Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([OH:19])[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([O:19][C:2]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:18][CH2:17][CH2:16]1
Reactant: OC1CCC1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OC2CCC2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) and cyclobutanol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 269.3 ([M−H]−, 100%).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5](P(OCC)(OCC)=O)[O:6]CC)C.C([N-]C(C)C)(C)C.[Li+].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:37])([CH3:36])[CH:34]=O)=[CH:29][CH:28]=1.S(=O)(=O)(O)O>O1CCCC1.O1CCCC1.CCCCCCC.C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:37])([CH3:36])[CH2:34][C:5](=[O:6])[C:4]([OH:3])=[O:17])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(OCC)P(=O)(OCC)OCC
Reactant: CC(C)(C=O)c1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(CC(=O)C(=O)O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
A solution of 15.04 g of 2-diethylphosphono-2-ethoxyacetic acid-ethyl ester in 50 ml of tetrahydrofuran is mixed while being cooled with ice within 20 minutes with 30 ml of a 2 M solution of lithium diisopropylamide in tetrahydrofuran-heptane-toluene, and it is stirred for 15 minutes at 0° C. Within 30 minutes, a solution of 10.2 g of 2-(4-chlorophenyl)-2-methylpropanal in 50 ml of tetrahydrofuran is added in drops thereto at 0° C. After 20 hours at room temperature, 2N sulfuric acid is added, it is extracted with ethyl acetate, dried (Na2SO4) and concentrated by evaporation. The crude product is saponified with 200 ml of 2 M sodium hydroxide solution/400 ml of ethanol. 13.8 g of acid, which is refluxed for 3 hours with 300 ml of 2N sulfuric acid and 100 ml of glacial acetic acid while being stirred vigorously, is obtained. After extraction with ethyl acetate and washing with water, 10.9 g of 4-(4-chlorophenyl)-4-methyl-2-oxo-valeric acid is obtained as a red oil.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]([C:16]([O:18][CH3:19])=[O:17])=[N:12][CH:13]=[CH:14][N:15]=1>CN(C)C=O>[NH2:9][C:10]1[C:11]([C:16]([O:18][CH3:19])=[O:17])=[N:12][C:13]([I:1])=[CH:14][N:15]=1
Reactant: COC(=O)c1nccnc1N
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: COC(=O)c1nc(I)cnc1N
Temperature: 65 °C
Yield: 88 %

Procedure:
1.5 equivalents of N-iodosuccinimide are added at room temperature to 5 g (32.7 mmol) of a methyl 3-aminopyrazine-2-carboxylate solution in 25 ml of dimethylformamide. The reaction medium is heated at 65° C. for 1 hour, added together with 0.5 equivalents of N-iodosuccinimide and maintained at 65° C. for 24 hours. After returning to room temperature, the solvent is evaporated and then the product is extracted several times with dichloromethane. The organic phases are combined, washed with 10% sodium bisulfite solution, dried on magnesium sulfate and concentrated to yield 8 g (88%) of methyl 3-amino-6-iodopyrazine-2-carboxylate in the form of a yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[C:8]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=2[O:34][CH3:35])=[CH:7]1)(=[O:3])[NH2:2].Cl.CN(C)CCCN=C=NCC.[C:48]1([CH3:58])[C:49]([S:54]([NH2:57])(=[O:56])=[O:55])=[CH:50][CH:51]=[CH:52][CH:53]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:12][CH:13]=2)[C:8]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:57][S:54]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[CH3:58])(=[O:55])=[O:56])=[O:30])=[CH:27][C:26]=2[O:34][CH3:35])=[CH:7]1)(=[O:3])[NH2:2]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(CCC(N)=O)c2ccc(C(=O)NCC3CCCC3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(CCC(N)=O)c2ccc(C(=O)NCC3CCCC3)cc12
Yield: 36.4 %

