Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH:18]([C:19]2([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[N:28]=[C:29]=[O:30])[N:21]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:20]2=[O:36])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[O:36]=[C:20]1[C:19]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])([CH:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:28]=[C:29]=[O:30])[N:21]1[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCN1C(=O)C(CCC(=O)OCC)(C2Cc3ccccc3CN2C(=O)OC(C)(C)C)c2c(N=C=O)cccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCN1C(=O)C(CCC(=O)OCC)(C2Cc3ccccc3CN2)c2c(N=C=O)cccc21
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Under ice cooling, a hydrochloric acid gas was passed through a stirred solution of 6.79 g of ethyl 3-[3-(2-t-butoxycarbonyl-1,2,3,4-tetrahydro-3-isoquinolinyl)-carbonylamino-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl]-propionate in ethyl acetate (75 ml) until the gas was saturated. The mixture was stirred at 0° C. for 2.5 hours. After removal of solvent, the residue was triturated in isopropyl ether to afford 6.05 g of ethyl 3-[2,3-dihydro-2-oxo-1-pentyl-3-(1,2,3,4-tetrahydro-3-isoquinolinyl)-carbonylamino-1H-indol-3-yl]propionate hydrochloride as a pale yellow amorphous solid. IR (Nujol) (cm-1): 3180, 1725, 1690, 1610, FAB-MS (m/z): 478 (MH+), 132 (base).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[C:26]([Cl:28])[CH:27]=1)=[O:9])([CH3:6])[CH3:5].[O-:31][CH2:32][CH3:33].[Na+].O.Cl>CCO>[Cl:28][C:26]1[CH:27]=[C:22]([CH2:21][O:20][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:2])=[O:30])=[O:9])[CH:23]=[N:24][C:25]=1[O:31][CH2:32][CH3:33]
Reactant: CC[O-]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ncc(COc2c(C(=O)NC(C)(C)C(=O)O)ccc3ccccc23)cc1Cl
Yield: 80.8 %

