Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:31])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:22])=[O:21])=[C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)(C)(C)C.CO.[OH-].[Na+]>C1COCC1>[CH2:24]([O:23][C:11]1[CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:31])=[O:5])[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid tert-butyl ester (2.2 g, 5.18 mmol) in THF (14 mL)/MeOH (7 mL) is added 3.5 mL (20.7 mmol) of 6N NaOH solution and the mixture is stirred at RT for 18 h. The solvent is removed under reduced pressure and water is added to the residue. The mixture is acidified with 1N HCl and is extracted with methylene chloride. The organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as a reddish solid: ): (M−1)−=387.
Reaction SMILES: [Li]CCCC.[CH2:6]([N:13]([CH2:18][CH2:19][OH:20])[C:14]([NH:16][CH3:17])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C1COCC1>[CH2:6]([N:13]([CH2:18][CH2:19][O:20][S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=1)(=[O:30])=[O:29])[C:14]([NH:16][CH3:17])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNC(=O)N(CCO)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)N(CCOS(=O)(=O)c1ccc(C)cc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
nBuLi (2.8 N, 1.01 g, 0.0157 mol) was added at −78° C. to a solution of 1-benzyl-1-(2-hydroxy-ethyl)-3-methyl-urea (3 g, 0.0143 mol, from (i) above) in 30 ml of dry TBF and stirred at same temperature for 30 min under nitrogen atmosphere. P-Toluenesulfonyl chloride (3 g, 0.0157 mol) in 20 ml of dry THF was added dropwise at −78° C. and stirred for 3 h under nitrogen atmosphere. The reaction was quenched with methanol and solvent evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 12% methanol in dichloromethane as eluent to yield 2.5 g of the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:25]([N:27]([CH2:42][CH3:43])[CH2:28][CH2:29][NH:30][C:31]([C:33]1[C:37]([CH3:38])=[C:36]([CH:39]=O)[NH:35][C:34]=1[CH3:41])=[O:32])[CH3:26].N1CCCCC1>C(O)C>[CH2:42]([N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][NH:30][C:31]([C:33]1[C:37]([CH3:38])=[C:36](/[CH:39]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=2)(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:35][C:34]=1[CH3:41])=[O:32])[CH3:43]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3cccc(C(F)(F)F)c3)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(C(F)(F)F)c4)cc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.2 %

Procedure:
To a solution of 5-(3-Trifluoromethyl-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (100 mg, 0.28 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (75 mg, 0.28 mmol) in ethanol (4 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 25° C. for three days. The solvent was evaporated and the residue was purified on a silica gel column eluting with MeOH—CH2Cl2 1:9 to provide 105 mg (62%) of 2,4-dimethyl-5-[2-oxo-5-(3-trifluoromethyl-phenylmethanesulfonyl)-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:21]=[C:20](I)[S:19][C:13]=3[N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([OH:29])[C:27]#[CH:28]>C(NCC)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[CH:21]=[C:20]([C:28]#[C:27][CH2:26][OH:29])[S:19][C:13]=3[N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-2-iodo-7-isopropyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 26) (0.717 g) in diethylamine (20 mL) is added copper iodide (0.084 g) and Pd(PPh3)2Cl2 (0.052 g) followed by addition of propargyl alcohol (0.12 mL). The reaction is stirred at rt for 18 h. The diethylamine is removed in vacuo and the resulting brown solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield an orange solid which is recrystallized from ethanol then methanol to yield 0.281 g (46%) of the title compound as a yellow, crystalline solid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[C:23]=3[CH3:31])[C@H:15]2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:30][C:24]1[C:23]([CH3:31])=[C:22]([C:14]2[C@@H:15]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)[C@@H:16]3[C@@H:9]([OH:8])[CH2:10][CH2:11][N:12]3[N:13]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2OCC2CC2)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C2=NN3CC[C@H](O)[C@H]3[C@@H]2OCC2CC2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-((3S,3aR,4S)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopropylmethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-2-chloro-3-methylbenzonitrile (60 mg, 0.13 mmol) in THF (2 mL) at 0° C. was added TBAF (0.26 mL, 0.26 mmol, 1M Solution in THF) and stirred for 1 h at room temperature. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with ethyl acetate. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Crude product was purified by preparative TLC method (50% EtOAc in hexane).
