Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[N:3]=1.B1(C=C)OB([CH:17]=[CH2:18])OB(C=C)O1.C1C=CN=CC=1>COCCOC.C([O-])([O-])=O.[K+].[K+].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>[Br:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([CH:17]=[CH2:18])[N:3]=1
Reactant: COc1cc(Br)nc(Br)c1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1cc(OC)cc(Br)n1
Temperature: 85 °C
Reaction time: 2 h
Yield: 159.3 %

Procedure:
To a suspension of 2,6-dibromo-4-methoxy-pyridine (5.90 g, 22.1 mmol) in DME (60 mL) and 2 M aq. K2CO3-solution (20 mL), 2,4,6-trivinylcyclotriboroxane pyridine complex (3.19 g, 13.2 mmol) is added and the mixture is degassed and put under N2 before Pd(PPh3)4 (460 mg, 0.398 mmol) is added. The mixture is stirred at 85° C. for 2 h before it is again cooled to rt, diluted with water and extracted with EA. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-bromo-4-methoxy-6-vinyl-pyridine (4.50 g) as a yellow solid; LC-MS: tR=0.90 min, [M+1]+=213.83.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CO>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1cnc(Cl)nc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CN1CCNCC1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(C)CC2)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
2-Chloropyrimidine 5-carboxylic acid (100 mg, 0.631 mmol, 1 eq) was suspended in a mixture of toluene (3 ml) and methanol (0.8 ml) under nitrogen and cooled in an ice-bath. Trimethylsilyldiazomethane (2M solution in hexanes, 0.347 ml, 0.694 mmol, 1.1 eq) was added dropwise. The solution was stirred at 0° C. for 10 min, then allowed to warm to room temperature and stirred for a further 1 h. 1-Methylpiperazine (70 μl, 0.631 mmol, 1 eq) and triethylamine (88 μl, 0.631 mmol, 1 eq) were added dropwise and stirring continued at room temperature for 2 h. The solvent was evaporated and the residue was taken up in ethyl acetate (20 ml) and water (15 ml). The layers were separated and the aqueous extracted with further portions of ethyl acetate (2×10 ml). The combined extracts were dried over MgSO4, filtered and evaporated. The reaction was repeated as above and the extracts combined with those above to afford methyl 2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate as a gummy yellow solid (76 mg, 25% yield).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C:11]1[N:15]=[C:14]([NH:16][C:17]2[N:22]=[CH:21][C:20]([S:23]CCC(OC)=O)=[CH:19][C:18]=2[O:30][C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[CH3:36])[S:13][N:12]=1.CC([O-])(C)C.[K+].Br[CH2:46][CH2:47][O:48][CH3:49].CN(C=O)C>C1COCC1>[CH3:49][O:48][CH2:47][CH2:46][S:23][C:20]1[CH:19]=[C:18]([O:30][C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[CH3:36])[C:17]([NH:16][C:14]2[S:13][N:12]=[C:11]([C@H:2]3[CH2:3][O:4][C:5]4([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]4)[O:1]3)[N:15]=2)=[N:22][CH:21]=1
Reactant: COCCBr
Reactant: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2c(C)nn(C)c2C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2c(C)nn(C)c2C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.1 %

