Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7](S(C)(=O)=O)[N:6]=[C:5]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15](S(C3C=CC=CC=3)(=O)=O)[CH:14]=2)[CH:4]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN1CCCC1=O>[NH:31]([C:7]1[NH:8][C:3](=[O:2])[CH:4]=[C:5]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[N:6]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(S(C)(=O)=O)n1
Reactant: Nc1ccccc1
Solvent: CN1CCCC1=O
Product: O=c1cc(-c2c[nH]c3ncccc23)nc(Nc2ccccc2)[nH]1

Procedure:
A mixture of EXAMPLE 1B (0.089 g, 0.20 mmol), and aniline (0.2 mL) in N-methylpyrrolidone (3 mL) was heated in a microwave at 235° C. for 1.5 hours. The mixture was concentrated and purified by reverse phase HPLC to provide the title compound. MS (ESI) m/e 304 (M+H)+; 1H NMR (DMSO-d6) δ 6.33 (s, 1H), 7.06-7.18 (m, 2H), 7.34-7.45 (m, 2H), 7.68 (d, J=7.67 Hz, 2H), 8.23 (s, 1H), 8.26-8.31 (m, 1H), 8.56 (d, J=7.67 Hz, 1H), 8.84 (s, 1H), 12.22 (s, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:8](=[O:31])[C:9]3[CH:30]=[CH:29][CH:28]=[N:27][C:10]=3[N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:14]=3)[N:12]=2)=[O:6])[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:37]>ClCCl>[CH:1]1([NH:4][C:5]([C:7]2[C:8](=[O:31])[C:9]3[CH:30]=[CH:29][CH:28]=[N:27][C:10]=3[N:11]([C:13]3[CH:14]=[C:15]([C:19]#[C:20][C:21]4[CH:22]=[N+:23]([O-:37])[CH:24]=[CH:25][CH:26]=4)[CH:16]=[CH:17][CH:18]=3)[N:12]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(NC1CC1)c1nn(-c2cccc(C#Cc3cccnc3)c2)c2ncccc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(NC1CC1)c1nn(-c2cccc(C#Cc3ccc[n+]([O-])c3)c2)c2ncccc2c1=O
Yield: 17.7 %

Procedure:
N-cyclopropyl-4-oxo-1-[3-(pyridin-3-ylethynyl)phenyl]-1,4-dihydropyridino[2,3-c]p yridazine-3-formamide (0.15 g, 0.36 mmol) was dissolved in 50 mL of dichloromethane solution, m-chloroperoxybenzoic acid (0.062 g, 0.36 mmol) was added and reacted at room temperature. After reaction was complete, separation was purified by liquid preparation chromatography column to obtain product 27 mg.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:25]([N+:26]([O-])=O)=[CH:24][C:8]2[CH:9]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][C:11]([CH3:14])([CH3:13])[O:12][C:7]=2[CH:6]=1.C([OH:31])C>[C].[Pd]>[NH2:26][C:25]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C@@H:10]([OH:31])[C@H:9]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:24]=1
Reactant: COCOc1cc2c(cc1[N+](=O)[O-])C(NCCc1ccccc1)CC(C)(C)O2
Reactant: CCO
Agent: [Pd]
Product: COCOc1cc2c(cc1N)[C@@H](NCCc1ccccc1)[C@H](O)C(C)(C)O2
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 7-methoxymethoxy-2,2-dimethyl-6-nitro-4-(2-phenylethylamino)-3,4-dihydro-2H-1-benzopyrane (265 mg, 0.66 mmol) in ethanol (5 mL), 5% palladium-carbon (AER type, 13 mg) was added at room temperature, and the resulting mixture was stirred under hydrogen stream overnight. Upon the completion of the reaction, the resulting solution was filtered through celite, concentrated, and the aimed product was obtained (yield: 98%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][C:25](O)=O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:23][CH2:24][C:25]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1ccc(CCC(=O)O)cc1Cl
Product: COc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1Cl

