Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]=[CH:11][C:12]([OH:14])=[O:13].[CH3:15][CH:16](O)[CH3:17].Cl>C(Cl)(Cl)Cl.CN(C=O)C>[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1/[CH:10]=[CH:11]/[C:12]([O:14][CH:16]([CH3:17])[CH3:15])=[O:13]
Reactant: CC(C)O
Reactant: O=C(O)C=Cc1ccco1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)OC(=O)/C=C/c1ccco1
Temperature: 70 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
1.46 ml of thionyl chloride (20 mmol) were added to a solution of 1.38 g of 3-(2-furyl)acrylic acid (10 mmol) in 10 ml of chloroform and 0.1 ml of DMF. The solution was warmed to 70° C. and kept at this temperature for 1 h, then the solvents were removed under reduced pressure and the residue was dissolved in 6.6 ml of DCM and 3.3 ml of pyridine and subsequently cooled to 0° C. 0.96 ml of 2-propanol (12.5 mmol) was added, the temperature was increased to RT and the reaction mixture was stirred for 2.5 h. It was acidified with 30 ml of 1 M hydrochloric acid and extracted with 150 ml of ethyl acetate. The organic phase was washed with aqueous sodium hydrogencarbonate solution, dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. 1.72 g (yield: 96%) of the title compound were obtained. LC/MS (Method D) (M+H-isopropyl)+ 139
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:10]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[C:8](/[CH:14]=[CH:15]/[C@@H:16]([OH:24])[CH2:17][C@@H:18]([OH:23])[CH2:19][C:20]([OH:22])=[O:21])=[C:7]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C:5]=2[CH:6]=1.[Na].C([O-])(=O)C.[Ca+2:37].C([O-])(=O)C>O.C(O)C>[CH:1]1[CH:2]=[CH:3][C:4]2[N:10]=[C:9]([CH:11]3[CH2:12][CH2:13]3)[C:8](/[CH:14]=[CH:15]/[C@H:16]([CH2:17][C@H:18]([CH2:19][C:20]([O-:22])=[O:21])[OH:23])[OH:24])=[C:7]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:5]=2[CH:6]=1.[CH:1]1[CH:2]=[CH:3][C:4]2[N:10]=[C:9]([CH:11]3[CH2:12][CH2:13]3)[C:8](/[CH:14]=[CH:15]/[C@H:16]([CH2:17][C@H:18]([CH2:19][C:20]([O-:22])=[O:21])[OH:23])[OH:24])=[C:7]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:5]=2[CH:6]=1.[Ca+2:37]
Reactant: O=C(O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Ca+2]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C([O-])C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Pitavastatin sodium (5.22 g) prepared according to U.S. Pat. Nos. 5,011,930 A, 5,856,336 A and 5,872,130 A is dissolved in a mixture of 75 ml of water and 15 ml of ethanol and stirred at room temperature under a nitrogen atmosphere. Successively 12 ml of 1 mol/L calcium acetate in water is added drop wise thereto over 20 minutes. The reaction mixture is stirred at the ambient temperature for 3 hours, and the resulting precipitate is collected, washed with water and dried to give 4.5 g of crude pitavastatin calcium salt material.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:15]([CH3:17])[CH3:16])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[O:5][C:4](=[O:18])[CH:3]=1.[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.C(Cl)Cl>[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32][C:3]1[C:4](=[O:18])[O:5][C:6]([CH:15]([CH3:16])[CH3:17])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][C:2]=1[OH:1])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2cccs2)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccs3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 4-hydroxy-6-isopropyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-21; 1 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.2 mmol), potassium carbonate (4 mmol) in DMF (3 mL). The product was isolated via flash chromatography over silica gel using 10:90 EtOAc:CH2Cl2, mp 73-77° C. MS (APCI): 475 (M+H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:27][CH3:28])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:29]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][CH3:28])=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])[N:9]=1)#[N:30]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3CC)cc2c1O
Reactant: NCC(=O)O
Product: CCc1cccc(C)c1Oc1ccc2c(C#N)nc(C(=O)NCC(=O)O)c(O)c2c1

