Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH2:8].C(N(C(C)C)CC)(C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27](Cl)=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:32]([N+:33]([O-:35])=[O:34])=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccccc1OCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1OCCNC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 23 °C
Yield: 74.3 %

Procedure:
A mixture comprising 2-(2-methoxyphenoxy)ethylamine (10 g, 59.9 mmol), diisopropylethylamine (13.9 mL, 81.6 mmol) and dichloromethane (80 mL) was cooled to 0° C. and then a solution of 3-methoxy-4-nitrobenzoyl chloride (11.76 g, 54.4 mmol) in dichloromethane (50 mL) was added dropwise. The mixture was allowed to warm to 23° C. over two hours, quenched with aqueous hydrochloric acid (3M, 20 mL), washed with water (3×20 mL), dried (Na2SO4) and concentrated in vacuo to provide N-[2-(2-methoxyphenoxy)ethyl]-3-methoxy-4-nitrobenzamide (14 g, 74% yield) an off white solid; MS (PB-PCI) C17H18N2O6 m/e calc 346.34; found 347 (MH+).
Reaction SMILES: [NH3:1].[ClH:2].[Br:3][C:4]1[C:12]([F:13])=[CH:11][C:7]([C:8](=[NH:10])O)=[CH:6][C:5]=1[F:14]>C(O)C>[ClH:2].[Br:3][C:4]1[C:12]([F:13])=[CH:11][C:7]([C:8]([NH2:1])=[NH:10])=[CH:6][C:5]=1[F:14]
Reactant: N=C(O)c1cc(F)c(Br)c(F)c1
Reactant: N
Agent: Cl
Solvent: CCO
Product: N=C(N)c1cc(F)c(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
450 cm3 of anhydrous ethanol saturated with dried gaseous ammonia was added to 4-bromo-3,5-difluorobenzimidate hydrogen chloride and stirred overnight at room temperature. About one-half of the volume of the solvent was distilled off and the residue was recrystallized to yield 90 g (0.36 mol) of 4-bromo-3,5-difluorobenzamidine hydrogen chloride.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1>CO>[CH3:1][O:2][C:5]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: [Na+]
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cn1
Yield: 134.3 %

Procedure:
To a solution of sodium methoxide (0.090 g of sodium) in MeOH (12 mL) was added 0.486 g (3.03 mmol) of 2-chloro-5-nitropyrimidine, and the mixture was heated under reflux for 1 hr. After cooling, the mixture was concentrated in vacuo, extracted with EtOAc, and washed with water. The aqueous layer was extracted with CHCl3 and the combined organic layers were dried (Na2SO4), and concentrated, to give 0.347 g (75% yield) of 2-methoxy-5-nitropyrimidine as a yellow powder: 1H NMR (CDCl3) δ9.31 (s, 2H), 4.17 (s, 3H); LCMS (APCI+) m/z: 156 (MH+, 100%).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[O:19]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][NH:22][C:21](=[O:30])[CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:27]3[CH2:26][CH2:25][C:24]4([O:19][CH2:20][C:21](=[O:30])[NH:22][CH2:23]4)[CH2:29][CH2:28]3)=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: O=C1COC2(CCNCC2)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COC2(CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2)CN1
Yield: 82.2 %

