Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[O:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>C1COCC1>[Cl:14][C:9]1[CH:8]=[C:7]([C:16]2([OH:15])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
n-BuLi (2.5 M, 2 mL, 5.21 mmol) was added into a solution of 4-bromo-1,2-dichlorobenzene (1.07 g, 4.74 mmol) in dry THF (10 mL) at −78° C. The mixture was stirred for 20 mins and then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.95 g, 4.74 mmol) in THF (5 mL) was added. The mixture was further stirred at −78° C. for 1 h. After this time, the reaction was quenched with NH4Cl (aq., 15 mL), extracted with ethyl acetate (50 mL×3), dried over Na2SO4 and concentrated to yield a residue. The residue was purified by flash chromatography using 10-30% ethyl acetate in hexanes as an eluent to provide tert-butyl 4-(3,4-dichlorophenyl)-4-hydroxypiperidine-1-carboxylate (1.6 g, 90% purity, 88% yield) as a colorless oil. MS found: 346.3 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:24])=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.[O:42]=O>O1CCCC1>[OH:42][C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:10][C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:24]
Reactant: COC(=O)C1C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Reactant: O=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1(O)C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Reaction time: 2.5 h

Procedure:
Dry oxygen gas was bubbled through a cooled (ice bath) solution of 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (13 g, 40.2 mmol) in 130 ml of dry tetrahydrofuran for 30 minutes. Potassium hexamethyldisilazide in toluene (180 ml, 0.67M, 120.5 mmol) was then added over a 7 minute period under a continuous stream of oxygen. After stirring for 2.5 hours, the oxygen flow was terminated and the reaction was quenched by the addition of 200 ml of 5% potassium bisulfate. Solid sodium sulfite (15 g) was then added followed by the addition of 100 ml of methanol and the mixture was stirred for an additional 30 minutes. The mixture was then extracted twice with ethyl acetate and the combined organic layers were washed three times with 1M hydrochloric acid, once with saturated bicarbonate solution followed by brine and then dried over sodium sulfate. Concentration afforded 15 g of crude product which was triturated with ether-hexane to yield 9.3 g of high purity product.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.Cl.[NH:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.C(N(CC)CC)C>C(O)C>[Br:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)=[N:3][CH:4]=1
Reactant: Cc1nc(Br)ncc1Br
Reactant: OC1CNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(N2CC(O)C2)ncc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from example 135 step (i) (0.75 g), azetidin-3-ol hydrochloride (0.66 g) and triethylamine (0.9 ml) in ethanol (10 ml) was stirred at RT for 2 h. The solvent was removed under reduced pressure and the residue purified by chromatography on silica eluting with 60% diethylether/isohexane as eluant, yield 0.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]=[N:16][C:15]2[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=[C:13]([C:12]([F:11])([F:24])[F:25])[CH:14]=2)[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=Cc1cc(Cl)ccc1O
Product: Oc1ccc(Cl)cc1C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 76.6 %

Procedure:
Using 5-chlorosalicylaldehyde and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 14(1) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[F:17])[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:18])[C:6]([C:19](OCC)=[O:20])=[C:5]2[OH:24].C(N(C(C)C)C(C)C)C.Cl.[NH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[F:17])[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:18])[C:6]([C:19]([NH:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:20])=[C:5]2[OH:24]
Reactant: CCOC(=O)C1=C(O)c2cc(F)c(F)cc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)c(F)cc2C2(CCOCC2)C1=O
Reaction time: 0.17 h

Procedure:
Ethyl 6,7-difluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (1.06 g, 3133 μmol) was dissolved in 1,4-dioxane (3133 μL) and N-ethyl-N-isopropylpropan-2-amine (1637 μL, 9400 μmol). tert-Butyl 2-aminoacetate hydrochloride (788 mg, 4700 μmol) was added, and the reaction was placed in a microwave at 140° C. for 10 minutes. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound as a white solid after purification via preparatory LC. MS (m/z)=424 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][N:6]=1)([F:4])[CH3:3].[Si]([C:17]#[N:18])(C)(C)C.Cl.[F:20][C:21]1([F:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>C1COCC1.[I-].[Zn+2].[I-]>[F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]([N:24]2[CH2:25][CH2:26][C:21]([F:27])([F:20])[CH2:22][CH2:23]2)[C:17]#[N:18])=[CH:7][N:6]=1)([F:4])[CH3:3]
Reactant: FC1(F)CCNCC1
Reactant: C[Si](C)(C)C#N
Reactant: CC(F)(F)c1ncc(C=O)cn1
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)c1ncc(C(C#N)N2CCC(F)(F)CC2)cn1
Reaction time: 0.25 h
Yield: 24 %

