Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O)=[O:2].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([N:17]1[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]1)=[O:10])=[O:2]
Reactant: O=Cc1cccc(OCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
2-(3-formylphenoxy)acetic acid (48)/(1 eq), tert-butyl piperazine-1-carboxylate (1.5 eq) were taken in DCM to which HATU (1.3 eq) and DIPEA (2 eq) along with cat. DMAP were added and the traction mixture was stirred at rt for 16 h when TLC indicated completion of reaction. The reaction mixture was diluted with DCM and the organic extract was washed with water, dried and purified by column chromatography using silica gel (100-200 mesh) to afford the pure product (29%) as a colorless oil. LCMS: 91.65% (M++1-Boc).
Reaction SMILES: C(=O)=[O:2].CC(C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:18][C:19]1[N:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:27]([CH3:28])=[C:23]2[N:22]=[C:21]([CH3:36])[C:20]=1[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C1(C2ON2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:18][C:19]1[N:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:27]([CH3:28])=[C:23]2[N:22]=[C:21]([CH3:36])[C:20]=1[CH:37]([OH:2])[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: O=C=O
Reactant: CCOC(=O)Cc1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Reaction time: 0.33 h
Yield: 51.9 %

Procedure:
To a cold (−78° C. dry ice/acetone) stirred solution of 0.91 M KHMDS in THF (32 ml, 29.1 mmol) in additional THF (100 ml) was added ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (8.3 g, 21.94 mmol) in THF (100 ml), by dropwise addition over 30 min. The mixture was stirred for 20 min, and then a solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (7.45 g, 28.5 mmol) in THF (50 ml) was added. The reaction was stirred for 2.5 hrs at −78° C. The orange reaction mixture was quenched with sat. NH4Cl (100 mL), diluted with EtOAc (300 mL), washed with water (200 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to give a yellow solid. The crude residue was loaded onto a flash silica gel column and eluted with 10%-30% EtOAc in hexanes. Product fractions were pooled and concentrated under reduced pressure, affording ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (5.4 g, 11.40 mmol, 51.9% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.89-7.84 (m, 1H), 7.74 (dt, J=7.2, 1.6 Hz, 1H), 7.44-7.36 (m, 2H), 5.73 (s, 1H), 4.32-4.26 (m, 2H), 3.65 (br. s., 1H), 2.63 (s, 3H), 2.51 (s, 3H), 1.24 (t, J=7.02 Hz, 3H). LCMS (M+H)=394.06.
Reaction SMILES: [Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:5][N:6]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Yield: 90.5 %

Procedure:
A solution of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (50 mg, 0.144 mmol), ethyl 2-bromo-2-methylpropanoate (22 μL, 0.144 mmol) and diisopropylethylamine (76 μL, 0.433 mmol) in DMF (1 mL) was heated to 60° C. for 20 hours. The mixture was then concentrated, sonicated in ethyl ether until fully dissolved, and washed with 1N HCl. The mixture was extracted with diethyl ether (2×5 mL), and the combined organic extracts dried over sodium sulfate, filtered, and concentrated to provide ethyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a brown oil (60 mg, 91%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][N:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=[N:2][CH:3]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cncc2ccccc12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cncc3ccccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of isoquinoline-4-carboxylic acid (211 mg, 1.22 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (250 mg, 1.22 mmol), HATU (696 mg, 1.83 mmol) in anhydrous DMF (8 mL) is added DIPEA (302 μL, 1.83 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (51) as white solid (359 mg, 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:9]1[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]O)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:32]>C(O)C>[NH2:32][CH:7]=[C:6]([C:9]1[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: [NH4+]
Reactant: CCOC(=O)C(=CO)c1c(C(=O)OCC)ccn1Cc1ccc(OC)cc1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)C(=CN)c1c(C(=O)OCC)ccn1Cc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
A mixture of ethyl 2-{1-[(ethyloxy)carbonyl]-2-hydroxyethenyl}-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrrole-3-carboxylate (6.59 g), ammonium acetate (6.47 g) and ethanol (80 ml) was stirred at 60° C. under argon for 4 h, at room temperature over night then heated at 60° C. for a further hour. After cooling the solvent was evaporated and the residue partitioned between ethyl acetate and water, extracting the separated aqueous layer three times with ethyl acetate. The combined organic layers were washed with brine then dried (MgSO4), filtered and evaporated. The residue was stirred in n-hexane for 1 h and then the mixture was allowed to settle. The n-hexane was decanted off and the oil dried to afford the title compound as a brown oil (4.99 g).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1)[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[CH:13][CH:12]=1)[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CCc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(-c2nc3ccccc3[nH]2)cc1
Reaction time: 4 h

