc1ccc2c(c1)c(CC(=O)NN)cn2Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: COc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1
Yield: 95.6 %

Procedure:
One gram of Raney nickel was added to 790 mg (2.4 mmol) of 5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide in 120 mL of EtOH and the mixture heated at reflux for 2 hours. After filtering off the catalyst, the filtrate was concentrated at reduced pressure and the residue triturated with ether to give 675 mg (89% yield) of 5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 156-158° C.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16]>C(O)C>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][N:12]1[CH2:13][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][C:11]1=[O:14])[CH3:16]
Reactant: O=C1CC(c2ccc(Cl)cc2)CN1
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CN1CC(c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13 g (565 mmol) of sodium are added in portions to 410 ml of ethanol. After it has dissolved completely, 107 g (545 mmol) of 4-(p-chlorophenyl)-2-oxopyrrolidine are added, the whole is stirred at room temperature for 2 hours, concentrated to dryness by evaporation under reduced pressure and dried overnight at 100° under reduced pressure. The resulting sodium 4-(p-chlorophenyl)-2-oxopyrrolidine is made into a slurry in 340 ml of toluene, and a solution of 63.7 ml (95.9 g; 574 mmol) of bromoacetic acid ethyl ester is added dropwise, while stirring, at 20° to 25°. The whole is stirred for a further 16 hours, concentrated to dryness by evaporation under reduced pressure at approximately 70° and partitioned between 300 ml of water and 600 ml of ethyl acetate. The organic phase is separated off, washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness by evaporation under reduced pressure. 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid ethyl ester is obtained which, for purification, is distilled under reduced pressure; b.p.=176°-178° at 0.02 torr (0.027 mbar).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=1.C(=O)(O)[O-:14].[K+].[O-]Cl.[Na+].Cl>C(#N)C.O.CC1(C)N([O])C(C)(C)CCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:14])=[O:11])[CH2:7][C:6]=2[CH:12]=1
Reactant: OCC1Cc2cc(F)ccc2O1
Reactant: O=C([O-])O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)C1Cc2cc(F)ccc2O1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.7 %

Procedure:
To a 500 ml round-bottomed flask that contained a solution of (5-fluoro-2,3-dihydro-benzofuran-2-yl)-methanol (3.0 g, 17.8 mmol) in 100 ml of acetonitrile was added a solution of potassium bicarbonate (7.14 g, 71.4 mmol, 4 eq) in 30 ml of water. The mixture was cooled to 0° C. and TEMPO (56 mg, 0.36 mmol, 2 mol %) was added, followed by the dropwise addition of NaOCl(aq) (60 ml, 1.1 eq). The mixture was then stirred for 1.5 hours at room temperature. The pH was then adjusted to 4 using aqueous hydrogen chloride (3N). The mixture was then extracted with 3×80 ml of ethyl acetate. The organic fractions were combined, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 2.0 grams of the crude product as a yellow solid.
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10](OC)=[O:11])[CH3:5])[CH2:3][CH2:2]1.[BH4-].[Li+]>O1CCCC1>[CH:1]1([CH:4]([O:6][C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[CH:14]=[CH:15][CH:16]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(OC(C)C2CC2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(Oc1cccc(CO)c1)C1CC1
Temperature: 50 °C

