Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.C[Si]([C:31]#[CH:32])(C)C>C(N(CC)CC)C.O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:31]#[CH:32])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: C#Cc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A solution of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (50 mg, 0.11 mmol) in triethylamine (2 mL) containing CuI (2.1 mg, 0.011 mmol) was degassed with bubbling nitrogen for 10 min. Pd(PPh3)4 (13 mg, 0.011 mmol) was added followed by trimethylsilylacetylene (5 equiv). The reaction vessel was sealed and heated in the microwave at 130° C. for 30 min. The cooled mixture was diluted with water and extracted with ethylacetate. The combined organics were concentrated and the residue dissolved in 2 mL methanol. The solution was treated with potassium carbonate (100 mg) and the suspension stirred for 2 hr at room temperature. The reaction mixture was concentrated, diluted with water and extracted with ethylacetate. The combined organics were concentrated and the residue purified by reverse phase HPLC to give 133. MS: (ESI+) 394.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([NH:19][C:20]1[C:25]([Cl:26])=[CH:24][N:23]=[N:22][C:21]=1Cl)([CH3:18])[CH3:17]>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([N:14]([CH3:15])[C:21]2[N:22]=[N:23][CH:24]=[C:25]([Cl:26])[C:20]=2[NH:19][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNN1CCN(Cc2ccccc2)CC1
Reactant: CC(C)Nc1c(Cl)cnnc1Cl
Product: CC(C)Nc1c(Cl)cnnc1N(C)N1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-methylaminopiperazine (EXAMPLE 9, 2.30 g, 11.4 mmol) and 4-isopropylamino-3,5-dichloropyridazine (EXAMPLE 157, 1.0 g, 4.8 mmol) are heated in a sealed tube under a nitrogen atmosphere to 155° for 3 hr. The mixture is then chromatographed (silica gel, 150 g; 50-100% ethyl acetate/hexane) to give the title compound, NMR (300 MHz, CD3OD) 8.43, 7.30, 4.5, 3.51, 2.90, 2.72, 2.05, 1.75 and 1.21δ.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([NH2:18])[N:15]=[C:16](Cl)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:21]=1[NH2:22].FC(F)(F)C(O)=O>FC(F)(F)CO>[CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([NH2:18])[N:15]=[C:16]([NH:22][C:21]3[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=3[CH3:19])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: Cc1cc(C)c(Nc2nc(N)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 100 °C
Yield: 90 %

Procedure:
To a suspension of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (200 mg, 0.78 mmol) and 2,4,6-trimethylaniline (0.44 mL, 3.08 mmol) in 2,2,2-trifluoroethanol (4 mL) was added trifluoroacetic acid (0.48 mL, 6.24 mmol). The resulting solution was heated at 100° C. for 2 days and cooled to room temperature. The reaction was concentrated to brown oil and diluted with CH2Cl2 (30 mL). The organic solution was washed with aqueous NaHCO3 solution (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (CH2Cl2:MeOH=95:5) yielded 251 mg (90%) of 7-benzyl-N4-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:25]([O-])=O)[CH:8]=2)[N:3]=1>CCOC(C)=O.[Pd]>[NH2:25][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])=[C:10]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(N)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.3 %

Procedure:
A mixture of the product of Step 1 (1.05 g, 3.25 mmol) and 10% Pd/C (0.222 g, 32.5) in EtOAc was degassed under reduced pressure and saturated with H2 gas. The resulting mixture was stirred overnight under H2 balloon at room temperature, filtered through Celite bed and filtrate evaporated to dryness to give product as an yellowish solid (1.46 g, 98%), which was used in next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.9 Hz, 1H), 7.43-7.48(m, 3H), 7.27-7.34(m, 2H), 7.10 (dd, J=2.5, 8.9 Hz, 1H), 6.55(d, J=2.5 Hz, 1H), 3.79(broad s, 2H), 2.69(s, 3H), 1.2(s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[N:18]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:17]1=[O:36])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[N:18]([CH2:28][C:29]([OH:31])=[O:30])[C:17]1=[O:36])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@H]1CSC[C@@H](c2cccs2)N(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@@H](c2cccs2)N(CC(=O)O)C1=O

Procedure:
160 mg of isomer B of t-butyl α-{6(R)-[1-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetate [prepared as described in Example 16(h)] were subjected to de-t-butylation with trifluoroacetic acid in the manner described in Example 3, to give 118 mg of the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[S:3]([N:6]1[CH:10]=[C:9]([CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])[N:8]=[C:7]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])(=[O:5])=[O:4]>CO.[Pd]>[CH3:23][N:2]([CH3:1])[S:3]([N:6]1[CH:10]=[C:9]([CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])[N:8]=[C:7]1[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:4])=[O:5]
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C=CC(=O)OC)n1
Agent: [Pd]
Solvent: CO
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCC(=O)OC)n1
Reaction time: 8 h

