Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]#[CH:12])=[CH:9][S:8][C:7]=1[NH2:13])=[O:5])[CH3:2].I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(NC(C)C)(C)C>CC#N.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]#[C:12][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][S:8][C:7]=1[NH2:13])=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: C#Cc1csc(N)c1C(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: CCOC(=O)c1c(C#Cc2ccccc2)csc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
2-Amino-4-ethynyl-thiophene-3-carboxylic acid ethyl ester (0.075 g, 0.385 mmol) was dissolved in anhydrous CH3CN (2.0 mL). This was treated with iodobenzene (0.129 mL, 1.15 mmol) followed by diisopropylamine (0.272 mL, 1.92 mmol). The solution was then degassed and treated with copper iodide (0.0018 g, 0.010 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.014 g, 0.019 mmol). The reaction was then stirred at room temperature for 30 min. The reaction was concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 15 EtOAc/85 hexanes) to afford the title compound (0.081 g, 78%). MS m/e (CI) 272.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]([O:26][Si](CC)(CC)CC)[CH2:8][NH:9][C@H:10]([CH3:25])[CH2:11][C:12]2[C:20]3[C:15](=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH:2]=1>FC(F)(F)C(O)=O>[OH:26][C@H:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:8][NH:9][C@H:10]([CH3:25])[CH2:11][C:12]1[C:20]2[C:15](=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CN[C@H](C)Cc1c[nH]c2c(C(=O)OC)cccc12)c1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
methyl 3-[(2R)-2-(2-pyridin-3-yl-(2R)-2-(triethylsilyloxy)ethyl-amino)propyl]-1H-indole-7-carboxylate (0.72 g, 1.54 mmol) is dissolved in trifluoroacetic acid (20 mL), and the mixture is stirred at room temperature for one day. After concentrated, to the residue is added ethyl acetate, and the mixture is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (methanol/chloroform=1/100→1/3) to give the desired methyl 3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)-propyl]-1H-indole-7-carboxylate (440 mg, yield: 81%).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[C:12]([CH3:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:15])[C:4]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.[NH3:25]>>[C:18]1([C:17]2[N:25]=[CH:1][C:3]3[C:4](=[C:5]([CH3:15])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH3:14])[CH:13]=3)[N:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N
Reactant: CCOC(=O)c1c(C)cc(C=O)c(NC(=O)c2ccccc2)c1C
Product: CCOC(=O)c1c(C)cc2cnc(-c3ccccc3)nc2c1C

Procedure:
Ethyl 4-formyl-2,6-dimethyl-3-benzoylaminobenzoate was used instead of the compound of formula (II) used in Example 1 and reacted with ammonia in the same way as in Example 1. The reaction product was chromatographed on a silica gel column in the same way as in Example 1. The solvent was evaporated, and the residue was recrystallized from diethyl ether/n-hexane to give 2-phenyl-7-ethoxycarbonyl-6,8-dimethylquinazoline having a melting point of 85° to 86° C. in a yield of 35% by weight.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:8][C:7]([C:9]([NH2:11])=[O:10])=[N:6][N:5]=1)[CH3:2].[OH:12]O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[S:8][C:7]([C:9]([NH2:11])=[O:10])=[N:6][N:5]=1)=[O:12])[CH3:2]
Reactant: OO
Reactant: CCSc1nnc(C(N)=O)s1
Solvent: CC(=O)O
Product: CCS(=O)c1nnc(C(N)=O)s1
Reaction time: 3 h

