Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:3]1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.ClCCl>[O:24]1[C:2]2([CH2:7][CH2:6][O:5][CH:4]([CH2:8][O:9][S:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)(=[O:11])=[O:12])[CH2:3]2)[O:1][CH2:22][CH2:23]1
Reactant: O=C1CCOC(COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CC3(CCO2)OCCO3)cc1
Yield: 101.9 %

Procedure:
4-Nitro-benzenesulfonic acid 4-oxo-tetrahydro-pyran-2-ylmethyl ester (0.5 g, 1.59 mmol), ethylene glycol (986 mg, 15.9 mmol) and p-toluene sulfonic acid (61 mg, 0.32 mmol) were refluxed in benzene (20 ml) for 20 hours. The solvent was removed in vacuo to afford a solid. The solid was dissolved in dichloromethane (30 ml) and successively washed with a saturated aqueous solution of sodium bicarbonate (2×5 ml) and water (2×5 ml). The organic phase was dried (Na2SO4), filtered and the solvent removal in vacuo afforded 582 mg (100%) of 4-nitro-benzenesulfonic acid 1,4,8-trioxa-spiro[4.5]dec-7-ylmethyl ester as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.Cl.C([O:25][C:26](=[O:35])[C@H:27]([NH2:34])[CH2:28][O:29]C(C)(C)C)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([NH:34][C@H:27]([CH2:28][OH:29])[C:26]([OH:35])=[O:25])=[O:19])[N:3]=1
Reactant: CC(C)(C)OC[C@@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)Oc1ccc2c(Cl)nc(C(=O)O)c(O)c2c1
Agent: Cl
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)N[C@H](CO)C(=O)O)c(O)c2c1

Procedure:
Prepared in analogy to Example A-2 e) and f) from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and (R)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester hydrochloride; MS-(+)-ion: M+1=369.0 amu.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH3:10].C([Li])CCC.[CH:16](=[O:25])[C:17]1[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[Br:8][C:4]1[C:3]([O:9][CH3:10])=[C:2]([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[OH:25])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1c(Br)cccc1Br
Reactant: COc1ccccc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)c1cccc(Br)c1OC
Temperature: -63 °C

Procedure:
2,6-Dibromoanisole (138.0 g, 0.51 mol) was dissolved in 750 ml of tetrahydrofuran and the solution cooled to -63° C. Butyl lithium (319 ml of 1.6 M, 0.51 mol) was added slowly with stirring and the mixture stirred at -60° C. for 4.5 hours and then 69.4 g (0.51 mol) of o-anisaldehyde in 250 ml of tetrahydrofuran was added slowly with stirring and the mixture allowed to stir cold for 1 hour. The mixture was allowed to warm to ambient temperature and was then poured into a mixture of ice and saturated aqueous ammonium chloride. The resulting mixture was extracted with ether and the ether extract dried over magnesium sulfate and then concentrated by evaporation under reduced pressure to obtain the title compound. This was purified by preparative liquid chromatography eluting with a 5:95 mixture of ethyl acetate and hexane to obtain 44.6 g (24 percent of theory) of material having a proton nmr spectrum consistent with the assigned structure.
Reaction SMILES: C(Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([OH:20])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14]>C(O)C.[OH-].[Na+]>[CH:2]([S:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[C:11]([OH:20])=[O:19])=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccccc1S
Reactant: BrCC=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccccc1SC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.2 %

