Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]([CH3:14])[C:7](=[CH2:15])[C:6]2([CH3:17])[CH3:16].COC1C=C2C(=CC=1)N(CCCCCC)C1(C=[CH:38][C:37]3[CH:40]=[C:41]([N+:46]([O-:48])=[O:47])[CH:42]=[C:43]([O:44][CH3:45])[C:36]=3[S:35]1)C2(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]([CH3:14])[C:7]1([CH:15]=[CH:38][C:37]3[CH:40]=[C:41]([N+:46]([O-:48])=[O:47])[CH:42]=[C:43]([O:44][CH3:45])[C:36]=3[S:35]1)[C:6]2([CH3:17])[CH3:16]
Reactant: C=C1N(C)c2c(OC)cc(OC)cc2C1(C)C
Reactant: CCCCCCN1c2ccc(OC)cc2C(C)(C)C12C=Cc1cc([N+](=O)[O-])cc(OC)c1S2
Product: COc1cc(OC)c2c(c1)C(C)(C)C1(C=Cc3cc([N+](=O)[O-])cc(OC)c3S1)N2C
Yield: 147 %

Procedure:
3.4 g of the indoline and 3.2 g of the 3-methoxy-5-nitrosalicylaldehyde obtained in Example 2 were reacted in the same manner as in Example 2 to obtain 4.3 g of intended 5',7'-dimethoxy-1',3',3'-trimethyl-6-nitro-8-methoxyspiro[2H-1-benzothiopyran-2,2'-indoline] (yield 69%, melting point 131° C.).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH2:22]([P:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([O:35][CH3:36])[CH:29]=1)([CH2:26][CH3:27])=[O:25])[CH3:23].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([P:24]([CH2:26][CH3:27])([CH2:22][CH3:23])=[O:25])=[CH:29][C:30]=2[O:35][CH3:36])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Reactant: CCP(=O)(CC)c1ccc(N)c(OC)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: CCP(=O)(CC)c1ccc(Nc2nnc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC)c1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(Diethylphosphoryl)-2-methoxyaniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:12][CH:11]([CH3:13])[N:10]([CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH2:24][C:25]([OH:27])=[O:26])[CH:20]=[CH:21][C:22]=3[CH3:23])[CH:9]([CH3:28])[CH2:8]2)=[N:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[C:2]1[S:6][C:5]([N:7]2[CH2:12][CH:11]([CH3:13])[N:10]([CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]([CH2:24][C:25]([OH:27])=[O:26])[CH:20]=[CH:21][C:22]=3[CH3:23])[CH:9]([CH3:28])[CH2:8]2)=[N:4][CH:3]=1
Reactant: Cc1ccc(CC(=O)O)cc1OCCN1C(C)CN(c2ncc(Br)s2)CC1C
Reactant: OB(O)c1cc(F)ccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CC(=O)O)cc1OCCN1C(C)CN(c2ncc(-c3cc(F)ccc3F)s2)CC1C
Yield: 86.1 %

Procedure:
A mixture of [3-[2-[4-(5-bromothiazole-2-yl)-2,6-dimethyl piperazine-1-yl]ethoxy]-4-methylphenyl]acetic acid (400 mg), 2,5-difluorophenyl boronic acid (270 mg), tetrakis(triphenylphosphine) palladium (100 mg), 1M sodium carbonate (4.3 mL) and dimethylformamide (8 mL) was reacted with a microwave reaction device at 180° C. for 5 minutes. To the reaction solution was added water and extracted with chloroform. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel to give the title compound (369 mg). Yield: 87%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]([OH:24])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.O[NH:31][C:32](=[NH:34])[CH3:33].C(N(CC)C(C)C)(C)C>C(Cl)Cl.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]2[O:24][N:34]=[C:32]([CH3:33])[N:31]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=N)NO
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OCC(=O)O)C1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(COc2ccc(Cl)cc2OC2CN(C(=O)OC(C)(C)C)C2)n1
Temperature: 155 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To the title compound of Step B (0.15 g, 0.42 mmol) in CH2Cl2 (4 mL) was added DMF (catalytic) and 2M COCl2 in CH2Cl2 (0.3 mL, 0.6 mmol). After 2 h, the reaction was concentrated and THF (2 mL) was added. This solution was added to N-hydroxy-acetamidine (0.035 g, 0.46 mmol) and N,N-diisopropylethylamine (0.065 g, 0.088 mL, 0.50 mmol) in THF (2 mL). The mixture was then heated for 20 min at 155° C. in a microwave reactor, cooled to rt and concentrated. Silica gel chromatography (5-30% EtOAc in hexanes) gave 0.155 g (93%) of the title compound as a clear oil. MS (ESI): mass calcd. for C18H22ClN3O6, 395.1; m/z found, 295.3 [M-100]+. 1H NMR (400 MHz): 6.94 (d, J=8.6 Hz, 1H), 6.91 (dd, J=8.6, 2.2 Hz, 1H), 6.57 (d, J=2.1 Hz, 1H), 5.27 (s, 2H), 4.89-4.85 (m, 1H), 4.32-4.29 (m, 2H), 4.04 (dd, J=10.4, 4.2 Hz, 2H), 2.43 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][NH2:12])=[C:4]([F:10])[S:5][C:6]=1[CH2:7][C:8]#[CH:9].CC[O:15][C:16]([CH:18]1[C:23](=O)[CH2:22][CH2:21][CH2:20][CH2:19]1)=O.C(O)(=O)C>O>[Cl:1][C:2]1[C:3]([N:11]2[C:16](=[O:15])[CH:18]3[C:19]([CH2:20][CH2:21][CH2:22][CH2:23]3)=[N:12]2)=[C:4]([F:10])[S:5][C:6]=1[CH2:7][C:8]#[CH:9]
Reactant: C#CCc1sc(F)c(NN)c1Cl
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: CC(=O)O
Solvent: O
Product: C#CCc1sc(F)c(N2N=C3CCCCC3C2=O)c1Cl
Yield: 56.1 %