Procedure:
38 g of 5-ethylthio-1,3,4-thiadiazole-2-carboxamide are dissolved at 40° C. in 400 ml of glacial acetic acid and are then slowly reacted with 22.6 ml of a 30% hydrogen peroxide upon stirring. The solution is kept for another 3 hours at the same temperature. At the end of this period the oxidation is sufficiently complete not to require any further addition of heat. After standing overnight the reaction mixture is stirred into two liters of icewater resulting in the precipitation of a solid material which is removed by suction and recrystallized from isopropanol.
Reaction SMILES: C(O[C:4](=[O:29])[C:5](=[O:28])[N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH:20]=[C:21]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:13]=2)[CH2:8][CH2:7]1)C.[NH2:30][OH:31].Cl.[OH-].[K+].CO>CO>[C:21]1(=[CH:20][C:14]2[CH:13]=[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([C:5](=[O:28])[C:4]([NH:30][OH:31])=[O:29])[CH2:7][CH2:8]3)[CH:17]=[CH:16][C:15]=2[O:18][CH3:19])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NO
Reactant: CCOC(=O)C(=O)N1CCC(c2ccc(OC)c(C=C3CCCCCC3)c2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2CCN(C(=O)C(=O)NO)CC2)cc1C=C1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-[4-(3-cycloheptylidenemethyl-4-methoxy-phenyl)-piperidin-1-yl]-oxo-acetic acid ethyl ester (0.6 mmol, 0.250 g) in methanol (5 mL) was added hydroxylamine.HCl (2.4 mmol, 0.167 g, followed by KOH/MeOH solution (5M, 600 μL) dropwise at room temperature. A white solid precipitated out of solution at this reaction continued to stir overnight at room temperature. The reaction went to completion as seen by TLC. The reaction mixture was diluted with H2O (150 mL), acidified with 1N HCl and then extracted with EtOAc (3×100 mL). Each organic phase was washed with H2O (1×100 mL) and the combined organics were dried (Na2SO4) and concentrated to yield a white solid. The solid was triturated in Et2O/hexane to afford the pure title compound, mp 135°-136° C. (0.3 mmol, 0.125 g, 54%).
Reaction SMILES: [CH:1]([N:4]([CH3:22])[C:5]1[C:6](=[O:21])[NH:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([O:19][CH3:20])[CH:9]=2)([CH3:3])[CH3:2].N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH:1]([N:4]([CH3:22])[C:5]1[C:6]([O:21][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([O:19][CH3:20])[CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2nc(N(C)C(C)C)c(=O)[nH]c2cc1OC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc2nc(N(C)C(C)C)c(OS(=O)(=O)C(F)(F)F)nc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-7-methoxy-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (2.0 g, 6.55 mmol) in dichloromethane (80 mL) was added Pyridine (2.0 g, 25.28 mmol) and Tf2O (3.66 g, 12.97 mmol) with stirring overnight under an atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (50 mL) and extracted with dichloromethane (3×80 mL). The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-(isopropyl(methyl)amino)-7-methoxy-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (2.50 g, crude), which was used in the next step directly.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[C:6]([CH3:15])[CH:7]=[CH:8][C:9]=2[CH3:14])[N:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH3:13])[C:10]3[C:5](=[C:6]([CH3:15])[CH:7]=[CH:8][C:9]=3[CH3:14])[N:4]=2)=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: Cc1ccc(C)c2c(C)cc(NN)nc12
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Product: Cc1ccc(C)c2c(C)cc(NNC(=O)Nc3cc(Cl)cc(Cl)c3)nc12

