Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH:11][C:10]1[C:9](=[O:19])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:20]([Cu])#[N:21]>CN1C(=O)CCC1.O>[O:19]=[C:9]1[C:10]2[NH:11][C:12]3[C:4](=[CH:3][C:2]([C:20]#[N:21])=[CH:14][C:13]=3[C:15]([F:18])([F:17])[F:16])[C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: N#C[Cu]
Reactant: O=C1CCCc2c1[nH]c1c(C(F)(F)F)cc(Br)cc21
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c2[nH]c3c(c2c1)CCCC3=O
Temperature: 210 °C
Reaction time: 15 h
Yield: 79.9 %

Procedure:
6-Bromo-8-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-one (600 mg, 1.8 mmol) and CuCN (480 mg, 5.4 mmol) were mixed together in NMP (6 mL) and stirred at 210° C. under N2 atmosphere for 15 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and filtered through a pad of Celite®. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to obtain the crude material which was purified by washing with 10% EtOAc-hexane to afford the title compound as a pale brown solid (400 mg, 80%). 1H NMR (200 MHz, CDCl3, δ in ppm) 9.26 (bs, 1H), 8.22 (s, 1H), 7.86-7.90 (m, 1H), 3.09 (t, J=12.0 Hz, 2H), 2.77-2.70 (m, 2H), 2.40-2.31 (m, 2H). IR cm−1 2240 (CN)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[C:21]1([N:27]=[C:28]=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[C:21]1([NH:27][C:28]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:6]=[C:7]([C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[O:15])[C:8]3[S:13][CH:12]=[CH:11][C:9]=3[N:10]=2)=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: S=C=Nc1ccccc1
Reactant: NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cccs1)c1nc(NCCNC(=S)Nc2ccccc2)nc2ccsc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A solution of 2-(2-aminoethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (50 mg, 0.16 mmol) in anhydrous DMF (1 mL) was treated with phenyl isothiocyanate (33 mg, 0.25 mmol), shaken at room temperature for 2 h, poured into water (20 mL) and the resulting yellow precipitate was filtered and dried in vacuo to give the title compound (44 mg, 61%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][O:6][C:5]2([CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9][CH2:8]2)[O:4][CH2:3]1.C[N:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=C([N+]([O-])=O)C1=O.N>CO>[CH3:1][C:2]1([CH3:16])[CH2:7][O:6][C:5]2([CH2:14][CH2:13][CH2:12][C:11]3=[N:18][CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:10]3[CH2:9][CH2:8]2)[O:4][CH2:3]1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CC1(C)COC2(CCCC(=O)CCC2)OC1
Agent: N
Solvent: CO
Product: CC1(C)COC2(CCCc3ncc([N+](=O)[O-])cc3CC2)OC1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
A mixture of 3,3-dimethyl-1,5-dioxaspiro[5.7]tridecan-10-one (compound of formula (Ca)) (1.32 g, 5.83 mmol), 1-methyl-3,5-dinitro-1H-pyridin-2-one (compound of formula (Cb)) (1.07 g, 5.3 mmol) and 7N ammonia solution in methanol (45 mL) was heated at 80° C. in sealed vessel overnight. The solvent was evaporated and the residue was dissolved in dichloromethane (DCM). The soluble portion was concentrated and purified by flash chromatography on silica gel (hexane/ethyl acetate, 3:1) to give the compound of formula (Cc), 5′,5′-dimethyl-3-nitro-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane] (1.5 g, 92.5%); 1H NMR (DMSO-d6, 300 MHz) 9.09 (s, 1H), 8.40 (s, 1H), 3.37 (m, 4H), 3.02 (t, 2H), 2.89 (m, 2H), 2.02 (m, 2H), 1.77 (m, 2H), 1.58 (t, 2H), 0.86 (d, 6H) ppm; MS (ES) 306.99 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[C:14]([C:18]1[CH:19]=[C:20]2[C:25](=O)[O:24][C:22](=[O:23])[C:21]2=[CH:27][CH:28]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:19]=[C:20]2[C:21](=[CH:27][CH:28]=1)[C:22](=[O:23])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:25]2=[O:24])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: COC(=O)C(CN)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2ccc(C(C)(C)C)cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5-t-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.14 g, 14%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.50 g, 2.64 mmol) and 4-t-butylphthalic anhydride (0.70 g, 3.43 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [CH3:1]I.[H-].[Na+].[CH2:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:36]([C:37]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:17](=[O:56])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:57]([OH:60])[CH2:58][CH3:59])[CH:15]=2)[N:10]=1)[CH2:6][CH2:7][CH3:8]>C1COCC1>[CH2:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[N:36]([C:37]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:35]=[N:34][N:33]=3)=[CH:24][CH:25]=2)[C:17](=[O:56])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:57]([O:60][CH3:1])[CH2:58][CH3:59])[CH:15]=2)[N:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CI
Reactant: CCCCc1nc2ccc(C(O)CC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(C(CC)OC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.556 ml of methyl iodide in 5.0 ml of THF is added 0.071 g of 60% sodium hydride followed by 0.657 g of 2-butyl-6-(1-hydroxypropyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]4(3H)-quinazolinone. The reaction is stirred for 16 hours at room temperature, then quenched with saturated NH4Cl solution and extracted with ether. The organics are dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 1:5 ethyl acetate/hexanes to provide 0.59 g of the desired product as a white solid. FAB MASS SPEC 751(M+H) .
