Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[S:25][C:7]3[NH:8][C:9](=[O:24])[N:10]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=4[O:22][CH3:23])[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([C:4]2[S:25][C:7]3[N:8]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:34]5[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:32][CH:33]=4)[C:9](=[O:24])[N:10]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=4[O:22][CH3:23])[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: COc1ccc(Cn2c(=O)[nH]c3sc(C4CC4)cc3c2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)c3cc(C4CC4)sc3n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A mixture of 6-cyclopropyl-3-(2,4-dimethoxybenzyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.82 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (1.38 g) and potassium carbonate (1.4 g) and acetonitrile (100 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (2.4 g, 86%).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:41]=[CH:40][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:41][CH:40]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: COc1cccc(C[C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: COc1cccc(C[C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)N(C(=O)Cn3cncn3)C2)c1
Yield: 82 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide, gave Compound 70, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide (160 mg, 82%). 1H-NMR (400 MHz, CDCl3): σ 9.00 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.41 (d, 2H), 7.00 (t, 2H), 6.93-6.89 (m, 4H), 6.80-6.73 (m, 4H), 5.03 (d, 1H), 4.95 (d, 1H), 4.80 (d, 1H), 3.81 (s, 3H), 3.63 (dd, 1H), 3.27-3.16 (m, 1H), 3.02-2.88 (m, 2H), 2.68-2.59 (m, 2H), 1.76-1.68 (m, 1H). MS (EI) for C29H28FN5O4. found 530.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>C(#N)C>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([O:1][CH2:17][CH:19]2[O:21][CH2:20]2)=[CH:3][CH:4]=1
Reactant: ClCC1CO1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCc1ccc(OCC2CO2)cc1
Yield: 100 %

Procedure:
30.0 g p-hydroxyphenethyl alcohol, 60 g of anhydrous potassium carbonate and 50.28 g of epichlorohydrin were refluxed in 250 mL of acetonitrile for 5 hrs. After cooling, filtering and removing acetonitrile at reduced pressure, 300 mL of toluene were added and the toluene removed under reduced pressure. The residual oil solidifies on standing and is used directly in the next step. Yield=43.2 g, c. 100% yield. This solid after recrystallization in water has a melting point of 56°-58.5° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:21])=[O:22])[CH:19]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(Br)ccc2OC)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 5-bromo-2-methoxybenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (14.4 mg) with purity >90%. LCMS (pos) m/z 437.0.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:13]=[N:14][CH:15]2[C:34](=[O:35])[N:17]3[C:18]([C:23]([O:25][CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:24])=[C:19]([CH3:22])[CH2:20][S:21][C@H:16]23)[CH2:9][CH2:8]1)=[N+]=[N-].O.[ClH:37]>C(OCC)(=O)C.[Pd]>[ClH:37].[ClH:37].[NH2:1][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:13]=[N:14][CH:15]2[C:34](=[O:35])[N:17]3[C:18]([C:23]([O:25][CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])=[O:24])=[C:19]([CH3:22])[CH2:20][S:21][C@H:16]23)[CH2:9][CH2:8]1
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N=CN3CCC(CCCN=[N+]=[N-])CC3)[C@H]2SC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N=CN3CCC(CCCN)CC3)[C@H]2SC1

Procedure:
To a stirred solution of pivaloyloxymethyl 7-[(4-(3-azidopropyl)-1-piperidyl)-methyleneamino]-3-methyl-3-cephem-4-carboxylate (1.5 g) in ethyl acetate (25 ml) were added water (30 ml) and hydrochloric acid to pH=3. 10% palladium-on-carbon (0.5 g) was added, and hydrogen was bubbled through the stirred mixture, a pH-value of 3 being maintained by addition of 0.2 N hydrochloric acid. When the consumption of acid ceased, the catalyst was filtered off. The aqueous phase was separated and freeze-dried to yield the desired compound as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([O:19][CH2:20][CH:21]([O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22]Br)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[C:11]([O:19][CH2:20][CH:21]([O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: O=C(OCC(CBr)OC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCC(Cn1ccc2ncnc(Cl)c21)OC(=O)c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg), 3-bromopropane-1,2-diyl dibenzoate (1.77 g), cesium carbonate (1.59 g) and N,N-dimethylformamide (6.5 mL) was stirred at 80° C. for 4 hrs. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→40/60) to give the title compound (401 mg) as a white powder.
Reaction SMILES: [Br-].C([P+](CCCC)(CCCC)[CH:7]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[C:9](=[O:16])[O:8]1)CCC.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=O)[CH:29]=1.C(N(CC)CC)C>ClCCl>[O:16]=[C:9]1[C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:7](=[CH:34][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([O:26][CH3:25])=[O:36])[O:8]1
Reactant: CCCC[P+](CCCC)(CCCC)C1OC(=O)C2=C1CCCC2
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C=C2OC(=O)C3=C2CCCC3)c1

