Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([O:12]C)[C:6]([CH2:7][CH3:8])=[C:5]([CH3:9])[CH:4]([O:10]C)O1.O1CCCC1.[Cl-].[Na+]>O>[CH3:9][C:5]1[CH:4]([OH:10])[CH2:1][C:2](=[O:12])[C:6]=1[CH2:7][CH3:8]
Reactant: CCC1=C(C)C(OC)OC1(C)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1=C(C)C(O)CC1=O
Yield: 61.4 %

Procedure:
2,4-Dimethyl-3-ethyl-2,5-dimethoxy-2,5-dihydrofuran (9.3 g) was added to a mixture of 100 ml of a buffer solution (pH 5; prepared from potassium hydrogen phthalate and sodium hydrogen carbonate) and tetrahydrofuran (50 ml), and the mixture was refluxed for 1 hour. The reaction solution was poured into water, saturated with sodium chloride and extracted three times with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was distilled to obtain 4.3 g of 2-methyl-3-ethyl-cyclopent-2-en-4-on-1-ol.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:7]=2[NH:6][S:5]1(=[O:19])=[O:18])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:39][C:40]1[CH:48]=[C:47]2[C:43]([C:44]([C:49]3[CH2:50][CH2:51][N:52]([CH2:55][CH2:56]O)[CH2:53][CH:54]=3)=[CH:45][NH:46]2)=[CH:42][CH:41]=1.C(OCC)(=O)C>CN(C=O)C.O>[F:39][C:40]1[CH:48]=[C:47]2[C:43]([C:44]([C:49]3[CH2:50][CH2:51][N:52]([CH2:55][CH2:56][N:6]4[C:7]5[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][C:8]=5[CH2:9][N:4]([CH:2]([CH3:1])[CH3:3])[S:5]4(=[O:19])=[O:18])[CH2:53][CH:54]=3)=[CH:45][NH:46]2)=[CH:42][CH:41]=1
Reactant: CC(C)N1Cc2cc(S(C)(=O)=O)ccc2NS1(=O)=O
Reactant: OCCN1CC=C(c2c[nH]c3cc(F)ccc23)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1Cc2cc(S(C)(=O)=O)ccc2N(CCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)S1(=O)=O
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
To a stirred solution of 3,4-dihydro-3-(1-methylethyl)-6-methylsulfonyl-1H-2,1,3-benzothiadiazine-2,2-dioxide (0.38 g, 0.00125 mol), triphenylphosphine (0.39 g, 0.0015 mol) and 2-(4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethanol (0.26 g, 0.0015 mol) in DMF (10 ml) at −5° C. was added dropwise under nitrogen diethyl azodicarboxylate (0.24 ml, 0.0015 mol). The reaction was stirred at −5° C. for 10 mins then allowed to warm to room temperature stirring for a further 20 mins. After the addition of ethyl acetate (30 ml) and water (20 ml), the organic layer was washed with water (4×20 ml) the organics dried (MgSO4) and concentrated in vacuo to afford 0.52 g of 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3,4-dihydro-3-(1-methylethyl)-6-methylsulfonyl-1H-2,1,3-benzothiadiazine-2,2-dioxide as a yellow solid. Mp 118-120° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[CH2:10]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]#N)[CH2:16][CH2:15]1)[CH2:11][CH2:12][CH3:13].C[OH:26]>CCOCC.C(Cl)Cl>[CH2:10]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[CH3:9])=[O:26])[CH2:16][CH2:15]1)[CH2:11][CH2:12][CH3:13]
Reactant: Cc1ccc(I)c(C)c1
Reactant: CCCCC1CCN(CCCC#N)CC1
Reactant: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC1CCN(CCCC(=O)c2ccc(C)cc2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
In a 10 mL oven-dried flask charged with Mg turnings (95 mg, 3.9 mmol) which was activated under vacuum by the use of a heat-gun. Under inert atmosphere was added a suspension of 1-iodo-2,4-dimethylbenzene (0.69 g, 2.9 mmol) in Et2O (4.5 mL) under spontaneously reflux, and the reaction mixture was allowed to reflux for 3 hours. Compound 4 (0.41 g, 2.0 mmol) dissolved in CH2Cl2 (2 mL) was added under inert atmosphere to the reaction mixture and left stirring at rt overnight. The reaction mixture was quenched by addition of H2SO4 (8 mL, 2 M) and stirred at rt for 4 hours, then the reaction mixture was basified by addition of NaOH (20 mL, 2 M). Addition of THF (20 mL) was followed by extraction with ethyl acetate (3×50 mL) and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), and the organic phases were dried (MgSO4) and evaporated to dryness to produce 0.61 g of crude 20. The crude product was subjected to CC [eluent: CH2C2: MeOH (99:1)] to give pure 20 (0.21 g, 35 %); LC-MS [M+H]+ 315 (cald. 315.5).