Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:15](=O)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1.O=P(Cl)(Cl)Cl.O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[C:15]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:14][CH2:13][CH2:12][C:6]2=1
Reactant: COc1ccc2[nH]cc(CCNC(=O)CCc3ccc(C(F)(F)F)cc3)c2c1
Solvent: CC#N
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c3c(c2c1)CCN=C3CCc1ccc(C(F)(F)F)cc1
Yield: 15.4 %

Procedure:
A mixture of 0.61 g (1.57 mmol) N-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-3-(4-trifluoromethyl-phenyl)-propionamide and 1 mL POCl3 in 2.5 mL acetonitrile was heated to reflux for 16 h. Water was added and the mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The combined product fractions were evaporated to dryness to yield 0.09 g (15%) of the title compound as yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O:6]C)=[O:5].[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].Cl>[OH-].[Na+]>[CH3:10][C:9]([CH3:12])([CH3:11])[C:8]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)C(=O)NCCC(=O)O
Reaction time: 4 h

Procedure:
558 mg (4.03 mmol) of methy 3-aminopropionate was dissolved in 20 ml of 1 N aqueous sodium hydroxide solution. 362 mg (3.00 mmol) of pivaloyl chloride was immediately added to the obtained solution, and they were stirred for 4 hours. 15 ml of 2 N aqueous hydrochloric acid was added to the reaction mixture. After extracting with ethyl acetate 3 times followed by drying under anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: OC1C(C(CC)(C)C)=CC(C(CC)(C)C)=CC=1N=NC1C=CC=CC=1[N+]([O-])=O.[OH:29][C:30]1[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][C:33]([CH3:40])=[CH:32][C:31]=1[N:41]=[N:42][C:43]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=1[N+:50]([O-])=O.[N+](C1C=CC=CC=1N=NC1C=CC=CC=1)([O-])=O>>[Cl:49][C:47]1[CH:46]=[CH:45][C:44]2=[N:50][N:41]([C:31]3[CH:32]=[C:33]([CH3:40])[CH:34]=[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]=3[OH:29])[N:42]=[C:43]2[CH:48]=1
Reactant: Cc1cc(N=Nc2cc(Cl)ccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: O=[N+]([O-])c1ccccc1N=Nc1ccccc1
Product: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1

Procedure:
When in Example 1, the 2'-hydroxy-3',5'-di-tert-amyl-2-nitroazobenzene is replaced by an equivalent amount of 2'-hydroxy-3'-tert-butyl-5'-methyl-5-chloro-2-nitroazobenzene and the ratio of the moles of alkali to moles of o-nitroazobenzene intermediate is 0.848/1, the product 5-chloro-2-(2-hydroxy-3-tert-butyl-5-methylphenyl)-2H-benzotriazole is obtained.
Reaction SMILES: Cl.[CH:2]1[C:15]2[C:14](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:25])[CH2:23][NH2:24])[CH2:18][CH2:17]3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClC(Cl)C.ClCCl>[O:25]=[C:22]([N:19]1[CH2:20][CH2:21][C:16](=[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:7][C:6]3[C:15]2=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH2:17][CH2:18]1)[CH2:23][NH:24][C:34](=[O:35])[O:36][CH2:37][CH3:38]
Reactant: CCOC(=O)Cl
Reactant: NCC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)NCC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1
Reaction time: 0.25 h

Procedure:
50 mg (0.134 mmol) of 2-[4-(9H-thioxanthen-9-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was dissolved in dichloroethane. 41 mg (0.405 mmol) of triethylamine was added to the obtained solution. A solution of 17.5 mg (0.161 mmol) of ethyl chloroformate in 0.5 ml of dichloromethane was added to the resultant mixture. After stirring for 15 minutes, the product was purified by the thin-layer silica gel chromatography (hexane:ethyl acetate=85:100) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.O.Cl.[NH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1>O1CCOCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1
Reactant: Clc1ncccn1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCN(c2ncccn2)CC1
Temperature: 80 °C
Yield: 69 %