Procedure:
The title compound was synthesized from 1-Cyano-6-(2-ethyl-6-methyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=404.4.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][OH:38])[CH2:32][CH2:31]2)[CH:24]=1>>[OH:38][CH2:37][CH2:36][N:33]1[CH2:32][CH2:31][N:30]([C:25]2[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([NH:1][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:12]=[C:13]([S:17]([NH:20][CH3:21])(=[O:18])=[O:19])[CH:14]=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)[CH:24]=2)[CH2:35][CH2:34]1
Reactant: CNS(=O)(=O)c1cccc(-c2csc3cnc(N)nc23)c1
Reactant: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Product: CNS(=O)(=O)c1cccc(-c2csc3cnc(Nc4cc(N5CCN(CCO)CC5)nc(C)n4)nc23)c1
Yield: 53.7 %

Procedure:
3-(2-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thieno[3,2-d]pyrimidin-7-yl)-N-methylbenzenesulfonamide (18 mg, 53% yield) was prepared in the same manner as Step 10 of Example 1 using 3-(2-aminothieno[3,2-d]pyrimidin-7-yl)-N-methylbenzenesulfonamide (20 mg, 0.062 mmol) and 2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol (17 mg, 0.062 mmol).
Reaction SMILES: C([Li:5])CCC.CCCCCC.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>C(OCC)C>[CH-:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.[Li+:5]
Reactant: [Li]CCCC
Reactant: C1=Cc2ccccc2C1
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li+]
Product: c1ccc2[cH-]ccc2c1
Temperature: -78 °C

Procedure:
A 500 mL Schlenk flask is charged with diethyl ether, 225 mL, and n-butyllithium, 13.6 mL of a 2.93M solution in hexane (45 mmole). The mixture is stirred magnetically and chilled to -78° C. in a dry ice/acetone bath. Indene, 5.25 mL (45 mmole), is added to the solution which is then allowed to warm to room temperature. The solution is stirred at least 12 hours at room temperature prior to further reaction. Titration of the sample shows the reaction is complete.
Reaction SMILES: [CH3:1][CH:2]([SH:18])[CH2:3][NH:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6].[Na].[C:20](=[S:22])=[S:21].C(O[C@H:27]1[NH:30][C:29](=[O:31])[C@@H:28]1[C@H:32]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH3:33])(=O)C>CO.C(OCC)(=O)C.C(O)(=O)C>[Si:35]([O:34][C@@H:32]([C@@H:28]1[C@@H:27]([S:21][C:20]([S:18][CH:2]([CH3:1])[CH2:3][NH:4][C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:6])=[S:22])[NH:30][C:29]1=[O:31])[CH3:33])([C:38]([CH3:41])([CH3:39])[CH3:40])([CH3:37])[CH3:36]
Reactant: CC(S)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: S=C=S
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)SC(=S)S[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 76.5 %

Procedure:
168 mg (0.59 mmole) of 1-methyl-2-(p-nitrobenzyloxycarbonylamino)ethanethiol were added to a solution of 12.5 mg (0.57 mmole) of metallic sodium in 4 ml of methanol at -10° C., and then the mixture was stirred for 5 minutes. 45 mg (0.59 mmole) of carbon disulphide were added to the resulting solution at the same temperature, followed by stirring for 10 minutes. Then 154 mg (0.54 mmole) of (3R, 4R)-4-acetoxy-3-[(R)-1-t-butyldimethylsilyloxyethyl]azetidin-2-one were added to the solution at the same temperature. The bath temperature was slowly elevated to 0° C. over a period of about 1 hour. After completion of the reaction, the reaction solution was made slightly acidic by the addition of a drop of acetic acid, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried. After evaporation of the solvent, the resulting residue was subjected to column chromatography through 10 g of silica gel eluted with a 10-15% v/v solution of ethyl acetate in benzene, to give 237 mg (yield 77%) of the desired product as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][NH:16][C:15](=O)[CH:14]=[C:9]12)(=[O:3])[CH3:2].O=P(Cl)(Cl)Cl.[CH2:26]([C:28]1[N:29]=[CH:30][NH:31][CH:32]=1)[CH3:27].C([O-])(O)=O.[Na+]>ClCCCl.O>[C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][N:16]=[C:15]([N:31]3[CH:32]=[C:28]([CH2:26][CH3:27])[N:29]=[CH:30]3)[CH:14]=[C:9]12)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Reactant: CCc1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cn(C2=NCC(=O)N3CCc4c(C(C)=O)cccc4C3=C2)cn1
Temperature: 110 °C
Yield: 128.2 %

