Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.[Br:12][C:13]1[CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][C:18]=1F.C1OCCOCCOCCOCCOCCOC1.[F-].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([O:10][C:18]2[CH:17]=[CH:16][C:15]([C:20](=[O:22])[CH3:21])=[CH:14][C:13]=2[Br:12])[CH:7]=[N:6][CH:5]=1
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: COC(=O)c1cncc(O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cncc(Oc2ccc(C(C)=O)cc2Br)c1
Yield: 27.8 %

Procedure:
Methyl-5-hydroxynicotinate (1.0 g, 6.53 mmol), 3′-bromo-4′-fluoroacetophenone (1.42 g, 6.53 mmol), 18-crown-6 (155.3 mg, 0.59 mmol) and potassium fluoride (40 wt. % on alumina, 996 mg, 6.86 mmol) were dissolved in ACN (10 mL). The reaction was refluxed for three days. After cooling the mixture was quenched with 2N aqueous potassium carbonate solution, extracted with ether, dried with sodium sulphate, filtered, evaporated and purified by silica gel chromatography (ethyl acetate:n-heptane 1:4). 635 mg (yield: 28%) of the pure compound was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([OH:14])=O.[CH3:20][CH:21]([NH2:23])[CH3:22]>>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([NH:23][CH:21]([CH3:22])[CH3:20])=[O:14]
Reactant: COc1ccc(C(=O)O)cc1OC1CCCCC1O
Reactant: CC(C)N
Product: COc1ccc(C(=O)NC(C)C)cc1OC1CCCCC1O

Procedure:
Prepared as in Example 24a from (±)-3-((2-hydroxycyclohexyl)oxy)-4-methoxybenzoic acid (Example 129e) and propan-2-amine as a white solid (80%). 1H NMR (400 MHz, DMSO-d6) δ 1.14 (d, J=8.0 Hz, 6H), 1.25-1.30 (m, 4H), 1.61 (m, 2H), 1.85 (m, 2H), 3.56 (m, 1H), 3.79 (s, 3H), 4.03-4.12 (m, 2H), 4.81 (d, J=4.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 7.45-7.49 (m, 2H), 8.01 (d, J=8.0 Hz, 1H). MS 308 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[CH:12]=1)[CH3:8].F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CN(C=O)C>[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[C:15]([O:17][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH:14]=[C:13]([O:18][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH:12]=1)[CH3:8]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(C#N)cc2)cc(Oc2ccc(C#N)cc2)c1
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
Potassium carbonate 0.611 g (4.4 mmol) was added to a stirred solution of 3,5-dihydroxy-benzoic acid ethyl ester 0.5 g (1.7 mmol) dissolved in 15 ml of DMF and stirred for 10 min. This was followed by dropwise addition of 4-fluorobenzonitrile 0.82 g (6.8 mmol), dissolved in 5 ml of DMF, and the contents of the flask were stirred at 80° C. for 4 h. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic phase was washed with Na2CO3 and saturated brine solution, dried over sodium sulphate and concentrated to afford an oily residue which was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.4 g of the required product. The yield was 0.6 g. 1H NMR (DMSO-d6): δ 1.30 (3H, t), 4.30 (2H, q), 7.25 (2H, d), 7.32 (1H, t), 7.46 (2H, d), 7.90 (2H, d).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FS([C:26]([F:31])([F:30])C(O)=O)(=O)=O>C(#N)C.[Cu]I>[F:30][CH:26]([F:31])[O:21][C@H:10]1[C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](O)C1
Agent: [Cu]I
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](OC(F)F)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
Dissolve trans-tert-butyl-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate (0.9 g, 3.1 mmol) and copper(I) iodide (116 mg, 609 mmol) in ACN (7.6 mL) and heat to 50° C. Add fluorosulfonyldifluoroacetic acid (336.7 mg, 1.83 mmol) dropwise over 15 minutes. Stir the solution for 2 hours at 50° C. and then cool to ambient temperature. Quench with a 50% solution of sodium bicarbonate; separate layers; and extract the aqueous layer twice with EtOAc. Combine the organic extracts; dry over sodium sulfate; filter; collect the filtrate; and concentrate under vacuum. Purify the crude material with silica gel flash column chromatography, with a gradient of 0-20% EtOAc in hexane to give the title compound (0.18 g, 17%). 1H-NMR (d6-DMSO) δ 0.74 (s, 1H), 1.42 (s, 9H), 1.5-1.79 (m, 2H), 2.6-2.85 (m, 2H), 3.59-4.82 (m, 4H), 6.4 (dd, J=76.8 Hz, 77.9 Hz, 1H), 7.0-7.1 (m, 2H), 7.27-7.33 (m, 2H).
Reaction SMILES: Cl[Si:2]([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].C[Si]([C:18]1([Li])[CH:22]=[CH:21][CH:20]=[CH:19]1)(C)C.O>O1CCCC1>[CH3:3][Si:2]([CH2:3][Si:2]([CH:21]1[CH:20]=[CH:19][CH:18]=[CH:22]1)([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:4])([CH3:5])[CH3:4]
Reactant: C[Si](C)(Cl)C1=Cc2ccccc2C1
Reactant: [Li]C1([Si](C)(C)C)C=CC=C1
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C[Si](C)(C1=Cc2ccccc2C1)C1C=CC=C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 54.6 %

