Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1.FC(F)(F)C(O)=O>ClCCl>[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1)=[O:34]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)C(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and biphenyl-2-carboxylic acid as starting materials and by an operation similar to that of Example 312-1 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.CCCCCC.[F:20][CH2:21][C:22](OCC)=[O:23]>C1COCC1>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[C:22](=[O:23])[CH2:21][F:20]
Reactant: CCOC(=O)CF
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(CF)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a cooled (−78° C.) solution of 1,2-difluorobenzene (8.81 mL, 89 mmol) in THF (175 mL) was added dropwise butyllithium solution, 1.6M in hexane (61.5 mL, 98 mmol). After stirred for 2 h, ethyl fluoroacetate (8.64 mL, 89 mmol) ethyl fluoroacetate was added dropwise. The reaction was stirred for 1 h, the reaction was quenched with saturated NH4Cl and then warmed to room temperature. The resulted mixture was extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-30% EtOAc/hexane) to afford 6.3 g of desired product as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:16]=[C:17]=[S:18].[NH2:19][C:20]1[C:21]([NH:44][CH3:45])=[N:22][C:23]([O:39][CH2:40][CH:41]([F:43])[F:42])=[C:24]([CH:38]=1)[C:25]([NH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]1)=[O:26]>CC#N>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[NH:16][C:17]([NH:19][C:20]1[CH:38]=[C:24]([C:25](=[O:26])[NH:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([C:34]([F:37])([F:35])[F:36])[CH2:30][CH2:29]2)[C:23]([O:39][CH2:40][CH:41]([F:42])[F:43])=[N:22][C:21]=1[NH:44][CH3:45])=[S:18]
Reactant: CNc1nc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Solvent: CC#N
Product: CNc1nc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1NC(=S)Nc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(4-Chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (68 mg, 0.24 mmol) is added to 5-amino-2-(2,2-difluoro-ethoxy)-6-methylamino-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (95 mg, 0.24 mmol) in MeCN (3.5 mL) and stirred at rt overnight. The reaction mixture is concentrated and used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]1(CCO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[CH3:6][C:5]([O:4][CH2:1][CH2:2][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: OCCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: ClCCl
Product: CC(=O)OCCc1ccccc1
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
In a dry 50-mL, two-necked, round-bottomed flask, vanadyl acetylacetonate (13.7 mg, 0.05 mmol) in 3 mL of anhydrous CH2Cl2 was placed. To the above solution, acetic anhydride (153.1 mg, 141.5 μL, 1.5 mmol) was slowly added at ambient temperature. After about 10 min, a solution of 2-phenylethanol (122 mg, 119.3 μL, 1.0 mmol) in CH2Cl2 (2 mL) was slowly added to the above dark green solution, and the reaction mixture was stirred for 5 hours. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with cold, saturated aqueous NaHCO3 solution (5 mL). The resulting separated organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. The crude product was purified by column chromatography on silica gel to yield 139.4 mg of 2-phenethyl acetate (85%) as colorless oil. The substrate, reaction time, and yield of this test are summarized in Entry 1 of the following Table 1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][N:3]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14].CC([O-])(C)C.[K+].C1COCC1>CN(C=O)C>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][C:6]=2[O:10][CH3:11])[S:14][C:13]=1[C:12]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CS
Reactant: COc1ccnc(Cl)c1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc2nccc(OC)c2c1N
Reaction time: 0.33 h

Procedure:
To 2-chloro-3-cyano-4-methoxypyridine (2.02 g) and methyl thioglycolate (1.1 mL) in DMF (24 mL) at 5° C. was added a 1.0M solution of KOtBu/THF (14.6 mL). The reaction was stirred 20 min at 5°, then 1 h at RT, quenched in saturated NH4Cl, the solid collected, washed with water and sucked dry. This was recrystallized from EtOAc to give 0.89 g of the title compound.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[C:14](OCC)(=[O:16])C.CCCCCC>CO>[OH:16][CH2:14][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:7][CH3:6])=[O:8]
Reactant: CCOC(C)=O
Reactant: O=C1CCCCCO1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)CCCCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
ε-Caprolactone (12.50 g, 109.51 mM) was dissolved in methanol (125 ml), and a sulfuric acid solution (1 ml, 0.01 mM) was slowly added thereto. The resulting mixture was stirred at room temperature for 2 days. After the completion of reaction, methanol was removed under reduced pressure, and then ice water was poured into the residue. The resulting mixture was extracted with ethyl ether. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to obtain 10.18 g of the title compound (yield 64%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>N#[Ti]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: N#[Ti]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated with 14.1 g of a powdered titanium nitride from H. C. Starck at 140° C. After 2 hours' reaction time, phenol conversion was 21.6%, wherein 0.03 g of phenyl chloroformate and 34.3 g of diphenyl carbonate were formed. Selectivity for carbonates was approximately 99%.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[C:9](=[O:18])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH:5]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].[BH4-].[Na+]>CN(C=O)C.O>[OH:3][CH:1]([C:4]1[O:8][C:7]2[C:9](=[O:18])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH:5]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:2]
Reactant: CC(=O)c1cc2c(o1)C(=O)c1ccccc1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)c1cc2c(o1)C(=O)c1ccccc1C2=O
Yield: 79.5 %

