Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][C@@H:18]4[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]4)[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:28][C:29]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:30]=1[NH2:31].C1(C)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(C)(C)C>[F:28][C:29]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:30]=1[NH:31][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][C@@H:18]4[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]4)[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC1(C)OC[C@@H](CCOc2ccc3c(c2)C(=O)c2ccc(Cl)cc2CC3)O1
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@@H](CCOc2ccc3c(c2)C(=O)c2ccc(Nc4ccc(F)cc4F)cc2CC3)O1
Yield: 45 %

Procedure:
In accordance with general method AA, 0.70 g (1.8 mmol) of 2-chloro-7-(2((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one (360, 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-, 4′-,6′-triisopropyl-biphenyl, 0.60 g (6.2 mmol) of Na—O-tert-butylate, 5 ml of toluene and 1 ml of tert-BuOH are used. Reaction time: 1 h. Purification is carried out via flash chromatography (SiO2, hexane/ethyl acetate 7+3). Yield: 45%;
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]#[C:17][CH3:18])[CH2:13][C:14]#[N:15])=[CH:8][CH:7]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]#[C:17][CH3:18])[CH2:13][C:14]2[NH:25][N:24]=[N:23][N:15]=2)=[CH:8][CH:7]=1
Reactant: CC#CC(CC#N)c1ccc(OCc2ccccc2C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(Cc1nnn[nH]1)c1ccc(OCc2ccccc2C)cc1
Temperature: 110 °C
Reaction time: 48 h
Yield: 2.9 %

Procedure:
To a solution of 23.3 (200 mg, 0.51 mmol) in DMF (5 mL) was added sodium azide (35 mg, 0.54 mmol) and ammonium chloride (29 mg, 0.54 mmol). The solution was stirred at 110° C. for 48 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (2×25 mL). The combined organic layers were concentrated under reduce pressure, and the resulting residue was purified via HPLC to yield 5 mg (3%) of 5-{2-[4-(2-Methyl-benzyloxy)-phenyl]-pent-3-ynyl}-1H-tetrazole (23) as a film. LC/MSD m/e: 333.1 (M+H). 1H NMR (400 MHz) (acetone-d6) δ 7.45 (1H, m), 7.34 (2H, m), 7.25 (3H, m), 7.00 (2H, m), 5.11 (2H, s), 4.17 (1H, m), 3.37 (2H, d, J=7 Hz), 2.39 (3H, s), 1.79 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[C:25](Cl)(=[O:35])[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1>>[OH:24][C:13]1([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:14][CH2:15][CH:10]([N:8]2[CH2:9][CH:6]([NH:5][C:3]([CH2:2][NH:1][C:25]([C:26]3[CH:34]=[CH:33][C:32]4[O:31][CH2:30][O:29][C:28]=4[CH:27]=3)=[O:35])=[O:4])[CH2:7]2)[CH2:11][CH2:12]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4ccc5c(c4)OCO5)C3)CC2)cn1

Procedure:
The title compound was prepared as yellow solid from coupling of 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, and piperonoyl chloride (Aldrich) using the procedure described in Example 18.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[Cl:8][C:9]1[C:14]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][C:12]([N:20]=[C:21]=[S:22])=[C:11]([F:23])[CH:10]=1>O1CCOCC1>[Cl:8][C:9]1[C:14]([O:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][C:12]([N:20]=[C:21]2[N:4]3[CH2:5][CH2:6][CH2:7][CH:3]3[CH2:2][S:22]2)=[C:11]([F:23])[CH:10]=1
Reactant: CS(=O)(=O)Oc1cc(N=C=S)c(F)cc1Cl
Reactant: OCC1CCCN1
Solvent: C1COCCO1
Product: CS(=O)(=O)Oc1cc(N=C2SCC3CCCN23)c(F)cc1Cl