Procedure:
To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 80° C. overnight and concentrated under reduced pressure. The residue was treated with EtOAc (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2×10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give 1-pyrimidin-2-yl-piperidin-4-one (320 mg, 53%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J=6.4 Hz, 2H), 6.61 (t, J=6.4 Hz, 9H), 4.16 (t, J=5.6 Hz, 2H), 2.53 (t, J=5.6 Hz, 2H).
Reaction SMILES: ClC(OC)=O.C(=O)([O-])[O-].[K+].[K+].[C:12]([O:15][CH2:16][CH3:17])(=[O:14])C.O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[CH2:16][O:15][C:12]1=[O:14]
Reactant: CCOC(C)=O
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Agent: COC(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl chloroformate (1.2 equiv) is added to a solution of a 2-(aminophenyl)alkanol (1 equiv) and DMAP (0.10 equiv) in pyridine (1 M) at 0° C. Additional pyridine is added as needed to keep the precipitates from accumulating. The solution is allowed to warm to room temperature and stirred for 2 hours. Sodium bisulfate (2N) and ethyl acetate are added, resulting in an aqueous layer and a first organic layer. The first organic layer is collected and the aqueous layer extracted with ethyl acetate. The organic layer from that extraction is combined with the first organic layer and that combined organic layer is washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a solid. To the solid is added potassium carbonate (2 equiv) in DMF (0.5-0.7 M) and that mixture is heated to 100° C. for 1-4 hours. The mixture is cooled and poured into ethyl acetate:water, resulting in a first organic layer and an aqueous layer. The first organic layer is collected and the aqueous layer is extracted with ethyl acetate. The organic layer from that extraction is combined with the collected first organic layer, and the combined organic layers are washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated to afford the 1,4-dihydro-2H-3,1-benzoxazin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[C:12]([Cl:16])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Si](C)(C)C)=[CH:20][C:19]=1[F:28])=[O:5])[CH3:2].[I:29]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[C:12]([Cl:16])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:29])=[CH:20][C:19]=1[F:28])=[O:5])[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cncc(Cl)c2n1C
Solvent: ClCCl
Product: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cncc(Cl)c2n1C
Temperature: 25 °C
Yield: 73 %

Procedure:
To a cooled (0° C.) solution of 7-chloro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (3.25 g, 7.74 mmol) in DCM (50 mL) was added iodine monochloride (1M in DCM, 17.0 mL) dropwise over 15 minutes. The mixture was allowed to warm to ambient temperature then partitioned between ethyl acetate and a saturated solution of sodium thiosulphate. The organic layer was separated, washed with water then brine, dried (Na2SO4), filtered and evaporated to give a residue. The residue was triturated with diethyl ether to provide the title compound as a yellow solid (2.62 g, 73%). LCMS (method B): RT=3.95 min, M+H+=474.
Reaction SMILES: [C:1]1([N:7]2[CH2:22][CH2:21][N:11]3[C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=4[NH:14][C:15](=[S:16])[N:10]3[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23]C(C)([O-])C.[K+].CI>CN(C)C=O>[CH3:23][S:16][C:15]1[N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:22][CH2:21][N:11]2[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[N:14]=1
Reactant: CC(C)(C)[O-]
Reactant: S=C1Nc2ccccc2N2CCN(c3ccccc3)CCN12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSC1=Nc2ccccc2N2CCN(c3ccccc3)CCN12
Reaction time: 8 h

Procedure:
To a mixture of 2,3,4,5-tetrahydro-3-phenyl-1H-[1,2,5]triazepino[1,2-a][1,2,4]benzotriazine-7(8H)-thione (3.1 g from Example 12) and potassium t-butoxide (1.29 g) in N,N-dimethylformamide (50 ml, dried over 4A molecular sieves) was added methyl iodide (2 ml) and the reaction flask was sealed rapidly. An exothermic reaction ensued. The solution was left at room temperature overnight. The solution was evaporated and the residue was extracted with chloroform. The extract was applied to a column (71×3.2 cm) of dry column grade neutral alumina prepacked in chloroform. Elution with chloroform furnished a major component. Appropriate fractions were evaporated to a syrup. Trituration with heptane gave crude titled product; wt. 2.21 g, (65%), mp=125°-127°. Recrystallization (with decolorization) from dichloromethane-heptane furnished pure product; mp=128°-130°, m/e (E.I.) 324; maxKBr 1589, 765, 748, 693 cm-1 ; pmr (100 MHz, DMSO-D6) 2.42 (3H, singlet), 3.29 (2H, triplet, J=6 Hz), 3.67 (2H, triplet, J=6 Hz), 3.81 (2H, triplet, J=6 Hz), 3.89 (2H, triplet, J=6 Hz), 6.64-7.34 (9H, overlapping multiplets).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-]>C(Cl)CCl.[Cu]Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:19])[C:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cn1cccc1CCNS(=O)(=O)c1ccc(F)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: Cl[Cu]
Solvent: ClCCCl
Product: CCOC(=O)Cc1ccc(CCNS(=O)(=O)c2ccc(F)cc2)n1C
Reaction time: 0.33 h

