Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:19][CH:20]([CH3:24])[C:21](Br)=[O:22]>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:21](=[O:22])[CH:20]([Br:19])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCc1ccccc1
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Br)C(=O)OCCOCc1ccccc1
Temperature: -5 °C

Procedure:
15.2 g of 2-benzyloxyethanol and 10.6 g of triethylamine were dissolved in 150 ml of toluene, and the solution was cooled to -5° C. A solution of 21.6 g of 2-bromopropionylbromide in 30 ml of toluene was added dropwise thereto at -5° to 0° C. with stirring. The reaction mixture was further maintained at room temperature for two hours. The mixtue was then washed successively with 1% strength by weight sodium hydroxide solution and water, and the toluene solution was then dried and filtered. The toluene was distilled off under reduced pressure, and the end product of 2-benzyloxyethyl-2-bromopropionate was obtained in a yield of 26.7 g (nD20.5 1.5182)
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[CH3:40][N:41]1[C:45]([CH3:46])=[C:44](B(O)O)[CH:43]=[N:42]1>>[NH2:32][C:4]1[S:3][C:2]([C:44]2[CH:43]=[N:42][N:41]([CH3:40])[C:45]=2[CH3:46])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cc1c(B(O)O)cnn1C
Product: Cc1c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)c(N)s2)cnn1C

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid gave 257. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.25 (s, 2H), 4.79 (dd, J=10.7, 3.6 Hz, 1H), 4.41 (ddd, J=49.5, 4.9, 2.7 Hz, 1H), 4.26-3.94 (m, 2H), 3.76 (d, J=5.4 Hz, 6H), 3.30-3.16 (m, 1H), 2.52 (s, 3H), 2.04 (dq, J=11.8, 4.1 Hz, 1H), 1.81 (dd, J=13.6, 10.0 Hz, 1H), 1.73-1.64 (m, 2H). LCMS (ES+) m/z 449 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]3[CH:12]=[C:13]([I:16])[CH:14]=[N:15][C:8]=3[NH:7][C:6]2=[S:17])[CH2:3][CH2:2]1.[CH2:18](I)[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]3[CH:12]=[C:13]([I:16])[CH:14]=[N:15][C:8]=3[N:7]=[C:6]2[S:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3]1
Reactant: O=c1c2cc(I)cnc2[nH]c(=S)n1CC1CC1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2ncc(I)cc2c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of the title compound of Step A (0.5 g, 1.39 mmol), n-propyl iodide (0.36 g, 2.09 mmol) and potassium carbonate (1.9 g, 13.9 mmol) in DMF (14 mL) were stirred at ambient temperature overnight. The reaction mixture was then concentrated to dryness in vacuo and the residue partitioned between 200 mL of ethyl acetate and 100 mL of H2O. The organic phase was separated, washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to provide 0.5 g of crude product. Purification of this crude product was achieved via column chromatography (silica gel, 70:30 hexanes:ethyl acetate eluent) to deliver 0.19 g of the title compound of Step B, a compound of the invention, as a solid melting at 159-161° C. 1H NMR (300 MHz, CDCl3): δ 0.50-0.62 (m,4H), 1.10 (t,3H), 1.31-1.43 (m,1H), 1.79-1.94 (m,2H), 3.41 (t,2H), 4.10 (d,2H), 8.82 (s,1H), 9.02 (d, 1H). Mass Spectrum: m/e 402 (protonated parent molecular ion measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+); the ion shown corresponds to the M+H+ ion calculated from the integral values of the atomic weights of the most abundant isotope of each element present).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][CH:7]([C:9]1[N:14]=[N:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:11][CH:10]=1)[CH3:8])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]1[N:14]2[C:9]([CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:13]2)=[C:7]([CH3:8])[N:6]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccccc3Cl)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccccc4Cl)n3n2)cc1
Yield: 32.3 %

Procedure:
Applying the Cyclization Procedure 1, 2-chloro-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 53) (127 mg, 0.33 mmol), 1,2-dichloroethane (6.6 mL) and phosphorus oxychloride (0.250+0.154 mL, 4.33 mmol), to afford 7-(2-chlorophenyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (39 mg) as a yellow solid. MS m/z 366 (M+1).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:12]1([N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(-n2cccc2)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2.96 g (0.02 mole) of phthalic anhydride and 5.72 g (0.04 mole) of N-phenylpyrrole in 50 ml of chlorobenzene, maintained at 0°-5° C. in an ice bath, 810 g (0.06 mole) of aluminum chloride was added in small portions. The reaction mixture was held at 0°-5° C. for approximately two hours. The reaction was allowed to warm to room temperature and then set aside overnight at ambient temperature. The reaction mixture was worked up in a manner similar to that described in part A of Example 15 to obtain 2-[(1-phenyl-2-pyrrolyl)carbonyl]benzoic acid (Formula IX: Ro =R1 =R2 =R3 =H; R7 =C6H5) which melted over the range 159°-168° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][OH:13]>>[C:4]([O:13][CH3:12])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CO
Product: COC(=O)c1ccccc1C(=O)O