Procedure:
In a 250 ml beaker, 2 grams (8.3 mmoles) of 2-acetyl-naphtho[2,3-b]furan-4,9-dione (prepared in example 2 or 3) was dissolved in 40 ml of DMF with heating. To the solution with stirring, 1 gram (26.4 mmoles) of sodium borohydride in 10 ml of water was added. The mixture was stirred in open air for 30 minutes, then diluted by adding 250 ml of water. The resulting mixture was extracted with 100 ml of dichloromethane twice. The combined organic phase was washed with 200 ml of water, dried with anhydrous sodium sulfate, and evaporated to dryness. The residue was crystallized in ethyl acetate to yield 1.6 gram (6.6 mmoles) of pure product with overall yield 80%. Pure product was characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 1.47 (d, J=7, 3H), 4.88 (m, 1H), 5.83 (d, J=5, 1H), 6.91 (s, 1H), 7.84-7.90 (m, 2H), 8.06-8.11 (m, 2H). Mass (M+H) is 243.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][S:21](Cl)(=[O:23])=[O:22])=[C:15]([O:25][CH3:26])[CH:14]=1>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][S:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:22])=[O:23])=[C:15]([O:25][CH3:26])[CH:14]=1
Reactant: COc1cc(Cl)ccc1C=CS(=O)(=O)Cl
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Product: COc1cc(Cl)ccc1C=CS(=O)(=O)Nc1ccccc1S(N)(=O)=O
Reaction time: 1 h
Yield: 40.4 %

Procedure:
2-Aminobenzene sulfonamide (194 mg, 1.13 mmol) was added in one portion to a solution of 2-(4-chloro-2-methoxyphenyl)-ethenesulfonyl chloride (300 mg, 1.13 mmol) in pyridine (3 mL) at RT. After 1 h stirring, no more starting material was detected by tlc. The reaction mixture was concentrated and the residue was taken up in ethyl acetate with a small amount of methanol. The organic phase was washed with 1N HCl, saturated sodium bicarbonate, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on silica gel using DCM/methanol, 99:1 to afford material which was further purified by recrystallization from methanol to give the title compound (184 mg, 41%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:27]1([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(-c2ccccc2)c2c(c1O)c1ccccc1n2-c1ccccc1
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
A mixture of 1-bromo-4-hydroxy-9-phenyl-9H-beta-carboline-3-carboxylic acid ethyl ester (91 mg, 0.221 mmol), phenyltributyltin (98 mg, 0.265 mmol), and Pd(PPh3)2Cl2 (8 mg, 0.011 mmol) in DMF (1 mL) was stirred at 130° C. for 40 min. The mixture was then diluted with EtOAc, washed with water and saturated NaCl aqueous solution, respectively; the EtOAc phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column to give a white solid, the desired title compound. The title compound, ESI MS (m/z): 409 (M+H+).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[C:8]1([Si:14]([Cl:17])([Cl:16])Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1([SiH](Cl)Cl)C=CC=CC=1.C1C=CC=CC=1>[C:8]1([Si:14]([C:7]2[CH:6]=[CH:10][CH:9]=[CH:8][CH:13]=2)([Cl:16])[Cl:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCN(CC)CC
Reactant: Cl[Si](Cl)(Cl)c1ccccc1
Agent: Cl[SiH](Cl)c1ccccc1
Solvent: c1ccccc1
Product: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Yield: 253.1 %

Procedure:
Triethylamine (3.9 g) was added to a flask containing 83.3 g of the crude product mixture described in Example 1. This mixture was stripped by the process described in Example 1. The volatiles were condensed and analyzed by GC-TCD. About 77.4 g of a liquid was recovered comprising 24.7 g of diphenyldichlorosilane (yield of 77 percent), 1.4 g of phenyldichlorosilane, 24.5 g of phenyltrichlorosilane, and 10.1 g of benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]2[C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=3[C:14]2=[O:17])=[CH:5][CH:4]=1.[CH2:21](O)[CH3:22]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:16]=[C:15]2[C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:13]=3[C:14]2=[O:17])=[CH:5][CH:4]=1
Reactant: CCO
Reactant: COc1ccc2oc3ccc(C(=O)O)cc3c(=O)c2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2oc3ccc(OC)cc3c(=O)c2c1
Yield: 84 %

