Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].[CH3:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[N:44][CH:45]=1>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:42]4[CH:43]=[N:44][CH:45]=[C:40]([CH3:39])[CH:41]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1cncc(B(O)O)c1
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Br)cc2)CC1)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cncc(-c2ccc(S(=O)(=O)N[C@H]3CC[C@H](C(=O)N[C@H](C)c4ccc(F)cc4)CC3)cc2)c1

Procedure:
Trans-4-(4-Bromo-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 115, 100 mg, 0.206 mmol), Pd(dppf)Cl2.DCM (34 mg, 0.04 mmol), 2M Na2CO3 (1 ml, 2.06 mmol) and 5-methyl-3-pyridine boronic acid (51 mg, 0.37 mmol) were dissolved in DMF (1-2 ml) under N2. The reaction mixture was microwaved at 160° C. for 20 min., after which LCMS indicated that the reaction was complete. The mixture was diluted with EtOAc and washed with H2O (×2). The organic layer was concentrated in vacuo, and the crude material purified via column chromatography using a biotage SP1 25+S column with a gradient of 80-100% EtOAc in heptane. Product fractions combined and concentrated to give the title compound as a white solid (44 mg, 43%). MS MH+ 496.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[N:3]=1.[OH-].[K+].Br[CH:21]([CH3:23])[CH3:22]>CS(C)=O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH:21]([CH3:23])[CH3:22])[CH:12]=2)[N:3]=1
Reactant: Nc1cc(Cl)nc(SCc2cccc(O)c2)n1
Reactant: CC(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)Oc1cccc(CSc2nc(N)cc(Cl)n2)c1
Reaction time: 8 h

Procedure:
4-amino-6-chloro-2-(3-hydroxyphenylmethylthio)-pyrimidine (135 mg, 0.50 mmol; Cpd 108) is added to a solution of KOH (280 mg, 5 mmol) in DMSO (2.5 ml) at room temperature. 2-Bromopropane (615 mg, 5 mmol) is added and the reaction stirred overnight, then poured onto water. The aqueous solution is extracted with ethyl acetate, dried with MgSO4, filtered, and concentrated in vacuo. The sample is purified by chromatography using 1:3 ethyl acetate/hexanes, mp 71° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:17](=[O:18])[C:16]([OH:19])=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[C:14]2=[O:20])=[C:9]1[C:30]([O:32][CH3:33])=[O:31])([CH3:4])([CH3:3])[CH3:2].[CH3:35][Si](C=[N+]=[N-])(C)C.CCCCCC>ClCCl.CO>[C:1]([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:17](=[O:18])[C:16]([O:19][CH3:35])=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[C:14]2=[O:20])=[C:9]1[C:30]([O:32][CH3:33])=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COC(=O)c1c2c(c(O)c(=O)n1CC(=O)OC(C)(C)C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c2c(c(OC)c(=O)n1CC(=O)OC(C)(C)C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
A mixture of methyl 2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.70 g, 1.41 mmol) and a solution of trimethylsilyldiazomethane in hexane (1.0 mL, 2.0 mmol; 2M) in dichloromethane-methanol (4 & 2 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The residue was subject to column chromatography on silica gel eluting with 2% methanol in dichloromethane. Collection and concentration of appropriate fractions provided the title compound. ES MS M+1=509
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C@H:30]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42](O)=[O:43])[CH2:31]2)[CH:24]=1.[NH2:51][CH2:52][CH2:53][NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58]>ClCCl.C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:57]([O:56][C:55]([NH:54][CH2:53][CH2:52][NH:51][C:42](=[O:43])[C@@H:32]1[CH2:31][C@@H:30]([O:29][C:25]2[CH:24]=[C:23]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:34][N:33]1[C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])=[O:61])([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cccc(-c3ccccc3)c2)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@@H]1C[C@@H](Oc2cccc(-c3ccccc3)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Triethylamine (56 μL), 1-hydroxybenzotriazole (25 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg) were added to a solution of trans-4-(3-biphenyloxy)-N-tert-butoxycarbonyl-L-proline (B), (141 mg) and tert-butyl N-(2-aminoethyl)carbamate (65 mg) in dichloromethane (3 mL). After stirring at room temperature overnight, the reaction mixture was diluted with chloroform and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography chloroform:methanol=100:1, v/v to give the titled compound (175 mg) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 2.37 (m, 1H), 2.59 (m, 1H), 3.28 (m, 1H), 3.29 (s, 2H), 3.40 (m, 1H), 3.73 (m, 2H), 4.41 (m, 1H), 5.01 (m, 1H), 5.18 (m, 1H), 6.86 (m, 2H), 7.08 (s, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.35 (t, J=7.3 E4z, 2H), 7.43 (t, J=7.3 Hz, 2H), and 7.56 (d, J=7.3 Hz,2H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2[CH:8]=[C:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Cc2ccccc2)cc1Br
Product: Nc1ccc(Cc2ccccc2)cc1-c1ccc(Cl)c(Cl)c1

