Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1>C(O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve N-Boc-4-aminopiperidine (0.9 g, 4.8 mmol) in dry ethanol and add solid sodium carbonate (0.8 g, 7.9 mmol) at 0° C., followed by 2-chloro-5-nitro-pyridine (0.6 g, 3.9 mmol). Stir the solution at room temperature overnight, then heat the solution at 9° C. for 6 hours. Stir at room temperature overnight. Evaporate the solvent under reduced pressure and partition the crude mixture between EtOH and water. Extract with EtOAc and wash the organic layer with saturated aq. sodium chloride solution. Combine organic layers and dry over MgSO4. Filter and evaporate the solvent in order to obtain 4-(5-Nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[N:10]=[C:11]([S:14][CH3:15])[N:12]=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]2=[O:16])[CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:24])C=CC=CC=1>C(Cl)Cl>[CH:1]1([N:4]2[C:9]3[N:10]=[C:11]([S:14]([CH3:15])=[O:24])[N:12]=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]2=[O:16])[CH2:3][CH2:2]1
Reactant: CSc1ncc2ccc(=O)n(C3CC3)c2n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(=O)n(C3CC3)c2n1
Yield: 74.1 %

Procedure:
A solution of 8-cyclopropyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.5 g, 2.1 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (0.84 g, 3.2 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 20 hours. The white solid formed was collected by filtration and washed with hexane, then dried to give 8-cyclopropyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.388 g, 74%). 1H NMR: δ(400 MHz, DMSO) 9.15 (s, 1H), 8.0 (d, J=9.5 Hz, 1H), 6.74 (d, J=9.5 Hz, 1 H), 2.92(s, 1H), 1.18˜1.14(m, 2H), 0.83˜0.79 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25]C)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1CCNS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(NCCc1ccccc1O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
620 mg (1.54 mmol) of 4-(4-fluorophenoxy)-N-[2-(2-methoxyphenyl)ethyl]benzene-sulfonamide are dissolved in 10 ml of dichloromethane and, at −40° C., 3.09 ml (3.09 mmol) of a 1 M solution of boron tribromide in dichloromethane are added. The solution is warmed to room temperature and stirred for a further four hours. It is subsequently added to water, the phases are separated, and the organic phase is washed twice more with H2O. The dichloromethane phase is dried with MgSO4 and concentrated, allowing the desired phenol to be isolated as a brown oil. Crude yield 89%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[C:10]2[C:11]([OH:14])=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.O[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:21][CH2:20]1.C(CP(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[C:10]2[C:11]([O:14][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:21][CH2:20]3)=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: Oc1noc2cccc(OCC(F)(F)F)c12
Reactant: COC(=O)C1(CN2CCC(CO)CC2)CCOCC1
Agent: CCCC[PH](CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC(F)(F)F)c34)CC2)CCOCC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
A mixture of 4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-ol (230 mg, 1 mmol, EXAMPLE 1, step 2), methyl 4-{[4-(hydroxymethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate (270 mg, 1 mmol, EXAMPLE 1, step 4), and cyanomethyltributylphosphorane (400 mg, 1.5 mmol) in toluene (1.0 mL) was stirred at 100° C. for 16 h. After cooling, the mixture was concentrated in vacuo to give a dark brown oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 2:1) to give 250 mg (51%) of the title compound as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([CH2:15]O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1.N1C=CC=CC=1>C1C=CC=CC=1>[CH:5]1([CH2:15][Cl:3])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1
Reactant: OCC1OCCc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: ClCC1OCCc2ccccc21
Yield: 97.8 %

Procedure:
8.4 g (70.6 mmol) of thionyl chloride was dropwise added to a solution of 10 g (61 mmol) of (isochroman-1-yl)methanol [J. Med. Chem., 28, 1026 (1985)] and 5 g (63 mmol) of anhydrous pyridine in dried benzene, and the resulting mixture was heated under reflux for 2 hours. Excessive amounts of thionyl chloride and benzene were evaporated, and the residue was dissolved in ether. The ethereal solution was washed with water and dried, and the solvent was then evaporated. The residue was distilled under reduced pressure (140° C./20 mmHg) to give 10.9 g (98%) of the desired compound as an oily.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:28]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Product: CSc1nc(-c2cccc(OC(=O)Oc3ccccc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) with phenyl chloroformate (324 μl) was performed according to the methods described in example 1g. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:12]([N:15]=[C:16]=[O:17])[CH:13]=[CH2:14]>C1C=CC=CC=1>[CH2:12]([NH:15][C:16]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)=[O:17])[CH:13]=[CH2:14]
Reactant: CCCCNc1nc(C)co1
Reactant: C=CCN=C=O
Solvent: c1ccccc1
Product: C=CCNC(=O)N(CCCC)c1nc(C)co1

