Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:35])[C:22]([C:29]4[N:30]=[C:31]([NH2:34])[S:32][CH:33]=4)=[N:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[C:18](=[O:36])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1.C([O-])(=O)C.[Na+:41]>CO>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:35])[C:22]([C:29]4[N:30]=[C:31]([NH2:34])[S:32][CH:33]=4)=[N:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[C:18](=[O:36])[N:13]3[C:14]=2[C:15]([O-:17])=[O:16])=[N:4][N:3]=1.[Na+:41].[Na+:41].[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:35])[C:22](=[N:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[C:29]4[N:30]=[C:31]([NH2:34])[S:32][CH:33]=4)[C:18](=[O:36])[N:13]3[C:14]=2[C:15]([O-:17])=[O:16])=[N:4][N:3]=1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NOCC(=O)O)c4csc(N)n4)[C@H]3SC2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nnc(SCC2=C(C(=O)[O-])N3C(=O)C(NC(=O)C(=NOCC(=O)O)c4csc(N)n4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.1 g of animal black was added at room temperature to a stirred solution of 1.1 g of the product of Example 7, 25 ml of methanol and 7.7 ml of a solution of sodium acetate in methanol and the mixture was vacuum filtered. The filter was rinsed with methanol and the filtrate was evaporated under reduced pressure at less than 30° C. to a volume of about 5 ml. 50 ml of pure ethanol were added thereto at room temperature and the mixture was stirred at 20°-25° C. for 15 minutes and was vacuum filtered. The product was rinsed 3 times with 5 ml of pure ethanol and 3 times with 10 ml of ether and was dried under reduced pressure to obtain 0.965 g of the syn isomer of disodium 3-[(5-methyl-1,3,4-thiadiazol -2-yl)-thiomethyl]-7-[2-(2-amino-4-thiazolyl)-2-(carboxymethyloxyimino)-acetamido]-ceph-3-eme-4-carboxylate with a specific rotation of [α ]D20 =-55.5°±1.5° (c=1% in water).
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].Br[C:31]1[CH:32]=[CH:33][C:34]([CH:37]([OH:39])[CH3:38])=[N:35][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:29][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:13]=[CH:14][C:15]([C:31]3[CH:36]=[N:35][C:34]([CH:37]([OH:39])[CH3:38])=[CH:33][CH:32]=3)=[CH:16][CH:17]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CC(O)c1ccc(Br)cn1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (3 g, 7.26 mmol) and 1-(5-Bromo-pyridin-2-yl)-ethanol (1.46 g, 7.26 mmol) in toluene: ethanol:water (15:15:7 mL) is added Na2CO3 (2.3 g, 21.79 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 30 minutes then Pd(PPh3)4 (0.839 g, 0.726 mmol) is added. The reaction mixture is heated to 100° C. for 16 hours. Solvent is evaporated in vacuo and the crude material is purified by combi-flash using 55% ethyl acetate in hexane as an eluent to afford the title compound (2.2 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.39 (d, J=6.6 Hz, 3H), 1.53 (s, 3H), 1.60 (s, 3H), 4.57-4.58 (m, 0.5H), 4.69-4.70 (m, 1H), 4.75-4.77 (m, 1H), 4.78-7.80 (m, 0.5H), 4.89-4.94 (m, 1H), 5.26 (d, J=3.88 Hz, 1H), 5.41 (d, J=4.6 Hz, 1H), 6.64 (t, J1=52.32 Hz, 1H), 7.57-7.64 (m, 3H), 7.77 (d, J=8.16 Hz, 2H), 8.08 (dd, J1=8.2 Hz, J2=2.32 Hz, 1H), 8.80 (d, J=2.04 Hz, 1H). LC-Ms (m/z): 409 [M+H].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[C:16]3[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:20][C:15]=3[N:14]=[CH:13]1)[CH:8]=[CH:7]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.C([O-])([O-])=O.[Cs+].[Cs+].[C:83]([O:87][C:88](=[O:96])[NH:89][CH:90]1[CH2:95][CH2:94][NH:93][CH2:92][CH2:91]1)([CH3:86])([CH3:85])[CH3:84]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:83]([O:87][C:88](=[O:96])[NH:89][CH:90]1[CH2:95][CH2:94][N:93]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([N:12]2[C:16]4[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:20][C:15]=4[N:14]=[CH:13]2)[CH:8]=[CH:7]3)[CH2:92][CH2:91]1)([CH3:86])([CH3:84])[CH3:85]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1cccc2ccc(-n3cnc4cc(OCCCN5CCOCC5)ccc43)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)NC1CCN(c2cccc3ccc(-n4cnc5cc(OCCCN6CCOCC6)ccc54)nc23)CC1

Procedure:
