Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][NH:12][NH2:13]>C(O)C>[CH3:11][N:12]1[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][CH:1]=[N:13]1
Reactant: CNN
Reactant: O=CC=Cc1ccccc1
Solvent: CCO
Product: CN1N=CCC1c1ccccc1
Yield: 22.5 %

Procedure:
Cinnamaldehyde (13.2 g) was added dropwise to a solution of 5 g methylhydrazine in 50 ml ethanol, and the mixture was heated under reflux for six hours. At the end of reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in 50 ml ether. The solution was washed with water and concentrated, and the concentrate was distilled under reduced pressure, giving 3.6 g (yield: 22%) of pure product. B.p.: 95°-105° C./5 mmHg; NMR (CDCl3): 2.2-3.3 (2H, m), 2.65 (3H, s), 3.76 (1H, dd, J=10, 14 Hz), 6.51 (1H, t, J=2 Hz), 7.1-7.6 (5H, m).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:21]1[N:26]=[C:25]([CH:27]([OH:41])[CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:24]=[CH:23][CH:22]=1>>[NH2:9][C:7]([C:6]1[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][CH:11]=2)[S:3][C:2]=1[NH:1][C:21]1[N:26]=[C:25]([CH:27]([OH:41])[CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:32][CH2:33]2)[CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2cccc(Br)n2)CC1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4)cc3C(N)=O)n2)CC1

Procedure:
The title compound was prepared as described in Example 1 with 2-amino-5-[4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.20 g, 0.73 mmol) and tert-butyl 4-[(6-bromopyridin-2-yl)(hydroxy)methyl]piperidine-1-carboxylate (0.27 g, 0.71 mmol) as the starting materials.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[C:19](=O)([O-])[O-:20].[K+].[K+]>CN(C=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=[O:20]
Reactant: Cc1ccc(-n2cccc2)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-n2cccc2C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To ice-cooled DMF (4.0 g) was added phosphorous oxychloride (8.4 g) dropwise and the mixture was stirred at room temperature for 15 minutes. To the stirred reaction mixture was added a solution of 1-(2-chloro-4-methylphenyl)pyrrole (9.7 g) in DMF (8 ml) dropwise and the mixture was stirred at 50° C. for 1.5 hours followed by addition of ice-water. Stirring was continued for a while and then the mixture was made basic with potassium carbonate, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-hexane afforded yellow prisms (7.1 g, 59%), m.p. 111°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:32][NH:33][CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:31]=[CH:30][C:27]([CH2:28][N:33]([CH3:34])[CH3:32])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CNC
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C=O)cc5)nn34)ccnc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(CN(C)C)cc5)nn34)ccnc2c1
Reaction time: 0.33 h

Procedure:
A mixture of 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzaldehyde (prepared according to General Method A) (0.150 g, 0.36 mmol) and dimethylamine, 2.0 m solution in thf (0.36 ml, 0.73 mmol) in THF (5 mL) was allowed to stir for 20 min. Added sodium triacetoxyborohydride (0.15 g, 0.73 mmol) and stirred for 4 h. Concentrated. Suspended in DMSO, filtered through a 0.45 uM acrodisc. Purified on RPHPLC. Took fractions that contained product and made basic with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=441.2 [M+1]+. Calc'd for C25H24N6O2: 440.2.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1([CH3:27])[C@H:21]2[CH2:22][C@@H:17]1[CH2:18][CH2:19][C@H:20]2[CH2:23][C:24](O)=[O:25]>>[C:1]([C:5]1[C:6]([NH:14][C:24](=[O:25])[CH2:23][C@@H:20]2[CH2:19][CH2:18][C@H:17]3[CH2:22][C@@H:21]2[C:16]3([CH3:15])[CH3:27])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)C[C@@H]2CC[C@H]3C[C@@H]2C3(C)C)nn2cccnc12

