Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]3[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1.[S:34]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35]1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[S:34]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]([C:17]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:20]4[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=4[N:18]=3)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[N:7]=2)=[CH:35]1
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2ccsc2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Temperature: 85 °C
Reaction time: 4 h

Procedure:
44 mg of 6-chloro-2-(2-trimethylsilanylethoxymethyl)-4-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-yl]-2H-pyridazin-3-one, 14 mg of thiophene-3-boronic acid and 36 mg of potassium carbonate are dissolved 1.5 ml of a 1:2 mixture of water and dimethoxyethane, and argon is passed through the solution for degassing. Addition of 7 mg of (1,1′-bis(diphenylphosphine) -ferrocene)palladium(II) chloride-dichloromethane complex is followed by stirring at 85° C. for 4 hours. For workup, it is diluted with water and extracted several times with ethyl acetate. The combined organic phases are dried using a silica gel cartridge, and the solvent is distilled off. The crude product is purified by silica gel chromatography (n-heptane/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=1.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCc1cnc(Cl)nc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(O)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ncc(CC)cn3)cc2OC1C(F)(F)F
Temperature: 130 °C
Yield: 97.8 %

Procedure:
To a mixture of ethyl 6-chloro-7-hydroxyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.2g, 0.62 mmol) and potassium carbonate (342 mg, 2.48 mmol) in 3 mL of dry DMF was added a reagent of 2-chloro-5-ethylpyrimidine (450 uL, 3.72 mmol). The reaction was then heated at 130° C. for 51 hours. After cooling to room temperature, to the reaction was added 150 mL of EtOAc. The resulting organic phase was washed with brine, and dried over anhydrous magnesium sulfate. After removing the solvents, the residue was purified on a short silica gel column with EtOAc/Hexane to afford 260 mg of a brown oil, which was used in the next step without further purification.
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:6]([O:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].N([O-])=[O:25].[Na+].N#N>Cl.O>[OH:25][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:6]([O:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=N[O-]
Reactant: CCOC(=O)C(OC)C(Oc1ccccc1N)c1ccccc1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(OC)C(Oc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
To a solution of 8 g of ethyl 3-(2-amino-phenoxy)-3-phenyl-2-methoxy-propionate, dissolved in 23% HCl (11.6 ml) at 4°-5° C., water (30 ml) was added and, always under cooling, a solution of NaNO2 (1.73 g) dissolved in water (30 ml) was slowly dropped. The solution was stirred at room temperature for 30 minutes and then heated at 50° C. for 15 minutes; evolution of N2 was noted. After extraction with CH2Cl2 and appropriate washings, the CH2Cl2 was evaporated to dryness so obtaining an oil, which was separated by column chromatography to give 4.0 g of ethyl 3-(2-hydroxy-phenoxy)-3-phenyl-2-methoxy-propionate (50%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:15]2[O:14][C:13]3[C:16]([CH:22]=[O:23])=[C:17]([OH:21])[CH:18]=[C:19]([CH3:20])[C:12]=3[C:11](=[O:24])[O:10][C:9]=2[C:8]([CH3:25])=[C:7]([O:26][CH3:27])[CH:6]=1)=[O:4].[I-].[Li+].Cl>CN(C)P(=O)(N(C)C)N(C)C>[CH3:20][C:19]1[C:12]2[C:11]([O:10][C:9]3[C:8]([CH3:25])=[C:7]([O:26][CH3:27])[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:15]=3[O:14][C:13]=2[C:16]([CH:22]=[O:23])=[C:17]([OH:21])[CH:18]=1)=[O:24]
Reactant: COC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Temperature: 90 °C
Reaction time: 5 h

