Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C:10](B(O)O)=[CH:9][CH:8]=1)=[O:5].I[C:37]1[N:41]2[CH:42]=[CH:43][C:44]([CH3:46])=[CH:45][C:40]2=[N:39][C:38]=1[C:47]1[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:32]([O:31][C:29](=[O:30])[N:2]([CH3:1])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:37]2[N:41]3[CH:42]=[CH:43][C:44]([CH3:46])=[CH:45][C:40]3=[N:39][C:38]=2[C:47]2[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=2)=[C:11]([C:13]#[C:14][Si:15]([CH:19]([CH3:20])[CH3:21])([CH:22]([CH3:23])[CH3:24])[CH:16]([CH3:18])[CH3:17])[N:12]=1)=[O:5])([CH3:34])([CH3:33])[CH3:35]
Reactant: CC(C(=O)Nc1ccc(B(O)O)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Reactant: Cc1ccn2c(I)c(-c3ccncc3)nc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccn2c(-c3ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc3C#C[Si](C(C)C)(C(C)C)C(C)C)c(-c3ccncc3)nc2c1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of [6-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoylamino]-2-[2-tri(propan-2-yl)silylethynyl]pyridin-3-yl]boronic acid D1a (1.5 g, 3.0 mmol), 3-iodo-7-methyl-2-pyridin-4-ylimidazo[1,2-a]pyridine Za (1.3 g, 3.9 mmol), Na2CO3 (0.95 g, 8.9 mmol), Dichlorobis(triphenylphosphine)palladium(II) (209 mg, 0.3 mmol), dioxane (30 ml) and water (5 ml) is stirred under argon atmosphere for 17 h at 70° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 965 mg (49%). HPLC-MS: M+H=667; tR=2.04 min (*Method—3).
Reaction SMILES: [OH-].[Na+:2].[Na+].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.Cl[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH3:27])[CH:18]=1.[I-].[Na+]>C(O)C>[Na+:2].[CH3:27][C:19]1[CH:18]=[C:17]([CH2:16][O:4][C:5]2[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:12])=[O:13])=[CH:7][CH:6]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(COc2ccc(S(=O)(=O)[O-])cc2)c2ccccc2n1
Temperature: 25 °C
Yield: 73 %

