Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].O.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1NCCC[C@@H]1O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1CCCNC1=O
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 460 mg of (S)-(-)-3-hydroxy-2-piperidone [A. Hunter, Biochemical Journal, 35, 1298 (1941); mp. 170°-171° C., [α]D26 =-3.0°±0.1° (c=7.027, H2O)] in 6 ml of pyridine is added 2 ml of acetic anhydride, and the mixture is allowed to stand at room temperature overnight and concentrated under reduced pressure. The residue is crystallized from ether and then recrystallized from ether to give 560 mg of (S)-(-)-3-acetoxy-2-piperidone as pillar crystals in 89% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([Cl:12])=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:13]([O:15][C:16](=[O:23])[CH:17]=[C:18]([NH2:22])[O:19][CH2:20][CH3:21])[CH3:14]>C(O)(C)C>[CH2:13]([O:15][C:16]([C:17]1[CH:7]([C:6]2[C:9]([Cl:12])=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:17]([C:16]([O:15][CH2:13][CH3:14])=[O:23])[C:18]([O:19][CH2:20][CH3:21])=[N:22][C:18]=1[NH2:22])=[O:23])[CH3:14]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1Cl

Procedure:
Upon heating a solution of 9.3 g of 3-nitro-6-chlorobenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of isopropanol for 6 hours, 2-amino-4-(3-nitro-6-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 136°-37°C (isopropanol) is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([O:19][CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:21][CH2:22][CH2:23][C:24](OCC)=[O:25])[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([O:19][CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[C:6]=2[C:5]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2cnc(OC)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(OC)cc3C)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.2 %

Procedure:
To a solution of ethyl 4-{4-chloro-7-(1-ethylpropyl)-2-[(6-methoxy-4-methylpyridin-3-yl)amino]-1H-benzimidazol-1-yl}butanoate (170 mg, 0.359 mmol) in tetrahydrofuran (3 mL) was added lithium borohydride (24 mg, 1.08 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 12 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (109 mg, 0.252 mmol, 70%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([NH2:28])=[CH:27][C:22]=2[O:21][CH2:20]1>>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5][NH:28][C:26]1[CH:25]=[CH:24][C:23]2[O:19][CH2:20][O:21][C:22]=2[CH:27]=1
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Reactant: Nc1ccc2c(c1)OCO2
Product: COC(=O)C(=CNc1ccc2c(c1)OCO2)C(=O)c1ccc(C)c(C)c1

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1, from crude 2-(3,4-dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester (4.03 g, 16.3 mmol) and benzo[1,3]dioxol-5-ylamine (2.45 g, 17.9 mmol). Yield: 3.14 g of a yellow crystalline solid: LC-MSD, m/z for C20H20NO5 [M+H]+=354.4; HPLC retention time: 2.8 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1oc(-c2cccs2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cccs3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with 4-chloromethyl-5-methyl-2-thiophen-2-yl-oxazole in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-[2-methyl-4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-[2-methyl-4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-phenyl]-propionic acid as light yellow solid. MS: 400.3 (M−H)−, 354.1, 281.2. NMR: (CDCl3, 1H, 300 MHz, δ, TMS) 1.13 (t, J=7.2, 3H), 2.34 (s, 3H), 2.41 (s, 3H), 2.93 (d×d, J=15.2, J=8.8, 1H), 3.12 (d×d, J=15.2, J=4, 1H), 3.30-3.38 (m, 1H), 3.49-3.57 (m, 1H), 4.01 (d×d, J=8, J=4.8, 1H), 4.94 (s, 2H), 6.78 (d×d, J=8, J=1.6, 1H), 6.82 (d, J=1.6, 1H), 7.08-7.14 (m, 2H), 7.40 (d×d, J=4.8, J=0.8, 1H), 7.64 (d×d, J=4.0, J=0.8, 1H).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:33])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([C:44]2([C:47](O)=[O:48])[CH2:46][CH2:45]2)=[O:43])=[CH:37][CH:36]=1.C(N(CC)CC)C.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)C=O>[C:1]1([O:7][C:8](=[O:33])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:47]([C:44]4([C:42](=[O:43])[NH:41][C:38]5[CH:37]=[CH:36][C:35]([F:34])=[CH:40][CH:39]=5)[CH2:45][CH2:46]4)=[O:48])=[CH:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reaction time: 15.5 h
Yield: 70.4 %