Procedure:
Chloro-2-indenyldimethylsilane (5.15 g, 0.025 mol.) according to Example 1 was dissolved in 10 ml of tetrahydrofuran. The solution was cooled to 0° C. and a solution of trimethylsilylcyclopentadienyllithium (3.60 g, 0.025 mol.) in 20 ml of tetrahydrofuran was added. Stirring was carried out for 15 hours at 25° C. 50 ml of water were then added, and the organic phase was washed with water again and dried over Na2SO4. After removal of the solvents under an oil pump vacuum, the yellowish oil that remained was purified by means of column chromatography. The solvents were removed to yield 2.12 g (34%) of trimethylsilylcyclopentadienyl-2-indenyl-dimethylsilane in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:7]2[C:6]3[C:10](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1cccc2cc[nH]c12
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3c(Br)cccc23)CC1
Yield: 28.5 %

Procedure:
A stirred solution of 7-bromoindole (390 mg, 2.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (438 mg, 2.2 mmol), and pyrrolidine (0.42 mL, 5.0 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (215 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:20])[N:10]=2)[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:28]([C:29](O)=[O:30])=[C:27]([F:32])[C:26]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][CH:24]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:22][C:23]1[C:28]([C:29]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([CH3:20])[N:10]=[C:9]3[NH:8][CH:5]2[CH2:4][CH2:3][C:2]([CH3:21])([CH3:1])[CH2:7][CH2:6]2)=[O:30])=[C:27]([F:32])[C:26]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:25][CH:24]=1
Reactant: Cc1nc(NC2CCC(C)(C)CC2)c2cccc(N)c2n1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(NC2CCC(C)(C)CC2)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 7.2 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4,4-dimethylcyclohexyl)-2-methylquinazoline-4,8-diamine (Intermediate-47, 180 mg, 0.63 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 271 mg, 0.95 mmol), oxalyl chloride (180 mg, 1.43 mmol), DMF (1 drop) and DIPEA (244 mg, 1.89 mmol) in CH2Cl2 (8 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.18 (s, 1H), 8.66 (d, J=7.8 Hz, 1H), 8.14 (t, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.93 (d, 1H), 7.43 (m, 2H), 7.37 (d, J=7.8 Hz, 1H), 4.31 (d, 2H), 4.17 (m, 1H), 2.44 (s, 3H), 1.72 (m, 2H), 1.64-1.60 (m, 2H), 1.41-1.28 (m, 4H), 1.14 (s, 9H), 0.98 (s, 3H), 0.94 (s, 3H); MS (m/z): 554.35 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8].Cl.[CH3:31][N:32]([CH3:37])[CH2:33][C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:31][N:32]([CH3:37])[CH2:33][C:34]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])=[O:35]
Reactant: CN(C)CC(=O)O
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCN)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)NCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Yield: 83.2 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(2-dimethylamino-acetylamino)-ethyl]-amide (64 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-amino-ethyl)-amide dihydrochloride (75 mg), N,N-dimethylglycine hydrochloride (24 mg), HBTU (79 mg), and DIEA (46 uL). LC/MS: m/z 486.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.64-8.44 (m, 1H), 8.22 (bs, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.83-7.59 (m, 2H), 7.55-7.45 (m, 1H), 7.41 (d, 1H), 3.79-3.56 (m, 5H), 3.44-3.34 (m, 2H), 3.20-3.09 (m, 2H), 2.71 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].CCCCCC>CN(C=O)C.C(OCC)(=O)C>[Si:18]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.9 %