Procedure:
Methyl 3-(1-cyclopropylethoxy)benzoate (11.7 g, 53.1 mmol) in tetrahydrofuran (212 mL) was added lithium borohydride (80.0 ml, 159 mmol). The reaction was heated at 50° C. for twelve hours. The reaction was quenched with methanol. The solvents were concentrated. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3. The aqueous layer was extracted three times with dichloromethane and the organics were combined, washed twice with water, dried with MgSO4, filtered, and concentrated. The enantiomers were resolved on the chiral OD column (10 cm) with a flow rate of 300 ml/mn wavelength 275 nm running 97/3 hexanes/ethanol as the solvent system.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([F:15])[CH:3]=1.C([Li])CCC.[CH:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O1CCCC1>[F:15][C:4]1[CH:3]=[C:2]([CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cc1F
Reactant: CCCCCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A solution of N-(4-bromo-2-fluorophenyl)-2,2-dimethylpropanamide (22.6 g, 82.5 mmol) in anhydrous tetrahydrofuran (410 mL) was placed under a nitrogen atmosphere, cooled in a dry ice-acetone bath, and stirred while butyllithium (83 mL of a 2.5M solution in hexanes, 207.5 mmol) was added dropwise by syringe pump over 2.5 hours. The resulting mixture was aged at −78° C. for 30 minutes and then treated with hexanal (25 mL, 208 mmol) added dropwise by syringe pump over 135 minutes. After stirring at −78° C. for an additional 70 minutes, the mixture was removed from the cooling bath, treated with aqueous 50% saturated NH4Cl, and the layers separated. The aqueous portion was extracted with EtOAc. The combined organics were washed with aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under vacuum to an oil. The crude product was purified by flash chromatography on a Biotage 75 L KP-Sil column, eluting with 4:1 hexanes-EtOAc (25×400 mL fractions). Fractions 9–22 were combined and evaporated under vacuum to afford N-[2-fluoro-4-(1-hydroxyhexyl)phenyl]-2,2-dimethylpropanamide (18.5 g, 76%) as a clear oil.
Reaction SMILES: N#N.C[O:4][C:5](=[O:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:15])[O:14][CH2:13][CH2:12][O:11]1.O.[OH-].[Li+]>C1COCC1.O>[CH3:15][C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:16])=[O:4])[O:14][CH2:13][CH2:12][O:11]1
Reactant: COC(=O)CCCCC1(C)OCCO1
Agent: N#N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(CCCCC(=O)O)OCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(2-methyl-[1,3]dioxolan-2-yl)-pentanoic acid methyl ester (5.43 g, 26.85 mmol) in a mixture of THF (70 mL) and water (70 mL) was treated at rt with lithium hydroxide monohydrate (1.45 g, 34.55 mmol) and the mixture was stirred for 3 h at rt. The THF was removed under reduced pressure and the aqueous phase was washed with EA, concentrated under reduced pressure and poured in cold sat. aq. NH4Cl. The pH was adjusted to 4-5 using 1N HCl and the aqueous phase was extracted with EA (3×). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1→1:2 hept-EA) gave the title compound as a white solid. LC-MS-conditions 02: tR=0.68 min [M+H]+=189.52.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:16][C:7]=2[C:6]([C:17](OC)=[O:18])=[CH:5][CH:4]=1)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3.[Cl:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:29])[C:27]=1[CH3:28].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH4+].[Cl-]>O1CCCC1>[Cl:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:29])[C:27]=1[CH2:28][C:17]([C:6]1[C:7]2[O:16][C:10]3([CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:18]
Reactant: COC(=O)c1ccc(OC)c2c1OC1(CCOCC1)O2
Reactant: Cc1c(Cl)cncc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OC1(CCOCC1)O2
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A solution of methyl 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-pyran]-4-carboxylate (1.80 g, 6.42 mmol) and 3,5-dichloro-4-picoline (1.46 g, 8.99 mmol) in tetrahydrofuran (33 mL) was cooled to 0° C. A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (19.3 mL, 19.3 mmol) was added and the reaction mixture was allowed to reach room temperature overnight. Saturated aqueous NH4Cl (70 mL) was added. The aqueous phase was extracted with dichloromethane (3×100 mL). The combined organic phase was washed with water (50 mL), dried over MgSO4 and evaporated to dryness under reduced pressure. Standard silica gel column chromatography followed by recrystallization from isopropanol afforded 2-(3,5-dichloropyridine-4-yl)-1-(7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-pyran]-4-yl)ethanone (1.90 g, 71%). 13C NMR (DMSO) δ 189.1, 148.2, 147.7, 147.0, 141.2, 134.5, 132.8, 122.0, 118.0, 113.0, 107.8, 64.4, 56.3, 43.5, 35.2.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9]C)[CH2:7]C)=[O:5].NC1C=CC(Br)=CC=1C(N(C)C)=O>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH3:7])[CH3:9])=[O:5]
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Agent: CN(C)C(=O)c1cc(Br)ccc1N
Product: CN(C)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Yield: 39 %