Procedure:
5.5 g. of o-phenylenediamine, 7.6 g. of p-ethylbenzoic acid and 40 g. of polyphosphoric acid were heated at 160°-180° C. under nitrogen gas current with stirring for 4 hours. The reaction mixture was diluted with 400 ml. of water and then neutralized with sodium carbonate. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate. 8.2 g. (73% of theory) of the product was obtained. M.P. 258°-258.4° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].[N:12]1[CH:17]=NC=N[CH:13]=1>CCO>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[N:10]1[CH:17]=[N:12][CH:13]=[N:11]1
Reactant: c1ncncn1
Reactant: NNc1cc(F)ccc1Br
Agent: Cl
Solvent: CCO
Product: Fc1ccc(Br)c(-n2cncn2)c1
Temperature: 90 °C
Yield: 61.3 %

Procedure:
Prepared according to the procedure described in J. Org. Chem., 1956, 21, 1037. A stirred mixture of (2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (31.9 g, 0.132 mol) and s-triazine (10.7 g, 0.132 mol; Aldrich) in EtOH (250 mL) was heated at 90° C. for 3 h. After cooling, the insoluble material was filtered off and the filtrate was concentrated. The residue was partitioned between CH2Cl2 (200 mL) and water (200 mL), and the aqueous phase was extracted once more with CH2Cl2 and the combined extracts were dried (MgSO4), filtered and concentrated to a red semi-solid which was triturated with hexanes to give 19.6 g of the title compound as an orange solid: HPLC rt=1.68 min. LC/MS m/z 242 (M+H); 1H NMR (CDCl3, 500 MHz) δ ppm 7.02–7.15 (1H, m, 5-CH), 7.29 (1H, dd, J=8.4, 2.9 Hz, 3-CH), 7.68 (1H, dd, J=8.8, 5.5 Hz, 6-CH), 8.10 (1H, s, 8-CH), 8.54 (1H, s, 7-CH); 13C NMR (CDCl3, 125.8 Hz) δ ppm 112.54, 112.57 (d, J=1.5 Hz, 1-C), 115.68, 115.88 (d, J=25 Hz, 3-CH), 118.07, 118.25 (d, J=22 Hz, 5-CH), 135.11, 135.18 (d, J=8.6 Hz, 6-CH), 137.43, 137.52 (d, J=11 Hz, 2-C), 144.4 (7-CH), 152.6 (8-CH), 160.95, 162.94 (d, J=251 Hz, 4-CF); HRMS (ESD) calcd for C8H6FBrN3 (M+H) 241.9727. found 241.9733 (δ 1.6 ppm); UV (MeOH) λmax 275 nm (ε 1.45×103); Anal. calcd for C8H5BrFN3: C, 39.69; H, 2.08; N, 17.36. found C, 39.63; H, 1.83; N, 17.22.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][C:8]=2[F:24])[CH2:2]1.Cl[C:26]1[N:35]=[C:34]2[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]2[CH:36]2[CH2:38][CH2:37]2)=[CH:28][C:27]=1[F:43].C[Si](C)(C)Cl.C(N(CC)CC)C>CN1CCCC1=O>[C:20]([NH:19][CH2:18][CH:16]1[O:15][C:14](=[O:23])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:3]3[CH2:4][N:1]([C:26]4[N:35]=[C:34]5[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]5[CH:36]5[CH2:38][CH2:37]5)=[CH:28][C:27]=4[F:43])[CH2:2]3)=[C:8]([F:24])[CH:9]=2)[CH2:17]1)(=[O:22])[CH3:21]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3CNC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CN(c2ccc(OCC3CN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)C3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.12 h