Procedure:
115-1. A mixture of 9-acetyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione [example 100-1] (128 mg, 0.47 mmol) in DCE (4 mL) was treated with POCl3 (0.053 mL, 0.57 mmol) and heated to 110° C. for 1 h. The mixture was then allowed to cool to RT and then poured onto cooled H2O. The mixture was extracted with DCM and the combined org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was taken up in DCE (4 mL) and 4-ethyl-1H-imidazole (182 mg, 1.89 mmol) was added. The mixture was heated to 110° C. for 1 h, then allowed to cool to rt and poured onto a saturated aq. solution of NaHCO3. The mixture was extracted with DCM and the combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (210 mg) that was used as it is in the next step. UPLC-MS: MS 349.2 (M+H+); UPLC rt 0.71 min.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[O:35]1[CH2:39][CH2:38][CH:37]=[C:36]1B1OC(C)(C)C(C)(C)O1.CC(N)CC1C=CC=CC=1.[OH:59]P(O)(O)=O>C(OCC)(=O)C.O.O1CCOCC1>[NH2:26][C:23]1[O:24][CH2:25][C@:5]2([N:22]=1)[C:6]1[CH:7]=[C:8]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:4]2=[CH:3][C:2]([C:37](=[O:36])[CH2:38][CH2:39][CH2:35][OH:59])=[CH:15][CH:14]=1
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(-c3cccnc3)cc12
Reactant: CC1(C)OB(C2=CCCO2)OC1(C)C
Reactant: O=P(O)(O)O
Agent: CC(N)Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@]2(CO1)c1cc(C(=O)CCCO)ccc1Oc1ccc(-c3cccnc3)cc12
Temperature: 100 °C

Procedure:
A 2-5 ml microwave vial was charged with (S)-2′-bromo-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (96 mg, 0.235 mmol), potassium phosphate (150 mg, 0.705 mmol), 2-(4,5-dihydrofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (92 mg, 0.470 mmol) and AmPhos (16.65 mg, 0.024 mmol). 1,4-Dioxane (1176 μL) and water (392 μL) were added and the vial was sealed and heated in microwave reactor for 1 hr at 100° C. The mixture was diluted with ethyl acetate, filtered through celite, and concentrated on 2 g of silica gel. Purification by flash chromatography on 12 g rediSep column using 5-50% gradient of DCM/MeOH/NH4OH (90:10:1) in DCM provided (S)-1-(2-amino-2′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)-4-hydroxybutan-1-one as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[C:25]1([C:31]([NH2:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C:31]([NH:39][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:23])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(N)(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(C)(c4ccccc4)c4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 61 %