Procedure:
A solution of 2-butylamino-4-methyloxazole (12.0 g, 0.078 mol) and allyl isocyanate (6.46 g, 0.078 mol) in dry benzene was heated under reflux for 4 hours, and worked up as described in Example 3. The product was further purified by chromatography on a silica-gel column, eluting with a 1:1 mixture of benzene and ethyl acetate.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1.[Br:13]N1C(=O)CCC1=O>ClCCl>[Br:13][C:8]1[CH:9]=[C:4]([O:3][C:2]([F:1])([F:11])[F:12])[C:5]([NH2:10])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1OC(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(Br)cc1OC(F)(F)F
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of 3-(trifluoromethoxy)pyridin-2-amine (300 mg, 1.68 mmol) in dichloromethane (8 mL) was added N-bromosuccinimide (450 mg, 2.53 mmol) at 20° C. The reaction mixture was stirred at the same temperature for another 5 min and subsequently concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 15% ethyl acetate in petroleum ether) affording product (220 mg, 51%): 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J=2.0 Hz, 1H), 7.75-7.74 (m, 1H), 6.68 (brs, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][CH2:18]Cl)[CH3:16]>CC(C)=O>[Br:1][C:2]1[C:3]([O:8][CH2:18][O:17][CH2:15][CH3:16])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCCl
Reactant: Oc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCOc1ncccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a round-bottomed flask was added 3-bromo-2-hydroxypyridine (5 g, 28.7 mmol) and potassium carbonate (9.93 g, 71.8 mmol) in Acetone (300 mL). The suspension was stirred at ambient temperature for 30 min and then treated with the drop-wise addition of chloromethyl ethyl ether (2.78 mL, 30.6 mmol) via addition funnel. The mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and the filtrate partitioned between EtOAc and water. The combined organic layers were washed with water, saturated solution of sodium bicarbonate and brine, dried over Mg2SO4, filtered and concentrated. The crude material was to afford 2.46 g of desired product as a clear oil which was used without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][O:12][C:13](=[O:18])[C:14]([NH2:17])([CH3:16])[CH3:15].F[C:20]1[C:21]([CH3:40])=[N:22][C:23]2[C:28]([N:29]=1)=[C:27]([C:30]1[NH:38][C:37]3[CH2:36][CH2:35][NH:34][C:33](=[O:39])[C:32]=3[CH:31]=1)[CH:26]=[CH:25][CH:24]=2>CS(C)=O>[CH3:15][C:14]([NH:17][C:20]1[C:21]([CH3:40])=[N:22][C:23]2[C:28](=[C:27]([C:30]3[NH:38][C:37]4[CH2:36][CH2:35][NH:34][C:33](=[O:39])[C:32]=4[CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[N:29]=1)([CH3:16])[C:13]([O:12][CH3:11])=[O:18]
Reactant: COC(=O)C(C)(C)N
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 95 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
Prepared according to Example 131, using DIPEA (1761 μl, 10.12 mmol), aminoisobutyric acid methyl ester hydrochloride (778 mg, 5.06 mmol, Sigma Aldrich), and 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 500 mg, 1.687 mmol) in DMSO (8437 μl) stirring at 95° C. for 2 h. Purification by column chromatography (silica gel: 0 to 10% MeOH/DCM) provided methyl 2-methyl-2-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)propanoate (557 mg, 81%). 1H NMR (CDCl3) δ: 11.16-11.25 (m, 1H), 7.96-8.01 (m, 1H), 7.69-7.74 (m, 1H), 7.40-7.46 (m, 1H), 7.08-7.12 (m, 1H), 5.56-5.71 (m, 1H), 5.15-5.20 (m, 1H), 3.66-3.73 (m, 2H), 3.56 (s, 3H), 3.25 (s, 2H), 2.65 (s, 3H), 1.79 (s, 6H). m/z (ESI, +ve) 394.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23]2[C:6](=[CH:7][C:8]3[C:9](=[O:36])[C:10]4[C:19]([C:20](=[O:29])[C:21]=3[CH:22]=2)=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:33][CH2:34][CH3:35])=[C:15]([CH2:30][CH2:31][CH3:32])[CH:16]=2)[CH:11]=4)[CH:5]=1)[CH2:2][CH3:3].C([BH-](CC)CC)C.[Li+].Cl>C1COCC1>[OH:29][CH:20]1[C:19]2[C:10](=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([CH2:30][CH2:31][CH3:32])=[C:14]([CH2:33][CH2:34][CH3:35])[CH:13]=3)[CH:9]([OH:36])[C:8]2[CH:7]=[C:6]3[C:23]([CH:24]=[C:25]([CH2:26][CH2:27][CH3:28])[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5]3)=[CH:22][C:21]1=2
Reactant: CCCc1cc2cc3c(cc2cc1CCC)C(=O)c1cc2cc(CCC)c(CCC)cc2cc1C3=O
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1cc2cc3c(cc2cc1CCC)C(O)c1cc2cc(CCC)c(CCC)cc2cc1C3O

