Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13].[N+](N[C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[CH:24][N:23]=1)([O-])=O>N1C=CC=CC=1>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[CH:24][N:23]=1
Reactant: CN(C)CCOc1cccc(OCCCN)c1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCOc3cccc(OCCN(C)C)c3)[nH]c2=O)cn1

Procedure:
Equimolar amounts of 3-(3-(2-(dimethylamino)ethoxy)phenoxy)propylamine and 2 -nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone are heated under reflux in dry pyridine for 24 hours to give 2-[3-(3-(2-dimethylaminoethoxy)phenoxy)propylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[N:21]1([CH2:26][CH:27]2[O:32][CH2:31][CH2:30][NH:29][CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH2:31][O:32][CH:27]([CH2:26][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CCN(CC2CNCCO2)C1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCOC(CN4CCCC4)C3)c(F)cc2c1=O

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(1-pyrrolidinylmethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[2-(1-pyrrolidinylmethyl)morpholino]quinoline-3-carboxylic acid.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34]OS(C)(=O)=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(O)C>[NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Solvent: CCO
Product: O=C1N(c2ccc(Cl)cc2Cl)Cc2cnc(Nc3ccccc3)nc2N1c1cccc(CCN2CCOCC2)c1
Yield: 45 %

Procedure:
A solution of 58 mg (0.1 mmol) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-methanesulfonyloxyethyl)phenyl]-pyrimido[4,5-d]pyrimidin-2(1H)-one (prepared in Example 74) and 0.5 ml of morpholine in 2 ml of ethanol was heated at 50° C. for 3 hours. The reaction mixture was evaporated and the crude material was purified by flash chromatography on silica gel, eluting with 5% methanol in dichloromethane. Product containing fractions were combined and evaporated to give 26 mg (45%) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[3-(2-morpholinoethyl)phenyl]-pyrimido[4,5-d]pyrimidin-2(1H)-one as a pale yellow solid of melting point 118° C. [Mass spectrum (ESI) MH+ =575].
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:8]=1[CH3:9].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)(C)C>[CH3:9][C:8]1[N:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:3]=1[CH2:2][N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CBr
Solvent: CC(C)O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CN1CCN(C)CC1

Procedure:
A mixture of 5-bromomethyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (1.5 g), N-methylpiperazine (1.17 g) in isopropyl alcohol (15 ml) was refluxed for 6 hours. After evaporating the solvent, the residue was dissolved in chloroform, washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The filtrate was evaporated under reduced pressure, and the residue was subjected to column chromatography on alumina (100 g) eluting with chloroform. The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 6-methyl-5-(4-methylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine. (0.30 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc2c(Cl)ncnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncnc2cc(CBr)ccc12
Yield: 51.3 %

Procedure:
To a solution of 4-chloro-7-methylquinazoline (7.0 g, 39 mmol) in carbon tetrachloride (140 mL) is added N-bromosuccinimide (8.0 g, 45 mmol), and benzoyl peroxide (0.8 g, 3.3 mmol). The solution is refluxed for 8 hours. After this time, the solution is filtered. The filtrate is concentrated and the residue is stirred with ether to give the title compound as an off-white solid (5.1 g, 20 mmol). 1H NMR (CDCl3, 300 MHz) δ9.10 (s, 1H), 8.30 (d, 1H), 8.10 (s, 1H), 7.82 (d, 1H), 4.68 (s, 2H). MS (EI): m/z 237 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][C:3]=1[CH3:23].[CH:24]1([C:27]2[S:28][CH:29]=[C:30]([CH2:32][NH2:33])[N:31]=2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:12][N:11]=[C:10]([C:20]([NH:33][CH2:32][C:30]3[N:31]=[C:27]([CH:24]4[CH2:26][CH2:25]4)[S:28][CH:29]=3)=[O:21])[CH:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: NCc1csc(C2CC2)n1
Reactant: Cc1cc(-c2cc(C(=O)O)ncc2OCC(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cc(C(=O)NCc3csc(C4CC4)n3)ncc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(4-chloro-3-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (example BN) and 2-cyclopropyl-4-thiazolemethanamine (CAN 1083299-53-9) as starting materials; LC-MS (UV peak area/ESI) 100%, 482.0911 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][OH:8])=[CH:5][CH:4]=[C:3]([OH:9])[CH:2]=1.C1(C)C=CC(S(O[CH2:20][CH2:21][CH:22]([C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O)=CC=1.[OH-].[Na+].Cl>C(O)C>[F:28][C:27]([F:29])([F:30])[CH:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH2:20][O:9][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][OH:8])=[CH:1][CH:2]=1
Reactant: OCc1ccc(O)cc1
Reactant: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(CCOc1ccc(CO)cc1)C(F)(F)F
Reaction time: 6 h
Yield: 96.8 %

