Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-benzyloxycarbonyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (3.06 g, 10.0 mmol) in dry DMF (30 ml) was added dropwise to a slurry of sodium hydride (60% dispersion in oil/480 mg, 12.0 mmol) in dry DMF (20 ml) under nitrogen at room temperature. The reaction mixture was stirred for one hour at room temperature to which was added dropwise tert-butyl bromoacetate (1.48 ml, 10.0 mmol). The reaction was stirred for a further two hours, diluted with ethyl acetate (100 ml), washed with brine (2×100 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with ethyl acetate-hexane (2:5) as eluant. (3.28 g, 78%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Br:22]Br>C(O)(=O)C.C(Cl)Cl.C(=O)([O-])O>[Br:22][C:3]1[C:4]2[CH:9]=[C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2sccc2c1
Reactant: BrBr
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2scc(Br)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a solution of (1S,2R,3S,4R)-3-(1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide (30 mg, 0.1 mmol) in acetic acid (2 mL) was added bromine (5.5 μL, 0.1 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with methylene chloride (5 mL) and neutralised by careful addition of a saturated hydrogen carbonate solution. The layers were separated and the aqueous was extracted with methylene chloride (2×5 mL). The organic extracts were washed with water, dried over magnesium sulfate and evaporated in vacuo to give (1S,2R,3S,4R)-3-(3-bromo-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide as a glass (37 mg, 97%). M/e 378/380 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:27].[K+]>C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][CH:20]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C#N)cc3)ccc2C1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C(N)=O)cc3)ccc2C1
Reaction time: 72 h
Yield: 45.4 %

Procedure:
Combine 6-(4-Cyano-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.93, 5.51 mmol), t-butyl alcohol (50 ml), and KOH (1.56 g, 27.6 mmol). After the reaction stirs for 72 hours at room temperature, concentrate under reduced pressure then add ethyl acetate. Wash the ethyl acetate with a brine solution and dry the organic layer over Na2SO4. After concentrating the organic layer under reduced pressure, the reaction affords 1.93 g, 2.50 mmol (95% yield) of the title compound as a white solid:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[S:8][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][N:11]=1>C([O-])(O)=O.[Na+].C(OCC)(=O)C>[C:1]([NH:5][S:12]([C:9]1[S:8][C:7]([Cl:6])=[N:11][CH:10]=1)(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cnc(Cl)s1
Reactant: CC(C)(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred solution of commercially available tert-butylamine (5.03 g, 68.8 mmol) in saturated NaHCO3 solution (35 mL) and ethyl acetate (17 mL) was added at 0° C. (ice water bath) a solution of 2-chloro-thiazole-5-sulfonyl chloride [CAS-No. 88917-11-7] (5.0 g, 22.9 mmol). The reaction mixture was stirred at room temperature for 2 h, ethyl acetate (50 mL) was added followed by extraction. The water layer was again extracted with ethyl acetate (50 mL). The combined organic layers were washed with 2N HCl solution (40 mL) and brine (40 mL), dried (MgSO4) and evaporated to yield the title compound (4.9 g, 84%) as a yellow solid. MS (ISN) 253.1 [(M−H)−], mp 75° C.
Reaction SMILES: C(O)(=O)C.C1([SiH3])C=CC=CC=1.C([N:15]1[N:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]4[C:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[C:38]([OH:47])[C:37]([C:48]([F:51])([F:50])[F:49])=[CH:36][CH:35]=4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[N:16]1)C=C>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:47][C:38]1[C:37]([C:48]([F:51])([F:50])[F:49])=[CH:36][CH:35]=[C:34]([CH2:33][O:32][C:29]2[CH:30]=[CH:31][C:26]([C:23]3[CH:22]=[CH:21][C:20]([C:17]4[NH:18][N:19]=[N:15][N:16]=4)=[CH:25][CH:24]=3)=[CH:27][CH:28]=2)[C:39]=1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]
Reactant: C=CCn1nnc(-c2ccc(-c3ccc(OCc4ccc(C(F)(F)F)c(O)c4C(=O)OC(C)(C)C)cc3)cc2)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(-c4nnn[nH]4)cc3)cc2)ccc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (74 mg, 64.4 μmol), acetic acid (0.4 ml, 6.44 mmol) and phenylsilane (0.397 ml, 3.22 mmol) were added to a solution of the mixture (712 mg, 1.29 mmol) obtained in Example (95-3) in methylene chloride (6 ml) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. The formed solid was filtered and washed with methylene chloride to give the title compound (469 mg, yield: 71%).