Procedure:
A solution of 2-hydrazinyl-4,5,8-trimethylquinoline (100 mg, 0.50 mmol) and 93.53 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.43 (s, 3 H) 2.73 (s, 3 H) 2.77 (s, 3 H) 6.69 (s, 1 H) 6.92 (d, J=7.03 Hz, 1 H) 7.09 (t, J=1.90 Hz, 1 H) 7.23 (d, J=7.62 Hz, 1 H) 7.68 (br. s., 2 H) 8.35 (s, 1 H) 8.53 (s, 1 H) 9.24 (br. s., 1 H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][CH2:20][OH:21])[C:3]1=[O:22].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32](Cl)=[O:33].C(N(CC)CC)C>C(Cl)Cl>[OH:21][CH2:20][CH2:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:32]([C:24]2[NH:23][C:31]3[C:26]([CH:25]=2)=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:33])[C:3]1=[O:22]
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CCO)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCO)C1=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(RS)-Amino-1,3-dihydro-1-(2-hydroxyethyl)-5-phenyl-2H-1,4-benzodiazepin-2-one (69.0 mg, 0.234 mmole), indole-2-carbonyl chloride (43.1 mg, 0.240 mmole) and triethylamine (33.3 μl, 0.240 mmole) were combined in CH2Cl2 (3 ml). The reaction was stirred for 10 minutes at room temperature then chromatographed on silica gel (14% acetone in CH2Cl2). The product fractions were combined and evaporated to dryness in vacuo. The residue was triturated with Et2O to yield the title compound: (m.p. 160°-171° C.).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[N:11]1[C:16]2[N:17]=[C:18](S(C)(=O)=O)[N:19]=[C:20]([C:21]3[CH:22]=[C:23]([NH:28][C:29](=[O:38])[C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=4)[CH:24]=[CH:25][C:26]=3[CH3:27])[C:15]=2[CH2:14][NH:13][C:12]1=[O:43].[CH2:44]([OH:46])[CH3:45]>CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[N:11]1[C:16]2[N:17]=[C:18]([O:46][CH2:44][CH3:45])[N:19]=[C:20]([C:21]3[CH:22]=[C:23]([NH:28][C:29](=[O:38])[C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=4)[CH:24]=[CH:25][C:26]=3[CH3:27])[C:15]=2[CH2:14][NH:13][C:12]1=[O:43]
Reactant: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOc1nc(-c2cc(NC(=O)c3ccc(C)c(F)c3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
Dry ethanol (2 mL) was treated with NaH (0.0056 mg, 0.140 mmol, 60% in mineral oil) under argon and stirred for 10 min. The compound N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide (0.064 g, 0.110 mmol) was added in ethanol (2 mL). The reaction was stirred under argon for 1 h and then warmed to 70° C. for 2 h. The reaction mixture was diluted with EtOAc and the organics washed with water, brine (twice), dried over Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography on silica gel, eluting with a CH2Cl2—10% EtOAc/CH2Cl2 gradient to afford the title compound as a white solid. mp 257.3-262.5° C.; LC-MS m/z 548 (M+H)+, 2.37 min (ret. time).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:26]C)[C:10](=[O:25])[N:11]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][N:17]([CH3:23])[C:16](=[O:24])[C:12]3=2)[C:7]1=[O:28].Br>C(O)(=O)C.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:26])[C:10](=[O:25])[N:11]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][N:17]([CH3:23])[C:16](=[O:24])[C:12]3=2)[C:7]1=[O:28]
Reactant: COc1c2c(c3n(c1=O)CCC(=O)CN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CN1CC(=O)CCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-5,6,12,13-tetrahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,4,8,10(3H, 11H)-tetrone (25 mg, 0.05 mmol) and 33% hydrogen bromide in acetic acid (0.5 mL) in dioxane (1 mL) was stirred at room temperature for 1.5 hour. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:29]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1cccc(-c2ccc3oc(-c4ccc(OC)c([N+](=O)[O-])c4)nc3c2)c1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-methoxyphenylboronic acid (131 mg, 0.86 mmol) the subtitle compound was obtained, (98 mg, 45%). 1H NMR (DMSO) δ 8.71(d, 1H), 8.52(dd, 1H), 8.35(t, 1H), 8.17(d, 1H), 7.93(d, 1H), 7.82(dd, 1H), 7.69(d, 1H), 7.48(t, 1H), 7.36(m, 2H), 7.03(dd, 1H), 4.12(s, 3H), 3.90(s, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:38]=[CH:37][C:32]3[O:33][CH2:34][CH2:35][O:36][C:31]=3[CH:30]=2)[CH:22]=1)(=O)C.C[O-].[Na+]>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:6]2[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@H:8]([O:19][CH3:20])[O:7]2)=[CH:22][C:23]=1[CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1
Reactant: CO[C@@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CO[C@@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a suspension of compound 143 (40 mg, 0.07 mmol) in CH3OH (5.0 mL) was added NaOMe (100 μL, 25% solution in CH3OH) at room temperature. After 1 h, the resulting mixture was concentrated in vacuo. The crude was purified by preparative HPLC (reverse phase) to provide the title compound (12 mg, 42%) as a white solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1.[C:46]([O:50][CH3:51])(=[O:49])[CH2:47]O.CN(C)C=O>O>[Cl:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:28][C:15]=1[O:16][C:17]1[C:18]([O:23][CH2:24][C:25]([O:27][CH2:47][C:46]([O:50][CH3:51])=[O:49])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)O)c(Cl)cc2F)c1=O
Reactant: COC(=O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
First, 0.13 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added to a mixture of 0.30 g of [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetic acid (compound a-2), 60 mg of methyl glycolate, and 2 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred for 1.5 hours. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.18 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetoxyacetate (compound a-32).
Reaction SMILES: N1(C2C=CC=CN=2)CCC(N[C:8]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[O:9])CC1.Cl.Cl.[N:23]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[CH2:28][CH2:27][CH:26]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]2)=[O:31])[CH2:25][CH2:24]1>>[N:23]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[CH2:28][CH2:27][CH:26]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][CH:35]([NH:38][C:8]([N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)=[O:9])[CH2:34][CH2:33]2)=[O:31])[CH2:25][CH2:24]1
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Reactant: NC1CCN(C(=O)NC2CCN(c3ccccn3)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(c2ccccn2)CC1)N1CCC(NC(=O)n2ccnc2)CC1