Procedure:
A solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (500 mg, 1.43 mmol), 1-oxa-4,9-diaza-spiro[5.5]undecan-3-one (315 mg, 1.85 mmol) and potassium carbonate (450 mg, 3.26 mmol) in DMF (40 mL) was stirred at ambient temperature for 18 hours, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM: MeOH 100:0 to 98:2 to 95:5) to afford the title compound as a white solid (515 mg, 82%). LCMS (Method A): RT=2.51 min, [M+H]+ 438.1
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[NH2:12][C:13]1[O:17][N:16]=[C:15]([CH3:18])[C:14]=1Br.[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][C:13]1[O:17][N:16]=[C:15]([CH3:18])[C:14]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(C)noc2N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil, 52 mg, 1.3 mmol) in dry dimethylformamide (2.0 ml) was added 4-methoxyphenol (0.15 g, 1.2 mmol). After stirring the solution at room temperature of 10 min, 5-amino-4-bromo-3-methylisoxazole (0.20 g, 1.1 mmol) was added, followed by bis(triphenylphosphine)palladium(11) chloride (79 mg, 0.11 mmol). The mixture was heated to 50° C. for 2.5 h and then cooled to room temperature. The dark brown reaction mixture was worked up with ethyl acetate and 5% NaOH. The organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel using 20% ethyl acetate in hexanes as eluent to give 0.13 g (51% yield) of 5-amino-4-(4-methoxyphenoxy)-3-methylisoxazole.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([C:10]#[N:11])=[CH:8][N:7]=[CH:6][CH:5]=1.[CH2:12]([SH:14])[CH3:13].[Cl-].[Na+]>C1COCC1>[CH2:12]([S:14][C:4]1[C:9]([C:10]#[N:11])=[CH:8][N:7]=[CH:6][CH:5]=1)[CH3:13]
Reactant: N#Cc1cnccc1Cl
Reactant: CCS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1ccncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.72 g of sodium hydride (60% oil-based) was added to a mixture of 5.0 g of 4-chloronicotinonitrile, 3 ml of ethanethiol and 36 ml of THF under ice cooling, then the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium chloride solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 5.72 g of 4-ethylsulfanylnicotinonitrile. 4-ethylsulfanylnicotinonitrile
Reaction SMILES: [Cl:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5](=[S:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cccc(NC(=O)c2ccccc2)c1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=S)c2ccccc2)c1Cl

Procedure:
98 g (0.4 mol) of the compound from Example V and 162 g (0.4 mol) of Lawesson's reagent were boiled in 1 l of toluene overnight, and the mixture was concentrated and purified on SiO2 (cyclohexane/ethyl acetate=8:2)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=2)[N:16]([CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29]([Cl:35])=[CH:30][CH:31]=3)[N:26]=2)[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].CN1CCOCC1.[CH:43]1([O:48][C:49](Cl)=[O:50])[CH2:47][CH2:46][CH2:45][CH2:44]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:49]([O:48][CH:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:50])[CH:21]=2)[N:16]([CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29]([Cl:35])=[CH:30][CH:31]=3)[N:26]=2)[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C(Cl)OC1CCCC1
Reactant: COC(=O)c1ccc(Cc2cn(Cc3ccc4ccc(Cl)cc4n3)c3ccc(N)cc23)c(OC)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(Cc3ccc4ccc(Cl)cc4n3)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Reaction time: 0.25 h

Procedure:
To the solution of the amine from Step 2 in CH2Cl2 (4 ml) at r.t. was successively added N-methylmorpholine (130 μl, 3 eq.) followed by cyclopentylchloroformate (176 μl, 3 eq.). After 15 mins, the mixture was quenched with aq NH4Cl and worked up in the usual manner. Chromatography on silica gel (EtOAc/toluene, 1:9) afforded the title carbamate (170 mg).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[N:15]=[C:16]2[S:29][CH:28]=[C:27]([CH3:30])[N:17]2[C:18](=[O:26])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[CH3:30][C:27]1[N:17]2[C:18](=[O:26])[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[C:14]([CH:12]([NH:11][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:13])[N:15]=[C:16]2[S:29][CH:28]=1
Reactant: Cc1csc2nc(C(C)N)c(-c3ccccn3)c(=O)n12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3ccccn3)c(=O)n12

Procedure:
A mixture of 6-bromo-9H-purine (9.300 mg, 0.004673 mmol), 7-(1-aminoethyl)-3-methyl-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (11 mg, 0.039 mmol), and N,N-diisopropylethylamine (8.152 μL, 0.004680 mmol) in ethanol (0.3 mL) was refluxed under nitrogen overnight. The mixture was concentrated under reduced pressure and the residue was purified on RP-HPLC (eluting with a gradient of methanol/water containing 1% TFA) to provide the product as a TFA salt. LCMS calculated for C19H17N8OS (M+H)+: m/z=405.1. Found: 405.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:20][C:19]=1[N:39]1[CH2:48][C:47]2[C:42](=[N:43][C:44](S(C)(=O)=O)=[N:45][CH:46]=2)[N:41]([CH3:53])[C:40]1=[O:54]>CN1CCCC1=O.C(OCC)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:20][C:19]=1[N:39]1[CH2:48][C:47]2[C:42](=[N:43][C:44]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:14][CH3:15])=[CH:12][CH:11]=3)=[N:45][CH:46]=2)[N:41]([CH3:53])[C:40]1=[O:54]
Reactant: CN1C(=O)N(c2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CCN(CC)CCOc1ccc(N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2cc(NC(=O)c4ccc(-c5ccccc5)cc4)ccc2Cl)C3)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 35 %