Procedure:
2-bromo-4-benzylaniline and 3,4-dichlorobenzene boronic acid can be combined to form 2-(3,4-dichlorophenyl)-4-benzylaniline,
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]([S:17]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:31])=[CH:25][N:26]=[C:27]2[Cl:30])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])CCC.[C:33](OC(=O)CNCC1C=CC=CC=1C)([CH3:36])([CH3:35])[CH3:34].CCN(CC)CC>C(Cl)Cl>[C:33]([O:5][C:6](=[O:32])[CH2:7][N:8]([S:17]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:31])=[CH:25][N:26]=[C:27]2[Cl:30])=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1ccccc1CNCC(=O)OC(C)(C)C
Reactant: CCCCOC(=O)CN(Cc1ccccc1C)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-(2-methylbenzyl)glycine 1-butyl ester ##STR121## 1,4-Dichloro-7-isoquinolinesulphonyl chloride (400 mg, 1.35 mmol) was added to a stirred solution of N-(2-methylbenzyl)glycine t-butyl ester (380 mg, 1.61 mmol) in CH2Cl2 (20 mL) containing NEt3 (0.28 mL, 2.5 mmol) under N2 and the mixture was stirred at room temperature for 18 h. The mixture was diluted with CH2Cl2 and washed with dilute HCl (2 M), saturated aqueous NaHCO3, brine, dried (MgSO4) then and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (100:0 to 90:10) as eluant to give N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-N-(2-methylbenzyl)glycine t-butyl ester (480 mg, 0.97 mmol) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O.O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(CC(N)=O)c2cc(OCc3ccccc3)ccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
5-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (400 mg, 1.4 mmol) was dissolved in 50 mL of DMSO, 40 mg (1.0 mmol) of 60% NaH/mineral oil added, stirred approximately 0.5 hour, 0.2 mL of benzyl bromide added and stirring maintained 2.5 hours. The mixture was diluted with water, extracted with EtOAc, the EtOAc solution washed with water, saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica (eluted with a gradient, CH2Cl2 →2% MeOH/CH2Cl2) and crystallized from CH2Cl2 /MeOH to give 440 mg (82% yield) of 5-benzyloxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 118°-120° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([NH2:11])[C:8]([NH2:10])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:12](=S)=[S:13]>CO>[O:1]1[C:5]2[C:4](=[CH:9][C:8]3[NH:10][C:12]([SH:13])=[N:11][C:7]=3[CH:6]=2)[O:3][CH2:2]1
Reactant: Nc1cc2c(cc1N)OCO2
Reactant: S=C=S
Solvent: CO
Product: Sc1nc2cc3c(cc2[nH]1)OCO3
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.1 %

Procedure:
The mixture (6.48 g) containing 1,3-benzodioxol-5,6-diamine obtained in the step (78b) above was dissolved in methanol (100 ml). To the mixture, carbon disulfide (30 ml) was added and the mixture was stirred at room temperature for one day. The reaction mixture was concentrated under reduced pressure. To the solid residue, ethyl acetate was added and filtration was performed. The solid was washed by adding tetrahydrofuran, ethyl acetate and diluted hydrochloric acid and insoluble substance was collected by filtration, dried under reduced pressure at room temperature for 2 hours in a desiccator to obtain the title compound (3.8 g, 56.1% from 5,6-dinitro-1,3-benzodioxol) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C:13](=[O:19])[CH2:12]2.[OH-].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:12]2[C:13](=[O:19])[CH:14]3[CH2:17][CH2:18][N:11]2[CH2:16][CH2:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2cccc(Br)c2)N2CCC1CC2

