Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([NH:35]C(C1N(C)C(CNS(C2C=CC=CC=2)(=O)=O)=CC(=O)C=1OCC1C=CC=CC=1)=O)([CH3:34])[CH3:33]>>[CH:32]([NH:35][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:30])([CH3:34])[CH3:33]
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)n1C
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2)n1C
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)NC(C)C)n1C
Yield: 45.7 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-02) (250.0 mg, 45.70%) was synthesized as a yellow solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-02) (500.0 mg, 1.13 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-01).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[NH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=[O:15].C([O-])([O-])=O.[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu]I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[O:15])=[CH:6][CH:7]=1
Reactant: O=c1cccc[nH]1
Reactant: Nc1ccc(I)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Nc1ccc(-n2ccccc2=O)cn1
Temperature: 25 °C

Procedure:
2-Amino-5-iodopyridine (5.0 g, 22.7 mmol) was combined with 1H-pyridin-2-one (2.59 g, 27.27 mmol), CuI (0.65 g, 3.41 mmol), K2CO3 (3.45 g, 24.9 mmol), and 8-hydroxyquinoline (0.49 g, 3.40 mmol) in DMSO (20 mL). The mixture was degassed with a stream of argon and then heated at reflux for 18 h before cooling to RT. 10% aq. NH4OH and EtOAc were added, and the mixture was filtered through a plug of layered celite and decolorizing charcoal, eluting with EtOAc. The filtrate was concentrated under reduced pressure. Purification of the crude product by mplc revealed A (0.40 g, 10%) as a yellow solid. MS: APCI (AP+): 188.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[N:34]1([CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][NH:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:41]2[CH2:42][CH2:43][CH2:44][C@H:40]2[CH2:39][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:32])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)O
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)N1CCC[C@H]1CN1CCCC1

Procedure:
5-[5-(2,3-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (110 mg, 0.22 mmol) was coupled with (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (41 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) to give the titled compound. MS m/z 639 [M−1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=1[OH:11])[CH:6]=O.[C:15]([O:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18].N1(CC(O)=O)CCCCC1>C1C=CC=CC=1>[CH2:22]([O:21][C:15](=[O:20])[C:16]([C:17](=[O:18])[CH3:19])=[CH:6][C:5]1[CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: COc1cc(C=O)cc(C(C)C)c1O
Reactant: CC(=O)CC(=O)OCCC(C)C
Agent: O=C(O)CN1CCCCC1
Solvent: c1ccccc1
Product: COc1cc(C=C(C(C)=O)C(=O)OCCC(C)C)cc(C(C)C)c1O

Procedure:
Condensation of 3-methoxy-4-hydroxy-5-isopropyl benzaldehyde with isoamyl acetoacetate in the presence of piperidine-acetic acid and benzene as the reaction medium at reflux temperature under continuous azeotropic water removal yields the title product. The reaction takes about 4 hrs for completion. The yield obtained is typically 90-95%.
Reaction SMILES: [C:1](Cl)(=O)C.[S:5]1[CH:9]=[CH:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:6]1=2>CO>[CH3:1][O:15][C:14]([C:13]1[C:6]2[S:5][CH:9]=[CH:8][C:7]=2[CH:10]=[CH:11][CH:12]=1)=[O:16]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cccc2ccsc12
Solvent: CO
Product: COC(=O)c1cccc2ccsc12
Yield: 92.7 %

Procedure:
Acetyl chloride (14.8 mmol; 1.05 mL) is added to a solution of benzo[b]thiophene-7-carboxylic acid (4.94 mmol; 880 mg) in methanol (20 mL). The reaction mixture is stirred at reflux for 24 h. The solvent is removed under reduced pressure. The residue is taken up in ethyl acetate washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the title compound (880 mg, 92%) as colorless oil. 1H NMR (CDCl3): δ 8.12 (dd, 1H, J=7.2 Hz, 0.6 Hz), 8.03 (dd, 1H, J=7.6 Hz, 1.2 Hz), 7.58 (d, 1H, J=5.6 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.41 (t, 1H, J=5.2 Hz), 4.03 (s, 3H).
Reaction SMILES: [Cl:1][C@@H:2]([CH3:20])[CH2:3][C@H:4]([CH3:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)#[N:22].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[Cl:1][C@@H:2]([CH3:20])[CH2:3][C@H:4]([CH3:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(OC(=O)c3ccc(C#N)cc3)cc2)cc1
Yield: 46.2 %