Procedure:
To a solution of (S)-methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-3-ylthio)propanoate (0.420 g, 0.749 mmol) in THF (10 mL) was added potassium 2-methylpropan-2-olate (2.36 ml, 2.36 mmol) and the reaction was stirred at ambient temperature for 5 minutes. 1-Bromo-2-methoxyethane (0.132 g, 0.899 mmol) (as a solution in 2 mL THF) and DMF (1 mL) were added and the reaction was stirred for 20 minutes at ambient temperature. The solution was quenched with water, extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)-N-(5-(2-methoxyethylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.200 g, 50.1% yield).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)/[C:17](=[N:21]/[OH:22])/[CH2:16][CH2:15][CH2:14]2)=[CH2:10].[CH2:23]([C:27]1[CH:36]=[CH:35][C:30]([C:31](OC)=O)=[CH:29][C:28]=1[C:37]([F:40])([F:39])[F:38])[CH:24]([CH3:26])[CH3:25].S(Cl)(Cl)=O>C1COCC1.N1C=CC=CC=1>[CH2:23]([C:27]1[CH:36]=[CH:35][C:30]([C:31]2[O:22][N:21]=[C:17]3[C:18]4[C:13]([CH2:14][CH2:15][C:16]=23)=[CH:12][C:11]([CH:9]=[CH2:10])=[CH:20][CH:19]=4)=[CH:29][C:28]=1[C:37]([F:38])([F:39])[F:40])[CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)c1ccc(CC(C)C)c(C(F)(F)F)c1
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(CC(C)C)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
To the LDA solution was added 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.25 g, 1.335 mmol) dissolved in 1 mL of THF dropwise over a period of 1 min. at 0° C. After 15 min., methyl 4-isobutyl-3-(trifluoromethyl)benzoate (Preparation 23B, 0.347 g, 1.335 mmol) dissolved in 1 mL of THF was added dropwise over a period of 1 min. at 0° C. and the contents were stirred at 0° C. for 10 min. The reaction mixture was partitioned between 1N hydrochloric acid (5 mL) and ethyl acetate (10 mL)-THF. The 1N hydrochloric acid layer was back extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting yellow solid was azeotroped with toluene (5 mL). To the solid was added toluene (5.00 mL), followed by thionyl chloride (0.195 mL, 2.67 mmol) and 1 drop of pyridine. The contents were heated at 110° C. for 5 min. The dark reaction mixture was concentrated and partitioned between ethyl acetate (15 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated and subjected to silica gel column chromatography (hexane/ethyl acetate). Fractions corresponding to the product were collected and concentrated to yield 3-(4-isobutyl-3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.305 g, 0.767 mmol, 57.5% yield) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[CH3:24][O:25][C:26]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:27]=1[NH2:28]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH:28][C:27]1[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:26]=1[O:25][CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: COc1ccc(C)cc1N
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cc(C)ccc1OC)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate B and 2-methoxy-5-methylaniline. After completion, the reaction mixture was extracted with HCl and washed with a saturated NaHCO3 solution. The organic was dried (Na2SO4), filtered and concentrated. The product was used without further purification. tR: 1.40 min (LC-MS 2); ESI-MS: 520.1/522.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13]1>Cl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:19])=[CH:8][CH:7]=1
Reactant: Fc1ccccc1
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCCC(=O)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
Charge 250 g of anhydrous AlCl3 (1.87 moles) to a 2 L 3-neck round bottom flask, add 300 mL fluorobenzene (307.5 g; 3.2 moles) and cool the mixture in an ice bath to 5° C. Add a hazy suspension of 100 g glutaric anhydride (0.86 mole) in 400 mL fluorobenzene (4.3 moles) through an addition funnel over a period of 45 min., and maintain the temperature below 12° C. Warm the reaction mixture to ambient temperature gradually and agitate at r.t. for about 90 min.; check for completion by NMR. Cool the reaction mixture to 0 to 5° C., then add a cold aqueous solution (700 mL) of 1N HCl carefully to the mixture to destroy any unreacted AlCl3, keeping the temperature of the mixture below 20° C. during the early part of the acid addition, and below 40° C. for the rest of the time. Pour the entire mixture into a 2 L 1:1 mixture of water and ice (v/w) to precipitate out crude products, filter the white suspension and wash well with water. Add the white residue to 3 L of aqueous saturated solution (˜5%) of NaHCO3, heat the basic mixture on a steam bath for one hour and filter the batch while hot through a thin pad of celite. Cool the filtrate to r.t., add about 320 mL of concentrated HCl dropwise into the filtrate to pH 1 to crystallize out products, and agitate the white suspension in an ice bath for 30 min. Filter the batch, wash the wet cake with ice cold water and dry in a vacuum oven at 50° C. for 16 h to obtain 143.2 g of 4-(4-fluorobenzoyl)-butyric acid; m.p. 141 to 142° C., isolated yield: 79.3% .
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]3[CH2:11][CH2:12][NH:13][CH2:14][CH:5]3[C:4]=2[CH:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19]#[N:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:19]([CH2:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[CH:5]2[CH2:14]1)#[N:20]
Reactant: Cc1ccc2c(c1)C1CNCCC1N2
Reactant: N#CCCCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)C1CN(CCCC#N)CCC1N2

Procedure:
In toluene (60 ml) are dissolved 8-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (5.7 g), γ-bromobutyronitrile (4.5 g) and triethylamine (4.6 g), and the mixture is refluxed for 5 hours. After cooling, the reaction mixture is washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The resulting residue is treated with ethanolic hydrogen chloride in the same manner as described in Example 1 (1) to give the dihydrochloride of the titled compound (5.5 g), m.p. 160° - 165°C (recrystallized from aqueous ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:15]N(C)C)[C:10](OCC)=[O:11])=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[NH:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=1)[NH2:22].Cl.CCN(C(C)C)C(C)C>CC(O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:15]=[N:22][N:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=3)[C:10]=2[OH:11])=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2]
Reactant: NNc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1OC
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Temperature: 50 °C
Reaction time: 32 h
Yield: 48.5 %