Procedure:
A mixture of 4-chloro-2-fluoro-5-propargylthiophenylhydrazine (1.2 g), ethyl 2-cyclohexanonecarboxylate (0.85 g) and acetic acid (10 ml) was heated under reflux for 2 hours, followed by cooling. Water was added thereto, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and a saturated sodium hydrogen carbonate solution, dried and concentrated. The residue was crystallized from a mixture of n-hexane and ether to give 0.87 g of 2-(4-chloro-2-fluoro-5-propargylthiophenyl)-3,3a,4,5,6,7-hexahydro-2H-indazol-3-one. M.P., 170°-171° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.CN(C)C=O.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25]>O>[N+:24]([C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[CH3:1])([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: C[C@H]1CCCCN1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CCCCN1c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 99.2 %

Procedure:
(S)-2-methylpiperidine (270 μl, 2.24 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (211 mg, 1.00 mmol, commercially available product). The resulting mixture was stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=12/1). Thus, (S)-1-[2-nitro-4-(trifluoromethyl)phenyl]-2-methylpiperidine (286 mg, 99.2%) was yielded as an orange-colored oily material.
Reaction SMILES: C1(C([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]2=[O:21])=[O:11])=O)CCCCC1.Cl.[OH-:23].[K+]>>[NH:12]([C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:14][C:13]([OH:21])=[O:23])[C:10]([NH2:9])=[O:11]
Reactant: O=C(NC(=O)N1C(=O)Cc2ccccc21)C1CCCCC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: NC(=O)Nc1ccccc1CC(=O)O

Procedure:
A slurry of 2.9 g (0.01 mole) of N-cyclohexylcarbonyl-2-oxindole-1-carboxamide in 50 ml of 1N potassium hydroxide solution was stirred at room temperature for ca. 30 minutes, during which time the solid went into solution. At this point, the reaction mixture was acidified with concentrated hydrochloric acid, with ice cooling, and then it was extracted with ethyl acetate. The extracts were washed with saturated sodium chloride solution, dried (Na2SO4) and evaporated in vacuo to give an oily solid. The oily solid was washed with diisopropyl ether and then it was recrystallized from ethanol to give 70 mg of the title compound, m.p. 174.5° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[C:16]([C:18]1[CH:19]=[C:20]([CH:36]([CH3:38])[CH3:37])[C:21]2[O:25][C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH:35]=1)#[N:17]>>[C:16]([C:18]1[CH:19]=[C:20]([CH:36]([CH3:38])[CH3:37])[C:21]2[O:25][C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][CH:3]4[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]4)=[O:31])=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH:35]=1)#[N:17]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CN(C(=O)OC(C)(C)C)CCO4)cc3)oc12

Procedure:
The title compound was then prepared from tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (48 mg) and 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid, INTERMEDIATE 2) as described in EXAMPLE 35. Mass spectrum (ESI) 505.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:7](=[O:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:5]2.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.CC(C)([O-])C.[Na+]>N1C=CC=CC=1.CCCCCC.C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].C(OCC)(=O)C>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=2)[C:7](=[O:15])[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH2:5]3)[CH2:31][CH2:30]1
Reactant: O=C1c2c(cc(Br)cc2C(F)(F)F)CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: CN1CCNCC1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1=CCCC=CCC1
Solvent: CCCCCC
Product: CN1CCN(c2cc3c(c(C(F)(F)F)c2)C(=O)N(Cc2ccc(OC(F)(F)F)cc2)C3)CC1
Yield: 31.3 %

