Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:8](=[O:20])[C:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([OH:11])[C:5]=2[CH:4]=1)[CH3:2].IC.[H-].[Na+].O1CCC[CH2:42]1>C(OCC)(=O)C>[CH2:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:8](=[O:20])[C:9]([CH3:42])([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: C1CCOC1
Reactant: CCc1cc2c(O)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)C(C)(CCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
A mixture of 4′-{[2-ethyl-4-hydroxy-6-oxo-5-(2-phenylethyl)thieno[2,3-b]pyridin-7(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g), iodomethane (0.076 mL), 60% sodium hydride (0.049 g) and tetrahydrofuran (15 mL) was stirred at room temperature for 20 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.32 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl[C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]2[S:28][C:29]3[CH2:30][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32][CH2:33][C:34]=3[C:21]=12>>[C:26]([C:25]1[C:20]([NH:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[C:2]([F:1])[CH:3]=2)[N:7]=[CH:8]3)=[C:21]2[C:34]3[CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][C:29]=3[S:28][C:22]2=[N:23][CH:24]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Cl)c23)C1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C1

Procedure:
In analogy to Example 54A, the title compound was synthesized from 1-(3-fluorobenzyl)-1H-indazol-5-amine from Example 8A (138 mg, 0.57 mmol) and tert-butyl 4-chloro-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate (200 mg, 0.57 mmol) from Example 53A to yield 234 mg (74%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1>C1COCC1>[CH3:1][N:2]([CH3:3])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:24][CH:23]=1
Reactant: CCOC(=O)CN(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(C(=O)OC(C)(C)C)cc1)N(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl (dimethylamino)acetate (0.16 mL, 1.11 mmol) was dissolved in THF (10 mL) and cooled to −78° C. LiHMDS (1.2 mL, 1M solution in THF) was added. The reaction was allowed to stir about 30 minutes. Tert-butyl 4-(bromomethyl)benzoate (0.3063 g, 1.13 mmol) in THF (3 mL) was slowly added to the reaction. The reaction was allowed to stir overnight under nitrogen, slowly warming to room temperature. The reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The resulting mixture was separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried with sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography. 1H NMR 600 MHz (CDCl3) δ 7.87 (m, 2H), 7.24 (m, 2H), 4.08 (m, 1H), 4.06 (m, 1H), 3.41 (dd, 1H, J=9.2, 6.0), 3.07 (dd, 1H, J=13.5, 9.3), 2.97 (dd, 1H, J=13.4, 5.8), 2.39 (s, 6H), 1.56 (s, 9H), 1.16 (m, 3H). MS: cal'd 322 (MH+), exp 322 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:18][O-:19].[Na+]>CO>[NH2:1][C:2]1[C:3]2[C:10]([C:11](=[NH:12])[O:19][CH3:18])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[O-]
Reactant: N#Cc1cn(COCCO)c2ncnc(N)c12
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cn(COCCO)c2ncnc(N)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 4-amino7-(2-hydroxyethoxymethyl)pyrrolo[2,3-d]-pyrimidine-5-formimidate was prepared by first dissolving compound (17a) (0.5 g; 2.15 mmole) in dry MeOH (15 ML). A sodium methoxide (1 M) solution (5 mL) was added and the mixture was stirred at room temperature for 3 hours. This solution was adjusted to pH7 by adding small portions of Dowex 50 (H+ form, prewashed with dry CH3OH). The solution was then quickly filtered to remove the ion-exchange resin followed by concentration of the filtrate in vacuo to a semisolid mass. The residue was purified by a column (2×60 cm; prepacked in CH2Cl2) of silica gel (15 g; 60-200 mesh). Elution of the column with CH2Cl2 :CH3OH (96:4, V:V) afforded the desired nucleoside which was crystallized from dry CH3OH-ET2O to afford the pure imidate (0.13 g; yield 23%); mp. 124° C.; IR (KBr)γ3350 (OH) and 1600 cm-1 ; UVλmax nm:(pH 1), 237 (14700) 280 (12710); (MeOH), 278 (15770); (pH 11), 217 (26100) 278 (13880). 1H NMR (DMSO-d6): δ3.50 (nm, 4, CH2), 3.75 (s, 3, OCH3), 5.58 (s, 2, C1 ''CH2), 7.25 (brs 1, NH2), 7.75 (s, 1, C6 --H), 8.06 (s, 1, C2 --H), 8.20 (brs, 1, C=NH, 9.98 (brs,1,NH2). Anal. (C11H15N5O3) C,H,N.
Reaction SMILES: [CH2:1]([CH2:7][OH:8])[CH2:2][NH:3][CH2:4][CH2:5][NH2:6].CS[C:11](=[C:14]([C:17]#[N:18])[C:15]#[N:16])SC.C(OC(C)C)(C)C>C(Cl)Cl>[CH2:5]1[NH:6][C:11](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[N:3]([CH2:2][CH2:1][CH2:7][OH:8])[CH2:4]1
Reactant: CSC(SC)=C(C#N)C#N
Reactant: NCCNCCCO
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: N#CC(C#N)=C1NCCN1CCCO
Reaction time: 1 h
Yield: 88.7 %

