Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[C:48]([CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH:50]([C:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)=[O:49])[CH2:51][CH2:52]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-[1-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[C:37]1[C:41]([CH2:42]O)=[C:40]([CH:44]([CH3:46])[CH3:45])[O:39][N:38]=1>ClCCl>[Cl:9][C:3]1[CH:4]=[C:5]([O:8][CH2:42][C:41]2[C:37]([C:31]3[C:30]([Cl:29])=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:36])=[N:38][O:39][C:40]=2[CH:44]([CH3:46])[CH3:45])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(O)cc1Cl
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-amino-3-chlorophenol (1.14 g, 7.9 mmol), triphenylphosphine (2.08 g, 7.9 mmol), [3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methanol (2.27 g, 7.9 mmol) in dichloromethane (20 mL) was treated with diisopropylazidodicarboxylate (1.57 mL, 7.9 mmol) dropwise. After stirring at ambient temperature for 16 h, the material was chromatographed on silica gel eluting with dichloromethane. Yield=1.73 g (53%) of 2-chloro-4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}aniline.
Reaction SMILES: ClCCC1C2C(=CC(OC)=C(OC)C=2)NC=1C(OCC)=O.C1(CC2CCCCN2)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH:41]1([CH2:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][N:49]2[CH2:54][CH2:55][C:56]2[C:64]3[C:59](=[CH:60][C:61]([O:67][CH3:68])=[C:62]([O:65][CH3:66])[CH:63]=3)[NH:58][C:57]=2[C:69]([O:71][CH2:72][CH3:73])=[O:70])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.[H-].[Na+].[Na].[C:77](Cl)(=[O:84])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>CN(C=O)C.CC(C)=O>[C:77]([N:58]1[C:59]2[C:64](=[CH:63][C:62]([O:65][CH3:66])=[C:61]([O:67][CH3:68])[CH:60]=2)[C:56]([CH2:55][CH2:54][N:49]2[CH2:50][CH2:51][CH2:52][CH2:53][CH:48]2[CH2:47][CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]2)=[C:57]1[C:69]([O:71][CH2:72][CH3:73])=[O:70])(=[O:84])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2cc(OC)c(OC)cc2c1CCN1CCCCC1CC1CCCCC1
Agent: C1CCC(CC2CCCCN2)CC1
Agent: CCOC(=O)c1[nH]c2cc(OC)c(OC)cc2c1CCCl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)c1c(CCN2CCCCC2CC2CCCCC2)c2cc(OC)c(OC)cc2n1C(=O)c1ccccc1

Procedure:
Reaction of 3-(2-chloroethyl)-5,6-dimethoxy-2-carbethoxyindole (U.S. Pat. No. 3,562,278) with 2-cyclohexylmethylpiperidine in refluxing acetone in the presence of sodium carbonate and reaction of the resulting 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5,6-dimethoxy-2-carbethoxyindole with sodium hydride in DMF followed by reaction of the resulting sodium salt with benzoyl chloride affords 1-benzoyl-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5,6-dimethoxy-2-carbethoxyindole.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4](NC([C@H]1CSCN1C(=O)C)=O)[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].Cl>O1CCCC1.[OH-].[Li+]>[CH3:23][N:14]1[C:13](=[O:24])[C:12]2([CH2:25][CH2:26][N:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:38])=[O:2])=[O:8])[CH2:10][CH2:11]2)[N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15]1
Reactant: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NC(=O)[C@H]1CSCN1C(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CN(c2ccccc2)C2(CCN(C(=O)NCCC(=O)O)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 176 mg (0.32 mmol) of 2-(((S)-3-acetylthiazolidin-4-carbonyl)amino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 4 ml of tetrahydrofuran, 4 ml of 0.1M aqueous lithium hydroxide solution was added, and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, 0.1M hydrochloric acid was added, and the resulting mixture was extracted with ethyl acetate. Organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was reprecipitated from ether/chloroform to obtain 130 mg of 2-(3-acetylthiazolidine-4-carbonyl)amino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid (yield: 76%).
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:12])=[CH:5][C:6](=[O:11])[C:7]=1[C:8]([OH:10])=[O:9].[NH3:13]>Cl>[CH3:1][C:2]1[N:13]=[C:4]([CH3:12])[CH:5]=[C:6]([OH:11])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: N
Reactant: Cc1cc(=O)c(C(=O)O)c(C)o1
Agent: Cl
Product: Cc1cc(O)c(C(=O)O)c(C)n1
Yield: 69 %