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethoxy-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.110 g, 0.25 mmol), 1-methyl piperazine (0.037 mL, 0.33 mmol), Ni(COD)2 (0.013 g, 0.004 mmol), 1,10-phenanthroline (0.005 g, 0.025 mmol), and sodium tertiary-butoxide (0.034 g, 0.35 mmol) in pyridine (2 mL) was heated to reflux for 3 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-(4-methyl-piperazin-1-yl)-2-(4-trifluoromethoxy-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.037 g, 31%). 1H NMR (300 MHz, CDCl3/CD3OD): δ (ppm) 2.26 (s, 3H), 2.52 (m, 2H), 2.80 (m, 4H), 3.40 (m, 2H), 4.36 (s, 2H), 4.76 (s, 2H), 7.20-7.52 (m, 6H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Reactant: NCc1ccc(Oc2ccc(Cl)cc2)cc1
Product: O=c1c(NCc2ccc(Oc3ccc(Cl)cc3)cc2)c(Nc2cccnc2)c1=O
Yield: 68 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and 4-(4-chlorophenoxy)-benzylamine.
Reaction SMILES: [Li]CCCC.[O:6]1[C:10]2([CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1.[C:21](=[O:23])=[O:22]>C1COCC1>[O:9]1[C:10]2([CH2:15][CH2:14][CH:13]([C:16]3[S:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][N:20]=3)[CH2:12][CH2:11]2)[O:6][CH2:7][CH2:8]1
Reactant: c1csc(C2CCC3(CC2)OCCO3)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cnc(C2CCC3(CC2)OCCO3)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 5 mL, 12 mmol) was added dropwise into 2-(1,4-dioxa-spiro[4.5]dec-8-yl)-thiazole (2.50 g, 11 mmol) in THF (10 mL) at −78° C. The reaction was kept at −78° C. for 30 min. The solution was added to solid dry ice (˜5 g) dropwise. After addition, the reaction was warmed to room temperature slowly over 1 hour and quenched with 1 N NaOH (˜10 mL) solution. The solvent was removed and the residue was partitioned between ether and water. The aqueous layer was adjusted to pH=6 with 5% HCl and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as white solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:13][CH:14]=2)[CH:5]=1.[OH-].[Na+]>>[S:15]([C:12]1[S:11][C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:19])=[O:2])=[CH:14][CH:13]=1)(=[O:18])(=[O:17])[NH2:16]
Reactant: COC(=O)c1cccc(-c2ccc(S(N)(=O)=O)s2)c1
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(-c2cccc(C(=O)O)c2)s1

Procedure:
The title compound was prepared by hydrolyzing 3-(5-sulfamoyl-2-thienyl)benzoic acid methyl ester prepared above with an aqueous sodium hydroxide solution in accordance with a routine method.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[CH:20]([N-]C(C)C)([CH3:22])[CH3:21].[Li+].C(I)C=C.[Cl-].[NH4+]>C1COCC1>[CH2:22]([C:4]1([C:3]([O:2][CH3:1])=[O:19])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:20]=[CH2:21]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: C=CCI
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-benzyloxycarbonylproline methyl ester (13 g) in THF (20 ml) was added dropwise to lithium diisopropylamide (27.5 ml, 2M in hexane/THF) in THF (100 ml) at −78° C. under nitrogen. The mixture was stirred for 30 minutes and then allyl iodide (5.5 ml) was added dropwise and the mixture stirred for a further 30 minutes and then allowed to warm to ambient temperature. The mixture was then added to aqueous ammonium chloride (200 ml) and extracted with ether (2×200 ml). The ether layer was evaporated and the residue was purified by chromatography on silica using a gradient of hexane increasing to 20% ethyl acetate:hexane. The appropriate fractions, evaporated to dryness, gave methyl (RS)-2-allyl-N-(benzyloxycarbonyl)prolinate (9 g) as an oil.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.O[C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][C:23]([OH:30])=[CH:24][CH:25]=3)[C:20]([CH3:32])([CH3:31])[C:19]=2[CH:18]=1.B(O)(O)O>C1(C)C(C)=CC=CC=1>[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][C:17]2[CH:29]=[CH:28][C:27]3[C:26]4[C:21](=[CH:22][C:23]([O:30][C:11](=[O:12])[C:10]5[CH:14]=[CH:15][C:7]([OH:6])=[CH:8][CH:9]=5)=[CH:24][CH:25]=4)[C:20]([CH3:32])([CH3:31])[C:19]=3[CH:18]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC1(C)c2cc(O)ccc2-c2ccc(O)cc21
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1C
Product: CC1(C)c2cc(OC(=O)c3ccc(O)cc3)ccc2-c2ccc(OC(=O)c3ccc(O)cc3)cc21
Yield: 85.4 %