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:18]([N:25]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[NH:28][CH:27]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:26]1=[O:42])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:8]1([S:14]([N:32]2[CH2:33][CH2:34][C:29]3([N:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:26](=[O:42])[CH:27]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[NH:28]3)[CH2:30][CH2:31]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C(Cc2ccccc2)NC2(CCN(S(=O)(=O)c3ccccc3)CC2)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (0.12 ml, 0.89 mmol) and subsequently benzenesulfonyl chloride (0.19 ml, 0.26 mmol) were added to a solution of 1,3-dibenzyl-1,4,8-triazaspiro-[4,5]decan-2-one (250 mg, 0.75 mmol) in CH2Cl2 (6.7 ml) with stirring under a blanket of nitrogen at RT. The reaction mixture was stirred overnight. The organic phase was rendered alkaline using saturated aqueous sodium carbonate solution (20 ml), and the aqueous phase was extracted with CH2Cl2 (15 ml). The combined organic phases were dried over Na2SO4. After filtration, removal of the solvent, and column chromatography, the desired product 8-benzenesulfonyl-1,3-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 259 mg (73% of theory).
Reaction SMILES: [C:1]([C:3]1[N:4]=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:11][OH:12].C(N(CC)CC)C>CO>[OH:12][N:11]=[C:1]([C:3]1[N:4]=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)[NH2:2]
Reactant: Cc1ccc(C#N)nn1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(N)=NO)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyano-6-methyl pyridazine (U.S. Pat. No. 5,914,319) (0.77 g, 6.4 mmol) was dissolved in methanol (20 mL), then hydroxylamine hydrochloride (0.66 g, 9.6 mmol) and triethylamine (1.3 mL, 9.6 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was chilled in an ice-bath, then the solid was collected by filtration, washed with methanol and dried to give the title compound as a pale yellow solid (0.84 g).
Reaction SMILES: [F:1][C:2]1([F:18])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:10][C:4]=2[O:3]1.C([O:23][C:24]([N:26]1CC[N:29]([CH2:32][C:33]2[CH:43]=CC3OC(F)(F)OC=3C=2)[CH2:28][CH2:27]1)=O)(C)(C)C>>[N:29]1[CH:32]=[CH:33][CH:43]=[C:27]([NH:26][C:24]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:1])([F:18])[O:3][C:4]=4[CH:10]=3)[CH2:17][CH2:16]2)=[O:23])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: FC1(F)Oc2ccc(CN3CCNCC3)cc2O1
Product: O=C(Nc1cccnc1)N1CCN(Cc2ccc3c(c2)OC(F)(F)O3)CC1

Procedure:
1-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine. The title compound was prepared from 4-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester in analogy with Example 6.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:40])([F:39])[C:20]1[C:25]([C:26](O)=[O:27])=[CH:24][N:23]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:21]=1.C(OC(C1C(C(F)(F)F)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1)=O)C>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:26]([C:25]2[C:20]([C:19]([F:40])([F:18])[F:39])=[N:21][C:22]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)=[N:23][CH:24]=2)=[O:27])=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Agent: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C(F)(F)F)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C, 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared by saponification from 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester (example 107B]) in analogy to example 53B]) to give 2-methyl-2-[4-({[4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)C>[CH3:3][C:4]1([CH3:10])[CH2:8][CH2:7][C:6](=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)[C:5]1=[O:9]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1(C)CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCC(=Cc2ccc(Cl)cc2)C1=O