Procedure:
A mixture of 7-methoxy-9-oxoxanthene-2-carboxylic acid in ethanol (100ml) and concentrated sulfuric acid (10 ml) was refluxed under nitrogen for 24 hours. The reaction mixture was concentrated and cooled. The product, which precipitated, was filtered off and recrystallized from ethanol to give white crystals (2.53g, 84%), mp. 170°-172° C.
Reaction SMILES: O.C(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH:15]=[O:16])=[O:14])CCC.[CH3:17][C:18]([NH2:30])([CH3:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1>CS(C)=O>[CH3:29][C:18]([N:30]=[C:15]([O:16][CH2:12][CH2:7][CH2:8][CH3:9])[C:13]([C:8]1[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])([CH3:17])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1
Reactant: CC(C)(N)Cc1ccc2c(c1)OCO2
Reactant: CCCCOc1ccccc1C(=O)C=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCOC(=NC(C)(C)Cc1ccc2c(c1)OCO2)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 700 mg of 2-n-butoxyphenylglyoxal hydrate, 500 mg of α,α-dimethyl-3,4-methylenedioxyphenethylamine and 1.5 ml of dimethylsulfoxide is stirred at room temperature for 45 minutes, whereby a solution of α-(α,α-dimethyl-3,4-methylenedioxyphenethylimino)-2-n-butoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[N-:12]=[N+:13]=[N-:14].[Na+].[Cl-].C([NH+](CC)CC)C>C1(C)C=CC=CC=1>[C:6]1([C:2](=[O:1])[CH2:3][C:4]2[N:5]=[N:12][NH:13][N:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCC(=O)c1ccccc1
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(Cc1nn[nH]n1)c1ccccc1
Yield: 74 %

Procedure:
3-Oxo-3-phenyl-propionitrile (6.5 g, 45 mmol), sodium azide (3.3 g, 50 mmol) and triethylammonium chloride (6.7 g, 50 mmol) were stirred in dry toluene (100 mL) under argon at 90° C. for 18 h. A two-phase system was formed. The reaction mixture was cooled and extracted with NaOH (2M, 2×50 mL). The aqueous solution was poured into hydrochloric acid (4M, 200 mL) and the crude product precipitated and was filtered off and recrystalliced from acetonitrile. Yield: 74%.
Reaction SMILES: C[O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[CH:10]=2)=[CH:5][C:4]=1[C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH3:27])=[CH:24][CH:23]=[CH:22][CH:21]=2.C[Si](Cl)(C)C.[I-].[K+]>C(#N)C.O>[OH:16][C:12]1[C:13]([CH3:15])=[CH:14][C:9]([C:6]2[CH:5]=[C:4]([C:18]3[NH:19][C:20]4[C:25]([C:26]=3[CH3:27])=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:3](=[O:2])[NH:8][N:7]=2)=[CH:10][C:11]=1[CH3:17]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1[nH]c2ccccc2c1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2cc(-c3[nH]c4ccccc4c3C)c(=O)[nH]n2)cc(C)c1O
Temperature: 80 °C

Procedure:
6 mg of 4-[6-Methoxy-5-(3-methyl-1H-indol-2-yl) -pyridazin-3-yl]-2,6-dimethyl-phenol is suspended in 2 ml acetonitrile and 6.5 mg of trimethylsilyl chloride and 9.96 mg of potassium iodide are added. The solution is heated to 80° C. for 3 h. The reaction solution is diluted with water and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 3.8 mg. LC-MS (ES+) 346 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][CH:12]=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:22])([F:21])[CH2:19]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:1]1([C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:19][C:18]([F:22])([F:21])[F:17])[CH:12]=[N:11][C:10]=3[S:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)CI
Reactant: O=c1[nH]cnc2scc(-c3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(-c3ccccc3)csc2ncn1CC(F)(F)F
Temperature: 100 °C
Yield: 47.6 %

Procedure:
A mixture of 5-phenylthieno[2,3-d]pyrimidin-4(3H)-one (20 g, 88 mmol), 1,1,1-trifluoro-2-iodoethane (36.8 g, 175 mmol) and potassium carbonate (26.6 g, 193 mmol) in DMF (100 ml) was heated at 70° C. for 0.5 h and at 100° C. for 2 h. A further portion of 1,1,1-trifluoro-2-iodoethane (36.8 g, 175 mmol) was added and the resulting mixture was heated at 100° C. for a further 16 h. The reaction mixture was cooled down and diluted with water (750 ml) and the precipitate was filtered to give the title compound as a light yellow solid (13 g, 48%). LCMS RT=1.30 min, M+H+=311.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N+:22]([CH3:25])([O-:24])=[O:23].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:13])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH:8]=[CH:7][C:3]=1[C:4]([CH2:25][N+:22]([O-:24])=[O:23])=[O:6]
Reactant: Cc1ccccc1CC(=O)Nc1ccc(C(=O)O)c(Cl)c1
Reactant: C[N+](=O)[O-]
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)C[N+](=O)[O-])c(Cl)c1