Procedure:
Sodium hydroxide 3.0 M (8.7 ml) was added to a suspension of 4-hydroxybezenesulfonic acid sodium salt (5.0 g, 22.0 mmol), 4-chloromethyl-2-methylquinoline (5.0 g, 26.0 mmol) and sodium iodide (0.4 g, 2.7 mmol) in ethanol (80 ml). The reaction was heated to reflux for 18 h, allowed to cool to room temperature to crystallize a white solid. The solids were filtered off, washed with ethanol, chloroform and dried in vacuo to give 4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonic acid sodium salt (5.5 g, 73%) as a crystalline solid. MS found: (M−Na)−=328.
Reaction SMILES: [NH3:1].CO.Br[CH2:5][C:6]1[C:7]([F:23])=[C:8]([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:17]#[N:18])[C:9]([F:12])=[CH:10][CH:11]=1>C1COCC1>[NH2:1][CH2:5][C:6]1[C:7]([F:23])=[C:8]([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:17]#[N:18])[C:9]([F:12])=[CH:10][CH:11]=1
Reactant: N
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CBr)c2F)c1
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A 7M solution of ammonia in MeOH (45.8 mL, 321 mmol) was added to a solution of 3-{[3-(bromomethyl)-2,6-difluorophenyl]oxy}-5-chlorobenzonitrile (2.3 g, 6.41 mmol) in THF (30 mL) at RT. The reaction was capped and stirred for 16 h at RT then concentrated to dryness under vacuum. Ethyl acetate (200 mL) and saturated aqueous NaHCO3 solution (300 mL) were added. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (2×200 mL), water (200 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated to give a white solid. The crude product was purified on silica gel (10% MeOH/DCM) to give the title compound (1.63 g, 86%) as a white solid (N4011-13-100). 1H NMR (400 MHz, DMSO-d5) δ ppm 7.82 (s, 1H), 7.40-7.66 (m, 3H), 7.31 (t, 1H), 3.75 (s, 2H), 1.86 (br. s., 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:31])[N:21]3[O:26][S:27]([O-:30])(=[O:29])=[O:28])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[O:31]=[C:20]1[N:19]2[CH2:25][C@@H:22]([CH2:23][CH2:24][C@H:18]2[C:16]([NH:15][O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:17])[N:21]1[O:26][S:27]([OH:30])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NOC1CCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium ({[(2S,5R)-2-({[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 30 (0.64 g, 0.89 mmol) in DCM (36 mL) was added trifluoroacetic acid (1.78 mL, 23.1 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)-7-oxo-N-(piperidin-4-yloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 6 (Table 1) (0.08 g, 25%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:35])[N:13]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH:14]2[CH2:19][CH2:18][C:17]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl.CN(C)CCCN=C=NCC.[NH2:48][C:49]1[NH:53][N:52]=[N:51][N:50]=1.O>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:35])[N:13]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:48][C:49]3[N:50]=[N:51][NH:52][N:53]=3)=[O:31])=[CH:33][CH:34]=2)[CH:14]2[CH2:15][CH2:16][C:17]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:18][CH2:19]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(NC(=O)N(Cc2ccc(C(=O)O)cc2)C2CCC3(CCCCC3)CC2)c1
Reactant: Nc1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C2CCC3(CCCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-[3-(3-Methylsulfonylphenyl)-1-spiro[5.5]undec-3-yl-ureidomethyl]benzoic acid (32.2 mg, 64.6 μmol) was dissolved in DMF (1 mL) and added N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC) (16.5 mg, 86 μmol) and 5-aminotetrazole.H2O (16,5 mg, 160 μmol). The mixture was stirred at 25° C. for 1 day and concentrated in vacuo. Brine (5 mL) was added to the residue followed by a mixture of ethanol and chloroform (1:2, 10 mL). The phases were separated and the aqueous layer was extracted with a mixture of ethanol and chloroform (1:2, 2×10 mL). The combined organic extracts were dried over MgSO4 and evaporated. The residue was purified by preparative HPLC affording the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH:29]([CH2:37][CH3:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:29]([CH2:37][CH3:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C(CCc1ccc(O)c(F)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Product: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F)C(=O)OC(C)(C)C

Procedure:
Tert-butyl 2-(2-fluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-butanoate is prepared from 3-(3-fluoro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl 2-bromobutanoate according to general procedure D.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12](Br)=[CH:13][CH:14]=2)[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:22][CH:23]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1>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.C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:30]3[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][CH:23]([CH3:22])[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:28][CH:29]=3)=[CH:13][CH:14]=2)[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)CCCC(C)CCOc1ccc(OB(O)O)cc1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(C(=O)OCC)c2cc(-c3ccc(OCCC(C)CCCC(C)C)cc3)ccc12
Yield: 54.1 %

Procedure:
Under argon atmosphere and in a toluene/water mixed solvent, 6-bromonaphthalene-1,4-dicarboxylic-acid diethyl ester 4.5 g and 4-(3,7-dimethyloctyloxy)phenyl boric acid 4.0 g were reacted with using tetrakis(triphenylphosphine)palladium under a condition of usual Suzuki reaction. Purification by column treatment (silica gel/toluene) was carried out, and 6-(4-(3,7-dimethyloctyloxy)phenyl)naphthalene-1,4-dicarboxylic-acid diethyl ester 3.5 g was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]#[N:14])[C:11]#[N:12].[OH-].[Na+].S(OC)(O[CH3:21])(=O)=O>O>[CH3:21][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]1=[C:10]([C:13]#[N:14])[C:11]#[N:12]
Reactant: COS(=O)(=O)OC
Reactant: N#CC(C#N)=C1Nc2ccccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1C(=C(C#N)C#N)Oc2ccccc21
Reaction time: 1 h