Procedure:
A solution of EXAMPLE 1B (25.8 g, 61.5 mmol), methyl-3-formylbenzoate (10.01 g, 61.0 mmol), and triethylamine (8.7 mL, 62.4 mmol) in dichloromethane (125 mL) was stirred at room temperature for 16 hours, and concentrated. The residue was stirred with a mixture of ethyl acetate and water. The precipitated solid was filtered, washed with water, and dried to provide the title compound. MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:14](=[O:35])[N:15]([CH3:34])[C:16]2[C:21]([CH:22]=1)=[CH:20][N:19]=[C:18]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-])=O)[C:17]=2[CH3:33]>C(OCC)(=O)C>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:18]1[C:17]([CH3:33])=[C:16]2[C:21]([CH:22]=[C:13]([C:3]3[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[Cl:12])[C:14](=[O:35])[N:15]2[CH3:34])=[CH:20][N:19]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4ccccc4[N+](=O)[O-])c(C)c3n(C)c2=O)c1Cl
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4ccccc4N)c(C)c3n(C)c2=O)c1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a solution of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1,8-dimethyl-7-(2-nitrophenylamino)-1,6-naphthyridin-2(1H)-one (100 mg, 0.2 mmol) in ethyl acetate (20 mL) was added stannous chloride (150 mg, 0.8 mmol), and the mixture was stirred at 80° C. for 1 h. LCMS monitored the reaction was completed. The solid was filtered off, and the filtrate was concentrated. The residue was purified by Prep-HPLC to get the title compound (38.6 mg, 41%) as a yellow solid. MS (ES+) C24H22Cl2N4O3 requires: 484, 486. Found: 485, 487 [M+H]+; 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.24 (s, 1H), 7.76 (s, 1H), 7.67 (s, 1H), 7.03 (d, 1H, J=7.5 Hz), 6.97 (s, 1H), 6.92-6.89 (m, 1H), 6.75-6.73 (m, 1H), 6.57-6.54 (m, 1H), 4.77 (s, 2H), 3.95 (s, 6H), 3.66 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([CH3:25])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:26])[N:15]([CH3:25])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cc(C)ccc2n(C)c1=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2C
Yield: 96.9 %

Procedure:
Cyclohexylamine (2.85 mL, 24.95 mmol) was added to a solution of Compound 17 (3.26 g, 12.47 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 3.8 g (97%) of white solids. M.P. 218° C. 1H NMR (DMSO-d6): δ 1.28 (m, 1H), 1.36 (m, 4H), 1.55 (m, 1H), 1.68 (m, 2H), 1.87 (m, 2H), 2.40 (s, 3H), 3.59 (s, 3H), 3.87 (m, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.86 (s, 1H), 10.49 (s, 1H). EIMS m/z 315 (M+1), 337 (M+23).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[N+:9]([CH2:12][CH3:13])([O-:11])=[O:10].[OH-].[Na+]>CCO.O>[N+:9]([CH:12]([CH3:13])[CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[OH:8])([O-:11])=[O:10]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(O)c1ccncc1)[N+](=O)[O-]