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3-(3-chloro-4-methoxyphenyl)propionic acid (215 mg; 1 mmol) as described in method 2; yield: 0.071 g (20.1%); MS m/z: 355.4/357.1 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.06-3.08 (m, 2H); 3.24-3.27 (m, 2H); 3.80 (s, 3H); 7.04-7.06 (m, 1H); 7.21-7.23 (m, 1H); 7.39 (br s, 1H); 7.87-7.89 (m, 1H); 7.94-7.96 (m, 1H); 8.25 (br s, 1H); 8.92 (s, 1H); HPLC (METHOD [A]): rt 12.55 min (95.7%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][O:14][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:8]1)=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
Prepare by the method of Example 1.5 using (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and methanesulfonyl chloride to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Sn](C)(C)C)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)c1nn(Cc2ccccc2)c2ccccc12
Reactant: Clc1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: c1ccc(Cn2nc(-c3ncccn3)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
200 mg of 1-benzyl-3-trimethylstannylindazole (crude product, 70% according to GC), 35 mg of 2-chloropyrimidine (0.30 mmol) and 29 mg (0.025 mmol) of Pd(PPh3)4 in 2.5 ml of toluene were heated under reflux overnight in an argon atmosphere. The mixture was cooled to room temperature, saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and freed from the solvent on a rotary evaporator. Purification was carried out by chromatography over aluminium oxide using cyclohexane/ethyl acetate as the eluent (gradient from 10:1 to 1:1).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl.C(N(CC)CC)C>[CH2:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(O)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A 2-L round-bottom flask was charged with 25.832 g isonipecotic acid, 30.5 mL benzaldehyde, 41.8 mL triethylamine, and 500 mL 1,2-dichloroethane to which was added 63.6 g sodium triacetoxyborohydride in portions over 20 minutes with stirring. After 24 hours, 4 mL benzaldehyde was added along with 21.2 g sodium triacetoxyborohydride in portions with 400 mL 1,2-dichloroethane. After an additional 8 hours, 4 mL of benzaldehyde was added along with 8.8 g sodium triacetoxyborohydride in portions. After stirring for additional 20 hours, the reaction mixture was poured into a separatory funnel, 300 mL each of ice water and concentrated HCl was added, the layers were separated, and the organic layer was washed with 4×75 mL 0.5M HCl. The combined aqueous layer was washed with 2×200 mL ether and was then concentrated under reduced pressure to constant weight to give 142 g of crude 1-benzyl-piperidine-4-carboxylic acid. To this material was added 39.02 g of N,O-dimethyl hydroxylamine hydrochloride, 81.08 g 1-hydroxybenzotriazole hydrate and 750 mL DMF with stirring. Next was added 174 mL diisopropylethylamine with stirring followed by 76.68 g 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide in several portions over 5 minutes with stirring. After stirring for 72 hr, the cloudy reaction mixture was poured into 2 L ice water containing 100 mL 5N NaOH. The mixture was extracted with 500 and 4×250 mL ether, and the combined ether was washed with water (3×300 mL) and saturated brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 51.13 g of a yellow liquid. Flash chromatography on silica gel eluting with 40˜100% ethyl acetate in hexanes with 1% (v/v) Et3N gave 47.32 g title compound as a yellowish oil. RF: 0.16 (25% EtOAc in hexanes with 1% (v/v) Et3N). 1H NMR (500 MHz, CDCl3): δ7.31˜7.36 (m, 4H), 7.24˜7.28 (m, 1H), 3.71 (s, 3H), 3.53 (s, 2H), 3.20 (s, 3H), 2.94˜2.98 (m, 2H), 2.63˜2.70 (m, 1H), 2.01˜2.07 (m, 2H), 1.82˜1.90 (m, 2H), 1.70˜1.74 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 2 was prepared from bis(4-chlorophenyl) acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.34–7.13 (m, 12H), 4.75 (s, 1H), 3.41 (q, 2H, J=4.5 Hz), 2:94 (d, 2H, J=10.2 Hz), 2.51–2.40 (m, 4H), 1.97 (m, 2H), 1.82 (m, 2H), 1.68 (quintet, 2H, J=6.8 Hz), 1.59 (m, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 566.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([CH3:38])=[C:17]([NH:19][C:20](=[O:37])[CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:28]=2[C:29]([OH:31])=[O:30])=[O:25])[CH:18]=1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:27]([NH:26][C:24](=[O:25])[CH2:23][O:22][CH2:21][C:20]([NH:19][C:17]2[CH:18]=[C:13]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:14]=[CH:15][C:16]=2[CH3:38])=[O:37])=[C:28]([CH:32]=1)[C:29]([OH:31])=[O:30]
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1ccc(Br)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O
Product: COc1ccc(-c2ccc(C)c(NC(=O)COCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)cc1

