Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1ccccc1Sc1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccccc3Cl)cc2)c1C
Yield: 20.6 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-bromo-4-(2-chlorophenylsulfanyl)-benzene (0.165 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2-chloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.051 g, 20%) as a solid. MS calcd. for C26H21Cl2O2S [(M+H)+] 467, obsd. 467.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2O)=[CH:4][C:3]=1[O:20][CH3:21].O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2[Cl:24])=[CH:4][C:3]=1[O:20][CH3:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1Br
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1Br

Procedure:
Similar procedure as described in example 9B was used, starting from 7-Bromo-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol and POCl3 to give (7-Bromo-1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 367 (MH+).
Reaction SMILES: C(N([C:6]1[C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[O:9][C:10]=1[CH:11]=O)CC)C.[C:17]([C:20]1[C:21](=[O:35])[O:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[C:25](N(CC)CC)[CH:24]=2)(=[O:19])[CH3:18].[NH:36]1[CH2:41][CH2:40]C[CH2:38][CH2:37]1>C(O)C>[CH2:37]([N:36]([C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:22][C:21](=[O:35])[C:20]=1[C:17](=[O:19])[CH:18]=[CH:11][C:10]1[O:9][C:8]2[CH:13]=[C:14]([N:36]([CH2:37][CH3:38])[CH2:41][CH3:40])[CH:15]=[CH:16][C:7]=2[CH:6]=1)[CH2:41][CH3:40])[CH3:38]
Reactant: C1CCNCC1
Reactant: CCN(CC)c1ccc2cc(C(C)=O)c(=O)oc2c1
Reactant: CCN(CC)c1c(C=O)oc2ccccc12
Solvent: CCO
Product: CCN(CC)c1ccc2cc(C=CC(=O)c3c(N(CC)CC)c4ccccc4oc3=O)oc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 25 mL of absolute ethanol in a 50 mL round-bottomed flask was added 217 mg (1 mmol) of 6 (N,N diethylamino) 2 formylbenzo[b]furan and 259 mg (lmmol) of 3 acetyl 7 (N,N diethylamino)coumarin. After refluxing for several minutes to dissolve the solids, 100 mg of piperidine was added and reflux was continued for one hour. The solution was allowed to cool to room temperature and then placed in a freezer overnight. The solid was filtered and recrystallized from 50 mL of ethanol to yield the product as deep red needles. Field desorption was spectrum: m/e 458 (M+); m.p. 169°-171° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][C:14]=1[C:23]([F:26])([F:25])[F:24]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([C:23]([F:26])([F:24])[F:25])[CH:15]=2)(=[O:21])=[O:20])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1nccnc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1nccnc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
To a solution of 3-amino-pyrazine-2-carboxylic acid methyl ester (153 mg, 1.0 mmol) in 2.0 mL of pyridine was added 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (279 mg, 1.0 mmol) in 1.0 mL of pyridine. The mixture was stirred at room temperature for 16 h, diluted with 15 mL of ethyl acetate, washed twice with 1 M HCl (15 mL), dried on MgSO4 and the solvent was evaporated. The product was purified on silica gel column (15% ethyl acetate in hexane) to afford 185 mg of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyrazine-2-carboxylic acid methyl ester as white powder. MS: (M+H)/z=396.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.C(Br)(Br)(Br)[Br:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:13][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: OCc1cc2ccccc2o1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of benzofuran-2-ylmethanol (120 mg; 0.81 mmol) in anh. DCM (5 ml) was treated at rt with CBr4 (268 mg; 0.81 mmol), and with PPh3 (212 mg; 0.81 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 2-(bromomethyl)benzofuran as a yellow oil (128 mg; 75%) which was directly used for the next reaction.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([C:9]#[N:10])=[C:7](Cl)[N:6]=[C:5](NCC)[N:4]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[NH2:1][C:7]1[N:6]=[C:5]([NH:18][CH:15]([CH3:17])[CH3:16])[N:4]=[C:3]([Cl:2])[C:8]=1[C:9]#[N:10]