Procedure:
10 g (59.5 mmol) of 2,6-dimethyl-4-oxo-4H-pyran-3-carboxylic acid (prepared according to the method described in Collie, J. Chem. Soc.; 1907; 787) is stirred in 100 ml of 28% aqueous ammonia at room temperature overnight. The residue is diluted with little aqueous HCl, and the solid is filtered off. There is obtained 6.9 g (69% yield) of a solid.
Reaction SMILES: [Na+].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([O-:16])=O)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[N+:46]([C:49]1[CH:54]=[CH:53][C:52]([C@@H:55]([NH2:57])[CH3:56])=[CH:51][CH:50]=1)([O-:48])=[O:47]>CN(C=O)C>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([NH:57][CH:55]([C:52]2[CH:51]=[CH:50][C:49]([N+:46]([O-:48])=[O:47])=[CH:54][CH:53]=2)[CH3:56])=[O:16])=[CH:9][CH:10]=1)(=[NH:4])[NH2:3]
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Reactant: N=C(N)c1ccc(NC(=O)C(C(=O)[O-])c2ccccc2)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC(=O)C(C(=O)Nc1ccc(C(=N)N)cc1)c1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
75 mg (0.235 mmol) of the sodium salt from example 2 were dissolved in 2.5 ml DMF. 85 mg (0.265 mmol) TOTU in 2.5 ml DMF were added and stirred for 30 min at rt. Then 34 μl (0.265 mmol) NEM and 53.7 mg (0.265 mmol) of (S)-1-(4-nitrophenyl)-ethylamine in 0.5 ml of DMF was added and the mixture stirred at rt overnight. After filtration, the filtrate was evaporated to dryness and purified by prep. RP-HPLC.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]1[C@@H:9]([CH3:12])[CH2:10][OH:11].CO[C:15](OC)([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>ClCCl>[CH3:16][C:15]1([CH3:17])[O:11][CH2:10][C@H:9]([CH3:12])[C@H:4]2[C@@H:3]([C@@H:7]([CH3:8])[CH2:6][CH2:5]2)[CH2:2][O:1]1
Reactant: COC(C)(C)OC
Reactant: C[C@@H](CO)[C@H]1CC[C@H](C)[C@H]1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H]1COC(C)(C)OC[C@H]2[C@H]1CC[C@@H]2C
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.9 %

Procedure:
(2R)-2-[(1R, 2R, 3S)-2-(hydroxymethyl)-3-methylcyclopent-1-yl]propan-1-ol (100 mg, 0.00058 mol) (obtained in Definite Example 45) was dissolved in 5 ml of dichloromethane, and 2 ml of 2,2-dimethoxypropan and 5 mg of p-toluenesulfonic acid were added. After being stirred at room temperature for 12 hours, the reaction mixture was poured into 50 ml of ethyl acetate. After the organic layer was washed with an aqueous mixed solution of aqueous sodium bicarbonate (10 ml) and saturated sodium chloride solution (20 ml), it was dried by magnesium sulfate, filtered, and then concentrated under a reduced pressure. The residual substance was purified by a chromatography using silica gel. When the solvent of the fraction obtained from hexane:ether=8:2 eluent was distilled off, a colorless oily substance, i.e., (1R, 7R, 8S, 11S)-4,4,7,11-tetramethyl-3,5-dioxabicyclo[6.3.0]undecane (10 mg, yield=7.9%). This (1R, 7R, 8S, 11S)-4,4,7,11-tetramethyl-3,5dioxabicyclo[6.3.0]undecane had the following physicochemical properties:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:17])[C@H:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C@H:7]([OH:16])[CH2:6]1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CS(C)=O>[CH3:3][N:4]([CH3:17])[C@H:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C@H:7]([O:16][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH2:6]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CN(C)[C@H]1CCc2ccccc2[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)[C@H]1CCc2ccccc2[C@H](Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 104.2 %