8-Chloro-2-[5-(3-morpholinopropoxy)-1H-benzimidazol-1-yl]-quinoline 138D (226 mg, 0.53 mMol), racemic-BINAP (50 mg, 0.08 mMol), Cs2CO3 (243 mg, 0.75 mMol), piperidin-4-yl-carbamic acid tert-butyl ester (214 mg, 1.07 mMol), xylenes (1 mL), and Pd(OAc)2 (12 mg, 0.053 mMol) were combined under argon and heated at reflux for 2 days. After allowing the mixture to cool, hexanes were added and decanted off, several times, to remove hexane solubles. The residue was stirred with EtOAc and filtered, and the solids washed with additional EtOAc. The combined EtOAc solutions were evaporated, and the residue chromatographed on silica gel with EtOAc/MeOH elution. Fractions containing the title product 138E were combined and concentrated to provide 130 mg.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.C([C:14]1[S:18][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:16]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:15]=1)(O)=O>[Cu]>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[S:18][CH:14]=[CH:15][C:16]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc(-c2ccncc2)c(-c2ccc(F)cc2)s1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Fc1ccc(-c2sccc2-c2ccncc2)cc1
Temperature: 240 °C
Reaction time: 2.5 h
Yield: 109.6 %

Procedure:
Quinoline (42 ml) and copper powder (2.95 g, 46.4 mmol) were added to 5-carboxy-2-(4-fluorophenyl)-3-(pyridin-4-yl)thiophene (12.64 g (42.2 mmol), prepared as described in 2))), and the resulting mixture was stirred at 240° C. for 2.5 hours. At the end of this time, the reaction mixture was cooled to room temperature and was filtered off. The filtrate was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, hexane:ethyl acetate=1:1), to give the title compound (11.81 g) as a brown powder (yield quantitative).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH3:12][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:51])[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35](C#CC4N5C=CN=CC5=NC=4)[CH:34]=3)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C.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.[Cu]I>[CH3:14][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:51])[C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[C:37]([C:2]#[C:1][C:3]4[N:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:38]=3)[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: C#Cc1cnc2ccccn12
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-ethynylimidazo[1,2-a]pyridine (0.032 g, 0.22 mmol) in anhydrous DMF (1.26 mL) was added N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide (prepared as in Example 3), Pd(PPh3)4 (0.013 g, 0.011 mmol), CuI (0.0032 mg, 0.0165 mmol) and DIPEA (0.064 mL, 0.44 mmol). The solution was degassed with argon for 15 minutes then stirred overnight at rt. The solvent was removed and the resultant residue was chromatographed over silica gel eluting initially with EtOAc and then with methanol/methylene chloride (5:95) to furnish the desired product: (0.07 g, 59%) MS (M+H)+ 542.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13]O)[CH:11]=[CH:12][C:4]=2[O:3]1.C(N(CC)CC)C.CS([Cl:26])(=O)=O>C(Cl)Cl>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][Cl:26])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1Oc2ccc(CO)cc2NC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1Oc2ccc(CCl)cc2NC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4.59 g (23.8 mmol) of (±)-2-methyl-3-oxo-6-hydroxymethyl-3,4-dihydro-2H-1,4-benzoxazine is mixed with 5.53 g (54.6 mmol) of triethylamine after being dissolved in 900 ml of methylene chloride. At 0° C., 4.08 g (35.6 mmol) of methanesulfonic acid chloride is added in drops, and the batch is then stirred at room temperature for 5 hours. Another 3.8 ml of triethylamine and 1.4 ml of methanesulfonic acid chloride are added and stirred again for 20 hours at room temperature. A portion of methylene chloride (600 ml) is spun off. After dilution with 1 l of diethyl ether, the organic phase is washed twice with 50 ml of water each, once with 50 ml of saturated sodium bicarbonate solution and again with 50 ml of water. The organic phase is spun in after drying, and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol). 2.95 g (58.7%) of the desired product in addition to 1.1 g (16.6%) of the corresponding mesylate are obtained, melting point 162-169° C.