Reactant: CC(C)N
Reactant: CCNc1nc(Cl)c(C#N)c(Cl)n1
Reactant: N
Product: CC(C)Nc1nc(N)c(C#N)c(Cl)n1

Procedure:
This compound was prepared in the manner of Example XVII, substituting 4,6-dichloro-2-isopropylamino-5-pyrimidinecarbonitrile and aqueous ammonia for 4,6-dichloro-2-ethylamino-5-pyrimidinecarbonitrile and isopropylamine. The reaction product was recrystallized from benzene to give 6-amino-4-chloro-2-isopropylamino-5-pyrimidinecarbonitrile; mp, 162°-165°.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][S:7][CH2:6][NH:5]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:5]2[C:4](=[O:3])[CH2:8][S:7][CH2:6]2)(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CSCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CSCC2=O)cc1
Yield: 41.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (0.58 g) was added portionwise to a solution of 4-oxothiazolidine (1.50 g) and 4-methoxybenzenesulfonyl chloride (3.01 g) in tetrahydrofuran (30 ml) at 0° C. with stirring and the mixture was stirred for 1 hour at the same temperature. After the solvent was evaporated in vacuo, the residue was mixed with ethyl acetate (10 ml) and water (50 ml) and the resultant precipitate was collected by filtration. The cake was washed with water and diisopropyl ether and recrystallized from a mixture of ethanol and ethyl acetate to give 3-(4-methoxybenzenesulfonyl)-4-oxothiazolidine (1.65 g) as slightly brown prisms.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:26])[C:19]([O:21][CH2:22][CH:23]4[CH2:25][O:24]4)=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:27])[NH:6]2.[CH3:28][N:29]([CH3:34])[S:30]([NH2:33])(=[O:32])=[O:31].[C:35](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:26])[C:19]([O:21][CH2:22][CH:23]([OH:24])[CH2:25][CH2:35][NH:33][S:30]([N:29]([CH3:34])[CH3:28])(=[O:32])=[O:31])=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:27])[NH:6]2
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2c(F)c(Oc3ncnn4cc(OCC5CO5)c(C)c34)ccc2[nH]1
Reactant: CN(C)S(N)(=O)=O
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCC(O)CCNS(=O)(=O)N(C)C)c(C)c34)ccc2[nH]1
Yield: 24.6 %

Procedure:
A mixture of Example 2 (40 mg, 0.11 mmol), N,N-dimethylsulfamide (94 mg, 0.66 mmol) and potassium carbonate (91 mg, 0.66 mmol) in DMF (0.5 ml) was stirred at 80° C. for 1.5 h. The mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC, followed by chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford the title compound (13.7 mg, 25% yield) as a white solid. MS: (M+H)+=493.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]([NH:20][OH:21])=[NH:19])[N:9]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=O)=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([C:18]3[N:19]=[C:27]([C:26]4[CH:30]=[CH:31][C:23]([NH2:22])=[N:24][CH:25]=4)[O:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: N=C(NO)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Reactant: Nc1ccc(C(=O)O)cn1
Product: Nc1ccc(-c2nc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)no2)cn1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-N-hydroxy-6-trifluoromethyl-pyrimidine-2-carboxamidine (example C.1) (0.16 g, 0.5 mmol) and commercially available 6-amino-nicotinic acid (0.07 g, 0.5 mmol according to the general procedure VI. Obtained as an off-white solid (0.059 g, 28%). MS (ISP) 418.9 [(M+H)+]; mp 191° C.