Reaction SMILES: [OH:1][C:2]1([CH2:25][OH:26])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C=O.[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]3[CH:9]=[CH:10][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:12][CH:13]=3)[CH2:6][CH2:7]2)[CH2:25][O:26][CH2:29]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CO)CC3)cc2)C(=O)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: c1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)COCO4)cc2)C(=O)O1
Yield: 57 %

Procedure:
A mixture of (S)—N-{3-[4-(4-hydroxy-4-hydroxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.209 mmol), paraformaldehyde (0.233 mmol), p-toluene sulfonic acid (0.248 mmol), 4° A molecular sieves (0.160 g) in benzene (20 ml) was heated at reflux for 2 to 3 hours under stirring. The solvent was removed under vacuum to provide a residue. The residue was extracted with ethyl acetate water mixture. The combined organic layer was dried and concentrated to afford a crude product. The silica gel column chromatography afforded title compound in 57% yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:20]=3[CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: Cc1ccncc1B(O)O
Product: CCCNC(=O)c1nnc2c(-c3cnccc3C)cccc2c1N
Yield: 86 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and (4-methylpyridin-3-yl)boronic acid (274 mg, 2.000 mmol) were reacted to afford the title compound (134 mg, 86% yield). 1H NMR (300 MHz, CDCl3) δ 8.59-8.45 (m, 3H), 7.98-7.92 (m, 1H), 7.80-7.66 (m, 2H), 7.27 (m, 1H), 3.44 (m, 2H), 2.11 (s, 3H), 1.65 (m, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=322 (M+H). HPLC 1.27 min.
Reaction SMILES: C[Si](C)(C)Cl.[CH2:6]([O:8][P:9](C(OCC)(OCC)C)([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[CH3:7].ClCCl>C(O)C>[CH2:6]([O:8][PH:9]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[CH3:7]
Reactant: CCOC(C)(OCC)P(=O)(CC1CCCCC1)OCC
Agent: C[Si](C)(C)Cl
Solvent: CCO
Solvent: ClCCl
Product: CCO[PH](=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
150 g of trimethylchlorosilane are added to a solution of 213 g of 1,1-diethoxyethyl(cyclohexylmethyl)phosphinic acid ethyl ester in 600 ml of a mixture of dichloromethane and ethanol (90:10% by volume) and the batch is stirred for 2 to 3 days at room temperature. The solvent is removed and the residue is distilled under reduced pressure to give P-(cyclohexylmethyl)phosphinic acid ethyl ester having a boiling point of 50° (2×10-4 mbar).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[S:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:34](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[N:12][C@H:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[S:11][CH3:34])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(=S)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC(CNC(=O)OC(C)(C)C)=N[C@@H](CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.1 g (2.43 mmol) of 4-benzyl 1-tert-butyl N-[(1-tert-butoxyformamido)thioacetyl]-L-aspartate, 1.95 ml of methyl iodide and 0.92 g of potassium carbonate in 50 ml of acetone is stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure and the residue is taken up in ether. The organic phase is washed with water, dried over sodium sulphate and evaporated. 4-Benzyl 1-tert-butyl N-[2-(1-tert-butoxyformamido)-1-(methylthio)ethylidene]-L-aspartate is obtained as a mixture of the E- and Z-isomers; MS: 467 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:32])[N:24]([CH2:28][CH2:29][C:30]#[N:31])[CH:25]([CH3:27])[CH3:26])[CH:20]=[C:19]([Cl:33])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[C:30]([CH2:29][CH2:28][N:24]([CH:25]([CH3:27])[CH3:26])[C:23](=[O:32])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=[C:19]([Cl:33])[CH:20]=1)(=[O:38])[NH2:31]
Reactant: CC(C)N(CCC#N)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CCC(N)=O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 12 h

Procedure:
A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-isopropyl-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.071 g) in a mixture of dichloromethane (4 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 12 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.045 g) was obtained as a yellow oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].Br[CH2:35][CH2:36][O:37][Si](C(C)(C)C)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:35][CH2:36][OH:37])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(CCO)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (200 mg) in DMF (5 mL) was added sodium hydride (60%, 31.6 mg) under ice-cooling, and the mixture was stirred for 30 min under a nitrogen atmosphere. (2-Bromoethoxy)(tert-butyl)dimethylsilane (113 μL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the residue in THF (2 mL) was added TBAF (1M THF solution, 439 μL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (26.9 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].O>Cl>[C:19]([O:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([OH:6])=[O:5])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCC(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCC(CC(=O)O)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Then 5.0 g of this β-hydroxynonanoic acid was mixed with 20 ml of anhydrous pyridine and 3.2 ml of acetic anhydride under ice cooling, and the mixture was stirred at room temperature overnight and cooled with ice. Then, 5 ml of distilled water was added to the mixture, the mixture was dissolved in 1N hydrochloric acid, and the solution was extracted with ether. The ether layer was washed with a saturated aqueous sodium chloride solution and dehydrated on magnesium sulfate. Then, the ether was evaporated and the residue was concentrated to obtain 5.4 g of β-acetoxynonanoic acid.
Reaction SMILES: [O:1]=[C:2]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21](=[O:27])[NH:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[O:15])[N:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]=1)=[O:6].C(N(CC)CC)C.[CH3:47][O:48][CH2:49][CH2:50][O:51][C:52](Cl)=[O:53]>ClCCl>[CH3:47][O:48][CH2:49][CH2:50][O:51][C:52]([N:37]1[CH2:38][CH2:39][N:34]([C:2](=[O:1])[CH2:3][NH:4][C:5]([C:7]2[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21](=[O:27])[NH:22][CH:23]3[CH2:24][CH2:25][CH2:26]3)=[O:15])[N:9]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:8]=2)=[O:6])[CH2:35][CH2:36]1)=[O:53]
Reactant: COCCOC(=O)Cl
Reactant: O=C(NCC(=O)N1CCNCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 100 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide in 5 ml dichloromethane were added at 0° C. 56 l triethylamine and 24 l chloroformic acid 2-methoxyethyl ester. After stirring for 12 h it was concentrated and the residue obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[CH:22][C:23]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:25])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)O)cc2)CC1
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)N3CCOCC3)cc2)CC1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a stirred solution of 3-[4-(1-t-butyloxycarbonyl piperidin-4-yloxy)phenyl]prop-2-ene-1-oic acid (38 grams, 0.109 moles, obtained in above step) and triethylamine (38.4 mL, 0.273 moles) in dichloromethane (500 mL) was added ethylchloroformate (13.6 mL, 0.142 moles) at 0° C. The reaction mass was further stirred for 2 hours at 0-5° C. Morpholine (19.2 mL, 0.219 moles) was added to above mass at 0-5° C. and the resulting mixture were stirred for 2 hours. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the mass was quenched by adding water (100 mL). Layers were separated and the organic layer was washed with brine solution (100 mL) and dried over sodium sulphate. The organic phase was concentrated under vacuum to obtain the crude residue, which was further purified by flash chromatography using methanol:triethylamine:chloroform in the ratio of 1:1:98 to afford the title compound (34 grams).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11](Br)[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.CS(C)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(Br)C1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NCc2ccc(OC)cc2)C1
