Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[NH2:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:16]1=[O:29].[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH:31]1[C:40](O)=[O:41].ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.C(Cl)Cl>[O:29]=[C:16]1[CH:15]([NH:14][C:40]([CH:31]2[CH2:32][CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30]2)=[O:41])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]1[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCN1C(=O)C(N)c2ccccc21
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCN1C(=O)C(NC(=O)C2CCc3ccccc3C2)c2ccccc21
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Under ice cooling, 1.10 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added to a stirred mixture of 1.22 g of 3-amino-2,3-dihydro-1-pentyl-1H-indol-2-one hydrochloride, 0.93 g of 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid, 0.72 g of 1-hydroxybenzotriazole and 40 ml of methylene chloride. After the reaction mixture was stirred under ice cooling for 1 hour, 1.0 ml of triethylamine was added to the mixture. The resulting mixture was stirred under ice cooling for 2 hours and then stirred at room temperature for 2 hours. The solvent was removed by evaporation under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed and dried. After removal of solvent, the residual solid was recrystallized from ethyl acetate-hexane to afford 1.36 g of N-(2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide as colorless crystals. Melting point: 127° to 132° C., IR (Nujol) (cm-1): 3280, 1725, 1640, 1610, MS (m/z): 376 (M+), 218 (base), 147, 31.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([OH:27])=O)=[O:14])[N:4]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:41]2[N:42]=[CH:43]C=C[C:40]=2[N:39]=N1.C([O:58][C:59](=[O:65])N(CCN)C)(C)(C)C.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:43][NH:42][CH2:41][CH2:40][NH:39][C:25]([C:17]1[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=2[S:20][C:16]=1[NH:15][C:13](=[O:14])[CH2:12][N:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:3]([C:2]([F:28])([F:1])[F:29])=[N:4]1)=[O:27].[C:59]([OH:58])([C:2]([F:29])([F:28])[F:1])=[O:65]
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1sc2c(c1C(=O)O)CCCC2
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNCCNC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 445.9 %

Procedure:
2-[2-(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (25 mg, 0.059 mmol) was dissolved in a solution of DCM (1 mL) and DMF (0.2 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (27 mg, 0.070 mmol) was added, followed by N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (12 mg, 0.070 mmol) and N,N-diisopropylethylamine (12.2 μL, 0.070 mmol). The resultant mixture was stirred at RT overnight. The solvent was removed under reduced pressure, and the residue obtained purified by preparative reverse phase HPLC. The resulting residue was dissolved in a solution of DCM (0.5 mL) and TFA (0.5 mL) and stirred at RT for 30 min, before concentration in vacuo. The residue obtained was purified by preparative reverse phase HPLC to yield the title compound as a TFA salt (15 mg, 0.025, 42%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][S:30]([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([CH:40]([F:42])[F:41])[CH:39]=1)(=[O:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:36]2[CH:35]=[C:34]([NH:33][S:30]([CH3:29])(=[O:31])=[O:32])[CH:39]=[C:38]([CH:40]([F:42])[F:41])[CH:37]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CS(=O)(=O)Nc1cc(B(O)O)cc(C(F)F)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(NS(C)(=O)=O)cc(C(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 16.5 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added (3-(methylsulfonamido)-5-(difluoromethyl)phenyl)boronic acid (598 mg, 20% purity, 0.34 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) and 284 μl of a 2M aqueous solution of cesium carbonate in dioxane (3 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by flash chromatography (0 to 85%, hexane-ethyl acetate) using SP1® Purification System to give 22 mg (17% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[OH:38][N:39]1[C:44]([CH3:46])([CH3:45])[CH2:43][CH:42]([OH:47])[CH2:41][C:40]1([CH3:49])[CH3:48].[CH2:50]([N:54]=[C:55]=[O:56])[CH2:51][CH2:52][CH3:53]>C(Cl)(Cl)(Cl)Cl>[CH2:50]([NH:54][C:55](=[O:56])[O:47][CH:42]1[CH2:43][C:44]([CH3:45])([CH3:46])[N:39]([OH:38])[C:40]([CH3:49])([CH3:48])[CH2:41]1)[CH2:51][CH2:52][CH3:53]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CCCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCNC(=O)OC1CC(C)(C)N(O)C(C)(C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.1 g of di-n-butyltin dilaurate is added to a solution of 1.0 g (5.8 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine and 0.58 g (5.8 mmol) of butyl isocyanate in 10 mL of carbon tetrachloride. After stirring for four hours at ambient temperature, the solution is concentrated and the title compound is isolated as a red oil after column chromatography.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:5][CH2:4]1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:12](=[O:14])[CH2:11][CH2:10][O:9][C@H:6]2[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[S:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=3)(=[O:16])=[O:17])[CH2:4][CH2:5]2)[CH2:31][CH2:30]1