Procedure:
1.69 g of 2-(2-(4-fluorobenzenesulphonylamino)-ethyl)-1-methylpyrrol are dissolved in 6 ml of ethylene chloride and 0.06 g of copper(I)chloride are added. Under a nitrogen atmosphere the mixture is refluxed and then a solution of 0.34 g of ethyl diazoacetate in 6 ml of ethylene chloride is slowly added dropwise. After 20 minutes the evolution of nitrogen has ended and the suspension is concentrated to dryness by rotary evaporation. Then the residue is chromatographed over a silica gel column (ethylene chloride/ethyl acetate=100/1).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])[CH3:3].O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].C1CCC(N=C=NC2CCCCC2)CC1>O1CCOCC1>[CH3:4][C:2]([O:5][C:6]([CH2:8][C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([O:12][N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28])=[O:11])=[O:7])([CH3:1])[CH3:3]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resulting 11.45 g (39.7 mmoles) of oily BOC--Asp(OtBu)--OH and 4.6 g (40 mmoles) of N-hydroxy-succinimide are dissolved in 100 ml of dry dioxane. The solution is cooled until freezing, and then 8.25 g (40 mmoles) of DCC are added. The reaction mixture is stirred at room temperature overnight, the separated DCU is filtered off, and the filtrate is evaporated. The oily residue is solidified with a mixture of n-hexane and diisopropyl ether. The resulting crude product, weighing 13.8 and melting at 98°-102° C., is recrystallized from a threefold amount of isopropanol. 12.1 g (78.3%) of white, crystalline BOC--Asp (OtBu)--OSu are obtained; m.p.: 103°-105° C., [α]D : -25.6° (c: 1.0, in dioxane).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[CH2:23]([C@@H:30]1[CH2:32][O:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:32][C@H:30]([OH:31])[CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: c1ccc(C[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCN(C[C@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 222 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=82-84° C., (DMSO-d6) δ: 7.88-7.72 (m, 3H), 7.3-7.1 (m, 5H), 4.46-4.4 (m, 1H), 3.9-3.8 (m, 1H), 3.08 (s, 2H), 2.82-2.67 (m, 3H), 2.63-2.55 (m, 1H), 2.4-2.25 (m, 4H), 2.06-1.93 (m, 2H), 1.9-1.78 (m, 2H); LCMS=514 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17].CC(N(C)C)=O.[H-].[Na+]>CCOC(C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([O:17][CH2:16][CH:12]2[CH2:13][CH2:14][CH2:15][O:11]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1Cl
Reactant: OCC1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1cnc(N)cc1OCC1CCCO1
Temperature: 70 °C

Procedure:
6-amino-4-chloronicotinonitrile (intermediate 16, 70 mg, 0.456 mmol) and (tetrahydrofuran-2-yl)methanol (233 mg, 2.28 mmol) were charged into a vial. DMA (1 ml) was added to the mixture at room temperature followed by NaH (60% in mineral oil dispersion, 109 mg, 2.73 mmol). The mixture was then heated at 70° C. for 16 h. The reaction mixture was cooled to room temperature, diluted in EtOAc and washed with aq. pH7 buffer (2×) and brine. The organic layer was dried over
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7](/[C:10](=[N:13]\S(C(C)(C)C)=O)/[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:4])=[O:3].[CH2:20]([Mg][Cl:23])[CH3:21].Cl.O1CCOCC1>C1COCC1.C(OCC)C.CO>[ClH:23].[CH2:20]([C:10]([NH2:13])([C:7]1[S:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[N:9][CH:8]=1)[CH2:11][CH3:12])[CH3:21]
Reactant: CC/C(=N/S(=O)C(C)(C)C)c1cnc(S(C)(=O)=O)s1
Reactant: CC[Mg]Cl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: CCC(N)(CC)c1cnc(S(C)(=O)=O)s1
Reaction time: 2.5 h

Procedure:
To a chilled (0° C.) solution of 2-methyl-propane-2-sulfinic acid [1-(2-methanesulfonyl-thiazol-5-yl)-prop-(Z)-ylidene]-amide (100 mg, 0.3 mmol) in THF (5 mL) was added a 2 M solution of ethylmagnesium chloride (0.19 mL, 0.38 mmol) in diethyl ether. After 2.5 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane to yield an oil. The oil was dissolved in methanol (5 mL) and a 4 N solution of HCl in dioxane (0.5 mL, 2 mmol) was added. After 1 hour, the solution was concentrated to obtain the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25]>O1CCCC1>[CH3:22][O:21][C:19](=[C:16]1[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)[O:20][Si:24]([CH3:26])([CH3:25])[CH3:23]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)C1CCOCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(O[Si](C)(C)C)=C1CCOCC1
Reaction time: 0.33 h

Procedure:
To a stirred solution of diisopropylamine (5.2 mL, 37 mmol) in tetrahydrofuran (15 mL) was added dropwise n-butyllithium (1.6 M in hexane, 21 mL, 34 mmol) at 0° C. and stirred for 20 min. A mixture of methyl tetrahydro-2H-pyran-4-carboxylate (4.5 g, 31 mmol) and trimethylsilyl chloride (4.3 mL, 34 mmol) was added to the mixture at −40° C., then trimethylsilyl chloride (0.4 mL, 0.3 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 h. The volatile components were removed by evaporation and the residual mixture was filtered through a pad of celite washing with hexane. The filtrate was evaporated to give 6.9 g (quant.) of the title compound as a clear yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]3[C:26](=[O:27])[C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[S:23][CH2:22]3)=[O:20])=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([CH:21]3[C:26](=[O:27])[C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[S:23][CH2:22]3)=[O:20])=[CH:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(Cc2ccc(NC(=O)C3CSc4ccccc4C3=O)cc2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1ccc(Cc2ccc(O)c(O)c2)cc1)C1CSc2ccccc2C1=O
Temperature: 0 °C
Yield: 63.9 %