Procedure:
Using the same method as in Example 19-(ii), 4-methoxybenzene boronic acid was reacted with the 2-[((2-[(5-bromo-2-methylphenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 38-(i) to give 5-chloro-2-[((2-[(4′-methoxy-4-methylbiphenyl-3-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 84%).
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([OH:22])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:22][CH:19]([C:9]1[N:10]=[C:11]2[CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:13](=[O:14])[C:8]=1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH3:21])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(OS(C)(=O)=O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Temperature: 0 °C
Yield: 100 %

Procedure:
A mixture of 0.084 g (0.28 mmol) of the product (24) from Step 8 and 0.08 mL (0.56 mmol) of triethylamine in 2.5 mL of anhydrous DCM was cooled to 0° C. Then was added dropwise 0.03 mL (0.34 mmol) of methanesulfonyl chloride and the resulting mixture was allowed to warm to ambient temperature under nitrogen. Excess DCM was added and the reaction mixture was washed with water, saturated NaHCO3 and brine. The organic layer was then dried over MgSO4 and the solvent was removed in vacuo yielding 0.106 g (0.28 mmol, 100%) of 1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)propyl methanesulfonate (25) as a tan oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[CH3:12][S:13][CH:14]([S:28]([CH3:30])=O)[C:15](=O)[CH:16]=[CH:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C1C=CC=CC=1>[CH3:12][S:13][C:14]1([S:28][CH3:30])[C:19]2[NH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=2[CH2:17][C:16](=[O:8])[CH2:15]1
Reactant: CSC(C(=O)C=Cc1c[nH]c2ccccc12)S(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CSC1(SC)CC(=O)Cc2c1[nH]c1ccccc21
Yield: 885.5 %

Procedure:
680 mg of p-toluenesulfonic acid was added to a mixture of 10.6 g of 3-(4-methylthio-4-methylsulfinyl-3-oxobutene-1-yl)indole, as obtained in Example 1(b), in 150 ml of tetrahydrofuran and 40 ml of benzene. The reaction mixture was next refluxed for 3 hours and then neutralized by the addition of a saturated aqueous solution of sodium hydrogencarbonate. The solvent was removed from the resulting mixture by evaporation under reduced pressure and ethyl acetate was added to the residue. The aqueous layer was then extracted with ethyl acetate, and the organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 300 g of silica gel with a 9:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 9.7 g of the title compound as an amorphous solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:36])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH:34]=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[CH:34]=[CH:33][N:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:36])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-(isobutyl-amino)-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M127) (0.22 g, 0.42 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (90 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:30])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH2:23]O)=[N:21][N:20]=[C:19]1[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28].[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:30])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH2:23][N:35]2[C:31](=[O:41])[C:32]3=[CH:40][CH:39]=[CH:38][CH:37]=[C:33]3[C:34]2=[O:36])=[N:21][N:20]=[C:19]1[CH2:25][CH2:26][N:27]([CH3:28])[CH3:29]
Reactant: CN(C)CCc1nnc(CO)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1B, 2'-chloro-5-nitro-2-[3-[2-(dimethylamino)ethyl]-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in 1,2-dimethoxyethane is treated with phthalimide, triphenylphosphine and diethyl azodicarboxylate to give 2'-chloro-5-nitro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13](=[N:15][O:16][CH2:17][CH:18]=[CH2:19])[CH3:14])=[C:9]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:25]1(=O)[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH2:26]1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>>[Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13](=[N:15][O:16][CH2:17][CH:18]=[CH2:19])[CH3:14])=[C:9]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:25]1[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH:26]=1)=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: C=CCON=C(C)COc1c(S(=O)(=O)CC)ccc(C(=O)O)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Product: C=CCON=C(C)COc1c(S(=O)(=O)CC)ccc(C(=O)OC2=CC(=O)CCC2)c1Cl

Procedure:
0.526 g (1.40 mmol) of 2-chloro-3-(2-allyloxyiminopropyloxy)-4-ethanesulfonylbenzoic acid, 0.173 g (1.50 mmol) of cyclohexane-1,3-dione, 0.274 g (1.40 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 0.002 g of dimethylaminopyridine were reacted analogously to preparation c).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[F:16][C:17]([F:22])([F:21])[C:18](O)=[O:19]>>[CH3:14][O:13][C:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:18](=[O:19])[C:17]([F:22])([F:21])[F:16])[CH:10]=1)=[O:12]
Reactant: COC(=O)c1ccc(C(=O)O)c(N)c1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)c(NC(=O)C(F)(F)F)c1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution (15 ml) of 2-amino-4-methoxycarbonylbenzoic acid (3.00 g) in trifluoroacetic acid was added dropwise anhydrous trifluoroacetic acid (7 ml) at 0° C. This mixture was stirred for 1 hr. and poured into water. The crystals were collected by filtration to give 4-methoxycarbonyl-2-trifluoroacetylaminobenzoic acid (4.40 g, yield 98%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 185–186° C.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[C:3]1[CH2:11][NH2:12].S1C2C=CN=CC=2C=[C:14]1C(O)C>>[S:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[C:3]1[CH:11]([NH2:12])[CH3:14]
Reactant: NCc1cc2cnccc2s1
Reactant: CC(O)c1cc2cnccc2s1
Agent: Cl
Product: CC(N)c1cc2cnccc2s1

