Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C-:5]#N.[Na+].[C:8]([Si:12]([CH3:42])([CH3:41])[O:13][C@H:14]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C@@H:27]([CH2:31][CH2:32][CH2:33][C:34]3[S:38]C(C=O)=[CH:36][CH:35]=3)[CH2:28][CH2:29][CH:30]=2)=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:11])([CH3:10])[CH3:9]>CO.O=[Mn]=O>[CH3:5][O:3][C:1]([C:2]1[S:38][C:34]([CH2:33][CH2:32][CH2:31][C@H:27]2[CH2:28][CH2:29][CH:30]=[C:26]2[C:23]2[CH:22]=[CH:21][C:20]([C@@H:14]([O:13][Si:12]([C:8]([CH3:10])([CH3:9])[CH3:11])([CH3:41])[CH3:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=2)=[CH:35][CH:36]=1)=[O:4]
Reactant: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C=O)s2)cc1
Reactant: [C-]#N
Reactant: CC(=O)O
Agent: O=[Mn]=O
Agent: [Na+]
Solvent: CO
Product: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 18 h
Yield: 98.8 %

Procedure:
Acetic acid (12 μL, 0.21 mmol), NaCN (25 mg, 0.51 mmol) and MnO2 (152 mg, 1.7 mmol) were added to a mixture of 42a (43 mg, 0.084 mmol) in methanol (0.5 mL). The mixture was stirred for 18 h and then was filtered through Celite, washing with ethyl acetate. The filtrate was washed with water (20 mL) and the aqueous layer was further extracted with ethyl acetate (20 mL). The combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated to give the title compound (45 mg, 0.083 mmol, 99%).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C(OCC)(=O)C>CN(C=O)C>[CH2:31]([CH:30]([CH2:33][CH3:34])[CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH3:32]
Reactant: CCC(CC)CBr
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)CN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 25 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 3-bromomethylpentane (0.183 g, 1.11 mmol) in DMF (5.3 mL). Beat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2324, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.9 min, 100% purity.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:16])([CH3:15])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:7])[CH3:2].Cl[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([CH3:30])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:16])([CH3:15])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:12][CH:13]=1)=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc(O)cc1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)C(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reaction time: 24 h
Yield: 68.2 %

Procedure:
The 3-(4-hydroxy-phenyl)-2,2-dimethyl-3-oxo-propionic acid ethyl ester (0.72 g, 3.07 mmol) was combined with 4-chloromethyl-2-methyl-quinoline (0.69 g, 3.07 mmol) and cesium carbonate (12.0 mmol) in DMSO under nitrogen at room temperature. The reaction was stirred for 24 h, filtered to remove the solids, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 2,2-dimethyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-3-oxo-propionic acid ethyl ester (0.82 g, 70%) as a viscous oil. MS found: (M+H)+=392.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nn(-c2cccc([N+](=O)[O-])c2)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc(N)c2)c1C

Procedure:
The compound of Example 2 (1.8 g,) was dissolved in ethanol then 0.2 g 5% Pd/C was added to the solution. The mixture was treated with hydrogen gas at 45 psi. Upon completion of the reaction, the solution was filtered through Celite, and the filtrate concentrated under vacuum. The named product slowly crystallized upon standing (m.p. 93° C.-95° C.).
Reaction SMILES: C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:30])[CH:27]=2)[NH:22][C:21]1=[O:31].CCN=C=NCCCN(C)C.[Cl:43][C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48]([C:53](O)=[O:54])=[CH:47]2>CN(C=O)C.O>[Cl:43][C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48]([C:53]([NH:19][CH:20]1[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:30])[CH:27]=3)[NH:22][C:21]1=[O:31])=[O:54])=[CH:47]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NC1Cc2cc(F)ccc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1Cc2cc(F)ccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
Triethylamine (184 μL, 1.32 mmol), HOBt (89 mg, 0.66 mmol), 3-amino-6-fluoro-3,4-dihydro-2(1H)-quinolinone monohydrochloride (CAS Reg. No: 82420-54-0) (143 mg, 0.66 mmol), and EDAC (127 mg, 0.66 mmol) were added to a solution of 5-chloroindole-2-carboxylic acid (129 mg, 0.66 mmol) in anhydrous DMF (3.5 mL). The reaction was stirred at ambient temperature for approximately 16 h, and then poured into water (50 mL). This was stirred vigorously for about 10 mins. and filtered. The collected precipitate was washed with water and dried in vacuum at 40° C., to give the title compound (200 mg, 85%) as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[OH-:12].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].[OH2:20]>>[NH2:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([C:1]([OH:20])=[O:12])=[CH:7][CH:6]=1)(=[O:10])=[O:9]
Reactant: [OH-]
Reactant: O
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: NS(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 70 °C
Yield: 90 %

Procedure:
To the solution of 17.1 g (0.1 mol) of p-toluenesulfonamide prepared in Example 1, 20 g (0.5 mol) of sodium hydroxide in 300 ml of water was added in portions 20 g (0.13 mol) of potassium permanganate. The temperature raised to 70° C. spontaneously, keep the reaction mixture in 90° C. for 2 h. The mixture was then cooled and filtered, and the filtrate was acidified with HCl. The resulting precipitate was filtered, and washed with water, dried in vacuo to give the title compound (18.1 g) as white powder, yield 90%, m.p. 291-292° C.
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1.[OH2:18]>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:1])=[O:18])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 34 %

Procedure:
To a stirring solution of KMnO4 (76 g, 483 mmol) in water (1 L) was added 4-fluoro-2-nitrotoluene and the solution was heated to reflux. After 4 h, the hot mixture was filtered and the filtrate was cooled with ice, washed with diethyl ether, acidified with conc HCl, and then extracted twice with diethyl ether. The combined ether extracts were washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 12.07 g (34%) of a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=O)NC=1)=[O:2].[H-].[Na+].CI.N1C=CC(=O)NC1=O.[CH3:23][N:24]([CH:26]=[O:27])[CH3:25]>O.CO>[CH3:23][N:24]1[CH:25]=[C:3]([CH:1]=[O:2])[C:4](=[O:10])[N:5]([CH3:6])[C:26]1=[O:27]
Reactant: O=Cc1c[nH]c(=O)[nH]c1=O
Reactant: CN(C)C=O
Agent: O=c1cc[nH]c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CO
Product: Cn1cc(C=O)c(=O)n(C)c1=O
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a slurry of 400mg of 5-formyluracil (2.8 mM) in DMF (10 mL) at room temperature was added sodium hydride (280 mg, 7 mM, 60% in oil). After stirring for 30 min., MeI (1.013 g, 7.2 mM) was added. When the turbid reaction mixture became a homogeneous yellow solution tlc revealed the absence of starting uracil. The reaction mixture was treated with MeOH and water, concentrated on the rotovap and the residue partitioned between MeOH and hexane. The MeOH fraction was concentrated and the residue partitioned between chloroform and water. The organic phase dried (MgSO4), filtered and concentrated to give 420 mg (89% yield) of 1,3-dimethyl-5-formyluracil as an off-white waxy solid. 1H-NMR (DMSO-d6), δ=9.82 (s, 1H), 8.52 (s, 1H), 3.43 (s, 3H), 3.2 (s, 3H). LC/MS; rt=0.34 mins. m/z=169, [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O
Reactant: N
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384 , substituting 2-(3-chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 102 mg, 61.8%). mp 154-156° C. 1H NMR (300 MHz, DMSO-d6) δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 7.54 (s, 2H), 7.6 (m, 1H), 7.69 (m, 2H), 7.93 (dd, 1H), 8.05 (m, 2H). MS (DCI/NH3) m/z 450 (M+H)+, 468 (M+NH4)+. Anal. calc. for C22H22FN2O3SCl.0.25H2O: C, 58.86; H, 4.94; N, 6.24. Found: C, 59.23; H, 5.12; N, 6.00.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:17]=3)[CH2:13][C:12]2=[O:30])[CH:6]=1)C.[BH4-].[Na+].O>CCO>[CH:25]1([O:24][C:18]2[CH:17]=[C:16]([CH:14]3[CH2:15][N:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][OH:3])[CH:6]=4)[C:12](=[O:30])[CH2:13]3)[CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cccc(N2CC(c3ccc(OC)c(OC4CCCC4)c3)CC2=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2CC(=O)N(c3cccc(CO)c3)C2)cc1OC1CCCC1

Procedure:
A solution of 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]benzoic acid ethyl ester (20 mg, 0.05 mmol) in EtOH (0.5 mL) was added NaBH4 (5 mg, 0.135 mmol)). The mixture was stirred at r.t. for 12 h when water (1 mL) was added to quench the reaction. The mixture was poured into water (4 mL) and extracted twice with EtOAc. The combined organic layer was concentrated and purified by preparative LC-MS.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[F:18])[C:7]([O:19][CH3:20])=[CH:6][C:5]=1[F:21].[OH-].[Na+].O.Cl>CN1CCCC1=O>[Cl:17][C:13]1[C:12]([F:18])=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][C:8]1[C:7]([O:19][CH3:20])=[CH:6][C:5]([F:21])=[C:4]([CH:9]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(F)c(C(=O)O)cc1Cc1cccc(Cl)c1F
Temperature: 25 °C
Yield: 93.4 %

Procedure:
5-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid methyl ester (100 g) obtained in Example 2, Step III was dissolved in 1-methyl-2-pyrrolidinone (500 ml), and 2.5% V/W aqueous alkali solution prepared from 8N-aqueous sodium hydroxide solution (54.7 ml) and water (192.6 ml) was added dropwise with stirring at room temperature. After the dropwise addition, the mixture was stirred for 3.5 hr, and acidified by dropwise addition of 2N-hydrochloric acid (240 ml) with stirring at room temperature. The precipitated crystals were stirred for 2 hr and collected by filtration. The filtrate was washed with 50% methanol aqueous solution (100 ml) and dried at an outer temperature of 70° C. to give 5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid (89.4 g, yield 93.4%).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([Cl:14])=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=O)C.B(F)(F)F.CCOCC>CO>[NH2:4][C:5]1[S:6][C:7]([Cl:14])=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(Cl)sc1NC(C)=O
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)sc1N

Procedure:
A mixture of 14.2 parts of methyl 2-acetamido-5-chlorothiophene-3-carboxylate, 360 parts by volume of methanol and 30 parts by volume of boron trifluoride-etherate is refluxed for 4 hours. After evaporation of the solvent the residue is treated in a manner similar to that used in Reference Example 19, whereby methyl 2-amino-5-chlorothiophene-3-carboxylate is obtained as crystals melting at 100°-102.5° C. This product is identical with that obtained in Reference Example 19.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([CH2:22]Br)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:24]#[N:25].[NH:26]1[CH2:45][CH2:44][CH2:43][C@H:27]1[C:28]([NH:30][C@H:31]([C:36]([NH:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33])=[O:29].C(N(CC)CC)C>ClCCl>[N:24]#[N:25].[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([CH2:22][N:26]1[CH2:45][CH2:44][CH2:43][C@H:27]1[C:28]([NH:30][C@H:31]([C:36]([NH:38][CH2:39][CH:40]([CH3:41])[CH3:42])=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33])=[O:29])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CBr)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)NCC(C)C
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1CC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)NCC(C)C

Procedure:
A solution of 8.86 g of [N-(benzyloxycarbonyl)-L-phenylalanyl]methyl bromide 6.71 g of N2 -L-prolyl-N1 -isobutyl-L-isoleucinamide and 2.60 g of triethylamine in 400 ml of dichloromethane was stirred at room temperature overnight. The solvent was removed by evaporation and the crude product was chromatographed on silica gel using ethyl acetate for the elution. The resulting product was triturated with a mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate to give 8.70 g of N2 -[N-[[N-(benzyloxycarbonyl)-L-phenylalanyl]methyl]-L-prolyl]-N1 -isobutyl-L-isoleucinamide as an off-white solid of m.p. 80°-81° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][F:26]>CS(C)=O.CO>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][F:26])[C:4]=2[N:3]=1
Reactant: FCCCCBr
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCF
Temperature: 120 °C
Yield: 60.1 %

Procedure:
To a solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.88 mmol, 1 eq) in anhydrous DMSO (1 ml) in a 1.5 ml microwave vial equipped with a stirrer was added sodium bicarbonate (113 mg, 1.07 mmol, 1.2 eq) followed by 1-bromo-4-fluorobutane (114 ul, 165 mg, 1.06 mmol, 1.2 eq). The vial was sealed and heated with stirring using a microwave, maintaining the temperature at 120° C. for 25 min with a maximum power output of 300 W. The resulting dark brown solution was diluted with methanol (1 ml) and purified by mass directed autopreparative HPLC to give the title compound as a white solid (159 mg, 60%). m/z 301.3 [MH+]
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:7][C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:10]=3[N:9]=2)=[CH:4][S:5][CH:6]=1.[Br:18]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>C(O)(=O)C>[ClH:1].[Br:18][C:4]1[S:5][CH:6]=[C:2]([Cl:1])[C:3]=1[NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:10]=2[N:9]=1
Reactant: Fc1ccc2[nH]c(Nc3cscc3Cl)nc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cl
Product: Fc1ccc2[nH]c(Nc3c(Cl)csc3Br)nc2c1

Procedure:
(4-Chloro-thiophen-3-yl)-(5-fluoro-1H-benzoimidazol-2-yl)-amine (50 mg, example 54b) was dissolved in acetic acid (4 ml) and at room temperature with vigorous stirring N-bromosuccinimide (33 mg) dissolved in acetic acid (4 ml) was slowly added. After stirring for 45 min at room temperature toluene (20 ml) was added and the solvent mixture distilled off. The residue was dissolved in ethyl acetate and washed with saturated potassium carbonate solution. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by preparative HPLC, the product containing fractions were combined, the acetonitrile was removed, the aqueous residue set basic and three times extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and filtered. After removal of the solvent water and 2 N HCl were added to the residue. After freeze drying the desired product (27 mg) was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][NH:9][CH2:10][C@@H:11]([CH3:24])[CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH:36]=O.COC(=O)C.[Cl:49]C1C(C(F)(F)F)=CC=CC=1C=O.Cl.CCOCC>CCOCC>[ClH:49].[F:42][C:32]([F:31])([F:43])[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][N:9]([CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:10][C@@H:11]([CH3:24])[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: C[C@H](CNCC(c1ccccc1)c1ccccc1)COc1cccc(CC(=O)O)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: Cl
Solvent: COC(C)=O
Solvent: CCOCC
Product: C[C@@H](COc1cccc(CC(=O)O)c1)CN(Cc1ccc(F)c(C(F)(F)F)c1)CC(c1ccccc1)c1ccccc1

Procedure:
Following the procedure of Example 7(d) except (R)-2-(3-{3-[(2,2-diphenylethyl)amino]2-methyl-propoxy}phenyl)acetic acid and 3-trifluoromethyl-4-fluoro-benzaldehyde were used instead of (R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)acetic acid methyl ester and 2-chloro-3-trifluoromethylbenzaldehyde in step (d) the corresponding carboxylic acid was obtained. The resulting amine/carboxylic acid was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give the title compound as a white solid, 72 mg (67%). MS (ESI) 580.4 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH2:23]([N:30]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:30]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[N:10]([O:11][CH:12]([C:14]4[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=4[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=2)[CH:32]=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Product: CC(On1ccc2ncc(-c3cnn(Cc4ccccc4)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and (1-benzyl-1H-pyrazol-4-yl)boronic acid according to the procedure described in example 4.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O=[C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:34])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19])[C@H:12]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[SH:73]>C(#N)C.CN(C1C=CN=CC=1)C>[NH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[S:73][C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:19])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:34])[C:12]=1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37]
Reactant: Nc1ccccc1S
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccccc3N)C[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
A solution of N,N-diisopropyl-N-ethylamine (0.247 ml) in acetonitrile (2.2 ml) was added to a solution of 4-nitrobenzyl (2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (640 mg) and 4-(N,N-dimethylamino)pyridine (14.4 mg) in acetonitrile (32 ml) at 0° C. A solution of diphenyl chlorophosphate (0.257 ml) in acetonitrile (2.3 ml) was then added thereto at 0° C. After the mixture was stirred at 0° C. for 30 minutes, N,N-diisopropyl-N-ethylamine (0.824 ml) and a solution of 2-aminobenzenethiol (155 mg) in acetonitrile (1.4 ml) were added at 0° C. After stirring at 0° C. for an hour, the mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate (50 ml). This solution was washed twice with water (X2) and an aqueous sodium chloride, dried over magnesium sulfate, and then evaporated in vacuo. The residue was chromatographed on silica gel (20 g) eluting with a mixture of benzene and acetone (50:1 to 10:1) to give 4-nitrobenzyl (5R,6R)-3-(2-aminophenylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (603 mg) as an oil.