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([O:23]CC=C)[CH:14]=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCOCCO[CH2:35][CH2:36]OC.Cl[CH2:40]Cl>>[CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([OH:23])[C:14]([CH2:40][CH:35]=[CH2:36])=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:10])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOc1ccc(OCC)c2c1S(=O)(=O)N(Cc1ccccc1)C2=O
Reactant: COCCOCCOCCOC
Reactant: ClCCl
Product: C=CCc1cc(OCC)c2c(c1O)S(=O)(=O)N(Cc1ccccc1)C2=O
Temperature: 200 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
A mixture of 2-benzyl-4-ethoxy-7-allyloxysaccharin (0.25 g) and triglyme was heated at 200° C. for 20 minutes, examined for extent of reaction by thin layer chromatography, heated at 200° C. for 20 minutes more, stirred overnight and poured into ice-water. The resulting tacky, brown solid was dissolved in dichloromethane. The dichloromethane solution was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and stripped of dichloromethane. Column chromatography of the residue (0.29 g) on silica using dichloromethane and dichloromethane-acetone (up to 99:1) as eluants afforded 2-benzyl-4-ethoxy-6-allyl-7-hydroxysaccharin (90 mg, 36% yield) whose mass spectrogram showed a molecular ion at mass 373.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C@@H:8]([NH:21][C:22](=[O:36])[C@@H:23]([NH:31][C:32]([O:34][CH3:35])=[O:33])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17](=[O:20])(=[O:19])[OH:18])=[CH:12][CH:11]=2)[S:6][CH:7]=1)[CH3:2].[OH-].[Na+].N(C)(C)C.COS(O[Na:49])(=O)=O>CO.O>[CH2:1]([C:3]1[N:4]=[C:5]([C@@H:8]([NH:21][C:22](=[O:36])[C@@H:23]([NH:31][C:32]([O:34][CH3:35])=[O:33])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17](=[O:18])(=[O:19])[O-:20])=[CH:12][CH:11]=2)[S:6][CH:7]=1)[CH3:2].[Na+:49]
Reactant: CCc1csc([C@H](Cc2ccc(NS(=O)(=O)O)cc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC)n1
Reactant: COS(=O)(=O)O[Na]
Agent: CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1csc([C@H](Cc2ccc(NS(=O)(=O)[O-])cc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 4-((S)-2-(4-ethylthiazol-2-yl)-2-((S)-2-(methoxycarbonylamino)-3-phenylpropanamido)ethyl)-phenylsulfamic acid (75) (150 g, 0.272 mmol) in methanol (1.2 L) was added 50% NaOH (11.3 g, 0.272 mol, 1.0 equiv.) at room temperature. The resulting mixture was stirred at rt for 30 min and then concentrated under reduced pressure to give the crude product, which contained a small amount of Me3N and MeOSO3Na. To a stirred slurry of the crude product (75 g) in H2O (150 mL) was added aq. NaOH (2 g, 0.05 mol; in 50 mL H2O) in dropwise at room temperature. The slurry was continued to stir for 20 min, filtered and washed with water (10 mL) and ethyl ether (50 mL). Then the filter cake was dried under reduced pressure at 50° C. to give 62 g (83%) of the desired compound. LC/MS (M−1): 531; H-NMR (300 MHz, CD3OD) δ: 7.21-6.98 (m, 10H), 5.40-5.36 (t, 1H, J=6.9 Hz), 4.38-4.34 (t, 1H, J=7.5 Hz), 3.61 (s, 3H), 3.24-3.23 (m, 1H), 3.11-3.01 (m, 2H), 2.81-2.74 (m, 3H), 1.31-1.26 (t, 3H, J=7.5 Hz); HPLC: 98.5%.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:34][C:35]1[CH:40]=[C:39]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:4][CH2:3][C:2]([F:1])([F:33])[CH2:7][CH2:6]2)=[O:9])[CH:38]=[CH:37][CH:36]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCC(N2CCOCC2)CC1
Yield: 64 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white solid (64%).