Reactant: OC1CCNCC1
Reactant: CN([C@H]1CC[C@H](OCCC(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN([C@H]1CC[C@H](OCCC(=O)N2CCC(O)CC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
100 mg (0.24 mmol) of trans-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid in 3 mL of CH2Cl2 were treated with 21.3 mg (0.36 mmol, 1.5 eq) of 4-hydroxypiperidine and 0.40 mL (0.36 mmol, 1.5 eq) of NMM. The solution was cooled to 0° C. and 60.9 mg (0.31 mmol, 1.3 eq) of EDCI and 7.5 mg (0.05 mmol, 0.2 eq) of HOBT were added. The mixture was stirred at RT over night, and was then partitioned between CH2Cl2 and a saturated aqueous solution of Na2CO3. The organic phase was washed with a solution of KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with CH2Cl2:MeOH 98:2 gave 97.1 mg (81%) of trans-N-{4-[3-(4-hydroxy-piperidin-1-yl)-3-oxo-propoxy]-cyclohexyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as white powder, MS: 493 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=1.C([Li])CCC.[CH:19](N1CCOCC1)=[O:20].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:13][O:12][C:4]1[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=[C:2]([CH:19]=[O:20])[CH:3]=1
Reactant: O=CN1CCOCC1
Reactant: COc1cc(Br)cc2c1OCOC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)cc2c1OCOC2
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
To a solution of 31.2 g of 6-bromo-8-methoxy-4H-benzo[1,3]dioxine in 500 ml of THF there was added dropwise 55 ml of n-butyllithium (2.55 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −72° C. for 30 minutes, 20 ml of N-formylmorpholine was added and the temperature was raised from −78° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (21.28 g) as a white solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][C:12]([C:16]([O:18]CC)=[O:17])=[C:13]([CH3:15])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].C(O)(=O)C>O1CCCC1.O>[C:1]([NH:9][C:10]1[S:11][C:12]([C:16]([OH:18])=[O:17])=[C:13]([CH3:15])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(NC(=O)c2ccccc2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)O
Temperature: 50 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A mixture of ethyl 2-benzamido-4-methylthiazole-5-carboxylate (3.00 g, 10.00 mmol) and lithium hydroxide (2.50 g, 103.00 mmol) in a mixture of tetrahydrofuran (40 mL) and water (10 mL) was stirred at 50° C. for 20 h. The mixture was then cooled to 0° C. and neutralized with acetic acid to pH 7. The precipitate obtained was collected by filtration, washed with water and dried in vacuo to afford the title compound as a white solid in 75% yield (2.0 g); 1H NMR (DMSO-d6, 300 MHz) δ 12.92 (s, br, 1H), 8.06-8.04 (m, 2H), 7.63-7.48 (m, 3H), 2.53 (s, 3H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[CH:11]=[C:10]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1.[CH2:26]([N:30]1[C:34]([C:35]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)=[O:36])=[CH:33][N:32]=[CH:31]1)[CH2:27][CH2:28][CH3:29].O>CCCCCC.C1COCC1>[CH2:26]([N:30]1[C:34]([C:35]([C:37]2[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=2)([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([O:17][CH3:18])[CH:11]=[C:10]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[OH:36])=[CH:33][N:32]=[CH:31]1)[CH2:27][CH2:28][CH3:29]
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Reactant: CCCCn1cncc1C(=O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(OC)cc(-c3cccc(Cl)c3)c2c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
Butyllithium in hexane (1.6 M) (12.75 ml) was added dropwise at −20° C. under N2 to a solution of 6-bromo-4-(3-chlorophenyl)-2-methoxyquinoline (6.7 g) in THF (60 ml) and the mixture was stirred at −20° C. for 30 minutes. A solution of (1-butyl-1H-imidazol-5-yl)(4-chlorophenyl)methanone (3.35 g) in tetrahydrofuran (30 ml) was added at −20° C. under N2 and the mixture was stirred at room temperature for one night. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried, filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1). The pure fractions were collected and evaporated, yielding 2.5 g (total 48%) of (±)-α-(1-butyl-1H-imidazol-5-yl)-4-(3-chlorophenyl)-a-(4-chlorophenyl)-2-methoxy-6-quinoline-methanol (interm. 2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23](Br)=[CH:22][C:20]=2[CH:21]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[CH2:31](OB(C=C)OCCCC)[CH2:32]CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH:31]=[CH2:32])=[CH:22][C:20]=2[CH:21]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(Br)ccc2o1
Reactant: C=CB(OCCCC)OCCCC
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: C=Cc1ccc2oc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Temperature: 90 °C
Yield: 86 %

Procedure:
To a mixture of 2027 mg (4.7 mmol) {2-[(5-Bromo-benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (56) and 289 mg (0.25 mmol) Pd(Ph3)4 in 40 ml toluene were added 1.84 ml of a 5.4M solution of sodium methoxide in methanol and 957 mg (5.2 mmol) vinylboronic acid dibutyl ester and the solution was heated at 90° C. for 3 h. The reaction mixture was poured on 5% aqueous citric acid. Extraction with ethyl acetate, washing of the organic phase with brine. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (petrolether/ethylacetate 2:1) to give 1530 mg (4.04 mmol) {2-[(5-Vinyl-benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (57).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH:18](I)([CH3:20])[CH3:19]>CC(C)=O>[CH:18]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11])([CH3:20])[CH3:19]
Reactant: COc1cc(C#N)ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C#N)ccc1OC(C)C
Temperature: 25 °C

Procedure:
25 g 4-Hydroxy-3-methoxy-benzonitrile, 27.8 g potassium carbonate and 33.5 mL isopropyl iodide were placed in 250 mL acetone and heated to reflux where they were maintained for 22 h. After this time the mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude product was partitioned between ethyl acetate and water and the aqueous phase was separated and extracted with additional ethyl acetate. The combined organic fractions were dried, filtered and the solvent was removed from the filtrate under reduced pressure to give the title compound which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[Si](C)(C)C.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[F-].[Cs+]>O1CCCC1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]([C:6]2[S:5][CH:4]=[N:3][C:2]=2[CH3:1])[OH:17])=[CH:14][CH:13]=1
Reactant: Cc1ncsc1[Si](C)(C)C
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ncsc1C(O)c1ccc(Cl)cc1

Procedure:
4-Methyl-5-trimethylsilylthiazole (3 g), 4-chlorobenzaldehyde (4.9 g) and caesium fluoride (2.7 g) in dry tetrahydrofuran (150 ml) were heated under reflux for 30 hours. The mixture was cooled, evaporated to dryness and the residue thus obtained was purified by flash chromatography to afford the title compound. M.p. 133.5°-134.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]4)=[O:21])[CH:14]=3)/[O:7][C:8]2=O)=[CH:4][CH:3]=1.CN(C)C=O.O.[NH2:36][NH2:37]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]4)=[O:21])[CH:14]=3)=[N:36][NH:37][C:8]2=[O:7])=[CH:4][CH:3]=1
Reactant: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4cc(Cl)ccc43)ccc2F)CC1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cc(Cl)ccc34)ccc2F)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
(Z)-6-chloro-3-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (67) (25 mg, 0.06 mmol) was taken up in water (1 mL) and N,N-dimethylformamide (0.5 mL) and treated with Hydrazine monohydrate (20 μL, 0.41 mmol). The resulting mixture was stirred at 105° C. for 1 hour. The reaction mixture was cooled and diluted with water (˜5 mL) and mixture extracted with DCM (2×5 mL). Combined organics were evaporated to dryness to afford the crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white foam (10 mg, 39% yield); 1H NMR (400.132 MHz, DMSO) δ 1.26-1.35 (1H, m), 1.40-1.49 (1H, m), 1.67-1.74 (1H, m), 1.83-1.90 (1H, m), 2.99-3.06 (1H, m), 3.26 (3H, s), 3.26-3.36 (2H, m), 3.39-3.45 (1H, m), 3.88-3.95 (1H, m), 4.33 (2H, s), 7.22 (1H, t), 7.31 (1H, dd), 7.38-7.42 (1H, m), 7.94 (1H, dd), 8.00 (1H, d), 8.21 (1H, d), 12.72 (1H, s); m/z (LC-MS, ESI+), RT=2.23 (M+H 430.7).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18][C@@H:19]([C:32]2[CH2:36][CH2:35][CH2:34][CH:33]=2)[O:20]C(=O)NC[C@@]2(C)C=CC=CC2)=[C:16]([O:37][CH3:38])[C:15]([CH3:39])=[C:14]2[C:10]=1[C:11](=[O:40])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[SiH](Cl)Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:1]([O:8][C:9]1[C:17]([CH2:18][C@@H:19]([C:32]2[CH2:36][CH2:35][CH2:34][CH:33]=2)[OH:20])=[C:16]([O:37][CH3:38])[C:15]([CH3:39])=[C:14]2[C:10]=1[C:11](=[O:40])[O:12][CH2:13]2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C[C@H](OC(=O)NC[C@@]1(C)C=CC=CC1)C1=CCCC1)C(=O)OC2
Agent: Cl[SiH](Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C[C@H](O)C1=CCCC1)C(=O)OC2
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-{2-[4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-1-(S)-[N-(1-(R)-methylbenzyl)carbamoyloxy]eth-1-yl}cyclopent-1-ene (9.0 g) and triethylamine (4.6 ml) in toluene (60 ml) was added trichlorosilane (2.5 ml) dropwise in toluene (20 ml). After addition, the reaction was submerged in an oil bath pre-heated to 110° C. and stirred for 15 minutes, then cooled to room temperature. The reaction was diluted with ethyl acetate (500 ml) and washed sequentially with aqueous ammonium chloride, dilute hydrochloric acid, aqueous sodium bicarbonate, brine, then dried over magnesium sulfate and evaporated onto 90 g of silica gel. This was placed on top of a silica gel column and eluted with 4:1 hexane:ethyl acetate to afford the product 1-[2-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-1-(S)-hydroxyeth-1-yl]cyclopent-1-ene, m.p. 112.0°-112.7° C. (ethyl acetate), [α]D =33.11 (CH3OH).
