Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]([CH3:33])[CH3:32])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.C1C=CC2N(O)N=NC=2C=1.C[C:50]1[S:54][C:53]([C:55]2C=CC=CC=2)=N[C:51]=1[CH2:61][C:62]([OH:64])=O>CC(N(C)C)=O>[CH3:32][N:31]([CH2:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:62](=[O:64])[CH2:61][C:51]5[CH:55]=[CH:53][S:54][CH:50]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:33]
Reactant: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Reactant: Cc1sc(-c2ccccc2)nc1CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5ccsc5)c4)nn4ccccc34)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.8 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-{3-[(dimethylamino)methyl]phenyl}-2-pyrimidinamine (50 mg, 0.115 mmol) (see Example 24, Step A) in 5:1 THF:DMA (2 mL) was added HOBT (46 mg, 0.34 mmol), 0.28 g polystyrene-bound carbodiimide resin (280 mg, 0.34 mmol), and (5-methyl-2-phenyl-1,3-thiazol-4-yl)acetic acid (80 mg, 0.34 mmol). After stirring at rt for 48 h, excess Dowex 550A OH anion-exchange resin was added and the resulting mixture was allowed to stir overnight. The solids were then removed by vacuum filtration and rinsed with THF (25 mL) and MeOH (25 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: 0-100% 90:9:1 DCM:MeOH:NH4OH(aq)) to afford the title compound (50.1 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ 2.11 (s, 6H), 2.43 (s, 3H), 3.31 (s, 2H), 3.81 (s, 2H), 6.45 (d, 1H, J=5.31 Hz), 6.84 (d, 1H, J=6.96 Hz), 7.08-7.11 (m, 1H), 7.14-7.18 (m, 1H), 7.23-7.25 (m, 1H), 7.38-7.46 (m, 5H), 7.59-7.62 (m, 1H), 7.68 (s, 1H), 7.75-7.81 (m, 3H), 7.89 (s, 1H), 8.21 (d, 1H, J=5.49 Hz), 8.48-8.51 (m, 1H), 8.79 (d, 1H, J=6.96 Hz) 9.50 (s, 1H), 10.35 (s, 1H). ES-LC/MS m/z=651 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][C:18]([CH2:42][C:43]#[N:44])([N:20]4[CH:24]=[C:23]([C:25]5[C:26]6[CH:33]=[CH:32][N:31](COCC[Si](C)(C)C)[C:27]=6[N:28]=[CH:29][N:30]=5)[CH:22]=[N:21]4)[CH2:17]3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:5][CH:4]=[N:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[CH2:19][C:18]([CH2:42][C:43]#[N:44])([N:20]4[CH:24]=[C:23]([C:25]5[C:26]6[CH:33]=[CH:32][NH:31][C:27]=6[N:28]=[CH:29][N:30]=5)[CH:22]=[N:21]4)[CH2:17]3)[CH2:14][CH2:15]2)(=[O:9])=[O:8])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1S(=O)(=O)N1CCC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1S(=O)(=O)N1CCC(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
To a solution of {1-{1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (56 mg, 0.1 mmol) in methylene chloride (1.5 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in 2 mL of a methanol solution containing 20% ethylenediamine. After being stirred at room temperature for 1 hour, the mixture was purified by HPLC (method B) to give 20 mg (64.5%) of {1-{1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. LC-MS: 507.2 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 12.08 (brs, 1H), 8.72 (d, 1H), 8.62 (s, 1H), 8.34 (s, 1H), 7.55 (d, 2H), 6.99 (d, 1H), 6.75 (s, 1H), 3.95 (s, 3H), 3.62 (dd, 2H), 3.45 (dd, 2H), 3.40 (m, 2H), 3.25 (s, 2H), 3.19 (m, 1H), 2.75 (m, 2H), 1.70 (m, 2H), 1.25 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@@H:3]([O:17][CH3:18])[CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][C@H:3]([O:17][CH3:18])[C:2]([F:1])([F:19])[F:20])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:23][CH:24]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CO[C@@H](CN1CCc2ccc(N)cc2CC1)C(F)(F)F
Product: CO[C@@H](CN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2CC1)C(F)(F)F