Procedure:
A crude product of [4-(4-aminophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (820 mg) was dissolved in N,N-dimethylformamide (15 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (830 mg), triethylamine (0.519 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.65 g) were added in this order under a nitrogen atmosphere at room temperature, followed by stirring for 15.5 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture. The resultant organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give residue, which was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:1). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as white foam (845.8 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(F)cc1
Yield: 53.3 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)lactate (10.0 g), which is the product of Reference example 1(b), 4-fluorophenol (4.15 g), triphenylphosphine (10.6 g) and diethylazodicarboxylate (6.40 ml) and the reaction mixture was treated to afford the desired compound (7.00 g) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][NH:8]C(OC(C)(C)C)=O)[CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:22]>>[ClH:22].[ClH:22].[O:1]1[CH2:6][CH2:5][CH:4]([NH:7][NH2:8])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NNC1CCOCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NNC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (1.82 g) was dissolved in 4N hydrogen chloride-ethyl acetate solution (85 mL) under ice-cooling, and the solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (1.52 g).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][N:11]([CH2:15][CH:16]=[CH2:17])[C:10]=2[C:9](=[O:18])[NH:8][C:7]1=[O:19])[CH2:2][CH2:3][CH2:4][CH3:5].[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:20][N:8]1[C:9](=[O:18])[C:10]2[N:11]([CH2:15][CH:16]=[CH2:17])[CH:12]=[N:13][C:14]=2[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]1=[O:19]
Reactant: O=C([O-])[O-]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCCC
Yield: 100 %

Procedure:
3-Pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.20 g, 0.76 mmol), potassium carbonate (0.4 g, 2.9 mmol) and methyl iodide (0.5 ml, 4.9 mmol) were stirred and heated at 50° C. in DMF (5 ml) for 3 h. The solution was allowed to cool and separated between ethyl acetate and brine. The organics were isolated, dried (MgSO4) and concentrated to provide the title compound (0.21 g, 100%). m/z 277 [MH+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[CH2:21]([O:24][NH2:25])[CH:22]=[CH2:23].CC([O-])=O.[Na+]>CCO>[CH2:21]([O:24][N:25]=[C:16]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH2:17][CH3:18])[CH:22]=[CH2:23]
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: C=CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCON=C(CC)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 31.3 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (316 mg, 1.0 mmol), O-allylhydroxylamine hydrochloride (119 mg, 1.05 mmol) and anhydrous NaOAc (86 mg, 1.05 mmol) in EtOH (5 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with EtOAc/PE, 1:9). The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:99 to 1:19) to afford N-[2-(1-allyloxyiminopropyl)-4-chlorophenyl]trifluoromethanesulfonamide 156 (116 mg, 31%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 11.57, br s, 1H; 7.67, d, J=8.8 Hz, 1H; 7.48, d, J=2.4 Hz, 1H; 7.33, dd, J=2.4 and 8.8 Hz, 1H; 6.00, m, 1H; 5.42, d, 3J=17.2 Hz, 1H; 5.36, d, 3J=10.4 Hz, 1H; 4.68, d, J=6.0 Hz, 2H; 2.83, q, J=7.6 Hz, 2H; 1.19, t, J=7.6 Hz, 3H. HRMS (M+) 370.0350.
Reaction SMILES: [I:1]I.C[Si](C)(C)[CH:5]=[CH:6][C:7]1[C:8](=[O:14])[CH2:9][CH2:10][CH2:11][C:12]=1[CH3:13].ClCCl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[I:1][CH:5]=[CH:6][C:7]1[C:8](=[O:14])[CH2:9][CH2:10][CH2:11][C:12]=1[CH3:13]
Reactant: CC1=C(C=C[Si](C)(C)C)C(=O)CCC1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1=C(C=CI)C(=O)CCC1
Reaction time: 8 h