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[Na].Cl[C:12]([O:14][CH3:15])=[O:13]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:12](=[O:13])([O:9][C:3]1([C:1]#[CH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[O:14][CH3:15]
Reactant: C#CC1(O)CCCCC1
Reactant: COC(=O)Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: C#CC1(OC(=O)OC)CCCCC1
Temperature: 25 °C

Procedure:
A solution of 36.0 gm of 1-ethynylcyclohexanol in 50 ml of benzene was slowly added drop-by-drop to an agitated suspension, cooled to 0° to 5° C, of 5.5 gm of finely distributed sodium in 50 ml of absolute toluene and 250 ml of benzene, and was agitated at room temperature until reaction had been completed. 26.0 gm of methyl chloroformate were added under cooling to the sodium salt which has been formed. The mixture was allowed to react for 12 hours at room temperature and was washed several times with water and dried. After distilling off the solvent, the raw ester was fractionated by means of a 20 cm Vigreux column. The methyl 1 -ethynylcyclohexyl carbonate thus obtained constitutes a colorless liquid having a fruity, herbal, complex odor and a distinctive fragrance of dill, and has the following characteristic values;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].C([Li])CCC.CCCCCC.[CH3:25][C:26]1([CH3:33])[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1>O1CCCC1>[OH:32][C:29]1([C:3]2[C:2]([NH:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11])=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:30][CH2:31][C:26]([CH3:33])([CH3:25])[CH2:27][CH2:28]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(O)(c2cccnc2NC(=O)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
To a solution of N-(pyridin-2-yl)pivalamide (1.1 g, 6 mmol) in tetrahydrofurane (30 mL) was added at −78° C. under nitrogen and stirring a solution of 1.6M n-butyllithium in hexane (7.88 mL, 12.6 mmol). The reaction is exotherm and it turns light yellow. The reaction was stirred for 15 minutes at −78° C. and then for 2 hours at 0° C. The reaction was cooled to −78° C. and 4,4-dimethylcyclohexanone (937 mg, 7.2 mmol) dissolved in tetrahydrofurane (5 mL) was added dropwise. The reaction was warmed to room temperature over night. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as the eluent to yield the title compound as a white powder (1.034 g, 57%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[N:14]2CC2C=CC=CC=2)=[O:12])[CH:7]=[CH:8][CH:9]=1>C1COCC1.CO.[Pd]>[F:27][C:2]([F:1])([F:28])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[NH:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-1-benzyl-5-hydroxymethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (500 mg, 1.27 mmol) in THF (5 mL) containing 5 drops of MeOH was added Pd/C (10%, 27 mg). The solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere overnight. The catalyst was removed through a pad of Celite and washed with THF. Solvents were concentrated and the resulting material was used without purification in the next step. MS (LC/MS): 305 [M+H]+; tR (HPLC conditions b): 2.89 min.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([OH:15])[C:5]=2[CH:6]=1.[S:16]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]O)=[CH:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([O:15][CH2:22][CH2:21][C:18]3[CH:19]=[CH:20][S:16][CH:17]=3)[C:5]=2[CH:6]=1
Reactant: OCCc1ccsc1
Reactant: COC(=O)c1cc(O)c2cc(C)oc2c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCCc2ccsc2)c2cc(C)oc2c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
To a solution of 2-methyl-4-hydroxy-6-methoxycarbonylbenzofuran (Method 12; 1.24 g, 6.0 mmol) and 2-(3-thienyl) ethanol (768 mg, 0.67 ml, 6.0 mmol) in DCM (DCM, 50 ml) was added polymer-supported triphenyl phosphine (2.5 g, ca 3 mmol/g, 1.5 eq), and the suspension cooled to 5° C. under an argon atmosphere. To this was added di t-butyl azodicarboxylate (1.725 g, 7.5 mmol, 1.5 eq), and the reaction mixture stirred overnight, allowing to warm to ambient temperature. It was then filtered through diatomaceous earth, washed through with DCM, and the filtrate and washings evaporated in vacuo to ˜50 ml total volume. To this was added trifluoroacetic acid (2 ml), and the solution evaporated in vacuo to give a red oil. This was chromatographed (70 g Bondelut, eluting with hexane containing ethyl acetate, 0-50%) to give a red solid; this was re-chromatographed (as previous) to give the title compound as a colourless crystalline solid (150 mg, 8% yield). NMR: 2.46 (s, 3H), 3.10 (t, 2H), 3.83 (s, 3H), 4.33 (t, 2H), 6.64 (s, 1H), 7.12 (dd, 1H), 7.28 (s, 1H), 7.32 (d, 1H), 7.46 (dd, 1H), 7.66 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[C:32](O)(=[O:35])[CH2:33][CH3:34]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:28][CH2:27]2)[N:10]=1