Procedure:
Combined ethyl 2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylate (1.427 g, 5.20 mmol), 6-hydrazinylnicotinic acid (0.664 g, 4.34 mmol), and HCl (4.34 mL, 4.34 mmol) in 2-propanol (21.7 mL) and stirred at room temperature for 8 hours to give a solid. The solid was collected by filtration and combined with Hunig's base (1.50 mL, 8.61 mmol) in 2-propanol (10 mL) and water (1 mL) and stirred for 32 hours at 50° C., then 10 mL of 1 N HCl was added and the reaction was filtered to give a solid. The solid was washed with 30 mL MeOH and 30 mL of ether and dried in vacuo to give the title compound (708 mg, 73.3%) as a beige solid. MS m/z [M+H]+ 337.3.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1>ClCCl>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:15]2([C:5]#[N:6])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(N)cc1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCCC1
Solvent: ClCCl
Product: Cc1ccc(NC2(C#N)CCCC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
Trimethylsilyl cyanide (0.865 ml, 7 mmol) was added dropwise to a mixture of p-toluidine (0.535 g, 5 mmol) and cyclopentanone (0.589 g, 7 mmol). The reaction mixture was stirred at room temperature for 6 h and then concentrated under vacuum to obtain a brown liquid which was subjected to chromatography (dichloromethane) to yield 1-(4-methylphenyl)aminocyclopentanenitrile, 8a (0.981 g, 4.9 mmol, 98%) as a yellowish solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4][CH:3]1Cl.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[N:10]=[C:9]([NH:15][CH2:14][CH2:13][NH2:16])[CH:8]=[CH:7][C:6]=2[CH2:11]1
Reactant: CN1c2ncccc2C=CC1Cl
Reactant: NCCN
Product: CN1CCc2nc(NCCN)ccc2C1
Temperature: 138 °C

Procedure:
The product from Step A was dissolved in 10 equiv. of ethylenediamine and heated at 138° C. in a sealed tube for 18 h. The excess ethylenediamine was removed by distillation to provide the title compound as a brown oil. MS (M+H)+=207.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH2:22][CH3:23])=[N:10][CH:9]2[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)([Cl:39])=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([C:37]([Cl:39])=[O:38])[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH2:22][CH3:23])=[N:10][CH:9]2[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (160 mg, 0.387 mmol) in methylene chloride (15 mL) cooled to 0° C. were sequentially added triethylamine (108 μL, 0.774 mmol) and phosgene (589 μL, 1.161 mmol, 1.97 M in toluene). The reaction mixture was stirred at 0° C. under Argon for 30 min. The solvent and excess reagents were removed by rotovap, and the residue was purified by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with 20–25% ethyl acetate in hexanes to give 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (132.6 mg, 72%) as white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:27]([C@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[Li+]>O1CCCC1>[CH2:27]([C@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 74.4 %

Procedure:
An oven-dried, three-necked, 1 L 24/40 round-bottom flask equipped with a mechanical stirrer, a septum and a nitrogen inlet was charged with a solution of 20.00 g (0.110 mol) of 4-chlorocinnamic acid in 400 mL of anhydrous tetrahydrofuran. The reaction mixture was purged with nitrogen and stirred at −20° C. and then 19.93 mL (0.143 mol) of triethylamine and 14.84 mL (0.120 mol) of pivaloyl chloride were added via syringe. The reaction mixture was stirred at −20° C. for 30 min, then at room temperature for 1.5 h. A separate, oven-dried, three-necked, 2 L 24/40 round-bottom flask was equipped with a mechanical stirrer, and a nitrogen inlet. The contents were purged with nitrogen gas and then charged with 16.243 g (0.092 mol) of (S)-(−)-4-benzyl-2-oxazolidinone, 4.274 g (0.101 mol) of finely powdered anhydrous lithium chloride, 400 mL of anhydrous tetrahydrofuran and 16.61 mL (0.119 mol) of triethylamine. The reaction flask was fitted with an oven-dried fritted vacuum filtration funnel in one of its necks, and the reaction mixture was stirred at −20° C. The mixed anhydride prepared in the first reaction flask was separated from precipitated triethylamine hydrochloride by rapid filtration into the second flask with the aid of a slight vacuum applied to the filtration funnel. The reaction mixture in the second flask was again purged with nitrogen, stirred for 30 min at −20° C., then allowed to warm to room temperature and stirred an additional 5 h. At this point the reaction mixture was filtered again and concentrated in vacuo. The crystalline residue was dissolved in methylene chloride, washed with 0.5 M hydrochloric acid, water, saturated aqueous sodium bicarbonate, brine, then dried (MgSO4), filtered and evaporated. The residue was purified by rapid filtration through a six inch bed of silica gel 60 eluted with methylene chloride. Evaporation of the purified fractions and drying in vacuo afforded 23.38 g of the title compound.
Reaction SMILES: COC1C=CC(/C=[C:16]2/[C:17]([NH:19][C:20]([S:22]/2)=[NH:21])=[O:18])=CC=1OC1CCCC1.C(O[Na])(C)=O.[CH:28]([C:30]1[N:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][C:34]([C:40]#[N:41])=[C:33]2[O:42][CH:43]([CH3:45])[CH3:44])=O>CC(O)=O>[NH2:21][C:20]1[S:22][C:16](=[CH:28][C:30]2[N:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]=[CH:35][C:34]([C:40]#[N:41])=[C:33]3[O:42][CH:43]([CH3:45])[CH3:44])[C:17](=[O:18])[N:19]=1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(N)=NC3=O)nc12
Temperature: 90 °C
Yield: 22.8 %