Procedure:
N-((1R,2R)-2-{5-Chloro-2-[3-((S)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 3-((S)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 335. Product isolated as a pale yellow solid (53 mg, 27%). m.p.=175-177° C.; LCMS (m/e) 591 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.33-7.25 (m, 2H), 7.06 (d, 1H, J=7.8 Hz), 6.86 (s, 1H), 5.46-5.36 (m, 2H), 3.94-3.82 (m, 1H), 3.77-3.66 (m, 1H), 3.62 (s, 3H), 3.30-3.20 (m, 1H), 2.96-2.88 (m, 4H), 2.87-2.72 (m, 6H), 2.80 (s, 3H), 2.28-2.17 (m, 2H), 1.90-1.78 (m, 2H), 1.45-1.37 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:12](F)=[CH:11][N:10]=1>CN(C)C=O>[Cl:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:12]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:11][N:10]=1
Reactant: Fc1cnc(Cl)nc1-c1ccc(Cl)cc1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc(Cl)ncc2OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.948 mL cyclopropanemethanol in 13 mL dimethylformamide was added 0.468 g sodium hydride 55% in mineral oil and the reaction mixture was stirred at room temperature for 15 min. The resulting solution was added drop wise to a solution of 2.586 g 2-chloro-4-(4-chloro-phenyl)-5-fluoro-pyrimidine at 0° C. and the mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=10:90 to 80:20 to yield 2.50 g of the title compound as white solid, MS 295.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([Cl:21])=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C>[CH2:26]([O:7][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[C:9]([Cl:21])[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=2)=[CH:11][C:2]=1[Br:1])[CH:25]=[CH2:24]
Reactant: CCc1ccc(Cc2cc(Br)c(OCCO)cc2Cl)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCCOc1cc(Cl)c(Cc2ccc(CC)cc2)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of 2-(2-bromo-5-chloro-4-(4-ethylbenzyl)phenoxy)ethanol (AU) (1.85 g, 5 mmol) in anhydrous DMF (10 mL), NaH (0.36 g 15 mmol) was added in portions, and the mixture was stirred at room temperature for 2 hours. Then allyl bromide (1.82 g, 15 mmol) was added dropwise, and the mixture was heated to 45° C. overnight. The reaction was quenched with the saturated NH4Cl and the mixture was extracted with EtOAc, and then washed with water and brine. After drying with anhydrous Na2SO4, the organic portion was filtered and concentrated. The residue was purified by flash chromatography to give AV as an oil (1.74 g, yield 85%). 1H-NMR (CDCl3, 300 MHz) δ 7.31 (s, 1H), 7.13 (m, 4H), 6.94 (s, 1H), 5.94 (m, 1H), 5.26 (m, 2H), 4.14 (m, 4H), 3.96 (s, 2H), 3.84 (m, 2H), 2.64 (q, J=7.5 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([C:4]1([CH2:20][CH2:21][NH:22][CH2:23][CH:24]2[CH2:27][CH2:26][CH2:25]2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][C:5]21OCCO2)[CH:2]=[CH2:3].Cl>C(O)C>[CH2:1]([C:4]12[C:13]3[CH:12]=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:8]=3[CH2:7][CH:6]=[C:5]1[N:22]([CH2:23][CH:24]1[CH2:25][CH2:26][CH2:27]1)[CH2:21][CH2:20]2)[CH:2]=[CH2:3]
Reactant: C=CCC1(CCNCC2CCC2)c2cc(OC)ccc2CCC12OCCO2
Agent: Cl
Solvent: CCO
Product: C=CCC12CCN(CC3CCC3)C1=CCc1ccc(OC)cc12

Procedure:
Preparation From 1-allyl-1-[2-(N-cyclobutylmethylamino)ethyl]-2,2-ethylenedioxy-7-methoxy-1,2,3,4-tetrahydronaphthalene (XIXb). Compound XIXb (33.7 g) treated with hydrochloric acid in aqueous ethanol according to Example 39(b) afforded 27.5 g (98%) IIf identical with the material obtained in Example 40(a) above.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][CH2:11][C:12]([CH3:16])([CH2:14]O)[CH3:13]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:10][CH2:11][C:12]([CH3:16])([CH3:14])[CH2:13][O:7]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)COC(c2ccc(Br)cc2)OC1
Yield: 92.9 %