Procedure:
To a solution of 1.28 g (6.49 mmol) of cinnamyl bromide in 8 ml of ethanol at room temperature under an atmosphere of nitrogen was added a solution of 1 g (6.49 mmol) of thiosalicylic acid in 5.3 ml of 10% aqueous sodium hydroxide solution. The solution was stirred at room temperature for 16 hours and the solvent then removed under reduced pressure. The residue was dissolved in water and concentrated hydrochloric acid was added. The resultant solid was filtered off and dried. There was obtained 1.7 g of 2-styrylsulfanylbenzoic acid as a white solid, MS: m/e 270 M+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:17])[CH2:11][C:12](OCC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:17])[CH2:11][C:12]([NH:19][NH2:20])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@H](O)COCc1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)C[C@H](O)COCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
In a 100 ml flask were put 4.15 g (17.4 mmol) of ethyl (S)-4-benzyloxy-3-hydroxybutyrate (optical purity: 89%e.e.) prepared in Reference Example 2, 20 ml of ethanol, and 2.62 g (52.2 mmol) of hydrazine monohydrate in a nitrogen stream, and the mixture was heated under reflux for 20 hours. The reaction mixture was cooled to room temperature (22 to 24° C.), and ethanol was removed by evaporation under reduced pressure. To the residue was added 40 ml of diethyl ether, followed by heating under reflux to dissolve the crude crystals. The solution was cooled to 5° C., followed by stirring for 1 hour. The crystals thus precipitated were collected by filtration and washed with 10 ml of diethyl ether to give 2.90 g (74%) of the title compound. Melting point: 96.9° C. Optical purity: >99.9%e.e.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11]([CH:14]([CH2:18][CH2:19][CH3:20])[C:15](Cl)=[O:16])[CH2:12][CH3:13]>>[CH2:11]([CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([C:7]1[CH:8]=[C:2]([C:1]([OH:10])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1)=[O:16])[CH2:12][CH3:13]
Reactant: O=C(O)c1ccccc1O
Reactant: CCCC(CCC)C(=O)Cl
Product: CCCC(CCC)C(=O)c1ccc(O)c(C(=O)O)c1
Yield: 52 %

Procedure:
This compound is prepared by a Friedel-Crafts reaction from salicylic acid and 2-propylpentanoyl chloride. The acid yield is 52%. The recrystallization is done in petroleum ether. The melting point is 118° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1>C1(C)C(C)=CC=CC=1>[N+:15]([C:4]1[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][N:6]=2)[CH:3]=1)([O-:17])=[O:16]
Reactant: O=c1c([N+](=O)[O-])cc(Br)cn1-c1ccccc1
Solvent: Cc1ccccc1C
Product: O=c1c([N+](=O)[O-])cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
1.27 g of 5-bromo-3-nitro-1-phenyl-1,2-dihydropyridin-2-one, 2.38 g of 2-tri-n-butyl stannyl pyridine and 248 mg of tetrakistriphenylphosphine palladium were added to 20 ml of xylene, followed by stirring at 120° C. overnight in nitrogen atmosphere. The reaction mixture was purified by silica gel chromatography (ethyl acetate/hexane system), to give 638 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)CCc1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 69.1 %

Procedure:
tert-Butyl 3-(2-cyano-4-pyridyl)propionate (0.51 g, 2.2 mmol) and methyl thiosalicylate (0.55 g, 3.3 mmol) were dissolved in toluene (2 ml), and triethylamine (0.47 ml, 3.4 mmol) was added thereto. The mixture was refluxed for 8 hrs and subjected to a silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (0.56 g, 69%) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[OH:26].C(=O)([O-])[O-].[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12
Reactant: Clc1ccnc2cc(-c3nccs3)sc12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Temperature: 180 °C
Yield: 66.1 %

Procedure:
To a suspension of 10 (194 mg, 0.77 mmol) in Ph2O (10 mL) was added 2-fluoro-4-nitrophenol (240 mg, 1.53 mmol) and potassium carbonate (425 mg, 3.08 mmol) and the reaction mixture was heated at 180° C. for 4 hrs. The reaction mixture was cooled to room temperature and diluted with EtOAc. The resultant solution was washed with water and the organic layer was collected, dried over anhydrous sodium sulfate and filtered. The solvents were removed under reduced pressure; the residue was dissolved in DCM, and purified by column chromatography (eluent EtOAc-hexane 4:1) to afford 11 (190 mg, 66% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm: 8.61 (d, J=5.5 Hz, 1H), 8.46 (dd, J=2.74 and 10.37 Hz), 8.24 (s, 1H), 8.20-8.10 (m, 1H), 7.95 (s, 2H), 7.73 (t, J=8 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H).
Reaction SMILES: [CH3:1][Li].[CH:3]1([C:9]2[CH:10]=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C1COCC1>[CH:3]1([C:9]2[CH:10]=[N:11][O:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])([CH3:1])[CH3:21])=[CH:18][CH:19]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(=O)c1ccc(-c2oncc2C2CCCCC2)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-c2oncc2C2CCCCC2)cc1
Reaction time: 0.25 h