Reaction SMILES: [I-].[Br:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][CH:7]([C:13]([O:15]C)=[O:14])[CH2:8][N+](C)(C)C.[OH-].[Na+].Cl>>[Br:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][C:7](=[CH2:8])[C:13]([OH:15])=[O:14]
Reactant: COC(=O)C(Cc1cccc(Br)c1)C[N+](C)(C)C
Agent: Cl
Agent: [I-]
Agent: [Na+]
Product: C=C(Cc1cccc(Br)c1)C(=O)O
Temperature: 105 °C
Yield: 84.9 %

Procedure:
To a 10 ml round bottom flask containing 2-(3-bromobenzyl)-3-methoxy-N,N,N-trimethyl-3-oxo-1-propanaminium iodide (0.95 g, 2.15 mmol) was added 1 N aqueous NaOH (4.3 ml). The mixture was heated at 105° C. for 2 hours, then cooled to room temperature and acidified with 0.5 N HCl to pH ˜1. The white precipitate was isolated by filtration, washed with water, and air-dried to give 2-(3-bromobenzyl)acrylic acid 0.44 g, 85% yield, HPLC purity: 93.0%.
Reaction SMILES: [F:1][C:2]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:20])=[C:12]([C:15](OCC)=[O:16])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1.CC(C[AlH]CC(C)C)C.O.[OH-].[Na+].O>ClCCl>[F:1][C:2]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:20])=[C:12]([CH2:15][OH:16])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1
Reactant: CCOC(=O)c1c(C)nc2c(ccn2Cc2cccc(F)c2F)c1I
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1nc2c(ccn2Cc2cccc(F)c2F)c(I)c1CO
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
To a solution of ethyl 1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (10 g, 21.92 mmol) in dichloromethane (DCM) (160 mL) at −55° C. under nitrogen atmosphere was added dropwise DIBAL-H (129 mL, 129 mmol) (1M/toluene) in ˜20 min and then the mixture was allowed to warm to 0° C. in 1 h and stirred at 0° C. for 1.5 h. The mixture was cooled to −20° C. and water (5.2 mL) was added dropwise followed by 15% NaOH/water (5.2 mL) and water (12.9 ml) and stirring at ambient temperature continued for 30 min. The mixture was filtered through celite washing with dichloromethane. The filtrate was concentrated and dried in vacuo to provide (1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (8.76 g, 19.67 mmol, 90% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.70 (t, J=6.05 Hz, 1 H), 2.82 (s, 3 H), 4.99 (d, J=6.05 Hz, 2 H), 5.51 (s, 2 H), 6.32 (d, J=3.52 Hz, 1 H), 6.81-6.89 (m, 1 H), 6.90-7.00 (m, 1 H), 7.07 (dd, J=9.67, 1.86 Hz, 1 H), 7.19 (d, J=3.52 Hz, 1 H); LCMS (m/z) ES+=415 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>COCCOC>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Reactant: CCOc1ccccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCOc1ccccc1OC[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring mixture at room temperature of (S)-2-hydroxymethyl-morpholine-4-carboxylic acid, tert-butyl ester, 2-ethoxyphenol and triphenylphosphine in DME was added dropwise diisopropyl azodicarboxylate. The solution was stirred at room temperature for 24 h, concentrated (to remove most of the DME), then suspended into hexanes. The solid that formed was filtered. The filtrate was concentrated, redissolved into diethyl ether, then washed with 1 N NaOH (2×), sat. KH2PO4 and brine solutions. The organic extract was dried (MgSO4), filtered, concentrated and chromatographed (MPLC, silica gel, 20% EtOAc in hexanes) to give (S)-2-(2-ethoxy-phenoxymethyl)-morpholine-4-carboxylic acid, tert-butyl ester as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[N:32]1[C:41]2[C:36](=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[C:41]3[C:36]=2[CH:35]=[CH:34][CH:33]=[N:32]3)[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=1