Procedure:
14.4 ml of anhydrous dimethylsulfoxide were added at room temperature to 1.44 g of sodium hydride as a 50% dispersion in oil and the mixture was heated in a bath at 55° C. for one hour and was then cooled to 20° C. 5.13 g of trans 7-dimethylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-ol were added thereto and the mixture was stirred at room temperature for 10 minutes. Then, 4.73 g of p-chloro-nitrobenzene were added thereto all at once and the mixture was stirred at room temperature for 3 hours. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 9.5 g of raw product. The latter was extracted with 0.5 N hydrochloric acid and the neutral fraction was extracted twice with 100 ml of ether. The combined aqueous phases were made alkaline with a strong excess of ammonium hydroxide and were extracted with methylene chloride. The organic phase was dried over magnesium sulfate and filtered and the filtrate was evaporated to dryness under reduced pressure to obtain 8.5 g of trans N,N-dimethyl-5-[4-nitrophenoxy]-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-amine. The said product was dissolved in 20 ml of ethyl acetate and an excess of a solution of gaseous hydrogen chloride in ethyl acetate was added thereto. Crystallization was induced and the mixture was held in the refrigerator for 12 hours and was then vacuum filtered. The recovered precipitate was washed with methyl ethyl ketone and was dried at 100° C. under reduced pressure to obtain 5.5 g of the hydrochloride of the trans compound in the form of colorless crystals melting at 192°-196° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][C:12]([C:18]#[N:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.COC(OC(OC)=O)=O.[O-][Si]([O-])=O.[Mg+2]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O1CCOCC1>[CH2:1]([O:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][C:12]([C:18]#[N:19])=[C:13]([C:14](=[O:16])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[F:22])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: COc1cc(C#N)c(C(=O)O)cc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)OC(=O)OC
Agent: O=[Si]([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(C#N)c(C(=O)c2ccccc2F)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1.25 h
Yield: 52.8 %

Procedure:
A mixture of 5-benzyloxy-2-cyano-4-methoxybenzoic acid (reference example 5-3) (502 mg), 2-fluorophenylboronic acid (297 mg), tetrakis(triphenylphosphine)palladium(0) (205 mg), dimethylpyrocarbonate (2 mL) and 1,4-dioxane (10 mL) was stirred at 80° C. under an argon atmosphere for 1.25 hours. Ethyl acetate and Florisil (registered mark) (2 g) were added. After stirring for 15 minutes, the mixture was passed through a layer of Celite (registered mark). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5%-30% ethyl acetate/hexane, gradient elution) to give the title compound (338 mg).
Reaction SMILES: [C:1]1([C:7]2([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:20][CH2:21][CH2:22][CH2:23][C:24]([NH:13][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:25]
Reactant: O=C(Cl)CCCCl
Reactant: NC1(c2ccccc2)CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCCCl)NC1(c2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Dissolve 1-phenyl-cyclohexylamine (Preparation 28) (0.41 g, 2.32 mmol) in dichloromethane (50 mL) and cool to 0° C. Add pyridine (1.18 g, 11.61 mmol) and 4-chloro-butyryl chloride (0.65 g, 4.64 mmol). Stir the reaction mixture for one hour under nitrogen. Add water (50 mL), and extract the aqueous layer with ethyl acetate (3×100 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 10-50% of EtOAc/Hexane) to give 0.58 g (89%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([O:24]C4C=CC=CC=4)=O)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=4)[C:13]3=[O:32])=[N:9]2)=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C(#N)C.C(Cl)Cl.C(OCC)(=O)C>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:22]([O:21][CH:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=3)[C:13](=[O:32])[N:12]2[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)=[O:24])[CH2:36][CH2:35]1
Reactant: O=C(Oc1ccccc1)OC1c2cc(Cl)ccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)OC2c3cc(Cl)ccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 59.2 %

Procedure:
The procedure of Example 11 is followed but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-phenoxycarbonyloxy-isoindolin-1-one (1.25 g.) and 4-methylpiperazine (1.07 g.) in acetonitrile (33 cc.) and stirring for 24 hours at a temperature of about 20° C. From the reaction mixture, the resulting precipitate is filtered off and washed successively with acetonitrile (6 cc.) and diethyl ether (6 cc.). The product obtained (0.93 g.) is dissolved in methylene chloride (35 cc.), and the solution passed through a column of silica gel (10 g.). Elution is carried out with methylene chloride (16 × 20 cc.); the corresponding eluates are discarded. Elution is the carried out with ethyl acetate (5 × 20 cc.); the corresponding eluates are combined and concentrated under reduced pressure. A crystalline residue (0.9 g.) is obtained and is suspended in ethyl acetate (20 cc.). The crystals are filtered off and dried to yield 3-(4methylpiperazin-1-yl)carbonyloxy-5-chloro- 2-(7-chloro-1,8-naphthyridin-2-yl)isoindolin-1-one (0.75 g.) melting at 255° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[CH3:24][S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:24][S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CSc1ccccc1C(=O)O
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2ccccc2SC)n1
Temperature: 150 °C
Yield: 29.9 %