Procedure:
A solution of 1.0 eq. of 4-pyridinecarboxaldehyde (63, Aldrich, cat. no. P6,240-2) and 1.5 eq of nitroethane (Aldrich, cat. no. 22,787-0) in absolute EtOH was stirred at 0° C. as a solution of 2.0 eq. of NaOH in water was added. After a time sufficient for reaction completion, the reaction mixture was concentrated by rotary evaporation and neutralized (pH 7-8) with conc. HCl. A white precipitate formed. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and the solvent removed by rotary evaporation. The material was purified by flash chromatography on silica gel using a mixture of MeOH—CH2Cl2 as eluant to afford 64 as a mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The procedure was adapted from that reported in J. Med. Chem. 1976, 19, 1072. 6-Methylpyrimidine-2,4(1H,3H)-dione (7.0 g, 55.56 mmol) was added to concentrated sulfuric acid (26 mL) cooled in ice at such a rate that the internal temperature did not exceed 40°. To this mixture fuming nitric acid (5.2 mL) was added dropwise whilst maintaining the temperature below 15°. The cooling bath was removed and the mixture was stirred at room temperature for 30 min then dumped into 100 ml of crushed ice. After stirring for 10 min the solid was collected and washed with cold water then dried in vacuo over phosphorus pentoxide. A yellow-green solid of 6-methyl-5-nitropyrimidine-2,4(1H,3H)-dione was obtained (7.92 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)[S:5][C:6]=1[C:7]([OH:9])=O.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26]>>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:7]([C:6]1[S:5][C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)=[N:3][C:2]=1[CH3:1])=[O:9]
Reactant: NCC(F)(F)F
Reactant: Cc1nc(CCc2conc2-c2ccccn2)sc1C(=O)O
Product: Cc1nc(CCc2conc2-c2ccccn2)sc1C(=O)NCC(F)(F)F
Yield: 93 %

Procedure:
As described for example 19, 4-methyl-2-[2-(3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (70 mg, 0.22 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (82 mg, 93%) which was obtained as an off white solid MS: m/e=397.1 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.O.[OH-].[Na+]>C(O)(=O)C.[Zn]>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[S:6][CH:2]=[C:3]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2csc(COc3ccc(F)c(C(N)=O)c3F)n2)cc1
Temperature: 120 °C
Yield: 48.6 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (2.0 g, 4.37 mmol) in the 50 ml of acetic acid was added Zn dust (2.0 g). The reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and pH was adjusted to 8-9 with NaOH solution and extracted with ethyl acetate (3×150 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.8 g, 50%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[C:11]([C:25]([NH2:27])=[O:26])=[C:12]([NH:14][C:15](=[O:24])[NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[S:13][C:7]=2[CH2:6]1.C(N(CC)CC)C.[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH2:44][CH2:45][C:46](O)=[O:47])=[CH:36]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]([NH:14][C:12]2[S:13][C:7]3[CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:46](=[O:47])[CH2:45][CH2:44][C:37]4[C:38]5[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=5)[NH:35][CH:36]=4)[CH2:10][CH2:9][C:8]=3[C:11]=2[C:25]([NH2:27])=[O:26])=[O:24])=[CH:18][CH:19]=1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: NCCCN1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCN(CCCNC(=O)CCc1c[nH]c3ccccc13)C2
Yield: 38.2 %

Procedure:
To a stirred solution of 6-(3-aminopropyl)-2-{[(4-chlorophenyl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide (0.14 mmol) in anhydrous THF (1.5) were added triethyl amine (93 μL, 0.66 mmol), 3-indolepropionic acid (31 mg, 0.16 mmol), EDC.HCl (31 mg, 0.16 mmol), HOBt (25 mg, 0.16 mmol) and the resultant mixture was stirred at room temperature for 8 h. Upon completion, the solvent was removed in vacuo and the oil was taken up in DCM. The organics were washed with water (×2) and dried (anhydrous Na2SO4) and evaporated to afford the crude product which was purified by flash chromatography Isolera system (SiO2 gel as stationary phase, 12 g HP column, dry loading) using DCM-DCM/MeOH (0%-12% MeOH in DCM) to afford the title compound as a brown solid (31 mg, 37% yield). 1H NMR (300 MHz, MeOH-d4) δ 7.55 (d, J=15.5 Hz, 1H), 7.50-7.43 (m, 2H), 7.34-7.24 (m, 3H), 7.12-6.95 (m, 3H), 3.38 (bs, 2H), 3.17 (t, J=6.7 Hz, 2H), 3.06 (t, J=7.2 Hz, 2H), 2.82-2.74 (m, 2H), 2.68-2.61 (m, 2H), 2.55 (t, J=7.2 Hz, 2H), 2.36-2.27 (m, 2H), 1.67-1.54 (m, 2H). LRMS [M+H]579.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:14])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[CH:5]=[O:6].ClC1C=CC=C(C(OO)=[O:23])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:14])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[C:5]([OH:23])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CCOc1c(F)cc(C=O)cc1F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C#CCOc1c(F)cc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 184.9 %

