Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]([CH3:16])[C:12]([SH:15])=[N:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[N:11]([CH3:16])[C:12]([S:15][CH2:24][CH2:25][CH2:26][Cl:27])=[N:13][CH:14]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: Cn1c(C(O)c2ccc(Cl)cc2)cnc1S
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cn1c(C(O)c2ccc(Cl)cc2)cnc1SCCCCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
The product of Example I, Step A (0.09 g) in acetone (2 mL) and DMF (2 mL) was treated with K2CO3 (0.2 g) followed by 1-bromo-3-chloropropane (0.11 g). The mixture was allowed to stir at rt for 16 h and was then partitioned between EtOAc (50 mL) and brine (50 mL). The organic layer was separated and washed with brine (2×200 mL), dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by silica gel chromatography using 2-5% MeOH/CH2Cl2 as the eluent to provide (4-Chloro-phenyl)-[2-(3-chloro-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanol (0.08 g, 69%); M calc=330; M+H found=331.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[C:3]=1[Cl:12].[Sn](Cl)Cl.O.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Br)c(Cl)c1N
Temperature: 25 °C
Yield: 78.9 %

Procedure:
4-Bromo-3-chloro-2-nitroaniline (4.78 g, 19.01 mmol) was dissolved in ethanol (112 mL). Tin (II) chloride (14.42 g, 76 mmol) was added, and the resulting mixture was stirred at reflux for 12 hours. The mixture was cooled to room temperature, poured into water, and adjusted to pH 5 with saturated sodium bicarbonate solution. The resulting solid was filtered and rinsed well with ethyl acetate. The filtrate was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-50% EtOAc in hexane to give the title compound (3.32 g, 79%). 1H NMR (400 MHz, CDCl3) δ ppm 6.94 (d, 1H), 6.51 (d, J=7.0, 1H), 3.87 (br s, 2H), 3.46 (br s, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH:16]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[CH3:20][S:17]([N:14]1[CH2:15][CH:16]=[C:11]([C:9]2[NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:3]=3[CH:10]=2)[CH2:12][CH2:13]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(N4CCOCC4)ncnc3[nH]2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of Example 41A (100 mg, 0.320 mmol) and morpholine (2.52 mL, 3 mmol) in 3 mL tetrahydrofuran/1 mL N,N-dimethylformamide was added N-ethyl-N-isopropylpropan-2-amine (0.084 mL, 0.480 mmol). The resulting reaction was stirred at 60° C. overnight. The solvent was removed in vacuo and the residue dried under high-vacuum for 2 hours. The crude solid was triturated with ethyl acetate, collected by filtration, and dried under high-vacuum to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.93 (s, 1H) 8.17 (s, 1H) 6.68 (s, 1H) 6.41 (s, 1H) 3.66-3.93 (m, 8H) 3.37 (t, J=5.65 Hz, 2H) 3.02-3.12 (m, 2H) 2.89-2.98 (m, 3H) 2.62 (s, 2H). MS (ESI+) m/z 364.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:25])[C:19]4[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=4)=[C:13]([C:15]([OH:17])=O)[N:14]=[C:7]3[C:6]=2[CH:26]=1.[Cl-].[NH4+:29]>>[Br:1][C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([OH:25])[C:19]4[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=4)=[C:13]([C:15]([NH2:29])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:26]=1
Reactant: [NH4+]
Reactant: Cn1nccc1C(O)c1c(C(=O)O)nc2n1CCOc1cc(F)c(Br)cc1-2
Agent: [Cl-]
Product: Cn1nccc1C(O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Yield: 50 %

Procedure:
10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid was reacted with ammonium chloride and purified by flash chromatography to afford 79 mg (50% yield) of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1Br)(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:31]1[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(F)ccc1Br
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(F)ccc1-c1ccncc1
Yield: 79 %