Procedure:
4-Formyl-3-hydroxy-8-methoxy-1,9-dimethyl-11-oxo-11H-dibenzo[b,e][1,4]dioxepine-6-carboxylic acid methyl ester (42.0 mg) and lithium iodide (250 mg) were taken in hexamethylphosphoric triamide (5 ml). The mixture was stirred at 90° C. for 5 h and then lithium iodide (250 mg) was added again. The mixture was heated at 90° C. for 21 h. When the reaction was completed, the mixture was cooled and poured into hydrochloric acid cooled by an ice bath. The mixture was extracted with ethyl acetate. The organic extract was washed in turn with water, saturated aqueous sodium thiosulphate, and finally saturated brine, and was dried over anhydrous magnesium sulfate. The crude product was crystallized from dimethyl sulphoxide to afford psoromic acid, m.p. 264-265° C., 1HNMR (300 MHz, d6-DMSO): δ 2.20 (s, 3H), 2.46 (s, 3H), 3.83 (s, 3H), 6.83 (s, 1H), 7.08 (s, 1H), 10.46 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH2:3][CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=2[CH3:14].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[C:6]([CH3:14])=[CH:7][C:8]([O:12][CH3:13])=[CH:9]2
Reactant: COc1cc(C)c2c(c1)C=C(Br)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1cc(C)c2ccc(Br)cc2c1

Procedure:
To the solution of 3-bromo-6-methoxy-8-methyl-1,2-dihydro-naphthalene (8.0 g, 0.03 mol) from Step 3 in 1,4-dioxane (40 ml), DDQ (7.9 g, 0.03 mol) was added and the mixture was refluxed for 2 h. The solvent was removed and the crude product was purified by chromatography (silica gel:hexane:ethyl acetate/20:1) to provide 6-bromo-3-methoxy-1-methyl-naphthalene, 3.7 g.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[O:13]1[CH2:16][CH2:15][CH:14]1[CH2:17][OH:18].[OH-].[Li+]>>[O:13]1[CH2:16][CH2:15][CH:14]1[CH2:17][O:18][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCC1CCO1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCC2CCO2)nc1
Temperature: 75 °C
Yield: 42 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 42% yield starting from ethyl 6-chloronicotinate and oxetan-2-ylmethanol. The reduction was performed using 3 equiv of lithium hydroxide while heating to 75° C. for 3.5 h. The final aqueous solution was extracted with ethyl acetate in order to collect the product; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (d, 1 H), 8.16 (dd, 1 H), 6.96 (dd, 1 H), 4.96-5.06 (m, 1 H), 4.41-4.57 (m, 4 H), 2.64-2.75 (m, 1 H), 2.46-2.56 (m, 1 H); S (ESI) m/z 210[M+H+], m/z 208[M−H+].
Reaction SMILES: O[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C(=O)O)c(O)n1
Product: Cc1ccc(C(=O)O)c(Cl)n1
Yield: 72 %

Procedure:
2-Hydroxy-6-methyl-nicotinic acid (3.6 g, 0.02 m) was heated at 125° for 2 hours with phosphorus oxychloride (10 ml). The reaction mixture was poured onto ice, the solid was collected and crystallised from aqueous ethanol to give colourless fine needles of 2-chloro-6-methylnicotinic acid (72%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N:16]=[C:17]=S)[C:10]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:23]([N:31]2[CH2:36][CH2:35][CH2:34][CH:33]([C:37]([F:40])([F:39])[F:38])[CH2:32]2)=[CH:24][C:25]([NH:29][CH3:30])=[C:26]([CH:28]=1)[NH2:27].CC(C)N=C=NC(C)C>CC#N>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]2[N:29]([CH3:30])[C:25]3[CH:24]=[C:23]([N:31]4[CH2:36][CH2:35][CH2:34][CH:33]([C:37]([F:39])([F:40])[F:38])[CH2:32]4)[C:22]([Cl:21])=[CH:28][C:26]=3[N:27]=2)[C:10]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(N2CCCC(C(F)(F)F)C2)c(Cl)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(Cl)c(N3CCCC(C(F)(F)F)C3)cc21