Procedure:
A solution of 357 mg of 2,3,9,10-tetrapropyl-6,13-pentacenequinone dissolved in 50 mL of THF was added to 11 mL of a 1 mol/1000 mL THF solution of lithium triethylborohydride, and the mixture was heated for 24 hours under reflux in a nitrogen atmosphere. The resulting solution was neutralized with diluted aqueous hydrochloric acid, and the organic phase was separated, concentrated and dried under a vacuum to produce 6,13-dihydro-6,13-dihydroxy-2,3,9,10-tetrapropylpentacene almost stoichiometrically.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:7]=[C:8]([CH3:43])[C:9]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]4[O:40][CH2:39][CH2:38][C@H:21]5[S:22](=[O:37])(=[O:36])[C:23]([CH3:35])([CH3:34])[C:24]([NH:26]C(=O)OC(C)(C)C)=[N:25][C@:20]5([CH3:41])[C:19]=4[CH:42]=3)=[O:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[NH2:26][C:24]1[C:23]([CH3:35])([CH3:34])[S:22](=[O:36])(=[O:37])[C@@H:21]2[CH2:38][CH2:39][O:40][C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:9]4[C:8]([CH3:43])=[N:7][C:6]([O:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)=[CH:11][N:10]=4)=[O:13])=[CH:42][C:19]=3[C@@:20]2([CH3:41])[N:25]=1
Reactant: Cc1nc(OCC2CC2)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(OCC2CC2)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(N)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Temperature: 85 °C
Yield: 68.9 %

Procedure:
To a reaction mixture of tert-butyl ((4aR,11bR)-10-(5-(cyclopropylmethoxy)-3-methylpyrazine-2-carboxamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (40 mg, 0.065 mmol) in DMF 1 ml was added K2CO3 (40 mg, 0.29 mmol). It was heated to 85° C. for 3 h. It was cooled to RT, diluted with water, and extracted with EtOAc. The organic phase obtained was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 15% to 25% to 40% EtOAc/MeOH/Et3N in (40% EtOAc in Heptane) to yield 23 mg of desired product. MS m/z: 514.2 [M+H].
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.[H-].[Na+].[CH3:32]I.O>O1CCCC1>[CH3:32][N:3]1[CH:4]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[C:5]2[C:20](=[O:21])[CH2:19][CH2:18][C:6]=2[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C:2]1=[O:1]
Reactant: CI
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Reaction time: 0.33 h

