Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[N:6]=[C:5]2[OH:13].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([OH:12])[N:6]=[C:5]3[OH:13])=[CH:23][CH:22]=1
Reactant: Oc1nc(O)c2cc(Br)ccc2n1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Oc1nc(O)c2cc(-c3ccc(F)cc3)ccc2n1
Temperature: 170 °C
Yield: 66 %

Procedure:
A mixture of 6-Bromo-quinazoline-2,4-diol (1 g, 4.15 mmol), potassium carbonate (11.6 ml, 0.4 M), tetrakis(triphenylphosphine) palladium (550 mg) and 4-fluorophenyl boronic acid (0.716 g, 5.1 mmol) in DME (40 ml) was heated at 170° C. for 10 minutes by microwave. Solvents were concentrated in vacuo and the residue was purified by RP HPLC with a gradient of H2O, 0.1% TFA-acetonitrile, to provide the desired product in 66% yield (760 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(OO)(=[O:28])C>CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:28])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Reactant: CC(=O)OO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Nc1ccc(S(=O)Cc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.42 G. 1-acetamido-2-nitro-4-benzylthiobenzene in 25 ml. chloroform is treated at -20° to -15° C with 1.6 g. 40% peracetic acid in 2 ml. methanol. The mixture is allowed to warm slowly to room temperature, held for 6 hours and washed with sodium bisulfite solution and sodium bicarbonate solution, dried and stripped. The residue is recrystallized from methanol giving 1-acetamido-2-nitro-4-benzylsulfinylbenzene.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[CH3:5][O:6][C:7](=[O:26])[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])=[CH:9][OH:10].C1OCCOCCOCCOCCOC1.[OH-].[Na+].Cl>CN1CCCC1=O.O>[CH3:5][O:6][C:7](=[O:26])[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])=[CH:9][O:10][CH:2]([F:4])[F:3]
Reactant: FC(F)Cl
Reactant: COC(=O)C(=CO)c1ccccc1COc1ccccc1C
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C(=COC(F)F)c1ccccc1COc1ccccc1C
Temperature: 5 °C

Procedure:
With vigorous stirring at 5° C., chlorodifluoromethane is passed into a solution of 5.7 g of 3-hydroxy-2-[2-(2-methylphenoxymethyl)phenyl]-acrylic acid methyl ester and 0.19 g of 15-crown-5 in 95 ml of N-methylpyrrolidone while simultaneously adding dropwise a solution of 5.34 g of sodium hydroxide in 6.7 ml of water and the reaction mixture is left to react for 1.5 hours. The reaction mixture is then poured onto ice-water, acidified with 4N hydrochloric acid and extracted exhaustively with ethyl acetate. The combined organic phases are washed with a sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica gel with hexane/ethyl acetate (9:1) yields pure 3-difluoromethoxy-2-[2-(2-methylphenoxymethyl)phenyl]-acrylic acid methyl ester in the form of a highly viscous oil that crystallises upon being left to stand. M.p.: sinlets from 68° C., clear molten at 77° C. MS: role 348 M+ (6), 241 (100)
Reaction SMILES: CN(C[N:5]1[C:9]2=[N:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]3)=[CH:12][CH:13]=[C:8]2[N:7]=[CH:6]1)C.C(NC(C)C)(C)C.[Li].C[O:32][C:33](=O)[C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[C:36]([C:42]2[C:46]([CH3:47])=[N:45][N:44]3[CH2:48][CH2:49][CH2:50][C:43]=23)[CH:35]=1.CCOC(C)=O>C1COCC1>[CH3:22][N:20]([CH3:21])[CH:17]1[CH2:16][CH2:15][N:14]([C:11]2[N:10]=[C:9]3[NH:5][C:6]([C:33]([C:34]4[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[C:36]([C:42]5[C:46]([CH3:47])=[N:45][N:44]6[CH2:48][CH2:49][CH2:50][C:43]=56)[CH:35]=4)=[O:32])=[N:7][C:8]3=[CH:13][CH:12]=2)[CH2:19][CH2:18]1
Reactant: CN(C)Cn1cnc2ccc(N3CCC(N(C)C)CC3)nc21
Reactant: COC(=O)c1ccc(C#N)c(-c2c(C)nn3c2CCC3)c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Cc1nn2c(c1-c1cc(C(=O)c3nc4ccc(N5CCC(N(C)C)CC5)nc4[nH]3)ccc1C#N)CCC2
Temperature: -78 °C
Yield: 10 %

