Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[NH2:22][O:23][C@H:24]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:26]([C:36]([O:38][CH3:39])=[O:37])[CH2:25]1>[Hg](OC(C)=O)OC(C)=O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2=[C:6]([CH2:8][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[NH:10]/[C:11]/2=[N:22]\[O:23][C@H:24]2[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[C@H:26]([C:36]([O:38][CH3:39])=[O:37])[CH2:25]2)[N:7]=1
Reactant: COC(=O)[C@@H]1C[C@@H](ON)CN1C(=O)OC(C)(C)C
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](O/N=C2\N[C@@H](c3ccc(F)cc3Br)Cc3nc(N)nc(C)c32)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 72.5 %

Procedure:
A mixture of (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (150 mg, 0.4 mmol), (2S,4R)-1-tert-butyl 2-methyl 4-(aminooxy)pyrrolidine-1,2-dicarboxylate (416 mg, 1.6 mmol), Hg(OAc)2 (256 mg, 0.8 mmol) and toluene (2 mL) was heated at 100° C. for 2 h. Cooled to rt, filtered through celite and purified to afford (2S,4R)-1-tert-butyl 2-methyl 4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)pyrrolidine-1,2-dicarboxylate (172 mg, 570%) as off white solid. MS (ES) [M+H] calculated for C25H31BrFN6O5, 593.14. found 593.10.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([CH2:7][CH2:8][OH:9])[CH2:4][O:3]1.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18](CCl)=[CH:17][CH:16]=1>C1COCC1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([O:9][CH2:8][CH2:7][C@H:5]2[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]2)=[CH:17][CH:16]=1
Reactant: CC1(C)OC[C@H](CCO)O1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(OCC[C@H]2COC(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (Aldrich, 5 g, 34.2 mmol) in THF was added sodium hydride 60% (1.504 g, 37.6 mmol, 1.1 eq) portionwise and the mixture stirred for 1 h (cloudy solution). The mixture was cooled to 0° C. and to it was added 4-methoxybenzyl chloride (5.89 g, 37.6 mmol, 1.1 equivalent (eq.)) in one portion and the mixture stirred at the temperature for 30 min and heated to 65–70° C. overnight. After cooling to rt and quenching with saturated NH4Cl/water, the mixture was extracted with ethyl acetate (2×) and the organic extracts were washed with water, brine and dried over MgSO4. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (15% ethyl acetate/hexanes) to give desired product as a colorless oil. 1H NMR (400 MHz, Acetone-d6): δ7.28 (2 H, d), 6.93–6.91 (2 H, m), 4.43 (2 H, s), 4.20–4.14 (1 H, m), 4.04–3.98 (1 H, m), 3.80 (3H, s), 3.56–3.50 (3H, m), 1.88–1.76 (2H, m), 1.31 (3H, s), 1.28 (3 H, s).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:25]=[C:26]=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26](=[O:27])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=NCc1ccccc1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(NCc1ccccc1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with benzylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (17.0 mg, 31%) having the following characteristics.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:20][CH3:21])([CH3:19])[C:16](O)=[O:17])[N:13]=2)=[N:6][CH:7]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:57]([NH:60][NH2:61])(=[O:59])[CH3:58]>C(Cl)Cl.CN(C=O)C>[C:57]([NH:60][NH:61][C:16](=[O:17])[C:15]([O:20][CH3:21])([CH3:19])[CH2:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[C:4]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[S:10][CH:11]=1)(=[O:59])[CH3:58]
Reactant: COC(C)(Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1)C(=O)O
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(C)(Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1)C(=O)NNC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 20 mL scintillation vial, 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoic acid (0.087 g, 0-187 mmol) was dissolved in CH2Cl2 (5 mL) and DMF (2 mL) and N-methylmorpholine (0.0309 mL, 0.281 mmol), followed by addition of HOBT. The mixture was cooled to 0° C. and EDCI (0.047 g, 0.244 mmol) was added. The resulting mixture was agitated for 30 minutes and acetohydrazide (0.021 g, 0.28 mmol) was added. The mixture was then agitated overnight, diluted with 50 mL of CH2Cl2 and washed with citric acid solution, sodium bicarbonate solution twice, dried and evaporated to give the title compound (0.0975 g, quantitative yield). Crude product was used in the next step.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])(=[O:21])=[O:20])=[CH:15][CH:14]=1.CN.CO>>[NH2:3][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])(=[O:20])=[O:21])=[CH:15][CH:14]=1
Reactant: CCCN(CCC)CCCCNS(=O)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: CN
Solvent: CO
Product: CCCN(CCC)CCCCNS(=O)(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 98.4 %