Procedure:
Prepared analogously to Compound 3C replacing Compound 3D with 2-amino-5-bromo-N,N-dimethyl benzamide (Compound 11D, 1.47 g, 6.06 mmol) to afford 689 mg of the title compound (39%). 1H NMR (400 MHz, CD3OD) δ 7.86 (d, J=0.5 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.36 (dd, J=2.2, 8.5 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 4.24 (t, J=6.8 Hz, 2H), 3.54 (t, J=6.1 Hz, 2H), 3.07 (br. s., 6H), 2.05 (quin, J=6.6 Hz, 2H). MS (ESI): m/z 289.56 [M+H]+. UPLC: tR=0.57 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1.O.O.[Sn](Cl)Cl>CCO>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)=[O:8])=[CH:14][CH:13]=1
Reactant: Cn1cncc1C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cn1cncc1C(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of (1-methyl-1H-imidazol-5-yl)(4-nitrophenyl)methanone (1.30 g, 5.62 mmol, Intermediate 15: step b and tin(II)chloride dihydrate (6.54 g, 28.1 mmol) in EtOH (35 mL) was stirred at reflux for 1 hour, cooled to room temperature and evaporated in vacuo to remove most of the EtOH. The residue was poured into a 3 M aqueous NaOH/ice solution rinsing with EtOAc. The mixture was stirred at room temperature for 15 minutes then layers were separated. The aqueous layer was again extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to provide the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C([O-])([O-])=O.[K+].[K+].C[O:12][C:13]1[CH:14]=[C:15](O)[CH:16]=[C:17](OC)[CH:18]=1.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[O:12]([NH:4][CH2:1][C:2]#[CH:3])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C#CCN
Reactant: COc1cc(O)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CCNOc1ccccc1

Procedure:
Part A: To a solution of the propargyl amine of Part B, Example 38 (2 g, 5.6 mmol) and powdered K2CO3 (1.9 g, 13.7 mmol) in N,N-dimethylformamide (20 mL) was added 3,5-dimethoxyphenol (2.18 g, 13.7 mmol) at ambient temperature. The resulting composition was heated to 90 degrees Celsius for 36 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H2O and dried over MgSO4. Chromatography (on silica, ethyl acetate/hexane) provided phenoxy propargyl amine as light yellow gel (2.76 g, quantitative yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:32]2[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Reactant: OC1CCNCC1
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCC(O)CC4)ccc3OCC)nn12

Procedure:
By the same method, starting with 531 mg (1.29 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 393 mg (3.88 mmol) of 4-hydroxypiperidine, 400 mg (64%) of 2-[2-ethoxy-5-(4-hydroxy-piperidine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:33])=[C:18]([CH3:23])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(C)c3)c2cc1OC

