Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[C:13]([O-:16])(O)=O.[Na+]>C1CCCCC1>[CH3:12][C@@H:2]1[CH:7]=[CH:6][CH2:5][C:4]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[C@H:3]1[C:13](=[O:16])/[CH:3]=[CH:2]/[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: C/C=C/C(=O)[C@H]1[C@H](C)C=CCC12CCCC2
Temperature: 0 °C
Yield: 79 %

Procedure:
At −70° C., a solution of diisopropylamine (0.5 g, 4.93 mmol) in tetrahydrofuran (4 ml) was treated with n-butyl lithium (3.3 ml, 1.6M in hexane, 5.14 mmol). The resulting solution was stirred at −70° C. for 20 min. and treated with a solution of 1-(rel-(6S,7R)-7-methylspiro[4.5]dec-8-en-6-yl)ethanone (0.79 g, 4.11 mmol) in tetrahydrofuran (4 ml). The resulting solution was stirred 20 min. at −70° C. warmed to 0° C., cooled to −70° C., and treated with a solution of acetaldehyde (0.9 g, 20.5 mmol) in tetrahydrofuran (4 ml). After 20 min. stirring, the reaction mixture was warmed to −5° C., treated with a 1:1 mixture of a 2N aqueous HCl solution and saturated aqueous NaCl solution (25 ml) and extracted three times with MTBE (60 ml). The combined organic phases were washed with a saturated solution of NaHCO3, with a saturated solution of NH4Cl, and with water, dried (MgSO4), and concentrated. Fluid chromatography (FC, SiO2, hexane/MTBE 35:1) of the crude product (1.3 g) gave the desired intermediate β-hydroxyketone (0.47 g, 1.98 mmol, 48%) which was dissolved in cyclohexane (1 ml). The resulting solution was treated with para-toluene sulfonic acid monohydrate (13 mg, 6.7 mmol) and refluxed 1.5 h. The reaction mixture was cooled to 0° C., treated with a saturated aqueous solution of NaHCO3 and the aqueous phase was extracted twice with MTBE. The combined organic phases were washed with water, dried (MgSO4) and concentrated. FC (SiO2, hexane/MTBE 50:1) of the crude product (0.42 g) gave (E)-1-(rel-(6S,7R)-7-Methylspiro[4.5]dec-8-en-6-yl)but-2-en-1-one (0.34 g, 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].C1(O)C=CC=CC=1.[CH2:18]([O:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>C(Cl)Cl>[CH2:18]([O:25][NH:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NOCc1ccccc1
Reactant: COc1c(Cl)ccnc1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: COc1c(NOCc2ccccc2)ccnc1C

Procedure:
16 g of 4-chloro-3-methoxy-2-methylpyridine, 63 g of phenol and 40 g of O-benzylhydroxylamine are stirred at 120° C. under nitrogen for 4 hours. After cooling, the mixture is shaken with 500 ml of 2N NaOH and CH2Cl2. The aqueous phase is extracted a second time with CH2Cl2. After concentrating the combined CH2Cl2 phases, excess O-benzylhydroxylamine is distilled off in vacuo at 0.6 mm. The residue crystallizes on stirring with hexane. After filtering off with suction and washing with hexane 21.6 g=88.4% of product remain. The product is recrystallized from ethyl acetate. M.p.: 130° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21].Cl>>[C:20](#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: N#CCCCCBr
Reactant: CCCCCOCCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCCCCOCCCCCOCCCCC#N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60%, 0.75 g) was added to a solution of 3 g of 5-pentyloxy-1-pentanol prepared in the above-described step (1) in 50 ml of N,N-dimetnylformamide. Then 2 ml of 5-bromopentanenitrile was added thereto and the mixture was stirred at 60° C. for 2 h. 3% hydrochloric acid was added to the reaction solution. After extraction with ether, the organic layer was dried and concentrated and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1) to obtain 1 g of the intended product.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH:24]1([C:27]([C:29]2[CH:53]=[CH:52][C:32]([O:33][C@@H:34]([C:37]3[O:41][N:40]=[C:39]([C:42]4[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[C:44]([F:51])[CH:43]=4)[N:38]=3)[CH2:35][CH3:36])=[CH:31][CH:30]=2)=[O:28])[CH2:26][CH2:25]1.[NH2:54][C@H:55]1[C@H:59]([OH:60])[CH2:58][O:57][C:56]1=[O:61]>C(OCC)(=O)C.O.CN(C)C=O>[CH:24]1([C:27]([C:29]2[CH:30]=[CH:31][C:32]([O:33][C@@H:34]([C:37]3[O:41][N:40]=[C:39]([C:42]4[CH:50]=[CH:49][C:45]([C:46]([NH:54][C@H:55]5[C@H:59]([OH:60])[CH2:58][O:57][C:56]5=[O:61])=[O:47])=[C:44]([F:51])[CH:43]=4)[N:38]=3)[CH2:35][CH3:36])=[CH:52][CH:53]=2)=[O:28])[CH2:25][CH2:26]1
Reactant: N[C@@H]1C(=O)OC[C@H]1O
Reactant: CC[C@@H](Oc1ccc(C(=O)C2CC2)cc1)c1nc(-c2ccc(C(=O)O)c(F)c2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@H](Oc1ccc(C(=O)C2CC2)cc1)c1nc(-c2ccc(C(=O)N[C@@H]3C(=O)OC[C@H]3O)c(F)c2)no1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
1-Hydroxybenzotriazole monohydrate (46.1 mg, 0.301 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (57.7 mg, 0.301 mmol) were added to an N,N-dimethylformamide (0.5 mL) solution of the 4-(5-{(1R)-1-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1,2,4-oxadiazol-3-yl)-2-fluorobenzoic acid synthesized in Reference Example 8 (103 mg, 0.252 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Subsequently, an N,N-dimethylformamide (1.0 mL) solution of the (3S,4S)-3-amino-4-hydroxydihydrofuran-2-(3H)-one synthesized in Reference Example 13 (44.2 mg) was added, and the mixture was further stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30→30:70, v/v) to give the title compound (48.5 mg, yield: 38%).