Reaction SMILES: C([O:4][C:5](=[O:31])[NH:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1)CC.Cl.CCO[CH2:36][CH3:37].[CH2:38](Cl)[Cl:39]>>[ClH:39].[CH2:38]([N:6]([CH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1)[C:5](=[O:31])[OH:4])[CH2:36][CH3:37]
Reactant: CCCOC(=O)NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Reactant: ClCCl
Reactant: CCOCC
Agent: Cl
Product: CCCN(C[C@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1)C(=O)O
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A solution of propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (232 mg, 0.552 mmol) in CH2Cl2 (2 mL) was stirred under an N2 atmosphere. A 2.0 M HCl solution in ether (0.276 mL, 0.552 mmol) was added dropwise to this solution. After 10 minutes, ether (8 mL) was added until a precipitate formed, which was filtered and dried to obtain propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate hydrochloride (223 mg, 88%). LC/MS: m/z 421 (M+H)+ at 2.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=8.7 Hz, 1H), 8.24 (dd, J=7.9, 1.4 Hz, 1H), 7.82 (s, 1H), 7.54-7.49 (m, 2H), 7.41-7.37 (m, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.06-7.02 (m, 1H), 4.29-3.78 (m, 7H), 3.24-3.08 (m, 2H), 2.54 (s, 3H), 2.18-2.12 (m, 1H), 1.84-1.79 (m, 1H), 1.59-1.50 (m, 2H), 0.87 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]2[CH:18]=[CH:19][CH:20]=[C:9]2[CH2:8]1)=[O:6].NN>C(O)C.[Pd]>[NH2:24][C:23]1[CH:22]=[CH:21][C:4]([C:5]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][N:10]3[CH:18]=[CH:19][CH:20]=[C:9]3[CH2:8]2)=[O:6])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Yield: 85.2 %

Procedure:
A mixture of 1.22 g 10,11-dihydro-10-(3-methyl-4-nitro-benzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.2 g of 10% Pd/C and 0.35 g of anhydrous hydrazine in 50 ml of absolute ethyl alcohol is heated on a steam bath for 1 hour. The reaction mixture is filtered hot through diatomaceous earth and evaporated in vacuo to a residue. The residue is crystallized from methylene chloride-hexane to give 0.95 g of the desired product as crystals, m.p. 232-234° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4]([CH:5]=[C:6](Br)Br)[C@H:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([Li])CCC.Cl[C:23]([O:25][CH3:26])=[O:24].P(O)(O)([O-])=O.[Na+]>C1CCCCC1.O1CCCC1>[CH3:1][C:2]1([CH3:16])[C@@H:4]([C:5]#[C:6][C:23]([O:25][CH3:26])=[O:24])[C@H:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C=C(Br)Br)C1(C)C
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
55 g of tert-butyl (1R,cis) 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-carboxylate were introduced into 550 cm3 of tetrahydrofuran and the mixture was cooled to -70° C. 132 cm3 of a 20% solution of butyllithium in cyclohexane were added over 40 minutes to the mixture which was stirred for 30 minutes at -65° C. 12.5 cm3 of methyl chloroformate were then added thereto and after 2 hours reaction at -70° C., the temperature was allowed to rise again to -20° C. The mixture was poured into an aqueous solution of monosodium phosphate and the mixture was extracted with ether. The organic phase was washed, dried and evaporated to dryness under reduced pressure. 38.3 g of the residue were chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 17.2 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[2-(methoxy carbonyl)-ethynyl]-cyclopropane-carboxylate.