Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:10][CH2:9]1)(=O)=O.[O:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].CN(C)C(N(C)C)=N>O1CCCC1>[F:21][C:20]([F:23])([F:22])[C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][CH2:6][N:26]3[C:27](=[O:29])[CH2:28][O:24][C:25]3=[O:30])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C1COC(=O)N1
Reactant: CS(=O)(=O)OCCC1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: O=C1COC(=O)N1CCC1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
A solution of 2.3 g (6.545 mmol) of 2-{1-[3-(trifluoromethyl)phenyl]-4-piperidyl}ethyl methanesulfonate, prepared in step 3.2, 0.694 g (6.87 mmol) of 1,3-oxazolidine-2,4-dione (J. Med. Chem., 1991, 34, 1538–1544) and 1.5 g (13.09 mmol) of 1,1,3,3-tetramethylguanidine in 30 ml of tetrahydrofuran is refluxed for 12 hours under an inert atmosphere.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[I:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=2)[CH3:2].CN(C=O)C.[CH2:21](I)[CH3:22]>C(OCC)(=O)C>[CH2:21]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=2)[C:11]([I:12])=[C:3]1[CH2:1][CH3:2])[CH3:22]
Reactant: CCc1[nH]c2cc([N+](=O)[O-])ccc2c1I
Reactant: CCI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1c(I)c2ccc([N+](=O)[O-])cc2n1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
Add to a solution of 2-ethyl-3-iodo-6-nitro-1H-indole (0.30 g, 00.95 mmol) in anhydrous DMF (5 mL) sodium hexamethyldisilylamide (1.0M in THF, 1.0 mL, 1.00 mmol) dropwise followed by ethyl iodide (0.23 mL, 2.85 mmol) and stir 3 hours at ambient temperature. Quench the reaction with 1N HCl and add ethyl acetate. Wash the organic layer 2×1N HCl, 1× brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate hexane to afford 0.28 g (86%) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:14]=2)[CH:9]=[CH:8]1)C.O1CCCC1.[OH-].[Li+].O[Li].O>O>[F:31][C:27]1[C:28]([F:30])=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:13]3[CH:14]=[C:15]4[C:10]([CH:9]=[CH:8][N:7]4[CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[CH:11][CH:12]=3)=[CH:19][CH:20]=2)=[C:25]([O:32][CH3:33])[CH:26]=1
Reactant: CCOC(=O)CCn1ccc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Agent: [Li+]
Agent: [Li]O
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(CCC(=O)O)c3c2)cc1
Temperature: 25 °C
Yield: 103.1 %

Procedure:
To 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid ethyl ester (24 mg, 0.051 mmol, 1 eq.) was added tetrahydrofuran (1 mL), water (1 mL) and lithium hydroxide (LiOH—H2O (4.5 mg, 0.1 mmol, 2.2 eq.). The reaction was stirred and at room temperature for 2 and then DOWEX resin (50WX4-400, acid washed, 2 g) was added. The mixture was stirred at room temperature, filtered, dried, and then lyophilized from acetonitrile/water to yield 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid as an off-white solid (23 mg, 98%). LC-MS (ES) calculated for C25H21F2NO4, 437.12; found m/z 438 [M+H]+.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([Cl:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:25](Cl)=[O:26].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:1]([O:11][C:25]([C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:22]([Cl:24])=[O:23])[CH:17]=2)[CH:12]=1)=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)c1ccc2cc(C(=O)Cl)ccc2c1
Reactant: CCCCCCCCCCO
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCOC(=O)c1ccc2cc(C(=O)Cl)ccc2c1
Yield: 56.3 %