Procedure:
A solution of 4-[1-(2-carbamoylethyl)-5-(N-cyclopentylmethylcarbamoyl)indol-3-ylmethyl]-3-methoxybenzoic acid (77 mg), 4-(dimethylamino)pyridine (20 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (37 mg), and ortho-toluenesulphonamide (28 mg) in dichloromethane (2.0 ml) was stirred under a nitrogen atmosphere for 48 hours. The mixture was diluted with dichloromethane; washed with 10% v/v hydrochloric acid, water, and brine; and evaporated. The resulting white solid was crystallized from ethyl acetate/hexane to give the title compound (37 mg; 37%) as a white solid; mp 140°-145° C. (d).
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C@H:3]1[OH:10].CC=CCCCC(=O)C>>[Cl:1][C:2]1([Cl:11])[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C:3]1=[O:10]
Reactant: O[C@@H]1[C@@H]2CCC=C[C@@H]2C1(Cl)Cl
Agent: CC=CCCCC(C)=O
Product: O=C1[C@@H]2CCC=C[C@@H]2C1(Cl)Cl

Procedure:
Similarly, starting from (1S,6R,7R)-8,8-dichlorobicyclo[4.2.0]oct-2-en-7-ol, prepared as shown in Preparation 23, and following the procedure of Paragraph 24.A. above, (1S,6R)-8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one is prepared, the compound of formula (XXXIX).
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1[CH2:14][C@@H:13]([N:15]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][CH:24]=2)[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:11][N:10]1C(OC(C)(C)C)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[CH2:2]([C@@H:9]1[CH2:14][C@@H:13]([N:15]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][CH:24]=2)[C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[CH2:12][CH2:11][NH:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 ml of 6N hydrogen chloride in dioxane is added dropwise over the course of 3 minutes to 7.73 g (14.7 mmol) of (2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine while cooling in ice, and the mixture is subsequently stirred at room temperature for 1 hour. The reaction mixture is concentrated in a rotary evaporator, basified with 1N sodium bicarbonate solution and extracted with methylene chloride. The organic phases are dried over magnesium sulfate and evaporated to dryness. The brownish oil (7.14 g) is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (700:50:1). The title compound is obtained as yellow oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.42, DCI-MS: (M+H)+ =428, IR: 1690 cm-1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([N:14]3[CH2:18][CH2:17][C@@:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[N:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([N:14]3[CH2:18][CH2:17][C@@:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Oc1ccccn1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(CO)cc4)CC3)C2)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(COc5ccccn5)cc4)CC3)C2)c2ccccc21
Reaction time: 8 h

Procedure:
To a mixture of (1R)-1′-({1-[4-(hydroxymethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (16.0 mg, 0.0000440 mol, prepared in example 237), triphenylphosphine (17 mg, 0.000066 mol), and 2-hydroxypyridine (4.0 mg) in tetrahydrofuran (2 mL, 0.02 mol) was added diisopropyl azodicarboxylate (14 μL, 0.000070 mol) at room temperature, and the mixture was stirred overnight. The product was isolated and purified by prep-HPLC. LC-MS: 441.2 (M+H+)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[C:13](Cl)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCC(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
138.1 g (1.0 mol) of para-hydroxybenzoic acid were first dissolved in 500 ml of water and 500 ml of isopropanol and this solution was admixed at 0 to 5° C. with 230.0 g of KOH solution (50% strength by weight aqueous solution, 2.05 mol). The resulting pH was 13.5. Metered into this solution over the course of one hour, then, at 0 to 5° C., were 176.6 g (1.0 mol) of nonanoyl chloride, and the batch was stirred for 30 minutes at 0 to 5° C. thereafter. At the end of the after-stirring, the pH of the reaction mixture was 9.0. The reaction mixture was subsequently adjusted to a pH of 8 at 0 to 5° C. using 25.0 g of HCl solution (32% strength by weight aqueous solution), and the complete solution was heated to 55 to 60° C. and then adjusted to a pH of 1.5 to 3 using 100 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to 20 to 25° C. and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 255.95 g (92.0% of theory). According to HPLC and NMR measurement, the product was free from nonanoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][N:10]2[C:11]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=3)[CH2:7][CH2:8][C:9]2=[O:14])[CH2:20][CH2:21]1
Reactant: ClCCN1CCOCC1
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 58 %