Procedure:
A suspension of 179 mg N-{(5S)-3-[4-(Azetidin-3-ylmethoxy)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (MW: 337.35, 0.31 mmol), 100 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-Naphthyridine-3-carboxylic acid (MW: 282.66, 0.25 mmol), 0.134 ml trimethylchlorosilane (MW: 108.64, d=0.859, 1.059 mmol) and 0.197 ml triethylamine (MW: 101.19, d=0.726, 1.41 mmol) in 2 ml N-methyl-pyrrolidin-2-one was heated under stirring in a micro wave oven at 150° C. for 7 min. The N-methyl-pyrrolidin-2-one was evaporated, the residue was purified by chromatography. Yield: 82 mg, 40%. MS: 583.5 (M+H)+, Method ESI+. Molecular Weight=584
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH2:17][OH:18])=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH:17]=[O:18])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCCCC1CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ncccc1CN1CCCCC1CC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 4.2 g of pyridine-sulfurtrioxide complex dissolved in dimethyl sulfoxide (DMSO) was added dropwise into a solution of 3 g of 2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]-1-ethanol and 7.3 ml of triethylamine dissolved in 15 ml of DMSO, while keeping the bulk temperature at 20° C. or less. After completing the dropwise addition, the mixture was stirred at room temperature for one hour. An aqueous sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the solvent was evaporated. The residue was purified by silica gel chromatography (methanol), to give 2.5 g of a red brown oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]([C:14]3[S:15][C:16]([CH3:20])=[C:17]([NH2:19])[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]([C:14]3[S:15][C:16]([CH3:20])=[C:17]([NH:19][C:29]([NH:28][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:30])[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1sc(C(=O)OCc2ccc3c(c2)OCO3)cc1N
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1sc(C(=O)OCc2ccc3c(c2)OCO3)cc1NC(=O)NCc1ccccc1
Reaction time: 72 h
Yield: 66 %

Procedure:
5-Methyl-4-amino-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester from Step 2 (0.15 g, 0.5 mmol) was dissolved in hot 1,4-dioxane (6-8 mL) under an inert atmosphere, stirred, and treated with benzyl isocyanate (0.07 g, 0.5 mmol). After 72 hours at room temperature, the mixture was diluted with diethyl ether (50 mL). After another hour the precipitate was filtered off, rinsed with ether, and dried to afford 0.14 g of 4-(3-benzyl-ureido)-5-methyl-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester; mp 216-217° C.
Reaction SMILES: Br[C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li:20])CCC>CCCCCCC>[Li:20][C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2c1ccc1ccccc12
Reactant: [Li]CCCC
Solvent: CCCCCCC
Product: [Li]c1cccc2c1ccc1ccccc12

Procedure:
2.1 Grams (8.3 mmols) of a 1-bromophenanthrene was dissolved in 43 ml of heptane, 5.3 ml (1.6 mols/l, 8.5 mmols) of butyl lithium was added thereto at room temperature to obtain a 1-lithiophenanthrene, which was cooled down to −5° C., followed by the addition of 2.2 g (5.2 mmols) of the above DBBF. The mixture was stirred for one hour and to which was further added the THF at a temperature of not higher than 0° C. The mixture was stirred at this temperature for 2 hours. The conversion was 99%.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:23])[N:8]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[N:9]=[C:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:11]=1[OH:12])=[O:5])C.[NH2:24][C:25]1[CH:29]=[C:28]([Cl:30])[S:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>>[Cl:30][C:28]1[S:27][C:26]([S:31](=[O:33])(=[O:32])[NH2:34])=[C:25]([NH:24][C:4]([C:6]2[C:7](=[O:23])[N:8]([CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])[N:9]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:11]=2[OH:12])=[O:5])[CH:29]=1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CCOC(=O)c1c(O)c(-c2cccs2)nn(CCC(C)C)c1=O
Product: CC(C)CCn1nc(-c2cccs2)c(O)c(C(=O)Nc2cc(Cl)sc2S(N)(=O)=O)c1=O
Temperature: 160 °C
Reaction time: 0.17 h