Procedure:
A solution of 50 mg 2-{[1-(5,6-dichloro-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester and 30 mg sodium ethoxide in 3 ml EtOH containing 5% of water was heated to 120° C. for 2 min using a microwave reactor. The reaction mixture was acidified to pH 4 with 2 M HCl and the precipitated solid was collected by filtration and purified by RP-HPLC to yield 40 mg 2-{[1-(5-chloro-6-ethoxy-pyridin-3-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:24])[C:7]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11](OS(C(F)(F)F)(=O)=O)=[CH:10][C:9]=1[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].[C:31](=[NH:44])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:24])[C:7]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N:44]=[C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:10][C:9]=1[CH3:23]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cncc(C)c1-c1c(C)cc(OS(=O)(=O)C(F)(F)F)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1cncc(C)c1-c1c(C)cc(N=C(c2ccccc2)c2ccccc2)cc1C
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A flame-dried sealable Schlenk tube was charged with triflate 8 (0.359 g, 1.00 mmol), Cs2CO3 (0.456 g, 1.40 mmol), Pd(OAc)2 (6.7 mg, 0.030 mmol), and BINAP (28.2 mg, 0.0450 mmol). The tube was evacuated and then backfilled with N2. Next, a solution of benzophenone imine (0.224 g, 1.20 mmol) in dry THF (4 mL) was added with stirring under an N2 flow. The Schlenk tube was sealed, the mixture was degassed by three freeze-thaw cycles, and backfilled with N2. The mixture was then stirred at 65° C. for 15 h. The reaction mixture was next cooled to room temperature, diluted with methylene chloride (40 mL), filtered, and the filtrate was concentrated in vacuo. The resulting yellow solid was purified by flash chromatography on silica gel, eluting with 1:1 hexane:ethyl acetate, to give 0.381 g (97.7%) of the title compound as a colorless solid: mp 44-45° C.; 1H NMR (400 MHz, CD2Cl2): δ 8.305 (s, 2H), 7.774 (d, 2H, J=8.0 Hz), 7.494-7.408 (m, 3H), 7.271 (m, 3H), 7.144 (d, 2H, J=6.8 Hz), 6.476 (s, 2H), 1.828 (s, 6H), 1.706 (s, 6H); 13C NMR (100 MHz, CD2Cl2): δ 168.647, 151.523, 148.783, 148.611, 140.013, 136.737, 135.099, 132.206, 131.678, 131.114, 130.040, 129.685, 128.912, 128.583, 128.038, 120.459, 19.842, 16.594; MS (ESI): m/z 391.5 [(M+H)+, 100]; Anal. Calcd. for C28H26N2: C, 86.12; H, 6.71; N, 7.17. Found; C, 85.86; H, 6.74; N, 7.17.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18]([O:25][CH3:26])(=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([CH:19]([C:18]([O:25][CH3:26])=[O:24])[C:20]([O:22][CH3:23])=[O:21])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccccc1)c1ccc(I)cc1
Reactant: COC(=O)CC(=O)OC
Product: COC(=O)C(C(=O)OC)C(CC(=O)c1ccc(I)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-iodophenyl)-3-phenylprop-2-en-1-one and dimethyl malonate, dimethyl 2-(3-(4-iodophenyl)-3-oxo-1-phenylpropyl)malonate was obtained as yellowish solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: OCCc1ccc(Br)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Product: OCCc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A mixture of 2-(4-bromophenyl)ethanol (0.70 mL, 5 mmol), morpholine (0.52 mL, 6 mmol), LHMDS (11 mL, IM solution in THF), Pd2 (dba)3 (46 mg, 0.05 mmol), and CyMAP (24 mg, 0.06 mmol) was heated to reflux for 16 hours. Cooled to room temperature. Acidified with IM HCl, stirred for 10 minutes, and neutralized with saturated NaHCO3. Partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 520 mg (50%) of the desired product. MS (ESI) m/e 208 (M+H)+, 1H NMR (300 MHz, CDCl3): □ 7.15 (d, J=8.48 Hz, 2H), 6.88 (d, J=8.48 Hz, 2H), 3.78-3.87 (m, 6H), 3.11-3.14 (m, 4H), 2.79 (t, J=6.61 Hz, 2H), 1.43 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.I[C:17]1[N:18]=[CH:19][N:20]([CH2:22][CH2:23][N:24]([CH2:32][CH2:33][O:34][CH3:35])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:17]3[N:18]=[CH:19][N:20]([CH2:22][CH2:23][N:24]([CH2:32][CH2:33][O:34][CH3:35])[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH:21]=3)[S:10][C:3]=12
Reactant: COCCN(CCn1cnc(I)c1)C(=O)OC(C)(C)C
Reactant: Clc1ccnc2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COCCN(CCn1cnc(-c2cc3nccc(Cl)c3s2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (1.39 g, 8.20 mmol) in THF (30 mL) at −15° C. was added n-BuLi (3.28 mL, 8.20 mmol). After 30 min, ZnCl2 (1.12 g, 8.20 mmol) was added at −15° C. and the reaction mixture was allowed to warm to RT over 45 min. A solution of palladium tetrakistriphenylphosphine (0.126 g, 0.11 mmol) and iodide 249 (2.16 g, 5.47 mmol) in THF (10 mL) was added and the mixture was heated to reflux for 45 min then concentrated. The reaction mixture was diluted with water and ammonium hydroxide and extracted with DCM. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV), to afford the title compound 250 (2.37 g, 5.43 mmol, 99% yield) as light brown solid. MS (m/z): 437.45 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(=O)[O:14]C(Cl)(Cl)Cl>O1CCOCC1>[CH3:12][S:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CSc1ccc(N)c(C(=O)O)c1
Solvent: C1COCCO1
Product: CSc1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred mixture of 9.16 parts of 2-amino-5-(methylthio)benzoic acid and 100 parts of 1,4-dioxane were added dropwise slowly 9.8 parts of trichloromethyl carbonochloridate. Upon completion, stirring was continued for 2 hours. The reaction mixture was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 8 parts (76%) of 6-(methylthio)-2H-3,1-benzoxazine-2,4(1H)-dione; mp. 219.4° C. (intermediate 153).
Reaction SMILES: [C:1]([C@@H:4]([N:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])=[CH:23][CH:22]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:9]([C@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:1]([NH2:2])=[O:3])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29][CH2:30][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:23][CH:22]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: C1CCNCC1
Reactant: C=CC(=O)Nc1ccc(CN([C@@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CCN2CCCCC2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 86.9 %