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].Br[C:9]1[S:10][C:11]([C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:16])=[C:12]([CH3:14])[N:13]=1>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][NH:17][C:15]([C:11]2[S:10][C:9]([N:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]3=[O:7])=[N:13][C:12]=2[CH3:14])=[O:16])=[CH:24][CH:23]=1
Reactant: O=c1cccc[nH]1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Product: Cc1nc(-n2ccccc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 45 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 2-bromo-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 45% yield: mp 170-172° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.80-8.77 (m, 1H), 7.47-7.42 (m, 1H), 7.34-7.28 (m, 2H), 7.03 (t, J=8.6 Hz, 2H), 6.75 (d, J=9.4 Hz, 1H), 6.44 (d, J=6.9 Hz, 1H), 6.06 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 2.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.9, 162.1, 160.6, 153.2, 152.5, 139.9, 133.5, 131.2, 129.6, 129.5, 122.9, 121.3, 115.8, 115.5, 107.8, 43.4, 17.3; (ES+) m/z 344.2 (M+1).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([C:28]([OH:30])=O)=[C:8]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([B:18]3[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]3)[C:13]=2[CH3:27])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[C:28](=[O:30])[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([B:18]4[O:19][C:20]([CH3:26])([CH3:25])[C:21]([CH3:23])([CH3:24])[O:22]4)[C:13]=3[CH3:27])[CH2:10][C:8]=2[N:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1c(NCc2nc(C(C)(C)C)sc2C(=O)O)cccc1B1OC(C)(C)C(C)(C)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a mixture of 2-tert-butyl-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)methyl)thiazole-5-carboxylic acid 109e (430.37 mg, 0.0010000 mol) in methylene chloride (10 mL) was added N,N-diisopropylethylamine (870.91 uL, 5.0 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium hexafluorophosphate (1.1407 g, 0.0030000 mol). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with water. The organic layer was separated, and dried with anhydrous magnesium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified on silica eluted with a gradient of 0 to 20% Ethyl acetate in Heptane to afford 2-tert-butyl-5-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 109f (163 mg, 40%).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12](Br)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:28]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]1)#[CH:27].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12]([C:27]#[C:26][C:28]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1(O)CCCC1
Reactant: OC1(C#Cc2ncc(Br)cc2Cc2ccccc2)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2cnc(C#CC3(O)CN4CCC3CC4)c(Cc3ccccc3)c2)CCCC1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
100 mg of 3-(3-benzyl-5-bromo-2-pyridyl)ethynyl-3-quinuclidinol (Example 22-a), 55 mg of 1-ethynylcyclopentanol, 50 mg of tetrakis (triphenylphosphine)palladium(0), 10 mg of cuprous iodide and 1 ml of triethylamine were mixed in 5 ml of N,N-dimethylformamide, followed by stirring in an oil bath kept at 80° C. for one hour. An aqueous sodium carbonate solution was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 10% methanol/ethyl acetate, to give 93 mg of the target compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC#N>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:22]
Reactant: C1CNCCNC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CCCN1CCCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
Sodium carbonate (2.12 g) was added to the solution of homopiperazine (10.0 g; 5 eq.) and ethyl 4-bromobutyrate (3.90 g; 1 eq.) in CH3CN (120 mL). The reaction was stirred at room temperature for 6 h. The reaction mixture was filtered thru a celite pad. The filtrate was concentrated. The remaining residual was dissolved in CHCl3 (120 mL), washed by H2O (50 mL×3) and brine (50 mL×1), dried by Na2SO4 and concentrated to give 4-[1,4]diazepan-1-yl-butyric acid ethyl ester (3.8 g), which was carried on for the next step without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:50][C:51]1[CH:52]=[CH:53][C:54]2[O:59][CH2:58][CH2:57][N:56]([NH2:60])[C:55]=2[CH:61]=1>CN(C=O)C>[F:50][C:51]1[CH:52]=[CH:53][C:54]2[O:59][CH2:58][CH2:57][N:56]([NH:60][C:23]([C:20]3[CH:21]=[N:22][C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=4)=[N:18][CH:19]=3)=[O:25])[C:55]=2[CH:61]=1
Reactant: NN1CCOc2ccc(F)cc21
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
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: O=C(NN1CCOc2ccc(F)cc21)c1cnc(-c2cccc(F)c2)nc1