Procedure:
To a solution of [1-(3-dimethylaminomethyl-3H-imidazo[4,5-b]pyridin-5-yl)-piperidin-4-yl]-dimethyl-amine (0.36 g, 1.2 mmol) in THF (5 mL) at −78° C. under N2 was added dropwise a freshly prepared solution of lithium diisopropylamine (1M, 1.5 mL, 1.5 mmol) in THF. After 10 m at −78° C. a solution of 4-cyano-3-(2-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-benzoic acid methyl ester (0.28 g, 1.0 mmol) in THF (5 mL) was added. The reaction mixture was stirred at −78° C. under N2 for 15 m before quenching with a 1:1 solution of acetic acid and water (2 mL). After warming to room temperature the quenched reaction was diluted several fold EtOAc and washed with dilute NH4OH followed by brine. The organic layer was dried over Na2SO4, filtered and concentrated. After purifying the crude product by reverse phase HPLC, the product was neutralized with aqueous Na2CO3 yielding the desired product as a orange-colored solid (50 mg, 0.10 mmol). 1H NMR (400 MHz, DMSO-d6) □ ppm 1.32-1.44 (m, J=12.00, 11.81, 11.81, 3.79 Hz, 2H) 1.85 (d, J=10.61 Hz, 2H) 2.20 (s, 6H) 2.25 (s, 3H) 2.33-2.46 (m, 1H) 2.53-2.63 (m, 2H) 2.89-3.02 (m, 4H) 4.43 (d, J=13.14 Hz, 2H) 7.04 (d, J=9.09 Hz, 1H) 7.95 (d, J=9.09 Hz, 1H) 8.10 (d, J=8.08 Hz, 1H) 8.36 (d, J=7.58 Hz, 1H) 8.52 (s, 1H); MS m/z 495.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:15][CH2:16][C:17](Br)=[O:18]>C1(C)C=CC=CC=1>[Br:15][CH2:16][C:17]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:18]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Br)CBr
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(CBr)Nc1ccc(Cl)cc1

Procedure:
To a solution of 5 g 4-Chloro-phenylamine and 1.5 ml pyridine in 30 ml toluene, 8 g bromo-acetyl bromide dissolved in 10 ml toluene was added dropwise under ice cooling. After 2 h the precipitate was isolated by filtration and recrystallized from toluene to yield a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:16]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:16])[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CCCCO)ccc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCCCO)cc(Br)c12
Temperature: -20 °C
Reaction time: 3 h
Yield: 144.6 %