Procedure:
Intermediate D′ was prepared from 1-(thieno[3,2-c]pyridin-2-yl)ethanol (D′-4) following similar procedures for synthesizing intermediate A from A-3, as described above.
Reaction SMILES: [C:1]1([CH2:7][C:8]([N:10]2[C@@H:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](I)[CH:24]=[CH2:25]>C1COCC1>[C:1]1([C@H:7]([CH2:25][CH:24]=[CH2:23])[C:8]([N:10]2[C@@H:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C=CCI
Solvent: C1CCOC1
Product: C=CC[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 15.5 gm of 3-phenylacetyl-4-(S)-benzyl-2-oxazolidinone (52 mmol) in 100 mL of THF at −78° C. in a nitrogen atmosphere was added dropwise 63 mL of a 1M solution of lithium bis(trimethylsilyl)azide (63 mmol). The reaction mixture was warmed to 0° C. over the period of 1 hr and then recooled to −78° C. To the reaction mixture was added 5.3 mL of allyl iodide (57 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 12 hr. The reaction was quenched with saturated NH4Cl solution and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with solutions of saturated NaHCO3 and NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography (silica, 2:1 hexanes:ethyl acetate) to give the title compound.
Reaction SMILES: [O:1]=[P:2]([Cl:5])(Cl)[Cl:3].N1C=CC=CC=1.[CH2:12]([OH:17])[C:13]([F:16])([F:15])[F:14]>C1(C)C=CC=CC=1>[P:2]([Cl:5])([Cl:3])(=[O:1])[O:17][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: OCC(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=P(Cl)(Cl)OCC(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 17.3 g (0.113 mol) of POCl3 in 50 mL of toluene held at 0° C. was added 7.9 g (0.10 mol) of pyridine, followed by addition of 10.0 g (0.10 mol) of trifluoroethanol, at a rate to maintain the temperature of the mixture at 0°-10° C. The mixture was stirred one hour at ice bath temperature, and then overnight at room temperature. After filtering, the solution was distilled to give the desired 2,2,2-trifluoroethyl phosphorodichloridate, bp 140°-146° C. The dichloridate, 4.5 g (0.21 mol) was treated with 10 g NH3 in 50 mL CH2Cl2 at -40° C. After warming to room temperature, the product was filtered and purified by Soxhlet extraction with CH2Cl2 for two days. After drying over P2O5, the 2,2,2-trifluoroethyl phosphorodiamidate had mp 142°-144° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[NH:12][C:11]([CH:17]=O)=[CH:10][C:9]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH2:28][C:29](=[O:35])[NH:30]3)[CH:23]=[CH:24][CH:25]=1>N1CCCCC1.C(O)C>[F:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2/[C:28](=[CH:17]/[C:11]2[NH:12][C:13]4[CH2:14][CH2:15][CH2:16][CH:8]([CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:9]=4[CH:10]=2)/[C:29](=[O:35])[NH:30]3)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: O=Cc1cc2c([nH]1)CCCC2CCN1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(-c3cccc(F)c3)c2/C1=C/c1cc2c([nH]1)CCCC2CCN1CCCC1

Procedure:
4-(2-Pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (0.2 was condensed with 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (0.2 mmol) and piperidine (2 drops) in ethanol at rt for overnight. The solvent was removed and the residue was purified on a silica gel column to give 25 mg of the titled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].FC1C=CC(C2C=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=2)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)c1ccc(F)c(F)c1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)nc1
Product: O=C(O)c1ccc(-c2ccc(F)c(F)c2)nc1

Procedure:
The title compound was prepared from 3′,4′-difluoroacetophenone using the procedures outlined for 6-(4-fluorophenyl)nicotinic acid (D1-D3).