Procedure:
To 100 ml of chloroform were added 20 g of 3,5-difluoro-4-(2-propynyloxy)benzaldehyde and 25 g of 3-chloroperbenzoic acid and the mixture obtained was stirred at room temperature for overnight. Then, aqueous sodium sulfite solution was added to the reaction mixture and extracted with chloroform and ethyl acetate in order. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure to obtain 40 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:15][C:9]=3[C:8](=[O:22])[CH2:7][C:6]=2[CH:23]=1.CO.[OH-].[K+]>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:21])[C:17]([OH:19])=[O:18])=[CH:15][C:9]=3[C:8](=[O:22])[CH2:7][C:6]=2[CH:23]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)C(=O)Cc1cc(N)ccc1S2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc(N)ccc1S2
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.6 %

Procedure:
To a mixture of 78 mg of methyl 2-(8-amino-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionate and 3 ml of methanol was added with ice cooling 200 mg of potassium hydroxide in 3 ml of water, and the resulting mixture was stirred at room temperature for 6 hours. After filtrating the reaction mixture to remove insoluble substances, the filtrate was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain a yellow solid substance, which was chromatographed over 2 g of silica gel and eluted with chloroform/methanol (50/1), and there were obtained yellow crystals. The thus obtained crystals were recrystallized from chloroform-methanol to obtain 49 mg (yield: 75%) of 2-(8-amino-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as light yellow crystals having a melting point of 189°-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][CH:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCC(O)Cc2cccc(Cl)c2)N1
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(Cl)c1
Yield: 81.1 %

Procedure:
Analogous to the procedure described for Example 1A, Step C, 5-[4-(3-chloro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (1.53 g, 5.71 mmol) was reacted with tert-butyldimethylsilyl chloride (0.97 g, 6.4 mmol). Purification by medium pressure chromatography using a solvent gradient (1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-chloro-phenyl)-butyl]-pyrrolidin-2-one (1.77 g). 1H NMR (CDCl3) δ7.16 (m, 3H), 7.01 (m, 1H), 5.61 (d, 1H), 3.83 (m, 1H), 3.58 (m, 1H), 2.68 (m, 2H), 2.28 (m, 3H), 1.73-1.36 (m, 5H), 0.84 (s, 9H), −0.05 (s, 3H), −0.2 (d, 3H).
Reaction SMILES: [C:1](O)(=[O:4])[C:2]#[CH:3].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>O1CCCC1.CN(C)C=O>[C:1]([NH:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1)(=[O:4])[C:2]#[CH:3]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#CC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
To a solution of propiolic acid (27 mg, 0.387 mmol) in tetrahydrofuran (2 mL) and N,N-dimethylformamide (2 mL) was added N,N′-dicyclohexylcarbodiimide (100 mg, 0.484 mmol) under ice-cooling, and the mixture was stirred for 30 min. To the reaction mixture was added N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol), and the mixture was stirred under ice-cooling for 4 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0) to give the title compound (24 mg, 21%) as a pale-orange powder.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH2:8][CH:9]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[CH:10]([CH3:18])[C:11](=O)[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34]>>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH2:8][CH:9]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=4)[CH:10]([CH3:18])[C:11](=[N:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: CC1C(=O)c2c([nH]c3ccc(Cl)cc3c2=O)CC1c1ccc(C(F)(F)F)cc1
Reactant: CN(C)CCCN
Product: CC1C(=NCCCN(C)C)c2c([nH]c3ccc(Cl)cc3c2=O)CC1c1ccc(C(F)(F)F)cc1

Procedure:
By following the procedure of Example 3, and using 7-chloro-2-methyl-3-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1,9(2H,10H)-acridinedione instead of 7-chloro-3-(3,4-dichlorophenyl)-3,4-dihydro-1,9(2H,10H)acridinedione and N,N-dimethyl-1,3-propanediamine instead of N,N-diethylenediamine one obtains 7-chloro-1-[[3-(dimethylamino)propyl]imino]-1,3,4,10-tetrahydro2-methyl-3-[4-(trifluoromethyl)phenyl]-9(2H)-acridinone; mp 169°-170° C. after chromatography on silica eluted with chloroform/methanol 7:1.