Procedure:
The title product is prepared analogously to imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide (Intermediate A1) by replacing 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylamine dihydrochloride with 4-amino-piperidine-1-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amide dihydrochloride (Intermediate H2).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[S:17][CH:18]=[C:19]([CH3:25])[C:20]=1[C:21]([O:23][CH3:24])=[O:22]>>[CH3:25][C:19]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:16]([NH:15][C:12](=[O:14])[CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[S:17][CH:18]=1
Reactant: COC(=O)c1c(C)csc1N
Reactant: O=C(O)Cc1cccc2ccccc12
Product: COC(=O)c1c(C)csc1NC(=O)Cc1cccc2ccccc12

Procedure:
The title compound was prepared from 2-(naphthalen-1-yl)acetic acid (10 g, 54 mmol) and methyl 2-amino-4-methylthiophene-3-carboxylate (9.2 g, 54 mmol) according to protocol A (15.4 g, 85%) as a white solid. 1H NMR (CDCl3) δ11.0 (s, 1H), 8.05-7.85 (m, 3H), 7.63-7.50 (m, 4H), 6.36 (s, 1H), 4.29 (s, 2H), 3.57 (s, 3H), 2.28 (s, 3H); 13C NMR (CDCl3) δ168.3, 165.6, 149.3, 135.0, 134.0, 132.1, 129.8, 128.9, 128.6, 127.0, 126.2, 125.7, 123.7, 112.9, 112.2, 51.1, 41.9, 17.7; MH+ 340.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][N:6]=[C:5]([CH3:11])[C:4]=2[C:3]=1[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][NH:6][CH:5]([CH3:11])[C:4]=2[C:3]=1[CH3:12]
Reactant: CC1=NCCc2sc(C)c(C)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1sc2c(c1C)C(C)NCC2
Yield: 14 %

Procedure:
In close analogy to the procedure described above, 2,3,4-Trimethyl-6,7-dihydrothieno[3,2-c]pyridine is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5](I)[CH:6]=[CH:7][CH:8]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=2)([OH:25])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: OC1(c2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Yield: 47.3 %