Procedure:
To a cooled (−20° C.) solution of 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)butan-1-ol (1.20 g, 5.82 mmol) in tetrahydrofuran (30 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (832 mg, 2.91 mmol) in 4 portions over 10 min. The mixture was allowed to stir (−20° C.) for 3 h. The reaction was quenched with the addition saturated aqueous Na2SO3 (30 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×25 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 75% to 100% ethyl acetate in hexanes to afford 1.2 g (72%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.81 (s, 1 H), 6.60 (s, 1 H), 4.37 (t, 1H), 3.39 (q, 2 H), 2.80 (t, 2 H), 1.70-1.60 (m, 2 H), 1.48-1.39 (m, 2 H); ES-MS m/z 285.1 [M+H]+, HPLC RT (min) 1.55.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3](O)=[O:4].[NH2:28][CH2:29][CH2:30][OH:31].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([NH:28][CH2:29][CH2:30][OH:31])=[O:4]
Reactant: NCCO
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)O)ccc2-3)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)NCCO)ccc2-3)cc1
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (Example 127, 18 mg, 0.050 mmol) in DMF (1 mL) was added 2-aminoethanol (5.45 mg, 0.089 mmol), 4-methylmorpholine (0.033 mL, 0.29 mmol) and BOP (39.4 mg, 0.089 mmol). The reaction mixture was stirred overnight and was then purified by preparative HPLC (Phenomenex Luna 5 u C18 21.2×100 mm, Solvent A: 90% water with 10% MeOH and 0.1% TFA, Solvent B: 90% MeOH with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.9 min) to give 2-hydroxy-N-(2-hydroxyethyl)-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetamide (14.5 mg, 0.033 mmol, 67.4% yield): product HPLC ret. time=8.79 min. (condition G); LC/MS M+1=407.1; 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (1H, d, J=7.92 Hz), 7.72 (2H, d, J=8.36 Hz), 7.44-7.55 (2H, m), 7.37 (2H, d, J=8.36 Hz), 5.07 (1H, s), 3.58-3.69 (2H, m), 3.34-3.43 (2H, m), 3.05 (4H, s), 2.59-2.74 (2H, m), 1.61-1.80 (2H, m), 0.97 (3H, t, J=7.37 Hz).
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]2[C:20]=1[CH:21]=[C:22]([C:29]([O:31][CH3:32])=[O:30])[NH:23]2>C(#N)C>[C:1]([C:21]1[C:20]2[C:24](=[C:25]([CH3:28])[CH:26]=[CH:27][C:19]=2[Cl:18])[NH:23][C:22]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc2c(Cl)ccc(C)c2[nH]1
Reactant: CC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1[nH]c2c(C)ccc(Cl)c2c1C(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
To 10 ml of anhydrous acetonitrile were added 0.74 ml (12.9 mmol) of acetic acid and 0.4 g of polyphosphoric acid. After the air in the reaction system was replaced with nitrogen, 1.86 ml (12.9 mmol) of trifluoroacetic anhydride was added and the reaction mixture was stirred at room temperature for 10 minutes. 10 ml of a solution of 1.0 g (4.3 mmol) of methyl 4-chloro-7-methylindole-2-carboxylate in acetonitrile was added dropwise over a period of 15 minutes and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into 100 ml of ice water and extracted with 15 ml of ethyl acetate three times. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude crystals were purified by silica gel column chromatography to provide 270 mg of white crystals. Yield: 25%
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[CH:28]([CH:30]4[CH2:32][CH2:31]4)[OH:29])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:43]([OH:45])=[O:44])[CH2:42][O:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:30]1([CH:28]([OH:29])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]5([C:43]([OH:45])=[O:44])[CH2:42][O:41][CH2:40][O:39][CH2:38]5)=[CH:3][CH:4]=4)[N:9]=3)[CH3:13])=[O:16])[NH:18]2)=[O:34])=[O:33])[CH2:32][CH2:31]1
Reactant: C=CC1(C(=O)O)COCOC1
Reactant: C[C@H](NC(=O)C(O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](NC(=O)C(O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COCOC4)cc3n2)N1
Temperature: 50 °C

Procedure:
A solution of (S)-1-[(S)-2-(2-cyclopropyl-2-hydroxy-acetylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (592 mg, 1.11 mmol), 5-vinyl[1,3]dioxane-5-carboxylic acid (176 mg, 1.11 mmol), triethylamine (343 mg, 472 μL, 3.39 mmol) and tri(o-tolyl)phosphine (67 mg, 0.22 mmol) in 1,4-dioxane (15 mL) was degassed with nitrogen for 5 minutes and then warmed to 50° C. under nitrogen with stirring. Tris(dibenzylideneacetone)dipalladium(0) (101 mg, 0.11 mmol) was added and the mixture was heated to reflux for 20 minutes and then allowed to cool to room temperature. The suspension was filtered through Celite and the filtrate evaporated to give crude 5-((E)-2-{2-[(R)-1-({(S)-1-[(S)-2-(2-cyclopropyl-2-hydroxy-acetylamino)-propionyl]-hexahydro-pyridazine-3-carbonyl}-amino)-ethyl]-quinolin-7-yl}-vinyl)-[1,3]dioxane-5-carboxylic acid.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH2:29]([S:31][C:32]1[N:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35])[CH3:30]>>[CH2:29]([S:31][C:32]1[N:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:35])[CH3:30]
Reactant: CCSc1ncccc1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CCSc1ncccc1C(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-(ethylsulfanyl)nicotinoyl chloride: ESMS m/e: 545.3 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)=[C:8]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:7]=1>C(Cl)Cl>[Cl:3][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:9]2[C:8]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:7][C:6]([NH2:5])=[N:11][C:10]=2[CH3:12])=[CH:15][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (1 ml) was added to a mixture of the product from step (v) (1.2 g) in DCM (20 ml) and stirred at rt for 2 h. The solvent was evaporated under reduced pressure and the residue used crude in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9]C(=O)C)[C:3]1=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[OH-].[Na+].C(O)(=O)/C=C/C(O)=O>CN(C)C=O.O.CO>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[C:3]1=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: CC(=O)OCCN1CCN(C)C1=Nc1ccccc1N1CCOCC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(CCO)C1=Nc1ccccc1N1CCOCC1

