Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:12][CH:13]=1.[C:21]([C:23]1[CH:36]=[CH:35][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1)#[CH:22]>C1COCC1.[Cu]I>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:22]#[C:21][C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:35][CH:36]=3)=[CH:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2ccc(Br)cn2)cc1
Reactant: C#Cc1ccc(OCCN2CCCC2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under an N2 atmosphere 773 mg (2.25 mmol) Cs2CO3, 14 mg (0.08 mmol) CuI and 87 mg (0.08 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 403 mg (1.5 mmol) 5-bromo-2-(4-chloro-phenyl)-pyridine and 322 mg (1.5 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine in 10 mL THF and the reaction mixture is stirred for 4 h at RT. Then it is heated to 60° C. for 16 h. The mixture is evaporated down i.vac., the residue is combined with 30 mL water, 5 mL 3% NH3 solution and 60 mL EtOAc, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified first by chromatography (silica gel, EtOAc/MeOH/NH3 19:1:0.1) and then by HPLC.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35](Br)=[CH:36][CH:37]=1)(=[O:32])=[O:31]>>[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)=[CH:36][CH:37]=1)(=[O:32])=[O:31]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bomo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (170 mg, 60%). MS (ISP) 570.2 [(M+H)+]; mp 132° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[O:33]=[C:34]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36][N:35]1[CH2:44][CH2:45][CH2:46][C:47](O)=[O:48]>ClCCl.CN(C)C1C=CN=CC=1.O>[CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:47](=[O:48])[CH2:46][CH2:45][CH2:44][N:35]1[C:34](=[O:33])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCn1nnc2ccccc2c1=O
Reactant: O=C1N[C@@H](Cc2ccccc2)CS1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCn1nnc2ccccc2c1=O)N1C(=O)SC[C@@H]1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of the compound obtained from step c above (2.1 g) in dichloromethane (25 mL) cooled to 0° C., 4-dimethylaminopridine (0.334 g) and triethylamine (5.7 mL) were added. After stirring the reaction mixture for 10 minutes, 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (3.9 g) and 4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid (3 g) were added, and the reaction mixture was stirred at room temperature for 14 hours. Dichloromethane and water were added to the reaction mixture. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 25% ethyl acetate in hexane as eluant to afford the title compound (4.4 g). Mass (m/z): 409.16
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]([NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1)[CH3:6])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>ClCCCl>[CH3:1][NH:2][C:3]1[S:25][C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:5]=1[CH3:6]
Reactant: CNC(=O)C(C)NC(=O)c1cccnc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCCl
Product: CNc1sc(-c2cccnc2)nc1C
Temperature: 130 °C
Yield: 68.7 %

Procedure:
To a 10 mL microwave vessel containing DCE (5 mL) was added N-(1-methylcarbamoyl-ethyl)nicotinamide (207 mg, 1.0 mmol) followed by Lawesson's reagent (2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide, 404 mg, 1.0 mmol) in one portion. The heterogeneous mixture was heated in a microwave for 5 min at 130° C. The reaction mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate (NaHCO3). The layers were separated and the organic layer was washed once with brine. The solution was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (ethyl acetate) to give the desired product as an orange solid (141 mg, 68%): mp 84-87° C.; 1H NMR (300 MHz, CDCl3) δ 8.98 (d, J=1.7 Hz, 1H), 8.51 (dd, J=4.9, 1.7 Hz, 1H), 8.08 (dt, J=8.0, 1.7 Hz, 1H), 7.29 (m, 1H), 3.00 (s, 3H), 2.30 (s, 3H); ESIMS m/z 206.4 (M+1), m/z 204.2 (M-1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH2:4][CH2:3]1.[C:16]1([CH2:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O-].[Na+].N#N>C(OCC)(=O)C.CN(C)C=O.C1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Reactant: O=C(Cc1ccccc1)Nc1ccccc1
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CN1CCN(c2ccccc2C=C(C(=O)Nc2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 11.4 %