Procedure:
The product from Example 105B and the product from Example 4B were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.65-9.70 (bs, 1H), 8.92 (dd, J=6.3, 1.8 Hz, 1H), 8.48 (dd, J=4.1, 1.8 Hz, 1H), 6.99 (dd, J=6.7, 3.9 Hz, 1H), 2.52-2.59 (m, 1H), 2.25-2.47 (m, 3H), 1.78-2.00 (m, 5H), 1.48-1.52 (m, 1H), 1.45 (s, 9H), 1.15-1.21 (bs, 3H), 1.02-1.11 (bs, 3H), 0.91 (d, J=9.3 Hz, 1H); MS (DCI) m/z 355 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:9][C:8]=1[CH3:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:50]>CN(C=O)C>[Br:50][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:9][C:8]=1[CH3:29]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCO)c(C)c3)nc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCBr)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(4-hydroxy-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (675 mg, 1.69 mmol) in DMF (10 mL) were added PPh3 (489 mg, 1.86 mmol) and CBr4 (619 mg, 1.86 mmol). The reaction mixture was stirred at room temperature for 16 hours. Solvent was removed under reduced pressure. The residue was triturated with ether and ethyl acetate. The solid was dried and then purified by the Simpliflash system using 5% methanol in CH2Cl2 as the eluent to give 2-[4-(4-bromo-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as a white solid. Yield: 494 mg (63%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][N:21]=3)[C:7]=2[CH:27]=1)#[N:2].Br[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][O:13][CH3:14])([CH2:15][O:16][CH3:17])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:29][CH2:30][CH3:31])[N:21]=3)[C:7]=2[CH:27]=1)#[N:2]
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)[nH]n2)[C@@H]1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1nc(N[C@@H]2c3cc(C#N)ccc3OC(COC)(COC)[C@H]2O)ccc1=O
Yield: 49.8 %

Procedure:
(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (60 mg, 0.16 mmol) obtained in Example 8 and 1-bromopropane (0.017 ml, 0.19 mmol) were dissolved in dimethylformamide (1.0 ml). Potassium carbonate (45 mg) was added and the mixture was reacted at 70° C. for 3 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (methanol:chloroform=4:96) to give 33 mg of the title compound (50%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=1>>[F:19][C:18]([F:21])([F:20])[C:14]1[N:13]=[C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OCCc1ccc(O)cc1
Reactant: FC(F)(F)c1cccc(Cl)n1
Product: OCCc1ccc(Oc2cccc(C(F)(F)F)n2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 4-(2-hydroxyethyl)phenol and 2-chloro-6-(trifluoromethyl)pyridine, LC-MS (ESI): m/z 284 [M+H]+; 3.00 min (ret time).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([C@@:10]1([OH:32])[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:20](=[O:22])[CH3:21])[CH2:11]1)#[CH:9]>>[OH:32][C@:10]1([C:8]#[C:9][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:20](=[O:22])[CH3:21])[CH2:11]1
Reactant: C#C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reactant: Brc1cccnc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@](O)(C#Cc5cccnc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 16.2 %