Procedure:
Reaction of 4-((2-[1-methyl-3-(2-acetoxyethyl)-2-imidazolidinylideneamino]phenyl))morpholine (2.7 g) in dimethylformamide (10 ml) with sodium hydroxide (0.4 g) in water (10 ml) for one hour at 10° C. gave an oil which was dissolved in methanol (10 ml) and treated with fumaric acid (0.4 g) to give 4-((2-[1-methyl-3-(2-hydroxyethyl)-2-imidazolidinylideneamino]phenyl))morpholine (m.p. 129°-131° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:15][O:16]3)=[CH:11][C:10]=2[Cl:24])=[C:6]([N+:27]([O-])=O)[CH:5]=1)(=[O:3])[NH2:2].[Cl-].[NH4+]>C1COCC1.[Zn]>[NH2:27][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[NH2:2])[CH:26]=[CH:25][C:7]=1[O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:15][O:16]2)=[CH:11][C:10]=1[Cl:24]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3[N+](=O)[O-])c(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3N)c(Cl)cc21
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a stirred solution of ethyl 7-(4-carbamoyl-2-nitrophenoxy)-6-chlorochroman-4-carboxylate (7.74 g, 18.4 mmol) in THF (130 mL) at ambient temperature was added zinc dust followed by saturated ammonium chloride solution (50 mL). The resulting mixture was stirred at ambient temperature. After 30 minutes the reaction was filtered through a glass microfibre filter and the insoluble material was washed twice with THF. The combined filtrate and washings were concentrated and the residue was diluted with ethyl acetate (250 mL) and water (125 mL). The organic layer was separated and washed with brine (75 mL), dried over sodium sulfate and evaporated to provide the desired product (5.95 g, 83%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH:12]([NH:16][C:17]([NH:19][C:20]2[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=2[CH:22]=[N:23][N:24]4C(OC)=O)=[O:18])[CH2:11][CH2:10]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1(C([O-])=O)C2C(=CC=CC=2)C=N1>>[NH:24]1[C:25]2[C:21](=[C:20]([NH:19][C:17]([NH:16][CH:12]3[C:13]4[C:9](=[CH:8][C:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:15][CH:14]=4)[CH2:10][CH2:11]3)=[O:18])[CH:28]=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCc4cc(N5CCCCC5)ccc43)cccc21
Agent: O=C([O-])n1ncc2ccccc21
Product: O=C(Nc1cccc2[nH]ncc12)NC1CCc2cc(N3CCCCC3)ccc21