Procedure:
To 4-(2-hydroxyethoxy)benzaldehyde (commercial, 0.5 g, 3 mmol) dissolved in DMF (10 mL) is added imidazole (0.4 g, 6 mmol) and tert-butyldimethylsilylchloride (0.53 g, 3.5 mmol). Reaction mixture is stirred for 20 h. at room temperature. TLC analysis (hexane:ethyl acetate,7:3) shows small amounts of unreacted starting material. Additional tert-butyldimethylsilylchloride (0.25 g, 1 mmol) is added and stirring continued for 16 h. The reaction is quenched with saturated aqueous ammonium chloride (20 mL) and diluted further with ethyl ether (20 mL). Aqueous layer is separated and extracted thrice with ether (10 mL). Combined organics dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel using a gradient of 2% to 5% ethyl acetate in hexanes to provide 0.42 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][OH:11]>C1(C)C=CC=CC=1>[OH:11][CH2:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: OCCCBr
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: OCCCN1CCOCC1
Temperature: 80 °C
Yield: 51 %

Procedure:
Morpholine (94 g, 1.08 mol) was added dropwise to a solution of 3-bromo-1-propanol (75 g, 0.54 mol) in toluene (750 ml) and the reaction then heated at 80° C. for 4 hours. The mixture was allowed to cool to ambient temperature and the precipitated solid was removed by filtration. The volatiles were removed from the filtrate and the resulting yellow oil was purified by distillation at 0.4-0.7 mmHg to give 4-(3-hydroxypropyl)morpholine (40 g, 50%) as a colourless oil.
Reaction SMILES: C(Cl)Cl.O[CH2:5][C@H:6]1[C@@H:10]([CH2:11][OH:12])[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:7]1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1>[CH2:11]1[CH:10]2[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:7][CH:6]2[CH2:5][O:12]1
Reactant: O=C(OCc1ccccc1)N1C[C@@H](CO)[C@@H](CO)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CC2COCC2C1

Procedure:
To a mixture of DCM (3 mL) and pyridine (3 mL) was added phenylmethyl (cis)-3,4-bis(hydroxymethyl)-1-pyrrolidinecarboxylate (250 mg, 0.94 mmol) followed by tosyl-chloride (540 mg, 2.8 mmol) and the resulting solution was refluxed for 4 hours. The solvents were evaporated and the residue was azeotroped once with hexane before being purified by RP-HPLC. This yielded phenylmethyl tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate (170 mg, 73%). LCMS: (M+H)+: 248.4.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([NH:11][NH2:12])[CH:7]=[CH:8][C:9]=1[F:10])#[N:3].ClC1C=C(N2[C:25]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)=[CH:24][C:23]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=N2)C=CC=1F>>[Cl:33][C:28]1[CH:27]=[C:26]([C:25]2[N:11]([C:6]3[CH:7]=[CH:8][C:9]([F:10])=[C:4]([C:2]#[N:3])[CH:5]=3)[N:12]=[C:23]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:24]=2)[CH:31]=[C:30]([F:32])[CH:29]=1
Reactant: N#Cc1cc(NN)ccc1F
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(C#N)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 1A and 3-cyano-4-fluorophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 2.66 g of the title compound with 49% purity (100% of theory) are obtained.
Reaction SMILES: [C:1]([N:4]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][C@@H:5]1[C:10]1[C:15](F)=[CH:14][C:13]([NH:17][C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=O)=[C:12]([N+:26]([O-])=O)[CH:11]=1)(=[O:3])[CH3:2].[CH3:29][O:30][CH2:31][C:32]1[N:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[C:1]([N:4]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][C@@H:5]1[C:10]1[C:15]([O:38][C:35]2[CH:36]=[N:37][C:32]([CH2:31][O:30][CH3:29])=[CH:33][CH:34]=2)=[CH:14][C:13]2[N:17]=[C:18]([C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[NH:26][C:12]=2[CH:11]=1)(=[O:3])[CH3:2]
Reactant: COCc1ccc(O)cn1
Reactant: CC(=O)N1[C@@H](c2cc([N+](=O)[O-])c(NC(=O)c3cnccn3)cc2F)CC[C@@H]1C
Product: COCc1ccc(Oc2cc3nc(-c4cnccn4)[nH]c3cc2[C@H]2CC[C@H](C)N2C(C)=O)cn1

Procedure:
The entitled compound was obtained as a pale yellow oily substance in the same method as in Example 595 (step 9) or in accordance with the method or by combining it with an ordinary method but using N-(4-((2R,5S)-1-acetyl-5-methylpyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyrazine-2-carboxamide obtained in Example 595 (step 8) and 6-(methoxymethyl)pyridin-3-ol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].[CH:19]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20]1.O>CS(C)=O>[CH:19]1([O:7][N:8]2[C:9](=[O:18])[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:13])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.6 %