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
100 ml of a 10% aqueous solution of sodium hydroxide were added to a mixture of 10 g of 2,2-dimethylcyclopentanone and 13.8 g of 4-chlorobenzaldehyde in 100 ml of ethanol at 0° C. After 30 minutes, a thick slurry was filtered off and the solid washed and then dried. 12.5 g of 2,2-dimethyl-5-(4-chlorobenzylidene)-1-cyclopentanone with a melting point of 120° C. were obtained. This compound, dissolved in 50 ml of THF, was added to a solution formed in the following manner: 1.9 g of sodium hydride (80% dispersion in mineral oil) in 50 ml of anhydrous DMSO were heated to 80° C. until complete dissolution of the solid. The solution was then diluted with 100 ml of THF, then cooled to -10° C. A solution of 11.5 g of trimethylsulphonium iodide in 80 ml of dimethyl sulphoxide were added to the mixture in the course of ten minutes and the mixture was stirred for 15 minutes at -10° C. A solution of 11.8 g of 2,2-dimethyl-4-chloro-5-(4-chlorobenzylidene)-1-cyclopentanone was then added in 100 ml of THF.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([S:19][CH3:20])=[C:13]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:14]=2)=[O:8])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl>[CH3:20][S:19]([C:12]1[CH:11]=[CH:10][C:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=2)=[CH:14][C:13]=1[S:15]([NH2:18])(=[O:17])=[O:16])=[O:28]
Reactant: COc1ccc(C(=O)c2ccc(SC)c(S(N)(=O)=O)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(S(C)=O)c(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
To a solution of 5-(4-methoxy-benzoyl)-2-methylsulfanyl-benzenesulfonamide (0.06 g, 0.18 mmol) dissolved in methylene chloride (3 mL) at 0° C. is added m-chloroperoxybenzoic acid (0.061 g, 0.36 mmol). The reaction mixture is stirred at room temperature for 30 minutes. Then, the reaction is quenched with saturated sodium sulfite and sodium bicarbonate solution. The aqueous layer is extracted with methylene chloride three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (75% ethyl acetate-hexane) followed by recrystallization (methylene chloride-hexane) provides 0.022 g (35%) of the title compound as a pale yellow solid. 1H NMR (CDCl3): δ 8.35 (d, J=8 Hz, 1H), 8.10 (dd, J=8, 1 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.00 (d, J=9 Hz, 2H), 5.60 (s, 2H), 3.95 (s, 3H), 3.00 (s, 3H). Analytics calculated for C15H15NO5S2: C, 50.98; H, 4.28; N, 3.96. Found: C, 50.17; H, 4.46; N, 3.40. MS (m/z): 352 (M−1).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH3:7][O:8][CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH3:13]>C(=O)([O-])O.[Na+]>[CH3:7][O:8][CH:9]1[C:10]([CH3:14])=[CH:11][CH:12]([CH3:13])[CH:2]([C:1]([O:5][CH3:6])=[O:4])[O:3]1
Reactant: COC(=O)C=O
Reactant: CC=CC(C)=COC
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C1OC(OC)C(C)=CC1C
Temperature: -70 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
In the same manner as in Example 1, a solution of an (R)-binaphthol-dichlorotitanium complex was obtained. This solution was cooled to -70° C. in a dry ice-acetone bath. To this solution were successively added 88 mg (1 mmole) of methyl glyoxylate and 224 mg (2 mmole) of 1-methoxy-2-methyl-1,3-pentadiene. Reaction was then allowed to proceed at -30° C. for 1 hour, and 10 ml of a sodium hydrogencarbonate aqueous solution was added to the reaction mixture to terminate the reaction. This reaction mixture was filtered through Celite and then subjected to extraction once with 20 ml of diethyl ether and twice with 20 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Thereafter, the solvents were removed by evaporation, and the residue was purified by silica gel column chromatography (200 mesh; developing solvent: hexane/ethyl acetate=10/1), thereby obtaining 108 mg of desired optically active 2-methoxy-6-methoxycarbonyl-3,5-dimethyl-5,6-dihydropyran (yield: 54%).