Procedure:
Methyl lithium (159 μL, 1.6 M solution in Et2O, 0.25 mmol) was added dropwise to a solution of 1-(4-(4-cyclohexylisoxazol-5-yl)phenyl)ethanone obtained above (57 mg, 0.21 mmol) in THF (2 mL) at 0° C. After stirring for 15 min, another 100μL of the methyl lithium solution was added to the reaction mixture. After being stirred for an additional 1 h at 0° C., the mixture was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with NaCl, dried with magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. The crude material was purified by flash column chromatography (20%→40% EtOAc/hexanes) to afford 2-(4-(4-cyclohexylisoxazol-5-yl)phenyl)propan-2-ol as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.62 (m, 4H), 2.77 (m, 1H), 2.09 (m, 1H), 1.86 (m, 5H), 1.63 (s, 6H), 1.37 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]([CH:18]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][NH:22][CH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]([CH2:18][N:22]([CH3:23])[CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C(C=O)C1
Reactant: CNC
Agent: Cl
Product: CN(C)CC1CN(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Yield: 91 %

Procedure:
Reductive amination of 3-formyl-4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester (160 mg) with dimethylamine hydrochloride (67 mg) according to General Procedure C followed by an aqueous work-up and purification on silica gave 3-dimethylaminomethyl-4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester (160 mg). This was treated with 2M HCl to give desired (1-methanesulfonyl-piperazin-2-ylmethyl)-dimethyl-amine dihydrochloride (140 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[CH:27]=[C:26](F)[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[CH:27]=[C:26]([NH:36][CH2:35][C:34]4[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=4)[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1
Reactant: Fc1cc2c(Nc3ccc(OCc4cccc(Cl)c4)c(Cl)c3)ncnc2cn1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc3c(Nc4ccc(OCc5cccc(Cl)c5)c(Cl)c4)ncnc3cn2)cc1
Temperature: 71.5 °C
Reaction time: 91 h

Procedure:
A mixture of compound 201 (2.60 g, 6.27 mmol) and 4-methoxybenzylamine (8.24 mL, 62.7 mmol) in dry DMSO (15 mL) was stirred under a nitrogen atmosphere at 71-72° C. (bath temperature) for 91 h. It was partitioned in between ethyl acetate (500 mL) and water (300 mL). The ethyl acetate layer was separated and washed further with water (3×300 mL); dried (MgSO4) and evaporated to give a crude product of N4-(3-chloro-4-(3-chlorobenzyloxy)phenyl)-N6-(4-methoxybenzyl)prido[3,4-d]pyrimidine-4,6-diamine (210). Chromatography on silica gel (ethyl acetate/petroleum ether=1:1) gave pure 210 (2.02 g, 61%) as a yellow/orange solid, mp 120-122° C.; 1H NMR δ [(CD3)2SO] 9.59 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.48-7.38 (m, 3H), 7.36-7.19 (m, 4H), 7.15 (br s, 1H), 6.91-6.85 (m, 2H), 5.25 (s, 1H), 4.48 (d, J=6.3 Hz, 2H, 3.71 (s, 3H). Anal. Calcd for C28H23Cl2N5O2: C, 63.16; H, 4.35; N, 13.15. Found C, 62.96; H, 4.63; N, 13.12.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.[CH:11](O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[NH:9][CH:11]=[N:8][C:6]=2[CH:7]=1
Reactant: Cc1cc(Br)cc(N)c1N
Reactant: O=CO
Product: Cc1cc(Br)cc2nc[nH]c12
Yield: 97 %