Procedure:
The title compound was prepared in a yield of 61% in a similar manner to that described in Example 2 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and 1,1-diphenylethylamine.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][OH:5])#[N:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:22][S:23]([O:5][CH2:4][C:3]([C:1]#[N:2])([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:25])=[O:24]
Reactant: CCCCCCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCC(C#N)(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-cyano-2-(2,4-dichlorophenyl)decan-1-ol (40g., 0.12 mole) and methane sulfonyl chloride (15.3g., 0.13 mole) in 2 liters of benzene is added dropwise at 10° C., 14.8g., (0.14 mole) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 41.3g. of product, which is identified by nmr.
Reaction SMILES: [CH3:1][N:2]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])[C@@H:3]([C:24]([OH:26])=[O:25])[CH2:4][NH:5][C:6](=[O:23])[CH2:7][CH:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH2:22])=[N:20][OH:21])=[CH:15][CH:14]=2)[CH2:9]1.[C:34](OC(=O)C)(=O)[CH3:35]>C(O)(=O)C>[CH3:1][N:2]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28])[C@@H:3]([C:24]([OH:26])=[O:25])[CH2:4][NH:5][C:6](=[O:23])[CH2:7][CH:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:22]=[C:34]([CH3:35])[O:21][N:20]=3)=[CH:17][CH:18]=2)[CH2:9]1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCOC(=O)N(C)[C@H](CNC(=O)CC1CC(c2ccc(C(N)=NO)cc2)=NO1)C(=O)O
Solvent: CC(=O)O
Product: CCCCOC(=O)N(C)[C@H](CNC(=O)CC1CC(c2ccc(-c3noc(C)n3)cc2)=NO1)C(=O)O
Yield: 95.1 %

Procedure:
To a suspension of (R)-Methyl-3-[[[3-[4-[amino (hydroxyimino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl] acetyl]amino]-N-(butoxycarbonyl)-L-alanine (1.05 g) in acetic acid (7 mL) was added acetic anhydride (0.35 g) dropwise. After the completion of addition, the reaction mixture was refluxed for 3 h. The solvent was distilled under vacuum and the solid was dried to give (R)-methyl-N-(butoxycarbonyl)-3-[[[4,5-dihydro-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-5-isoxazolyl]acetyl]amino]-L-alanine (1.05 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:4][C:5](O)=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:32])=O>>[Br:1][C:2]1[C:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:4][C:5]([Cl:32])=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCc1nc(O)nc(CCCCCC)c1Br
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCCCCCc1nc(Cl)nc(CCCCCC)c1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To 19.6 g (57.1 mmol) of 5-bromo-4,6-dihexylpyrimidin-2-ol was added 2.8 g (23 mmol) of N,N-dimethylaniline, and 40.8 g (266 mmol) of phosphoryl chloride was added under a nitrogen atmosphere, and the mixture was stirred at 100° C. for 2 hours. The resultant mixed liquid was cooled down to room temperature, then, 200 g of ice water was added, and the mixture was extracted with MTBE, washed with water and saturated saline in this order, dried over magnesium sulfate and concentrated. The resultant concentrate was purified by a silica gel column (hexane•ethyl acetate) to obtain 20.5 g (56.7 mmol) of 5-bromo-2-chloro-4,6-dihexylpyrimidine represented by the following formula:
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10][C:11]1[CH:12]=[C:13]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][C:15]1([CH2:17][CH2:16]1)[C:14]2=[N:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25]>CCOCC.C1COCC1.[Zn]>[Br:10][C:11]1[CH:12]=[C:13]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][C:15]1([CH2:17][CH2:16]1)[C:14]2([C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25]
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2OCC12CC2
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2OCC12CC2
Reaction time: 4 h
Yield: 96.6 %