Reaction SMILES: [CH3:1][CH2:2]CC[O-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:10][C:9]=1[CH:27]=[C:28]([Cl:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl.O>C(O)CCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:10][C:9]=1[CH:27]=[C:28]([Cl:34])[C:29]([O:31][CH2:32][CH2:33][CH2:1][CH3:2])=[O:30]
Reactant: CCCC[O-]
Reactant: CCOC(=O)C(Cl)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CCCCOC(=O)C(Cl)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 5 h

Procedure:
50 ml of a sodium n-butylate solution in n-butanol (prepared from 0.3 g of 80% strength sodium hydride and 50 ml of n-butanol) were added to a solution of 4.4 g of 3-[4-chloro-3-(2-chloro-2-ethoxycarbonylethen-1-yl)-phenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 50 ml of n-butanol, and stirring was carried out for 5 hours at room temperature. Thereafter, the mixture was neutralized with 10% strength hydrochloric acid at 0-5° C. and the resulting solution was stirred into 100 ml of water at 0-5° C. The aqueous phase was extracted with 100 ml of toluene, and the combined organic phases were washed with three times 50 ml of water, dried over sodium sulfate and evaporated down. The oil obtained was chromatographed over silica gel (dichloromethane), and the oil obtained therefrom was stirred with petroleum ether. The resulting solid was filtered off, washed with petroleum ether and dried.
Reaction SMILES: N#N.[OH:3][CH:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21]=[CH:22][O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:19])=[N:13]2)=[CH:9][N:10]=1)[CH3:5]>C(C#N)(C)=O.O=[Mn]=O>[C:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21]=[CH:22][O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:19])=[N:13]2)=[CH:9][N:10]=1)(=[O:3])[CH3:5]
Reactant: CC(O)c1ncc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1ncc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-phenyl-oxazole-4-carboxylic acid {1-[2-(1-hydroxy-ethyl)-oxazol-5-ylmethyl]-1H-pyrazol-3-yl}-amide (140 mg, 0.37 mmol) in AcCN (4.0 mL) was treated at rt with MnO2 (267 mg, 2.77 mmol) and the reaction mixture was stirred at rt overnight before being filtered through Celite. Purification of the residue by FC (3:7 hept-EA) gave the title compound as a white foam. TLC: rf (3:7 hept-EA)=0.28. LC-MS-conditions 02: tR=0.95 min; [M+H]+=378.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:15]([C:9]2[C:10]3[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=3[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=2[CH3:18])=[O:16])=[CH:26][CH:25]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Product: COc1ccc(NC(=O)c2c(C)c([N+](=O)[O-])cc3nc(OC)c(OC)nc23)cc1
Reaction time: 24 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and 4-anisidine 207 mg (1.68 mmol). Reaction was continued for 24 hours, and the crude product was eluted through a flash column (3:2 hexanes:ethyl acetate), 210 mg (66%), mp 206-208° C.; 1H NMR (CDCl3): δ 8.33 (s, 1H), 7.71 (d, 2H, J=9.0 Hz), 7.60 (s, 1H), 6.88 (d, 2H, J=8.8 Hz), 4.16 (s, 3H), 4.00 (s, 3H), 3.79 (s, 3H), 2.57 (s, 3H); MS (APCI): m/z 399 (M+H). Anal. Calcd. for C19H18N4O6: C, 57.29; H, 4.55; N, 14.06. Found: C, 57.23; H, 4.73; N, 14.01.