Procedure:
In 10 ml of methylene chloride was dissolved 10.4 g of N-(2-aminoethyl)propanolamine, and the solution was added to 15.0 g of [bis(methylthio)methylene]propanedinitrile. The mixture was allowed to stand at room temperature for 1 hour under reduced pressure. Diisopropyl ether was added to the mixture, and the solid was collected by filtration. The crystals were purified by silica gel column chromatography (chloroform:methanol=5:1) to give 15.0 g (87%) of Compound (VIa) as pale yellow crystals.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH2:12]Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C1C=CC=CC=1.O>[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH2:12][C:5]([CH3:12])([CH3:6])[CH:4]=[O:1]
Reactant: COc1ccc(CCl)c(Br)c1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(CC(C)(C)C=O)c(Br)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 103.7 %

Procedure:
A mixture of NaOH (4.9 g), and (Bu)4NI (1 g) in benzene (14 mL) and water (4.9 mL) was heated at 70° C. under argon to obtain a homogeneous mixture. To this mixture was added dropwise a mixture of isobutylaldehyde (10.1 g, 140 mmoles), and the product of Step 1 (25 g, 106 mmoles) in benzene (38 mL). After the addition, the resulting mixture was stirred at 70° C. for 6 h under argon. It was cooled, diluted with water, and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with water, dried (Na2SO4) and concentrated to dryness. This residue was purified by silica gel flash chromatography using 5% EtOAc in hexane. The appropriate fractions (monitored by TLC) were combined and concentrated to dryness to give the desired product (14.9 g, ˜50%). NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[N:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1O.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.CCCCCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]2[O:16][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=2)=[N:2]1
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCOC(C)=O
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1-c1nc2ccccc2o1
Yield: 5.1 %

