Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[Br:21][CH:22]([CH2:26][Br:27])[C:23](Cl)=[O:24]>C(N(CC)CC)C>[C:1]1([CH:7]2[N:11]([C:23](=[O:24])[CH:22]([Br:21])[CH2:26][Br:27])[CH2:10][CH:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(Br)CBr
Reactant: c1ccc(C2CNC(c3ccccc3)O2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C(Br)CBr)N1CC(c2ccccc2)OC1c1ccccc1
Reaction time: 0.5 h

Procedure:
Four and five tenths (4.5) grams of 2,5-diphenyl oxazolidine was dissolved in 50 ml. of methylene chloride and 5 g. of 2,3-dibromopropionyl chloride was added and the mixture stirred in an ice bath, while 2.1 g. of triethylamine was added dropwise. After standing for about 30 minutes, the mixture was washed with water, separated and dried over magnesium sulfate and stripped under vacuum. There was obtained a yield of 7.1 g. of an oil, the title compound, ND30 =1.5734.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:24])([CH3:23])[CH:9]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:24])([CH3:23])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC1(C)C=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1

Procedure:
10% Palladium-carbon (water-content ca. 50%, 20 mg) was added to a solution of N-[4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-7-yl]methanesulfonamide (a compound obtained in Example 5, 20 mg) in ethanol (4 mL), and the mixture was stirred under atmospheric pressure of hydrogen at room temperature for 20 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=95/5 to 70/30) to give the titled compound (20 mg) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]([C@H:19]2[CH2:23][CH2:22][C@H:21]([CH2:24]Br)[C@H:20]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:5][CH:4]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]([C@H:19]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C@H:20]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@H]2CC[C@H](CBr)[C@H]2c2ccc(F)cc2)cc1
Reactant: C1CCNC1
Solvent: CC#N
Product: COc1ccc(CN(C(=O)OCc2ccccc2)[C@H]2CC[C@H](CN3CCCC3)[C@H]2c2ccc(F)cc2)cc1
Temperature: 90 °C

Procedure:
To a solution of 500 mg of product from Step C in 3.0 mL of acetonitrile was added 0.40 mL of pyrrolidine. The reaction was heated at 90° C. for 3 days in a sealed vial and then concentrated. The residue was purified by flash chromatography eluting with 0 to 5% methanol in methylene chloride to obtain 483 mg of title compound. Mass spec (NH3 /CI): 517 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:35][CH:36]([CH3:38])[CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:42]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[NH2:42][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[C:19]2[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCCCCC(=O)O)cc23)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCCCCC(N)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77 %