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (1.00 g, 5.20 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.94 g, 10.40 mmol), sodium iodide (390 mg, 2.61 mmol) and potassium carbonate (4.32 g, 31.3 mmol) in DMF (5 mL) was stirred at room temperature for 60 hours. The mixture was transferred to a separatory funnel, diluted with water (45 mL) then extracted with ethyl acetate (3×35 mL). The combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was subject to flash chromatography on silica gel using 2.5% 2M NH3 methanol/CH2Cl2, which resulted in a yellow solid, compound 2 (0.9211 g, 58%).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:28])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[C:15]([CH:26]=O)[C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Yb]>C(Cl)Cl>[CH3:1][CH2:2][C@@:3]1([OH:28])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[C:15]([CH:26]=[N:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: Nc1ccccc1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2C=O
Agent: [Yb]
Solvent: ClCCl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2C=Nc1ccccc1
Reaction time: 3.5 h
Yield: 51.1 %

Procedure:
100 mg (0.26 mmoles) of 7-formylcamptothecin, dissolved into 20 ml of methylene chloride, and 25 μl (0.26 mmoles) of aniline, dissolved into 0.5 ml of methylene chloride, were added to a suspension of ytterbium triphlate (16.5 mg. 0.026 mmoles, 10% mol) in 5 ml of methylene chloride containing MS 4A and were left 3.5 hours under stirring at room T, then the solvent was evaporated under vacuum. The product was purified by means of flash chromatography on silica gel using a mixture of methylene chloride/methanol 98/2 as eluant. 60 mg of a yellow solid were obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)=[CH:9][N:4]2[CH:3]=1.O.O.[Sn](Cl)Cl.C(Cl)Cl.CCOC(C)=O>CCO>[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)=[CH:9][N:4]2[CH:3]=1
Reactant: Cc1cn2cc(-c3ccc([N+](=O)[O-])cc3)nc2s1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cn2cc(-c3ccc(N)cc3)nc2s1
Yield: 74.6 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-methyl-6-(4-nitrophenyl) imidazo[2,1-b][1,3]thiazole (0.10 g, 0.386 mmol) and tin (II) chloride dihydrate (0.69 g, 3.09 mmol) in EtOH (15 ml) to give a pale orange solid (66 mg, 75%) after work-up and flash chromatography (1:1 DCM/EtOAc).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:11]([C:13]([C:19]#[N:20])=[C:14](SC)[NH:15][CH3:16])#[N:12]>>[C:11]([C:13]([C:19]#[N:20])=[C:14]([NH:15][CH3:16])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)#[N:12]
Reactant: NCCSCc1nccs1
Reactant: CNC(SC)=C(C#N)C#N
Product: CNC(NCCSCc1nccs1)=C(C#N)C#N

Procedure:
By the procedure of Example 1(ii), reacting 2-[(2-aminoethyl)thiomethyl]thiazole with 1,1-dicyano-2-methylthio-2-methylaminoethylene gives the title compound.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH2:7][CH3:8])[CH3:6].CN(C)C(N(C)C)=O>>[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:1]([Cl:4])=[O:2])([CH2:7][CH3:8])[CH3:6]
Reactant: O=C(Cl)Cl
Reactant: CCC(C)c1ccccc1O
Solvent: CN(C)C(=O)N(C)C
Product: CCC(C)c1ccccc1OC(=O)Cl
Temperature: 100 °C
Yield: 97 %