Procedure:
After a solution of n-decyl alcohol (0.5 g), naphthalene-2,6-dicarboxylic acid dichloride (0.6 g), and triethylamine (0.27 g) and a very small amount of dimethylaminopyridine in methylene chloride (50 ml) was stirred at room temperature overnight, the solution was distilled to remove the solvent, until the titled compound (about 0.5 g) was obtained.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH:18](OCC)[O:17][C:16](=O)[CH2:15]1)[CH:5]=[CH2:6].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[CH2:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH:18]=[N:3][NH:2][C:16](=[O:17])[CH2:15]1)[CH:5]=[CH2:6]
Reactant: NN
Reactant: C=CCOc1ccccc1C1CC(=O)OC1OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CCOc1ccccc1C1C=NNC(=O)C1

Procedure:
Hydrazine hydrate (2.8 ml) was added to a solution of 4-(2-allyloxyphenyl)-5-ethoxydihydro-2-furanone (9.8 g) in acetic acid (30 ml) and water (27 ml). The solution was refluxed for 90 minutes, poured into aqueous sodium bicarbonate, extracted into diethyl ether, evaporated under reduced pressure and the resultant solid recrystallised from benzene to afford 5-(2-allyloxyphenyl)-4,5-dihydro-3[2H]-pyridazinone (6.5 g) as white crystals, m.p. 93°-95° C.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14]OS(O)(=O)=O>[OH-].[K+]>[NH2:14][N:11]1[CH:12]=[CH:13][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10]1
Reactant: O=C(c1ccccc1)c1cc[nH]c1
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Product: Nn1ccc(C(=O)c2ccccc2)c1

Procedure:
A 3-benzoylpyrrole of the formula ##STR25## in potassium hydroxide or other suitable base is reacted with hydroxylamine-O-sulfonic acid to yield a 1-amino-3-benzoylpyrrole of the formula ##STR26## This reaction typically takes place in the presence of a suitable solvent such as dimethylformamide at a temperature of about 0° to 25° C. (or at room temperature) for 0.5 to 4 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:11])=[O:10])=[C:5]([N+:23]([O-])=O)[CH:4]=1.[Sn](Cl)Cl>Cl>[NH2:23][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Product: COc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Yield: 56.9 %

Procedure:
In the similar fashion using route 1 general procedure 4, 4-methoxy-2-nitro-N-quinolin-8-yl-benzenesulfonamide (Example Compound 34) (600 mg, 1.6 mmol), tin (II) chloride (950 mg, 5.0 mmol) and 6N HCl (2 drops) gave the title compound (300 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Br[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1O
Reactant: Brc1ccc2ccccc2c1
Product: Cc1cc(Cl)ccc1Oc1ccc2ccccc2c1
Yield: 9 %

Procedure:
Following Example 1, the title compound was synthesized (yield; 9%) from 4-chloro-2-methylphenol and 2-bromonaphthalene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][O:21][CH3:22])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][O:21][CH3:22])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(CCOC)CCNCC1
Reaction time: 2 h

Procedure:
4-(2-Methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (8 g) was dissolved in methylene chloride (40 ml), trifluoroacetic acid (75.57 g, 50.72 ml) was added under an argon atmosphere at RT and the mixture was stirred for 2 hours until completion of the reaction. The reaction mixture was diluted with dichloromethane (500 ml), and then 3M NaOH (220.9 ml) was slowly added. The layers were separated, the organic layer washed with brine, dried over sodium sulphate and concentrated to give 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester a brown oil (3.76 g) which was essentially pure according to NMR and used in next reaction step without further purification. MS (ESI): 216.3 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].Br[CH:28]([CH2:30][CH2:31][CH:32](Br)[CH3:33])[CH3:29]>>[CH3:33][CH:32]1[CH2:31][CH2:30][CH:28]([CH3:29])[N:1]1[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=1[O:24][CH3:25]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: CC(Br)CCC(C)Br
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1N1C(C)CCC1C