Yield: 22 %

Procedure:
DIPEA (174 μL) is added to a mixture of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (218 mg), HATU (380 mg) and 6-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-ylamine (220 mg) in DMF (15 mL) and then heated at 800 C. overnight. The reaction mixture is concentrated in vacuo and the residue is purified by silica gel column chromatography eluting with 30% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-amide (81 mg). MS: 369 (M+H); 1H NMR (300 MHz, DMSO-D6): δ 11.05 (s, 1H), 9.35 (s, 2H), 8.32 (dd, 1H), 8.18 (dd, 1H), 7.65 (m, 1H), 7.5 (m, 1H), 6.8-6.7 (m, 2H), 6.52-6.45 (m, 1H), 4.36-4.33 (m, 2H), 3.65 (m, 2H). IC50=12 nM.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:3]2[N:9]=[N:10][N:11]=[C:4]2[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cccc2nnnn12
Yield: 25.4 %

Procedure:
2,5-Dibromopyridine (1.0 g, 4.2 mmol), sodium azide (412 mg, 6.3 mmol) and NH4Cl (339 mg, 6.3 mmol) were heated in 20 mL DMF to 100° C. for 16 h. The mixture was diluted with 150 mL EtOAc, washed with H2O (2×) and sat'd NaCl then dried over Na2SO4 and concentrated. Flash chromatography (30 g silica, 2/1 hexane/EtOAc eluant) afforded 212 mg (25%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2/[C:12](=[O:35])[C:13]3[C:18]([CH2:19]/2)=[C:17]([CH2:20][N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:16]([OH:34])=[CH:15][CH:14]=3)=[CH:2]1.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:36].[ClH:36].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2/[C:12](=[O:35])[C:13]3[C:18]([CH2:19]/2)=[C:17]([CH2:20][N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[C:16]([OH:34])=[CH:15][CH:14]=3)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2C/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Cc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of tert-butyl (E)-4-({2-[(1H-indol-3-yl)methylene]-5-hydroxy-1-oxo-2,3-dihydro-1H-inden-4-yl}methyl)piperazine-1-carboxylate (0.030 g, 0.063 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 1 hour. The mixture was azeotroped twice with toluene under reduced pressure, and the residual solid was suspended in methylene chloride and thereby washed to obtain (E)-2-[(1H-indol-3-yl)-methylene]-5-hydroxy-4-(piperazin-1-ylmethyl)-2,3-dihydro-1H-inden-1-one dihydrochloride (0.024 g, 85%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH:32]1(CCCC(O)=O)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:5]1([CH2:4][CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:6][CH2:7][CH2:2][CH2:3][CH2:32]1
Reactant: O=C(O)CCCC1CCCCC1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCC2CCCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-cyclohexyl-butyric acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH:15]([CH3:17])[CH3:16])[N:11]([CH3:18])[S:10]2(=[O:20])=[O:19])C=CC=CC=1.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl>[Cl:24][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH:15]([CH3:17])[CH3:16])[N:11]([CH3:18])[S:10]1(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)C1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Solvent: ClCCl
Product: CC(C)C1C(=O)N(CCl)S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 2-phenylthiomethyl-4-isopropyl-5-methyl -1,2,5-thiadiazolidin-3-one 1,1-dioxide (6.38 g, 23.31 mmol) in 150 ml of methylene chloride was added sulfuryl chloride (2.5 ml, 30.4 mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo and the residue triturated in hexane to afford 4.32 g (88%) of 2-chloromethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =isopropyl; R3 =methyl; X'=Cl) as a solid, m.p. 118.5°-119.5° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([NH:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([OH:15])[CH2:13][OH:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[S:22]1[C:26]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1.CN1C(=O)CCC1>O>[S:22]1[C:26]2[CH:27]=[C:28]([NH:31][C:2]3[CH:9]=[C:8]([NH:10][C@@H:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@H:12]([OH:15])[CH2:13][OH:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=3)[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: N#Cc1cnc(Cl)cc1N[C@@H](c1ccccc1)[C@H](O)CO
Reactant: Nc1ccc2ncsc2c1
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(Nc2ccc3ncsc3c2)cc1N[C@@H](c1ccccc1)[C@H](O)CO