Procedure:
To a mixture of 2-(4-methylpiperazin-1-yl)benzaldehyde (0.157 g, 0.77 mmol), 2,N-diphenylacetamide (0.162 g, 0.77 mmol), benzene (1.0 mL) and N,N-dimethylformamide (1.1 mL) was added anhydrous sodium methoxide (0.087 g, 1.62 mmol). Under a nitrogen atmosphere (N2), the mixture was heated to 80° C. for 16 hours, at which time another 46 mg of sodium methoxide (NaOCH3) was added and heating continued at 130° C. for 7 hours. The reaction was cooled to room temperature and was diluted with ethyl acetate (EtOAc), washed twice with 1N lithium chloride (LiCl), once with saturated aqueous sodium chloride, and dried over calcium sulfate (CaSO4). After filtration, the crude product was absorbed onto 450 mg of silica gel and added to a 4.0×8 inch column packed with silica gel and ethyl acetate. Elution with ethyl acetate (200 mL) followed by 1% methanol: 99% ethyl acetate (100 mL) gave 35 mg of a light yellow oil which was crystallized from methylene chloride:hexanes to give the title product, 5 mg, as a yellow powder.
Reaction SMILES: CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.[F:29][C:30]([F:71])([F:70])[C:31]1[CH:32]=[C:33]([NH:41][C:42](=[O:69])[N:43]([CH:59]2[CH2:64][CH2:63][CH:62]([C:65]([CH3:68])([CH3:67])[CH3:66])[CH2:61][CH2:60]2)[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([C:51](=[O:58])[CH2:52][C:53]3[N:54]=[N:55][NH:56][N:57]=3)=[CH:47][CH:46]=2)[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1>C1COCC1>[F:71][C:30]([F:29])([F:70])[C:31]1[CH:32]=[C:33]([NH:41][C:42](=[O:69])[N:43]([CH:59]2[CH2:60][CH2:61][CH:62]([C:65]([CH3:66])([CH3:67])[CH3:68])[CH2:63][CH2:64]2)[CH2:44][C:45]2[CH:46]=[CH:47][C:48]([CH:51]([OH:58])[CH2:52][C:53]3[N:54]=[N:55][NH:56][N:57]=3)=[CH:49][CH:50]=2)[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1
Reactant: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)Cc3nn[nH]n3)cc2)C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(O)Cc3nn[nH]n3)cc2)C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c]-[1,3,2]oxazaborole in toluene (17 μl, 0.17 mmol, 1 M) in THF (1 ml) was added boran-THF complex (328 μl, 0.32 mmol, 1 M in THF). Then a solution of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-tert-butylcyclohexyl)-1-[4-(2-2H-tetrazol-5-yl-acetyl)-benzyl]urea (100 mg, 0.17 mmol) in THF (1.0 ml) was added dropwise over a period of 30 min. The reaction mixture was stirred at room temperature overnight and then quenched with 1 N aqueous HCl (100 μl). Solvent was removed by rotary evaporation. The residue was dissolved in THF (500 μl) and injected into a preparative HPLC on a Gilson 2.11 with auto sampler (Xterra MS C18 5 μm 19 mm×100 mm, gradient: 10% acetonitrile in water→100% acetonitrile).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:11][C:12]([C:14]1([C:17]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:18])[CH2:16][CH2:15]1)=[O:13])[CH3:10].O>CS(C)=O>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:17]2([C:14]3([C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:15][CH2:16]3)[CH2:4][O:18]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1(C(=O)COc2ccc(Cl)cc2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1(C2(COc3ccc(Cl)cc3)CO2)CC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
3.6 g (0.13 mol) of 80% strength sodium hydride are added under an argon atmosphere and with stirring at 10° to 20° C. to a suspension of 24 g (0.11 mol) of trimethylsulphoxonium iodide in 100 ml of dimethyl sulphoxide. After stirring for 30 minutes at 20° C., 17.1 g (0.061 mol) of 4-chlorophenoxymethyl 1-ethoxycarbonylcycloprop-1-yl ketone are added. The mixture is warmed to 60° C. for 1 hour. After this, the mixture is poured into 300 ml of water and extracted with methylene chloride. The combined organic extracts are washed with water, dried over magnesium sulphate and concentrated. 14 g (77.8% of theory) of 2-[(4-chlorophenoxy)-methyl]-2-(1-ethoxycarbonyl-cycloprop-1-yl)-oxirane are obtained as an oil which is further reacted without additional purification. ##STR18##
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[Cl:13]>CN(C=O)C>[ClH:3].[Cl:3][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: OCc1cnccc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cl
Product: ClCc1cnccc1Cl
Reaction time: 0.75 h
Yield: 83.8 %