Procedure:
The ester (13a) made by Method 4 (86 mg, 0.26 mmol) and 3-Amino-5-chloro-thiophene-2-sulfonic acid amide (14b) (54 mg, 0.26 mmol) were mixed in a reaction vial and stirred in a preheated oil-bath at 160° C. for 10 mins to give the corresponding 5-hydroxy-2-(3-methyl-butyl)-3-oxo-6-thiophen-2-yl-2,3-dihydro-pyridazine-4-carboxylic acid (5-chloro-2-sulfamoyl-thiophen-3-yl)-amide (15a) as a dark yellow solid which was used directly in next step without further purification. LC-MS (ESI+): m/e=503.09 [M+1]+(exact ms: 502.02).
Reaction SMILES: [CH2:1]([CH:3]1[O:20][C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6][N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:4]1)[CH3:2].Cl.O1CCOCC1>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([CH:3]1[O:20][C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:4]1)[CH3:2]
Reactant: CCC1CN(c2ccccn2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCC1CN(c2ccccn2)CC2(CCNCC2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
Tert-butyl 10-ethyl-8-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (480 mg, 1.33 mmol) was dissolved in dichloromethane (5 mL) at 0° C. and treated dropwise with HCl in dioxane (2.65 mL of 4 M, 10.6 mmol). The reaction was then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with dichloromethane (50 mL) and saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer extracted with dichloromethane (3×20 mL). The aqueous layer was further diluted with 25 mL of 1 N NaOH and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide 10-ethyl-8-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane (345 mg, 1.32 mmol, 99%) an orange-colored oil. ESI-MS m/z calc. 261.2. Found 262.3 (M+1)+; Retention time: 0.3 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 8.08 (dd, J=4.9, 1.4 Hz, 1H), 7.50 (ddd, J=8.8, 7.1, 2.0 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.60 (dd, J=6.6, 5.0 Hz, 1H), 4.17 (t, J=11.3 Hz, 2H), 3.58-3.54 (m, 2H), 2.96-2.84 (m, 1H), 2.81-2.71 (m, 1H), 2.71-2.65 (m, 2H), 2.55 (d, J=12.9 Hz, 1H), 2.40 (dd, J=12.6, 11.0 Hz, 1H), 1.93 (d, J=13.9 Hz, 1H), 1.59-1.38 (m, 5H), 0.96 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([O:4][CH2:5][CH2:6][O:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([O:24]C)[N:14]2[CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:10]([NH2:26])[N:9]=1)[CH3:3].Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:26][C:10]1[N:9]=[C:8]([O:7][CH2:6][CH2:5][O:4][CH:2]([CH3:3])[CH3:1])[N:16]=[C:15]2[C:11]=1[NH:12][C:13](=[O:24])[N:14]2[CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: COc1nc2c(N)nc(OCCOC(C)C)nc2n1CC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)OCCOc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
To a solution of 2-({2-[(1-methylethyl)oxy]ethyl}oxy)-8-(methoxy)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (165 mg) in dry methanol (17 ml) was added 4.0M hydrogen chloride in 1,4-dioxane (2.95 ml) in one go. The reaction was left to stir at room temperature for 5 hours. The reaction was neutralised by the addition of 2.0M sodium hydroxide solution and concentrated in vacuo to give an off-white solid. The solid was triturated in water, and filtered under vacuum, washing with more water, to give an off-white solid (120 mg).
Reaction SMILES: [Br:1][C:2]1[C:25]([Br:26])=[CH:24][C:5]2[N:6]([CH2:22][CH3:23])[C:7]([N:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)=[N:8][C:4]=2[C:3]=1[C:27]#[N:28].[ClH:29].C(OCC)C>O1CCOCC1>[ClH:29].[Br:1][C:2]1[C:25]([Br:26])=[CH:24][C:5]2[N:6]([CH2:22][CH3:23])[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[C:3]=1[C:27]#[N:28]
Reactant: CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c(C#N)c(Br)c(Br)cc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCn1c(N2CCNCC2)nc2c(C#N)c(Br)c(Br)cc21
Temperature: 25 °C