Procedure:
0.30 g of (S,S)-4-[4-(3"-chloro-1"-methylbutoxy)-phenyl]phenol, 0.16 g of 4-cyanobenzoic acid, 0.22 g of dicyclohexylcarbodiimide, 0.04 g of 4-pyrrolidinopyridine and 6 ml of methylene chloride were stirred together at room temperature for five hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The crude product thus obtained was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (7:3) as a developing solvent to thereby give 0.2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]([CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1)[C:22]2=[O:27].C(N(CC)C(C)C)(C)C.CO>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][N:21]([CH2:28][C:29]2[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)[C:22]3=[O:27])=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cccc2c(=O)n(Cc3ccc(C(F)(F)F)nc3)ccc12
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(Cc1ccc(Cl)c(C(F)(F)F)c1)Nc1cccc2c(=O)n(Cc3ccc(C(F)(F)F)nc3)ccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
2-(4-Chloro-3-(trifluoromethyl)phenyl)acetic acid (142 mg, 0.000595 mol) was dissolved in thionyl chloride (10 mL) and the mixture was stirred at 60° C. for 3 hours. The volatiles were removed and the residue was dissolved in tetrahydrofuran. 5-Amino-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)isoquinolin-1(2H)-one (100.0 mg, 0.0002975 mol) and N,N-diisopropylethylamine (0.104 mL, 0.000595 mol) were added and the mixture was stirred for 1 hour at room temperature. Methanol was added to quench the reaction and the volatiles were removed. The residue was dissolved in ethylacetate, washed with water, sodium carbonate solution and brine and purified by column to obtain the product as a beige solid (120 mg). MS m/z=540.4(M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Br:18])=[N:16][NH:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>ClCCl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Br:18])=[N:16][NH:17][C:11]=2[N:10]=[C:9]1[CH:19]([N:22]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:42](=[O:43])[C:41]1[CH:45]=[CH:46][C:38]([Br:37])=[CH:39][CH:40]=1)[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(NCCN(C)C)c1nc2[nH]nc(Br)c2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1nc2[nH]nc(Br)c2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 2 h

Procedure:
A solution of 5-benzyl-3-bromo-6-(1-{[2-(dimethylamino)ethyl]amino}propyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1-4, 144 mg, 0.33 mmol, 1 equiv) and N,N-diisopropylethylamine (43 mg, 0.33 mol, 1 equiv) in dichloromethane (5 mL) was treated with 4-bromobenzoyl chloride (73 mg, 0.33 mmol, 1 equiv), and the resulting mixture was stirred under ambient conditions for 2 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, then brine, and dried (MgSO4) and concentrated. The residue was purified by flash chromatography. Elution with CH2Cl2 to 10% NH3-EtOH/CH2Cl2 gave N-[1-(5-benzyl-3-bromo-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-5) as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 10.9 (bs, 1H), 7.56 (m, 2H), 7.33 (m, 5H), 7.15 (m, 2H), 6.04 (d, J=15 Hz, 1H), 5.94 (m, 1H), 5.03 (d, J=15 Hz, 1H), 3.42 (m, 2H), 2.18 (m, 2H), 2.01 (m, 2H), 1.86 (s, 6H), 0.62 (m, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:18])=[C:13](F)[C:14]=3[F:16])[C:9](=[O:19])[C:8]([C:20]([OH:22])=[O:21])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)[CH3:24]>C(#N)C>[CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:18])=[C:13]([N:29]4[CH2:30][CH2:31][CH:27]([CH2:26][NH:25][CH2:23][CH3:24])[CH2:28]4)[C:14]=3[F:16])[C:9](=[O:19])[C:8]([C:20]([OH:22])=[O:21])=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cn(C2CCCC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CCCC4)c3c2F)C1
Yield: 74.2 %