Procedure:
To a mixture of pseudothiohydantoin (Aldrich, 97%, 23.2 mg, 0.20 mmol), AcONa (160 mg, 1.95 mmol), molecular sieves, and 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (53.1 mg, 0.22 mmol) (prepared as described below) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 85-95° C. for 1.5 h. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water. The solid was then suspended in hot DMF (20 mL) and filtered again. The filtrate was concentrated to give a brown solid: 55.8 mg, which was then purified by Biotage flash column (1%-6% MeOH in CH2Cl2) to give 6-(2-amino-4-oxo-4H-thiazol-5-ylidenemethyl)-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile as a yellowish solid (15.5 mg, 22.8%). HR-ES (+) m/e calcd for C16H13N5O2S (M+H)+ 340.0863. found 340.0863.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[Cl:8][C:9]([Cl:13])([Cl:12])[CH2:10][OH:11].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH2:18].C(N(CC)CC)C.Cl>ClCCl>[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH:18][S:2]([NH:5][C:6](=[O:7])[O:11][CH2:10][C:9]([Cl:13])([Cl:12])[Cl:8])(=[O:4])=[O:3]
Reactant: COC(CN)OC
Reactant: O=C=NS(=O)(=O)Cl
Reactant: OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CNS(=O)(=O)NC(=O)OCC(Cl)(Cl)Cl)OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
A solution of chlorosulfonylisocyanate (6.96 mL, 80 mmol) in dichloromethane (120 mL) was cooled to 0° C. 2,2,2-trichloroethanol (7.67 mL, 80.0 mmol, 1.0 equiv.) was added via addition funnel at 0° C. This mixture was stirred at 0° C. for 1.5 h. To this mixture was then added a solution of aminoacetaldehyde dimethyl acetal (8.76 mL, 80.0 mmol, 1.0 equiv.) and triethylamine (TEA, 33.4 mL, 240 mmol, 3.0 equiv.) in dichloromethane (DCM, 120.0 mL) added drop-wise via addition funnel at 0° C. The reaction was warmed to room temperature and stirred at room temperature overnight. The reaction was treated with 0.1 N hydrochloric acid and the collected organic phase was washed with brine, dried over Na2SO4, and concentrated to give the desired product (28.01 g, 97%) as a crude off-white solid, which was used in the subsequent reaction without further purification. 1H NMR (300 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.08 (t, 1H, J=5.9 Hz), 4.90 (s, 2H), 4.37 (t, 1H, J=5.5 Hz), 3.23 (s, 6H), 3.00 (dd, 2H, J=5.7 Hz).
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.BrCC1CCCCO1.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]2([C:54]3[C:45](=[CH:46][C:47]4[O:52][CH2:51][CH2:50][O:49][C:48]=4[CH:53]=3)[O:44][CH2:43]2)[C:35]1=[O:55].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:55]=[C:35]1[C:36]2([C:54]3[C:45](=[CH:46][C:47]4[O:52][CH2:51][CH2:50][O:49][C:48]=4[CH:53]=3)[O:44][CH2:43]2)[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:34]1[CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)CC1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, tert-butyl 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate was obtained (99%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.34-7.26 (m, 1H), 7.14-7.19 (m, 1H), 7.08-7.01 (m, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.19 (s, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.62 (d, J=9.0 Hz, 1H), 4.23-4.06 (m, 6H), 3.80-3.44 (m, 2H), 2.76-2.59 (m, 2H), 2.11-1.93 (m, 1H), 1.74-1.60 (m, 2H), 1.45 (s, 9H), 1.37-1.20 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=O>>[CH:34]([N:8]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:38][CH:37]=1)[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1)([CH3:36])[CH3:35]
Reactant: O=C(CCl)N1CCOCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCOCC3)cc2)C(C)C)c1
Yield: 71.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-morpholin-4-ylethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (22 mg) was obtained.