Procedure:
A solution of 3-bromopyridine (70 mg, 0.44 mmol), 3β-ethynyl-3α-hydroxy-5α-pregnan-20-one (150 mg, 0.44 mmol) in dry degassed diethylamine (1 mL) was stirred under argon at 23° C. Bis(triphenylphosphine)palladium chloride (10 mg) and CuI (5 mg) were added and the mixture was stirred at this temp. for 45 min. CH2Cl2 (4 mL) was added and the mixture was stirred at 23° C. for 1.5 hr. TLC showed 100% conversion of the starting material, hence, the solvent was removed and the residue was purified by chromatography on silica gel. Elution with hexane:acetone (3:1) gave 3α-hydroxy-3β-(3-pyridyl)ethynyl-5β-pregnan-20-one (30 mg) as a colorless solid; mp 230--35° C., TLC Rf (hexane:acetone 7:3)=0.24.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.O>CC(N(C)C)=O>[Cl:11][C:12]1[N:13]=[CH:14][N:15]=[C:16]([O:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:3])=[N:9][CH:8]=2)[CH:17]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2cc(Cl)ncn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
A −10° C. suspension of NaH (60% in mineral oil, 0.73 g, 18.2 mmol) in DMA (15 mL) was treated with 6-aminopyridin-3-ol (1.0 g, 9.1 mmol), stirred for 0.5 h, treated drop-wise with a solution of 4,6-dichloropyrimidine (2.03 g, 13.6 mmol) in DMA (10 mL), warmed to RT and stirred for 2 h. The mixture was treated with water, extracted with DCM (3×) and the combined organics were washed with 5% LiCl, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc) to afford 5-((6-chloropyrimidin-4-yl)oxy)pyridin-2-amine (1.0 g, 50%). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (d, 1 H), 7.79 (d, 1 H), 7.33-7.26 (m, 2 H), 6.48 (d, 1 H), 6.00 (s, 2 H); MS (ESI) m/z: 223.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:19][O:18][C:17]4[CH:20]=[C:21]5[C:25](=[CH:26][C:16]3=4)[CH2:24][CH2:23][O:22]5)[C:8]2=[O:27])=[CH:4][CH:3]=1.OC1C=C(C=CC=1)C[N:35]1C2C(=CC=CC=2)[C:37]2(COC3C=C4C(=CC2=3)CCO4)[C:36]1=[O:55]>>[O:27]=[C:8]1[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:37][C:36]([NH2:35])=[O:55])=[CH:29][CH:28]=1
Reactant: O=C1N(Cc2cccc(O)c2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1N(Cc2ccc(O)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Product: NC(=O)COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 13 and making non-critical variations using 1′-(4-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 1′-(3-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 2-{4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetamide was obtained (81%) as a colorless solid: mp 215-216° C.; 1H NMR (300 MHz, CDCl3) δ 7.35-7.29 (m, 2H), 7.25-7.14 (m, 2H), 7.06-6.99 (m, 1H), 6.93-6.87 (m, 2H), 6.83-6.78 (m, 1H), 6.52 (br s, 1H), 6.46 (s, 1H), 6.43 (s, 1H), 5.67 (br s, 1H), 5.04-4.95 (m, 2H), 4.85-4.76 (m, 1H), 4.73-4.66 (m, 1H), 4.59-4.50 (m, 2H), 4.48 (s, 2H), 3.10-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.9, 170.7, 161.8, 160.3, 156.7, 142.0, 132.7, 129.6, 129.0, 128.6, 123.9, 123.4, 120.1, 119.9, 118.8, 115.0, 109.1, 93.2, 80.6, 72.4, 67.1, 57.7, 43.4, 29.0; MS (ES+) m/z 443.0 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][N:32]=2)[CH:28]=O)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][N:32]=[C:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1ccnc(N2CCCC2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(N2CCCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 2-(pyrrolidin-1-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.58 min.; [M+H]+: 396.07 g/mol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:8][C:7]=2[CH:17]=1)#[CH:2].Br[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH:25]=2)[N:20]=1>>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]4[O:10][C:9]([CH2:11][N:12]5[CH2:16][CH2:15][CH2:14][CH2:13]5)=[N:8][C:7]=4[CH:17]=2)[CH:28]=[CH:27]3)=[CH:34][CH:33]=1
Reactant: Clc1ccc(-c2ccc3nc(Br)ccc3c2)cc1
Reactant: C#Cc1ccc2oc(CN3CCCC3)nc2c1
Product: Clc1ccc(-c2ccc3nc(C#Cc4ccc5oc(CN6CCCC6)nc5c4)ccc3c2)cc1