Temperature: 85 °C
Reaction time: 15 h
Yield: 61.9 %

Procedure:
To a suspension of 8.20 g (20.80 mmol) of 9-bromo-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester in 208 mL of toluene was added 8.56 g (62.40 mmol) of 4-methoxybenzylamine and 14.77 mL (208.00 mmol) of dimethylsulfoxide. The reaction mixture was stirred at 85° C. for 15 hours. The cooled solution was evaporated to remove solvent. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with dichloromethane, washed with saturated solution of sodium chloride. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane methanol/ammonia 98/2/0.2 to 97/3/0.3) to afford 5.80 g (62%) of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1>[Ni].C(O)C.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccc(F)cc2[nH]1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1c2ccccc2-c2c(-c3nc4ccc(F)cc4[nH]3)cccc21
Yield: 97.1 %

Procedure:
Carry out the procedure as in Example 6, starting from 1.7 g of 4-(6-fluoro-1H-benzimidazol-2-yl)-fluoren-9-one oxime (Z,E), obtained in Example 70, and 6 mg of Raney Nickel in 90 ml of ethanol and 90 ml of tetrahydrofuran for 4 hours at 60° C. under a hydrogen pressure of 1 bar. After purification by making a paste in diisopropyl ether, we obtain 1.58 g of 4-(6-fluoro-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a beige powder with the following characteristics:
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[CH3:13][N:14]1[C:22]2[CH:21]3[CH2:23][CH:18]([CH2:19][CH2:20]3)[C:17]=2[C:16]([CH2:24]O)=[N:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:13][N:14]1[C:22]2[CH:21]3[CH2:23][CH:18]([CH2:19][CH2:20]3)[C:17]=2[C:16]([CH2:24][O:1][N:2]2[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[N:15]1
Reactant: Cn1nc(CO)c2c1C1CCC2C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nc(CON2C(=O)c3ccccc3C2=O)c2c1C1CCC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a mixture of 2-hydroxy-1H-isoindole-1,3(2H)-dione (4.10 g, 25.2 mmol), (1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)methanol 147 (2.24 g, 12.6 mmol) and triphenylphosphine (6.59 g, 25.2 mmol) in THF (100 mL) was added DIAD (5.35 mL, 27.6 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue, which was subjected to chromatography to give 148 (1.80 g, 62%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:13])[CH:6]=[CH:5][CH:4]=1.Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.O>[CH3:21][C:15]([O:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[N:3]=[CH:4][CH:5]=[CH:6]2)([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Oc1cccc2cccnc12
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc2cccnc12
Reaction time: 0.08 h
Yield: 44.8 %

Procedure:
To a solution of compound NaH (248 mg, 10.2 mmol) in DMF (10 mL) was added quinolin-8-ol (500 mg, 3.44 mmol) at 28° C. After stirring for 5 minutes, ethyl 2-bromo-2-methylpropanoate (806 mg, 4.13 mmol) was added and the reaction mixture was stirred for an additional 16 h at 28° C. until the reaction was complete by TLC. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the crude product (400 mg, 44.8%) as colorless oil which was used in next step without further purification.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH:15]=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][Mg]Br>C1COCC1>[OH:16][CH:15]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8])[CH3:17]
Reactant: O=Cc1cnccc1C(=O)c1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cnccc1C(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzoyl-pyridine-3-carbaldehyde (114 mg, 0.54 mmol) in THF (3 mL) at −78° C. was added 3.0 M methylmagnesium bromide in THF (0.27 mL) and the reaction mixture was stirred for 15 min. The- reaction mixture was then quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by chromatography of silica gel with 5% methanol in dichloromethane to yield [3-(1-hydroxy-ethyl)-pyridin-4-yl]-phenyl-methanone as white crystals.