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[C:11](=[O:20])[NH:12][C:13]([CH:17]2[CH2:19][CH2:18]2)=[CH:14][C:15]=1[CH3:16])C(=O)[O-])(C)C.CCOC(C)=O.[ClH:27].O1CCOCC1>CO>[ClH:27].[NH2:5][CH2:9][C:10]1[C:11](=[O:20])[NH:12][C:13]([CH:17]2[CH2:18][CH2:19]2)=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1cc(C2CC2)[nH]c(=O)c1CN(C(=O)[O-])C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C2CC2)[nH]c(=O)c1CN
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
1,1-Dimethylethyl[(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate (0.28 g, 1.006 mmol) was added to EtOAc (9 mL) and methanol (1.0 mL). The suspension was stirred at room temperature for 5 min., followed by addition of 4M HCl in dioxane (5.03 mL, 20.12 mmol), and the contents were stirred at room temperature overnight. The volatiles were then removed in vacuo to afford a solid. The solid was triturated with ether, filtered, and dried in a vacuum oven at 45° C. for 4 h. The title compound was collected as 0.22 g (100% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78-0.86 (m, 2H), 0.95-1.03 (m, 2H), 1.83 (tt, J=8.46, 5.05 Hz, 1H), 2.16-2.22 (m, 3H), 3.75 (q, J=5.47 Hz, 2H), 5.79 (s, 1H), 8.02 (br. s., 3H), 11.92 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=3[F:23])[N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35])=[CH:29][CH:28]=1.C1(C)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[O:38])=[CH:18][C:17]=3[F:23])[CH:14]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc(N)cc3F)ncn2)cc1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of N-(4-methoxybenzyl)-6-(4-amino-2-fluorophenoxy)pyrimidin-4-amine (88 mg, 0.26 mmol) in THF (2 mL) was treated with 0.36 M 2-(4-fluorophenyl)acetyl isocyanate in toluene (0.72 mL, 0.26 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo and the solid obtained was triturated with isopropyl ether to give the title compound (125 mg, 93%) as an off-white solid. 1H NMR (DMSO-d6) δ 11.00 (s, 1H), 10.50 (s, 1H), 8.09 (s, 1H), 7.85 (br s, 0.5H), 7.66 (d, 1H, J=12.6 Hz), 7.36-7.15 (m, 9.5H), 6.88 (d, 1H, J=8.1 Hz), 5.91 (s, 1H), 4.42 (br s, 2H), 3.72 (s, 2H), 3.71 (s, 3H); MS (ESI+) m/z 520.14 (M+H)+.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]([N:25]3[C@@H:34]4[C@@H:29]([C:30]5[CH:38]=[CH:37][C:36]([C:39]([NH2:41])=O)=[CH:35][C:31]=5[CH2:32][CH2:33]4)[CH2:28][CH2:27][CH2:26]3)=[O:24])=[CH:22][C:17]=2[N:16]=[CH:15]1.C(N(CC)CC)C>ClCCl>[NH:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]([N:25]3[C@@H:34]4[C@@H:29]([C:30]5[CH:38]=[CH:37][C:36]([C:39]#[N:41])=[CH:35][C:31]=5[CH2:32][CH2:33]4)[CH2:28][CH2:27][CH2:26]3)=[O:24])=[CH:22][C:17]=2[N:16]=[CH:15]1
Reactant: NC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic anhydride (0.4 mL) is added to a solution of cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid amide (140 mg) and triethylamine (0.6 mL) in dichloromethane (4 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room temperature for 3 h. Another portion of trifluoroacetic anhydride (0.4 mL) and triethylamine (0.6 mL) are then added and stirring is continued at 35° C. overnight. The solution is diluted with dichloromethane and washed with water and brine. After drying (MgSO4), the solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 20:1→1:1) to furnish the title compound as a yellowish solid. Yield: 50 mg (38% of theory); Mass spectrum (ESI+): m/z=357 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.Cl.[NH2:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:10]([OH:29])[CH2:11][N:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:13]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH2:37]([OH:39])C>>[CH2:30]([C@H:9]([NH:8][C:37](=[O:39])[O:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1)[C@H:10]([OH:29])[CH2:11][N:12]([CH2:25][CH:26]([CH3:27])[CH3:28])[S:13]([C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O[C@H]1CCOC1
Reactant: CCO
Reactant: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CCOC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 82 %

Procedure:
1,1′-carbonyidiimidazole (27.66 kg, 170.58 mol) was added to ethyl acetate (314.3 kg) with stirring to give 3-(S)-tetrahydrofuryl imidazole-1-carboxylate. (S)-3-hydroxytetrahydrofuran (157 kg, 178.19 mol) was added over 30 minutes, washed in with ethyl acetate (9.95 kg), then the mixture was stirred for a further hour. (2R,3S)-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzene sulphonamide hydrochloride (65.08 kg, 142.10 mol) was added and the mixture heated to reflux for approximately 22 hours. The solution was cooled slightly, and denatured ethanol (98 l) was added. The solution was stirred at 60° C. for 10 minutes then cooled and the product allowed to crystallise. The mixture was cooled to <10° C. and stirred for 2 hours. The product was isolated by filtration, washed with denatured ethanol (33 l) and dried at approximately 50° C., under vacuum to give (3S)-tetrahydro-3-furyl N-[(1S,2R)-1-benzyl-2-hydroxy-3-(N-isobutyl-4-nitrobenzene sulphonamido)propyl]carbamate in a yield of 82% of theory.