Procedure:
In a round flask provided with stirrer, thermometer, an introduction tube for phosgene and a reflux cooler operating at about -30° C a mixture of 150 g of o-sec.-butylphenol and 4 g of N,N,N',N',-tetramethyl urea was heated at 100° C and phosgene was introduced to such a degree that the phosgene reflux in the deep-freezing cooler did not increase so much as to reduce the sump temperature. After a reaction time of about 5 hours and a phosgene consumption of about 190 g the reflux cooler was replaced by a descending cooler so that the greatest part of the excess phosgene could be separated from the reaction mixture by distillation. The rest of phosgene was blown out with dry nitrogen. Thus, a yield of about 97% of chloroformic acid-o-sec.-butyl-phenyl-ester was obtained which was practically free from the starting product (GC).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])/[C:4](/OCC1C=CC=CC=1)=[C:5](/N=C=O)\[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([CH3:20])=[CH:8][C:7]=1Br.C([O-])(=O)C.[Cs+].[NH3:39]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:4]1[NH:39][C:7]2[C:6]([CH:5]=1)=[CH:11][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:9]([CH3:20])[CH:8]=2)=[O:33]
Reactant: COC(=O)/C(OCc1ccccc1)=C(/N=C=O)c1cc(OCc2ccccc2)c(C)cc1Br
Reactant: N
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1cc2cc(OCc3ccccc3)c(C)cc2[nH]1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of (Z)-3-(5-benzyloxy-2-bromo-4-methylphenyl)-2-benzyloxy-carbonylaminoacrylic acid methyl ester (0.2 g) and copper (I) iodide (0.075 g) in dimethylsulfoxide (8 mL) was added cesium acetate (0.38 g) at room temperature and this mixture was stirred under argon atmosphere at 90° C. for 5 hours. To this reaction mixture was added aqueous ammonia solution (28%) and the precipitated solid was collected by filtration, and washed with water, dried under reduced pressure to give the title compound (0.073 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([C:24]2[C:29]3[CH:30]=[CH:31][O:32][C:28]=3[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>ClCCCl.CO>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:21]2[CH2:22][CH2:23][N:18]([C:24]3[C:29]4[CH:30]=[CH:31][O:32][C:28]=4[CH:27]=[CH:26][N:25]=3)[CH2:19][CH2:20]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cc2occc2c(N2CCNCC2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Reaction time: 18 h

Procedure:
trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester [CAS-Nr. 215790-29-7] (4.1 g, 17 mmol) was added to a solution under N2 of commercially available 4-piperazine-1-yl-furo[3,2-c]pyridine [CAS-Nr. 81078-84-4] (3.1 g, 15 mmol) in 1,2-dichloroethane (40 ml) and MeOH (0.5 ml). The resulting yellow solution was stirred 8 h at room temperature before addition of Na(AcO)3BH (4.9 g, 23 mmol). Stirring was continued at room temperature for 18 h. The reaction mixture was poured on sat. aq. NaHCO3 sol. (130 ml) and the product was extracted with EtOAc (3×100 ml). The combined organic layers were washed with H2O (130 ml) and brine (100 ml). After drying (MgSO4) the solvent was evaporated and the product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0 to 95:5) to yield trans-{4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as white crystals (3.4 g, 52%), MS (ISP) m/z=429.4 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH2:18][CH2:19][C:20]([OH:22])=O)[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>S(=O)(=O)(O)O>[O:22]=[C:20]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[C:7]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:6]=2)[CH:14]([C:15]([OH:17])=[O:16])[CH2:18][CH2:19]1
Reactant: O=C(O)CCC(C(=O)O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: O=S(=O)(O)O
Product: O=C1CCC(C(=O)O)c2cc(Cl)c(C3CCCCC3)cc21
Reaction time: 8 h
Yield: 72.2 %

Procedure:
While cooling well, 17.9 g of 2-(3-chloro-4-cyclohexylphenyl)-glutaric acid are dissolved in 90 ml of 100% sulfuric acid and the solution is kept overnight at 35°C, then cautiously poured out over ice and the aqueous mixture is extracted with ethyl acetate and evaporated. The remaining crystals are recrystallized from toluene, to yield 12.2 g of 4-oxo-6-cyclohexyl-7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid melting at 204°-205°C, of the formula ##SPC8##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9](=[O:11])[NH2:10])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])=[S:14].[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[CH:7]=[C:6]([S:8][C:9](=[O:11])[NH2:10])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])=[S:14])(=[O:22])[CH3:21]
Reactant: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1N
Reactant: CC(=O)Cl
Product: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1NC(C)=O
Reaction time: 2 h