Procedure:
The manner in which 2-[(2-, 3-, and 4-substituted phenyl)methyl]-1-azabicyclo[2.2.2]octanes are synthesized can vary. For example, in one method, 3-bromobenzaldehyde can be subjected to an aldol reaction with 3-quinuclidinone hydrochloride (commercially available from Aldrich Chemical Company) using potassium hydroxide in methanol to give 2-[(3-bromophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-one. The latter unsaturated ketone can be reduced by hydrogenation using palladium over charcaol to give 2-[(3-bromophenyl)methyl]-1-azabicyclo[2.2.2]octan-3-one. Depending upon the choice of hydrogenation catalyst, it may be necessary to use suitable inhibitors to suppress dihologenation. For suitable catalysts and inhibitors, see Rylander, Catalytic Hydrogenation in Organic Synthesis, pp. 125-126 (1979). The resulting ketone can be reduced under Wolff-Kishner conditions with hydrazine and base (or under modified Wolff-Kishner conditions with tosylhydrazine and sodium cyanoborohydride) to yield 2-[(3-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane. Methods similar to those described by A. D. Yanina et al., Khim.-Farm. Zh. 21(7):808-811 (1987) can be used. The isomeric compounds, 2-[(2-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane and 2-[(4-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane can be prepared in a similar manner by replacing 3-bromobenzaldehyde with 2-bromobenzaldehyde and 4-bromobenzaldehyde, respectively in the above synthetic approach. Alternatively, 2-[(3-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane can be prepared form the previously described 2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane by conversion to the intermediate diazonium salt compound using sodium nitrite and acid at 0° C., followed by treatment with cuprous bromide under Sandmeyer reaction conditions. In a similar manner, 2-[(2-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane and 2-[(4-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane can be prepared from the corresponding amino compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1.Cl.[OH-].[Na+]>O>[Cl:19][C:20]1[N:21]=[C:22]([NH2:27])[N:23]=[C:24]([NH:8][C:6]2[CH:5]=[CH:4][C:3]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)=[C:2]([Cl:1])[CH:7]=2)[CH:25]=1
Reactant: Nc1ccc(Nc2ccnc3[nH]ccc23)c(Cl)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Nc3ccnc4[nH]ccc34)c(Cl)c2)n1
Temperature: 100 °C

Procedure:
27 mg (0.10 mmol) of 2-chloro-N1-1H-pyrrolo[2,3-b]pyridin-4-ylbenzene-1,4-diamine and 24 mg (0.15 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 5 ml of water. 0.14 ml of 1 M hydrochloric acid are added, and the mixture is heated at 100° C. overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off and washed with water. The crude product is purified by preparative HPLC.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][C:4]1([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17].I([O-])(=O)(=O)=[O:26].[Na+].O>O.[Ru](=O)=O.C(Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([CH3:24])[CH2:3][C:4]1([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][C:7](=[O:26])[N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:17]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)CC1(CC(C)C)CCN(CCc2ccccc2)C1=O
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC1(CC(C)C)CC(=O)N(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Ruthenium(IV) oxide hydrate (27 mg, 0.20 mmol) is added to a mixture of ethyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (prepared similarly to that described in EXAMPLE 1, steps 1-3; 900 mg, 2.71 mmol), sodium periodate (2.71 g, 12.7 mmol), water (27 mL), and CCl4 (27 mL) at room temperature. After stirring overnight at room temperature, aqueous workup (CH2Cl2, MgSO4) and purification by column chromatography (20% EtOAc/hexane) gives 611 mg of the title compound (65%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cccc(OC)c3)c(N(C)C(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (120 mg, 0.41 mmol, 1.00 equiv), 3-methoxyphenylboronic acid (188 mg, 1.23 mmol, 3.00 equiv), Pd(PPh3)4 (94 mg, 0.08 mmol, 0.20 equiv), K3PO4 (346 mg, 1.64 mmol, 4.00 equiv), 1,4-dioxane (4 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 50 mg (33%) of methyl 3-(isopropyl(methyl)amino)-2-(3-methoxyphenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: C(=O)(O)[O-:2].[Na+:5].O[C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18])[CH:10]=[CH:11][CH:12]=1>O>[OH:2][C:10]1[CH:11]=[CH:12][CH:7]=[CH:8][C:9]=1[NH:13][C:14](=[O:20])/[CH:15]=[CH:16]\[C:17]([O-:19])=[O:18].[Na+:5]
Reactant: O=C(O)/C=C\C(=O)Nc1cccc(O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C([O-])/C=C\C(=O)Nc1ccccc1O
Reaction time: 4 h

Procedure:
A dry 2-liter beaker was charged with 135 ml of distilled water and 84 grams (1.0 moles) of sodium bicarbonate. The resulting mixture was stirred as 207 grams (1.0 mole) of N-(3-hydroxyphenyl)maleamic acid was slowly added with gas evolution. The thick mixture was stirred for 4 hours after the addition was complete and vacuum filtered to remove as much aqueous as possible. The filter cake was dried below 50° C. in a draft hood to give sodium N-(hydroxyphenyl)maleamate which is a tan solid melting above 200° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[C:1]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCC(CCO)CC1
Reaction time: 16 h
Yield: 93.6 %