Procedure:
This compound was obtained by carrying out the procedure as in Example 42 starting with 19 g (62.5 mmol) of 2-chloro-4-[(2-methylbenzyl)carbonylamino]benzoic acid obtained in step a), 3.18 g of nitromethane, 11 g (67.6 mmol) of diethyl cyanophosphonate, 16.8 g (167 mmol) of triethylamine in 205 ml of DMF dried over a molecular sieve. After chromatography on a silica column (eluent: dichloromethane-methanol 95:5) and recrystallization from a hexane-ethyl acetate mixture, 0.2 g (Yield=1) of a pale yellow powder is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[C:13](=[O:21])[O:14][C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][OH:23]>>[CH3:22][O:23][C:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH:12]([C:13]([OH:14])=[O:21])[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:20]
Reactant: O=C1OC(=O)C2CCCC1N2C(=O)OCc1ccccc1
Reactant: CO
Product: COC(=O)C1CCCC(C(=O)O)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
2,4-Dioxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 2, 10 g, 34.51 mmol) was dissolved in methanol (50 ml). The reaction mixture was stirred at room temperature for 2 hours. The MeOH was evaporated to afford Compound 232 (10 g, 96%). Rf=0.47 (10% MeOH/CH2Cl2). The material was of sufficiently good quality to be used in the next reaction without purification.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[N:20]([CH3:29])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:5][CH2:4]1.[Cl:33][C:34]1[C:47]([N:48]=[C:49]=S)=[C:46]([Cl:51])[CH:45]=[CH:44][C:35]=1[CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40].CC(C)N=C=NC(C)C>CN(C=O)C>[F:31][C:2]([F:1])([F:32])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:20]([CH3:29])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:13][C:14]3[N:18]([CH3:19])[C:49]([NH:48][C:47]4[C:46]([Cl:51])=[CH:45][CH:44]=[C:35]([CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C:34]=4[Cl:33])=[N:17][C:15]=3[CH:16]=2)=[O:30])[CH2:7][CH2:8]1
Reactant: CNc1cc(N(C)Cc2ccc(F)cc2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccc(F)cc1)c1cc2c(cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1)nc(Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl)n2C

Procedure:
The title compound is prepared in analogy to 1e from N-(trans-4-trifluoromethyl-cyclohexyl)-2-[N-methyl-N-(4-fluorobenzyl)amino]-4-methylamino-5-amino-benzoic acid amide (68 mg, 0.15 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (48 mg, 0.15 mmol), DIC (23 μL) and DMF (2.0 mL).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([CH3:28])[N:22]=1>CS(C)=O>[Cl:20][C:21]1[N:22]=[C:23]([CH3:28])[N:24]=[C:25]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH:26]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: CNS(=O)(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNS(=O)(=O)Cc1ccc(Oc2cc(Cl)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
Under nitrogen atmosphere add potassium carbonate (26.4 g, 190.8 mmol) to a solution of 1-(4-hydroxyphenyl)-N-methyl-methanesulfonamide (19.2 g, 95.4 mmol), and 4,6-dichloro-2-methylpyrimidine (15.6 g, 95.4 mmol) in DMSO (192.0 mL). Stir the resulting mixture at room temperature for 2 hours. Pour the mixture into 400 mL of ice/water (1:1 v/v) to induce precipitation. Stir the resulting suspension for 30 minutes. Collect the solid; wash with water; and dry under reduced pressure overnight to provide the title compound as a pale brown solid (27.7 g, 89%). MS (m/z): 328 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:21][CH2:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=3)[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:37][CH3:38])=[O:4].N1C=CC=CC=1.Cl[C:46]([O:48][CH3:49])=[O:47]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([N:21]([CH2:22][C:23]3[CH:24]=[C:25]([C:33]([F:34])([F:36])[F:35])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=3)[C:46]([O:48][CH3:49])=[O:47])[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:37][CH3:38])=[O:4]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 135.1 %

Procedure:
cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (335 mg, 0.61 mmol) was dissolved in anhydrous dichloromethane (5 mL), and pyridine (0.20 mL, 2.5 mmol) was added. Methyl chloroformate (0.057 mL, 0.73 mmol) was slowly added and the reaction was stirred at room temperature for 3 h. Additional aliquots of reagents were added to drive the reaction to completion. The reaction mixture was then diluted with 35 ml dichloromethane, washed with an aqueous 1N HCl solution (2×7 mL) and with a saturated sodium bicarbonate solution (2×7 mL) saturated NaHCO3. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 20% acetone/hexanes as eluent afforded the title product (0.50 g, 90%). MS m/z 607 (M++1); 1H NMR (CDCl3) δ 1.5-1.75 (br, 1H), 6.42 (s, 1H).