Procedure:
To a solution of N-(4-{[N-((1S)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-phenyl)-acrylamide (0.10 g, 0.22 mmol) in toluene (5 mL) was added piperidine (20 mg, 0.24 mmol). The mixture was heated at a gentle reflux for 1 h and then the solvent was removed in vacuo. Purification by flash chromatography (SiO2, 10% MeOH/CH2Cl2) afforded the title compound (105 mg) in 86% yield. MS (ESI), (M+H)+449.16, 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, 2H, J=8.0), 7.63 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 7.23 (d, 2H, J=8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.75 (d, 1H, Jab=16), 4.38 (d, 1H, Jab=16), 3.25 (t, 1H, J=6.0), 2.65 (t, 2H, J=6.0), 2.56-2.44 (m, 6H), 1.95 (m, 1H), 1.68-1.45 (m, 8H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:16])[NH:5][C:6]=1[C:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[H][H]>C(O)(=O)C.O=[Pt]=O>[CH3:1][CH:2]1[NH:3][C:4](=[O:16])[NH:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)CCCCC(=O)O
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC1NC(=O)NC1CCCCCC(=O)O
Yield: 63.4 %

Procedure:
A solution of 1.5 g (6.63 mmol) of 4-methyl-5-(5-carboxypentanoyl)-4-imidazolin-2-one in 30 ml of acetic acid was hydrogenated in a Parr shaker apparatus over 0.4 g of PtO2 at 3 atmospheres and ambient temperature for 3 hours until hydrogen uptake ceased. The Pt was removed by filtration and the filtrate concentrated to an oil comprising 1.1 g. The oil was dissolved in water and cooled overnight to afford 0.9 g (64%) of dl-desthiobiotin identical in all respects to authentic material.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17].Br.N>C(Cl)(Cl)Cl.C(O)(=O)C>[OH:8][C:7]1[CH:2]=[C:3]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]2=[O:17])[CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCCCC(C2=C(Br)C(=O)CCC2)C1=O
Agent: Br
Agent: N
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN1CCCCC(c2cccc(O)c2)C1=O
Reaction time: 4 h

Procedure:
A solution of 3-(2-bromo-3-oxocyclohex-1-enyl)-hexahydro-1-methylazepin-2-one (6 g) in chloroform (60 ml) was treated with 48% HBr in acetic acid (1 ml). After 4 hours, NMR indicated completion. Aqueous ammonia was added and the organic solvent removed under reduced pressure to yeild the title compound as a crystalline solid, m.p. 192°-3° (EtOAc).
Reaction SMILES: CCCCC([N:7]([C@H:26]([C:30]([OH:32])=[O:31])[CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2NN=N[N:25]=2)=[CH:13][CH:14]=1)=O.Br[CH2:34]C1C=CC(C2C=CC=CC=2C#N)=CC=1.Cl.COC(=O)[C@H](C(C)C)N.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:34][O:32][C:30](=[O:31])[C@H:26]([CH:27]([CH3:28])[CH3:29])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]#[N:25])=[CH:11][CH:10]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C

Procedure:
Bioorganic & Medicinal Chemistry Letters (1994), 4(1), 29-34, reported a process for the preparation of Valsartan by reacting 4′-bromomethyl-2-cyanobiphenyl (II) with (L)-valine methyl ester hydrochloride (V) in the presence of diisopropylethylamine in methylenechloride to produce N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VI), followed by reacting with valeryl chloride in the presence of diisopropylethylamine in methylenechloride to produce N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII), which is further reacted with tributyltin azide in xylene to produce N-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-N-valeryl-(L)-valine methyl ester (VIII), followed by hydrolysis with aqueous base to produce Valsartan of formula (I).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:6]=1.[C:12]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>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>[C:12]([C:16]1[CH:17]=[C:18]([C:2]2[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:6]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1csc(Br)c1
Reactant: COc1ccc(B(O)O)cc1C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc(-c2ccc(OC)c(C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.7 %