Procedure:
Under an atmosphere of argon, 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 200 mg, 0.50 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 24 mg, 0.60 mmol) in dry tetrahydrofuran. After 20 min, methyl iodide (41 μL, 0.66 mmol) is added. After 20 min water is added and the mixture is concentrated. The residue is purified by flash a) chromatography on silica (gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate). Yield: 49 mg; ESI mass spectrum [M+H]+=412; Retention time HPLC: 0.59 min (X012_S01).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.CON(C)[C:18](=[O:20])[CH3:19].[Cl-].[NH4+]>CCOCC>[S:6]1[C:10]([C:18](=[O:20])[CH3:19])=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2
Reactant: CON(C)C(C)=O
Reactant: c1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)c1cc2ccccc2s1
Temperature: -70 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
n-Butyllithium (1.6 M solution in hexanes; 74.6 ml) was added dropwise under nitrogen at 0° C. to a stirred solution of benzo[b]thiophene (25.0 g) in ether (350 ml), then the mixture cooled to −70° C. and a solution of N-methoxy-N-methylacetamide (19.21 g) in ether (100 ml) was added dropwise. The mixture was stirred at ambient temperature for 18 hours, then it was poured into saturated aqueous ammonium chloride solution (400 ml). The organic phase was separated, washed with water (300 ml) and saturated aqueous sodium chloride solution (300 ml), dried (Na2SO4) and the solvents were removed in vacuo. The residue was triturated with petroleum ether (b.p. 60-80° C.) (50 ml) and the resulting solid was collected by filtration and dried in vacuo to give 1-(benzo[b]thiophen-2-yl]ethan-1-one (18.7 g) as a brown solid, m.p. 78-81° C.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33]C)=[O:32])[O:25][C:26]=3[CH3:27])=[CH:18][CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:40](P(=O)(OCC)OCC)[P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44].CN(C)C=O.[H-].[Na+]>O>[CH2:43]([O:42][P:41](/[CH:40]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([OH:33])=[O:32])[O:25][C:26]=3[CH3:27])=[CH:38][CH:39]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:45][CH2:46][CH3:47])=[O:48])[CH3:44]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3)c(C)o2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)O)c3)oc2C)cc1)OCC
Reaction time: 15 h
Yield: 64.5 %

Procedure:
To a mixture of methyl 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (0.29 g), tetraethyl methylenediphosphonate (0.18 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.03 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give an oily substance (0.28 g) from a fraction eluted with ethyl acetate-hexane (8:1, v/v). To a mixture of the oily substance, tetrahydrofuran (2 mL) and methanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added dilute hydrochloric acid to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as colorless crystals (0.23 g, yield 88%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 153-155° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29](O)=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:65]1[CH2:70][CH2:69][CH:68]([N:71]2[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]2)[CH2:67][CH2:66]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)[C:29](=[O:30])[N:74]3[CH2:73][CH2:72][N:71]([CH:68]4[CH2:69][CH2:70][O:65][CH2:66][CH2:67]4)[CH2:76][CH2:75]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Reaction time: 16 h

Procedure:
A solution of 70 mg (0.15 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 51 mg (0.16 mmol) TBTU and 25 μL (0.18 mmol) triethylamine in 1 mL DMF was stirred for 1 h at RT. Then 25 mg (0.15 mmol) 1-(tetrahydropyran-4-yl)-piperazine was added and the reaction solution was stirred for 16 h. The reaction solution was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10]Br>>[Br:10][C:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrBr
Reactant: O=C(O)C1CCCCC1
Product: O=C(O)C1(Br)CCCCC1

Procedure:
35 g (0.275 mol) cyclohexanecarboxylic acid and 28.4 ml (0.548 mol) bromine with the addition of 3 g red phosphorus.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:11][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:9]1.[Br:31][C:32]1[N:37]=[C:36]([C:38]([OH:40])=O)[C:35]([NH2:41])=[CH:34][CH:33]=1>>[NH2:41][C:35]1[C:36]([C:38]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH2:11][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:9]2)=[O:40])=[N:37][C:32]([Br:31])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN(c2ccncc2N)C1
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO)CN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1

Procedure:
Following Method 11 of Example 305, cis (+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-5-((tert-butyldimethylsilyloxy)methyl)piperidin-3-ylcarbamate and 6-bromo-3-aminopicolinic acid were coupled. Following purification by RP HPLC the product fractions were allowed to stand at it overnight in the 0.1% TFA acetonitrile/water solution which removed the silyl group. Upon subsequent lyophilization, cis (+/−)-tert-butyl 1-(3-(3-amino-6-bromopicolinamido)pyridin-4-yl)-5-(hydroxymethyl)piperidin-3-ylcarbamate was obtained and used in Suzuki reactions directly. LCMS (m/z): 521.0/523.1 (MH+); LC Rt=2.58 min.