Procedure:
A suspension of Pd (10 wt % on carbon) in a solution of methyl 3-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]acrylate (2.39 g, 7 mmol) in methanol (75 mL) was stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through Celite and concentrated in vacuo. Chromatography of the residue over silica gel eluting with 0-60% ethyl acetate/hexane afforded methyl 3-[1-[(dimethylarnino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]propanoate.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C>[ClH:29].[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[C:16](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:15]\[O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(/c2ccccc2)c2ccccc2Cl)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CCCN(CCO/C=C(/c2ccccc2)c2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 114.4 %

Procedure:
E or Z-(R)-1-[2-[[2-(2-Chlorophenyl)-2-phenylethenyl]oxy]-ethyl]-3-piperidine carboxylic acid ethyl ester (1.0 g, 0.0024 mol) (opposite geometric isomer of example 6) was dissolved in ethanol (20 ml) and 10N sodium hydroxide solution (2.42 ml) was introduced. After stirring the reaction mixture at room temperature for 16 h, water (100 ml) was added and the mixture was neutralized with 2N hydrochloric acid solution Evaporation of ethanol under reduced pressure gave an aqueous solution, which was acidified to pH 1 with 2N hydrochloric acid and extracted with dichloromethane (4 × 100 ml). The combined extracts were dried (Na2SO4) and evaporated to a solid, which was recrystallized from methanol/toluene to give the title compound (0.58 g, 56%) as white crystals (after drying in vacuo), m.p. 227°-8°.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2([C:12]([O:14]CC)=[O:13])[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2([C:12]([OH:14])=[O:13])[CH2:10][CH2:11]2)=[O:7])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To ethyl 1-[(4-chlorobenzoyl)amino]cyclopropanecarboxylate (157 g, 0.58 mol) in 1,4-dioxane (2.4 L), add a solution of lithium hydroxide (123.05 g, 2.93 mol) in water (1.2 L). Stir the reaction mixture at ambient temperature for 4 hours and then concentrate it under reduced pressure. Dilute the mixture with water (1 L) and immerse it in an ice water bath. Adjust the pH to approximately 2 with aqueous 5N HCl. Filter the precipitate, wash the cake with water (3×1 L), and dry (50° C., vacuum oven) to give (132 g, 94%) the title compound as a white powder: MS (m/z): 240 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=O)[NH:12][CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[N:4][N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)=[CH:8][CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nnc(-c2ccc3c(=O)[nH]cnc3c2)o1
Product: Cc1nnc(-c2ccc3c(Cl)ncnc3c2)o1

Procedure:
7-(5-Methyl-[1,3,4]oxadiazol-2-yl)quinazolin-4-one (0.09 g) was treated with phosphorous oxychloride (5 ml) at reflux under nitrogen for 2 hours. The mixture was cooled, evaporated and partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic phase was dried, concentrated in vacuo to give the title compound which was used crude in the subsequent synthetic step.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6](CS([O-])(=O)=O)[CH2:5][O:4]2)[CH2:2]1.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]4[C:35](=[O:47])[N:36]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:37]([CH3:40])[C:38]=4[CH3:39])=[O:33])=[N:29][CH:30]=3)=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:2]1[C:3]2([CH2:7][CH:6]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([O:24][C:25]5[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]6[C:35](=[O:47])[N:36]([C:41]7[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=7)[N:37]([CH3:40])[C:38]=6[CH3:39])=[O:33])=[N:29][CH:30]=5)=[CH:19][CH:20]=[N:21]4)=[CH:16][CH:15]=3)[CH2:5][O:4]2)[CH2:1]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: O=S(=O)([O-])CC1COC2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC5COC6(CC6)C5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C

Procedure:
The title compound was prepared according to the procedure described in Example 6 by using (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (220 mg, 1.14 mmol), N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (300 mg, 0.64 mmol), and cesium carbonate (450 mg, 2.4 mmol, Aladdin) in DMA (6 mL). The title compound was purified with a silica gel column chromatography (EtOAc) to give a white solid (140 mg, 39%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[N+](=[CH2:11])=[N-]>>[C:1]([O:8][CH3:11])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C=[N+]=[N-]
Reactant: C#CCCCC(=O)O
Product: C#CCCCC(=O)OC

Procedure:
The starting material methyl 5-hexynoate was prepared by the reaction of 5-hexynoic acid with diazomethane according to Method E above.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.7 %