Procedure:
The title compound was prepared from (2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (5.47 g, 16.4 mmol), 5-chloro-2-methylamino-4-(3-(trifluoromethyl)piperidin-1-yl)aniline (5.05 g, 16.4 mmol) and DIC 4.48 ml, 29 mmol) in MeCN in analogy to example 6 step (c).
Reaction SMILES: [NH2:1][C@@H:2]([CH:15]([CH3:17])[CH3:16])[C:3]([NH:5][C@@H:6]([CH3:14])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[C:18]1(=[O:33])[N:22]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:21](=[O:32])[CH:20]=[CH:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[O:32]=[C:21]1[CH:20]=[CH:19][C:18](=[O:33])[N:22]1[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][C@@H:2]([CH:15]([CH3:17])[CH3:16])[C:3]([NH:5][C@@H:6]([CH3:14])[C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])=[O:4])=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(N2C(=O)C=CC2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)c1ccc(N2C(=O)C=CC2=O)cc1)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
To a mixture of the 97 (100 mg, 0.41 mmol) and 4-maleimidobenzoic acid (101) (98 mg, 0.45 mmol) was added dichloromethane (5 mL), followed by TBTU (157 mg, 0.49 mmol) and DIPEA (212 uL, 1.23 mmol). The mixture was stirred at an ambient temperature for 16 h and then purified on a 2 mm radial chromatotron plate eluting with 50% ethyl acetate in hexanes to give 95 mg (51%) of 100: 1H-NMR (400 MHz, CDCl3) δ 7.85 (d, J=6.6 Hz, 2H), 7.42 (d, J=6.6 Hz, 2H), 6.81 (s, 2H), 6.38 (bs, 1H), 4.43 (m, 2H), 2.14 (sept, J=6.6 Hz, 1H), 1.41 (s, 9H), 1.31 (d, J=7.0 Hz, 3H), 0.98 (m, 6H); MS (ES−) m/z 441.90 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([NH:22][C:23]5[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.[C:31](Cl)(=[O:33])[CH3:32].N1C=CC=CC=1>C1COCC1>[CH3:1][C:2]1([CH3:30])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([N:22]([C:23]5[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=5)[C:31](=[O:33])[CH3:32])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Nc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)cn1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N(c1ccc(C)nc1)c1ccc2c(c1)N(c1nc3c(s1)C(=O)NC(C)(C)C3)CCO2
Yield: 47.5 %

Procedure:
A mixture of Example 60 (17 mg, 0.04 mmol), acetyl chloride (3.2 mg, 0.4 mmol) and pyridine (0.5 mL, 0.8 mmol) in THF (10 mL) was stirred at r.t. for 2 days. It was concentrated in vacuo and purified by preparative HPLC (Method 7) to give the title compound (8.8 mg, 47%) as an off-white solid. δH (CDCl3) 8.53-8.34 (1H, m), 8.31-8.18 (1H, m), 7.60-7.51 (1H, m), 7.24-7.11 (1H, m), 7.03-6.88 (2H, m), 5.23 (1H, br s), 4.47-4.28 (2H, m), 4.14-3.98 (2H, m), 2.94-2.80 (2H, m), 2.63-2.48 (3H, m), 2.27-2.07 (3H, m), 1.40 (6H, s). LCMS (ES+) 464 (M+H)+, RT 2.70 minutes (Method 2).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[OH:29][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH2:4][CH2:3][CH2:2][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:17]3[CH:16]=[C:15]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:14]4[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=4[C:12]=3[C:11]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCBr
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCN1CCNCC1
Reaction time: 20 h
Yield: 55 %