Procedure:
The title compound, MS: m/e=467.3 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 2,5-dibromohexane. The 3 diastereomers were not separated.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:40][O:41][C:42]1[CH:47]=[C:46]([NH2:48])[CH:45]=[CH:44][N:43]=1.CCN(CC)CC>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1[C:4]([NH:48][C:46]1[CH:45]=[CH:44][N:43]=[C:42]([O:41][CH3:40])[CH:47]=1)=[O:6]
Reactant: COc1cc(N)ccn1
Reactant: O=C(O)c1cc(OC(F)(F)F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2cc(OC(F)(F)F)ccc2F)ccn1
Yield: 64.9 %

Procedure:
A solution of 2-fluoro-5-(trifluoromethoxy)benzoic acid (5.3 g, 23.47 mmol), HATU (8.92 g, 23.47 mmol), 2-methoxypyridin-4-amine (2.9 g, 23.47 mmol) and Et3N (13.09 mL, 93.88 mmol) in dichloromethane (47.4 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes (0-50%) to yield 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethoxy)benzamide (5.03 g, 65%) as a white solid. ESI-MS m/z calc. 330.06. found 331.1 (M+1)+; Retention time: 1.48 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.10 (m, 1H), 7.73 (dd, J=5.1, 3.2 Hz, 1H), 7.66 (m, 1H), 7.55 (t, J=9.2 Hz, 1H), 7.21 (dd, J=3.7, 1.8 Hz, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:27])[CH2:7][C:8]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([OH:21])[CH2:9][CH2:10][NH:11][C:12](=[O:20])[CH2:13][CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)C>C(Cl)Cl>[CH:22]1([C:8]([OH:21])([CH2:9][CH2:10][NH:11][C:12](=[O:20])[CH2:13][CH2:14][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[CH2:7][C:6]([OH:27])=[O:5])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)CC(O)(CCNC(=O)CCc1ccco1)C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)CC(O)(CCNC(=O)CCc1ccco1)C1CCCC1
Temperature: 25 °C
Yield: 36.6 %

Procedure:
A solution of NaOH (0.3 M, 1.6 mL, 0.49 mmol) was added to 3-cyclopentyl-5-(3-furan-2-yl-propionylamino)-3-hydroxy-pentanoic acid ethyl ester (86 mg, 0.245 mmol) from Step 1 below and stirred at room temperature until complete by HPLC. The reaction was diluted with 10 mL CH2Cl2, and washed with 10 mL saturated NH4Cl. The aqueous layer was extracted with 2×10 mL CH2Cl2, and the organic layers were combined. After concentrating by rotary evaporation, the residue was purified by flash chromatography to give the desired compound (29 mg, 37% yield).
Reaction SMILES: [CH2:1]([N:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:21]1([C:27](=[O:31])[C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:6]=[C:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:28](=[O:29])[C:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:31])[CH3:2]
Reactant: O=C(Cl)C(=O)c1ccccc1
Reactant: CCN(C=Cc1ccccc1)CC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCN(C=C(C(=O)C(=O)c1ccccc1)c1ccccc1)CC
Reaction time: 1.25 h

Procedure:
Seven grams of N,N-diethylstyrylamine was dissolved in 100 ml. of diethyl ether and the solution was cooled to 0° C. Four grams of anhydrous triethylamine was added. A 7 g. portion of phenylglyoxyloyl chloride was dissolved in 50 ml. of diethyl ether and the solution was added dropwise, with stirring, to the first solution over about 75 minutes. As soon as the addition was complete, the reaction mixture was filtered, and the precipitated amine hydrochloride was washed with an additional 50 ml. of diethyl ether. The filtrate contained 1-diethylamino-2,4-diphenyl-1-buten-3,4-dione, in dissolved form, and was used in the next step of the synthesis without purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[NH:23]1[C:27]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH:31]=O)=[N:26][N:25]=[N:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:31][C:30]4[CH:33]=[CH:34][CH:35]=[C:28]([C:27]5[NH:23][N:24]=[N:25][N:26]=5)[CH:29]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1cccc(-c2nnn[nH]2)c1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4cccc(-c5nnn[nH]5)c4)c23)c1