Procedure:
Iodine (750 mg, 2.96 mmol) was dissolved in 10 mL of THF and the solution was added to a solution of 2-(2-(trimethylsilyl)ethenyl)-3-methyl-2-cyclohexen-1-one (Compound 3, 560 mg, 2.70 mmol) and dichloromethane (50 mL) at room temperature. The solution was stirred overnight, and then treated with 10% aqueous Na2S2O3 to remove the excess iodine. The layers were separated and the aqueous layer was extracted 3× with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (9:1, hexane:ethyl acetate) to give the product as a brown oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=O.C(OC(Cl)=O)C(C)C.CN1CCOCC1.[CH3:41][C:42]([CH3:47])([CH3:46])[CH2:43][CH2:44][NH2:45]>ClCCl>[CH3:41][C:42]([CH3:47])([CH3:46])[CH2:43][CH2:44][NH:45][C:23](=[O:25])[CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:2]1=[O:1]
Reactant: CC(C)(C)CCN
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)CCNC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a stirred solution of (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetic acid (0.25 g, 0.74 mmol), isobutylchloroformate (0.11 mL, 0.81 mmol), N-methylmorpholine (0.09 mL, 0.81 mmol) in dichloromethane (10 mL) was added 3,3-dimethylbutylamine (0.11 g, 1.1 mmol). The solution was stirred at ambient temperature for 16 h, diluted with dichloromethane (10 mL) and washed with 2 M sodium carbonate (2×25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (30% to 50% gradient) to afford N-(3,3-dimethylbutyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide (0.13 g, 41%) as a colorless solid: mp 161-163° C.; 1H NMR (300 MHz, DMSO-d6) δ8.14 (dd, J=5.4, 5.4 Hz, 1H), 7.25 (dd, J=7.6, 7.6 Hz, 1H), 7.11 (d, J=6.9 Hz, 1H), 7.03-6.95 (m, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.37 (s, 1H), 4.71 (ABq, 2H), 4.51-4.40 (m, 2H), 4.38-4.20 (m, 2H), 3.12-3.01 (m, 2H), 2.93 (t, J=8.6 Hz, 2H), 1.37-1.27 (m, 2H), 0.85 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ177.6, 166.3, 161.5, 160.9, 143.1, 132.7, 129.0, 123.8, 123.3, 121.3, 120.2, 119.8, 109.4, 92.8, 80.2, 72.5, 57.3, 43.2, 43.0, 35.9, 30.0, 29.7, 28.8; MS (ES+) m/z 421.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[SH:11].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([S:11][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:4]=[CH:5][C:6]=1[O:9][CH3:10]
Reactant: COc1ccc(S)c(Cl)c1Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Sc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl

Procedure:
A mixture of 2,3-dichloro-4-methoxybenzenethiol (6.0 g., 0.024 mole), p-fluoronitrobenzene (3.04 ml., 0.029 mole) and anhydrous potassium carbonate (5.15 g., 0.038 mole) in 60 ml. of DMF was stirred at room temperature for 2 hours and then poured into water. The resulting solid product was filtered and washed well with ethanol to give 9.1 g. (96%), m.p. 236°-237°.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:12]([NH2:14])[CH3:13].C(N(CC)CC)C>ClCCl>[CH3:13][O:12][NH:14][C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CON
Reactant: O=C(O)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CONC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Introduce into a round-bottomed flask 6.8 g (50 mmol) of phenylacetic acid and 4.6 g (55 mmol) of methoxylamine hydrochloride, 5.55 g (55 mmol) of triethylamine and finally 10.83 g (52.5 mmol) of N,N-dicyclohexylcarbodiimide. Dissolve in 150 cm3 of dichloromethane. Stir for 16 hours at room temperature. Remove the precipitate by means of filtration and wash it with dichloromethane. Treat the filtrate with 100 cm3 of 3% HCl, then with 100 cm3 of water and finally with 100 cm3 of 5% NaHCO3.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(O)C>CN(C)C=O>[CH3:13][C:5]1[NH:6][C:7]2[C:12]([C:4]=1[CH2:3][CH2:2][N:23]1[CH2:24][CH2:25][CH:20]([C:17]3[CH:16]=[CH:15][C:14]([CH3:26])=[CH:19][CH:18]=3)[CH2:21][CH2:22]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: Cc1[nH]c2ccccc2c1CCBr
Reactant: Cc1ccc(C2CCNCC2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1ccc(C2CCN(CCc3c(C)[nH]c4ccccc34)CC2)cc1