Procedure:
260 mg (0.5 mmol) of tetrakis(triphenylphosphine)palladium(0), 50 ml of toluene and 2.59 g (10.9 mmol) of ethyl 2-bromo-4-thiophenecarboxylate are introduced into a three-necked flask under a stream of nitrogen and the mixture is stirred at room temperature for 20 minutes. 3.7 g (16.5 mmol) of 3-tert-butyl-4-methoxyphenylboronic acid and 11 ml of aqueous sodium carbonate solution (2 N) are then added and the mixture is refluxed for 8 hours. The reaction medium is evaporated to dryness, the residue is taken up in water and ethyl ether and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and heptane (10/90% by volume). 3.53 g (69%) of ethyl 2-(3-tert-butyl-4-methoxyphenyl)-4-thiophenecarboxylate are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:16]=[CH:15][NH:14][N:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH3:19]I>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:16]=[CH:15][N:14]([CH3:19])[N:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(C)ccc1-c1cc[nH]n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1-c1ccn(C)n1
Reaction time: 1 h

Procedure:
To a solution of methyl 5-methyl-2-(1H-pyrazol-3-yl)benzoate (0.16 g, 0.744 mmol) in DMF (3 mL) at rt was added NaH (60%, 0.081 g, 2.02 mmol) under argon protection. The mixture was stirred atrt for 1 h, and then MeI (0.07 mL, 1.116 mmol) was added. The resulting mixture was stirred for another 1 h. The solvent was removed in vacuo. The crude was dissolved with EtOAc and washed with satd. NaHCO3, brine, and dried (MgSO4). The solvent was removed and the crude was purified by silica gel chromatography to obtain the faster eluting methyl 5-methyl-2-(1-methyl-1H-pyrazol-5-yl)benzoate as the minor product and the slower eluting methyl 5-methyl-2-(1-methyl-1H-pyrazol-3-yl)benzoate as the title compound and major product. ESI-MS (m/z): 231 [M+1]+.
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6]C[C:4]1=O)=C.[C:9](NCCCN(C)C)(=[O:13])[C:10]([CH3:12])=C.C(N1CCCC1=[O:28])=C.CN(CCCC=C(C)C(N)=O)C.CC(C(NCCC[N+](C)(C)C)=O)=C.C=CN1C(=O)CCC1.[Cl-]>>[C:9]([O:13][CH2:6][CH2:7][N:3]([CH3:1])[CH3:4])(=[O:28])[CH:10]=[CH2:12]
Reactant: C=C(C)C(=O)NCCCN(C)C
Reactant: C=CN1CCCC1=O
Agent: C=C(C)C(=O)NCCC[N+](C)(C)C
Agent: CC(=CCCCN(C)C)C(N)=O
Agent: [Cl-]
Product: C=CC(=O)OCCN(C)C

Procedure:
vinylpyrrolidone/methacrylamidopropyldimethylamine copolymers sold, for example, under the name STYLEZE CC 10 by ISP, quaternized vinylpyrrolidone/dimethylaminopropylmethacrylamide copolymers such as the product sold under the name GAFQUAT HS 100 by the company ISP, and crosslinked polymers of methacryloyloxy(C1-C4)alkyltri(C1-C4)alkylammonium salts such as the polymers obtained by homopolymerization of dimethylaminoethyl acrylate quaternized with methyl chloride, or by copolymerization of acrylamide with dimethylaminoethyl acrylate quaternized with methyl chloride, the homo- or copolymerization being followed by crosslinking with a compound containing olefinic unsaturation, such as methylenebisacrylamide. In at least one embodiment, a crosslinked acrylamide/methacryloyloxyethyltrimethylammonium chloride copolymer (20/80 by weight) in the form of a dispersion containing 50% by weight of the copolymer in mineral oil can be used. This dispersion is sold under the name SALCARE® SC 92 by the company Ciba. In some embodiments, a crosslinked methacryloyloxyethyltrimethylammonium chloride homopolymer containing about 50% by weight of the homopolymer in mineral oil or in a liquid ester can be used. These dispersions are sold under the names SALCARE® SC 95 and SALCARE® SC 96 by the company Ciba.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][N:9]1[C:8]2[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[N:11]=[CH:10]1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=[N+]([O-])c1ccc2[nH]cnc2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(Cn2cnc3ccc([N+](=O)[O-])cc32)c(OC)c1
Yield: 25.6 %