Procedure:
By carrying out the operation analogously to example 3, starting from 2-bromo-5-fluoro-phenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation V, and 4-pyridineboronic acid, the expected product is obtained in the form of a white solid with a yield of 79%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.S(=O)(=O)(O)O.[Br:18]N1C(=O)CCC1=O>CC#N>[Br:18][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([Cl:12])[N:3]=[C:2]2[Cl:1]
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: Clc1cc2c(Br)cccc2c(Cl)n1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 1,3-dichloroisoquinoline (1.0 g, 5.1 mmol) in CH3CN (25 mL) was added concentrated sulfuric acid (1.0 mL, 18 mmol), followed by N-bromosuccinimide (1.1 g, 6.1 mmol). The mixture was stirred at room temperature for 60 hours. The precipitate was collected by filtration, washed with water, then dried in air to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 8.35 (d, J=9.0 Hz, 1H), 8.09 (s, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H). LC6: 3.74 min. (M+H): 278.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=2)[N:3]=1.CO.[CH3:27][NH:28][CH3:29]>>[CH3:27][N:28]([CH3:29])[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc([N+](=O)[O-])cc23)cc1
Reactant: CNC
Solvent: CO
Product: COc1ccc(N(C)c2nc(N(C)C)nc3ccc([N+](=O)[O-])cc23)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of (2-chloro-6-nitroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine (48 mg, 0.14 mmol) in 2 mL of dimethylamine in methanol (2M, 25 mmol) was heated overnight in a seal tube at 70° C. for 48 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by chromatography (15% ethyl acetate/hexane) to give the title compound (39 mg, 79%). 1H NMR (CDCl3): 8.08 (dd, J=9.3, 2.4, 1H), 7.71 (d, J=2.4, 1H), 7.35 (d, J=9.3, 1H), 7.14 (m, 2H), 6.97 (2H), 3.85 (s, 3H), 3.55 (s, 3H), 3.33 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:8]([C:7]4[C:2]([Cl:1])=[N:3][C:4]([Cl:11])=[CH:5][CH:6]=4)=[O:10])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccc(Cl)nc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2,6-dichloropyridine-3-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (19% yield). 1H NMR (300 MHz, CDCl3) δ 8.06, 7.97, 7.65, 7.37, 7.01, 3.70-4.10, 3.29-3.61, 1.52, 0.68-0.80, 0.42-0.49, 0.06-0.13. MS (ES+) m/z 449 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)=[N:10][C:11]=2[NH2:17].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:17][C:11]1[N:10]=[C:9]([O:18][CH:19]2[CH2:22][CH2:21][CH2:20]2)[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1nc2c(N)nc(OC3CCC3)nc2n1CCCCCl
Reactant: C1CCNCC1
Product: Nc1nc(OC2CCC2)nc2c1[nH]c(=O)n2CCCCN1CCCCC1

Procedure:
Prepared similarly to Example 29 from 9-(4-chlorobutyl)-2-(cyclobutyloxy)-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [C:1]([NH:4][C:5]1([C:12]#[N:13])[CH2:10][CH:9]2[CH2:11][CH:6]1[CH2:7][CH2:8]2)(=[O:3])[CH3:2].[C:14](O)(=[O:16])[CH3:15]>C(OC(=O)C)(=O)C.[Pt]=O>[C:1]([NH:4][C:5]1([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:10][CH:9]2[CH2:11][CH:6]1[CH2:7][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1(C#N)CC2CCC1C2
Reactant: CC(=O)O
Agent: O=[Pt]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCC1(NC(C)=O)CC2CCC1C2

Procedure:
The procedure is as in Example 3, but starting from 2-acetylamino-2-cyano-bicyclo[2.2.1]heptane (7.14 g), in the form of the exo racemate in acetic acid (250 cc) and acetic anhydride (7.5 cc), in the presence of Adams platinum oxide (0.7 g); taking up the residue from the evaporation in water and ethanol (80/20 by volume) (100 cc), 2-acetylamino-2-acetylaminomethyl-bicyclo[2.2.1]heptane (8.7 g) is thus obtained in the form of fine white crystals which melt at 208° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.O>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:23][CH:24]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester prepared in Step C of Preparation 20, (0.497 g, 2.09 mmol) in MeOH (8 mL) was added 4-tert-butylbenzaldehyde (0.33 mL, 1.97 mmol), and the mixture was stirred at room temperature for 2 h. The solution was cooled to 0° C. and sodium borohydride (0.119 g, 3.15 mmol) was added in one portion. The mixture was stirred for 10 min, and a 1:1 solution of water:aqueous saturated sodium bicarbonate was added to the solution. The product was extracted into CH2Cl2 (3×) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo. The product was purified via silica gel chromatography (EtOAc followed by 5% MeOH in CH2Cl2) to give the title compound of Step A (0.691 g) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.30-7.38 (m, 2H), 7.19-7.28 (m, 3H), 6.87-6.96 (m, 2H), 6.77 (d, 1H), 4.50 (s, 2H), 3.77 (s, 2H), 3.75 (s, 2H), 1.46 (s, 9H), 1.30 (s, 9H); MS 384 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[O:24][CH2:23]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:13])([CH3:12])[C:8]([O:10]C)=[O:9].[OH-].[Li+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[O:24][CH2:23]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:13])([CH3:12])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C(C)(C)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)(C)C(=O)O)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
To a stirring solution of methyl 3-(2,3-dimethoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)-2,2-dimethylpropanoate (200 mg, 0.49 mmol) in tetrahydrofuran (15 mL) was added lithium hydroxide (102.5 mg, 2.45 mmol) in water (5 mL) and the resultant reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure, the residue was acidified using 1N HCl solution to pH 5 and then extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound as a solid (120 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:14][OH:15])[CH3:13].C(N(CC)CC)C.[CH2:34]([N:36]([CH2:40][CH3:41])[C:37](Cl)=[O:38])[CH3:35].Cl>O1CCCC1>[CH2:34]([N:36]([CH2:40][CH3:41])[C:37]([O:15][N:14]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=1[Cl:26])[CH3:13])=[O:38])[CH3:35]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)ON=C(C)COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl

Procedure:
First, 0.45 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime, 0.12 g of triethylamine, and 10 ml of tetrahydrofuran are placed in a reaction vessel, to which 0.16 g of N,N-diethylcarbamoyl chloride is slowly added dropwise with stirring under ice cooling. After completion of the addition, the reaction mixture is further stirred at room temperature for 30 minutes, poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-(N, N-diethylcarbamoyl)oxime.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:18])([CH2:15][CH2:16][CH3:17])[N:11]([CH2:19]C)[S:10]2(=[O:22])=[O:21])C=CC=CC=1.S(Cl)([Cl:26])(=O)=O>C(Cl)Cl>[Cl:26][CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:18])([CH2:15][CH2:16][CH3:17])[N:11]([CH3:19])[S:10]1(=[O:22])=[O:21]
Reactant: CCCC1(C)C(=O)N(CSc2ccccc2)S(=O)(=O)N1CC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCC1(C)C(=O)N(CCl)S(=O)(=O)N1C
Yield: 64.5 %

Procedure:
A solution of 2-Phenylthiomethyl-4-methyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.96 g) and sulfuryl chloride (0.28 ml) in 25 ml of dry methylene chloride was stirred for 1.75 hours at room temperature. The mixture was concentrated in vacuo and the residue triturated in 30 ml of hexane to afford 480 mg (64.5%) of 2-chloromethyl-4-methyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =propyl; R2 =CH3 ; R3 =CH3 ; X'=Cl) as a solid, m.p. 99°-100° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([O:7][CH3:8])=[N:4][CH:3]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].C(=O)(O)[O-].[Na+]>C(OCC)C>[CH3:8][O:7][C:5]1[S:6][C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:3][N:4]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1ncc(Br)s1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(OC)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A diethyl ether (1.8 mL) solution of 5-bromo-2-methoxythiazole (200 mg) was cooled to −78° C. followed by the dropwise addition of normal butyllithium (1.6 M, 0.7 mL; KANTO). The resulting mixture was stirred as it was for 1 hour, followed by the addition of tri-n-butyltin chloride (0.35 mL; TCI), and the resulting mixture was slowly raised to room temperature and then stirred for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture solution, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried and the solvent was evaporated under reduced pressure to give the'title compound.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]3)[CH2:13][CH2:14]2)[CH3:26])=[CH:21][CH:20]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(Br)cc1
Yield: 71 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-bromo-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 71% of theory; LC (method 1): tR=4.06 min; Mass spectrum (ESI+): m/z=426/428 (Br) [M+H]+.
Reaction SMILES: C(OP([CH2:9][S:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])(OCC)=O)C.[H-].[Na+].[F:28][C:29]([F:38])([C:34]([F:37])([F:36])[F:35])[CH:30](OC)O>C1COCC1>[CH3:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([S:10](/[CH:9]=[CH:30]/[C:29]([F:38])([F:28])[C:34]([F:37])([F:36])[F:35])(=[O:11])=[O:12])[CH2:18][CH2:17]2)[CH:24]=1
Reactant: COC(O)C(F)(F)C(F)(F)F
Reactant: CCOP(=O)(CS(=O)(=O)N1CCN(c2cc(C)ccn2)CC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccnc(N2CCN(S(=O)(=O)/C=C/C(F)(F)C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a solution of 1-(diethoxyphosphorylmethylsulfonyl)-4-(4-methyl-2-pyridyl)piperazine (242 mg, 0.618 mmol) in anhydrous THF (25 ml) were added molsieves 4A and sodium hydride (60%, 38 mg, 0.95 mmol) under nitrogen and the mixture was stirred at room temperature for 10 minutes. The mixture was cooled to 0° C. and 2,2,3,3,3-pentafluoro-1-methoxy-propan-1-ol (300 mg, 1.67 mmol) was added. The mixture was stirred at 0° C. for 30 minutes and then allowed to reach room temperature over one hour. The mixture was filtered through kieselguhr, concentrated under reduced pressure and the residue was purified by column chromatography (reveleris, gradient from 0 to 100% ethyl acetate in n-heptane) to yield 130 mg (0.337 mmol, yield 55%).