Procedure:
Bromide (204) (70 mg, 0.16 mmol) prepared as described in example 173 was reacted with piperazine according to The procedure described in example 179 except that the reaction was performed at room temperature for 20 h, to give amine (215) (40 mg, 55%) as a yellow powder, mp 178–183° C. 1H NMR δ [(CD3)2SO] 11.0 (br s, 1H), 9.35 (br s, 1H), 8.40 (d, J=2.4 Hz, 1H), 7.78 (s, 1H), 7.62 (m, 2H), 7.56 (d, J=8.8 Hz, 1H), 7.45 (m, 3H), 7.14 (dd, J=8.8, 2.4 Hz, 1H), 4.49 (t, J=6.3 Hz, 2H), 2.52 (m, 4H), 2.12 (m, 6H), 1.91 (m, 2H). Found: C, 69.31; H, 5.97; N, 11.49. C27H26N4O3.4/5H2O requires: C, 69.16; H, 5.93; N, 11.94.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:15](I)=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH:40]=1)[C:34](N(OC)C)=[O:35]>C1COCC1>[Br:28][C:29]1[CH:40]=[C:33]([C:34]([C:15]2[C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[N:13]([C:10]([CH3:12])([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:14]=2)=[O:35])[CH:32]=[N:31][CH:30]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnccc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(Br)c2)c2cnccc21
Temperature: -5 °C
Reaction time: 0.75 h
Yield: 51.2 %

Procedure:
1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 65, 1.81 g, 4.20 mmol) was dissolved in THF (25 mL) and the solution was degassed and cooled to −5° C. 2M iPrMgCl in THF (2.52 mL, 5.05 mmol) was added dropwise and the reaction stirred at this temperature for 45 minutes. A solution of 5-bromo-N-methoxy-N-methylnicotinamide (1.24 g, 5.05 mmol) in THF (3 mL) was added dropwise and the reaction warmed to room temperature for 4.5 hours. The reaction was partitioned between saturated aqueous ammonium chloride solution (20 mL) and EtOAc (30 mL). The organic layer was collected, dried and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 100% DCM to 50:50 DCM:EtOAc to afford the title compound as a colourless oil (1.05 g, 62%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][C:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[C:33]=4[CH2:38][CH:39]=[CH2:40])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]>OP([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>[CH2:12]([O:14][C:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[C:33]=4[CH2:38][CH:39]4[CH2:40][O:9]4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC4CO4)cc3)cc2)CC1
Reaction time: 8 h

Procedure:
m-Chloroperbenzoic acid (77%, 0.565 g, 2.52 mmol) was washed 4× with a solution of sodium phosphate dibasic (0.1 M aq., 7 mL) then dissolved in CH2Cl2 (4 mL). The solution was added to 1-[4′-(4-Allyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.244 g, 0.63 mmol) in CH2Cl2 (3 mL) followed by sodium phosphate dibasic (0.1 M aq., 7 mL). After 3.5 hours an additional portion of m-chloroperbenzoic acid (0.55 g) was rinsed 4× with sodium phosphate dibasic (0.1 M aq., 7 mL) and added to the reaction and stirring continued overnight. The reaction was then submitted to standard aqueous workup and purified via silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11]1>CO>[O:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH:10]([CH2:9][CH2:8][N:7]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:11]1
Reactant: C=CC(=O)OC
Reactant: NCCC1COc2ccccc2C1
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
6.63 g (77 mmol) of acrylic acid methyl ester are added at room temperature to a solution of 6.2 g (35 mmol) of 3-(2-aminoethyl)chroman in 50 ml of methanol and the whole is stirred for 16 hours at room temperature. The reaction mixture is then concentrated by evaporation in vacuo and yields 12.23 g (100%) of N-[2-(chroman-3-yl)ethyl]-N,N-bis(2-methoxycarbonylethyl)-amine in the form of a reddish oil.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:1]([NH:5][C:6]([N:33]1[CH2:32][CH2:31][CH:30]([C:17]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][C:16]=2[O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:35][CH2:34]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=O
Reactant: c1ccc(COc2ccc(C3CCNCC3)c(OCc3ccccc3)c2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
In a 10 ml round-bottomed flask, 0.25 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine is dissolved in 5 ml of tetrahydrofuran in the presence of 0.23 ml of N,N-diisopropylethylamine. 0.08 ml of butyl isocyanate is added and the reaction mixture is then stirred for 20 minutes at ambient temperature. The reaction mixture is extracted with ethyl acetate, and then the organic phases are combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (8/2 heptanelethyl acetate). 0.25 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid butylamide is obtained. Yield=78%.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][C:37]([N:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]3)=[N:38][CH:39]=2)O1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:39]=[N:38][C:37]([N:40]5[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]5)=[N:36][CH:35]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5cnc(N6CCN(C(=O)OC(C)(C)C)CC6)nc5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-1-carboxylate, (Frontier., Cat. P1821). LCMS (M+H)+: m/z=587.5.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH:13](O)([OH:15])[CH3:14]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:7]1([C:5]2([CH2:4][CH2:3][CH2:2][Cl:1])[O:15][CH2:13][CH2:14][O:6]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: CC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: ClCCCC1(c2ccccc2)OCCO1
Yield: 111.6 %