Procedure:
The title compound was prepared using the procedure in Example 9, except using methyl 4-({[(5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate instead of methyl 4-[({[5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino})carbonyl)amino]-1H-indazole-1-carboxylate. 1H NMR (DMSO-d6) δ 1.09 (t, 1.2H, Et2O), 1.40-2.20 (br m, 7H), 2.52-2.59 (m, 1H), 2.84-2.96 (m, 1H), 2.96-3.07 (m, 1H), 3.38 (q, 0.8H, Et2O), 3.52 (m, 4H), 5.24 (m, 1H), 5.76 (s, 0.2H, CH2Cl2), 7.05 (d, 1H), 7.21 (m, 1H), 7.33 (m, 1H), 7.50 (d, 1H), 7.65-7.77 (m, 3H), 8.29 (s, 1H), 9.15 (s, 1H); MS (ESI+) 376 (M+H)+; Elemental: Calculated for C22H25N5O.2HCl.0.1CH2Cl2.0.2Et2O: C, 58.31; H, 6.24; N, 14.85; Found: C, 58.22; H, 6.54; N, 15.00.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3)([O-:19])=[O:18]
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: O=[N+]([O-])c1ccccc1CBr
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccccc3[N+](=O)[O-])ccc12
Yield: 12.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (121 mg, 0.57 mmol) and 2-nitro-benzyl bromide (118 mg, 0.69 mmol) to provide 466 (24 mg, 12% yield) as a white powder. LC-MS (M+H=347, obsd.=347). 1H NMR (400 MHz, DMSO-D6) δ 8.56 (d, J=6.6, 1H), 8.41 (d, J=3.1, 1H), 8.07 (dd, J=8.3, 15.1, 2H), 7.51 (dt, J=6.5, 14.0, 2H), 7.43 (d, J=1.9, 1H), 7.35 (dd, J=4.7, 7.9, 1H), 7.03 (d, J=7.6, 1H), 6.91 (dd, J=2.0, 8.7, 1H), 6.25 (s, 2H), 5.89 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Cl[C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2ccccc2OC)c1

Procedure:
2-Methoxyphenylboronic acid (1.00 g) and ethyl 2-chloroisonicotinate (1.20 g) were treated in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].Cl.C([O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C:18]1=O)=O)C.C(O)(=O)C>CO.O>[CH2:23]([N:20]1[CH2:21][CH2:22][C:17]2[C:15](=[O:14])[NH:10][CH:8]=[N:9][C:18]=2[CH2:19]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N=CN
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=c1[nH]cnc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of sodium methoxide (1.67 g, 30.9 mmol) in anhydrous MeOH (10 mL) at room temperature was added formamidine acetate (1.15 g, 11 mmol) in one portion as solid followed by ethyl-1-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (2.63 g, 8.83 mmol) in one portion. The reaction mixture was stirred at rt for 20 h. The reaction was cooled at 0° C., and water (6 mL) was added followed by acetic acid (0.63 mL, 11 mmol) and the mixture was stirred at rt for 1 h. The mixture was concentrated under vacuum to remove the methanol and then stirred at rt overnight. The resulting solid was collected by filtration and washed with water (5 mL×3) and dried on filter to afford the title compound a (1.50 g, 70%) as an orange solid. LCMS [M+H]+ 242.16.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])=[N:10][C:9]=1[CH3:29])C.C(OC(=O)CCSC1SC(N)=NC=1C)C>>[CH:23]1([N:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[C:9]([CH3:29])[N:10]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)CCSc1sc(NC(=O)N(C2CCCCC2)C2CCCCC2)nc1C
Agent: CCOC(=O)CCSc1sc(N)nc1C
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SCCC(=O)O

Procedure:
Prepared as described in general procedures (A) and (B) using 3-[2-(3,3-dicyclohexyl-ureido)-4-methyl-thiazol-5-ylsulfanyl]-propionic acid ethyl ester and 3-(2-amino-4-methylthiazol-5-ylsulfanyl)-propionic acid ethyl ester
Reaction SMILES: COC1C=CC=CC=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15]C(C)(C)C=C2CSCCC(C)C.Br[CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])[CH:38]=2)[NH:33][C:32]([CH3:49])([CH3:48])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)CCS>>[CH3:47][O:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:49])([CH3:48])[CH:31]=[C:30]2[CH2:29][NH:15][C:16]1[CH:17]=[CH:18][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSCCC(C)C)=CC(C)(C)N2
Agent: CC(C)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-(3-methylbutylsulfanylmethyl)-1,2-dihydroquinoline 60 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 28 μL of 3-methyl-1-butanethiol reacted to give 3 mg of the title compound as a foam.