Procedure:
In a round-bottomed flask, a solution of 2.4 g of p-hydroxybenzyl alcohol in 10 ml of ethanol and 5.3 g of (+)-3-trifluoromethylheptyl p-toluenesulfonate were placed, and a solution of 0.8 g of sodium hydroxide in 10 ml of ethanol was added thereto dropwise, followed by 6 hours of heat-refluxing, cooling by standing and acidification with hydrochloric acid. The organic layer was extracted with diethyl ether. The resultant ether solution was dried with sodium sulfate and subjected to distilling-off of the solvent and purification by silica gel column chromatography to obtain 4.4 g of (+)-p-(3-trifluoromethylheptyloxy)benzyl alcohol. [α]D28 +1.0°, [α]43527 +2.4° (c 5.0, chloroform).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[OH-].[Na+].[O:12]1[C@H:14]2[CH2:15][C@H:16]3[C@:29]([CH3:31])([CH2:30][C@@H:13]12)[C@@H:28]1[C@H:19]([C@H:20]2[C@@:24]([CH2:26][CH2:27]1)([CH3:25])[C@@H:23]([C:32]#[N:33])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3.O>C(O)CO>[OH:12][C@@H:14]1[C@@H:13]([N:5]2[CH2:6][CH2:7][O:8][C:3]([CH3:9])([CH3:2])[CH2:4]2)[CH2:30][C@@:29]2([CH3:31])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[CH2:27][CH2:26][C@@:24]2([CH3:25])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:32]#[N:33])[CH2:15]1
Reactant: CC1(C)CNCCO1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C#N)CC[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](C#N)CC[C@@H]43)C[C@@H]2O)CCO1
Temperature: 135 °C
Yield: 54.3 %

Procedure:
2,2-Dimethylmorpholine hydrochloride (2.43 g) and sodium hydroxide (640 mg) were added to a mixture of (2α,3α,5α,17β)-2,3-epoxyandrostane-17-carbonitrile (1.2 g) (prepared as described in British patent 1,434,919) in 1,2-ethanediol (12 ml) and the mixture was heated at 135° C. in an atmosphere of nitrogen for 24 h. The reaction mixture was poured into water (100 ml) and the precipitated solid was filtered off and then dissolved in dichloromethane. The solution was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue (1.55 g) was chromatographed on silica gel. The purified product (1.18 g) was crystallised from ether-heptane to give (2β,3α,5α,17β)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)androstane-17-carbonitrile (903 mg). m.p. 170°-173° C.; [α]D +117.5° (c 0.8).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][C:18]([O:20]CC)=[O:19].Cl>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2c(Br)ccc(F)c12
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2c(Br)ccc(F)c2c1CCC(=O)O
Temperature: 80 °C

Procedure:
To a mixture of EXAMPLE 402A (2.3 g) in acetic acid (40 ml) was added concentrated hydrochloric acid (3 ml). The mixture was heated at 80° C. for 4 hours. After cooling to room temperature, precipitation of the product occurred. Water (50 mL) was added to further induce precipitation. The solid was filtered, rinsed with water and dried in vacuo.
Reaction SMILES: [OH:1][C@@H:2]([C@H:8]([OH:25])[C:9](=[O:24])[NH:10][C@H:11]([C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[S:26](Cl)(Cl)=[O:27]>C(Cl)(Cl)(Cl)Cl>[CH3:14][CH:13]([CH3:15])[CH2:12][C@H:11]([NH:10][C:9]([C@H:8]1[O:25][S:26](=[O:27])[O:1][C@@H:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:24])[C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CCOC(=O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)[C@H]1OS(=O)O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C