Procedure:
Methanol (300 ml) was added in a single portion to 148 g (1.00 mole) of phthalic anhydride and the resulting suspension was stirred and heated at reflux for 36 hours; solution occurred during heating. The solvent was removed and the product was recrystallized from a mixture of ethyl acetate and hexane to afford 114.6 g of the title compound (Lit.: Beilstein, 9 797-m.p. 82.5°-84°).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]2[C:11]=1[CH3:12].[CH3:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([CH3:23])[C:15]=1[CH2:16]Br.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:16][C:15]3[C:14]([CH3:13])=[CH:21][C:20]([F:22])=[CH:19][C:18]=3[CH3:23])=[CH:8][CH:7]=[CH:6][N:5]2[C:11]=1[CH3:12]
Reactant: Cc1cc(F)cc(C)c1CBr
Reactant: Cc1nc2c(O)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cc(F)cc(C)c1COc1cccn2c(C)c(C)nc12

Procedure:
2,3-Dimethyl-8-hydroxyimidazo[1,2-a]pyridine (1.7 g, 10 mmol), 2,6-dimethyl-4-fluorobenzylbromide (2.3 g, 10 mmol), sodium iodide (0.5 g, 0.3 mmol) and sodium carbonate (2.6 g, 28 mmol) were added to acetone (75 ml) and the mixture was refluxed for 6 h. Methylene chloride was added and the mixture was filtered and the solvents were evaporated under reduced pressure. Purification by column chromatography on silica gel using methylene chloride:ethylacetate(1:2) as eluent gave the title compound as a white powder. (0.85 g, 28%)
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:56]=[CH:57][CH:58]=[CH:59][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:43]=[C:44]([C:52]([F:55])([F:53])[F:54])[CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:56]=[CH:57][CH:58]=[CH:59][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.5 mg (0.06 mmol) LiOH in 1 mL water was added to a solution of 35 mg (0.04 mmol) of (R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 50) in 5 mL THF and the reaction solution was stirred overnight at RT. The mixture was evaporated down in vacuo, the residue was taken up in water, acidified with 1 N HCl, the precipitate was filtered off and dried in the vacuum drying cupboard.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:28][C:29]([OH:31])=O)[C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:32]>C(Cl)Cl>[NH2:32][C:29](=[O:31])[CH2:28][N:8]([C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: N
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)[C@@H]1C[C@H]1c1ccc(OCc2ccc(C#N)cc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CC(N)=O)[C@@H]1C[C@H]1c1ccc(OCc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75.1 %