Reaction SMILES: [C:1]12[C:8]3=[CH:9][CH:10]=[CH:11][CH:12]=[C:7]3[C:6](=[O:13])[O:5][C:3](=[O:4])[C:2]1=[CH:14][CH:15]=[CH:16][CH:17]=2.C[OH:19]>>[C:1]1([C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([OH:5])=[O:13])[C:2](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:3]([OH:19])=[O:4]
Reactant: CO
Reactant: O=c1oc(=O)c2ccccc2c2ccccc12
Product: O=C(O)c1ccccc1-c1ccccc1C(=O)O

Procedure:
Diphenic anhydride (10 g, 0.045 mol) was dissolved in 30 ml of methanol and refluxed overnight. Removal of the solvent and drying the product under vacuum afforded 11.8 g of diphenic acid momo-methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[NH:13][C:12](=[S:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[O:15](C)[S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[N:13]=[C:12]([S:14][CH3:19])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[O-:18][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:17])=[O:15]
Reactant: Fc1cccc([C@@H]2COCC(=S)N2)c1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CSC1=N[C@H](c2cccc(F)c2)COC1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a room temperature solution of (R)-5-(3-fluoro-phenyl)-morpholine-3-thione (128 mg, 0.61 mmol) in methylene chloride (5 mL) under N2 atmosphere was added methyl triflate (0.2 mL, 1.77 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then concentrated under reduced pressure to give crude (R)-3-(3-fluoro-phenyl)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]oxazine as a triflate salt, which was used directly without further purification.
Reaction SMILES: Cl[CH:2]([C:6](=O)[CH3:7])[C:3](=O)[CH3:4].[Cl:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[C:14]([Cl:16])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.[NH2:25][NH2:26]>CC(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[O:17][C:2]1[C:6]([CH3:7])=[N:25][NH:26][C:3]=1[CH3:4]
Reactant: NN
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1n[nH]c(C)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 60 °C
Yield: 31.5 %

Procedure:
A mixture of 3-chloro-2,4-pentanedione (5.00 g, 37.0 mmol), 3,5-dichlorophenol (6.03 g, 37.0 mmol), cesium carbonate (12.0 g, 37.0 mmol) and acetone (40 ml) was heated under reflux for 18 hours. After cooling the solid was removed by filtration and the filtrate concentrated under reduced pressure. The intermediate was dissolved in ethanol (30 ml) and hydrazine hydrate (1.85 g, 37.0 mmol) was added and the mixture heated at 60° C. for 30 minutes. After cooling the mixture was concentrated under reduced pressure and the residue purified by flash column chromatography on silica gel eluting with ethyl acetate:pentane (30:70, by volume) to provide the title compound (3.00 g) as a yellow oil which solidified on standing to leave a yellow solid, m.p. 85-87° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.Cl.[O:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:37][CH:34]1[CH2:35][CH2:36][O:31][CH2:32][CH2:33]1)=[O:6]
Reactant: NC1CCOCC1
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Nc1c(Br)cccc1C(=O)NC1CCOCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
A yellow mixture of 2-amino-3-bromobenzoic acid (Oakwood Products, Inc., West Columbia, S.C., 2.125 g, 9.83 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (6.37 mL, 10.82 mmol), tetrahydro-2H-pyran-4-amine hydrochloride (Combi-Blocks, Inc., San Diego, Calif., 4.06 g, 29.5 mmol), and DIEA (5.15 mL, 29.5 mmol) was stirred at 0° C. for 5 min; the reaction mixture was then warmed to RT and stir for 30 min when product was observed via LCMS. The reaction mixture was diluted with EtOAc (150 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (4×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated to give 2-amino-3-bromo-N-(tetrahydro-2H-pyran-4-yl)benzamide (515a, 1.54 g, 5.15 mmol, 52% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.49-1.63 (m, 2H) 2.00 (dd, J=12.52, 2.15 Hz, 2H) 3.53 (td, J=11.69, 2.05 Hz, 2H) 3.95-4.05 (m, 2H) 4.10-4.21 (m, 1H) 5.87 (d, J=7.24 Hz, 1H) 6.06 (br. s., 2H) 6.54 (t, J=7.92 Hz, 1H) 7.25-7.30 (m, 1H) 7.51 (dd, J=7.82, 1.17 Hz, 1H). MS (ESI, pos. ion) m/z: 299.0/301.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[CH2:7][CH:8]3[CH2:13][N:9]3[S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[CH2:18]([CH2:20][NH2:21])[OH:19].C(N(CC)CC)C>O1CCCC1>[OH:19][CH2:18][CH2:20][NH:21][CH2:13][CH:8]1[CH2:7][C:6]2[CH:14]=[CH:15][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[NH:9]1