Procedure:
A solution of 11.8 g of 3-(2-bromoethyl)-2-methylindole, 20.3 g of 4-(4-toluyl)piperidine [Example 5(a)] in 500 ml of dimethylformamide is treated according to the manipulative procedure described in Example 3(b) to give the off-white solid, mp 192°-194° C., 2-methyl-3-{2-[4-(4-toluyl)piperidyl]ethyl}indole from ethanol.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:11]=3[CH:10]=2)=[CH:3][CH:2]=1.CO[C:23]([CH2:29][CH3:30])=[CH:24][C:25]([O:27][CH3:28])=[O:26].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:28][O:27][C:25](=[O:26])[CH2:24][C:23]1([CH2:29][CH3:30])[C:16]2[NH:15][C:12]3[C:11]([C:17]=2[CH2:18][CH2:19][O:20]1)=[CH:10][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[CH:14][CH:13]=3
Reactant: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CCC(=CC(=O)OC)OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCC1(CC(=O)OC)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
A mixture consisting of 5-benzyloxytryptophol (24.0 g, 0.090 mol), methylene chloride (600 mL), methyl 3-methoxy-2-pentenoate (16.8 g, 0.177 mol) and borontrifluoride etherate (2 mL) is stirred at room temperature for 3 hours. The reaction mixture is washed with 5% NaHCO3 (2×200 mL), water (2×200 mL) and once with brine (200 mL), dried (MgSO4), filtered and concentrated to give 38.0 g crude product. The crude product is flash chromatographed on silica gel using 20% ethyl acetate/hexane as an eluent to afford 29.0 g pure title compound, m.p. 98°-100° C.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](=O)[C:4]([OH:6])=[O:5].[CH3:14][C:15]1[C:22]([C:23](=[S:25])[NH2:24])=[C:18]2[S:19][CH:20]=[CH:21][N:17]2[N:16]=1>CCO>[CH3:14][C:15]1[C:22]([C:23]2[S:25][C:2]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:3]([C:4]([OH:6])=[O:5])[N:24]=2)=[C:18]2[S:19][CH:20]=[CH:21][N:17]2[N:16]=1
Reactant: Cc1nn2ccsc2c1C(N)=S
Reactant: O=C(O)C(=O)C(Br)c1ccccc1
Solvent: CCO
Product: Cc1nn2ccsc2c1-c1nc(C(=O)O)c(-c2ccccc2)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A mixture of 3-bromo-2-oxo-3-phenylpropanoic acid (197 mg, 1.00 mmol) and 6-methylpyrazolo[5,1-b][1,3]thiazole-7-carbothioamide (267 mg, 1.10 mmol) in EtOH (10 ml) was stirred at 50° C. for 1 h. The reaction mixture was allowed to cool to rt, the resulting precipitate was collected by filtration and then washed with EtOAc to obtain title compound (328 mg, 96%) as a colorless solid. 1H-NMR (DMSO-d6) δ 2.61 (3H, s), 7.43-7.59 (6H, m) 8.31 (1H, d, J=4.2 Hz), 12.99 (1H, br s).
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=S)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:37])=[CH:6][C:5]=12.O>C1COCC1>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]6[O:34][CH2:33][C:32]([CH3:36])([CH3:35])[N:31]=6)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:37])=[CH:6][C:5]=12
Reactant: Cc1cc(Nc2ncnc3ccc(NC(=S)NC(C)(C)CO)cc23)ccc1Oc1ccn2ncnc2c1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2ncnc3ccc(NC4=NC(C)(C)CO4)cc23)ccc1Oc1ccn2ncnc2c1
Reaction time: 1 h

Procedure:
N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine was synthesized from 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea (322 g) in THF (3 L) at 0° C. Water (10 L) was added, and the solution was allowed to stir for 1 hour, at which point the material oiled out. The organics were then extracted into ethyl acetate (3×5000 mL), combined and washed with water (2×5000 mL) and brine (2×5000 mL). The organics were dried by rotoevaporation, and the material was concentrated to an oil. The oil was observed to solidify at room temperature to yield Form E.
Reaction SMILES: N.[C:2]([O:6][C:7](=[O:30])[N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=1[CH2:28][OH:29])[CH:9]1[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].[H][H]>CO.[Ni]>[C:2]([O:6][C:7](=[O:30])[N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=1[CH2:28][OH:29])[CH:9]1[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11][CH2:10]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C#N)cc1CO)C1CCCc2cccnc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(CN)cc1CO)C1CCCc2cccnc21
Yield: 54.6 %

Procedure:
Ammonia gas was bubbled through a solution of (4-cyano-2-hydroxymethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-carbamic acid tert-butyl ester (1.39 g, 3.55 mmol) in MeOH (40 mL) for 18 minutes. A prewashed mixture of Raney Nickel (˜1 gram) was added to the nitrile and the mixture was shaken for 16 hours under 30 psi hydrogen. The mixture was filtered through a celite plug and the filtrate was concentrated under reduced pressure. Purification via column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 94:5:1, v/v/v) afforded (4-aminomethyl-2-hydroxymethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-carbamic acid tert-butyl ester as an off-white solid (0.77 g, 55%). 1H NMR (CDCl3) δ 1.05 (s, 9H), 1.76 (m, 2H), 2.25 (m, 2H), 2.67 (m, 2H), 3.85 (s, 2H), 3.92 (d, 1H, J=15.0 Hz), 4.27 (m, 1H), 4.37 (d, 1H, J=9.0 Hz), 5.02 (d, 1H, J=12.0 Hz), 5.43 (d, 1H, J=15.0 Hz), 7.00 (m, 1H), 7.19 (m, 2H), 7.22 (m, 1H), 7.45 (m, 1H), 8.14 (d, 1H, J=3.0 Hz).