Procedure:
A mixture of 5-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}pentanoic acid (0.8 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 g, 2.0 mmol), 1-hydroxy-1H-benzotriazole ammonium salt (0.24 g, 1.6 mmol) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from isopropyl ether to give tert-butyl {{6-[(5-amino-5-oxopentyl)oxy]-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl}methyl}carbamate (0.6 g, yield 77%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:22])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1[N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CO.O>[Cl:1][C:2]1[C:3](=[O:22])[NH:4][N:5]=[CH:6][C:7]=1[N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(c1ccccc1)c1cnn(C2CCCCO2)c(=O)c1Cl
Agent: Cl
Solvent: CO
Solvent: O
Product: CN(c1ccccc1)c1cn[nH]c(=O)c1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
A solution of 4-chloro-5-(methyl-phenyl-amino)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (272.5 mg, 0.85 mmol) in methanol (1.7 mL, 0.5M) was treated with a 6N aqueous hydrochloric acid solution (0.71 mL). The reaction solution was heated to 110° C., where it stirred for 4 h and was then allowed to completely cool down to 25° C. where it stirred overnight. After this time, the reaction was then diluted with water. The resulting solids were collected by filtration, washed with water, and dried in vacuo to afford 4-chloro-5-(methyl-phenyl-amino)-2H-pyridazin-3-one (159.2 mg, 79%) as a yellow solid that was used without further purification.
Reaction SMILES: [C:1]([C:4]1([CH2:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:33]([O:40][C:41](=[O:45])[C@H:42]([CH3:44])[NH2:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>O1CCCC1>[C:16]([S:15][CH2:14][C:4]1([C:1]([NH:43][C@H:42]([C:41]([O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:45])[CH3:44])=[O:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)SCC1(C(=O)O)CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (278 mg, 1.0 mmol) in anhydrous tetrahydrofuran (10 mL). Add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (230 mg, 1.2 mmol), L-alanine benzyl ester hydrochloride (216 mg, 1.00 mmol) and triethylamine (0.132 mL, 1.00 mmol). Stir at room temperature under an argon atmosphere overnight. Partition between ethyl ether and 5% sulfuric acid. Separate the organic phase and wash with water, saturated sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (20% ethyl acetate/hexane) to give the title compound as a clear yellow oil (210 mg, 48%).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][C@@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH2:28][C:29](OC)=[O:30])[CH2:17]2)=[O:14])=[N:5]1)([CH3:3])[CH3:2].[BH4-].[Li+].O>O1CCCC1>[OH:30][CH2:29][CH2:28][C@@H:18]1[CH2:17][C@H:16]([NH:15][C:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)=[O:14])[CH2:20][N:19]1[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: COC(=O)C[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CCO)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl (2S,4S)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (200 mg, 0.45 mmol, step 5 of Example 9) in tetrahydrofuran (5 mL) was added lithium borohydride solution (2 M in tetrahydrofuran, 1.13 mL, 2.25 mmol) at room temperature. The mixture was stirred at room temperature for 20 h. To the resulting mixture water (10 mL) was added. The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (10 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:1) to give 182 mg (97%) of the title compound as a white amorphous solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[S:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[Cl:15][C:16]1[CH:25]=[C:24]([NH:26][C:12]([C:6]2[S:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(C)c1cc(C(=O)O)sc1C(C)C
Reactant: COC(=O)c1ccc(N)cc1Cl
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1Cl
Yield: 34.2 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylthiophene-2-carboxylic acid (80 mg, 0.377 mmol) and methyl 2-chloro-4-aminobenzoate (126 mg, 0.679 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [n-hexane-ethyl acetate (40:1)] and recrystallized to obtain methyl 2-chloro-4-[(4,5-diisopropylthiophene-2-carbonyl)amino]benzoate (49 mg, 34%) as colorless prisms.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>>[F:10][C:11]([F:21])([F:22])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([C:5]1[S:1][C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1)=[O:16]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cc1cccs1
Product: O=C(O)Cc1ccc(C(=O)c2cccc(C(F)(F)F)c2)s1

Procedure:
Using the procedure of Example 1, 7.1 gm of thiophene-2-acetic acid and 10.40 gm of m-trifluoromethyl-benzoyl chloride were reacted to obtain 5(m-trifluoromethyl-benzoyl)-thiophene-2-acetic acid melting at 120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[C:7]([CH3:13])=[N:8][N:9]([CH3:12])[C:10]=1[OH:11])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][N:28]([CH3:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[C:7]([CH3:13])=[N:8][N:9]([CH3:12])[C:10]=1[O:11][CH2:26][CH2:27][N:28]([CH3:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:5]
Reactant: CN(CCBr)c1ccccc1
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nn(C)c(OCCN(C)c2ccccc2)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 91.4 %

Procedure:
2.85 g of 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-5-hydroxypyrazole was dissolved in 50 ml of acetonitrile, and 1.38 g of potassium carbonate (anydrous) was added thereto. The resultant mixture was stirred at room temperature for 2 hours, 2.14 g of β-bromoethyl-N-methylaniline was added, and the mixture heated for 3 hours under reflux. After cooling, crystals were filtered off. The filtrate was distilled under reduced pressure and the residue was purified by silica gel chromatography (eluent, benzene:ethyl acetate at 8:1) to give 3.82 g of the desired product, Compound 2, having nD24 1.5975 (yield 91.4%).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[C:16]([O:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[C:33]([CH2:35][C:36](O)=[O:37])[N:32]=[CH:31]1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:22])[F:23])=[C:16]([O:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:36](=[O:37])[CH2:35][C:33]1[N:32]=[CH:31][NH:30][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)Oc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: O=C(O)Cc1c[nH]cn1
Product: O=C(Cc1c[nH]cn1)N1CCN(c2ccc(OC(F)F)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Yield: 26 %

Procedure:
Prepared using the same procedure described in Example 189 from (S)-3-benzyl-1-(3-cyclopentyloxy-4-difluoromethoxy-phenyl)-piperazine and (1H-imidazol-4-yl)-acetic acid to afford the title compound as colorless solid (46 mg, 26%). LC/MS (Method B) 2.77 min, [M+1]+ 511.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[CH2:12]1[CH2:21][O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13]1>>[CH2:12]1[CH2:21][O:20][C:14]2([CH2:19][CH2:18][N:17]([C:2]3[CH:3]=[C:4]([CH3:11])[C:5]4[N:6]([CH:8]=[N:9][N:10]=4)[N:7]=3)[CH2:16][CH2:15]2)[O:13]1
Reactant: Cc1cc(Cl)nn2cnnc12
Reactant: C1CC2(CCN1)OCCO2
Product: Cc1cc(N2CCC3(CC2)OCCO3)nn2cnnc12