Procedure:
A mixture of 4-bromobenzaldehyde (100 g, 0.54 mole), neopentyl glycol (15 g, 1.10 mole), and p-toluenesulfonic acid (800 mg, 4 mmole) in benzene (800 mL) was heated to reflux using a Dean Stark apparatus for 16 h. The reaction mixture was cooled to room temperature and most of the benzene was removed. The residue was partitioned between ethyl acetate (500 mL) and cold water (150 mL). The organic phase was washed with water (2×150 mL) and brine (1×150 mL), then dried (Na2SO4) and concentrated to give the desired product (136 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5](I)=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10]>CN(C=O)C.CCN(CC)CC.[Cu]I.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>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: Brc1cnc(I)cn1
Reactant: C#C[Si](C)(C)C
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(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
A mixture of 2-bromo-5-iodo-pyrazine (1.14 g, 4.0 mmol) and copper (I) iodide (80 mg, 0.42 mmol) in DMF/Et3N (2:1, 24 ml) was deoxygenated by evacuate/refill with nitrogen (×3). Ethynyl-trimethyl-silane (680 μl, 4.8 mmol) followed by Pd(PPh3)4 (230 mg, 0.2 mmol) were added and the mixture was deoxygenated again (×1). The reaction was stirred at RT for 16 hours, then partitioned between Et2O/H2O. The organic layer was washed with water (×1), brine (×1), then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (2∝34% Et2O/Petrol) to give the title compound (850 mg, waxy solid) as ˜3:1 mixture of mono coupled product to bis coupled. 1H NMR (400 MHz, CDCl3): 8.63 (1H, d), 8.43 (1H, d), 0.25 (9H, s), [Bis coupled product: 8.60 (s), 0.25 (s)] This material was used without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]>C(O)C.O=[Pt]=O>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2

Procedure:
A solution of 1-acetoxy-3-methoxyestra-1,3,5(10)-trien-17-one (4.9 g, 14.3 mM) in 250 ml of ethanol is shaken with PtO2 (1 g) under N2 at 40 psi for 7 hrs. After filtration and evaporation of the solvent in vacuo, the oily residue is chromatographed on 250 g of neutral silica gel, initially eluting with benzene and finally progressing to 5% ethyl acetate:benzene. Evaporation of the solvent in vacuo, followed by recrystallization from ether:hexane gives 1-acetoxy-3-methoxyestra-1,3,5(10)-trien-17β-ol, yield 2.35 g (48%), m.p. 107°-110° C.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[C:17]2[NH2:23]>O1CCOCC1>[F:25][C:13]([F:12])([F:24])[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[C:17]2[N:23]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccc(C(F)(F)F)cc12

Procedure:
Isobenzofuran-1,3-dione (4.24 g, 28.6 mmol) and 5-trifluoromethyl-1H-indazol-3-ylamine (5.76 g, 28.6 mmol) in dioxane (10 mL) in a sealed tube were heated at 100° C. overnight. The solvent was removed to give the crude product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]2[O:24][CH:23]=[C:22](Br)[C:15]=2[CH:16]=[N:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH3:11].CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]2[O:24][CH:23]=[C:22]([C:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(Oc1c([N+](=O)[O-])ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(Oc1c([N+](=O)[O-])ncc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 92.5 °C

Procedure:
A mixture of 7-(1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-3-bromo-6-nitrofuro[3,2-c]pyridine (12.6 g, 28.1 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (9.56 g, 30.9 mmol) and dioxane/water (4:1, 120 mL/30 mL) in a 500-mL round-bottom flask was stirred and degassed with nitrogen for 15 min. To the solution, Pd(PPh3)2Cl2 (400 mg, 0.57 mmol) was added followed by potassium carbonate (5.82 g, 42.19 mmol) was added and degassed with nitrogen for another 5 min. The mixture was heated at 90-95° C. for 2.5 h. TLC (5% methanol in dichloromethane) indicated completion of the reaction. The mixture was cooled to RT, and solvent was removed on rotary evaporator. To the residue, water (60 mL) and dichloromethane (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×60 mL). All organic layers were combined and washed with brine solution (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 1:1 ethyl acetate and dichloromethane to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=1.45 (s, 9H), 1.95 (d, J=6.6 Hz, 3H), 2.45 (brs, 2H), 3.62 (t, J=6.0 Hz, 2H), 4.18 (t, J=3.0 Hz, 2H), 6.25 (brs, 1H), 6.63 (t, J=6.0 Hz, 1H), 7.05 (m, 1H), 7.21 (m, 1H), 7.69 (s, 1H), 8.60 (s, 1H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:10][NH:11][C:12](=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[Na]>C1(C)C=CC=CC=1.CO>[CH3:17][O:16][C:14]([CH:13]1[C:4](=[O:5])[C:6]2([CH2:7][CH2:8][CH2:9]2)[CH2:10][NH:11][C:12]1=[O:18])=[O:15]
Reactant: CCOC(=O)C1(CNC(=O)CC(=O)OC)CCC1
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1C(=O)NCC2(CCC2)C1=O