Procedure:
Analogously to Example 32, 260 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine and 172 μl of acetic acid are dissolved in 25 ml of methanol and reacted with 261 mg (1.5 mmol) of 3-(tetrazol-5-yl)-benzaldehyde (Step 59.1) to form 4-(3-chloro-phenylamino)-3-{[3-(tetrazol-5-yl)-phenyl)-methyleneamino}-1H-pyrazolo[3,4-d]pyrimidine. With ice-cooling, 8 ml (8 mmol) of DIBAL-H are added to the above intermediate in 15 ml of DMEU and the reaction mixture is stirred for 30 min. 15 ml of ethyl acetate are added and the mixture is stirred for 15 min, diluted with 150 ml of methanol and 1 ml of water and concentrated by evaporation in a rotary evaporator. The residue is poured into 0.5 liter of water and 0.5 liter of ethyl acetate, and acidified to pH=3 with 1 N HCl, and the aqueous phase is separated off and extracted a further 3× with ethyl acetate. The organic phases are washed several times with water and finally with brine, dried (Na2SO4) and concentrated by evaporation. Stirring in ether yields 4-(3-chloro-phenylamino)-3-[3-(tetrazol-5-yl)-benzylamino-]-1H-pyrazolo[3,4-d]pyrimidine; TLC: Rf=0.13 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=7.4; FAB-MS: (M+H)+=419.
Reaction SMILES: [NH2:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[O:4][CH:3]=1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[Cl:13][C:8]1[CH:7]=[CH:6][C:5]2[O:4][CH:3]=[C:2]([NH:1][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:11](=[O:12])[C:10]=2[CH:9]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1coc2ccc(Cl)cc2c1=O
Product: CCOC(=O)C(=CNc1coc2ccc(Cl)cc2c1=O)C(=O)OCC
Yield: 68.6 %

Procedure:
A mixture of 3-amino-6-chlorochromone (1.95 g, 0.01 mole) and diethyl ethoxymethylenemalonate (3.5 g, 0.016 mole) was heated under nitrogen at 120° for 4 hrs. The reaction mixture was cooled. The product, which precipitated, was filtered off and washed with ethyl acetate. Recrystallization from ethyl acetate gave white crystals (2.51 g, 68%), m.p. 143°-145°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([NH:12][C:13](=O)[CH2:14][N:15]3[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([NH:12][C:13](=[S:34])[CH2:14][N:15]3[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)N1CC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(C)OC(=O)N1CC(=S)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared according to the procedure for Example 24 from isopropyl 7-(3-chlorophenyl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxylate and Lawesson's reagent. A yellowish solid: m.p. 208-212° C.; 1H-NMR (DMSO-d6) δ 1.27 (d, J=6.1 Hz, 6H), 4.62 (s, 2H), 4.94 (sep, J=6.1 Hz, 1H), 7.23 (m, 4H), 7.64 (t, J=1.8 Hz, 1H), 7.90 (s, 1H), 12.80 (s, 1H), MS (ESI) m/z 359/361 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=[O:10])=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)[C:17](=[O:18])C=1C#N)#N.CO>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]([O:18][CH3:17])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC=O)cc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(OC)cc1
Yield: 91 %

Procedure:
A homogeneous mixture containing 4-methoxycinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of AMBERLITE® IR 400 (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl 4-methoxycinnamate (from formula I where X1═H, X2═H, X3═OCH3, X4═H, X5═H, R═CH3) is isolated in 91% yield. 1H-NMR (CDCl3, 300 MHz) δ7.56 (1H, d, J=16.55 Hz), 7.37 (2H, d), 6.80 (2H, d), 6.22 (1H, d, J=16.55 Hz), 3.73 (3H, s), 3.70 (3H, s); 13C-NMR (CDCl3, 75.4 MHz) δ167.7, 161.4, 144.5, 129.7, 127.1, 115.2, 114.3, 55.3, 51.5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]([CH:13]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[CH3:14])=[N:8][CH:7]=1)=[O:5])[CH3:2].[CH:32]1(I)[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[N:10][C:9]([CH:13]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[CH3:14])=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(C(C)N2CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)[nH]c1=O
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(C(C)N2CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)nc1OC1CCCC1
Temperature: 90 °C