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methylaniline (50 mg) was dissolved in chloroform (3 ml), and p-fluorophenyl isocyanate (22 μl) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to quantitatively give the title compound.
Reaction SMILES: BrC1C=CC2N(C3CCCCO3)C3C(C=2C=1)=CC(Br)=CC=3.NC1C=CC=CC=1.[OH-].[K+].[C:31]1([NH:37][C:38]2[CH:39]=[CH:40][C:41]3[N:42](C4CCCCO4)[C:43]4[C:48]([C:49]=3[CH:50]=2)=[CH:47][C:46]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:45][CH:44]=4)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C(OCC)(=O)C.C1COCC1.C1(C)C=CC=CC=1>[C:52]1([NH:51][C:46]2[CH:45]=[CH:44][C:43]3[NH:42][C:41]4[C:49]([C:48]=3[CH:47]=2)=[CH:50][C:38]([NH:37][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:39][CH:40]=4)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: c1ccc(Nc2ccc3c(c2)c2cc(Nc4ccccc4)ccc2n3C2CCCCO2)cc1
Agent: Brc1ccc2c(c1)c1cc(Br)ccc1n2C1CCCCO1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Nc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(Nc2ccc3[nH]c4ccc(Nc5ccccc5)cc4c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a dried flask under N2, were added 3,6-dibromo-9-(tetrahydro-2H-pyran-2-yl)-9H-carbazole (1) (37.5 g), aniline (25 mL), hexadecyltrimethylammonium bromide (430 mg), aqueous potassium hydroxide (68.6 g, 45% in water), toluene (1.2 L). The stirred mixture was purged with N2 for 15 min. Then to this mixture, were added Pd2 dba3 (4.12 g) and tri-tert-butylphosphine (2.97 g in anhydrous toluene). The reaction was heated to reflux overnight. The reaction was cooled down to room temperature, and anhydrous MgSO4 was added, and filtered through a layer of silica gel and celite. The solvent was removed and crude product was used for next reaction without purification. To a 2 L flask under N2, was added all the crude product of N3,N6-diphenyl-9-(tetrahydro-2H-pyran-2-yl)-9H-carbazole-3,6-diamine (2), THF (1 L), and concentrated HCl (20 mL). The reaction mixture was stirred for 2 h. The THF (700 mL) was removed by evaporation, and then poured into ice water, filtered to obtain the solid crude product. The solid was stirring in ethyl acetate (500 mL) for 2 h, and filtration gave the final product (13.7 g) in 42% yield for two steps. 1H NMR was consistent with the compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:29]5[CH:30]=[CH:31][C:26]([CH2:25][OH:24])=[CH:27][CH:28]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: OCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CO)cc1
Temperature: 80 °C
Yield: 58.4 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide (3.0 g, 8.1 mmol), 4-(hydroxymethyl)phenylboronic acid (1.5 g, 9.7 mmol), 1 M K2CO3 (16 mL, 16 mmol), Pd-FibreCat 1007 (640 mg), and N,N-dimethylformamide (80 mL) were combined. The mixture was heated at 80° C. for 3 h. The volatiles were removed in vacuo and residue was redissolved in dichloromethane (100 mL). The organics were washed with 1N HCl (100 mL×2), then dried over Na2SO4 and evaporated. The crude product was purified by chromatography on silica gel to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(4′-(hydroxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide (1.9 g, 59%). ESI-MS m/z calc. 401.5, found 402.5 (M+1)+; retention time 3.18 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[C:5]([N+:22]([O-])=O)=[CH:4][N:3]=1.[NH4+].[Cl-].CCO.O>C(Cl)Cl.[Fe]>[NH2:22][C:5]1[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Br)ncc2[N+](=O)[O-])C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Br)ncc2N)C1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a mixture of tert-butyl 3-((2-bromo-5-nitropyridin-4-yl)amino)piperidine-1-carboxylate. (1.24 g, 3.01 mmol, 1.0 eq) and NH4Cl (2.43 g, 45 mmol, 15 eq) was added a 2:1 mixture EtOH/water (30 mL). The reaction mixture was heated to reflux, then iron powder (0.67 g, 12 mmol, 3.5 eq) was added in portions over 15 min and the suspension was continued to be heated at refluxed for 16 h. The reaction mixture was cooled to rt, diluted with CH2Cl2 (300 mL) and filtered through celite. The organic layer was washed with water (50 mL×2) and brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (1.2 g, 100%) which was used to next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 7.66 (s, 1H), 6.63 (s, 1H), 4.51-4.39 (m, 1H), 3.89-3.86 (m, 1H), 3.67-3.63 (m, 1H), 3.41-3.10 (m, 4H), 2.09-1.95 (m, 1H), 1.74-1.60 (m, 3H), 1.47 (s, 9H). ESI-MS (M+H+): 371.0.