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 20 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and propionic acid (Aldrich), to give 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-propan-1-one. H RMS, observed: 384.2034; Calcd for (M+H)+: 384.2030.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl>N1C=CC=CC=1.C(Cl)Cl>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:3][CH:4]=3)[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cn2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(NC(=O)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of N-{6-{2-(5-aminopyridin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (150 mg) in pyridine (2 ml) is added a solution of benzoyl chloride (43 mg) in methylene chloride (0.4 ml), and the mixture is stirred at room temperature for two hours. To the reaction solution is added 10% hydrochloric acid, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate/n-hexane to give N-(6-[2-{6-(4-tert-butylphenylsulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy}ethoxy]pyridin-3-yl)benzamide (161 mg) as crystals.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=2[O:38][CH3:39])[C:6]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:5]1=2)(=[O:3])[CH3:2].[ClH:46]>O1CCOCC1.CCOCC>[ClH:46].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=2[O:38][CH3:39])[C:6]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3ccccc23)c2ccc(C#N)cc2N(C(C)=O)[C@H]1C
Yield: 80 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (60 mg, 97.8 μmol) in 4 M HCl in dioxane (489 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (43.0 mg, 80%) as an off-white solid. MS m/z 514 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]([F:38])([C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[CH2:12][CH2:13][CH2:14][CH2:15]OC1(C)C=CC(S([O-])(=O)=O)=CC1>CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([F:10])([F:38])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])=[C:4]([F:9])[CH:3]=1
Reactant: CC1(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C=CC(S(=O)(=O)[O-])=CC1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 24 h

Procedure:
To a solution of commercially available 4-bromo-2-fluorophenol (25) (1 equi.) and 4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-tosylate (10) (1 equi.) in DMF (3 mL/mmole), cesium carbonate (1.25 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) and recrystallization from acetonitrile afforded 4-bromo-2-fluoro-1-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-benzene (26) a colorless oil (87%).
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>CCOCC>[Cl:14][CH2:15][C:16]([N:3]1[CH2:4][CH2:5][CH2:6][O:2]1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: C1CNOC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CCl)N1CCCO1
Reaction time: 4 h

Procedure:
To a stirred slurry of finely powdered isooxazolidine hydrochloride (H. King, J. Chem. Soc. 433,1942) (11.0 g) in dry ether (200 ml) at 0° C. was added triethylamine (28.0 ml) and a solution of chloroacetyl chloride (8.0 ml) in ether (50 ml). The reaction mixture was stirred for a further 4 hours, whilst the temperature rose to room temperature. The precipitate triethylamine hydrochloride was filtered off through diatomaceous earth and the filter bed washed well with ether. The combined ether solutions were evaporated to give N-chloroacetyl isooxazolidine as an oil (11.5 g) NMR (CDCl3) 2.38[quintet, 2H, CH2 ], 3.78[t,2H, NCH2 ], 4.05[t,2H, OCH2 ]and 4.22 [s,2H, ClCH2CO].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:26][NH2:27]>N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16]([NH:27][CH3:26])[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)c(N)c3)c2c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
1-(3-Amino-4-fluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg) and an aqueous solution (about 40%; 500 mg) of methylamine were added to pyridine (1,200 mg), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (2 ml) was added to the resultant residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (210 mg) as a pale brown powder.