Procedure:
In a similar manner to Example 28, (E)-2-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.20 g, 0.76 mmol) obtained in Step 1 of Example 47, 2-aminophenol (91 mg, 0.83 mmol), 1-hydroxybenzotriazole monohydrate (35 mg, 0.23 mmol), EDC (0.16 mg, 0.83 mmol) and THF/DMF (2/1, 3.0 mL) were reacted. Then, in a similar manner to Step 2 of Example 150, the reaction mixture was treated with p-toluenesulfonic acid monohydrate (0.26 mg, 1.5 mmol) and xylene (5.0 mL) to obtain Compound 183 (13 mg, 5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5](=[N:7][OH:8])[NH2:6].[CH:13](OCC)(OCC)OCC.C(#N)C>FC(F)(F)C(O)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[CH:13][O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(N)=NO)cc1F
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2ncon2)cc1F
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A suitable vessel equipped with a mechanical stirrer under a N2 atmosphere was charged with 3-fluoro-N′-hydroxy-4-methylbenzimidamide (302.52 g, 1.79 mol), triethyl orthoformate (382.5 mL, 341.1 g, 2.3 mol) and acetonitrile (1512 mL). The reaction mixture was heated to 45° C. and trifluoroacetic acid (6.72 mL, 10.08 g, 87.6 mmol) was added at this temperature. The reaction mixture was heated at 60° C. for an additional 90 minutes, then cooled to room temperature. Water (3 L) was added dropwise over a period of 60 minutes. The slurry was cooled to 4° C. and stirred at this temperature for 30 minutes. The solid was filtered and dried in vacuum at 50° C. for 12 hours to give 3-(3-fluoro-4-methylphenyl)-1,2,4-oxadiazole as a white solid (306 g, 95.6%). HPLC indicated 99.8% chemical purity. 1H-NMR (CDCl3, 400 MHz) δ8.67 (s, 1H), 7.71 (m, 2H), 7.23 (t, J=8 HZ, 1H), 2.28 (s, 3H); 13C-NMR (CDCl3, 400 MHz) δ166.9447, 164.7258, 162.5473, 160.1066, 132.0480, 132.0077, 128.5987, 122.9910, 122.9507, 114.2568, 114.0147, 14.6902. 19F-NMR (CDCl3, 400 MHz) δ−115.94, −115.96.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:34][C:20]1[N:21]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=2)[S:23][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:35])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], {6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid as yellow solid.
Reaction SMILES: B.[CH2:2]1[CH2:6][O:5][CH2:4][CH2:3]1.[Br:7][C:8]1[C:9]([CH3:33])=[N:10][O:11][C:12]=1[NH:13][S:14]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22]([NH:24]C1C=CC=C(OC)C=1)=O)(=[O:16])=[O:15].[CH2:34]1[CH2:38]OC[CH2:35]1>>[Br:7][C:8]1[C:9]([CH3:33])=[N:10][O:11][C:12]=1[NH:13][S:14]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[CH:22]([C:34]1[CH:38]=[CH:3][CH:2]=[C:6]([O:5][CH3:4])[CH:35]=1)[NH2:24])(=[O:15])=[O:16]
Reactant: COc1cccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Br)c1
Reactant: C1CCOC1
Agent: B
Product: COc1cccc(C(N)c2sccc2S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 12 %

Procedure:
BH3THF (15 ml, 1 M in THF) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide (Example 22) (1.0 g, 2.12 mmol) in dry THF (15 ml). The mixture was refluxed for 8 hours and cooled. THF was evaporated on a rotavap and MeOH was added to the residue. The resulting solution was concentrated. The final residue was purified by HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)-aminomethyl]thiophene-3-sulfonamide (113 mg., 12% yield) as a grey powder, m.p. 70-73° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]2[CH:12]=[CH:13][N:14]=[C:8]2[CH:7]=1.C1C(=O)N([Br:22])C(=O)C1>C(O)C.ClCCl>[Br:22][C:12]1[N:9]2[CH:10]=[CH:11][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:7][C:8]2=[N:14][CH:13]=1
Reactant: c1csc(-c2ccn3ccnc3c2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: ClCCl
Product: Brc1cnc2cc(-c3nccs3)ccn12
Yield: 67.5 %

Procedure:
Dissolve 7-thiazol-2-yl-imidazo[1,2-a]pyridine (1.14 g, 5.66 mmol) in 25 mL absolute ethanol, then add NBS (1.0 g, 5.66 mmol), stir the mixture at room temperature for 15 minutes, dilute with 35 mL dichloromethane and apply to a 10 g SCX Mega Bond-Elut™ cartridge (Varian) pre-washed with 150 mL 1:1 CH2Cl2:MeOH. Wash the SCX cartridge with 300 mL 1:1 CH2Cl2:MeOH, elute with 150 mL CH2Cl2:2 M NH3-MeOH, and concentrate the eluates and dry to provide 1.07 g (67%) of the title compound as a tan solid. MS (ES) 280, 282.
Reaction SMILES: [CH:1]([N:4]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[C:11]2[C:6](=[C:7]([CH3:21])[CH:8]=[CH:9][CH:10]=2)[NH:5]1)([CH3:3])[CH3:2].B(Br)(Br)Br.C1CCCCC=1>>[CH:1]([N:4]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[C:11]2[C:6](=[C:7]([CH3:21])[CH:8]=[CH:9][CH:10]=2)[NH:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C2c3cccc(C)c3NN2C(C)C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Cc1cccc2c1NN(C(C)C)C2c1ccc(O)cc1
Yield: 74.5 %