Procedure:
To 0.86 g (2.7 mmol) of the 1-cyclopentyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.40 g (2.7 mmol) of 1,8-diazobicyclo [5.4.0] undec-7-ene and 0.36 g (2.7 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for seven hours, cooled, filtered, and the solids washed with ether to give 0.84 g of 1-cyclopentyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic-acid, mp 214°-217° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:31][CH3:32])[C@H:10]([O:27]C(=O)C)[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[N:14][N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:10]([OH:27])[C:11]1[O:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:20][CH:21]=2)=[N:14][N:15]=1)[CH2:31][CH3:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NC(=O)OC(C)(C)C)[C@H](OC(C)=O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Acetic acid (S)-2-tert-butoxycarbonylamino-1-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-butyl ester (0.61 mmol, 0.28 g) is dissolved in a mixture of THF (10 mL) and water (10 mL). Lithium hydroxide hydrate (1.22 mmol, 0.051 g) is added and the reaction mixture stirred for 2 h. The solvents are evaporated under reduced pressure and the residue transferred into a separating funnel with 300 mL ethyl acetate and 50 mL water. The phases are separated and the organic phase washed with brine (100 mL). The organic phase is then dried with magnesium sulfate. The solvent is evaporated under reduced pressure and dried under high vacuum to yield ((S)-1-{hydroxy-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-methyl}-propyl)-carbamic acid tert-butyl ester as an oil (0.225 g, 89%) MS: m/z=440 (M+Na+), 418 (M+H+)
Reaction SMILES: [OH:1]O.[C:3]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:23])[CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1)([CH2:6][CH3:7])([CH3:5])[CH3:4]>C(O)(C)C.[Pt]>[C:3]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([CH3:23])[CH2:16][N+:17]2([O-:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:12][CH:13]=1)([CH2:6][CH3:7])([CH3:4])[CH3:5]
Reactant: OO
Reactant: CCC(C)(C)c1ccc(CC(C)CN2CCCCC2)cc1
Agent: [Pt]
Solvent: CC(C)O
Product: CCC(C)(C)c1ccc(CC(C)C[N+]2([O-])CCCCC2)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
7.2 g of 30% hydrogen peroxide are added dropwise at 40° C. to a solution of 5.8 g of 1-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-piperidine in 20 ml of isopropanol and this addition is repeated after 24 hours. After stirring at 40° C. for 60 hours, the mixture is cooled and the excess hydrogen peroxide is decomposed by addition of platinum sponge. The solution is filtered, the filtrate is evaporated, the residue is taken up in 50 ml of water and extracted with hexane. The aqueous solution is subsequently evaporated and the residue is dried in a high vacuum. There is obtained pure 1-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-piperidine-1-oxide; nD20 =1.5180.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:17]1(=O)[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CO>[N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH2:21][CH2:20][C:19](=[O:22])[CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1CCC(=O)C1
Reactant: Nc1cccc(-c2cnc3ccccn23)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C(Nc2cccc(-c3cnc4ccccn34)c2)CC1
Temperature: 25 °C

Procedure:
A solution of 3-imidazo[1,2-a]pyridin-3-yl-phenylamine (210 mg, 1.0 mmol), 1,3-cyclopentandione (110 mg, 1.1 mmol) and p-toluenesulfonic acid monohydrate (17 mg, 0.1 mmol) in toluene (2 ml) was stirred and heated at reflux under N2 for 8 hours. After cooling to RT the mixture was diluted with methanol (˜3 ml) then filtered. The solid was washed with Et2O then dried under vacuum to give the title compound. MS: [M+H]+ 290.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)C(C)C)(C)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH2:38][CH:37]([C:41](O)=[O:42])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:41]([CH:37]3[CH2:38][CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36]3)=[O:42])[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)piperazine-1-carboxamide hydrochloride (1.0 g) in dichloromethane (100 mL) was added N,N-di-iso-propylethylamine (0.56 mL) at room temperature. After 10 minutes N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide (617 mg) was added followed by 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (671 mg) and 1-hydroxybenzotriazole (435 mg). The reaction was stirred overnight at room temperature. The reaction mixture was partitioned between dichloromethane and water and the organic layer was washed with brine. The organic extract was dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 15% ethyl acetate in hexane to give the title compound as a white foam (1.4 g, 99%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1[CH:22]=[C:21]2[N:23]=NN(O)[C:20]2=CC=1.O.C1CCC(N=C=NC2CCCCC2)CC1.C(N)(C)C>CN(C=O)C.CC(O)=O>[CH:21]([NH:23][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:22])[CH3:20]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
N-Benzyloxycarbonyl-D-alanine (2.232 g, 10 mmol) and HOBt hydrate (1.53 g, 10 mmol) are dissolved in 40 mL freshly distilled DMF and cooled in an ice-H2O bath. DCC (2.06 g, 10 mmol) is added. The reaction mixture is stirred in the cold for 15 minutes, isopropylamine (0.85 mL, 10 mmol) is then introduced. It is stirred in the cold for 2 hours and room temperature overnight. HOAc (a few drops) is added and the reaction mixture stirred at room temperature for another 15 minutes. It is filtered to remove DCU and the filtrate layered with 50 mL EtOAc and 80 mL H2O. The phases are separated and the aqueous phase is extracted with 50 mL EtOAc. The pooled EtOAc extract is wazhed with H2O, 0.1N HCl (3×), H2O (3×), 0.1N NaOH (3×), H2O (3×), dried over anhydrous Na2SO4 and evaporated to dryness. The crude product is purified by liquid column chromatography on silica gel eluting with toluene/EtOAc mixtures.
Reaction SMILES: ClC1C=CC(N2CCN(S(N)(=O)=O)CC2)=CC=1.Cl[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[C:27]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[S:38](=[O:40])(=[O:39])[NH:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1>>[C:27]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:28]=[CH:29][C:30]([CH2:33][N:34]2[S:38](=[O:40])(=[O:39])[N:37]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:36][CH2:35]2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=S1(=O)NCCN1Cc1ccc(-c2ccccc2)cc1
Agent: NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Product: CC(C)(C)OC(=O)CN1CCN(Cc2ccc(-c3ccccc3)cc2)S1(=O)=O