Procedure:
Benzoyl chloride (13.3 mL, 0.115 mole) was added dropwise over 0.5 hour to a 0° C. solution of 4-piperidineethanol (14.8 g, 0.115 mole) and dry triethylamine (18 mL, 0.13 mole) in dichloromethane with mechanical stirring. After 16 hours at room temperature, the mixture was quenched with 1.0 M aqueous NaOH (150 mL), then extracted with ethyl acetate (1 L). The organic phase was extracted further with H2O (125 mL), then brine (125 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with chloroform to 6% methanol in chloroform, followed by concentration in vacuo and drying at 100° C. under high vacuum for 1.5 hour to yield a viscous oil (25.1 g, 94%). IR (neat): 3409 cm-1 (s,br), 1613(s). HRMS: Calculated for C14H19NO2 : 233.1416; found: 233.1410.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[NH:9])=[CH:3][CH:2]=1.[ClH:15].[Cl:16]([O-])(=O)=O.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[ClH:16].[Cl:15][C:5]1[CH:6]=[C:1]([CH3:14])[CH:2]=[CH:3][C:4]=1[NH:7][C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[NH:9]
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: Cc1ccc(NC(=N)NC(=N)N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(NC(=N)NC(=N)N)c(Cl)c1
Reaction time: 10 h

Procedure:
To 0.05 moles of 1-(p-tolyl)biguanide dissolved in 75 ml of acetic acid is added 9 ml of concentrated hydrochloric acid followed by 1.74 g. (0.0164 moles) of sodium chlorate in 4 ml of water. The temperature is held below 25°C with stirring for 10 hours and then cooled in an ice bath. To the reaction mixture is added 40% sodium hydroxide solution and extracted with ether. The ether is worked with water, dried over magnesium sulfite and evaporated to dryness. The hydrochloride salt is then prepared with ethanolic hydrochloric acid to obtain 1-(2-chloro-4-methylphenyl)biguanide hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[CH:4][C:3]=1[NH:16][C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[C:24]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]3)[C:25]([Cl:27])=[CH:26][C:19]=2[N:18]=1.ClC1C=C(C=CC=1)C(OO)=[O:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][S:8]([C:10]([CH3:11])([CH3:13])[CH3:12])(=[O:43])=[O:9])=[CH:4][C:3]=1[NH:16][C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[C:24]([N:28]3[CH2:29][CH2:30][CH:31]([C:34]([F:36])([F:35])[F:37])[CH2:32][CH2:33]3)[C:25]([Cl:27])=[CH:26][C:19]=2[N:18]=1
Reactant: Cn1c(Nc2cc(CNS(=O)C(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(Nc2cc(CNS(=O)(=O)C(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)benzyl)-2-methylpropane-2-sulfinamide (298 mg, 0.52 mmol), m-chloroperoxybenzoic acid (127 mg, 0.74 mmol) and DCM (20 mL) was stirred at rt overnight. The mixture was basicified to pH ˜8-9 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. Crystallization from DCM/Et2O gave the title compound.
Reaction SMILES: [C:1](O)(=[O:5])[CH:2]([CH3:4])[OH:3].[NH2:7][CH2:8][C@@H:9]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])[OH:10]>O>[C:1]([NH:7][CH2:8][C@@H:9]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])[OH:10])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: CC(O)C(=O)NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 120 °C

Procedure:
Equimolar quantities of lactic acid and glucamine were mixed together. This mixture was then heated at 120° C. for 2 hours and the resulting water of reaction was continuously removed. The final product was a viscous, amber colored liquid.
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH2:12]([N:15]1[C:24](=[O:25])[CH:23]=[C:18]2[S:19][CH2:20][CH2:21][CH2:22][N:17]2[C:16]1=[O:26])[CH2:13][CH3:14].CN([CH:30]=[O:31])C>>[CH:30]([C:23]1[C:24](=[O:25])[N:15]([CH2:12][CH2:13][CH3:14])[C:16](=[O:26])[N:17]2[CH2:22][CH2:21][CH2:20][S:19][C:18]=12)=[O:31]
Reactant: CCCn1c(=O)cc2n(c1=O)CCCS2
Reactant: CN(C)C=O
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1c(=O)c(C=O)c2n(c1=O)CCCS2
Yield: 95 %

Procedure:
The Vilsmeier reagent prepared from phosphorus oxychloride (3.7 ml) and DMF (6.2 ml) was added dropwise to a solution of 7-propyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (6 g) in DMF (38 ml) with stirring under ice cooling. The reaction solution was stirred at room temperature for 3 hours and then, poured on ice water. The mixture was stirred for a while and the precipitated crystals were recrystallized from ethyl acetate to give colorless crystals (6.46 g, 95%).