Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:30]([CH2:29][CH2:28][CH2:27][Cl:26])(=[O:32])=[O:31])[CH2:24][CH2:25]2)[N:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 59) and chloropropanesulfonyl chloride (Aldrich) in an analogous manner as described in Example 177. HR-MS (ES, m/z) calculated for C20H26N5O4SFCI [(M+H)+] 486.1373, observed 486.1375.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]1([S:23]([NH:26][C:27](=[O:49])[C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:39][CH:38]=3)[CH:29]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[K+]>CN(C)C=O>[C:17]1([S:23]([NH:26][C:27](=[O:49])[C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:8](=[O:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:30]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)[CH:29]=2)(=[O:24])=[O:25])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
Triethylamine (0.115 g) and 0.200 g of benzoyl chloride were added to a solution of 0.500 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 5 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 15 hours. A potassium hydrogencarbonate aqueous solution was added thereto to stop the reaction. The solvent was distilled off under reduced pressure. The residue was dissolved in a mixture of water and methanol, and the solution was adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystals precipitated were collected, and were dried to obtain 0.393 g of crude N-benzenesulfonyl-4-benzoylamino-3-(biphenyl-4-ylmethylamino)benzamide. This crude product was converted to 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-phenylbenzimidazole [(246), 0.270 g] in the same manner as in Example 183.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[CH3:20]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1
Reactant: CC(=O)N(C)C
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.056 g (0.0002 mole) of (rac)-2-chloro-9-cyclopentyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 0.5 mL of N,N-dimethylacetamide and 0.018 mL (0.0003 mole) of iodomethane was added 0.012 g (0.0003 mole) of 60% sodium hydride in oil at 0 degrees. The mixture was stirred at ambient temperature for 1 hour, then 10 mL of water was added. The precipitate collected by filtration to give 0.049 g of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-1) as an yellow solid.
Reaction SMILES: O.[C:2]1([CH3:13])[CH:7]=[CH:6][C:5]([S:8]([NH:11][NH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:15]1[C:24]2[C:19](=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1>C(Cl)Cl>[CH3:13][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][NH:12][C:15]2[C:24]3[C:19](=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)NNc2ncnc3c([N+](=O)[O-])cccc23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
p-Toluene sulphonyl hydrazine hydrate (390 mg, 2.1 mmol) was added to a solution of 4-chloro-8-nitro-quinazoline 477 (400 mg, 1.91 mmol) in DCM at (10 ml) and the mixture was stirred at room temperature for 24 h. The mixture was concentrated in vacuo and washed with Et20 to give the title compound (650 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].FC1C=CC(C2C=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=2)=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=1
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)nc1
Product: O=C(O)c1ccc(-c2ccc(F)cc2F)nc1

Procedure:
The title compound was prepared from 2′,4′-difluoroacetophenone using the procedures outlined for 6-(4-fluorophenyl)nicotinic acid (D1-D3).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19](Br)[S:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.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.[Cu]I>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:31]#[C:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3csc(Br)n3)cc2)C1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C1CCN(c2ccc(NC(=O)c3csc(C#Cc4ccccc4)n3)cc2)C1
Temperature: 150 °C

Procedure:
2-Bromothiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (100 mg) was dissolved in tetrahydrofuran (2 ml), and phenylacetylene (52 mg), triethylamine (52 mg), triphenylphosphine (17 mg), bis(triphenylphosphine)palladium dichloride (89 mg) and copper (I) iodide (9.6 mg) were added. The reaction mixture was heated at 150° C. in a microwave apparatus for 3 minutes and then concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 416.55 (C24H24N4OS); MS (ESI): 417 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]2[CH3:20])=[CH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30]>CN(C=O)C.CCOC(C)=O>[CH3:20][N:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]1[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:28][C:29]([OH:31])=[O:30])[CH:2]=1
Reactant: CN1C(=O)c2ccccc2C1c1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)c2ccccc2C1c1cn(CC(=O)O)c2ccccc12
Temperature: 100 °C

Procedure:
The product from example 20, step b) (450 mg, 1.72 mmol) was dissolved in DMF and treated with K2CO3 (284 mg, 2.06 mmol) followed by t-butyl bromoacetate (255 μL, 1.72 mmol). The reaction was heated to 100° C. for 5 h. The reaction was cooled, diluted with EtOAc, washed 3 times with water, and concentrated. The crude product was treated with TFA (neat) at room temperature for 45 minutes. The reaction was then concentrated to dryness and purified by preparative LCMS to give the title compound. 1H NMR (CD3OD) δ 7.74-7.78 (m, 1H), 7.43 (t, J=3.7 Hz, 1H), 7.41 (t, J=3.6 Hz, 1H), 7.36 (s, 1H), 7.28-7.31 (m, 1H), 7.20 (d, J=8.1 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 6.67 (t, J=7.2 Hz, 1H), 6.48 (d, J=7.8 Hz, 1H), 4.62 (s, 2H), 2.78 (s, 3H); MS: ESI (negative): 319 (M−H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([NH2:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>O1CCCC1>[NH2:13][C:11](=[S:24])[C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:14])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Yield: 48.8 %

Procedure:
N2-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalaninamide (3.87 g, 19.13 mmol), Lawesson's reagent (7.74 g, 19.13 mmol) and tetrahydrofuran (THF) (100 mL) was heated to 50° C. for 3 hours. The reaction was concentrated, added 150 cc of EtOAc and washed with sat'd NaHCO3 (3×100 cc), water and brine. The EtOAc layer was concentrated and the residue was purified via chromatography on silica gel eluted Hex to 1:1 Hex/EtOAc to obtain the title compound (2.04 g, 48% yield).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([F:24])[CH:16]=1)([CH2:11][CH:12]([CH3:14])[CH3:13])C(OCC)=O)C>CC(O)=O.O.OS(O)(=O)=O>[F:24][C:17]1[CH:16]=[C:15]([CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([OH:25])=[O:3])[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: CCOC(=O)C(CC(C)C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CC(C(=O)O)c1ccc([N+](=O)[O-])c(F)c1

Procedure:
2-(3-Fluoro-4-nitro-phenyl)-2-isobutyl-malonic acid diethyl ester (92.0 g, 0.26 mol) was dissolved in AcOH/H2O/H2SO4 (96%) (500 mL/200 mL/70 mL) and the reaction mixture was refluxed for 24 h. After cooling and evaporation, water (300 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). The evaporation of solvent under reduced pressure gave a brown oil (61 g, quantitative), which was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.07-8.01 (m, 1H), 7.33-7.26 (m, 2H), 3.79-3.73 (m, 1H), 2.05-1.95 (m, 1H), 1.76-1.66 (m, 1H), 1.52-1.43 (m, 1H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 178.3, 156.0 (d, 1JCF=232.5 Hz), 147.0, 136.0, 126.2, 124.3, 118.1 (d, 2JCF=30 Hz), 49.3, 42.0, 25.8, 22.4, 22.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14]>CC(C)=O>[CH2:11]([C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=O)CBr
Reactant: Nc1ccccn1
Solvent: CC(C)=O
Product: CCCCc1cn2ccccc2n1
Yield: 53.1 %

Procedure:
A mixture of 6 g of 2-amino pyridine and 60 ml of anhydrous acetone was added to a mixture of 16 g of the product of Stage B and 20 ml of acetone at ambient temperature. The mixture was refluxed for one hour and the acetone was partially distilled. The mixture was allowed to return to ambient temperature, ice-cooled, separated and washed with ethyl ether. The insoluble part was dissolved in a saturated solution of sodium carbonate and extraction was carried out with ethyl acetate. The extracts were washed with water saturated in sodium chloride, dried and filtered to obtain 5.9 g of the expected product in the form of a yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1([CH3:30])[CH:26]2[CH2:27][CH:22]1[CH2:23][CH:24]=[C:25]2[CH2:28]O.C(Cl)(Cl)(Cl)[Cl:32]>>[Cl:32][CH2:28][C:25]1[CH:26]2[CH2:27][CH:22]([CH2:23][CH:24]=1)[C:21]2([CH3:30])[CH3:20]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC1(C)C2CC=C(CO)C1C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1(C)C2CC=C(CCl)C1C2

Procedure:
A mixture of triphenylphosphine (7.87 g, 0.03 mol) and 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-methanol (3.04 g, 0.02 mol) in dry carbon tetrachloride (14.0 ml) was stirred and heated at 60° for 4.0 h. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford a semi crystalline mass. This residue was triturated with n-pentane (30 ml), and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the resulting oil was distilled, to afford 2-chloromethyl-6,6-dimethylbicyclo[3.1.1]hept-2-ene as a colourless oil, b.p. 32°-33°/0.2 mm Hg.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][CH:28]=[C:29]([CH:31]5[CH2:35][O:34]C(C)(C)[O:32]5)[N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][CH:28]=[C:29]([CH:31]([OH:32])[CH2:35][OH:34])[N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(c2csc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)n2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3nc(C(O)CO)cs3)[nH]2)cc1)C1CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 1039.9 %

Procedure:
A mixture of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-thiazole (0.19 g), 1M hydrochloric acid (4 mL) and tetrahydrofuran (6 mL) was stirred at 50° C. for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was m washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (1.83 g, yield 73%) as a colorless amorphous solid. MS: 503 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][S:22]([C:25]3[S:26][C:27]([N+:30]([O-])=O)=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[O:20])=[CH:14][CH:13]=2)[C:10](=[O:33])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(CC)CC)C>CO.[Pd]>[NH2:30][C:27]1[S:26][C:25]([S:22]([NH:21][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([N:11]3[C:10](=[O:33])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])=[CH:13][CH:14]=2)=[O:20])(=[O:23])=[O:24])=[CH:29][CH:28]=1
Reactant: O=C(Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1)NS(=O)(=O)c1ccc([N+](=O)[O-])s1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1ccc(S(=O)(=O)NC(=O)Nc2ccc(-n3c(=O)[nH]c4ccccc4c3=O)cc2)s1
Reaction time: 3 h
Yield: 32 %

Procedure:
To a solution of N-[4-(2,4-dioxo(1,3-dihydroquinazolin-3-yl))phenyl]{[(5-nitro(2-thienyl))sulfonyl]amino}carboxamide (from Example 1148) (20 mg, 0.041 mmol) in methanol (1.5 mL) and triethylamine (11 μL, 0.08 mmol) was added 10% Pd/C (5 mg, 0.005 mmol) under argon. The reaction mixture was hydrogenated under 1 atm H2 for 3 hr, filtered, concentrated and HPLC purified to give the aniline (6 mg, 33%). ES-MS (M+H)+=458.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[CH:9][CH:8]=[CH:7]2.[Br:15]Br.O>C(O)(=O)C>[Br:15][C:8]1[CH:9]=[C:10]([C:12]#[N:13])[C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([OH:14])[C:2]=2[Cl:1]
Reactant: BrBr
Reactant: N#Cc1cccc2ccc(O)c(Cl)c12
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(Br)cc2ccc(O)c(Cl)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a mixture of 8-chloro-7-hydroxy-1-naphthonitrile (0.127 g, 0.63 mmol) and glacial acetic acid (1 mL) in a pressure tube was added a solution of bromine (0.24 g, 1.5 mmol) in glacial acetic acid (2 mL). The tube was sealed and the mixture was stirred at 100° C. overnight. The reaction was cooled, poured into water (50 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate, filtered, stripped of solvent, and purified on a silica column (20% ethyl acetate—hexanes) to yield 0.10 g (56%) of the title compound as a yellow solid. An analytical sample was prepared by preparative reverse phase HPLC to yield the title compound as a white solid: mp 148-150° C.; 1H NMR (DMSO-d6): δ 7.47 (1H, d, J=8.98 Hz), 7.95 (1H, d, J=9.02 Hz), 8.32 (1H, d, J=2.08 Hz), 8.55 (1H, d, J=2.08 Hz), 11.33 (1H, s); MS (ESI) m/z 280/282/284 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:45]/[O:46][C:47]([CH3:52])([CH3:51])[C:48]([OH:50])=[O:49])/[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]([S:16]([OH:19])(=[O:18])=[O:17])[C@@H:12]2[CH2:20][N:21]2[CH:25]=[C:24]([CH2:26][NH:27][C:28]([NH:37]C(OC(C)(C)C)=O)=[N:29]C(OC(C)(C)C)=O)[N:23]=[N:22]2)=[O:9])[N:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:45]/[O:46][C:47]([CH3:52])([CH3:51])[C:48]([OH:50])=[O:49])/[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]([S:16]([OH:19])(=[O:17])=[O:18])[C@@H:12]2[CH2:20][N:21]2[CH:25]=[C:24]([CH2:26][NH:27][C:28]([NH2:37])=[NH:29])[N:23]=[N:22]2)=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)N=C(NCc1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nn1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cc(CNC(=N)N)nn1)c1csc(N)n1)C(=O)O
Yield: 3.1 %

Procedure:
To a solution of 2-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((4-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (0.15 mmol, assumed quantitative conversion) In DCM (1.5 mL) at 0° C. was added TFA (689 μL, 9 mmol). The cold bath was removed after 10 min. After 4 h at rt it was diluted with DCM (1.5 mL) and concentrated in vacuo. The crude residue was purified by reverse phase prep HPLC (X-Bridge, 30×100 mm, 5 μm, C18 column; acetonitrile-water with 0.1% formic acid modifier, 1 mL/min) to afford the title compound (2.7 mg, 3%). LCMS: m/z=572.0 (M−1); 1H NMR (400 MHz, D2O): δ 1H NMR (400 MHz, D2O): δ 7.91 (s, 1H), 6.80 (s, 1H), 5.31 (d, J=5.2 Hz, 1H), 4.54 (s, 1H), 4.35 (s, 2H), 3.50-3.35 (m, 2H), 1.19 (s, 3H), 1.18 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[C:16](=[O:20])[N:15]([CH:21]3[CH2:23][CH2:22]3)[CH2:14]4)[C:5]2=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1>>[CH:21]1([N:15]2[CH2:14][C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:10]4[C:5]5[C:6](=[N:7][C:2]([C:34]6[CH:33]=[C:32]([O:31][CH3:30])[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=6)=[CH:3][CH:4]=5)[N:8]([CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][O:25]5)[N:9]=4)[CH:12]=3)[C:16]2=[O:20])[CH2:23][CH2:22]1
Reactant: COc1cc(OC)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C1c2ccc(-c3nn(C4CCCCO4)c4nc(Cl)ccc34)cc2CN1C1CC1
Product: COc1cc(OC)cc(-c2ccc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)nn(C4CCCCO4)c3n2)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 72, Step 4 starting from 5-[6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-2-cyclopropylisoindolin-1-one and 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS (M+H)+=511.2.
Reaction SMILES: BrCC1C=CC(C(=O)CN2C(=O)C=C(OC[C:20]3[CH:25]=[CH:24][C:23](Cl)=[CH:22][N:21]=3)C=N2)=CC=1.Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:54])[CH2:37][N:38]2[C:43](=[O:44])[CH:42]=[C:41]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][N:48]=3)[CH:40]=[N:39]2)=[CH:32][CH:31]=1>>[F:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][O:45][C:41]2[CH:40]=[N:39][N:38]([CH2:37][C:36](=[O:54])[C:33]3[CH:34]=[CH:35][C:30]([CH2:29][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:20]4)=[CH:31][CH:32]=3)[C:43](=[O:44])[CH:42]=2)=[N:48][CH:49]=1
Reactant: O=C(Cn1ncc(OCc2ccc(F)cn2)cc1=O)c1ccc(CCl)cc1
Reactant: O=C(Cn1ncc(OCc2ccc(Cl)cn2)cc1=O)c1ccc(CBr)cc1
Product: O=C(Cn1ncc(OCc2ccc(F)cn2)cc1=O)c1ccc(CN2CCCCC2)cc1

Procedure:
The following examples are prepared as described for example 33.1 (Starting materials: either preparation 18d or 19d depending on substituent X). For example 33.6-33.10 3.0 eq of the corresponding amine are used.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([OH:24])[CH3:23])=[CH:17][CH:16]=1>>[OH:24][CH:22]([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CC(O)Cc1ccc(N)cc1
Product: CC(=O)c1cnc(Nc2ccc(CC(C)O)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 1-(6-chloro-5-nitro-3-pyridinyl)ethanone (Paul, B. et al. J. Med. Chem., 1990, 33, 2231-2239.) and 1-(4-aminophenyl)-2-propanol (step 1 of Example 6).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][CH:25]=1)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[C:14]([CH:23]=[CH:24][CH:25]=2)[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cccc(C(=O)c2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
With agitation, 4.9 g 4-chlorobenzoyl chloride are added bit by bit to a solution, cooled to 5° C., of 5 g 3-amino-benzophenone in 60 ml dimethylacetamide, in the presence of 4.9 g triethylamine.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[NH:12][CH:11]=[C:10]3[C:17]([O:19]C)=[O:18])=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[NH:12][CH:11]=[C:10]3[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4)cc3)cc12
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
A solution of methyl 5-(biphenyl-4-yl)-6-chloro-1H-indole-3-carboxylate (50 mg, 0.14 mmol) in methanol (1.5 mL) and sodium hydroxide (1M, 0.50 mmol, 0.50 mL) was stirred at 75° C. for 24 hours. The cooled reaction mixture was neutralized to an acidic pH with 1M HCl and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Methylene chloride was then added and solid precipitated. The slurry was stirred for 30 minutes then filtered and washed with methylene chloride and a small amount of ethyl acetate. The solids were dried in vacuo to provide the desired product as a tan solid (17 mg, 35% yield). MS (ES+) 348.1 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 12.14 (br. s., 1H), 11.98 (br. s., 1H), 8.10 (d, J=2.93 Hz, 1H), 8.01 (s, 1H), 7.75 (t, J=8.42 Hz, 4H), 7.67 (s, 1H), 7.54 (d, J=8.05 Hz, 2H), 7.50 (t, J=7.56 Hz, 2H), 7.32-7.45 (m, 1H).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>ClCCl.[OH-].[Na+]>[F:1][CH:2]([F:10])[C:3]1[C:4]([CH3:9])=[N+:5]([O-:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ncccc1C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(C(F)F)ccc[n+]1[O-]
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution of 3-(difluoromethyl)-2-methylpyridine (2.56 g, 17.9 mmol) in dichloromethane was added 3-chloroperbenzoic acid (6.01 g, 26.8 mmol) at ambient temperature. After stirring for 2 h, the mixture was diluted with a 1 M aqueous sodium hydroxide (50 mL) and extracted with dichloromethane (4×50 mL). The organic phase was washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-(difluoromethyl)-2-methylpyridine-1-oxide as a yellow oil (2.22 g, 78%): 1H NMR (300 MHz, CDCl3) δ8.36 (d, J=6.5 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.23 (m, 1H), 6.80-6.70 (m, 1H), 2.57 (s, 3H).