Procedure:
Prepared according to Method D step C from 2-isopropyl-3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.010 g, 0.035 mmol), boron tribromide (0.05 mL, 0.5 mmol) and 0.2 mL of cyclohexene to give the product (0.007 g).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:39][CH2:40][CH2:41][CH:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:44]([O:43][CH:42]([O:46][CH2:47][CH3:48])[CH2:41][CH2:40][NH:39][C:14](=[O:16])[C@@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:13])[CH3:45]
Reactant: CCOC(CCN)OCC
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(CCNC(=O)[C@H](C)NC(=O)OCc1ccccc1)OCC
Yield: 84.8 %

Procedure:
By using an analogous procedure to that described for Reference Example 13, carbobenzyloxy-L-alanine (2 g, 8.99 mmol), hydroxybenzotriazole (1.2 g, 8.99 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.72 g, 8.99 mmol), 1-amino-3,3-diethoxypropane (1.25 g, 8.53 mmol) and N,N-diisopropylethylamine (1.56 ml, 8.99 mmol) were reacted in anhydrous tetrahydrofuran (40 ml) at room temperature for 16 h, to provide benzyl (1S)-2-[(3,3-diethoxypropyl)amino]-1-methyl-2-oxoethylcarbamate (2.55 g, 85%) as a pale yellow solid.
Reaction SMILES: CN(P(N(C)C)N(C)C)C.[C:11]([O:14][CH:15]([C:24](=[O:26])[CH3:25])[CH2:16][CH:17]1[C:19]([CH3:21])([CH3:20])[CH:18]1[CH:22]=O)(=[O:13])[CH3:12].[C:27](Cl)(Cl)([Cl:29])[Cl:28].O>C(OCC)C>[C:11]([O:14][CH:15]([C:24](=[O:26])[CH3:25])[CH2:16][C@H:17]1[C:19]([CH3:21])([CH3:20])[C@H:18]1[CH:22]=[C:27]([Cl:29])[Cl:28])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(CC1C(C=O)C1(C)C)C(C)=O
Reactant: ClC(Cl)(Cl)Cl
Agent: CN(C)P(N(C)C)N(C)C
Solvent: CCOCC
Solvent: O
Product: CC(=O)OC(C[C@@H]1[C@H](C=C(Cl)Cl)C1(C)C)C(C)=O
Reaction time: 0.08 h
Yield: 52.8 %