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:19])([CH3:18])[CH2:10][N:11]1[CH:15]=[C:14](I)[N:13]=[C:12]1[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Br)C.[CH3:24][Sn:25](Cl)([CH3:27])[CH3:26]>C(Cl)Cl>[Si:1]([O:8][C:9]([CH3:19])([CH3:18])[CH2:10][N:11]1[CH:15]=[C:14]([Sn:25]([CH3:27])([CH3:26])[CH3:24])[N:13]=[C:12]1[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1nc(I)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Reactant: C[Sn](C)(C)Cl
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cc1nc([Sn](C)(C)C)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Yield: 26.8 %

Procedure:
To a mixture of 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-2-methyl-1H-imidazole (1.5 g, 3.8 mmol) in DCM (15 mL) was added ethylmagnesium bromide (1.9 mL, 3 mol/L, 5.7 mmol) at −78° C. The temperature of the mixture was allowed to warm up to about 10° C. slowly and cooled again. Trimethyltin chloride (6.5 ml, 1 mol/L, 6.5 mmol) was added dropwise at −78° C. After the addition, the temperature was allowed to slowly warm up to room temperature. The reaction mixture was pouted into saturate NH4Cl solution, then extracted with DCM, The organic was washed with water twice, dried over anhydrous Na2SO4, concentrated to give 0.44 g of 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-4-(trimethylstannyl)-1H-imidazole. Yield=63%. 1H NMR (CDCl3, 400 MHz): δ 7.04 (s, 1 H, ArH), 3.74 (s, 2 H), 2.43 (s, 3 H), 1.24-1.20 (m, 6 H), 0.88 (s, 9 H), 0.29 (s, 6 H), 0.03 (s, 8 H). LC-MS: m/z=375 [M+H+]
Reaction SMILES: N#N.[CH3:3][C:4]([Si:7]([CH3:21])([CH3:20])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[CH:11]=1)([CH3:6])[CH3:5].C([Li])CCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCCCCC.O1CCCC1>[Si:7]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[C:11]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])([C:4]([CH3:3])([CH3:5])[CH3:6])([CH3:20])[CH3:21]
Reactant: COCOc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Reactant: CCOC(=O)Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
Under nitrogen flush, in a 2-necked 100 ml round-bottomed flask equipped with a reflux condenser (flammed for 5 minutes under vacuum and then 3 cycles of N2/vacuum), (1,1-dimethylethyl)(dimethyl){[(3-{[(methyloxy)methyl]oxy}phenyl)methyl]oxy}silane (Intermediate 103, 1.5 g, 5.31 mmol) was dissolved in hexane (20 ml) to give a colourless solution. Butyllithium 1.6N in hexane (4.31 ml, 6.9 mmol) was added dropwise and the reaction mixture was stirred at room temperature. After 2 hours stirring in those conditions, the pale yellow reaction mixture was added to a solution of ethyl chloroformate (1.015 ml, 10.62 mmol) in tetrahydrofuran at −78° C. After 30 min, the reaction was quenched with a 2M aqueous solution of hydrochloric acid while the pH was allowed to reach ˜2 and diluted with 10 ml of ethyl acetate. Two phases were separated and the organic layer was dried over Na2SO4 and evaporated under vacuum affording the crude product as a yellowish oil that was purified by flash chromatography (Biotage system) on silica gel using cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound (1.396 g) as a yellow pale oil.