Procedure:
A mixture of 2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid ethyl ester (90 mg, 0.2 mmol), cyclopentyl iodide (46 μL, 0.4 mmol), and potassium carbonate (138 mg, 1 mmol) in DMF (1 mL) was heated to 90° C. for 1 day. The reaction mixture was then filtered and purified by HPLC (in the absence of TFA) to yield the product. 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 5.58 (m, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.89 (s, 3H), 3.84 (m, 1H), 3.04 (m, 4H), 2.73 (m, 4H), 1.83 (m, 8H), 1.40 (m, 6H); HPLC ret. time 2.80 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 519.5 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:21]1[CH2:23][CH:22]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH:21]1[CH2:23][CH:22]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CC1Br
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC1c1cc2cc(OCc3ccccc3)ccc2[nH]1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a suspension of NaH (0.355 g, 14.0 mmol) in 100 ml of dry N,N-dimethylformamide was added slowly 5-benzyloxyindole (3.0 g, 13.4 mmol). When the evolution of H2 ceased, ethyl 2-bromocyclopropanecarboxylate(2.85 g, 0.0148 mol), as prepared in the preceding step, was added to the mixture and the reaction was refluxed for a period of 17 h under argon. Then the reaction was cooled down at ambient temperature and quenched carefully with water. After evaporation of the solvent under vacuum, the crude product was purified by flash chromatography on silica gel to obtain the title compound (3.45 g, 77%). 1H NMR (400 MHz, CDCl3) δ 1.34 (t, 3H, J=7.1 Hz), 1.62 (m, 1H), 1.73 (m, 1H), 2.14 (m, 1H), 3.78 (m, 1H), 4.24 (c, 2H, J=7.1 Hz), 5.10 (s, 2H), 6.36 (dd, 1H, J=0.7, 3.2 Hz), 6.98 (dd, 1H, J=2.4, 8.8 Hz), 7.04 (d, 1H, J=3.2 Hz), 7.14 (d, 1H, J=2.4 Hz), 7.38 (m, 4H), 7.45 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C([N:21](CC)CC)C>C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([NH2:21])=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(N)=O)n2)s1
Temperature: 25 °C

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (110 mg; 0.36 mmol; 1 eq.), is dissolved in anhydrous THF (10 ml). Under nitrogen, triethylamine (0.08 ml; 0.55 mmol; 1.5 eq) is added. Ammonia (gas) is bubbled during 10 minutes. The flask is closed and the reaction mixture is stirred for 20 additional minutes at RT. The solvents are removed and the crude product is directly purified by preparative HPLC, affording Compound (62) as a white-off solid (25.6 mg; 22%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12](Br)[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:12]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:3][CH2:2][CH2:10][CH3:6])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCBr
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1cc(Br)ccc1OCCCC
Temperature: 100 °C
Yield: 100.2 %

Procedure:
A mixture of 5-bromo-2-hydroxy-benzoic acid (2.21 g, 10 mmol), butyl bromide (3.46 g, 25 mmol), potassium carbonate (2.76 g, 20 mmol) and DMF (20 mL) was heated at 100° C. for 1 h. The reaction mixture was partitioned between ether (120 mL) and brine (100 mL). Ether layer was separated and washed again with brine (100 mL), dried over MgSO4. Purification by flash chromatography (ethyl acetate/hexanes 1:99, 1:19, 1:9) gave 5-Bromo-2-butoxy-benzoic acid butyl ester as yellow oil (1.648 g, 5.01 mmol).