Procedure:
Beginning with 3-trifluoromethyl-iodobenzene (3 g) and 1-benzyl-4-piperidone (2.1 g), 1.75 g of the title compound was recovered by the procedure described in preparation 1. MS m/z (rel. intensity, 70 eV) 335 (M+, 29), 244 (22), 146 (19), 91 (bp), 56 (19).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23](SC)=[N:22][C:21]4=[O:27])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:30]([F:33])([F:32])[F:31])[CH:6]=1)(=[O:4])=[O:3].[CH3:34][NH:35][CH2:36][CH:37]([OH:40])[CH2:38][OH:39]>>[OH:40][CH:37]([CH2:38][OH:39])[CH2:36][N:35]([CH3:34])[C:23]1[S:24][C:20](=[CH:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:10]([CH2:9][C:8]2[CH:28]=[CH:29][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][C:7]=2[C:30]([F:32])([F:31])[F:33])[N:11]=[CH:12]3)[C:21](=[O:27])[N:22]=1
Reactant: CNCC(O)CO
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3C(F)(F)F)c2)S1
Product: CN(CC(O)CO)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3C(F)(F)F)c2)S1

Procedure:
2-[(2,3-Dihydroxy-propyl)-methyl-amino]-5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 3-Methylamino-propane-1,2-diol following General Procedure C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.[Na+]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: [Na+]
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(Cl)cc3)c(C)o2)cc1
Yield: 67.3 %

Procedure:
Reaction of chloride 2 (268 mg, 1.0 mmol) and sodium 4-chlorobenzenesulfinate (198 mg, 1.0 mmol) gave benzoate 19 (273 mg, 67%) as a white powder: mp (EtOAc) 186-188° C.; 1H NMR (CDCl3) δ 8.08 (ddd, J=8.7, 1.9, 1.6 Hz, 2H, H-2, H-6), 7.90 (ddd, J=8.7, 1.9, 1.6 Hz, 2H, H-3, H-5), 7.74 (ddd, J=8.7, 2.4, 2.0 Hz, 2H, H-2′, H-6′), 7.49 (ddd, J=8.7, 2.4, 2.0 Hz, 2H, H-3′, H-5′), 4.32 (s, 2H, CH2SO2), 3.94 (s, 3H, OCH3), 2.37 (s, 3H, CH3); MS m/z 407.0 (MH+, 100%), 409.0 (MH+, 35%). Anal. calcd for C19H16ClNO5S: C, 56.23; H, 3.97; N, 3.45. Found: C, 56.11; H, 3.80; N, 3.35%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:11].[Cl:12][C:13]1=[C:14]([Cl:20])[C:15]([O:17][C:18]1=[O:19])=[O:16]>C(Cl)CCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:15](=[O:16])[C:14]([Cl:20])=[C:13]([Cl:12])[C:18]([OH:19])=[O:17])=[C:3]1[CH3:11]
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: Cc1cc2ccccc2n1C
Solvent: ClCCCl
Product: Cc1c(C(=O)C(Cl)=C(Cl)C(=O)O)c2ccccc2n1C
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A mixture of 10.0 g (0.07 mole) of 1,2-dimethylindole, 12.0 g (0.07 mole) of dichloromaleic anhydride and 200 ml of ethylene dichloride was stirred at ambient temperature for approximately eighteen hours. The solid present in the reaction mixture was collected by filtration. After drying at 60° C. in vacuo there was obtained 20.0 g of 4-(1,2-dimethyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid (Formula VIII: R=R1 =CH3 ; Y=H) as a pale blue solid which melted over the range 150° to 153° C. Infrared spectral analysis showed a maximum at 1712 (C=0; s) cm-1.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].Br[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1>>[CH3:10][C:5]1[C:4]([C:1]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)([OH:3])[CH3:2])=[C:8]([CH3:9])[O:7][N:6]=1
Reactant: CC(=O)c1c(C)noc1C
Reactant: Brc1ccsc1
Product: Cc1noc(C)c1C(C)(O)c1ccsc1

Procedure:
The title compound was prepared following the general method of Example 4 but starting with 4-acetyl-3,5-dimethylisoxazole and 3-bromothiophene. M.p. 93.5°-95° C.