Reaction SMILES: [OH-].[K+].COC([C:7]1([C:20]2[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=O.O1CCOCC1>O>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:8][CH2:9]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)C1(c2ncnc3cc(Cl)ccc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(Cl)ccc23)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Solid KOH (224 mg, 4 mmol) was added to a suspension of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (29a; 41 mg, 0.1 mmol) in a 1:1 mixture of dioxane and water (1 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and concentrated in vacuo. The residue was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain crude 4-(7-chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (29b). This was dissolved in 2 mL of 3M HCl/MeOH was stirred at rt for 1 h and then concentrated in vacuo to obtain crude 4-(7-chloro-quinazolin-4-yl)-piperidine (29c) as a di-HCl salt. To a suspension of (29c) in anhydrous MeOH, was added DIEA (45 μL, 0.25 mmol) followed by (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (48 mg, 0.15 mmol) and the mixture was stirred at rt for 1 h. It was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 1% MeOH/DCM) to obtain 5 mg (12% overall yield from 29a) of pure 4-(7-chloro-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide. 1H-NMR (300 MHz, CDCl3): δ 9.25 (s, 1H), 8.15-8.06 (m, 2H), 7.62 (d, 1H), 7.23 (d, 2H), 6.85 (d, 2H), 6.30 (s, 1H), 4.49 (m, 1H), 4.26 (m, 2H), 3.70 (m, 1H), 3.15 (m, 2H), 2.23-2.05 (m, 2H), 2.05-1.92 (m, 2H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 424.2, found 425.4 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([I:34])[CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([I:34])[CH:27]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1I
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (4-fluoro-2-iodophenyl)methanamine. White solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.66 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2,), 4.57 (2H, d, J=6.6 Hz, NCH2), 7.05 (1H, m, aromatic), 7.3-7.38 (3H, m, aromatics), 7.42 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 7.53 (2H, m, aromatics), 7.56 (1H, dd, J=2.6 Hz and J=8.0 Hz, aromatic), 8.05 (1H, broad t, NH). HRMS (ESI+) calculated for C24H24FIN3O4 [M+H+]: 564.0796; found: 564.0809.
Reaction SMILES: [I-:1].[CH3:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[N:12]3[C:16]4[CH:25]=[CH:24][C:23]5[CH:22]=[C:21](F)[CH:20]=[CH:19][C:18]=5[N+:17]=4[CH:27]=[C:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=1)([CH3:5])[CH3:4].[CH3:28][N:29]([CH3:31])[NH2:30].CN1CCCC1=O>C(OCC)(=O)C>[I-:1].[CH3:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[N:12]3[C:16]4[CH:25]=[CH:24][C:23]5[CH:22]=[C:21]([NH:30][N:29]([CH3:31])[CH3:28])[CH:20]=[CH:19][C:18]=5[N+:17]=4[CH:27]=[C:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Reactant: CN(C)N
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CN(C)Nc1ccc2c(ccc3n4c(ccc5cc(C(C)(C)C)ccc54)c[n+]23)c1

Procedure:
A mixture of 1.46 g. of 10-(1,1-dimethylethyl)-3-fluoroimidazo-[1,2-a:3,4-a']diquinolin-15-ium iodide, 1.64 ml. of 1,1-dimethylhydrazine and 25 ml. of N-methyl-2-pyrrolidinone is heated at reflux for 15 hours, then cooled and diluted with 300 ml. of ethyl acetate. The precipitate is collected and stirred with 1% aqueous triethylamine hydroiodide. The solid is collected, washed with water and dissolved in 150 ml. of hot methanol. The methanol solution is treated with activated charcoal, filtered, evaporated to a volume of about 25 ml. and cooled. The resulting precipitate of 10-(1,1-dimethylethyl)-3-(2,2-dimethylhydrazino)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, washed with cold methanol and dried; m.p. 347°-350° C., after two crystallizations from 2-propanol/ethanol.