Procedure:
10 g 2-(Hydroxymethyl)pyrrolidine and 27.6 g 4-chloro-2-fluoro-5-methylsulphonyloxyphenyl isothiocyanate were heated under reflux for 4 hours in 200 ml dioxane. The solvent was removed and the residue heated with 50 ml 48% hydrobromic acid. After cooling, the reaction solution was added to an ice/water mixture, neutralised with 40% caustic soda and extracted with methylene chloride. After drying and concentrating, the crude product was purified by column chromatography (silica gel, eluent; hexane/ethyl acetate).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30](B(O)O)[CH:31]=2)[CH:26]=[CH:25]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:30]4[CH:31]=[C:32]5[C:27]([CH:26]=[CH:25][NH:24]5)=[CH:28][CH:29]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: OB(O)c1ccc2cc[nH]c2c1
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: O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3ccc4cc[nH]c4c3)c(C)sc2n1
Temperature: 120 °C
Yield: 16.9 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (16.6 mg, 0.038 mmol) was dissolved in 1,4-dioxane (0.6 mL) and water (0.2 mL). 1H-Indol-6-ylboronic acid (9.28 mg, 0.058 mmol), tetrakis(triphenylphosphine)palladium(0) (4.44 mg, 3.84 μmol) and potassium carbonate (10.63 mg, 0.077 mmol) were then added and the mixture heated in a microwave at 120° C. for 15 min. The crude mixture was purified by MDAP (acidic conditions) and then further purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, to give the title compound (3 mg). LCMS (A) m/z: 468 [M+1]+, Rt 1.45 min (acidic).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:12][C:13]1[C:14]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]2[CH3:39])=[N:15][C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:17][C:18]=1[CH2:19][OH:20]>ClCCl>[CH3:12][C:13]1[C:14]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]2[CH3:39])=[N:15][C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:17][C:18]=1[CH2:19][O:20][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1c(CO)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 108.1 %

Procedure:
Acetyl chloride (2.71 μl, 39.6 μmol) and triethylamine(20 μl, 142.6 μmol) were added to a suspension of 5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (10 mg, 26.4 μmol) in dichloromethane(1 ml) and stirred for 1 day at a room temperature. The reaction mixture was purified with a silica gel column chromatography (ethylacetate/n-hexane=1/1) to give 12 mg of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH2:12]1[CH2:17][O:16][CH:15]=[CH:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH:15]1[CH2:14][CH2:13][CH2:12][CH2:17][O:16]1)[N:6]=[CH:5]2
Reactant: Fc1cc(Br)cc2cn[nH]c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(Br)cc2cnn(C3CCCCO3)c12
Reaction time: 8 h

Procedure:
To a mixture of 5-bromo-7-fluoro-1H-indazole (9.3 g, 43.26 mmol) and DHP (4.36 g, 51.9 mmol) in dry dichloromethane (100 mL), was added PTSA (424 mg, 2.16 mmol) at room temperature. The resulting mixture was stirred overnight. Work-up: saturated aqueous NaHCO3 (30 mL) was slowly added to the reaction mixture. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜10% EtOAc in petroleum ether) to give 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as a light yellow solid. (7.8 g). 1H NMR (300 MHz, CDCl3): δ 7.98 (s, 1H), 7.64 (s, 1H), 7.22 (dd, 1H), 5.84 (dd, 1H), 4.07-4.02 (m, 1H), 3.78-3.71 (m, 1H), 2.62-2.53 (m, 1H), 2.16-2.07 (m, 2H), 1.79-1.71 (m, 2H), 1.63-1.33 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([OH:37])=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([OH:37])=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)O)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)O)OC(C)(C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([O:3]C)=[O:2]>O.O1CCOCC1>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:13]=[CH:14][C:15]([I:18])=[CH:16][CH:17]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([OH:3])=[O:2]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(I)cc2)C[C@@H]2CC[C@H]1N2C
Solvent: O
Solvent: C1COCCO1
Product: CN1[C@H]2CC[C@@H]1[C@@H](C(=O)O)[C@@H](c1ccc(I)cc1)C2

Procedure:
A round bottom flask filled with a solution of 100 mg of 2β-Carbomethoxy-3β-(4-Iodophenyl)tropane in 10 mL of 1:1 water/dioxane was heated to a gentle reflux for two days. The solvent was then removed and the white residue was triturated with hot ethyl acetate twice. The remaining solid was dried under in vacuo to yield 90 mg of CIT-acid 7, (93%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)#[N:16].C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[CH:7]3)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)#[N:16]
Reactant: N#Cc1cccc(N2CCNCC2)c1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(N2CCN(CCCCn3cnc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.1 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-cyanophenyl piperazine (5.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.7 g compound (I-10) with a yield of 62.4%. ESI-MS [M+H]+: m/z 360.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-])=O.O.NN>C(O)C.O.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Nc3ccccc3)c2c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc2ncnc(Nc3ccccc3)c2c1