Reaction SMILES: FC1C=C(F)C=CC=1C(Cl)=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([CH3:47])[C:41]=1[CH3:48].C1(C)C=CC=CC=1>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[C:41]([CH3:48])[C:42]=1[CH3:47])=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: O=C(N=C=S)c1ccc(F)cc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4F)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
2,4-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Difluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 74%).
Reaction SMILES: [S:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]1[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][CH2:3]1.C[N:16](C)C=O.Cl[C:21]1C=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][N:22]=1.O>CCOCC>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([O:8][CH2:7][C@H:5]2[O:6][CH:2]([S:1][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:3][CH2:4]2)[N:16]=1
Reactant: CN(C)C=O
Reactant: COc1ccnc(Cl)c1
Reactant: OC[C@@H]1CCC(Sc2ccccc2)O1
Solvent: CCOCC
Solvent: O
Product: COc1ccnc(OC[C@@H]2CCC(Sc3ccccc3)O2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To the phenyl 2,3-dideoxy-1-thio-D-glycero-pentofuranoside (465 mg, 2.21 mmol) was added dimethylformamide (10 ml) under an argon atmosphere and then, sodium hydride (50% oil, 230 mg) having been washed with hexane was added thereto. The resultant mixture was allowed to react at room temperature for 1 hour and cooled to 0° C. To the reaction mixture was added 2-chloro-4-methoxypyridine (519 mg) and a reaction was allowed to proceed for 3 hours. The resultant mixture was gradually heated to room temperature, so that a reaction is further allowed to proceed for 12 hours. After cooling the resultant mixture to 0° C., water and ether were added thereto to thereby extract the organic phase of the mixture with the ether. The thus obtained organic phase was dried over anhydrous magnesium sulfate and concentrated by evaporation of the ether under reduced pressure. The resultant concentrate was subjected to silica gel thin-layer chromatography (developing solvent; ether:hexane=1:2 to 3:1) to thereby obtain 631 mg of phenyl 2,3-dideoxy-5-O-(4-methoxy-2-pyrimidyl)-1-thio-D-glycero-pentofuranoside (yield: 90%). The structure of this compound was confirmed by 1H NMR. The 1H NMR spectrum is shown in FIG. 1, and the 1H NMR data is as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Si:9]([O:16][CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl>[C:12]([Si:9]([CH3:11])([CH3:10])[O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)[CH2:19][CH2:18]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: Nc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-chloroaniline (1.27 g, 10 mmol) in 1,2-dichloroethane (20 ml) were added molecular sieves (4 g, size 0.4 nM) and 4-(tert-butyldimethylsilyloxy)-cyclohexanone (4.57 g, 20 mmol). After stirring the mixture for 30 min at room temperature sodium triacetoxyborohydride (8.48 g, 40 mmol) and acetic acid (1.2 g, 20 mmol) were added. The reaction mixture was stirred at room temperature overnight. For workup dichloromethane (100 ml) and 1 M sodium bicarbonate solution (40 ml) were added and the mixture was shaken. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (heptane/ethyl acetate=1:1) to yield a colourless liquid (0.80 mg, 23.5%); MS (EI): 339.2; 341.3 (M+.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].C([O-])(=O)C.[K+].[S:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>CC(N(C)C)=O.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:22]1[S:18][CH:19]=[N:20][CH:21]=1
Reactant: c1cscn1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cc([N+](=O)[O-])ccc1-c1cncs1
Yield: 59 %

Procedure:
In a microwave vial, a mixture of 2-bromo-5-nitroanisole (300 mg, 1.27 mmol), potassium acetate (188 mg, 1.90 mmol) and tetrakis(triphenylphosphine)palladium(0) (74 mg, 0.634 mmol) in 4 ml dimethyl acetamide was flushed with argon. Thiazole (459 uL, 6.34 mmol) was added, the tube was sealed, and the mixture was heated for 1 h to 160° C. in a microwave oven. The mixture was diluted with ethyl acetate and water, the layers were separated and the aqueous layer was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residual material was subjected to column chromatography on silica gel using heptane/ethyl acetate (7:3) as eluent to afford the title compound as yellow solid (177 mg, 59%). Mp 125-128° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[O:27][CH3:28])[CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.O.