Reactant: OB(O)c1cccc2ncccc12
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1cccc2ncccc12
Yield: 66.9 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and quinolin-5-ylboronic acid (0.086 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.070 g (67%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]CC2C=CC=CC=2)[CH:5]=[C:4]([F:16])[CH:3]=1.CN(C)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:16])[CH:3]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Oc1cc(F)cc(Br)c1
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
To a solution of 1-bromo-3-fluoro-5-benzyloxybenzene (110.0 g, 0.39 mol; see step (i) above) and N,N-dimethylaniline (474.0 g, 3.92 mol) in anhydrous CH2Cl2 (1.0 L) at 0° C. was added aluminium chloride (156.0 g, 1.17 mol). After 10 min, the ice bath was removed and the stirring was continued for 2 h. The reaction was quenched by the cautious addition of 3N HCl (600 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×150 mL). The combined organic extracts were washed with 2N HCl (250 mL) and H2O (3×250 mL). To the organic layer was added 15% KOH (500 mL), and the layers were separated. The organic layer was further extracted with 2 N KOH (2×70 mL). The combined aqueous layers were washed with CH2Cl2 (3×100 mL) and then acidified with 4N HCl. The aqueous layer was extracted with Et2O (3×125 mL) then, the combined Et2O extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (69.0 g, 92%) as a brown oil that was used without further purification.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:17]([NH:19][C:20](=[O:22])C)[CH:18]=1)[CH2:4][CH2:5][CH3:6].[C:38]([N:42]=C=O)([CH3:41])([CH3:40])[CH3:39].Cl>C1COCC1.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[C:38]([NH:42][C:20]([NH:19][C:17]1[CH:18]=[C:13]([C:12]2[CH:11]=[C:10]([O:30][CH:31]3[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]3)[N:9]=[N:8][C:7]=2[CH2:3][CH2:4][CH2:5][CH3:6])[CH:14]=[CH:15][C:16]=1[O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)N=C=O
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NC(C)=O)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NC(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 126.4 %

Procedure:
To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenylamine (Example 62, 0.5 mmol, 219 mg) in dry THF (1.0 mL) was added tert-butyl isocyanate (1.5 mmol, 149 mg), and the mixture was stirred at room temperature over night. It was then condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (5.0 mL), 2N HCl in ether (5.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (193 mg). LCMS: m/z 539 [M+1]. 1H NMR (400 MHz, CD3OD): δ 8.09-8.12 (1H, m), 7.55 and 7.65 (1H, s), 7.12-7.18 (1H, m), 7.00-7.08 (1H, m), 5.36-5.56 (1H, m), 4.41-4.48 (1H, m), 3.25-3.67 (4H, m), 3.08-3.15 (2H, m), 2.93 (3H, s), 2.02-2.58 (6H, m), 1.83-1.89 (2H, m), 1.40-1.70 (8H, m), 1.38 (9H, s), 1.26-1.36 (2H, m), 0.83 (3H, t).