Procedure:
Proceeding as described in Example 7, Step 2 above, but substituting potassium tert-butoxide and [4-(4-chlorophenyl)piperazine-1-sulfonyl]amine with tert-butyl chloroacetate and 5-(biphenyl-4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine gave tert-butyl 5-(biphenyl-4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-acetate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:9]=[C:10]([CH:16]=[C:17]([S:30](=[O:33])(=[O:32])[NH2:31])[C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:11](OCC)=[O:12].C(OCC)(=O)C.O>COCCOC.C(O)(=O)C>[NH2:7][C:8]1[CH:9]=[C:10]([CH:16]=[C:17]([S:30](=[O:32])(=[O:33])[NH2:31])[C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=1)[CH2:11][OH:12]
Reactant: CCOC(=O)c1cc(N)c(Oc2cccc(C(F)(F)F)c2)c(S(N)(=O)=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Nc1cc(CO)cc(S(N)(=O)=O)c1Oc1cccc(C(F)(F)F)c1

Procedure:
To a stirred mixture of lithium aluminium hydride (5.0 g) and dry 1,2-dimethoxyethane (100 ml), a solution of ethyl 3-amino-4-(3'-trifluoromethylphenoxy)-5-sulfamylbenzoate (20 g) in dry 1,2-dimethoxyethane (100 ml) is dropwise added at 100° C during about 1 hour. After additional stirring and heating for 3 hours, the mixture is cooled, and ethyl acetate (10 ml) followed by water (20 ml) and 4 N acetic acid (125 ml) are very cautiously added dropwise. The solvents are thereafter removed in vacuo and the residue is extracted with ethyl acetate (300 ml). The insoluble inorganic material is removed by filtration, and the filtrate is washed with aqueous sodium hydrogen carbonate and with water, and is then dried in the presence of magnesium sulphate. After filtration, the solvent is removed in vacuo to yield crude 3-amino-4-(3'trifluoromethylphenoxy)-5-sulfamylbenzyl alcohol. After recrystallization from diethyl ether/petroleum ether it is obtained with a melting point of 133°-134° C.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[C:49]([Si:53]([CH3:71])([CH3:70])[O:54][C:55]1[CH:56]=[C:57](O)[CH:58]=[C:59]([O:61][Si:62]([C:65]([CH3:68])([CH3:67])[CH3:66])([CH3:64])[CH3:63])[CH:60]=1)([CH3:52])([CH3:51])[CH3:50].N(C(N(C)C)=O)=NC(N(C)C)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:65]([Si:62]([CH3:64])([CH3:63])[O:61][C:59]1[CH:58]=[C:57]([O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:56]=[C:55]([O:54][Si:53]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:71])[CH3:70])[CH:60]=1)([CH3:68])([CH3:67])[CH3:66]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(O)cc(O[Si](C)(C)C(C)(C)C)c1
Reactant: OCCOCCOCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(OCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cc(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a solution of Compound 2 (4.3 g, 8.9 mmol) in toluene (20 ml), tributylphosphine (2.35 g, 8.92 mmol) was added at room temperature; this was followed by stirring for 1 hour. This was gradually added to a solution of Compound 43 (3.3 g, 11.6 mmol) and 1,1′-azobis(N,N-dimethylformamide) (2.0 g, 11.6 mmol) in toluene (20 ml), and this was followed by overnight stirring at room temperature. Ethyl acetate (100 ml) was added; the resulting insoluble matter was removed by Celite filtration and washed with ethyl acetate. The combined organic phases were concentrated under reduced pressure; the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (n-hexane:ethyl acetate 3:1-2:1)) to yield Compound 44 (colorless oil 2.8 g, 39%).
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCOC4)c3s2)cc1

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 4-methoxy-benzoic acid, the title compound was prepared as white powder. MS: m/e=415(M+H+).