Procedure:
Ethyl (2S,3S)-2,3-dihydroxy-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]propionate (305 mg) obtained in Example 2 was dissolved in carbon tetrachloride (6 ml). Thionyl chloride (69 μl) was added to the resultant solution at room temperature, and the solution was heated under reflux for 40 minutes. The reaction solution was condensed under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (a developing solvent; hexane:ethyl acetate=2:1) to obtain 174 mg of a target compound as white crystals. This product was a diastereomer mixture due to 2-position asymmetry. Therefore, the mixture was subjected to silica gel column chromatography again to obtain a high-polarity isomer (compound A) and a low-polarity isomer (compound B). NMR data and SIMS data of the compounds A and B were as follows.
Reaction SMILES: C(OC([N:6]1[CH2:30][C@:29]2([C:31](=[O:33])[CH3:32])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:34])[CH2:7]1)=O)=C.[ClH:35].O1CCOCC1>C(Cl)Cl>[ClH:35].[C:31]([C@:29]12[C@@:11]3([CH3:34])[CH2:12][C@H:13]([OH:28])[C@@:14]4([F:27])[C@H:23]([C@@H:10]3[CH2:9][C@H:8]1[CH2:7][NH:6][CH2:30]2)[CH2:22][C@H:21]([F:24])[C:20]1[C@:15]4([CH3:26])[CH:16]=[CH:17][C:18](=[O:25])[CH:19]=1)(=[O:33])[CH3:32]
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(C)=O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of compound 176 (495 mg, 1.041 mmol) and HCl 4M in dioxane (5205 μl, 20.82 mmol) in DCM (20 ml) is stirred at RT for 30 minutes. The solvent is evaporated and the crude is dried in vacuo for 16 hours. The crude is dissolved in MeOH (30 ml) and stirred at 45° C. for 30 minutes. The solvent is evaporated and the crude is triturated with AcOEt/Et2O (1/1 mixture) to afford the title compound (457 mg, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH:17]=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32])[CH:25]=[CH:24]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][N:37]3[CH2:36][CH2:35][N:34]([S:31]([C:26]4[CH:25]=[CH:24][C:23]5[C:28](=[CH:29][CH:30]=[C:21]([Cl:20])[CH:22]=5)[CH:27]=4)(=[O:33])=[O:32])[CH2:39][CH2:38]3)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C=O)cc2C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2sc(CN3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1

Procedure:
In a similar manner to Referential Example 47 except for the use of 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[OH:10].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12]>C1COCC1>[Br:9][C:7]1[CH:6]=[CH:5][C:4]2[O:10][C:11](=[O:12])[NH:1][CH2:2][C:3]=2[CH:8]=1
Reactant: NCc1cc(Br)ccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1NCc2cc(Br)ccc2O1

Procedure:
A solution of 2-(aminomethyl)-4-bromophenol (I) (1.16 g, 5.7 mmol), triethylamthylamine (III) and carbonyldiimidazole (II) (1.86 g, 11.5 mmol) in anhydrous THF (100 ml) is refluxed for 4 hours. The solvent is evaporated and the residue dissolved in dichloromethane (DCM) (100 ml). The organic solution is washed with 1N HCl (20 ml×3) and then with brine (50 ml). The solvent is then evaporated and the resulting residue is purified by chromatography to give 6-bromo-3,4-dihydrobenzo[e][1,3]oxazin-2-one as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([N:8]=[C:9]=[S:10])[CH:5]=[CH:6][CH:7]=1.Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([N:8]2[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:9]2=[S:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC
Reactant: Cc1c(Cl)cccc1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1N1C(=O)CN(C)C1=S
Yield: 83.3 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 13.2 g of 3-chloro-2-methylphenyl-isothiocyanate, 11.0 g of sarcosine ethyl ester hydrochloride, 25 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the title compound (15.2 g) as a tan solid, m.p. 122°-124° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.96; H, 4.21; N, 11.05. Mass spectrum (EI, M.+) m/z 254/256.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:22]=1)=[O:16]
Reactant: NNC(=O)c1ccc(NC(=O)COc2ccccc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(COc1ccccc1)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl]-2-phenoxyacetamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 222 mg of the title compound (82%) as a yellow solid in 98.1% purity by HPLC (Rt: 4.41, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: CC(C)c1ccc(N=C=O)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(C(C)C)cc2)cc1-c1c(Br)cnn1C
Yield: 50 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 4-isopropylphenyl isocyanate (0.022 g, 21.0 μL, 10.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 23 (0.028 g, 0.06 mmol, 50%) as a solid film. LCMS m/z (%)=443 (M+H79Br, 100), 445 (M+H81Br, 99). 1H NMR (400 MHz, acetone-d6) δ: 8.08 (s, 1H), 8.00 (s, 1H), 7.68 (dd, J=2.6, 8.9 Hz, 1H), 7.49 (s, 1H), 7.40-7.46 (m, 3H), 7.09-7.17 (m, 3H), 3.81 (s, 3H), 3.68 (s, 3H), 2.78-2.92 (m, 1H), 1.21 (s, 3H), 1.20 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4]>[Pt](=O)=O.C(O)(=O)C>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(Nc1ccc(Cc2ccncc2)cc1)C(F)(F)F
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(Nc1ccc(CC2CCNCC2)cc1)C(F)(F)F
Reaction time: 16 h