Procedure:
The compound (160 mg) obtained in Example 24-3 was added with 2.0 ml of a 40% methylamine/methanol solution (manufactured by Tokyo Kasei Kogyo Co., Ltd.), followed by stirring at room temperature for 40 hours. After completion of the reaction, the solvent was distilled off and the residue was subjected to extraction by the addition of a 1 mol/l sodium hydroxide aqueous solution and chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off, thereby obtaining the subject compound (114 mg) as a colorless viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18]OS(C)(=O)=O)[CH2:13]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][N:35]4[CH2:34][CH2:33][N:32]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH3:24])[CH2:37][CH2:36]4)[CH2:13]3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCC1CCCN(CC2(c3ccc(Cl)cc3)CC2)C1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1N1CCN(CC2CCCN(CC3(c4ccc(Cl)cc4)CC3)C2)CC1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
To a solution of methanesulfonic acid 1-[1-(4-chloro-phenyl)-cyclopropylmethyl]-piperidin-3-ylmethyl ester (2.94 g, 8.20 mmol) in acetonitrile (40.0 mL) at room temperature was added 1-(2-methoxy-phenyl)-piperazine (1.58 g, 8.20 mmol) followed by potassium carbonate (13.35 g, 41.0 mmol). The reaction mixture was refluxed overnight. After cooling down to room temperature the reaction mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield a crude oil. The resulting residue was purified by silica gel chromatography (96:4 DCM: 2M NH3 in EtOH) to obtain the desired compound as an oil (2.04 g). 13C NMR (100 MHz, CDCl3) δ 152.5, 143.9, 141.8, 131.5, 130.4, 128.2, 123.1, 121.3, 118.4, 111.5, 67.8, 63.0, 59.5, 55.6, 55.2, 54.2, 51.0, 33.5, 29.8, 25.2, 23.1, 13.4, 13.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C(O)(=O)C>[CH3:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([N:14]3[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]3)=[CH:22][CH:21]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1N
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.0 g, 6.9 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (1.5 mL, 7.8 mmol) in acetic acid (15 mL) was heated at 100° C. for 2.5 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated. After filtration and washed with water, the title compound was obtained as a grey solid (1.3 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6](OC(CC=C)C)=[O:7])=[C:4]([O:16][C@H:17]([CH2:19][CH:20]=[CH2:21])[CH3:18])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][OH:7])=[C:4]([O:16][C@H:17]([CH2:19][CH:20]=[CH2:21])[CH3:18])[CH:3]=1
Reactant: C=CCC(C)OC(=O)c1ccc(Cl)cc1O[C@@H](C)CC=C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cc(Cl)ccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of pent-4-en-2-yl 4-chloro-2-((S)-pent-4-en-2-yloxy)benzoate (1.36 g, 4.40 mmol) in THF (15 ml) that was cooled to 0° C. was added dropwise over 30 min lithium aluminum hydride (2.64 ml, 5.28 mmol) and the resulting mixture was stirred at rt. After 3 h, the mixture was cooled to 0° C. and quenched by dropwise addition of brine. The mixture was diluted with EtOAc and the organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The oil was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane; 10 CV) to give (S)-(4-chloro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.9554 g, 4.21 mmol, 96% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J=7.8 Hz, 1H), 6.98-6.88 (m, 1H), 6.88 (d, J=1.7 Hz, 1H), 5.86 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.25-5.06 (m, 2H), 4.75-4.62 (m, 1H), 4.62-4.43 (m, 2H), 2.61-2.40 (m, 2H), 2.34 (t, J=6.5 Hz, 1H), 1.38 (d, J=6.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[C:17]([O:21][C:22](=[O:29])[NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:26]3[CH2:27][CH2:28][CH:24]([NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:29])[CH2:25]3)=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: COC(=O)C1(c2ccc(C(=O)Cl)cc2)CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(C(=O)N3CCC(NC(=O)OC(C)(C)C)C3)cc2)CC1
Temperature: 50 °C
Yield: 86.3 %

Procedure:
Part A. 1-(4-Chlorocarbonyl-phenyl)-cyclopropanecarboxylic acid methyl ester (0.78 g, 3.28 mmol), pyrrolidin-3-yl-carbamic acid tert-butyl ester (0.60 g, 3.22 mmol) and DIEA (1.18 mL, 6.44 mmol) were stirred in CH2Cl2 (10 mL) at rt under N2 overnight. H2O was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, filtered, dried in vacuo. The residue was dissolved in MeOH (20 mL) and 1N NaOH (10 mL) was added. The reaction was heated at 50° C. for 2.5 h. The solvents were evaporated. The residue was extracted with Et2O, the H2O layer was acidified with citric acid, and extracted with Et2O (2×), washed with brine, dried over MgSO4, filtered, and concentrated to dryness to yield 1-[4-(3-tert-butoxycarbonylamino-pyrrolidine-1-carbonyl)-phenyl]-cyclopropanecarboxylic acid methyl ester (1.08 g, yield: 83.0%).
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=O)[NH:12][C:11]2=O.CO.Cl>C1COCC1.O>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11]2
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Brc1ccc2c(c1)CNC2
Temperature: 22 °C
Reaction time: 2 h