Procedure:
reacting 6-chloro-8-methyl-1,2,4,triazolo[4,3-b]pyridazine with 4,4-ethylenedioxypiperidine to give 6-(4,4-ethylenedioxy-1-piperidinyl) -8-methyl-1,2,4-triazolo[4,3-b]pyridazine;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.[F:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][N:25]2[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[I:35])=[CH:21][C:20]=1[S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:36]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:19]=1[F:18])[N:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[I:35])[N:24]=[CH:23]2)(=[O:37])=[O:38]
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc2cnn(Cc3ccccc3I)c2cc1F
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3cnn(Cc4ccccc4I)c3cc2F)c(OC)c1
Reaction time: 0.5 h

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (0.61 g, 2.44 mmol, 1.1 equiv) in THF (5.55 mL) at −78° C. was added LIHMDS (2.441 mL, 2.44 mmol, 1.1 equiv) and stirred for 0.5 h followed by the slow addition of 6-fluoro-1-(2-iodobenzyl)-1H-indazole-5-sulfonyl chloride (2-2, 1.0 g, 2.22 mmol, 1.0 equiv) in THF (1.85 mL) and stirred overnight as the system approached ambient temperature. The reaction was quenched with ammonium chloride and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated and the residue was purified by normal phase chromatography (0→40% EtOAc in hexanes). ESI+ MS [M+H]+ C25H21FIN5O4S2: 666.1 found, 666.5 required.
Reaction SMILES: Cl[CH2:2][N:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.CCOCC>ClCCl>[CH2:9]([N:3]([CH2:2][N:22]1[CH:23]=[C:18]([Cl:17])[CH:19]=[N:20][C:21]1=[O:24])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CCOC(=O)N(CCl)Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)N(Cc1ccccc1)Cn1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
N-Chloromethyl-N-ethoxycarbonylbenzylamine (see German Offenlegungsschrift No. 2,119,518) (10 mmol) in dichloromethane (20 ml) was added dropwise with stirring to a solution of 5-chloropyrimidin-2-one hydrochloride (20 mmol) in dichloromethane (80 ml). The reaction mixture was stirred at room temperature for 2 hours, extracted with water, the solution dried (MgSO4) and evaporated. The residual crude product (yield 80%, 2.57 g) was triturated with ether to leave the title compound in 53% yield (1.70 g), m.p. 143° C. 1H NMR (CDCl3): δ1.31 and 4.22 (EtO), 4.73 (CH2Ph), 5.23 (CH2N), 7.20 (Ph), 8.03 and 8.38 (H-4, H-6, J 4 Hz). IR(KBr): 1670 cm-1 (CO), 1720 (CO-carbamate).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](O)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:8]=3[C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:21].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[Cl:21][C:4]1[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:8]=3[C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)c2c(n1)-c1cc(Cl)ccc1OCC2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c2c(n1)-c1cc(Cl)ccc1OCC2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of Example 45C (0.56 g, 2.1 mmol) in CHCl3 (4.2 mL) was treated with POCl3 (0.97 mL, 10.5 mmol), cooled to 0° C., treated with triethylamine (0.59 mL, 4.2 mmol), stirred at ambient temperature for 4 hours, diluted with CHCl3 (5 mL), treated with a stream of HCl gas for 2 minutes, stirred at ambient temperature overnight and partitioned between cold 1 M NaOH (50 mL) and CH2Cl2 (50 mL). The layers were separated and the aqueous was extracted with CH2Cl2 (2×50 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed eluting with CH2Cl2 and then 9:1 CH2Cl2:EtOAc to provide the title compound. 1H NMR (DMSO-d6) δ 2.87 (t, J=5.76 Hz, 2H) 4.43 (t, J=5.93 Hz, 2H) 7.12 (s, 2H) 7.15 (d, J=8.81 Hz, 1H) 7.52 (dd, J=8.65, 2.88 Hz, 1H) 7.88 (d, J=2.71 Hz, 1H); MS (M+H)+ m/z 282.
Reaction SMILES: [C:1]([O:9][C@@H:10]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:11](=[O:32])[CH2:12][C@@H:13]([CH3:31])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[C:1]([O:9][C@@H:10]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:11](=[O:32])[CH2:12][C@@H:13]([CH3:31])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CC(=O)[C@H](Cc1ccccc1)OC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](CC(=O)[C@H](Cc1ccccc1)OC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h