Procedure:
0.7 G. of 2-amino-4-carbamoylthio-1-(3-methoxycarbonyl-2-thioureido)benzene is treated with 1.5 ml. of acetyl chloride. The mixture is stripped after two hours and the residue recrystallized to afford 2-acetamido-4-carbamoylthio-1-(3-methoxycarbonyl-2-thioureido)benzene.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[S:28]1(=[O:35])(=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][S:28]5(=[O:35])=[O:34])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=S1(=O)CCCCN1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: O=C(c1ccc(N2CCCCS2(=O)=O)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 72.4 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (446 mg) described in Preparation Example 186 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (328 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[N:11]2[CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:18])[CH2:3]1.Cl[CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:15]2[CH2:16][CH2:17][CH:12]3[N:11]4[C:10]5[C:9]([CH:13]3[CH2:14]2)=[CH:8][CH:7]=[CH:6][C:5]=5[N:4]([CH3:18])[CH2:3][C:2]4([CH3:19])[CH3:1])=[CH:31][CH:30]=1
Reactant: CN1CC(C)(C)N2c3c(cccc31)C1CNCCC12
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CC(C)(C)N2c3c(cccc31)C1CN(CCCC(=O)c3ccc(F)cc3)CCC12
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
To a solution of 1,1,3-trimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline (from Example 283) (82 mg, 0.32 mmol) in dioxane (10 mL) at rt was added 4-chloro-1-(4-fluorophenyl)butan-1-one (83 mg, 0.42 mmol), K2CO3 (100 mg), KI (30 mg) and stirred at 25° C. for 24 hours. The solution was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford the title compound (58 mg, 43%). MS [M+H]+422. 1H NMR (CDCl3, 300 MHz): δ 8.01 (m, 2H) , 7.15 (t, 2H, J=7.7 Hz), 6.65 (t, 1H, J=7.7 Hz), 6.51 (d, 1H, J=7.0 Hz), 6.43 (d, 1H, J=7.0 Hz), 3.63 (m, 1H), 3.25 (d, 1H, J=11 Hz), 3.09 (m, 2H), 2.89 (s, 3H), 2.63 (m, 2H), 2.25 (m, 2H), 2.17 (m, 2H), 1.31 (s, 3H), 1.12 (s, 3H) ppm. This racemate was then separated into its corresponding enantiomers by HPLC utilizing a Chiralcel AD column with 50% Ethanol/Methanol solvent system.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:36]=[CH:35][C:18]3[O:19][C:20]([CH3:34])([CH3:33])[C@:21]([OH:32])([CH3:31])[C@H:22]([O:23][C:24]4[N:29]=[N:28][C:27]([OH:30])=[CH:26][CH:25]=4)[C:17]=3[CH:16]=2)=[N:13][N:12]=[N:11]1)=[O:5])[CH3:2].S(OC)(O[CH3:41])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:36]=[CH:35][C:18]3[O:19][C:20]([CH3:34])([CH3:33])[C@:21]([OH:32])([CH3:31])[C@H:22]([O:23][C:24]4[CH:25]=[CH:26][C:27](=[O:30])[N:28]([CH3:41])[N:29]=4)[C:17]=3[CH:16]=2)=[N:13][N:12]=[N:11]1)=[O:5])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)CCCCn1nnnc1-c1ccc2c(c1)[C@@H](Oc1ccc(O)nn1)[C@](C)(O)C(C)(C)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCn1nnnc1-c1ccc2c(c1)[C@@H](Oc1ccc(=O)n(C)n1)[C@](C)(O)C(C)(C)O2
Temperature: 25 °C

Procedure:
A mixture containing (3S,4R)-3,4-dihydro-6-(1-[4-ethoxycarbonylbut-1-yl]-1H-tetrazol-5-yl)-3-hydroxy-4-(3-hydroxypyridazin-6-yl)oxy-2,2,3-trimethyl-2H-benzo[b]pyran (see Example 11) (0.25 g), dimethyl sulfate (0.34 ml), anhydrous potassium carbonate (0.51 g) and acetone (10 ml) was heated under reflux for 4 hours. On cooling to room temperature the mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml).