Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1.BrBr.C([O:17]CC)C>CS(C)=O>[ClH:1].[ClH:1].[NH2:12][C:9]1[NH:8][C:7](=[CH:6][CH2:5][CH2:4][NH2:3])[C:11](=[O:17])[N:10]=1
Reactant: CCOCC
Reactant: NCCCc1c[nH]c(N)n1
Agent: BrBr
Agent: Cl
Solvent: CS(C)=O
Product: NCCC=C1NC(N)=NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-amino-propyl)-1H-imidazol-2-ylamine 16 (0.200 g, 0.930 mmol) was dissolved in anhydrous dimethyl sulfoxide (6 mL). Bromine (0.047 mL, 0.930 mmol) was added drop-wise and the solution was stirred at room temperature for 1 h. Diethyl ether (7 mL) was added and the organics were then decanted. The residue was purified by column chromatography (MeOH sat. with NH3) to yield the desired product as its free base. Addition of concentrated hydrochloric acid to a methanol solution (8 mL) of the free base followed by evaporation under reduced pressure afforded the target compound ((Z)-isomer exclusively) (0.141 g, 67%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 12.10 (br s, 1H), 9.20 (br s, 2H), 8.18 (br s, 2H), 5.92 (t, 1H, J=7.8 Hz), 2.96 (m, 2H), 2.66 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 164.13, 156.63, 130.88, 113.70, 37.57, 24.94; HRMS (FAB) calcd for C6H10N4O (MH+) 155.0933. Found 155.0943.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH3:5][N:6]([CH2:49][CH:50]=O)[C:7](=[O:48])[C:8]1[CH:47]=[CH:46][CH:45]=[C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:16][C:15]=2[C:26]2[CH:31]=[C:30]([C:32](=[O:44])[NH:33][C@@H:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37][CH2:36][CH2:35]3)[CH:29]=[CH:28][N:27]=2)=[O:12])[CH:9]=1.CN[CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH3:75].C(O)(=O)C>C(O)C.C(OCC)(=O)C>[CH3:5][N:6]([CH2:49][CH2:50][N:2]([CH3:1])[CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH3:75])[C:7](=[O:48])[C:8]1[CH:47]=[CH:46][CH:45]=[C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:16][C:15]=2[C:26]2[CH:31]=[C:30]([C:32](=[O:44])[NH:33][C@@H:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37][CH2:36][CH2:35]3)[CH:29]=[CH:28][N:27]=2)=[O:12])[CH:9]=1
Reactant: [BH3-]C#N
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: CNCCOCCOCCOCCOCCOCCOCCOC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: COCCOCCOCCOCCOCCOCCOCCN(C)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
Sodium cyanoborohydride (0.75 g, 11.9 mmol) was added portionwise to (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide 187a (1.5 g, 2.38 mmol), N-methyl-2,5,8,11,14,17,20-heptaoxadocosan-22-amine 135c.1 (2.52 g, 7.14 mmol) and acetic acid (0.41 mL, 7.14 mmol) in ethanol (15 mL) and the mixture stirred overnight at room temperature. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4). The residue was purified by PTLC (10% MeOH/20% ethyl acetate/dichloromethane) to give product as an orange oil (0.85 g, 37%); MS (ES, m/z): 969 [M+H]+; NMR (400 MHz, CDCl3, ppm): δ 12.8 (s, 1H); 8.80 (s, 1H); 8.55 (d, J=8.8 Hz, 1H); 8.10 (s, 1H); 7.98-8.02 (m, 2H); 7.47-7.55 (m, 3H); 7.06-7.24 (m, 5H); 6.69 (m, 1H); 5.41 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[Br:29]N1C(=O)CCC1=O>>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:23][CH:24]=3)(=[O:17])=[O:18])=[CH:11][C:9]=2[C:10]=1[Br:29])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2cc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ccc2s1
Product: CCOC(=O)c1sc2ccc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2c1Br
Yield: 94 %

Procedure:
According to Step 4, after reaction of 5-(4-tert-Butylbenzenesulfonylamino)-1-benzothiophene-2-carboxylic acid ethyl ester (5.34 mg, 12.79 mmol) from Example 1b) with N-bromosuccinimide (2.30 g, 12.7 mmol) followed by chromatographic purification (silica gel, hexane/ethyl acetate (0-70% ethyl acetate)), the desired compound is obtained at 94% yield (5.98 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:43])[O:39][CH:40]([CH3:42])[CH3:41]>C(Cl)Cl>[CH2:25]([NH:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:43])[O:39][CH:40]([CH3:42])[CH3:41])[CH:7]=[N:6][CH:5]=2)=[N:9][N:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reaction time: 5 h
Yield: 68.5 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-N-benzyl-8-phenylphthalazin-1-amine (60.0 mg, 0.149 mmol) in DCM (20 mL) was added pyridine (0.241 mL, 0.297 mmol) at room temperature followed by isopropyl carbonochloridate (18.2 mg, 0.149 mmol) and the reaction mixture stirred for 5 h. The volatile components were removed under reduced pressure and the resulting residue was purified by preparative HPLC (Condition 23 as described in general methods) to afford isopropyl (5-(4-(benzylamino)-5-phenylphthalazin-1-yl)pyridin-3-yl)carbamate (50.0 mg, 68.7%) as a white solid. LCMS (Condition 4): retention time 2.60 min, [M+1]=490.2. HPLC (Condition 28): retention time=7.65 min, purity 99.27%. 1H NMR (400 MHz, DMSO-d6) δ 1.29 (d, J=6.4 Hz, 6 H), 4.51 (d, J=4.8 Hz, 2 H), 4.93 (sept, J=6.4 Hz, 1 H), 5.06 (dd, J=4.8 Hz, J=5.2 Hz, 1 H), 7.01-7.03 (m, 2 H), 7.21-7.28 (m, 3 H), 7.42-7.52 (m, 5 H), 7.69 (dd, J=1.2 Hz, J=6.8 Hz, 1 H), 7.85-7.93 (m, 2 H), 8.16 (br s, 1 H), 8.47 (d, J=1.6 Hz, 1 H), 8.80 (d, J=2.4 Hz, 1 H), 10.00 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][OH:8].[H-].[Na+].[N+:11]([C:14]1[CH:15]=[N:16][CH:17]=[C:18]([N+]([O-])=O)[CH:19]=1)([O-:13])=[O:12]>CN(C=O)C.O.[Cl-].[Na+].O>[N+:11]([C:14]1[CH:19]=[C:18]([O:8][CH2:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])[CH:17]=[N:16][CH:15]=1)([O-:13])=[O:12]
Reactant: CN1CCCC1CO
Reactant: O=[N+]([O-])c1cncc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1COc1cncc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
1-Methylpyrrolidinylmethanol (0.46 ml, 3.9 mmol) was added to a suspension of NaH in DMF at room temperature. After stirring at room temperature for 30 minutes, 3,5-dinitro-pyridine (0.34 g, 4 mmol) was added, and the mixture was allowed to stir at room temperature for 16 hours. The mixture was diluted with 1:1 water/brine, and the aqueous solution was extracted with ether. The combined ether layers were dried over MgSO4, filtered and concentrated. The residue was chromatographed, eluting with CH2Cl2 : methanol (10:0.5) to afford 70 mg of the title compound. MS (DCI/NH3) m/e: 238 (M+1). 1H NMR (CDCl3, 300MHz) δ: 9.06 (m, 1H), 8.62 (d, 1H), 7.97 (m, 1H), 4.07 (m, 2H), 3.50 (s, 3H), 3.13 (m, 1H), 2.73 (m, 1H), 2.35 (m, 1H), 2.05 (m, 1H), 1.82 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7](O)[CH3:8])[N:2]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH:7]([C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:8]
Reactant: CC(O)c1cccnn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1cccnn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(pyridazin-3-yl)ethanol (3) (50 mg, 0.40 mmol) in DCM (1 mL), there was added sulfurous dichloride (0.2 mL). The resulting solution was stirred at room temperature for 3 hrs. Solvent was removed to give 3-(1-chloroethyl)pyridazine (4), which was used for the next step without purification.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[I:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>ClCCl.N1C=CC=CC=1>[I:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([I:21])[CH:23]=2)=[O:13])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1cccc(I)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc(I)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cccc(I)c1
Yield: 7.3 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (3.00 g, 8.74 mmol) in 75 mL of dichloromethane and 3-iodoaniline (3.82 g, 17.5 mmol) in 17 mL of pyridine. The crude product was triturated with hot ethanol, filtered, and recrystallized first from water-DMF, then from ethyl acetate-ether to yield 0.45 g of the title compound, mp 184°-186° C. (dec.).
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH2:27][S:28][CH3:29])[NH2:25]>>[CH2:1]([C:8]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:9]=1[C:10]([NH:25][CH:24]([CH2:26][CH2:27][S:28][CH3:29])[C:23]([O:22][CH3:21])=[O:30])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cc1ccccc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Product: COC(=O)C(CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1Cc1ccccc1

Procedure:
Compound 29 (2.45 mmol) was coupled with L-methionine methyl ester hydrochloride (540 mg, 2.7 mmol) to give methyl 2-[(2-benzyl-4-nitro-benzoyl)amino]-4-methylsulfanyl-butyrate (compound 30).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH3:18].[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH2:17][CH3:18])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-propoxypiperidine-1-carboxylate obtained by the method described in Example (113d) (125.5 mg, 0.49 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (74 mg, 0.42 mmol), WSC hydrochloride (235 mg, 1.23 mmol) and HOBT (56 mg, 0.41 mmol), to obtain 145.6 mg of the title compound as a white foamy substance (83%).
Reaction SMILES: CN(C)S([N:6]1[C:10]([CH3:11])=[C:9]([CH2:12][N:13]2[CH2:26][CH2:25][C:16]3[N:17]([CH3:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:15]=3[C:14]2=[O:27])[N:8]=[CH:7]1)(=O)=O.C(N(CC)CC)C>O1CCOCC1.C(#N)C>[CH3:24][N:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:15]2[C:14](=[O:27])[N:13]([CH2:12][C:9]3[N:8]=[CH:7][NH:6][C:10]=3[CH3:11])[CH2:26][CH2:25][C:16]1=2
Reactant: Cc1c(CN2CCc3c(c4ccccc4n3C)C2=O)ncn1S(=O)(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O
Yield: 69 %

Procedure:
A solution of N,N,5-trimethyl-4-[(2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido[4,3-b]indol-2-yl)methyl]-1H-imidazole-1-sulphonamide (401 mg) in a mixture of dioxane (150 ml) and acetonitrile (150 ml) containing triethylamine (1 ml) was irradiated at room temperature with a medium pressure mercury lamp for 24 h. The reaction mixture was then concentrated in vacuo onto FCC silica and purified by FCC eluting with System A (100:8:1) to give the title compound (203 mg) as a solid. The 1H-n.m.r. and t.l.c. data obtained for this material were consistent with those obtained for the product of Example 20.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[OH2:2].[O:25]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[C:3]([OH:26])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3cccnc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3cccnc3c2)cc1
Yield: 178 %

Procedure:
A mixture of alpha-oxo-4-[[2-(7-quinolyloxy)ethyl]oxy]benzeneacetic acid methyl ester (0.5 g) in hot methanol (5 mL) and tetrahydrofuran (5 mL) was treated with 1N sodium hydroxide (2.0 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was dissolved in hot water. Cold 2N hydrochloric acid (1.0 mL) was added dropwise and the product was allowed to crystallize and was filtered, washed with water and dried to give 0.45 g of alpha-oxo-4-[[2-(7-quinolyloxy)ethyl]oxy]benzeneacetic acid monohydrate as a colorless solid, mp 229°-231° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:2].[C:24](O)(=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:1]([O:3][C:4](=[O:23])[C:5]([N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:24](=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:18][CH:17]=1)=[O:6])[CH3:2]
Reactant: CCCCCCCCCCCCC(=O)O
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(N)cc1
Product: CCCCCCCCCCCCC(=O)Nc1ccc(CN(Cc2ccccc2)C(=O)C(=O)OCC)cc1
Yield: 39 %

Procedure:
The same procedure as employed in the preparation of Example 5, step d using ethyl[(4-aminobenzyl)(benzyl)amino](oxo)acetate and tridecanoic acid gave the title compound as a colorless oil (39%). M−(ESI): 507.2. HPLC (Condition A), Rt: 7 min (HPLC purity-91.3%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:23].N#N>CO.C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:14][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][C:7]=2[C:11]([O:13][CH3:23])=[O:12])=[CH:16][CH:17]=1
Reactant: O=C(O)c1[nH]c2cc(F)ccc2c1Sc1ccc(Cl)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1[nH]c2cc(F)ccc2c1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of impure 1g product (0.19 g, 0.59 mmol) in a mixture of methanol and toluene (6 mL, 1:2) was added TMSCHN2 (2.0 M solution in diethyl ether) (0.6 mL, 1.2 mmol) dropwise under N2. The reaction was allowed to warm to rt and stirred for 2 h. The reaction mixture was concentrated and purified by flash column chromatography eluting with a linear gradient ranging from 0 to 50% EtOAc-hexanes to provide 0.15 g (75%) of product 34 as an off white solid. 1H NMR (300 MHz, CDCl3) δ 3.93 (s, 3H), 6.88-6.95 (m, 1H), 7.06-7.16 (m, 5H), 7.45-750 (m, 1H), 9.22 (s, 1H). LC-MS (CI): m/z 336.0 [(M+H)+ C16H11ClFNO2S requires 335.02].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]1[CH:22]=[CH:21][C:15]([CH:16](O)[C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:22]=[CH:21][C:15]([CH:16]2[C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:19][C:17]2=[O:18])=[CH:14][CH:13]=1)[CH3:10]
Reactant: Cc1ccc(O)cc1
Reactant: CCOc1ccc(C(O)C(=O)O)cc1
Product: CCOc1ccc(C2C(=O)Oc3ccc(C)cc32)cc1
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of 162 g (1.50 mol) of 4-methylphenol and 196.2 g (1.0 mol) of 4-ethoxymandelic acid are stirred under nitrogen for 2 hours at 140°-150° C. Stirring is then continued for 1.5 hours at 150° C. under a slight vacuum (50 mbar). Excess 4-methoxyphenol is removed by distillation under a high vacuum. Crystallisation of the residue from xylene/ethanol yields 204 g (76%) of 3-(4-ethoxyphenyl)-5-methylbenzofuran-2-one of m.p. 82°-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:15]1[O:17][CH:16]1[CH2:18][OH:19]>C(O)(C)C>[NH3:14].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:17])[CH2:18][OH:19])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: OCC1CO1
Reactant: COc1ccc(CC(C)N)cc1OC
Solvent: CC(C)O
Product: COc1ccc(CC(C)NCC(O)CO)cc1OC
Product: N
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(3,4-dimethoxyphenyl)-2-propylamine (20.0 g., 0.10 m.) in isopropanol (20 ml.) is heated to 50° C. while a solution of glycidol (5.0 g., 0.067 m.) in isopropanol (5 ml.) is added over 15 minutes. The mixture is stirred at 50° C. for 0.5 hours and then at 70° C. for 16 hours. The solvent is concentrated under reduced pressure and the residue is chromatographed on silica gel, eluting with 10% MeOH--CHCl3 saturated with NH3 to yield (I) weighing 14.37 g. (80%).
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10](=[O:26])[CH:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>CN(C)C=O.[Pd]>[C:1]([O:7][CH2:8][O:9][C:10](=[O:26])[CH:11]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:12]([OH:14])=[O:13])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)CC(C(=O)OCOC(=O)C(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)O)C(=O)OCOC(=O)C(C)(C)C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
34.6 grams of isobutylmalonic acid benzyl ester pivaloyloxymethyl ester were dissolved in 150 ml of dimethylformamide and hydrogenated with 3.0 g of 5% palladium/charcoal. After 1 hour, the hydrogen uptake (2160 ml) had finished. The hydrogenation mixture was filtered off from the catalyst and the filtrate evaporated in a high vacuum at room temperature. The oily residue was dissolved in a 10% aqueous sodium bicarbonate solution and extracted twice with diethyl ether. The diethyl ether extracts were rejected. The sodium bicarbonate phase was acidified at 0° with citric acid and extracted twice with diethyl ether. The combined diethyl ether extracts were washed once with water, dried over magnesium sulfate and evaporated under reduced pressure. There was obtained 21.5 g of pure isobutylmalonic acid mono-pivaloyloxymethyl ester in the form of a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cnc(N)nc3)n2)n1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl (example E.26) (0.150 g, 0.38 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.092 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.080 g, 57%). MS (ISP) 407.3 [(M+H)+]; mp 219-222° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28](=[O:41])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH:21]=1)[C:4](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:5])[CH3:2].[OH:42]O.O.[OH-].[Li+].Cl>O.O1CCCC1>[CH2:1]([CH:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28](=[O:41])[NH:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=2)[CH:21]=1)[C:4]([OH:5])=[O:42])[CH3:2]
Reactant: CCC(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Reaction time: 0.03 h
Yield: 20 %

Procedure:
(4S)-3-[2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propionyl]-4-benzyl-2-oxazolidinone (860 mg, 1.51 mmol) was mixed with 8 ml of mixed solution of tetrahydrofuran with water (4:1 v/v), which was cooled with ice under an atmosphere of argon. Under stirring, 611 ml of 30% aqueous hydrogen peroxide was added over 2 minutes, further 101 mg of lithium hydroxide monohydrate dissolved in 2.7 ml of water was added thereto over 2 minutes. After the mixture was stirred for 1 hour under cooling with ice, sodium sulfite 7-hydrate dissolved in 4 ml of water was added, and the mixture was stirred for 5 minutes at 0° C. The reaction mixture was poured into 5% aqueous solution of hydrochloric acid, which was extracted with ethyl acetate. The extract was washed with brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized by adding ethyl acetate and n-hexane to obtain 125 mg (20%) of the title compound as colorless prisms.
Reaction SMILES: [NH2:1][CH2:2][C@:3]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([OH:5])[CH3:4].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15].[OH-].[Na+]>C1COCC1.CC(OC)(C)C>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C@@:3]([OH:5])([CH3:4])[CH2:2][NH:1][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])[CH:11]=1
Reactant: C[C@@](O)(CN)c1cc(Br)ccc1F
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C[C@@](O)(CNS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-amino-2-(5-bromo-2-fluoro-phenyl)-propan-2-ol (34.7 g, 140 mmol) in THF (400 ml) was added 2-nitro-benzenesulfonyl chloride (34.9 g, 154 mmol) at 0-5° C. and afterwards 1N aqueous NaOH over a period of 0.5 h. The reaction mixture was stirred for 2 h at 20° C. The reaction mixture was diluted with TBME and washed with water and NaH2PO4 solution and brine, dried over MgSO4, filtered and concentrated to provide the title compound after crystallization from TBME-hexane as beige crystals: TLC (toluene-EtOAc 3:1): Rf=0.51; HPLC RtH5=1.118 min; ESIMS: 450, 452 [(M+NH4)+]; 11H NMR (360 MHz, CDCl3): δ 7.98 (m, 1H), 7.81 (m, 1H), 7.65 (m, 2H), 7.59 (dd, 1H), 7.24 (m, 1H), 6.79 (dd, 1H), 5.60 (t, 1H), 4.16 (br s, 1H), 3.55 (dd, 1H), 3.44 (dd, 1H), 2.51 (s, 1H), 1.51 (s, 3H).