Procedure:
N,N′-Carbonyldiimidazole (27 mg, 0.17 mmol) was added to a solution of [(tert-butoxycarbonyl){(trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropyl}amino]acetic acid (50 mg, 0.12 mmol) in dry CH2Cl2 (3 mL) at 0° C. (ice-water bath). The solution was stirred for 40 min at room temperature and cooled again at 0° C.; NH3 (25% aqueous solution, 0.05 mL, 0.60 mmol) was added and the reaction was allowed to reach room temperature and stirred for additional 1.5 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with brine (10 mL) and HCl (10% aqueous solution, 1 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the crude product was purified by column chromatography on silica gel (5% MeOH/CH2Cl2) affording 38 mg of tert-butyl 2-amino-2-oxoethyl[(trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropyl]carbamate [Rf=0.6 (10% MeOH/CH2Cl2), colorless oil, 76% yield].
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([OH:21])=O)=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]([S:60][CH2:61][C@@H:62]([C:64]([NH2:66])=[O:65])[NH2:63])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:66][C:64](=[O:65])[C@@H:62]([NH:63][C:19](=[O:21])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:17][CH2:16][NH:15][C:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@@H:6]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:40])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])=[CH:31][CH:30]=1)=[O:14])[CH2:61][S:60][C:41]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
2.50 g (4.42 mmol) of the compound from example 2A was dissolved in 100 ml dichloromethane. 1.602 g (4.42 mmol) S-Trityl-L-cysteinamide, 0.77 ml (4.42 mmol) N,N-diisopropylethylamine and 1.68 g (4.42 mmol) HATU were added. The reaction mixture was split into 5 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1, dichloromethane/methanol 20/1 and dichloromethane/methanol 10/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.12 g (3.30 mmol, 75% of theory, 73% purity) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1.N(OC(C)(C)C)=O.O>C1COCC1>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(Cl)nc2ccc(Oc3ccc(F)cc3F)cc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(Oc2ccc3nc(Cl)ncc3c2)c(F)c1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
Compound (1G) (21 g, 0.07 mol) was dissolved in THF (200 mL) and the solution added dropwise to a solution of t-butyl nitrite (16.5 mL, 0.14 mol) in THF (100 mL). The mixture was heated to reflux for 4 h, and after cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (2×100 mL). The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The crude product was purified by chromatography (silica gel, hexane: EtOAc, 4:1) giving 9.05 g of 2-chloro-6-(2,4-difluoro-phenoxy)-quinazoline (1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([C:18]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])[CH3:17]>C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:7][NH:8][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:18]=1[CH2:16][CH3:17])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCc1c(OC)cccc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCc1c(OC)cccc1C(=O)NNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
Tert-butylcarbazate (80.0 g, 605 mmol) was stirred in 800 mL methylene chloride and cooled to 0° C. To this was added the potassium carbonate solution (937 g, 847 mmol). 2-Ethyl-3-methoxybenzoyl chloride (132 g, 666 mmol) was dissolved in 400 mL of methylene chloride and added to the reaction mixture dropwise over 15 minutes. The mixture was stirred at 0° C. for 15 min, then at room temperature for 18 hours. The reaction was diluted with more methylene chloride and water. The aqueous phase was separated. The remaining organic phase was washed with 1N HCl, water, saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was triturated with hexane to give a white solid, N′-(2-ethyl-3-methoxy-benzoyl)-hydrazinecarboxylic acid tert-butyl ester (167 g, 567 mmol) in 94% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.4 (br s, 1H), 7.22 (t, 1H), 7.03 (br d, 1H), 6.95 (d, 1H), 6.65 (br, 1H), 3.84 (s, 3H), 2.8 (q, 2H), 1.51 (s, 9H), 1.2 (t, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([C:11]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[C:12]([C:16]([O:18]CC)=[O:17])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.[OH-].[Li+]>O1CCCC1.O>[C:23]([CH2:22][CH2:21][C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13][C:12]=1[C:16]([OH:18])=[O:17])([OH:25])=[O:24]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(-c3ccccc3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1c(C(=O)O)[nH]c2cc(-c3ccccc3)ccc12
Temperature: 25 °C
Yield: 95 %