Procedure:
2,2,2-Trifluoro-N-(4-(pyridin-4-ylmethyl)phenyl)acetamide (28.5 g, 102 mmol) and acetic acid (205 ml) were added to platinum(IV) oxide (3.42 g, 15.06 mmol) in a 500 mL stainless steel pressure bottle and the mixture was stirred for 16 hours at 40 psi. The mixture was filtered through a nylon membrane and concentrated in vacuo; and the resulting residue was taken up in methanol (100 mL) and poured into diethyl ether (600 mL). The precipitate was filtered, washed with ether and dried to afford the title compound.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7].C(=O)([O-])O.[Na+].[Cl-].[Na+]>O>[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:10][CH:9]=1)[CH3:7]
Reactant: CCc1ccccc1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(S(=O)(=O)O)cc1
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
33 ml (0.6 mol) of conc. sulfuric acid was added to 62 ml (0.5 mol) of ethylbenzene, and the mixture was stirred for 1.5 hours under heating at 120 to 130° C. Layer separation will occur if unreacted ethylbenzene still remains, so the reaction was terminated when no layer separation was confirmed, and a solution containing p-ethylbenzenesulfonic acid as the major component was thus obtained. This solution was poured into 150 ml water and neutralized partially with sodium hydrogen carbonate, and the sodium chloride was added to precipitate crystals ol sodium p-ethylbenzene sulfonate. The resulting crystals were separated by filtration and dried in vacuo. This sodium p-ethylbenzenesulfonate is easily soluble in water and sparingly soluble in ethanol. A 1H-NMR spectrum of the resulting crystals is shown in FIG. 1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH3:26])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:26])[C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(c1ccc(F)cc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1

Procedure:
2,5-Difluoronitrobenzene (2.69 ml, 24.84 mmol), 1-benzyl-4-methylaminopiperidine (EXAMPLE 9, 5.00 g, 24.84 mmol), and potassium carbonate (4.12 g, 29.81 mmol) are refluxed in acetonitrile for 21 hr. The mixture is then poured into water and extracted with chloroform. The extract is dried over sodium sulfate, filtered and concentrated. The concentrate is chromatographed (silica gel; ethyl acetate/hexane) to give the title compound, NMR (300 MHz, CD3OD) 7.45, 7.37, 7.29, 3.46, 2.99, 2.87, 2.64, 1.98 and 1.67δ.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[F:31])O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:32]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[F:31])[Br:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](C(O)c2cc(F)c(OCc3ccccc3)cc2F)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCO[C@H](C(Br)c2cc(F)c(OCc3ccccc3)cc2F)C1
Reaction time: 1 h

Procedure:
To a solution of 7.5 g of ((S)-2-[(4-benzyloxy-2,5-difluoro-phenyl)-hydroxy-methyl]-morpholine-4-carboxylic acid tert-butyl ester in dichloromethane (90 ml) was added with cooling (0-5° C.) tetrabromomethane (12.5 g) and afterwards triphenylphosphine (13.5 g) in small portions. Stirring continued for 1 hour at room temperature before the mixture was added dropwise to diethyl ether (600 mL). Solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was then purified by column chromatography (heptane-ethyl acetate (3:1)/silica gel) to give 5.6 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][CH:31]([CH3:38])[CH2:32][CH2:33][CH2:34][C:35](Cl)=[O:36]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:31]([CH3:38])[CH2:32][CH2:33][CH2:34][C:35]([O:22][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:36]
Reactant: CC(C)CCCC(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Br)nc2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Br)nc2n1
Yield: 66.7 %

Procedure:
The procedure is as in Example 7, but starting with 2-(7-bromo-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (8.55 g) in methylene chloride (110 cc), triethylamine (11.1 g), 5-methylhexanoyl chloride (7 g) and 4-dimethylaminopyridine (50 mg). After the residue obtained has been crystallized in hexane and then recrystallized in ethanol, 2-(7-bromo-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (7.5 g), m.p. 136° C., is obtained.