Procedure:
Thionyl chloride (0.714 mL, 9.78 mmol) was added at room temperature to dry DMF (7 mL). After 30 min the above solution was cannulated into the solution of 3-hydroxymethyl-4-chloropyridine (700 mg, 4.89 mmol) in DMF (3 mL). After 45 min, the product was precipitated by addition of dry ether (100 ml), washed with ether, and dried in vacuum to yield 813 mg (84%) of the title compound. 1H NMR (CD3OD) δ 5.00 (s, 2H), 8.31 (d, 1H, J=5), 8.99 (d, 1H, J=5), 9.18 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8](Br)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[Mg].Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.O>C1COCC1.BrCCBr>[CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Reactant: Clc1ccc2ccccc2n1
Agent: [Mg]
Solvent: BrCCBr
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc(-c3ccc4ccccc4n3)c2C1
Reaction time: 1.5 h
Yield: 181.9 %

Procedure:
2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1 g, 3.22 mmol) was added to a refluxing mixture of magnesium turnings (120 mg, 4.9 mmol) in 50 ml THF. Formation of the Grignard reagent was initiated by addition of 0.2 ml 1,2-dibromoethane (0.002 mmol). After 1.5 hours, 220 mg (0.33 mmol) Ni[PPh3 ]2Cl2 in 10 ml of THF were added followed by 800 mg (4.89 mmol) of 2-chloroquinoline. The solution continued to reflux for 15 minutes after which it was cooled, poured into water, and extracted three times with methalene chloride. The extract was dried with sodium sulfate and concentrated to obtain 2.1 g of a black oil. The crude was purified by using two flash columns. The first was eluted with 1:1 hexanes:ether and the second with 20:1 methylene chloride:methanol. 130 mg of the title compound were collected as product. Following crystallization in ethanol and water, 66 mg of solid were recovered, m.p. 82° C. Analysis: Theory (.1/3 H2O): C, 82.37; H, 8.48; N, 7.68; Found: C, 82.33; H, 8.44; N, 7.73.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH2:9][CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:5]=2[N:4]([CH2:16][C:17]([N:19]2[CH2:25][CH:24]3[CH2:26][CH2:27][CH:21]([CH2:22][CH2:23]3)[CH2:20]2)=[O:18])[C:3]1=[O:28].[CH3:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1>O1CCCC1>[CH:21]12[CH2:22][CH2:23][CH:24]([CH2:26][CH2:27]1)[CH2:25][N:19]([C:17]([CH2:16][N:4]1[C:5]3[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:6]=3[C:7]([CH2:9][CH3:10])=[N:8][CH:2]([NH:1][C:37]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=3)=[O:38])[C:3]1=[O:28])=[O:18])[CH2:20]2
Reactant: CCC1=NC(N)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c(C)cccc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: CCC1=NC(NC(=O)Nc2cccc(C)c2)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c(C)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A mixture of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-2,3-dihydro-5-ethyl-9-methyl-1H-1,4-benzodiazepin-2-one (310 mg) and 3-methylphenyl isocyanate (113 mg) in tetrahydrofuran (8 ml) was stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuo to dryness. The residue was triturated in diisopropyl ether and collected by filtration to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl 2,3-dihydro-5-ethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (360 mg, 86.2% yield) as a crystalline powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[C:13]1([CH2:12][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1CCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To a solution of 5-hydroxyindanone (1.0 g, 6.2 mmol), benzyl alcohol (0.65 g, 5.6 mmol) and tributylphosphine (1.7 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.1 g, 8.4 mmol), and the mixture was stirred at room temperature for 16 hrs. Insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10:1) to give the title compound (1.3 g, yield 97%) as a powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=2)[CH2:12][NH:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[C:5]([Cl:28])=[CH:4][N:3]=1>O.CO.C(O)(=O)C.[Fe]>[NH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[C:14]([NH:13][CH2:12][C:11]1[CH:25]=[CH:26][CH:27]=[C:9]([NH:8][C:6]2[C:5]([Cl:28])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:10]=1)=[O:24]
Reactant: O=C(NCc1cccc(Nc2nc(Cl)ncc2Cl)c1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc(C(=O)NCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 117.2 %