Procedure:
0.1 g 4-(2-Diethylamino-ethoxy)-phenylamine were dissolved in 1 mL N-methylpyrrolidinone (NMP) and cooled to 0° C. 300 μl of a solution of aqueous HCl in diethyl ether were added and stirred for 45 min. Biphenyl-4-carboxylic acid [4-chloro-3-(7-methanesulfonyl-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-amide was dissolved in 2 ml NMP and added to the aforementioned solution and the reaction mixture was heated at 120° C. for 24 h. The reaction was quenched by addition of 5 mL of a saturated solution of sodium carbonate and the aqueous phase was extracted with dichloromethane. The organic phase was dried over sodium sulfate and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol) to give the title product in 35% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH2:30]([OH:32])[CH3:31]>>[CH2:30]([O:32][CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1)[CH3:31]
Reactant: CCO
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1CCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCc1cncn1C1c2ccccc2C(=O)OC1(C)C

Procedure:
To a solution of 4-(5-chloromethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (0.150 g, 0.516 mmol), prepared as described in Example 18, in anhydrous ethanol (5 mL) is added diisopropylethyl amine (0.100 g, 0.77 mmol) and the mixture is stirred at reflux overnight. The mixture is purified by semi-preparative reverse phase HPLC to give 4-(5-ethoxymethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as a white solid; MS (ESI) m/z 301.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.26 (s, 3 H), 1.29 (t, J=6.1 Hz, 3 H), 1.54 (s, 3 H), 3.62 (br. s, 2 H), 4.70 (br. s, 2 H), 5.59 (s, 1 H), 7.02 (s, 1 H), 7.29 (br. s, 1 H), 7.52 (d, J=7.8 Hz, 1 H), 7.63 (td, J=7.8, 1.3 Hz, 1 H), 7.74 (td, J=7.6, 1.3 Hz, 1 H), 8.21 (dd, J=7.8, 1.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[N:13]=2)[CH:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CN1CCCC1=O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCCc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Solvent: CN1CCCC1=O
Product: CCCc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 130 °C