Procedure:
To a suspension of activated zinc (3.44 g, 52.5 mmol) in Et2O-THF (50% v/v, 80 ml) under reflux was slowly added a solution of ethyl bromodifluoroacetate (8.00 g, 39.4 mmol) and N-(6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-ylidene)-2-methylpropane-2-sulfinamide (4.68 g, 13.1 mmol) in Et2O-THF (50% v/v, 80 ml) over 40 minutes, and the mixture was stirred for 4 hours at the same temperature. After cooling, the mixture was filtrated through celite pad and washed with EtOAc. To the filtrate were added saturated aqueous NH4Cl and EtOAc. After separation, the water layer was extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc:hexane=20:80-100:0) to give ethyl {6-bromo-4-[(tert-butylsulfinyl)amino]-4H-spiro[chromene-3,1′-cyclopropan]-4-yl}(difluoro)acetate (6.08 g).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][C:4](=[O:12])[CH2:3][C:2]1=[O:13].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1C=CC=CC=1>[C:14]1([CH3:26])[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:24]([CH:3]2[C:2](=[O:13])[CH2:1][C:6]3([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:5][C:4]2=[O:12])=[O:25])(=[O:21])=[O:22])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: O=C1CC(=O)CC2(CCCCC2)C1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C2C(=O)CC3(CCCCC3)CC2=O)cc1

Procedure:
Reaction of equimolar amounts of spiro[5.5]undecane-2,4-dione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 3-[N-(p-TOLUENESULFONYL)CARBAMOYL]SPIRO[5.5]UNDECANE-2,4-DIONE, m.p. 150.5°-152° C. (corr.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][C@@H:18]([C:20]([O:22]C)=[O:21])[CH3:19])=[O:16])=[C:5]2[OH:24].[OH-].[Na+].O.Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][C@@H:18]([C:20]([OH:22])=[O:21])[CH3:19])=[O:16])=[C:5]2[OH:24]
Reactant: COC(=O)[C@@H](C)NC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O)C(=O)O
Reaction time: 3 h

Procedure:
Methyl N-((6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)-D-alaninate (75 mg, 213 μmol) was dissolved in THF (2132 μL). 5N NaOH in water (2132 μL, 10660 μmol) was added at ambient temperature, and the reaction was stirred for 3 hours. The reaction mixture was acidified with 3N HCl, diluted with 50 mL of EtOAc, added to a separatory funnel, washed 2 times with 20 mL of brine (saturated, aqueous), separated, dried over Na2SO4, and concentrated to give the title compound as a white amorphous solid. MS m/e 338 (M+H)+. Calculated for C16H16ClNO5 337.07.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:13])C(O)=O)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)(=O)[C:15]([Cl:17])=[O:16]>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:13][C:15]([Cl:17])=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccc(F)c(F)c1
Reaction time: 24 h
Yield: 99.8 %

Procedure:
To a dichloromethane solution (200 mL) containing 3,4-difluorophenyl propionic acid (30.45 g, 163.6 mmol) and 2 drops of dimethylformamide was added oxalyl chloride (41.4 g, 327.1 mmol) over 20 min. The resulting solution was stirred for 24 hours at which time the solvent was removed in vacuo. The residual oil was then evaporated with toluene (˜100 mL) yielding 33.4 g of 3-(3,4-difluorophenyl)propanoyl chloride as a yellow liquid, which was taken directly into the next step.
Reaction SMILES: [CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6]O.[CH2:9]([O:13][CH:14]=[CH2:15])[CH:10]([CH3:12])[CH3:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][CH:14]([O:13][CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:15]
Reactant: C=COCC(C)C
Reactant: CSC(=S)NCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CSC(=S)NCCC(C)OCC(C)C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a mixture of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester (1.513 g) and isobutoxyethylene (2.59 ml) is added toluene-p-sulfonic acid monohydrate (9.5 mg). After stirring for 30 minutes, triethylamine (8 μl) is added to the mixture, and the resulting solution is concentrated under reduced pressure to give N-[2-(1-isobutoxyethyl)ethyl]dithiocarbamic acid methyl ester (3.2 g). Yield: 95%.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][CH2:11][C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[O:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:18]([C:14]2[S:13][C:12]([CH2:11][CH2:10][C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:24][CH2:25]1
Reactant: NC1CCOCC1
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NC2CCOCC2)s1
Yield: 60 %

Procedure:
As described for example 48e, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid (75 mg, 0.23 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (55 mg, 60%) which was obtained as a light brown oil. MS: m/e=392.1 [M+H]+.