Procedure:
Prepared analogously to Example 18d from 5-ethynyl-2-pyrrolidin-1-ylmethyl-benzoxazole and 2-bromo-6-(4-chloro-phenyl)-quinoline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[N:9]1([CH2:14][CH2:15][NH2:16])[CH2:13][CH2:12][CH2:11][CH2:10]1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:16][CH2:15][CH2:14][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: NCCN1CCCC1
Reactant: Fc1cc(Br)ccn1
Solvent: CN(C)C=O
Product: Brc1ccnc(NCCN2CCCC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a 4 mL screw-cap vial was added 4-bromo-2-fluoro-pyridine (100 mg, 0.57 mmol), 2-pyrrolidin-1-ylethanamine (1.1 equiv., 0.63 mmol, 71 mg), and dimethylformamide (0.25 mL). The reaction was capped and shaken at 100° C. for 3 h. TLC showed new spot, with no starting material present. The reaction was concentrated, and 4-bromo-N-(2-pyrrolidin-1-ylethyl)pyridin-2-amine was carried directly on to the Suzuki cross-coupling step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[NH2:16])([O-])=O>[Pd].C(O)C.CC(=O)OCC>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]2[CH:9]=[C:4]([NH2:1])[C:5]([NH2:16])=[CH:6][CH:7]=2)[CH:11]=1
Reactant: Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cccnc2)cc1N
Yield: 102.8 %

Procedure:
4-Amino-3-nitrophenylboronic acid pinacol ester (1.60 g, 6.06 mmol), 3-bromopyridine (1.10 g, 6.96 mmol), cesium carbonate (3.33 g, 10.22 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (491 mg, 0.60 mmol) were suspended in dimethylformamide (20 mL). The solution was degassed by vacuum several times and placed in an argon atmosphere. It was then heated to 65° C. for 6 hr. After cooling, EA (100 mL) and water (40 mL) were added. When additional water (50 mL) was added to the organic layer, a precipitate was formed in the separatory funnel. The biphasic solution was filtered, and the filtrate was transferred to the separatory funnel and separated. The organic phase was washed twice with water (50 mL each), then with brine, and then dried with sodium sulfate and concentrated under reduced pressure to give 2-nitro-4-(pyridin-3-yl)benzenamine (1.18 g). 2-Nitro-4-(pyridin-3-yl)benzenamine (700 mg, 3.26 mmol) in 1:1 ethanol/EA (40 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (90 mg, 0.08 mmol) at room temperature for 2 days. Filtration and concentration under reduced pressure gave 4-(pyridin-3-yl)-benzene-1,2-diamine (621 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C@@H:10]([NH:22]C(=O)OC(C)(C)C)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=1)#[N:9]>C(Cl)Cl>[NH2:22][C@@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=1)[C:8]#[N:9]
Reactant: CC(C)Oc1ccc(C[C@@H](C#N)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(C[C@H](N)C#N)cc1
Reaction time: 1 h
Yield: 111.8 %