Procedure:
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}-3-nitrobenzamide (400.0 mg, 0.956 mmol) in water (0.7 mL), methanol (3.7 mL) and acetic acid (1.5 mL) was added iron (130 mg, 2.4 mmol) powder in small quantities. When the addition was completed, the very cloudy mixture was stirred at 0° C. for 1 h and then heat at 40° C. for 3 h. The mixture was filtered, and the cake was washed with MeOH/EtOAc. The filtrate was concentrated and the residue was diluted with H2O, then the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off-white powder (435 mg). LCMS for C18H15Cl2N5O (M+H)+: m/z=388.0, 390.0, 392.0. 1H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 7.59 (t, J=2.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.24 (m, 2H), 7.20 (m, 2H), 6.93 (m, 1H), 4.60 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25](=[O:31])[C:26]([O:28]CC)=O)[CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:32][NH2:33]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25](=[O:31])[C:26]([NH:32][NH2:33])=[O:28])[CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)CC(C)C(=O)OCC
Reactant: NN
Solvent: CO
Product: CCOC(=O)C(C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)NN
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
To a solution of (4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-methylpentanoate (637 mg, 1.43 mmol) in MeOH (40 mL) is added a solution of 50% wt hydrazine (0.09 mL, 1.43 mmol) in MeOH (10 mL) at −20° C. After stirring for 18 hour at room temperature, the reaction mixture is concentrated under reduced pressure to give (4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2-methylpentanoate (542 mg). HPLC retention time=1.54 minutes (condition A); MS 432.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C

Procedure:
To a solution of (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (20.0 g) in dichloromethane (500 ml) were added triethylamine (13.5 ml) and methanesulfonyl chloride (7.4 ml) with stirring in an ice bath and the mixture was stirred at the same temperature for 4 hours. The solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4S)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (27.7 g) as a pale brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[C:13]([NH2:14])=[N:12][NH:11][C:10]=3[C:5]2=[C:4]([CH3:15])[CH:3]=1.[CH3:16][C:17]([CH3:19])=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH:17]([NH:14][C:13]1[C:9]2[S:8][C:6]3[C:5]([C:10]=2[NH:11][N:12]=1)=[C:4]([CH3:15])[CH:3]=[C:2]([CH3:1])[N:7]=3)([CH3:19])[CH3:16]
Reactant: Cc1cc(C)c2c(n1)sc1c(N)n[nH]c12
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(C)c2c(n1)sc1c(NC(C)C)n[nH]c12
Reaction time: 0.25 h

Procedure:
The 6,8-dimethyl-1H-pyrazolo[3′,4′:4,5]thieno[2,3-b]pyridin-3-amine (75 mg, 0.34 mmol) was stirred in DCE (3.4 mL). To this solution was added acetone (0.08 mL, 1.03 mmol) and acetic acid (0.060 mL, 1.03 mmol). The mixture was stirred 15 minutes, then NaBH(AcO)3 (150 mg, 0.70 mmol) was added. The resulting slurry was stirred about 2 hrs. LC/MS indicates the reaction is complete. The reaction was diluted with DCM (15 mL) and quenched with aqueous 2N NaOH. The aqueous layer was separated and extracted with DCM. The combined organic layers were dried over Na2SO4, and concentrated under vacuum to give a crude residue. The residue was purified by trituration with MeOH to give the pure product, 30 mg, (33%), as a light tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.09 (s, 1H), 5.65 (bs, 1H), 3.61 (bs, 1H), 2.63 (s, 3H), 2.50 (s, 3H), 1.17 (d, J=6.32, 6H). LC/MS: RT=0.55 min., m/z=261.0 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23].[Na]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]([C:20]([O:21][CH2:22][CH3:23])=[O:24])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(C(=O)OCC)c1cccc(Oc2ccccc2)c1

Procedure:
The method which comprises brominating m-methyldiphenyl ether with N-bromosuccinimide to form m-(bromomethyl)diphenyl ether, reacting it with sodium cyanide in dimethylsulfoxide to form m-(cyanomethyl)diphenyl ether, hydrolyzing and esterifying it to form ethyl α-(m-phenoxyphenyl)acetate, reacting the resulting ester with diethyl carbonate in the presence of metallic sodium to form diethyl 2-(m-phenoxyphenyl)malonate, reacting the product with methyl iodide to form diethyl 2-methyl-2-(m-phenoxyphenyl)-malonate, hydrolyzing the product to form 2-methyl-2-(m-phenoxyphenyl)malonic acid, and decarboxylating the product under heat to form α-(m-phenoxyphenyl)propionic acid (Japanese Pat. No. 45586/76).