Procedure:
A solution of 5-bromo-3-methyl-benzene-1,2-diamine (Maybridge, 3 g; 14.92 mmol) in formic acid (75 mL) was heated at reflux for 16 hours. Reaction mixture was concentrated under vacuum to give a brown oil. It was extracted by EtOAc from a saturated aqueous solution of NaHCO3, dried over MgSO4 and evaporated under vacuum to give the title compound as a pale yellow solid (3.07 g, 97%). 1H NMR (DMSO-d6) δ 12.92-12.34 (bs, 1H), 8.22 (s, 1H), 7.59 (br s, 1H), 7.17 (s, 1H), 3.33 (s, 3H). LC/MS (Method B): 211.0 (M+H)+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14])[N:9]=[C:8]([NH:18][C@H:19]([CH2:21][CH3:22])[CH3:20])[CH:7]=1>C1COCC1>[C@@H:19]([NH:18][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([S:12](=[O:17])(=[O:16])[N:13]([CH3:14])[CH3:15])[N:9]=1)[C:5]([OH:23])=[O:4])([CH2:21][CH3:22])[CH3:20]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(S(=O)(=O)N(C)C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(S(=O)(=O)N(C)C)n1
Reaction time: 8 h

Procedure:
Add 1 N lithium hydroxide (11.4 mL, 11.4 mmol) to a solution of (S)-2-sec-butylamino-6-dimethylsulfamoyl-isonicotinic acid methyl ester (1.43 g, 4.54 mmol) and THF (10 mL) at 0° C. Stir the mixture overnight, acidify the solution to about pH =2 and concentrate solvent to one half volume. Partition the residue between ethyl acetate and water, and extract the aqueous layer with ethyl acetate-(2×30 mL). Wash the combined organic extract with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].S(Cl)([Cl:27])(=O)=O>ClCCCl.CCOC(C)=O>[Cl:27][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:20]([F:21])([F:22])[F:23])[CH:4]=2)=[O:19])[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(CCc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(CCc1ccc(O)c(Cl)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 84 °C
Yield: 44.9 %

Procedure:
To a solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-3-(4-hydroxyphenyl)propanamide (1.33 g, 3.89 mmol) in DCE was added sulfuryl chloride (4.28 mL, 4.28 mmol) slowly over 45 min. The reaction mixture was heated at 84° C. overnight and then additional sulfuryl chloride was added. After heating for 2 h, the reaction mixture was cooled to rt and diluted with EtOAc. The combined organic solutions were washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give the title compound (0.66 g, 45%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH:25]=[N:24][C:23]3[C:22](=[O:26])[NH:21][C:20]([NH2:27])=[N:19][C:18]2=3)=[CH:12][CH:11]=1.O>C(O)(=O)C>[Br:1][C:25]1[N:17]([CH2:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[C:18]2[N:19]=[C:20]([NH2:27])[NH:21][C:22](=[O:26])[C:23]=2[N:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc2c(ncn2Cc2ccc(Cl)cc2)c(=O)[nH]1
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2c(nc(Br)n2Cc2ccc(Cl)cc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-Bromosuccinimide (1.3 g, 7.3 mmol) is added to a suspension of 9-(4-chlorophenyl)methylguanine (1.5 g; 5.4 mmol), Example 3, in glacial acetic acid (100 ml) and the mixture is stirred for 20 hours at room temperature. The solution is poured into water (400 ml) and the resulting precipitate is filtered, washed with water and methanol and dried. Yield: 1.0 g; mp>300° C.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH:8]1([CH2:11][N:12]2[CH:17]=[C:16]([C:18]3[C:23]([O:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=3)[CH:15]=[C:14]([CH3:37])[C:13]2=[O:38])[CH2:10][CH2:9]1>CN(C=O)C>[CH:8]1([CH2:11][N:12]2[C:13](=[O:38])[C:14]([CH3:37])=[CH:15][C:16]([C:18]3[C:23]([O:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])=[CH:22][N:21]=[C:20]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:19]=3)=[CH:17]2)[CH2:10][CH2:9]1
Reactant: CS(N)(=O)=O
Reactant: Cc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(CC2CC2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(NS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(CC2CC2)c1=O
Yield: 54.1 %