Procedure:
564.2 ml of a 1M borane/THF solution are added dropwise to 42.5 g (188 mmol) of 5-bromoisoindole-1,3-dione in 300 ml of THF (dry) at −5° C. over a period of 60 min. The mixture is subsequently stirred for 2 h at 22° C. and then for 16 h at 80° C. The mixture is then cooled to 0° C., before 200 ml of methanol (exothermic!) and 200 ml of 2M hydrochloric acid are slowly added. The resultant mixture is stirred for 3 h at 80° C., cooled to 22° C., and 100 ml of water are added. The aqueous solution is extracted three times with 150 ml of dichloromethane each time, dried over sodium sulfate, filtered and evaporated to dryness: 5-bromo-2,3-dihydro-1H-isoindole; yield 15.4 g of “13” (41.3%); MW 198.06; Rt 1.099 min (“polar” method).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:12]1([S:18]([N:21]=[C:8]=[C:7]2[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH2:6]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C1=CCC(=C=NS(=O)(=O)c2ccccc2)C=C1
Temperature: 25 °C

Procedure:
An equimolar mixture of 25.0 g (0.17 mol) 4-carboxybenzaldehyde and 26.7 g (0.17 mol) benzenesulfonamide was placed into toluene. 100 mg p-toluenesulfonic acid was added as a catalyst. The mixture was then heated under reflux on a water separator until the theoretically calculated quantity of water had separated. After cooling to room temperature, the precipitated solid was filtered off and dried under vacuum. Yield: 45.7 g (94.8%); 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.59 (m, 2H); 7.78 (d, 1H); 8.02 (m, 2H); 8.12 (d, 2H); 8.18 (d, 2H); 9.30 (s, 1H); 13C-NMR (400 MHz, DMSO-d6): δ [ppm]=127.8; 129.7; 131.4; 134.1; 135.8; 136.0; 137.9; 166.5; 171.2; 192.9.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[C:1]([NH:9][CH:10]([C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(NCC(=O)c1cccs1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1cccs1
Yield: 63.5 %

Procedure:
4.0 g of N-benzoyl-N-[(2-thienylcarbonyl)methyl]amine, one g of 50% sodium hydride and 2.7 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(4). 3.4 g of ethyl 3-benzoylamino-3-(2-thienylcarbonyl)propionate are obtained.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:12]([C@@H:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[OH:29])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:41]1[CH2:46][CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH2:43][CH2:42]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:12]([C@@H:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[OH:29])=[C:11]([C:44]3[CH2:45][CH2:46][O:41][CH2:42][CH:43]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC2(CCC2)Cc2nc(C3CCOCC3)c([C@H](O)c3ccc(C(F)(F)F)cc3)c(I)c21
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC2(CCC2)Cc2nc(C3CCOCC3)c([C@H](O)c3ccc(C(F)(F)F)cc3)c(C3=CCOCC3)c21

Procedure:
Obtained by starting from (R)—((S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-(tetrahydro-2H-pyran-4-yl)-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-yl)(4-(trifluoromethyl)phenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:45][C:46](=[O:52])[C@H:47]([CH:49]([CH3:51])[CH3:50])[NH2:48]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:48][C@H:47]([C:46]([OH:45])=[O:52])[CH:49]([CH3:51])[CH3:50])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)N[C@H](C(=O)O)C(C)C)cc2)cc1