Procedure:
Tri(dimethylamino)phosphine (40 mmol) was added with stirring at -20° C. to a solution of 1-(2-formyl-3,3-dimethylcyclopropyl)-3-oxo-2-butyl acetate (14.2 mmol) and carbon tetrachloride (40 mmol) in diethyl ether (160 ml) kept under nitrogen. Then, the temperature of the mixture was allowed to rise to 20° C. Water (50 ml) was added, the mixture was stirred for 5 minutes and, after settling, the organic phase was isolated. The organic phase was washed with two 50-ml portions of water. The washed organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried solution to leave a residue (2.2 g) containing 1-[2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropyl]-3-oxo-2-butyl acetate (100% (1R,cis), yield 54%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][C@H:27]1[CH:28]=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>ClCCCl.ClCCl>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][C@@H:27]1[CH2:28][NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
Sodium triacetoxyborohydride (15.9 g, 75.4 mmol) and enough acetic acid to bring the pH to 5 were added to a solution of N-tert-butoxycarbonyl-L-prolinal (5 g, 25 mmol) and 4-fluorobenzylamine (6.28 g, 50.3 mmol) in 200 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature overnight, and then it was diluted with dichloromethane, and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/ethyl acetate) afforded 6.0 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:52]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]1.[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:26])([CH3:25])[C:27]([NH:58][S:55]([CH:52]4[CH2:54][CH2:53]4)(=[O:57])=[O:56])=[O:29])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NS(=O)(=O)C2CC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of chiral (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (45 mg, 0.079 mmol) prepared in Example 7 and CDI (26 mg, 0.16 mmol) in DMF (0.5 mL) was heated at 60° C. for 2 h. Then to this solution was added a mixture of cyclopropanesulfonamide (48 mg, 0.4 mmol) and NaH (13 mg, 60%, 0.3 mmol) in DMF (1 mL), which had been stirred at room temperature for 1 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water (5 mL) and the aqueous solution was acidified to “pH” 2-3 by addition of concentrated aqueous hydrochloride acid. After the aqueous phase was extracted with EtOAc twice, the combined organic phases were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (38 mg).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[S:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:21][N:22]=1>>[C:23]([C:20]1[S:19][C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)=[N:22][N:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: CC(C)(C)c1nnc(N)s1
Agent: [I-]
Product: CC(C)(C)c1nnc(N=C2SC[C@@H]3Cc4ccccc4CN23)s1
Yield: 40.6 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.2 g) and 2-amino-5-tert.-butyl-1,3,4-thiadiazole (15.7 g) as the starting materials, (S)-3-[(5-tert.-butyl-1,3,4-thiadiazol-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (7.0 g) is obtained in the form of white crystals, m.p.=137° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[C:14]([O:15][CH2:16][CH:17]2[CH:21]=[CH:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[C:13]([C:29]([O:31][CH3:32])=[O:30])[C:12]([N:33](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:33][C:12]1[C:13]([C:29]([O:31][CH3:32])=[O:30])=[C:14]([O:15][CH2:16][CH:17]2[CH:21]=[CH:20][CH2:19][NH:18]2)[C:9]([Br:8])=[CH:10][CH:11]=1
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1OCC1C=CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(N)ccc(Br)c1OCC1C=CCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
TFA (5 mL) was slowly added to a suspension of tert-butyl 2-(6-bromo-3-[bis-(tert-butoxycarbonyl)amino]-2-methoxycarbonylphenoxymethyl)-2,5-dihydropyrrole-1-carboxylate (Intermediate 19, 3.55 g) in DCM (5 mL). The resultant dark solution was stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous potassium carbonate solution. The layers were separated and the aqueous layer was extracted with more ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give methyl 6-amino-3-bromo-2-(2,5-dihydro-1H-pyrrol-2-ylmethoxy)-benzoate (1.64 g) as a dark oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([OH:15])=[O:14].S(Cl)(O[CH2:20][Cl:21])(=O)=O>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([O:15][CH2:20][Cl:21])=[O:14]
Reactant: O=S(=O)(Cl)OCCl
Reactant: COCCOCCOCCOCC(=O)O
Product: COCCOCCOCCOCC(=O)OCCl

Procedure:
This compound was prepared from 2-(2-(2-methoxyethoxy)-ethoxy)-ethoxy-acetic acid and chloromethyl chlorosulfate as described in the general procedure given in Synthetic Communications 14, 857-864 (1984). The resulting oil was purified by distillation in vacuo, b.p.: 130-132° C. at 0.06 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10](O)([C:12]([F:15])([F:14])[F:13])=O.Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:10]([C:12]([F:15])([F:14])[F:13])=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: FC(F)(F)c1nc2cc(Br)ccc2[nH]1
Yield: 61.3 %

Procedure:
A mixture of 4-bromobenzene-1,2-diamine (3.0 g, 16.0 mmol), TFA (9.5 mL, 128.3 mmol) and aq. HCl (3 M, 32 mL) was heated to reflux overnight. The reaction mixture was concentrated and purified by column chromatography to afford the titled compound (2.60 g, 60%). LCMS: 265.0[M+1]+. 1HNMR (400 MHz, DMSO-d6): δ 7.52 (dd, J=8.8 Hz, 1.2 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 14.20 (br, 1H).