Temperature: 150 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of 6-chloro-4-((1S,2S)-2,3-dihydroxy-1-phenylpropylamino)nicotinonitrile (0.108 g, 0.356 mmol), benzo[d]thiazol-6-amine (0.187 g, 1.244 mmol) and NMP (1.422 mL) was stirred at 150° C. for 1 hour in a microwave reactor. The vessel was cooled to room temperature, diluted with water and filtered. Following drying on a buchner funnel, 6-(benzo[d]thiazol-6-ylamino)-4-((1S,2S)-2,3-dihydroxy-1-phenylpropylamino)nicotinonitrile (0.122 g, 0.292 mmol, 82% yield) was collected as a yellowish solid. LC-MS (m/z, M+1=418), Waters sunfire 4.6×50 mm C18 Sum 4 min/1 min hold time 0-100% (A-B) A=10% MeOH-90% water-0.1% TFA, B=90% MeOH-10% water-0.1% TFA RT=2.06.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[Br:13]Br>O1CCOCC1.N#N.ClC(Cl)C>[Br:13][C:6]1[N:2]([CH3:1])[C:3]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:5]=1
Reactant: BrBr
Reactant: Cn1ccnc1N1CCOCC1
Agent: N#N
Solvent: C1COCCO1
Solvent: CC(Cl)Cl
Product: Cn1c(Br)cnc1N1CCOCC1
Temperature: 60 °C
Yield: 31 %

Procedure:
4-(1-Methyl-1H-imidazol-2-yl)-morpholine (Nagarajan, K. et al. Indian J. Chem. Sect. B, 21, 10, 1982, 949–952) (1.02 g, 6.08 mmol) was dissolved in 35 mL of 1,4-dioxane under and N2 atmosphere. The mixture was heated to 60° C. and a solution of 0.34 mL (6.4 mmol) of Br2 in 10 mL of dichloroethane was added slowly. The mixture was heated for 1 h, then cooled. The mixture was concentrated and the residue was partitioned between 6.5 mL of 1 N NaOH and 25 mL of EtOAc. The NaOH solution was extracted twice more with EtOAc, and the extracts were washed with NaHCO3 and brine, dried with Na2SO4, filtered, concentrated, and chromatographed (0–4% MeOH (0.5% NH4OH) in CH2Cl2) to provide 464 mg of 4-(5-bromo-1-methyl-1H-imidazol-2-yl)-morpholine.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[C:12]#[N:13].C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.Cl>O1CCCC1>[C:12]([C:11]1[CH:14]=[C:7]([B:21]([OH:22])[OH:20])[CH:8]=[CH:9][C:10]=1[O:15][CH3:16])#[N:13]
Reactant: COc1ccc(Br)cc1C#N
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1C#N
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
16.23 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 5.00 g of 5-bromo-2-methoxybenzonitrile in 90 ml of dry tetrahydrofuran at −78° C. After stirring at this temperature for 45 minutes, 6.71 ml of triisopropylborate are added, and the mixture is then slowly warmed to −20° C. 50 ml of 1N HCl are added to the reaction mixture. The phase is separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether each time. The combihled organic phases are dried with sodium sulphate, filtered and evaporated. The remaining oil is mixed with pentane, and the precipitate which separates out is filtered off with suction and washed once with a little dichloromethane. Drying under high vacuum affords the title compound as a white solid. Rt=2.74.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]([Cl:22])[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2ccccc2Cl)nc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CS(=O)(=O)c1ccc(C(Cl)=Nc2ccccc2Cl)nc1

Procedure:
N-(2-chlorophenyl)-5-(methylsulfonyl)picolinamide 5 (1.26 g, 0.0040 mol) in anhydrous benzene (20 mL) was added to PCl5 (1.26 g, 0.0060 mol) and the mixture was heated to reflux overnight. The solvent was removed and the residue was further dried under high vacuum. Crude N-(2-chlorophenyl)-5-(methylsulfonyl)picolinimidoyl chloride 6 was obtained as a yellow solid (1.60 g). The compound 6 was dissolved into anhydrous THF (30 mL) and the reaction was cooled down to 0° C. and hydrazine hydrate (9.0 mL) was added. The reaction was kept at 0° C. for 10 min and warmed to ambient temperature in 0.5 h. The solvent was removed and the residue was purified by column chromatography (eluting with hexane and ethyl acetate 1:1) to give N′-(2-chlorophenyl)-5-(methylsulfonyl) picolinimidohydrazide 7 as a yellow solid. Yield: 1.22 g, 92.0%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl.[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][Cl:22])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:22].[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])[CH2:16][CH2:15]1
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(OCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 95 %

Procedure:
5-hydroxy-2-nitrobenzaldehyde (1.00 g, 5.98 mmol) was dissolved in DMF (15.0 mL) and the solution was added with morpholinoethyl chloride hydrochloride (1.11 g, 5.98 mmol) and potassium carbonate (1.65 g, 12.0 mmol), followed by heating at 80° C. for 40 minutes. The reaction mixture was concentrated under reduced pressure, added with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2.00 mL) and added with 4 mol/L hydrogen chloride-methanol solution (2.00 mL), followed by stirring at 0° C. The precipitated crystal was collected by filtration to obtain 5-(2-morpholinoethoxy)-2-nitrobenzaldehyde hydrochloride (1.80 g, 95%).