Procedure:
The product from Example 234B and L-valine methyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.15-12.77 (br.s, 1 H), 8.94 (s, 1 H), 7.92 (d, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.94 (m, 6 H), 6.82 (d, 2 H), 4.15 (dd, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.94 (t, 2 H), 2.91 (s, 3 H), 2.38 (s, 3 H), 2.23 (m, 2 H), 2.04 (m, 1 H), 1.67 (m, 4 H), 0.88 (dd, 6 H); MS (ESI+) m/z 688 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8](Cl)=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[N:17]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].[NH3:29]>CO>[NH2:29][C:8]1[C:9]2[C:14](=[N:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:28])[C:7]=1[C:16]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[S:18](=[O:26])(=[O:27])[N:17]=1
Reactant: CCCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(Cl)c2cccnc21
Reactant: N
Solvent: CO
Product: CCCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(N)c2cccnc21
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of the product of Example 165 (0.10 g, 0.24 mmol) and ammonia (2 ml of a 2 M solution in methanol, 4.0 mmol) was stirred in a sealed tube at 100° C. for 2 hours, allowed to cool to room temperature. The resulting solid collected by filtration and washed with methanol (2 ml) to give the title compound as a brown solid (0.019 g, 20%). MS (ESI−) m/z 396 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7.35 Hz, 3H), 1.38 (m, 2H), 1.66 (m, 2H), 4.44 (t, J=7.35 Hz, 2H), 7.48 (m, 2H), 7.55 (d, J=8.09 Hz, 1H), 7.70 (t, J=8.46 Hz, 1H), 7.84 (dd, J=7.72, 1.10 Hz, 1H), 8.77 (d, J=8.09 Hz, 1H), 8.82 (dd, J=4.78, 1.47 Hz, 1H), 9.84 (brs, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH:9]([F:49])[C:10]1[N:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([F:48])=[C:23]([C@:25]34[CH2:33][O:32][C@H:31]([C:34]([F:37])([F:36])[F:35])[C@H:30]3[C:29](=[O:38])[N:28]([CH3:39])[C:27]([NH:40]C(=O)OC(C)(C)C)=[N:26]4)[CH:24]=2)=[O:17])=[N:14][CH:15]=1>C(Cl)Cl>[NH2:40][C:27]1[N:28]([CH3:39])[C:29](=[O:38])[C@@H:30]2[C@@H:31]([C:34]([F:37])([F:36])[F:35])[O:32][CH2:33][C@:25]2([C:23]2[CH:24]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[N:11][C:10]([CH:9]([F:49])[F:8])=[CH:15][N:14]=3)=[O:17])[CH:20]=[CH:21][C:22]=2[F:48])[N:26]=1
Reactant: CN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)N=C1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)N=C1N
Yield: 95.5 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a stirred solution of tert-butyl ((4aS,5S,7aS)-7a-(5-(5-(difluoromethyl)pyrazine-2-carboxamido)-2-fluorophenyl)-3-methyl-4-oxo-5-(trifluoromethyl)-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (92 mg, 0.15 mmol) in DCM (2 mL) at RT. After 1 h at this temperature the volatiles were removed in vacuo and the residue was azeotroped with PhMe (×2). The residue was then taken up in MeOH and loaded on to a SCX cartridge (5 g). The cartridge was eluted with MeOH (2×20 mL) and then 2M NH3 in MeOH (2×20 mL). The relevant fraction was evaporated to give the title compound (72 mg, beige solid). 1H NMR (400 MHz, MeOH-d4) δ ppm 3.25 (s, 3H) 3.80 (d, J=8.34 Hz, 1H) 4.29-4.34 (m, 1H) 4.35-4.40 (m, 1H) 4.62-4.71 (m, 1H) 6.95 (t, J=54.30 Hz, 1H) 7.18 (dd, J=11.62, 8.84 Hz, 1H) 7.80 (ddd, J=8.72, 4.17, 2.78 Hz, 1H) 7.89 (dd, J=6.82, 2.53 Hz, 1H) 9.02 (s, 1H) 9.40 (s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16].Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:24][C:22]1[CH:23]=[C:18]([N:13]2[CH2:14][CH2:15][N:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:12]2=[O:16])[CH:19]=[N:20][CH:21]=1
Reactant: Fc1cncc(Br)c1
Reactant: O=C1NCCN1c1ccc2ccccc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cncc(F)c2)CCN1c1ccc2ccccc2c1
Yield: 57.3 %

Procedure:
Using the same reaction conditions as in Example 79, 1-naphthalen-2-yl-imidazolidin-2-one (I-79b: 120 mg, 0.5681 mmol) was reacted with 3-bromo-5-fluoro-pyridine (100 mg, 0.5681 mmol), 1,4-dioxane (5 mL), copper iodide (10.82 mg, 0.05681 mmol), trans-1,2-diamino cyclohexane (19.51 mg, 0.1704 mmol) and potassium carbonate (157.07 mg, 1.1362 mmol) to afford the crude product. Purification by column chromatography on silica gel (30% EtOAc in hexane) afforded 100 mg of the product (57.15% yield).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[O:36])[NH:20][C:21](=[O:35])[N:22]([CH2:24][C:25]4[O:29][C:28]([C:30]([O:32]CC)=[O:31])=[CH:27][CH:26]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2].O.[OH-].[Li+].Cl>CO.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[O:36])[NH:20][C:21](=[O:35])[N:22]([CH2:24][C:25]4[O:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(C)cc4C=Cc4oc(CC)nc43)c(=O)[nH]c2=O)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1cn(Cc2ccc(C(=O)O)o2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of the product of step (viii) (0.26 g) and lithium hydroxide monohydrate (0.063 g) in methanol (4 ml) and water (4 ml) was stirred at room temperature for 1.5 hours. The solution was neutralised by the addition of 2M hydrochloric acid and the solvents were evaporated under reduced pressure. Purification was by preparative HPLC followed by lyophilisation.