Procedure:
A suspension of 1.0 g (2.1 mmol) of N-[4-[(3,4-dimethoxyphenyl)methyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide, 1,1-dioxide and BBr3.S (CH3)2 (4.0 g, 12.6 mmol) in 150 ml of dichloromethane was heated under reflux under nitrogen for 18 hours. The resulting yellow suspension was poured onto 600ml of ice water, stirred for one and one-half hours and then filtered. The crude product was recrystallized from isopropanol-water to yield 544 mg (59%) of N-[4-[(3,4-dihydroxyphenyl)methyl]phenyl]-3,4-dihydro-4-oxo-2H-1-benzothiopyran-3-carboxamide, 1,1-dioxide, mp 216°-218° C.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7]>C1COCC1>[C:1]([NH:5][S:15]([C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=1)(=[O:16])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 94.8 %

Procedure:
To a solution of tert-butylamine (0.47 L, 6.4 mol) in THF (0.55 L) is slowly added, at 0° C., a solution of 4-nitrobenzenesulfonyl chloride (50 g, 0.23 mol) in THF (0.55 L) and the resulting mixture is stirred for 24 h at room temperature. The solvent is removed and the residue is taken up in a CHCl3/0.5 N HCl mixture, the layers are separated and the aqueous phase is extracted with CHCl3. The combined organic extracts are washed with H2O and brine and dried over MgSO4. The solvent is removed, yielding 56.3 g of a yellowish solid which is directly used in the next reaction (yield: 97%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[N:21]12[CH2:28][CH:25]([CH2:26][CH2:27]1)[NH:24][CH2:23][CH2:22]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:24]4[CH:25]5[CH2:28][N:21]([CH2:27][CH2:26]5)[CH2:22][CH2:23]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1CN2CCC(C2)N1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCN4CCC3C4)c(F)cc2c1=O
Temperature: 25 °C
Yield: 36.6 %

Procedure:
A mixture of 1.14 g (4 mmol) 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 0.62 g (5.5 mmol) 1,4-diazabicyclo[3.2.1]octane and 0.40 g (4 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene in 20 ml acetonitrile was refluxed 6.5 hours. After cooling to room temperature the solid product was filtered, suspended in 10 ml hot ethanol, cooled, and filtered to afford 0.55 g of 1-cyclopropyl-7-(1,4-diazabicyclo[3.2.1]octan-4-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 280° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][OH:28])[CH2:22]2)[NH:12][C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[N:10]1.[C:34](O)(=[O:38])[CH:35]([CH3:37])[CH3:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][O:28][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH2:22]2)[NH:12][C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CN2CCO[C@@H](CO)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Reactant: CC(C)C(=O)O
Product: CCOC(=O)C1=C(CN2CCO[C@@H](COC(=O)C(C)C)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 35 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((R)-2-(hydroxymethyl)morpholino)methyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (2 g, 3.8 mmol) was reacted with isobutyric acid (0.44 g, 5 mmol) according to the procedure as described in Example 49 to give the title compound as yellow oil (0.79 g, 35%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([C:21]#[N:22])([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:22][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CNC(=O)C1
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
3-Cyano-3-(3,4-dichloro-phenyl)-pentanedioic acid diethyl ester (10 g; 27.94 mmol) was dissolved in methanol (100 mL) and cobalt(II)chloride hexahydrate (13.2 g, 55.48 mmol) was added. The solution was then cautiously treated with one gram portions of sodium borohydride (11 g, 290 mmol) over 45 minutes at 20°-30° C. The solution was allowed to stir an additional 1.5 hours and the solution was concentrated in vacuo. The residue was partitioned between dichloromethane and 1N HCl the organic phase was and washed with 1N HCl (700 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (600 g) with a gradient of 3% to 6% methanol in dichloromethane to give 7.514 g (85%) of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:37])[CH3:36]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:30]2[CH:31]=[CH:32][C:33]([O:34][CH:35]([CH3:36])[CH3:37])=[C:28]([F:27])[CH:29]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(C)Oc1ccc(B(O)O)cc1F
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(OC(C)C)c(F)c2)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-fluoro-4-(1-methyl-ethoxy)phenylboronic acid, 5-[3-fluoro-4-(1-methylethoxy)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=82%).