Procedure:
To a solution of 2-bromo-5-trifluoromethylaniline (3.18 g, 13.25 mmol) in pyridine (18 ml) was added methanesulfonyl chloride (1.03 ml, 13.25 mmol) and the mixture was stirred for 6 hours at room temperature. The solvent was removed in vacuo and the residue was diluted with chloroform. The organic layer was washed with water, 1N hydrochloric acid, a saturated sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by recrystallization to give the subject compound (2.18 g, 52%).
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)([O-])=O>O.C1COCC1.[Zn]>[C:12]1([C:9]2[N:10]=[CH:11][C:6]([NH2:3])=[CH:7][CH:8]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2ccccc2)nc1
Yield: 82.3 %

Procedure:
Ammonium chloride (1.1 g, 0.020 mol) dissolved in water (15 mL) was added to a stirred solution of 5-nitro-2-phenyl-pyridine (0.5 g, 2.5 mmol) in THF (10 mL) Methanol (5 mL) was then added, affording a clear solution. Zinc powder (1.3 g, 0.020 mol) was then added portion wise at room temperature and the resulting mixture maintained for 1 hour, then filtered over celite. The filtrate was concentrated and the residue was extracted with ethyl acetate. The organics were washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 0.35 g (82%) of 6-phenyl-pyridin-3-ylamine. LCMS purity: 171.08 (M+1)+, 87.9%, 1H NMR (DMSO-d6): δ 8.12 (d, 1H), 8.0 (d, 2H), 7.72 (d, 1H), 7.48 (t, 2H), 7.36 (t, 1H), 7.1 (dd, 1H), 5.6 (s, 2).
Reaction SMILES: [OH-].[Na+].[S:3]1[CH2:8][CH2:7][S:6][CH:5]=[C:4]1[CH2:9][C:10]([O:12]CC)=[O:11]>C(O)C>[S:3]1[CH2:8][CH2:7][S:6][CH:5]=[C:4]1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CC1=CSCCS1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1=CSCCS1
Temperature: 50 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
10N Sodium hydroxide solution (71.4 cc.) is added to a solution of ethyl (5,6-dihydro-1,4-dithiin-2-yl)acetate (121.3 g.) in ethanol (800 cc.). The reaction mixture is heated for 3 hours at about 50° C. After evaporating the solvent under reduced pressure (25 mm.Hg), the residue is dissolved in distilled water (500 cc.). The alkaline aqueous solution is washed twice with ether (total 100 cc.), treated with decolourizing charcoal (0.2 g.), filtered and then acidified with excess hydrochloric acid (d = 1.19). The oil which separates out is extracted three times with diethyl ether (total 450 cc.). The combined ether solutions are washed three times with distilled water (total 300 cc.), dried over anhydrous magnesium sulphate and evaporated. The residue (102.2 g.) is dissolved in boiling diisopropyl ether (150 cc.) and then petroleum ether (b.p. 40°-60° C.) (50 cc.) is added. After 3 hours at 2° C., the crystals which have appeared are filtered off, washed twice with ice-cold diisopropyl ether (total 60 cc.) and dried under reduced pressure (25 mm.Hg) to give (5,6-dihydro-1,4-dithiin-2-yl)acetic acid (82.2 g.) melting at 82° C.
Reaction SMILES: [C:1]1([PH:7](=[O:15])[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][CH2:17][CH2:18]Br>>[C:1]1([P:7](=[O:15])([CH2:16][CH2:17][CH3:18])[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCBr
Reactant: CCOC(OCC)[PH](=O)c1ccccc1
Product: CCCP(=O)(c1ccccc1)C(OCC)OCC

Procedure:
Following a procedure analogous to that of Example 11 but using phenyl(diethoxymethyl)phosphine oxide instead of tertiary-butyl(diethoxymethyl)phosphine oxide and n-propyl bromide instead of iso-butyl bromide there is obtained phenyl(n-propyl)(diethoxymethyl)phosphine oxide as a colourless oil. 31P NMR 35.845 ppm (CDCl3)
Reaction SMILES: C(O)C.C([NH:11][C:12]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]2[C:13]=1[C:14](=[O:41])[C:15]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:16][N:17]2[C:25]1[CH:30]=[C:29]([NH:31][CH:32]=[O:33])[C:28]([F:34])=[CH:27][C:26]=1[F:35])C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH2:11][C:12]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]2[C:13]=1[C:14](=[O:41])[C:15]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:16][N:17]2[C:25]1[CH:30]=[C:29]([NH:31][CH:32]=[O:33])[C:28]([F:34])=[CH:27][C:26]=1[F:35]
Reactant: CCOC(=O)c1cn(-c2cc(NC=O)c(F)cc2F)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cc(NC=O)c(F)cc2F)c2c(F)c(F)c(F)c(N)c2c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.3 %