Procedure:
1-[(2-Methoxycarbonyl-acetylamino)-methyl]-cyclobutanecarboxylic acid ethyl ester (1.62 g, 6.3 mmol) dissolved in 15 ml toluene is added dropwise to a freshly prepared solution of sodium (0.15 g, 6.5 mmol) in methanol (20 ml). The reaction mixture is refluxed for 3 hours and then extracted 3 times with water. The aqueous phase is acidified using HClconc. and the now acidic solution is extracted with ethyl acetate. Drying and evaporation of the solvent delivered the crude product which is used in the next step without further purification.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]1[CH2:19][CH2:18][CH2:17][NH:16][C:15]2[C:14](=[O:20])[C:13](=[O:21])[C:12]1=2)(=[O:8])[O:5]CC)C.O>C(Cl)Cl>[O:20]=[C:14]1[C:13](=[O:21])[C:12]2[N:11]([CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])[CH2:19][CH2:18][CH2:17][NH:16][C:15]1=2
Reactant: CCOP(=O)(CCN1CCCNc2c1c(=O)c2=O)OCC
Solvent: O
Solvent: ClCCl
Product: O=c1c2c(c1=O)N(CCP(=O)(O)O)CCCN2
Reaction time: 15 h
Yield: 64.7 %

Procedure:
Under N2 bromotrimethylsilane (83 mL, 96.3 g, 0.63 mole; Aldrich 19,440-9) was added dropwise at a fast rate to a solution of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid diethyl ester (37.6 g, 0.12 mole) in methylene chloride (350 mL). The reaction mixture was kept in a water bath at approximately 20° C. for 15 hr. The clear solution was concentrated in vacuo and the foamy residue was taken up in acetone (600 mL) with vigorous shaking to result in a thin suspension. Water (50 mL, 2.78 moles) was added to give a gummy precipitate which solidified instantly. The suspension was shaken vigorously for 10 minutes, filtered and washed with acetone to give a yellow solid compound. The solids were taken up in boiling water (450 mL) and the hot solution was filtered through a fluted filter paper to remove a small amount of insoluble material. The clear aqueous solution was cooled in ice and crystallization began at once. The thick crystalline mass was diluted by slow addition of acetone (800 mL), kept cold for 1 hr, filtered and washed with acetone and then hexane to give the title compound as a pale yellow solid (20.2 g). A second crop from the mother liquor (100% purity by LC) yielded an additional amount (6.5 g) for a total yield of 87%.
Reaction SMILES: [F:1][C:2]([F:43])([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[N+:25]([O-])=O)=[O:12])=[CH:5][CH:4]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:43])([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[CH:31][CH:30]=1)[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=2[NH2:25])=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(CCOC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)c(N)c1
Yield: 71.5 %

Procedure:
5.11 g (8.38 mmol) of 2-(2,4-dinitrophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)-phenoxy]methyl}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-di-methyl-formamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 3.30 g of 2-(2,4-diaminophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27].[Na]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[NH:9][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2ccccc2)cc1-c1ccccc1
Reactant: Fc1ccccc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: Fc1ccccc1Nc1ccc(-c2ccccc2)cc1-c1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 61.9 %

Procedure:
2,4-diphenylaniline (12 mmol), 1-bromo-2-fluorobenzene (10 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.15 mmol), (±)-2,2′-bis(diphenylphosphine)-1,1′-binaphthalene (0.3 mmol) and sodium tert-butoxie (14 mmol) are put in a two-neck round-bottom flask and dissolved in toluene (30 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, toluene is removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering with dichloromethane and petroleum ether, 2,4-diphenyl-N-2-fluorophenylbenzenamine (2.1 g) is yielded.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14](O)[CH3:15].CCN(CC)CC.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]([NH:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[CH:36][CH:35]=1)[CH3:15]
Reactant: Nc1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(O)c1ccc(Cl)cc1Br
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Nc1ccc(-c2ccc(F)cc2)cc1)c1ccc(Cl)cc1Br
Temperature: 25 °C

Procedure:
Neat methanesulfonyl chloride (0.18 mL, 2.4 mmol) was added to a 0° C., DCM solution (20 mL) of 1-(2-bromo-4-chlorophenyl)ethanol (558 mg, 2.4 mmol) and Et3N (0.36 mL, 2.6 mmol) and the resulting mixture was allowed to warm to room temperature gradually. After 30 min Et3N (0.36 mL, 2.6 mmol) and 4′-fluoro-[1,1′-biphenyl]-4-amine (444 g, 2.4 mmol) were added sequentially and stirred at room temperature. After 16 h the resulting mixture was concentrated and purified via column chromatography to yield the title compound.