Reactant: NCCO
Reactant: O=S1(=O)c2cc(C(F)(F)F)ccc2CC2CN21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S1(=O)NC(CNCCO)Cc2ccc(C(F)(F)F)cc21
Yield: 147.1 %

Procedure:
A solution of 8,8a-dihydro-5-(trifluoromethyl)-1H-azirino[1,2-b][1,2]benzothiazine 3,3-dioxide (685 mg, 0.260 mmol), ethanolamine (0.785 mL, 13.0 mmol) and triethylamine (0.33 mL, 2.6 mmol) in tetrahydrofuran (25 mL) was heated in a sealed tube at 100° C. for 3 h. The cooled reaction was concentrated in vacuo. The residue was chromatographed (silica, 2%–20% methanol/dichloromethane gradient) to provide 3,4-dihydro-N-(2-hydroxyethyl)-7-(trifluoromethyl)-2H-1,2-benzothiazine-3-methanamine 1,1-dioxide as a white solid (124 mg) and additional impure material: LCMS (neg. ion spectrum) m/z 323.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:17][CH3:18])[C:9]3[C:14]([OH:15])=[CH:13][N:12]=[CH:11][C:10]=3[N:16]=2)=[N:4][O:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38]I)[CH2:34][CH2:33]1)=O)(C)(C)C.O>CC(C)=O>[CH2:17]([N:8]1[C:9]2[C:14]([O:15][CH2:38][CH:35]3[CH2:36][CH2:37][NH:32][CH2:33][CH2:34]3)=[CH:13][N:12]=[CH:11][C:10]=2[N:16]=[C:7]1[C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Reactant: CCn1c(-c2nonc2N)nc2cncc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCn1c(-c2nonc2N)nc2cncc(OCC3CCNCC3)c21
Reaction time: 6 h
Yield: 39 %

Procedure:
A mixture of the product from Example 283 (0.1 g, 0.406 mmol) and K2CO3 (0.112 g, 0.812 mmol) in acetone (3 ml) at −78° C. was treated with 4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester (Villalobos, A; et al, J. Med. Chem., 1994, 37(17), 2721) (0.145 g, 0.447 mmol) and heated at reflux for 18 hours. A further portion of 4-iodomethylpiperidine-1-carboxylic acid tert-butyl ester (0.145 g, 0.447 mmol) was then added and the heating continued for a further 6 hours. The reaction was then cooled, poured into water, extracted with dichloromethane, dried with NaSO4 and reduced. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound, (0.071 g, 39%); MS (ES+) m/e 444 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[N:8][O:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OCC)C>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[CH2:6]([O:5][C:3]([C:2]1[N:1]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[O:9][N:8]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(N)=NOC(=O)c1cnccc1C(F)(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1noc(-c2cnccc2C(F)(F)F)n1

Procedure:
20 g of ethyl 2-amino-2-(4-trifluormethyl-3-pyridinecarbonyloxyimino)-acetate are dissolved in 200 ml of a mixture of xylene and toluene and admixed with 5 g of Amberlyst 15. The mixture is boiled at 125-130° C. for 6 h using a Dean-Stark apparatus. After the reaction has ended, the mixture is cooled and admixed with a small amount of diethyl ether. The mixture is filtered with suction through a glass filter frit, and the solution is then concentrated. This gives 15.8 g of the product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][Cl:20]>CN(C)C=O>[Cl:20][CH2:19][CH2:18][CH2:17][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:2]([CH3:1])=[CH2:3])[C:5]1=[O:13]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a stirred solution of 8.5 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one in 45 parts of N,N-dimethylformamide are added portionwise 1.7 parts of a sodium hydride dispersion 78%. After stirring for 1 hour at room temperature, the whole is cooled to 0°-5° C. and 8.65 parts of 1-bromo-3-chloropropane are added dropwise (slowly). Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto crushed ice and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 5.5 parts (44%) of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one; mp. 115° C.