Procedure:
To 20 ml of ethanol and 10 ml of acetic acid were added 600 mg of ethyl 5-benzylamino-6,7,8-trifluoro-1-(2,4-difluoro-5-formylaminophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate and 100 mg of 10% palladium on carbon. Under a hydrogen atmosphere, the solution was stirred at room temperature for 2 days. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. Diethyl ether was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether to give 420 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[Cl:23]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[C:8]([Cl:23])[C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1[nH]c(-c2ccc3ccccc3c2)cc1C(N)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Nc1[nH]c(-c2ccc3ccccc3c2)c(Cl)c1C(N)=O
Yield: 45 %

Procedure:
A solution of 2-aminocarbonylamino-5-(2-naphthyl)pyrrole-3-carboxamide (Compound No. 1-1, 92 mg, 0.31 mmol) and N-chlorosuccinimide (46 mg, 0.34 mmol) in anhydrous N,N-dimethylformamide (2 mL) was stirred at 60° C. for 2 hours. After cooling, water (10 mL) was added thereto, the precipitated solid was filtered off, and washed with water (10 mL) and acetone (10 mL). The obtained solid was dried at 50° C. under reduced pressure to give the target compound (46 mg) as a pale brown solid (Yield 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:19]Br)=[C:15]([CH:18]=1)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOC(C)=O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:19][O:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: N#Cc1cc(Br)ccc1CBr
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Br)ccc1COc1ccc(Cl)c(Cl)c1
Temperature: 75 °C
Yield: 94.7 %

Procedure:
A mixture of 3,4-dichlorophenol (267.1 mg, 1.639 mmol), 5-bromo-2-(bromomethyl)benzonitrile (447.3 mg, 1.627 mmol), and potassium carbonate (674.1 mg, 4.877 mmol) in acetone (20 mL) was heated to 75° C. under nitrogen for 18 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL) and filtered through arbocel. The arbocel was then washed with EtOAc (2×20 mL), and the combined organics were washed with brine (3×20 mL), dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound as a white solid (549.9 mg, 95%).
Reaction SMILES: O[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cnc(O)c([N+](=O)[O-])c1
Product: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Temperature: 105 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A suspension of 6-hydroxy-5-nitronicotinic acid (8 g, 43.5 mmol) (prepared by literature nitration of 6-hydroxynicotinic acid) in phosphorus oxychloride (24.3 mL, 261.0 mmol) was heated to reflux (105° C.) for 3 h under a nitrogen atmosphere. At the end of this time period all of the solids had dissolved. The reaction was cooled to rt and poured over 500 mL crushed ice, and stirring was continued for 30 minutes until all of the ice had melted. The aqueous mixture was extracted with a 1:2 mixture of THF in diethyl ether (3×150 mL). The pooled organic extracts were washed with brine (1×), dried (MgSO4), and concentrated on a rotary evaporator to afford intermediate 56 as a light brown solid (8.37 g, 95%). ESI-MS m/e 405.3 (2M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[CH2:7][C:8]([CH3:23])([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[O:9]2)=[CH:4][C:3]=1[OH:25].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:25][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[O:9][C:8]([CH3:23])([CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[CH2:7][C:6]2=[O:24])(=[O:28])[CH3:27]
Reactant: CC1(COc2ccc([N+](=O)[O-])cc2)CC(=O)c2cc(O)c(Cl)cc2O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(cc1Cl)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O

Procedure:
A procedure similar to that described in Preparation 17 was repeated, except that 550 mg of 7-chloro-6-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)-4-oxochroman (prepared as described in Preparation 34), 1 ml of acetic anhydride and 10 ml of pyridine were reacted, to afford 580 mg of the title compound as a pale yellow glassy substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[S:15][CH:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[NH:10][C:9]2=O)=[CH:4][CH:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:38])=O>>[Cl:38][CH:9]1[NH:10][C:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][S:15][C:12]=2[C:13](=[O:14])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2c(-c3ccccc3)csc2c(=O)n1-c1ccc(Cl)cc1
Solvent: CCN(CC)c1ccccc1
Product: O=C1c2scc(-c3ccccc3)c2NC(Cl)N1c1ccc(Cl)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
3-(4-Chlorophenyl)-7-phenylthieno[3,2-d]pyrimidin-2,4(1H,3H)-dione (100 mg, 0.3 mmol), N,N-diethylaniline (0.014 ml, 0.09 mmol), and phosphoryl chloride (0.34 ml, 3.6 mmol) were placed in a reaction vessel. The mixture was heated with stirring at 130° C. overnight. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature and separated with NaHCO3 and dichloromethane. The extracted organic layer was washed with brine, dried over anhydrous MgSO4, and filtered. The filtrate was distilled under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hex=1:5) to give 2-chloro-3-(4-chlorophenyl)-7-phenyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (22.7 mg, 0.06 mmol, 20% yield).