Reaction SMILES: C([O:4][CH:5]([C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[O:24][N:23]=1)[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(=O)C.[OH-].[Na+]>CO>[OH:4][CH:5]([C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[O:24][N:23]=1)[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:14]1
Reactant: CC(=O)OC(CCCC1CCN(Cc2ccccc2)CC1)c1noc(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2nc(C(O)CCCC3CCN(Cc4ccccc4)CC3)no2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of 3-[1-acetoxy-4-(1-benzylpiperidin-4-yl)butyl]-5-(4-nitrophenyl)-1,2,4-oxadiazole (0.5 g) in methanol (10 ml) was added 4N an aqueous sodium hydroxide solution (0.5 ml) at 0° C. After stirring at 0° C. for 2 hours, ice water was added to the mixture and the precipitates were filtrated to give 3-[1-hydroxy-4-(1-benzylpiperidin-4-yl)butyl]-5-(4-nitrophenyl)-1,2,4-oxadiazole (0.44 g). The compound (100 mg) was dissolved in a solution of fumaric acid (27 mg) in ethanol to give 3-[1-hydroxy-4-(1-benzylpiperidin-4-yl)butyl]-5-(4-nitrophenyl)-1,2,4-oxadiazole fumarate (0.1 g).
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].Cl>>[Cl:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[Cl:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Br
Reactant: NCc1ccccc1Cl
Agent: Cl
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1NCc1ccccc1Cl
Yield: 53.1 %

Procedure:
2-Bromo-5-chloro-3-nitrobenzoic acid (2.30 g, 10 mmol) was refluxed with 2-chlorobenzyl amine (20 mmol, 2.82 g) overnight. The reaction mixture was then poured into 10% aqueous hydrochloric acid solution and the resulting solid was collected. Crystallization from aqueous methanol gave 1.81 g (53%) of 5-chloro[(2-chlorophenyl)methyl]amino-3-nitrobenzoic acid; mp 159.5°-161° C.
Reaction SMILES: [CH:1]1([C:7]2([CH2:14][NH2:15])[O:11][C@H:10]([CH3:12])[C@@H:9]([CH3:13])[O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[N:28]=[C:29]=[O:30])[CH3:18]>C(OC(=O)C)C>[CH3:18][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[C:20]=1[NH:28][C:29]([NH:15][CH2:14][C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[O:11][C@H:10]([CH3:12])[C@@H:9]([CH3:13])[O:8]1)=[O:30])[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: C[C@H]1OC(CN)(C2CCCCC2)O[C@@H]1C
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(C2CCCCC2)O[C@H](C)[C@@H](C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
To a stirred solution of [(4R, 5R)-2-cyclohexyl-4,5-dimethyldioxolan-2-yl]methylamine (2.13 g 0.100 mole) in 40 ml of ethylacetate is added dropwise at room temperature 2,6-bis(1-methylethyl)phenylisocyanate (1.94 g 0.105 mole). The reaction mixture is stirred at room temperature for two hours. Volatiles are removed under reduced pressure and the residue is crystallized from ethylacetate/n-hexane, yielding 3.45 g of N-[2,6-bis(1-methylethyl)phenyl]-N'-[(4R,5R)-2-cyclohexyl-4,5-dimethyl-dioxolan-2-yl]methylurea, [α]D26 =-9.1 (C=0.653, AcOH).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][C:2]1=[O:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][C:2]1=[O:13]
Reactant: O=C1CCC(=O)c2ccccc2N1
Reactant: ClCCCCBr
Product: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Yield: 58.7 %

Procedure:
Analogously to the procedure described in Example 1, reaction of 3,4-dihydro-1H-1-benzazepine-2,5-dione (11.42 mmol, 2.00 g) and bromo-4-chlorobutane (13.7 mmol, 2.35 g) afforded 1.78 g of the title compound, contaminated with reactants to an extent of 30%. The mixture thus obtained was reacted without further purification.