Procedure:
A solution of a 6-nitro-4-(phenylamino)quinazoline substituted by a polyalkylene glycol, prepared as described hereinabove, in ethanol/water is reacted at reflux temperature with hydrazine hydrate and Raney® Nickel (Ra—Ni). The reaction mixture is filtered and evaporated, to give the corresponding 6-amino-4-(phenylamino)quinazoline substituted by a polyalkylene glycol moiety (terminating with a hydroxyl group).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[CH:19]=[C:18](I)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[CH:19]=[C:18]([C:26]#[C:25][CH2:24][OH:27])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-2-iodo-7-methyl-4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamide (Example No. 23) (1.632 g) in diethylamnine (40 mL) is added copper iodide (0.210 g) and Pd(PPh3)2Cl2 (0.125 g) followed by addition of propargyl alcohol (0.29 mL). The reaction is stirred at rt for 18 h. The diethylamine is removed in vacuo and the resulting brown solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield an orange solid which is recrystallized from ethanol to yield 1.06 g (77%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1](I)I.[Cl:4][C:5]1[C:17]([Cl:18])=[C:16]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=[C:14]2[C:6]=1[C:7]1[C:12]([CH:26]=[CH2:27])([CH2:13]2)[CH2:11][CH2:10][C:9](=[O:28])[CH:8]=1>O1CCCC1.C1(C)C=CC=CC=1.[Cu].[Zn]>[Cl:4][C:5]1[C:17]([Cl:18])=[C:16]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=[C:14]2[C:6]=1[C:7]1[C:12]([CH:26]3[CH2:1][CH2:27]3)([CH2:13]2)[CH2:11][CH2:10][C:9](=[O:28])[CH:8]=1
Reactant: ICI
Reactant: C=CC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC)c(Cl)c1Cl)C2
Agent: [Cu]
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(C1CC1)C2
Reaction time: 24 h

Procedure:
A mixture of the zinc-copper couple, prepared as described above, (48 gm.) and methylene iodide (37.5 gm.) in tetrahydrofuran (300 ml.) is heated under reflux in a nitrogen atmosphere for an hour. Ethyl [(5,6-dichloro-3-oxo-9a-vinyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]-acetate (8.2 gm., 0.02 mole) is added to the cooled mixture and stirring continued at 25° C. for 24 hours. The mixture is diluted with toluene (200 ml.), filtered and the filtrate is washed successively with saturated aqueous solutions of ammonium chloride and sodium bicarbonate and then with water. The organic lager is dried over anhydrous magnesium sulfate and the solvent removed using a rotary evaporator at reduced pressure. The residue is purified by column chromatography using a silica-gel column to give ethyl [(5,6-dichloro-9a-cyclopropyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]-acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1nccc(Cl)c1I
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1ncc([N+](=O)[O-])c(Cl)c1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A solution of 4-chloro-3-iodopyridin-2-amine (4.00 g, 15.7 mmol, Adesis) in concd H2SO4 (45 mL) was cooled to about 0° C. in an ice bath. Potassium nitrate (3.50 g, 34.6 mmol) was added in four portions over about 10 min. The resulting solution was stirred at about 0° C. for about 1 h, then at ambient temperature for about 4 h. The reaction mixture was slowly poured over crushed ice (total volume 1 L) resulting in formation of a solid that was collected by vacuum filtration and dried under vacuum to give 4-chloro-3-iodo-5-nitropyridin-2-amine (2.2 g, 47%) as a yellow solid: LC/MS (Table 1, Method c) Rt=1.48 min; MS m/z 298 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.[C:16](=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:16])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccnc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 2-aminopyridine-3-carboxylic acid (4.3 g, 31 mmol) in methanol (62 mL) was added dropwise sulfuric acid (31 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was stirred at 70° C. for 15 hr. and neutralized with sodium bicarbonate under ice-cooling. The reaction mixture was extracted twice with ethyl acetate, and the extracts were combined, and washed with brine. The extract was dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (4.3 g, 90%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[S:9][C:5]=2[CH:4]=1)#[CH:2].[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([S:10][CH3:13])[S:9][C:5]=2[CH:4]=1)#[CH:2]
Reactant: O=C([O-])[O-]
Reactant: C#Cc1ccc2nc(S)sc2c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C#Cc1ccc2nc(SC)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 139.2 %