Procedure:
Solid potassium carbonate (8.64 g, 62.5 mmol) was added to a solution of N-hydroxyphthalimide (4.08 g, 25.0 mmol) in dimethyl sulfoxide (38 mL), and the mixture was stirred at 25° C. for 5 min. To the mixture cyclopentyl bromide (37.5 mmol, 4.02 mL) was added, and the mixture stirred at 80° C. for 3 h. After cooling in ice, the mixture was poured into cold water and the resulting precipitate was collected by filtration in vacuo, washed with water (25 mL) and hexanes (15 mL) and dried in vacuo to afford 2-cyclopentyloxy-isoindole-1,3-dione (4.89 g, 85%) as an off-white solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@@H:13]([C:16]([OH:18])=[O:17])[CH2:14][OH:15].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:12][C@H:13]([CH2:14][OH:15])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N[C@H](CO)C(=O)O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@H](CO)C(=O)O)ccc(C#N)c1Cl
Temperature: 75 °C
Reaction time: 24 h
Yield: 29.3 %

Procedure:
2-chloro-4-fluoro-3-methylbenzonitrile (500 mg, 2.95 mmol) was mixed together with H-D-Ser-OH (682 mg, 6.49 mmol) in DMSO (20 mL). K2CO3 (856 mg, 6.19 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly in to a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexanes/EtOAc and then with EtOAc, 100% to give the final product (220 mg): 1H NMR (500 MHz, DMSO-d6, δ in ppm) 7.47 (d, J=9 Hz, 1H), 6.57 (d, J=9 Hz, 1H), 6.13 (br s, 1H), 3.62 (m, 2H), 2.18 (s, 3H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([N:25]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[C:17]([F:43])[CH:16]=2)[C@@H:11]([C:44]2[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[CH3:42][O:41][C:34]1[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=1[CH2:32][N:25]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][N:27]=1)[S:22]([C:18]1[CH:19]=[C:20]([F:21])[C:15]([O:14][C@H:12]2[CH2:13][C@@H:9]([OH:8])[CH2:10][C@@H:11]2[C:44]2[N:48]([CH3:49])[N:47]=[CH:46][CH:45]=2)=[CH:16][C:17]=1[F:43])(=[O:23])=[O:24]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 110.2 %

Procedure:
A solution of the 4-{[(1S*,2R*,4S*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (1.25 g, 1.75 mmol) prepared in Example 120b and tetrabutyl ammonium fluoride (1.0 M solution in THF; 5.24 mL, 5.25 mmol) in THF (8.0 mL) was stirred at room temperature for 3 hours. To the reaction solution, 1 M hydrochloric acid (10 mL) was added, followed by extraction with ethyl acetate (100 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (methylene chloride/methanol) to yield the title compound (1.16 g, 99%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH2:48])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:49][C:50]#[N:51].[Na+].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][C:50]([NH2:51])=[O:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN)CCC3)cc1
Reactant: N#C[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCNC(N)=O)CCC3)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of 0.103 g (0.156 mmol) (3R,4R)-3-[1-(2-amino-ethyl)-1,2,3,4-tetrahydro -quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 15(b)] in 2 ml of tetrahydrofuran was added a solution of 0.101 g (1.56 mmol, 10.0 equiv.) of sodium cyanate in 1 ml of water. The resulting suspension was cooled to 0° C. and 0.156 ml (0.156 mmol, 1.0 equiv.) of 1 N HCl solution was added dropwise. The reaction flask was stoppered and the suspension was stirred for 2 h at 25° C. The reaction mixture was poured into 50 ml of an ice/water mixture, the pH was adjusted to 8 by addition of saturated sodium bicarbonate solution, and the aqueous phase was extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 25 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 100:10:1 v/v/v mixture of dichloromethane/methanol/28% ammonium hydroxide solution as eluent to yield 0.106 g (0.133 mmol, 85.3% of theory) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(2-ureido-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 799 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Cl[CH2:13][CH:14]=O.CCOCC>CCO>[OH:10][C:6]1[CH:7]=[CH:8][N:9]2[CH:13]=[CH:14][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: COc1ccnc(N)c1C#N
Reactant: O=CCCl
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1c(O)ccn2ccnc12
Temperature: 150 °C

Procedure:
To a mixture of compound D3 (2 g, 13.404 mmol) in EtOH (5 ml) was added chloroacetaldehyde (1.58 g, 20.11 mmol). The reaction mixture was subjected to microwave heating at 150° C. for 45 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue thus obtained was then treated with Et2O and a solid precipitated. The solid thus obtained was filtered off, washed with EtOAc and dried in vacuo to yield compound D21 (1.5 g, 70%).