Procedure:
A solution was prepared using 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol), 2-(methylthio)benzoic acid (0.076 g, 0.463 mmol), HATU (0.176 g, 0.463 mmol), triethylamine (1.0 mL, 13.6 mmol) and anhydrous DMF (10 mL). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.042 g (30% yield) of pure product: MS (ES) m/z 456 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:22])=[N:11][C:12]([O:16][CH:17]([CH3:21])[C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][CH3:37])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:30]1[CH2:35][CH2:34][CH:33]([N:36]([CH3:37])[C:18](=[O:20])[CH:17]([O:16][C:12]2[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:22])[N:11]=2)[CH3:21])[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: Cc1nc(OC(C)C(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OC(C)C(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 12 and 1-benzyl-N-methylpiperidine-4-amine in the same manner as in Example 49.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=5)[CH:20]=4)[OH:15])=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccc(Cl)cc2)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccc(Cl)cc5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:1]1([C:10]2[CH:11]=[CH:12][C:13]3[C:11]4[C:10](=[CH:9][C:8]([C:14]5[CH2:5][CH2:6][CH2:1][CH2:2][CH:3]=5)=[CH:13][CH:12]=4)[CH2:14][C:8]=3[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: O=C1CCCCC1
Product: C1=C(c2ccc3c(c2)Cc2cc(C4=CCCCC4)ccc2-3)CCCC1

Procedure:
The compound 2,7-di(1-cyclohex-1-enyl)fluorene can be prepared by first forming a Grignard reagent from 2,7-diiodofluorene and magnesium and bromoethane in THF by heating for several days in a Schlenk tube at about 60°-90° C. Then cyclohexanone is added. After acidic workup in hot toluene, the 2,7-dicyclohexenyl fluorene is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:27])[C:12]2[CH:17]=[C:16]([CH:18]=C)[CH:15]=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)[CH:13]=2)[CH3:9])=[N:6][CH:7]=1.I([O-])(=O)(=O)=[O:29].[Na+].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:27])[C:12]2[CH:13]=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)[CH:15]=[C:16]([CH:18]=[O:29])[CH:17]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(C(=O)N[C@H](C)c2ccc(F)cn2)cc(-c2ccc(C)cn2)c1
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C=O)cc(C(=O)N[C@H](C)c3ccc(F)cn3)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
To a solution of N-[(1R)-1-(5-fluoro-2-pyridinyl)ethyl]-3-(5-methyl-2-pyridinyl)-5-vinylbenzamide (1.14 g, 3.15 mmol) in tetrahydrofuran (11 mL) and water (11 mL) were added sodium periodate (2.0 g, 9.45 mmol) and osmium tetroxide (2.5% in tert-butanol, 2.0 mL, 0.157 mmol). The reaction mixture was stirred at ambient temperature for 18 h. Saturated aqueous sodium sulfite and saturated aqueous sodium bicarbonate were added. The mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (1.1 g). MS 364.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH2:25]([N:27]([CH2:39][CH3:40])[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29])[CH3:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:34]=[CH:35][C:30]([C:28]([N:27]([CH2:25][CH3:26])[CH2:39][CH3:40])=[O:29])=[CH:31][CH:32]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CCN(CC)C(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCN(CC)C(=O)c1ccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)cc1
Temperature: 120 °C
Yield: 27.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(diethylcarbamoyl)phenylboronic acid (23 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydro-spiro[chroman-4,4′-imidazole]-6-yl)-N,N-diethylbenzamide (6.95 mg, 28%). 1H-NMR (MeOD): 1.13 (s, 3H), 1.24 (d, 3H), 2.13 (d, 1H), 2.30 (s, 1H), 3.17 (s, 3H), 3.32 (d, 4H), 5.91 (d, 1H), 7.03 (d, 1H), 7.22 (s, 1H), 7.33 (m, 1H), 7.40 (m, 4H), 7.49 (m, 2H), 7.51 (m, 1H), 7.57 (m, 2H).