Procedure:
Ethyl 6-phenyl-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (3.65 g, 10 mmol) was dissolved in 25 ml tetrahydrofurane (THF) with stirring at rt. Then a solution of 1.26 g of lithium hydroxide trihydrate (3 equiv.) in 25 ml water was added and the resulting mixture was let to stir at rt for 24 h. After completion of the reaction THF was removed under reduced pressure and the pH was adjusted to 4-5, and the product was extracted with diethyl ether (3×25 ml). The organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield a light-beige-colored solid in 95-100% yield. mp. 238-239° C. 1H-NMR (DMSO-d6) δ 2.54 (m, 2H, 2′-H); 3.28 (m, 2H, 1′-H); 7.35 (m, 2H, 4-H, 5-H); 7.46 (m, 2H, 2″-H, 6″-H); 7.60 (dd, 1H, 4″-H); 7.63 (m, 2H, 3″-H, 5″-H); 7.75 (dd, 1H, 7-H); 11.55 (s, 1H, NH); 12.50 (b, 2H, 2CO2H). 13C-NMR (DMSO-d6) δ 20.1 (C2′); 35.3 (C1′); 110.2 (C-7); 119.2 (C-5), 121.1 (C-4); 121.4 (C-3); 124.8 (C-3a); 126.6 (C-2); 127.0 (C-3″, C-5″); 127.2 (C-4″); 129.1 (C-3″, C-6″); 136.8 (C-7a); 137.2 (C-6); 141.3 (C-1″); 163.1 (2′-CO2H); 174.1 (2-CO2H). LC-MS (m/z): 310 [M]+, 308 [M]−. Purity (LC-MS): 98%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([C:18](=[O:23])N(OC)C)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:31]([NH:32][C:33](=[O:35])[CH3:34])=[CH:30][CH:29]=[CH:28][N:27]=1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[C:18](=[O:23])[CH2:25][C:26]1[C:31]([NH:32][C:33](=[O:35])[CH3:34])=[CH:30][CH:29]=[CH:28][N:27]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Nc1cccnc1C
Reactant: CON(C)C(=O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C
Product: CC(=O)Nc1cccnc1CC(=O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2,5-Difluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (4.85 mmol; 1.67 g) and N-(2-Methylpyridin-3-yl)acetamide (12.12 mmol; 1.82 g) gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>>[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:31]
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1ccco1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccco1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.061 mMol) furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].C(O[C:16](=O)[CH2:17][C:18](=[O:24])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)C>C1(C)C=CC=CC=1>[N:1]1[CH:5]=[CH:4][N:3]2[C:2]=1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[N:8]=[C:16]2/[CH:17]=[C:18](/[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)\[OH:24]
Reactant: CCOC(=O)CC(=O)c1cccs1
Reactant: Nc1ccccc1-c1ncc[nH]1
Solvent: Cc1ccccc1
Product: O/C(=C\c1nc2ccccc2c2nccn12)c1cccs1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
A mixture of 2-(1H-imidazol-2-yl)aniline (60.0 mg, 0.38 mmol), ethyl3-oxo-3-(2-thienyl)propanoate (74.7 mg, 0.38 mmol) and p-tolenesulfonicacid monohydrate (36.1 mg, 0.19 mmol) in toluene (30 ml) was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was poured into aqueous saturate NaHCO3 solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (ethyl acetate/ hexane, 2/3-1/1) to give (Z)-2-imidazo[1,2-c]quinazolin-5-yl-1-(2-thienyl)ethenol (37.0 mg, 33% yield) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=O)[C:11]1=[O:20].Cl.[NH2:22][OH:23]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[N:22][OH:23])[C:11]1=[O:20]
Reactant: NO
Reactant: Cc1ccc(Cl)c(N2C(=O)C(=O)c3ccccc32)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(Cl)c(N2C(=O)C(=NO)c3ccccc32)c1Cl
Yield: 81.3 %

Procedure:
A solution of 1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione (0.3 g) and hydroxylamine hydrochloride (0.07 g) in pyridine (2 ml) is stirred at room temperature for 20 minutes. The reaction mixture is diluted with ethyl acetate (20 ml) and washed with 1 N HCl (2×100 ml). The organic layer is dried (MgSO4) and evaporated. Flash chromatography (silica, CH2Cl2) followed by recrystallization from isopropyl ether affords 1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione 3-oxime (256 mg, 80%), mp 190°-191° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[C:7](=O)[CH:8]=O.[CH2:12]([NH2:15])[CH2:13][NH2:14].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[CH:7]1[CH2:8][NH:15][CH2:12][CH2:13][NH:14]1
Reactant: O=CC(=O)c1cc(Cl)sc1Cl
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Clc1cc(C2CNCCN2)c(Cl)s1
Reaction time: 3 h

Procedure:
A 10.45 g portion of the above aldehyde was suspended in 200 ml of ethanol, cooled to 0°-5° C. and a solution of 3.3 g of ethylenediamine in 20 ml of ethanol added dropwise with stirring. The mixture was allowed to come to room temperature over 3 hours, then 3.8 g of sodium borohydride was added and the mixture was evaporated to dryness. The residue was dissolved in dichloromethane, water washed, filtered, dried and evaporated. The resulting gum was triturated with ether producing an oil. The oil was purified by chromatography, eluting with chloroform:methanol (9:1), giving an oil which crystallized, giving 3.3 g of 2-(2,5-dichloro-3-thienyl)piperazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[C:18](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH3:18])=[O:6]
Reactant: O=C([O-])O
Reactant: COc1ccc(C(=O)O)cc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OC)c(O)c1
Reaction time: 8 h

Procedure:
A mixture of 3-hydroxy-4-methoxybenzoic acid (Aldrich, 10 g, 59.5 mmol), methanol (250 ml) and concentrated sulfuric acid (1 ml) was stirred overnight and the product was poured into a mixture of sodium bicarbonate and ice. The aqueous mixture was then extracted three times with ethyl acetate. The resulting organic layers were combined, washed with water and brine, and dried over anhydrous magnesium sulfate. Rotary evaporation of the solution gave 9.5 g of the desired product as a colorless oil. NMR (δ):3.89 (s, 3H), 3.95 (s, 3H).