Procedure:
To a stirred solution of 6-ethynylbenzo[d]thiazole-2-thiol (4.0 g, 21 mmol) from Step 2 of this Example in 20 mL of DMF at 0° C. were added K2CO3 (7.25 g, 5.25 mmol), and MeI (5 mL). The mixture was stirred at rt for 2 h before it was partitioned between EtOAc and water, the organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 3:1 DCM/hexanes to afford 6-ethynyl-2-(methylthio)benzo[d]thiazole (1.5 g, 35%) as an off-white solid. LCMS (ESI) m/z 206 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=1>>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1ccc(I)cn1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nc2)CC1
Yield: 43.2 %

Procedure:
tert-butyl 4-piperidinylcarbamate (0.30 g, 1.50 mmol; Astatech) and 2-chloro-5-iodopyridine (0.287 g, 1.50 mmol; Aldrich) were processed according to the procedure of Example 1A to provide the title compound as a yellow oil (0.202 g, 43%). (DCI/NH3) m/Z 312 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][Cl:14].Cl.[N:17]([O-])=O.[Na+]>O>[Cl:14][CH2:13][CH2:12][C:11]1[C:10](=[O:15])[C:4]2[C:3](=[C:8]([CH3:9])[CH:7]=[CH:6][CH:5]=2)[NH:2][N:17]=1
Reactant: O=N[O-]
Reactant: Cc1cccc(C(=O)CCCCl)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cccc2c(=O)c(CCCl)n[nH]c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(2-amino-3-methylphenyl)-4-chlorobutan-1-one hydrochloride (20 g, 0.081 Mol) and concentrated hydrochloric acid (1000 ml) at 0° was added dropwise a solution of sodium nitrite (6.07 g, 0.088 mol) in water (50 ml) maintaining the temperature below 5°. The reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure to give a solid. The solid was washed with sodium acetate solution and collected by filtration and dried, 13.5 g. Recrystallization from methanol gave the title compound, m.p. 222-225°
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][C:4]([NH:6][NH:7][C:8]([O:10][CH3:11])=[O:9])=[S:5].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][S:5]/[C:4](=[N:6]\[NH:7][C:8]([O:10][CH3:11])=[O:9])/[CH2:3][C:2]([CH3:13])([CH3:12])[CH3:1]
Reactant: COC(=O)NNC(=S)CC(C)(C)C
Reactant: C=CC(=O)OC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)CCS/C(CC(C)(C)C)=N\NC(=O)OC
Yield: 92.7 %

Procedure:
A mixture of 20.5 g of 2-(3,3-dimethyl-1-thioxobutyl)hydrazinecarboxylic acid, methyl ester, 12.92 g of methyl acrylate, 1 ml of triethylamine and 300 ml of dry benzene was heated at reflux for 8 hours, then cooled and concentrated in vacuo. The residual oil was chromatographed through a bed of hydrous magnesium silicate, eluting with dichloromethane and evaporated, giving 27 g of (Z)-[1-[(3-methoxy-3-oxopropyl)thio]-3,3-dimethylbutylidene]hydrazinecarboxylic acid, methyl ester.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:11])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:13]([CH3:30])[CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1>C1C=CC=CC=1>[C:1]1([CH2:7][CH:8]([OH:11])[CH2:9][NH:10][CH:13]([CH3:30])[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:28][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC(O)Cc1ccccc1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Solvent: c1ccccc1
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)Cc1ccccc1
Reaction time: 2 h
Yield: 39.8 %

Procedure:
550 mg of 3-phenyl-2-hydroxypropylamine (prepared as described in Preparation 17) and 1.0 g of 5-[4-(2-oxo-propoxy)benzyl]thiazolidine-2,4-dione were suspended in 30 ml of anhydrous benzene, and the resulting suspension was heated under reflux for 30 minutes while removing water. Subsequently, the solvent was removed by evaporation under reduced pressure. The resulting oily product was dissolved in 20 ml of anhydrous methanol, 670 mg of sodium cyanoborohydride was added to the solution, whilst ice-cooling, and the mixture was stirred for 2 hours in a stream of nitrogen gas. After this, the reaction mixture was left to stand overnight, and then the solvent was removed by evaporation under reduced pressure. Water was added to the resulting residue, which was then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the extract by evaporation under reduced pressure, and the resulting residue was applied to a silica gel chromatography column, which was eluted with a 5:1 by volume mixture of ethyl acetate and ethanol, and crystallized from ethyl acetate, to give 590 mg of the title compound, melting at 145° C. to 152° C.