Procedure:
Trifluoroacetic acid (1 mL, 10 mmol) was added to a solution of the (S)-tert-butyl 1-cyano-2-(4-isopropoxyphenyl)ethylcarbamate (40 mg) in methylene chloride (2 mL). After stirring for 1 h., the reaction was concentrated under reduced pressure to give the crude product (2S)-2-amino-3-(4-isopropoxyphenyl)propanenitrile (30 mg, 90%).
Reaction SMILES: [CH:1]([C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=O.[NH2:13]O.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CO.CN(C=O)C>[C:1]([C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)#[N:13]
Reactant: NO
Reactant: CCOC(=O)c1coc(C=O)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc(C#N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
A solution of ethyl 2-formyloxazole-4-carboxylate (650 mg, 3.84 mmol) in methanol (25 mL) was cooled to 0° C. and 50% aqueous hydroxylamine (0.22 mL, 7.68 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. Solvent was removed under reduced pressure and the crude product (0.52 g) obtained was dissolved in DMF (20 mL). T3P (3.4 mL, 5.65 mmol; 50% in EtOAc) was added to the reaction mixture and heated to 100° C. for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution and the organic product was extracted with EtOAc. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10% EtOAc in petroleum ether) to afford ethyl 2-cyanooxazole-4-carboxylate (0.34 g, yield 53%) as an off white solid. 1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 4.48-4.41 (q, J=7.0 Hz, 2H), 1.44-1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: C1OCCOCCOCCOCCOCC[O:3]C1.[CH3:19][O:20][C:21]1[CH:31]=[CH:30][C:29]2[C:32]3[C:22]=1[C:23](=[O:34])[C:24](=[O:33])[C:25]=3[CH:26]=[CH:27][CH:28]=2.O.Cl>CS(C)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:32]2[C:29]([CH:28]=[CH:27][CH:26]=[C:25]2[C:24](=[O:33])[C:23]([OH:34])=[O:3])=[CH:30][CH:31]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: COc1ccc2cccc3c2c1C(=O)C3=O
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2cccc(C(=O)C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
In a reactor, 4 mg of 18-crown-6 ether and then 230 mg of NaNH2 are successively introduced into a suspension of 100 mg of 3-methoxyacenaphthoquinone in 1 ml of DMSO. The mixture is stirred for 30 minutes at ambient temperature. Water (2 ml) is then added, followed by 2N HCl solution (3 ml). After two extractions with ethyl acetate, the solvents are dried over Na2SO4 and then evaporated off to yield the title product in the form of a yellow solid in a yield of 88% and with a chemical purity of more than 94%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14]>CO.[C].[Pd]>[NH2:8][C:6]1[CH:5]=[C:4]([F:11])[C:3]([C:12]([CH3:17])([CH3:18])[C:13]([O:15][CH3:16])=[O:14])=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(C)(C)c1c(F)cc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)(C)c1c(F)cc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
A mixture of methyl 2-(2,6-difluoro-4-nitrophenyl)-2-methylpropanoate (3.2 g, 12.35 mmol) and 10% palladium-carbon (1.314 g, 0.617 mmol, 50%, wet) in MeOH (30 mL) was stirred overnight at room temperature under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give methyl 2-(4-amino-2,6-difluorophenyl)-2-methylpropanoate (2.87 g, 12.52 mmol, 101%) as a colorless oil.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[PH2](O)=[O:12].N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2](=[O:12])[NH:3][C:4]=1[CH3:10]
Reactant: Cc1cc(N)nc(C)c1Br
Reactant: O=[PH2]O
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(=O)[nH]c(C)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a solution of 2-amino-5-bromo-4,6-dimethylpyridine (0.7 g, 3.48 mmol) in water (6.4 mL) was added an aqueous solution of hypophosphorous acid (50%, 2.9 mL, 27.84 mmol). The mixture was cooled to about 0° C. and a solution of sodium nitrite (0.281 g, 4.07 mmol) in water (1.4 mL) was added with vigorous stirring, maintaining the temperature below 5° C. The mixture was stirred for 30 minutes at 0° C. and was then allowed to warm up to r.t. overnight. The solution was neutralized to pH 6-7 with an aqueous solution of sodium hydroxide (2.0M) and cooled to 5° C. for 5 h. The resulting precipitate was filtered off and washed with cold water. The solid obtained was dried in vacuo to give the title compound (0.681 g, 97%) as a white solid. δH (CDCl3) 6.35 (1H, s), 2.47 (3H, s), 2.29 (3H, s). LCMS (ES+) 201/203 (M+H)+, RT 2.16 minutes (Method 1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(OC(=O)C)(=[O:14])C.N1C(C)=CC=CC=1C>C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH:7]([OH:14])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=S1CCC2(CC1)OCCO2
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: OC1CC2(CCS1)OCCO2
Temperature: 150 °C

Procedure:
A mixture of 0.88 g of product from Example 393, 5.0 ml of acetic anhydride and 2.0 ml of lutidine is heated at 110°-115° C. for 2.5 hours, followed by increasing the temperature to 150° C. and then heated for 3 hours. The reaction mixture is diluted with ethyl acetate, washed 2× with 1N hydrochloric acid, water, saturated sodium chloride, dried and concentrated in vacuo. The residue is dissolved in methylene chloride, filtered through a pad of hydrous magnesium silicate and reconcentrated in vacuo to give 0.569 g of the desired product.