Procedure:
4-Chlorobutyrophenone (15.18 g, 0.083 moles), ethanediol (6.80 g, 0.110 moles) and p-toluene sulphonic acid (0.20 g) were heated in toluene at reflux and water was removed from the reaction using a Dean and Stark apparatus. After 17 hours the solvent was removed by distillation in vacuo to leave crude 2-phenyl-2-(3-chloropropyl)-1,3-dioxolane (21 g).
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:31][C:32]1([CH3:39])[C:36]([CH3:38])([CH3:37])[O:35][BH:34][O:33]1>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>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([B:34]4[O:35][C:36]([CH3:38])([CH3:37])[C:32]([CH3:39])([CH3:31])[O:33]4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Br)c3c2CC1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1(C)OB(c2cccc3[nH]c4c(c23)CCN(C(=O)c2ccccc2)CC4)OC1(C)C
Yield: 69.2 %

Procedure:
3-Benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (15.0 g, 40.6 mmol) was combined with dioxane (350 mL) at rt under N2. Et3N (34.0 mL, 24.7 g, 244 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.4 mL, 9.37 g, 73.2 mmol) were added to the mixture by syringe. trans-Dichlorobis(triphenylphosphine)palladium(II) (1.44 g, 2.04 mmol) was added and Ar was bubbled through the reaction mixture for 20 min. The reaction mixture was refluxed under N2 for 18 h. The cooled reaction mixture was concentrated and the residue was combined with EtOAc (500 mL) and H2O (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. The crude product (22.9 g) was recrystallized from CH3OH (50 mL) to give 3-benzoyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (11.7 g) in 69% yield. MS (ESI+) for C25H29BN2O3 m/z 417.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C@H:8]2[C@@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](O)[CH:15]=3)[O:10][CH2:9]2)=[CH:5][CH:4]=1.[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28](CCl)[CH:27]=[CH:26]2>C(Cl)Cl>[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([C:14]1[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C@@H:8]([O:7][C:6]1[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C@H:17]3[OH:18])[CH:27]=[CH:26]2
Reactant: COc1ccc(O[C@@H]2COc3ccc(O)cc3[C@@H]2O)cc1
Reactant: Fc1ccc2nc(CCl)ccc2c1
Solvent: ClCCl
Product: COc1ccc(O[C@@H]2COc3ccc(-c4ccc5cc(F)ccc5n4)cc3[C@@H]2O)cc1

Procedure:
By the method of Example 13, using flash chromatography with 35:1 CH2Cl2 :isopropanol as eluant and recrystallization from CH2Cl2 for purification of the product, the title product of Example 20 (0.20 g, 0.69 mmol) and 6-fluoro-2-chloromethylquinoline were converted to present title product, 0.104 g (34%), m.p. 151°-153.5° C. MS calculated: 447.1486, found: 447.1494.