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[O:27][CH3:28])[CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([OH:16])=[O:15])[CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CC1CC(N(Cc2ccc(OC)cc2OC)C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)C2CC(CC(=O)O)C2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To methyl 2-(3-(tert-butoxycarbonyl(2,4-dimethoxybenzyl)amino)cyclobutyl)acetate from step 2 in a mixture of MeOH, THF and H2O was added 1N NaOH (10 mL). The resultant reaction mixture was stirred at RT for 2 hr. Half of the solvents were removed under reduce pressure and 1N HCl was added to adjust pH of the solution to 4. The aqueous phase was extracted with EtOAc for three times. The combined organic phase was then dried and concentrated in vacuo to afford the acid (0.67 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.Cl[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[CH3:31][O:30][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:29]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
Methyl 4-aminobenzoate (Aldrich, 5.0 g, 33 mmol) was dissolved in 120 mL of anhydrous methylene chloride containing pyridine (3.2 mL, 39.6 mmol) and dimethylaminopyridine (DMAP, 500 mg) was added. To the ice-cooled mixture was added methyl chloroformate (2.80 mL, 36.3 mmol) while stirring. The stirring was continued for 16 h at room temperature. The reaction was quenched with water (50 mL) and the organic layer separated. The aqueous layer was extracted with chloroform (50 mL). The combined organic extract was dried over sodium sulfate. The volatiles were evaporated on a rotoevaporator to give a residue, which was crystallized from chloroform-methanol. The white solid was separated, dried in air followed by drying in a pistol at acetone reflux in vacuo to give 4.95 g (71.7%) of methyl 4-(methoxycarbonyl)aminobenzoate, mp 177°-178° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:38]([C:35]2[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:37][CH:36]=2)(=[O:40])=[O:39])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(-n3cccn3)cc2)Cc2cccc(OCC(=O)OC(C)(C)C)c2)cc1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13a, and 4-methoxybenzenesulfonyl chloride. MS 564 (M+1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:19](/[CH:21]=[CH:22]\[C:23]([O:25]CC)=O)#[N:20]>FC(F)(F)C(O)=O>[CH:5]1[C:4]2[CH2:3][C:2]3[C:10]4[NH:11][C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:18]=4[C:21]4=[CH:22][C:23](=[O:25])[N:20]=[C:19]4[C:1]=3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)/C=C\C#N
Reactant: C1=C(c2cc3ccccc3[nH]2)Cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=c2c(c3c(c4[nH]c5ccccc5c24)Cc2ccccc2-3)=N1
Temperature: 120 °C
Reaction time: 4 h
Yield: 12.2 %

Procedure:
A mixture of 2-(2-indenyl)indole 4 (75 mg; 0.32 mmol) and ethyl cis-β-cyanoacrylate (81 mg; 0.64 mmol) in trifluoroacetic acid (1 mL) was heated in a sealed reaction vial at 120° C. for 1 h., followed by 4 h at 160° C. The mixture was evaporated at reduced pressure and the residue was triturated with ether. The resulting solid was chromatographed (silica gel; EtOAc: hexanes; 1:1) to give 12 mg (12%) of tan solid product; mp 275°-280° C., MS (ES+) 310 (M+). This compound showed identical spectral data as that prepared in Method A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:14](O)[CH3:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:14][CH3:15])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CCOC(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
A solution of 59.5 g of 3,4-dichlorophenylacetic acid in 500 ml of absolute ethanol is saturated with anhydrous hydrogen chloride and then heated at reflux for 2 hours. The mixture is concentrated under reduced pressure to 200 ml, diluted with 200 ml of water and neutralized with concentrated ammonium hydroxide. This aqueous mixture is extracted 3 times with chloroform. Concentration and decolorization of the chloroform extracts gives ethyl 3,4-dichlorophenylacetate as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][NH2:7])=[O:5])[CH3:2].[CH2:8]([O:10][C:11](=O)[C:12]#[CH:13])[CH3:9].C([OH:17])C>>[CH2:1]([O:3][C:4]([NH:6][N:7]=[C:11]([O:10][CH2:8][CH3:9])[CH2:12][CH:13]=[O:17])=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)NN
Reactant: C#CC(=O)OCC
Product: CCOC(=O)NN=C(CC=O)OCC
Reaction time: 3 h

Procedure:
41.6 g (0.4 mole) hydrazinoformic acid ethyl ester are dissolved in 120 ml ethanol in a three necked 250 ml round flask with stirrer and temperature indicator and 39.2 g (0.4 mole) propiolic acid ethyl ester are added. The temperature rises to 30° C. during the addition and is kept constant for another three hours. After standing over night at room temperature the contents is thickened by evaporation at 40° C. in vacuo. The yellow oily residue crystallizes upon grinding. The crystals are ground with a mixture of 60 ml isopropylether and 60 ml cyclohexane, are sucked off, washed with 100 ml cyclohexane and are dried at room temperature in vacuo to constant weight.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.C[C:17]1NC(=O)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+]([O-])=O)[CH:23]=2)[N:18]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)(Cl)=O.[C:45]([O-])(O)=[O:46].[Na+]>C1(C)C=CC=CC=1>[CH3:45][O:46][C:22]1[CH:21]=[CH:20][C:19]([N:18]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[C:4]([CH3:15])[N:3]=2)[CH3:17])=[CH:24][CH:23]=1
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2c(=O)[nH]1
Reactant: Cc1nc(Cl)c2cc([N+](=O)[O-])ccc2n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(N(C)c2nc(C)nc3ccc([N+](=O)[O-])cc23)cc1
Temperature: 120 °C
Yield: 60 %

Procedure:
4-Chloro-2-methyl-6-nitro-quinazoline. A mixture of 2-methyl-6-nitro-quinazoline-4-one (100 mg, 0.49 mmol) and diisopropylethylamine (250 uL) in 3 mL of toluene was heated to 120° C. for 1 h, then phosphorylchloride (50 uL, 0.54 mmol) was added and the mixture was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature and poured into ice (about 15 g), basified with saturated NaHCO3 and extracted with 75 mL of ethyl acetate. The organic layer was washed with water (50 mL), 1N citric acid (50 mL), water (50 mL) and saturated NaCl, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (15% ethyl acetate/hexanes) on silica gel to give the title compound (65.5 mg, 0.29 mmol, 60%). 1H NMR (CDCl3): 9.17 (d, J=2.4, 1H), 8.69 (dd, J=9.3, 2.4, 1H), 8.13 (d, J=9.3, 1H), 2.93 (s, 3H).
Reaction SMILES: Cl.Cl.[NH:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)[NH2:4].O=[C:19]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21][CH:20]1[C:33](OCC)=[O:34].C(N(CC)CC)C>C(O)(C)(C)C>[O:34]=[C:33]1[CH:20]2[C:19]([CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[N:4][N:3]1[CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NNC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2=NN(C3CCN(Cc4ccccc4)CC3)C(=O)C2CC1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of 4-hydrazino-1-(phenylmethyl)piperidine dihydrochloride (commercially available from e.g. Aurora Screening Library) (2.68 g, 9.63 mmol) and tert-butanol (60 ml) was added to 1-(1,1-dimethylethyl) 4-ethyl 5-oxohexahydro-1H-azepine-1,4-dicarboxylate (may be prepared as described in Synthetic Communications (1992), 22(9), 1249-58) (2.50 g, 8.76 mmol) followed by triethylamine (7.33 ml, 52.59 mmol) and the resulting suspension warmed to reflux over ˜10 min under Argon. The resulting clear yellow solution was then kept at this temperature for 65 h. The mixture was then allowed to cool to room temperature over ˜2 h and the mixture reduced under vacuum to give a cream coloured solid residue. Purification by chromatography on silica gel eluting with dichloromethane:methanol 50:1→25:1→10:1 afforded a product which as partitioned between water and dichloromethane (100 ml each) the layers separated and the organic layer washed with more water (100 ml), followed by brine (100 ml) and then dried (Na2SO4), filtered and reduced to give the title compound (D47). MS (ES+) m/e 427 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][C:12]1[C:17]2[N:18]=[C:19]([N:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:20][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][C:12]1[C:17]2[N:18]=[C:19]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[S:20][C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2c(CBr)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(CNCc1cccc2sc(NC(=O)OC(C)(C)C)nc12)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a solution of 2,2-diethoxyethanamine (8.72 ml, 60.0 mmol) in acetonitrile (300 ml) were added 4-bromomethyl-2-bis(tert-butoxycarbonyl)aminobenzothiazole (Compound XIX-1) (1.33 g, 3.00 mmol) and potassium carbonate (3.14 g, 18.0 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (300 ml) and the mixture was washed with water (300 ml) and brine (200 ml). The organic layer was dried over magnesium sulfate (5 g) and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=100:0 to 80:20) to obtain the title compound (1.01 g, yield: 85%).