Procedure:
To a solution of 2-(1,1-difluoroethyl)pyrimidine-5-carbaldehyde (166 mg, 0.270 mmol, 28%) in THF (4 ml) was added TMS cyanide (79 mg, 0.1 ml, 0.8 mmol) and zinc iodide (2.2 mg, 6.89 μmol). The mixture was stirred for 15 min. To the mixture was added 4,4-difluoropiperidine hydrochloride (62 mg, 0.393 mmol) and DIPEA (37 mg, 0.05 ml, 0.286 mmol). The resultant mixture was stirred at room temperature overnight. The volatiles were removed by rotary evaporator and the reaction was purified by column chromatography on silica gel (petroleum ether: EtOAc=1:0 to 0:1) to afford 2-(2-(1,1-difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)acetonitrile (as a 1:1 mixture of nitrile and aldehyde) (39 mg, 24% yield). 1H NMR (CDCl3 500 MHz): δ 9.03 (s, 2H), 5.02 (s, 1H), 2.75 (m, 4H), 2.10 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[NH:4][N:3]=1.[C:19](=[O:22])([O-])[O-].[K+].[K+].ClC[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=O>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[N:4]([C:19](=[O:22])[CH2:27][CH2:28][N:30]2[CH2:31][CH2:32][N:33]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:34][CH2:35]2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Reactant: COc1ccc(N2CCN(C(=O)CCCl)CC2)cc1
Agent: [K+]
Product: COc1ccc(N2CCN(CCC(=O)n3nc(N)c4c3C(=O)N(c3ccc(C)cc3)CC4)CC2)cc1

Procedure:
A target compound (154.9 mg, 0.317 mmol, 76.9%) was yielded as white solid the same manner as in Example 1 by reacting 3-amino-5,6-dihydro-6-N-(p-tolyl)-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (100 mg, 0.412 mmol) with potassium carbonate (85.4 mg, 0.618 mmol) and 3-chloro-1-{4-(4-methoxyphenyl)piperazin-1-yl}propan-1-one (128.1 mg, 0.453 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:33][CH2:34][CH3:35])[C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:33][CH2:34][CH3:35])[C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 77.8 %

Procedure:
To a solution of ethyl [2-methyl-4-({propyl[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)phenoxy]acetate (88 mg, 0.18 mmol) in MeOH (2 ml) and THF (2 mL) at room temperature was added 2M NaOH (1 mL, 2 mmol). The resultant solution was stirred for 1 h, then the solvents were removed in vacuo. The residue was diluted with HCl (10 mL) and extracted with CH2Cl2 (2×10 mL), followed by EtOAc (2×10 mL). The organic solutions were dried (MgSO4) and the solvents were removed in vacuo affording the title compound as a white crystalline solid (64.1 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[C:12]([OH:14])=O)=[CH:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][C:43](=[NH:48])[O:44]C(C)C)=[CH:34]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42]2[C:43](=[O:44])[NH:48][C:12](=[O:14])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:34]1
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
A stirred solution of 406 mg (2 mmol) of 1-methyl-3-indolylglyoxylic acid in 20ml of dichloromethane was treated with 202 mg (2 mmol) of triethylamine and 273 mg (2 mmol) of isobutyl chloroformate. After 0.5 hour, the solution was added dropwise to a stirred solution of 533 mg (2 mmol) of isopropyl 1-methyl-3-indoleacetimidate hydrochloride and 808 mg (8 mmol) of triethylamine in 50 ml of dichloromethane. The solution obtained was heated to reflux under nitrogen for 18 hours, cooled and treated with 1.9 g (10 mmol) of p-toluenesulfonic acid. After 1 hour, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using dichloromethane/ethyl acetate (8:1) for the elution to give 107 mg(30% ) of 3,4-bis-(1 -methyl-3-indolyl)-1H-pyrrole-2,5-dione in the form of an orange colored solid of melting point >310° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:19][C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]=[CH:10][C:9]=3[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[C:1]1([N:7]2[CH2:19][C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][C:10](=[O:29])[C:9]=3[C:8]2=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2cnc3ccccc3c2CN1c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1c2c(c3ccccc3[nH]c2=O)CN1c1ccccc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A mixture of 2-Phenyl-pyrrolo[3,4-c]quinolin-3(1H)-one (60 mg), and m-chloroperbenzoic acid (105 mg) in 3 mL of methylene chloride was kept at room temperature for 24 h. The mixture was diluted with methylene chloride and washed with sodium carbonate solution. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was heated at 50° C. for 3 h with 1 mL of acetic anhydride. The reaction was quenched with methanol and made basic with ammonium hydroxide. The reaction mixture was concentrated in vacuo, and the resulting aqueous solution was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was triturated with ether to afford 2-Phenyl-pyrrolo[3,4-c]quinoline-3(1H),4(5H)-dione (Compound 16) as a white solid.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Cl:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]2[O:19][CH:7]2[CH:6]=1
Reactant: ClC=CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: ClC=CCC1=CC2OC2C=C1
Reaction time: 72 h
Yield: 55.6 %