Procedure:
Methanesulfonamide (68 mg, 0.71 mmol), NaH (28 mg, 0.7 mmol, 60% in mineral oil) and the title compound from step 3 (80 mg, 0.18 mmol) in DMF (2 mL) were reacted in a similar manner as Example 152, step 6 to give the title compound (45.00 mg, yield: 54.4%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 8.81 (s, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.14 (s, 1H), 8.12 (s, 1H), 7.05-6.98 (m, 2H), 6.91-6.89 (m, 1H), 3.87 (d, J=7.2 Hz, 2H), 3.45 (s, 3H), 2.23 (s, 3H), 1.25-1.22 (m, 1H), 0.64-0.59 (m, 2H), 0.40-0.37 (m, 2H). LCMS: 463.1 (M+H)+
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH3:18][S:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:21])=[O:20]>>[CH3:28][C:22]([S:19]([CH3:18])(=[O:20])=[O:21])([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: ICCc1ccc(COc2ccccc2)cc1
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Product: CCOC(=O)C(C)(CCc1ccc(COc2ccccc2)cc1)S(C)(=O)=O
Yield: 105.5 %

Procedure:
1-(2-Iodoethyl)-4-(phenoxymethyl)benzene (960 mg, 2.84 mmol) and ethyl 2-(methylsulfonyl)propanoate (512 mg, 2.84 mmol) were converted to the title compound (1.17 g, 106%) containing minor solvent impurities following the general procedure of step 2 in Preparation 2 for the formation of compound (1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22-1.31 (m, 3H) 1.68-1.75 (m, 3H) 2.16-2.27 (m, 1H) 2.45-2.59 (m, 2H) 2.69-2.85 (m, 1H) 2.89 (s, 3H) 4.21-4.33 (m, 2H) 5.01-5.09 (m, 2H) 6.94-7.01 (m, 2H) 7.21 (d, J=8.20 Hz, 1H) 7.26-7.33 (m, 4H) 7.36-7.46 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2)=[O:11]
Reactant: Nc1cccc2ncccc12
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc2ncccc12

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 5-aminoquinoline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[N:6]([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:19]=4[CH:20]=3)[CH:13]=[CH:12][N:11]=2)[C:5](=[O:28])[NH:4][C:3]1=[O:29].[H][H]>CO.[Pd]>[CH3:1][C:2]1([CH3:30])[N:6]([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:19]=4[CH:20]=3)[CH:13]=[CH:12][N:11]=2)[C:5](=[O:28])[NH:4][C:3]1=[O:29]
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc3cc([N+](=O)[O-])ccc3s2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc3cc(N)ccc3s2)n1
Yield: 26.8 %

Procedure:
5,5-Dimethyl-1-(2-(4-(5-nitrobenzothiophen-2-yl)pyrimidin-2-ylamino)ethyl)imidazolidine-2,4-dione (1.2 g, 2.82 mmol) was suspended in methanol (120 mL), 20% palladium on carbon (120 mg) was added, and the mixture placed on a Parr shaker under 50 psi of hydrogen gas for a total of 7 days. The reaction mixture was filtered through a thick bed of celite and washed with methanol (5×50 mL) to give a bright yellow solution. The crude material was purified by flash chromatography (MeOH/DCM) to give the title compound as a light yellow powder (300 mg, 63%). MS (M+H)+ 411.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:16].[Na+]>CC(C)=O.CCCCCC>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][I:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: ICc1cccc(Oc2ccccc2)c1
Reaction time: 8 h

Procedure:
To a solution of 3-phenoxybenzyl chloride (10.0 g, 45.7 mmol) in 200 ml acetone was added sodium iodide (7.6 g, 507 mmol). The mixture was stirred at temperature overnight. The mixture was diluted with 300 ml hexane and the organic layer was washed twice with 5% sodium bicarbonate, once with brine and then dried over MgSO4. Evaporation of the filtrate gave a light yellow oil. The product was used in next step without purification. 1H NMR (CDCl3) 4.4 (s,2H), 6.8-7.4 (m, 9H).