Procedure:
9.15 g. (0.05 M) of 2-benzoxazolinylidene-malononitrile and 16.0 g. (0.4 M) of sodium hydroxide are dissolved in 500 ml. of water. The solution is brought to 5° C. while stirring and, over a period of 1 hour, 25.2 g. (0.2 M) of dimethyl sulfate are added dropwise. The resulting crystals are filtered off under suction, washed with water and dried to obtain 3-methyl-benzoxazolinylidene-malononitrile of melting point 198°-200° C.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[C:3]1[CH:11]=[O:12].[C:13](Cl)(=[O:15])[CH3:14]>C(Cl)Cl>[C:13]([N:7]1[CH2:8][CH2:9][C:10]2[S:2][C:3]([CH:11]=[O:12])=[CH:4][C:5]=2[CH2:6]1)(=[O:15])[CH3:14]
Reactant: O=Cc1cc2c(s1)CCNC2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CCc2sc(C=O)cc2C1
Yield: 71.4 %

Procedure:
To a cold (0° C.) suspension of 1.5 g.(7.4 mmol) of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carbaldehyde hydrochloride in 50 mL methylene chloride, under N2 atm., dry conditions, was added dropwise under stirring 2.6 mL (2.5 eqs) of triethylamine. RM stirred for 30 min at 0°C. and a solution of 0.7 g.(8.1 mmol,1.1 eqs) of acetyl chloride in 15 mL methylene chloride was dropwise added, RM allowed to reach RT and stirred for 3 hours. Filtered trough a celite pad, filtrate washed with 3×50 mL water, dried, evaporated, gave 1.1 g.(71.4%) of the title compound, viscous oil, (M+H)+210.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(Cl)(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:20])[CH:18]=[CH2:19]
Reactant: O=C1CCCN1CCO
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CC(=O)OCCN1CCCC1=O
Reaction time: 2 h
Yield: 70 %

Procedure:
Into a solution of 50 mL of 1-(2-hydroxyethyl)-2-pyrrolidone and 85 mL of triethylamine in 150 mL of chloroform, a solution of 50 mL of acryloyl chloride in 100 mL of chloroform was dropped over 2 hours with stirring. The reaction mixture was stirred at 4° C. for 20 hours, then at 50° C. for 2 hours. After being cooled, the solution was filtered and the filtrate was washed with a 15% aqueous sodium carbonate solution and then concentrated under vacuum. The obtained oily material was distilled under vacuum to give the title compound in a yield of 70%.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[C:7]([CH2:13][C:14]#[N:15])=[CH:6][CH:5]=1)([O-])=O.[C:16](OC(=O)C)(=[O:18])[CH3:17].O1CCCC1>[Pd].C(OCC)(=O)C>[C:14]([CH2:13][C:7]1[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:4]([NH:1][C:16](=[O:18])[CH3:17])=[CH:5][CH:6]=1)#[N:15]
Reactant: N#CCc1ccc([N+](=O)[O-])c2ccoc12
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CC#N)c2occc12
Reaction time: 0.75 h
Yield: 67.8 %

Procedure:
Add (4-nitrobenzofur-7-yl)acetonitrile (600 mg, 2.96 mmol), acetic anhydride (600 mg, 5.88 mmol), and 5% palladium on carbon (300 mg) to tetrahydrofuran (25 mL). Stir under hydrogen (1 atm) for 45 minutes. Dilute with ethyl acetate, filter through a pad of Celite®, and concentrate under reduced pressure. Chromatograph on flash silica using 75% ethyl acetate, 25% hexane gives 430 mg (67%) of the title compound as an off-white solid. HRMS (M+H)=215.0816.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 27.2 %

Procedure:
The title compound (0.1 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 4-methoxybenzyl chloride (1.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C21H22ClN3O, 367.15; found, m/z 368.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.41-7.39 (m, 2H), 7.31 (d, J=7.7 Hz, 2H), 6.70 (d, J=7.7 Hz, 2H), 5.36 (s, 2H), 3.60 (s, 3H), 3.33-3.31 (br m, 2H), 3.21-3.19 (br m, 2H), 3.18-3.16 (br m, 2H), 2.96-2.94 (br m, 2H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:36])/[CH:23]=[C:24](\[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)/[CH:25]([CH3:27])[CH3:26])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[NH4+:47]>CO>[CH3:27][CH:25](/[C:24](/[C:28]1[CH:29]=[C:30]([C:34]([NH2:35])=[NH:47])[CH:31]=[CH:32][CH:33]=1)=[CH:23]/[C:22](=[O:36])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:20][CH:19]=1)[CH3:26]
Reactant: [NH4+]
Reactant: CC(C)/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)/C(=C/C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To a solution of crude (2Z)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-4-methylpent-2-enamide (190 mg, 0.379 mmol) in 10 ml 1:1 ethyl acetate:anhydrous methanol cooled to −78° C. was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (115 mg, 1.5 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1Z)-1-(methylethyl)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzene carboxamidine (75 mg, 43%) as a fluffy white powder after lyophilization. ES-MS (M+H+): 463.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)=O.O>CS(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[N:8]=[C:4]2[CH:3]=1
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: Nc1cc(Cl)ncn1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(-c2cn3cnc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
6-Chloropyrimidin-4-amine (50 mg, 0.39 mmol) and 2-bromo-1-(3-nitrophenyl)ethanone (94 mg, 0.39 mmol) were dissolved in 2 mL of DMSO and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into 5 mL of water and it was then extracted with ethyl acetate. The filtrate was dried (Na2SO4) and evaporated. The compound was purified by silica gel column chromatography by using hexane/ethyl acetate (3:1) as eluent (60 mg, 56% Yield). MS m/z 275.00 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=2[O:22][CH:23]([F:25])[F:24])[CH2:9]1)(OC(C)(C)C)=O.Cl.C(O)(=O)/C=C/C(O)=O>CC(O)C.C(OCC)C>[Br:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH:23]([F:25])[F:24])=[C:15]([CH:20]=1)[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cc(Br)ccc2OC(F)F)C1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: CCOCC
Product: FC(F)Oc1ccc(Br)cc1C[C@@H]1CNCCO1

Procedure:
N-Boc-(R)-2-(5-bromo-2-difluoromethoxy-benzyl)-morpholine, was deprotected using hydrogen chloride (4M, in methanol) and isolated using SCX-2 columns as described for example 4 followed by treatment with fumaric acid in IPA-diethyl ether afforded the morpholine example 61 as the fumarate salt as a white solid (108 mg, 30%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)=[C:6]([NH2:23])[CH:5]=1.CO[C:27](=N)[C:28]([Cl:31])([Cl:30])[Cl:29]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][C:12]3[CH:16]=[C:15]([C:17]4[S:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[O:14][N:13]=3)[C:27]([C:28]([Cl:31])([Cl:30])[Cl:29])=[N:23][C:6]=2[CH:5]=1)=[O:24]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(NCc2cc(-c3ccc(Cl)s3)on2)c(N)c1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)nc(C(Cl)(Cl)Cl)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
36.0 mg (0.098 mmol) 3-Amino-4-{[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-amino}-benzoic acid methyl ester were dissolved in 3 mL acetic acid. 17.4 μl (0.14 mmol) 2,2,2-trichloro-acetimidic acid methyl ester were added and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was co-distilled twice with 15 mL toluene to give crude 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester as a brown solid. Yield: 49 mg MS (ES+): m/e=491, chloro pattern.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].C([O-])(O)=O.[Na+].[H][H]>CO.O1CCOCC1.[Pd]>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:2]2
Reactant: COC(=O)c1cnc2ccc(OC)nc2c1Br
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cnc2ccc(OC)nc2c1
Yield: 96.7 %