Procedure:
tert-butyl 4-(5,6-dibromo-4-cyano-1-ethyl-1H-1,3-benzodiazol-2-yl)piperazine-1-carboxylate (Method 8A) (900 mg, 2.18 mmol) was dissolved in 1,4-dioxane (5.0 ml) and 4M HCl in dioxane (2.0 ml) was added. The mixture was stirred at room temperature until the reaction was complete (18 hrs) by LC/MS. Diethyl ether (10.0 ml) was added, product was filtered off, washed with diethyl ether and dried to afford 5,6-dibromo-1-ethyl-2-(piperazin-1-yl)-1H-1,3-benzodiazole-4-carbonitrile hydrochloride (820 mg, 1.8 mmol) 1H NMR (600 MHz, DMSO) δ 9.47 (s, 2H), 8.24 (s, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.67-3.62 (m, 4H), 3.29 (s, 4H), 1.32 (t, J=7.2 Hz, 3H), m/z 413.9; rt 2.2.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]([CH2:11]Br)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]([NH2:16])(=[S:15])[CH3:14].C1C=CC=CC=1>C(N(CC)CC)C>[OH:1][N:2]=[C:3]([C:9]1[N:16]=[C:13]([CH3:14])[S:15][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(=O)CBr
Reactant: CC(N)=S
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NO)c1csc(C)n1
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (22.0 g.), thioacetamide (7.5 g.) and benzene (100 ml.) was refluxed for 3 hours. After cooling triethylamine (10 g.) was added thereto and the mixture was stirred for 1 hour. An insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (8.6 g.). This substance was subjected to column chromatography on silica gel (80 g.) using benzene as developing solvent. Firstly the eluate containing anti isomer was eluted, collected and concentrated to give ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (2.5 g.), mp 90° to 92° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn].[Cl-].[CH2:26]([C:33]1[O:34][C:35]([CH3:39])=[C:36]([CH3:38])[CH:37]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.CN(C)C=O>[CH2:26]([C:33]1[O:34][C:35]([CH3:39])=[C:36]([CH3:38])[C:37]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(Cc2ccccc2)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Sn]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
At ambient temperature, to a stirred suspension containing 3,5-diisopropyl-p-anisic acid (1.95 g, 8.23 mmol, RN-1 17439-59-5) and oxalyl chloride (0.8 mL, 9.20 mmol) in CH2Cl2 (22.5 mL) was added N,N-dirnethylformamide (2 drops). After 2h, the reaction was cooled to −78° C. To the reaction was added tin (TV) chloride (1.05 mL) followed by a solution of 2-benzyl4,5-dimethylfuran (1.8 g, 9.68 mmol) in CH2Cl2 (10.0 mL). After the additions were complete, the reaction was allowed to warm to ambient temperature and stirred for 24 h. The reaction was quenched into crushed ice (100 g), diluted with sat. aq. KH2PO4 (100 mL) and extracted with ether. The combined ethereal extracts were washed with sat aq. NaHCO3 (2×60 mL), with brine (1×60 ml), dried (Na2SO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 1% EtOAc/pet. ether to give 2.07 g, (62%) of the title compound as an oil; 1H NMR (DMSO-d6)67 1.17 (d, 12 H), 1.81 (s, 3 H), 2.19 (s, 3 H), 3.29 (septet, 2 H), 3.74 (s, 3 H), 3.84 (s, 2 H), 7.01-7.03 (m, 2 H), 7.16-7.25 (m, 3 H), 7.47 (s,2H). mass spectrum (EI), m/z 404 (M+). Anal. Calcd. for C27H32O3 .0.6H2O: C, 78.07; H, 8.06; N, 0.00. Found: C, 78.04; H, 7.93; N, −0.02.