Procedure:
In a nitrogen atmosphere, concentrated sulfuric acid (0.2 mL) was added to a mixture of 4-hydroxybenzoic acid (12.2 g), 2,7-dihydroxy-9,9-dimethylfluorene (10.0 g), boric acid (0.3 g) and xylene (120 mL), and the mixture was heated under reflux for 6 hours while removing water. A deposited matter was filtered and rinsed with toluene. It was recrystallized from a mixed solvent of ethanol (75 mL) and acetone (75 mL) to provide 2,7-bis(4-hydroxybenzoyloxy)-9,9-dimethylfluorene (compound [H2]) (17.6 g) in the form of pale rose solid.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[C:1]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-(4-chlorophenyl)piperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(Cl)c(OCC2CO2)c1
Reactant: CC1CC(=O)NN=C1c1ccc(OCCN)cc1
Product: Cc1ccc(Cl)c(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3C)cc2)c1

Procedure:
Prepared analogously to Example 1 from 1-(2-chloro-5-methylphenoxy)-2,3-epoxypropane and 6-[4-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[N:6][CH:7]=1.[CH:29](OCC)(OCC)OCC>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[N:28]=[CH:29][N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(COc2ccc(CNc3ncc(I)cc3N)cc2OC)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a stirred suspension of 5-iodo-N2-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)pyridine-2,3-diamine (11.67 g, 23.70 mmol) in ethanol (175 mL) was added triethyl orthoformate (8.90 g, 60.05 mmol) and p-toluenesulfonic acid monohydrate (0.23 g, 1.19 mmol). As the mixture was warmed to reflux, the solids dissolved to provide a brown solution. After 30 min, the reaction mixture was cooled to 0° C., resulting in the formation of a precipitate. The solids were isolated by filtration, washed with a small amount of cold ethanol, and dried to provide 10.34 g (87%) of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH3:11])=[C:9]([C:12](=[O:14])[CH3:13])[N:8]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>O1CCOCC1.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].O>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:2]3[N:3]=[CH:4][C:5]4[C:10]([CH3:11])=[C:9]([C:12](=[O:14])[CH3:13])[N:8]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:6]=4[N:7]=3)=[CH:22][CH:23]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CC(=O)c1c(C)c2cnc(Cl)nc2n1C1CCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc2n1C1CCCC1
Temperature: 80 °C
Yield: 24.1 %

Procedure:
A solution of 1-(2-Chloro-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-ethanone (40 mg, 0.144 mmol), 1-[4-(4-Amino-phenyl)-piperazin-1-yl]-ethanone (37.9 mg, 0.172 mmol), Pd2(dba)3 (6.7 mg, 0.007 mmol), BINAP (9.15 mg, 0.014 mmol) and NaOtBu (20.7 mg, 0.216 mmol) in 1,4-dioxane (4 mL) is degassed and back-filled with nitrogen three times. The reaction mixture is heated to 80° C. for 2 hours. After cooling to room temperature water is added and the reaction mixture is extracted with ethyl acetate three times. The organic layers are combined, washed with brine and dried over anhydrous sodium sulfate. The solvent is evaporated and the crude material is purified by preparative HPLC to provide 1-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-7-cyclopentyl-5methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-ethanone (16 mg, 24%). [M+H]+=461.13.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=O>C(O)=O.[Zn]>[Cl:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)c2cccc(Cl)c2)CC1
Agent: Cl
Agent: [Zn]
Solvent: O=CO
Product: O=C(O)C1CCC(Cc2cccc(Cl)c2)CC1
Temperature: 25 °C

Procedure:
In a 50 ml beaker, Zn dust (3.6 g; 54 mmol) was added to 1N HCl and mixture was stirred with a glass rod. Aqueous was decanted off and solids were added to a mixture of trans-4-(3-chlorobenzoyl)cyclohexane-1-carboxylic acid (718 mg; 2.69 mmol) in 30 mL of formic acid. Mixture was heated to reflux for 2 hours. The reaction was cooled to room temperature and white solids were filtered off and rinsed with diethyl ether. Filtrate was concentrated and residue was taken up in a 40 mL mixture of diethyl ether and water (1:1). Organics were separated and aqueous was re-extracted with 2×20 mL of diethyl ether. Combined organics were washed with sat. NaHCO3, water, brine, and dried over MgSO4. Title compound was obtained as a crude oil. 550 mg (81% crude yield).