Procedure:
6-Chloro-4-(6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (289 mg, 991 μmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (425 mg, 1.98 mmol) were dissolved in N-methyl-2-pyrrolidinone (2 mL) and heated at 130° C. for 24 h. LCMS showed desired product mass, as well as starting material. A third equivalent of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate was added (213 mg, 0.991 mmol) and heating continued. After 8 h, a third portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.310 g) was added. After 24 h, the mixture was cooled and concentrated in vacuo (high vacuum, 100° C.) to a brown solid residue. Purification by chromatography (silica, 0 to 10% of a 9:1 MeOH:NH4OH solution in dichloromethane, 20 min) gave tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-propylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (271 mg, 577 μmol, 58%) as a light brown solid. LC-MS 470.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.[Cu]I>[N:11]1([C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1nc[nH]n1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cncn2)cc1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
To a stirred solution of 4-bromoacetophenone (10 g, 50 mmol) in DMF (100 mL), were added 1,2,4-triazole (5 g, 75 mmol), Cs2CO3 (32.6 g, 100.5 mmol) and CuI (1.4 g, 10.1 mmol) and the resultant reaction mixture was refluxed for 48 h. After completion of the reaction (by TLC), the reaction mixture was cooled to ambient temperature and diluted with water (200 mL) and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure. Purification by washing with diethyl ether afforded the title compound as a solid (5 g, 96%): 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.16, (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.6 Hz, 2H), 2.66 (s, 3H); ESIMS m/z 186.02 ([M−H]−).
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[CH:54]([C:57]1[O:58][C:59]([CH3:65])=[C:60]([C:62](O)=[O:63])[N:61]=1)([CH3:56])[CH3:55]>C(Cl)Cl>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:2])=[O:53])=[O:22])[N:24]([C:62]([C:60]5[N:61]=[C:57]([CH:54]([CH3:56])[CH3:55])[O:58][C:59]=5[CH3:65])=[O:63])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:38][CH:39]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1oc(C(C)C)nc1C(=O)O
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3nc(C(C)C)oc3C)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (30 mg) was reacted with 2-isopropyl-5-methyl-oxazole-4-carboxylic acid (according to a procedure in Synthesis, Vol. 10, pp. 1569-71 (2005)) in DCM (3.0 mL) according to General Procedure A and directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (8 mg). LCMS (m/z) 892.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36].[BrH:37].N([O-])=O.[Na+]>C(#N)C.O>[Br:37][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36]
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(N)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(Br)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A stirred suspension of 6-(N-(4-amino-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide (0.421 g, 0.773 mmol) in 25 mL of acetonitrile was treated with 25 mL of 48% aqueous HBr and the resulting suspension cooled in an ice water bath. To the mixture was added a solution of sodium nitrite (0.056 g, 0.812 mmol) in 2 mL of water. After stirring at 0° C. for 30 minutes an additional 14 mg portion of sodium nitrite in 1 mL of water was added. After stirring at 0° C. for another 30 minutes, the mixture was treated with CuBr (0.130 g, 0.906 mmol) in four portions over 5 minutes. The mixture was warmed to 60° C. for 30 minutes and then cooled to RT. The mixture was partitioned between EtOAc and 5% aqueous sodium bisulfite. The EtOAc solution was washed with 5% aqueous sodium bisulfite (2×), saturated aqueous sodium bicarbonate (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient from hexane to 3:7 hexane/EtOAc) followed by recrystallization from hexane/EtOAc to give the title compound (0.212 g, 45%) as a white solid. LCMS (m/z, ES+)=609 (M+H+).
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[S:25][C:26]1[S:30][N:29]=[N:28][C:27]=1[CH3:31])[C@H:20]([NH:32][C:33](=[O:63])[C:34]([C:56]1[N:57]=[C:58]([NH2:62])[S:59][C:60]=1[Cl:61])=[N:35][O:36]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]2=[O:64])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:62][C:58]1[S:59][C:60]([Cl:61])=[C:56]([C:34](=[N:35][OH:36])[C:33]([NH:32][C@@H:20]2[C:19](=[O:64])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([S:25][C:26]2[S:30][N:29]=[N:28][C:27]=2[CH3:31])=[C:17]3[C:15]([OH:16])=[O:14])=[O:63])[N:57]=1
Reactant: Cc1nnsc1SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC(c3ccccc3)(c3ccccc3)c3ccccc3)c3nc(N)sc3Cl)C2SC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnsc1SC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3nc(N)sc3Cl)C2SC1

Procedure:
To a solution of (7R)-7-[2-(2-amino-5-chlorothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(4-methyl-[1,2,3]thiadiazol-5-ylsulfanyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene 2-carboxylic acid benzhydryl ester (990 mg, 1.05 mmol) in dichloromethane (21 mL) was added triethylsilane (11 mL) followed by addition of trifluoroacetic acid (21 mL). After 1 hr at room temperature the reaction mixture was concentrated under vacuum. Disopropyl ether was added to the oily residue. The title compound precipitated and was filtered, washed with additional diisopropyl ether and dried under vacuum (528 mg, 95%).
Reaction SMILES: [S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[Cl:24])[O:6]1)[NH2:2].CCN(C(C)C)C(C)C.[C:36](Cl)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[C:36]([NH:2][S:1](=[O:26])(=[O:25])[O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:13])([CH3:14])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[Cl:24])[O:6]1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(Cl)ncnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(=O)(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@H]2n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of [(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl sulfamate (13.4 g, 33.1 mmol) in DCM (330 mL) at r.t. was added DIPEA (11.5 mL, 66.2 mmol) followed by Ph3CCl (9.23 g, 33.1 mmol). The reaction was stirred at r.t. for 4 hours. The mixture was diluted with DCM, the layers were separated, and the organic layer was washed with 1N HCl followed by brine. The combined organic phases were dried (Na2SO4) and concentrated to yield the title compound as a white solid (17.6 g, 82%).