Procedure:
A mixture of 1-[(5S,2R)-5-(benzoyloxy)-2-methyl-1,4-dioxo-6-phenylhexyl]-L-proline, phenylmethyl ester (230 mg., 0.435 mmole) and 10% palladium on carbon catalyst (50 mg.) in ethyl acetate (15 ml.) is stirred under hydrogen gas for 4 hours. The resulting mixture is filtered (millipore) and the filtrate concentrated to give the desired product as a colorless solid which is then dried under vacuum over P2O5 to give 144 mg. of 1-[(5S,2R)-5-(benzoyloxy)-2-methyl-1,4-dioxo-6-phenylhexyl]-L-proline; m.p. 130°-134°; [α]D20 =-110° (c=1.09, pyridine); Rf =0.37 [silica gel, ethyl acetate:pyridine:acetic acid; water (180:20:6:11)].
Reaction SMILES: C(OC1C=C2[C:11](=[CH:12][C:13]=1C)[N:10]([C:15](=O)[CH3:16])N=C2)(=O)C.[CH3:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][C:20]=1[OH:28]>>[CH3:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][C:20]=1[O:28][CH:13]1[CH2:12][CH2:11][NH:10][CH2:15][CH2:16]1
Reactant: Cc1cc2[nH]ncc2cc1O
Reactant: CC(=O)Oc1cc2cnn(C(C)=O)c2cc1C
Product: Cc1cc2[nH]ncc2cc1OC1CCNCC1

Procedure:
The following compound of Example 406 was synthesized by carrying out reactions according to the methods described in Example 372, (b) and Example 377, except for using the 6-methyl-1H-indazol-5-ol synthesized in Example 403, as a starting material.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18](=O)[C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH2:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:24][C:25]1[CH:26]=[C:27](/[N:28]=[C:18](/[C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([C:3]4[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[NH:10][C:11]=3[CH:17]=2)\[C:19]([F:22])([F:20])[F:21])[CH:29]=[CH:30][C:31]=1[CH3:32]
Reactant: Cc1ccc(N)cc1C
Reactant: Cc1cccc(C)c1-c1nc2ccc(C(=O)C(F)(F)F)cc2[nH]1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(/N=C(/c2ccc3nc(-c4c(C)cccc4C)[nH]c3c2)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[2-(2,6-dimethylphenyl)-3H-benzoimidazol-5-yl]-2,2,2-trifluoro-ethanone (710 mg), 3,4-dimethylaniline (150 mg) and diisopropylethylamine (150 mg) in methylene chloride (15 mL) was added dropwise 1.1 mL of a 1.0M solution of TiCl4 in methylene chloride. The mixture was stirred at ambient temperature for 10 min then was washed with NaHCO3 solution. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using 10% EtOAc/methylene chloride as eluent to give (3,4-dimethyl-phenyl)-[1-[2-(2,6-dimethylphenyl)-3H-benzoimidazol-5-yl]-2,2,2-trifluoroeth-(Z)-ylidene]-amine as an oil. This was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[CH2:9][CH2:8]2)=[O:4].[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[C:13]([Br:24])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[CH2:9][CH2:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(c1O)CCC(=O)N2Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(c1O)CCC(=O)N2Cc1ccccc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (300 mg, 0.96 mmol) and N-bromosuccinimide (180 mg, 1.01 mmol) in CH2Cl2 (3 mL) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo, and the residue was chromatographed (0-30% EtOAc/hexanes+2% AcOH) to give 296 mg of the title compound. MS: (+) m/z 390.98, 392.88 (M+H, 79/81Br)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([N+:16]([O-:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][CH:8]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]([N+:16]([O-:18])=[O:17])[CH2:9][C:5]=2[CH:4]=1
Reactant: COc1cccc(CC(CCC(=O)O)[N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc2c(c1)CC([N+](=O)[O-])CCC2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
A mixture of 5-(3-methoxyphenyl)-4-nitrovaleric acid (1.00 g) and thionyl chloride (0.34 ml) in 1,2-dichloroethane (2 ml) was refluxed for 1 hour. After cooling, aluminum chloride (0.53 g) was added to the solution at -12° C. and the whole was stirred for 0.5 hour. The solution was poured into ice water (15 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give 2-methoxy-8-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (772 mg).