Procedure:
24.6 g of p-chloroallylbenzene was dissolved in 100 ml of chloroform and to the mixture was added dropwise, while maintaining the temperature at 0° - 5° C, 34.5 g of m-chloroperbenzoic acid dissolved in 1l of chloroform. The resulting mixture was allowed to stand at the same temperature for 72 hours. After the separated m-chlorobenzoic acid was filtered off, the filtrate was washed with 10% sodium hydroxide solution, then with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was distilled under reduced pressure to give 15.1 g (yield 55.7%) of p-chloroallylbenzene oxide having a boiling point of 96° C/2.5 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[N:8][NH:9][N:10]=1)[CH3:2].S(=O)(=O)(O)O.C(OCC)(=O)C.[OH-].[Na+].[CH3:25][C:26](O)([CH3:28])[CH3:27]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[N:8][N:9]([C:26]([CH3:28])([CH3:27])[CH3:25])[N:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nn[nH]n1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1nnn(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
To a solution of (2H-tetrazol-5-yl)-acetic acid ethyl ester (2.0 g, 13 mmol) in 2-methyl-propan-2-ol (2.6 mL) and trifluoroacetic acid (6 mL) was added concentrated sulfuric acid (0.35 mL, 6.4 mmol) and the reaction was stirred at room temperature for 12 h. Ethyl acetate was added and the solution was neutralized by addition of an aqueous sodium hydroxide solution (2 N). The solution was extracted several times with ethyl acetate, and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography to provide (2-tert-butyl-2H-tetrazol-5-yl)-acetic acid ethyl ester (2.0 g, 52% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)=[O:18])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCc1cc(-c2ccc(C(=O)O)s2)c(C)[nH]c1=O
Reactant: c1ccc(CN2CCNCC2)cc1
Product: CCc1cc(-c2ccc(C(=O)N3CCN(Cc4ccccc4)CC3)s2)c(C)[nH]c1=O
Yield: 60 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-carboxylic acid and 4-benzyl-piperazine to afford the title compound (60% yield). LC/MS: RT 2.07 min; m/e 422 (M+H).
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.Cl.CN1CCOCC1.[NH:19]1[C:23]2[CH:24]=[C:25]([CH2:28][NH2:29])[CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1.[CH2:30]([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[CH2:39][NH:40][C:41]1[C:42](=[O:52])[N:43]([CH2:48][C:49](O)=[O:50])[C:44]([CH3:47])=[CH:45][N:46]=1)[CH:31]([CH3:33])[CH3:32]>CN(C)C=O>[NH3:7].[NH:19]1[C:23]2[CH:24]=[C:25]([CH2:28][NH:29][C:49](=[O:50])[CH2:48][N:43]3[C:44]([CH3:47])=[CH:45][N:46]=[C:41]([NH:40][CH2:39][C@H:35]4[CH2:36][CH2:37][CH2:38][N:34]4[CH2:30][CH:31]([CH3:32])[CH3:33])[C:42]3=[O:52])[CH:26]=[CH:27][C:22]=2[N:21]=[CH:20]1
Reactant: Cc1cnc(NC[C@H]2CCCN2CC(C)C)c(=O)n1CC(=O)O
Reactant: On1nnc2ccccc21
Reactant: NCc1ccc2nc[nH]c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cnc(NC[C@H]2CCCN2CC(C)C)c(=O)n1CC(=O)NCc1ccc2nc[nH]c2c1
Product: N
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
HOBT (25 mg, 0.19 mmol), WSCDl.HCl (31 mg, 0.16 mmol), N-methylmorpholine (41 ml, 0.37 mmol) and 1H-benzimidazol-6-ylmethylamine (21 mg, 0.14 mmol) were added to a solution of 2-[3-({[(2R)-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 62) (40 mg, 0.12 mmol) in N,N-dimethylformamide (2 ml), and the reaction was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and the residue preadsorbed on to silica gel, and then purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant to provide the title compound (6 mg, 10%).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(O)CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, rac-1-octyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 88 mg, 60%).
Reaction SMILES: NOC1C[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1.O[CH2:11][CH2:12][CH2:13][NH:14][NH:15][C:16]([NH:18]N)=O.[CH2:20]([OH:24])CCC>>[OH:24][CH2:20][CH2:11][CH2:12][C:13]1[N:18]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:16]2=[N:15][N:14]=1
Reactant: NOC1=CCCCCC1
Reactant: NNC(=O)NNCCCO
Reactant: CCCCO
Product: OCCCc1nnc2n1CCCCC2