Procedure:
A solution of 6-nitrobenzimidazole (2.0 g.) and methyl 4-bromomethyl-3-methoxybenzoate (B) (3.5 g.) in methyl ethyl ketone (61 ml.) was treated with potassium carbonate (1.9 g.) and then heated under reflux for 24 hours. The solvent was then evaporated. The residue was extracted with ethyl acetate and inorganic material removed by filtration. The filtrate was evaporated. The resultant residue was purified by flash chromatography on a 6×30 cm. silica gel column using 1:1 v/v hexane:ethyl acetate as the eluent to give methyl 3-methoxy-4-(6-nitrobenzimidazol-1-ylmethyl)benzoate (K) (1.07 g. , 26%); NMR: 3.9 (s,3H, OCH3), 4.0(s,3H, OCH3), 5.7(s,2H, NCH2), 7.4(d, 1H, Ar), 7.8(d,1H, H4 -benzimidazole), 8.1(dd, 1H, H5 -benzimidazole), 8.6 (br s, 2H, H2,7 -benzimidazole).
Reaction SMILES: [N:1]1([C:6]2[NH:10][N:9]=[C:8]([C:11]([OH:13])=O)[N:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl.Cl.[CH:16]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O>CN(C=O)C.CCN(CC)CC>[CH:16]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:11]([C:8]2[N:7]=[C:6]([N:1]3[CH:2]=[CH:3][CH:4]=[CH:5]3)[NH:10][N:9]=2)=[O:13])[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1n[nH]c(-n2cccc2)n1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(NC(=O)c2n[nH]c(-n3cccc3)n2)CC1
Reaction time: 16 h

Procedure:
To 100 mg 5-Pyrrol-1-yl-1H-[1,2,4]triazole-3-carboxylic acid in 1 ml DMF and 0.3 ml NEt3, 121 mg 1-Isopropyl-piperidin-4-ylamine dihydrochloride and 142 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. After addition of 5 ml of water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The obtained crude product was used without further purification in the next reaction step. Yield: 170 mg.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:19])[NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2Cl)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:1]1([C@H:7]([O:9][C:10](=[O:19])[NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:24]2[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](OC(=O)Nc1cnccc1Cl)c1ccccc1
Reactant: OB(O)c1ccc(O)cc1
Product: C[C@@H](OC(=O)Nc1cnccc1-c1ccc(O)cc1)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: (4-Chloro-pyridin-3-yl)-carbamic acid (R)-1-phenyl-ethyl ester and 4-hydroxyphenylboronic acid.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][C@H:17]([CH3:23])[CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:24][C:25]1[C:26]([F:34])=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1.[N-]=C=O.CN1CCOCC1>>[Cl:24][C:25]1[C:26]([F:34])=[C:27]([NH:31][C:32]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][C@H:17]2[CH3:23])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C=Nc1cccc(Cl)c1F
Reactant: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1
Agent: Cl
Agent: [N-]=C=O
Solvent: CN1CCOCC1
Product: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1C(=O)Nc1cccc(Cl)c1F

Procedure:
In analogy to the procedure described in example 58F, (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 58E) and 3-chloro-2-fluorophenyl isocyanate (but with 2.1 eq. of isocyanate and 5 eq. of 4-methylmorpholine) gave after extraction with sat. aq. sodium hydrogencarbonate solution/1 M aq. sodium hydroxide solution and dichloromethane (3 times) 0.016 g (12%) of the title compound as white foam. MS: 467.2 (MH+, 1Cl).