Procedure:
To a mixture of methyl 4-bromo-6-(methyloxy)-1,5-naphthyridine-3-carboxylate (1.67 g, 5.64 mmol)) and NaHCO3 (0.84 g, 10 mmol) in MeOH (20 ml) and 1,4-dioxane (15 ml) was added 10% Pd/C (0.75 g) and the mixture was then stirred at rt under 1 atmosphere of hydrogen for 3 h. The reaction mixture was then filtered through a thin pad of Celite, washing through with EtOH. The filtrate was evaporated and stirred in 50 ml of water, the solid was then filtered off and dried in vacuo to give the desired product (1.19 g, 96%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]2[C:10](=[O:15])[O:11][C:12](=O)[NH:13][C:8]=2[CH:7]=[C:6]([Cl:16])[CH:5]=1>CO>[NH2:13][C:8]1[CH:7]=[C:6]([Cl:16])[CH:5]=[C:4]([Cl:3])[C:9]=1[C:10]([O:11][CH3:12])=[O:15]
Reactant: O=c1[nH]c2cc(Cl)cc(Cl)c2c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(N)cc(Cl)cc1Cl
Temperature: 55 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a stirred solution of sodium hydroxide (0.070 g, 1.8 mM) in methanol (8.5 mL) was added 5,7-dichloro-2H-3,1-benzoxazine-2,4(1H)-dione (4.13 g, 17.8 mM). The reaction mixture was stirred at 55° C. for 2 hr, allowed to cool to room temperature and concentrated. The residue was diluted with water and the resulting mixture extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered and concentrated to leave the methyl 2-amino-4,6-dichlorobenzoate (3.61 g, 92.1%) as a brown solid; MS(CI): 220 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[C:7]1=[O:20].Cl.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([CH3:41])([C:38](O)=[O:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([C:38]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[CH2:5][N:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=3)[C:7]2=[O:20])=[O:39])([CH3:41])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc2ccn(Cc3cccc(N)c3)c(=O)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2ccn(Cc3cccc(NC(=O)C4(C)CCN(C(=O)OC(C)(C)C)CC4)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of methyl 2-(3-aminobenzyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate.HCl (0.22 g, 0.64 mmol) in pyridine (5 mL) was added 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (0.17 g, 0.70 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.37 g, 1.9 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was then concentrated and the crude residue was purified by flash silica gel chromatography (0% to 5% EtOAc/DCM) to afford methyl 2-[3-({[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]carbonyl}amino)benzyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.29 g, 83%). LC-MS: (FA) ES+ 434.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C(#N)C.[Cl:11][CH2:12][C:13](Cl)=[O:14]>ClCCCl>[Cl:11][CH2:12][C:13]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)=[O:14]
Reactant: O=C(Cl)CCl
Reactant: Nc1cncnc1
Solvent: CC#N
Solvent: ClCCCl
Product: O=C(CCl)Nc1cncnc1
Temperature: 80 °C

Procedure:
5-Aminopyrimidine (450 mg) was suspended in DCE (2 mL) and acetonitrile (2 mL) in a microwave vial. Chloroacetyl chloride (0.377 mL) was added with stirring. The vial was sealed and the reaction mixture was heated in the microwave at 80° C. for 5 minutes. The solid was filtered off, washed with acetonitrile (2×5 mL), DCE (2×5 mL) and pentane (2 ×30 mL) and then partioned between saturated sodium bicarbonate and DCE (50 mL/50 mL) ensuring the aqueous layer was still basic. The organic layer was separated and the aqueous layer was extracted with DCE (2×75 mL). The combined organic layer was dried over magnesium sulfate and evaporated to give the sub-titled compound (200 mg) as a yellow solid.