Procedure:
To a solution (150 ml) of 1-aza-2-methoxy-1-cycloheptene (23.6 g) in butanol was added 3-hydroxypropylcarbohydrazide (23 g) with stirring, and the mixture was refluxed under heating for 3 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give 29 g of 3-(3-hydroxypropyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine. To a solution of this compound (0.98 g) in dimethylformamide (20 ml) were added triethylamine (1.4 ml) and methanesulfonyl chloride (0.62 ml) with stirring. Then, 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (1.28 g), potassium carbonate (1.38 g) and potassium iodide (0.83 g) were added and the mixture was stirred for 4 hours at 60° C. After the completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give 3-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.N1[CH:28]=[CH:27]C=CC=1.[OH-:29].[NH4+].O>C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([O:29][CH2:27][CH3:28])=[O:14])[CH:8]=3)[NH:4][N:5]=2)=[CH:17][CH:18]=1
Reactant: c1ccncc1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: [OH-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Yield: 100 %

Procedure:
To a solution of 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (100 mg, 0.33 mmol) in ethanol (40 mL) was added pyridine (0.5 mL). The reaction was stirred overnight at room temperature when saturated ammonium hydroxide (1 mL) was added. The reaction was stirred overnight when water (150 mL) was added and the solution filtered. The solid was dried to recover the product (100 mg, 100% yield). 1H NMR (DMSO-d6) δ 13.6 (s, 1H), 8.62 (s, 1H), 8.03–7.9 (m, 3H), 7.70 (d, 1H), 7.61 (d, 1H), 7.42 (t, 2H); ES-MS (m/z) 285 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.[CH2:45](C1C=C(C)C=CC=1S([O-])(=O)=O)[CH2:46]C1C=C(C)C=CC=1S([O-])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1COCC1.C(Cl)Cl>[N:1]1([CH2:2][C@:3]23[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]2[C@@H:5]2[C@@:18]([CH3:21])([CH2:19][CH2:20]3)[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:38])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[CH:11][CH2:10]4)[CH2:7][CH2:6]2)[CH2:46][CH2:45]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCc2cc(C)ccc2S(=O)(=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(CN3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C

Procedure:
tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aminomethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (200 mg, 0.667 mmol) was dissolved in DMF (10.00 mL) and THF (10.00 mL), ethane-1,2-diylbis(4-methylbenzenesulfonate) (247 mg, 0.667 mmol) was added, followed by K2CO3 (184 mg, 1.333 mmol) and the mixture was stirred at 100° C. until no starting material was detected by LCMS. An M+1=626.7 was observed by LC-MS. The reaction mixture was redissolved in CH2Cl2 (100 mL), washed by water (2×50 mL) and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo and the resultant residue was purified by silica gel chromatography using a mixture of ethyl acetate/hexanes. A white foam was obtained (130 mg, 65%) LCMS: m/e 426.7 (MH+), 4.393 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.90 (d, J=8.3 Hz, 2H), 7.24-7.11 (m, 2H), 5.30 (d, J=1.8 Hz, 1H), 4.70 (d, J=2.0 Hz, 1H), 4.60 (dd, J=2.3, 1.3 Hz, 1H), 2.56 (d, J=21.1 Hz, 1H), 2.44-2.33 (m, 1H), 2.26-2.05 (m, 3H), 2.04-1.89 (m, 1H), 1.86 (d, J=12.0 Hz, 1H), 1.82-1.58 (m, 18H), 1.56-1.37 (m, 7H), 1.35-1.21 (m, 6H), 1.19-1.06 (m, 6H), 1.03 (s, 3H), 0.99 (s, 3H), 0.93 (m, 6H)