Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[C:33]([CH3:35])[N:32]=[C:31]([CH3:36])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:31]1[CH:30]=[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:37])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:15])([F:17])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[C:33]([CH3:35])[N:32]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M109) (0.26 g, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (110 mg, 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16](O)=[O:17])=[CH:11][C:10]=1[OH:20].S(Cl)(Cl)=O.[NH3:25]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([NH2:25])=[O:17])=[CH:11][C:10]=1[OH:20]
Reactant: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)c(O)c1
Reactant: N
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C(N)=O)c1ccc(-c2ccc(F)cc2F)c(O)c1

Procedure:
A solution of 2-(2',4'-difluoro-2-hydroxy-4-biphenylyl)propionic acid (1.75 g.) and thionyl chloride (1 ml.) in dry benzene (10 ml.) was refluxed for 1 hour and then cooled and added dropwise to stirred cold ammonia (d=0.880 g./ml; 20 ml.). The product was filtered and recrystallised first from aqueous industrial methylated spirits and then light petroleum (b.p. 62°-68° C.) to give 2-(2',4'-difluoro-2-hydroxy-4-biphenylyl)propionamide, m.p. 222°-224° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:15][N:16]1[CH:23]2[CH:19]([N:20]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)[CH2:18][CH2:17]1>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([N:20]3[CH2:21][CH2:22][CH:23]4[N:16]([CH3:15])[CH2:17][CH2:18][CH:19]34)=[CH:29][CH:28]=2)=[O:12])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN1CCC2C1CCN2c1ccc(N)cc1
Reactant: CCCCOc1ccc(C(=O)O)cc1
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC4C3CCN4C)cc2)cc1

Procedure:
4-Butoxybenzoic acid was reacted with 4-(4-methylhexahydropyrrolo[3,2-b]pyrrol-1-yl)phenylamine by method E. The product with the molecular weight of 393.53 (C24H31N3O2); MS (ESI): 394 (M+H+) was obtained in this way.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19](O)[CH:20]=[CH:21][C:22]3[CH:31]=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)CC.Cl.[Cl-].[Na+].O.[C:44]([CH3:54])(OCC)([O:48]CC)[O:45][CH2:46][CH3:47]>>[CH2:46]([O:45][C:44](=[O:48])[CH2:54][CH:21]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][CH2:7][C:6]2[CH:33]=[CH:34][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=1)[CH3:47]
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc(CNc2cccc(CCCCC(O)C=Cc3cnc4ccccc4n3)n2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: O
Product: CCOC(=O)CC(C=CCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cnc2ccccc2n1
Temperature: 150 °C
Yield: 48 %

Procedure:
A solution of the allylic alcohol 22-3 (0.26 g, 0.57 mmol) in (EtO)3CMe (10 mL) was treated with 100 μL of a 1 mL solution of (EtO)3CMe containing 10 μL of propionic acid. The yellow solution was heated at 150° C. for 90 minutes. The solution was cooled to room temperature and poured into 1N HCl/brine. The mixture was extracted with CHCl3, dried, concentrated, and purified on silica gel (90:5:5 CHCl3:EtOAc:MeOH) to give 0.143 g (48%)of 22-4.
Reaction SMILES: [C:1](S)(=S)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O.C1(C)C=CC=CC=1.CC1C=CC2[S:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:33])C=2C=1.CC1C=CC2C(=O)C3C(SC=2C=1)=CC=CC=3>S(=O)(=O)(O)O.O>[CH3:1][C:2]1[C:3]2[C:22](=[O:33])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:29][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccccc1C(=S)S
Reactant: Cc1ccc2sc3ccccc3c(=O)c2c1
Agent: Cc1ccc2c(=O)c3ccccc3sc2c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc2sc3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dithiosalicylic acid [product of Wako Pure Chemical Industries, Ltd.] (10 parts) was dissolved in sulfuric acid (139 parts), and the solution was stirred at room temperature (about 25° C.) for one hour and then cooled in an ice bath. Toluene (25 parts) was added dropwise in small portions to the cooled solution, while the temperature of the cooled solution was controlled to 20° C. or lower. Thereafter, the temperature was recovered to room temperature (about 25° C.), and the solution was further stirred for two hours. The resulting reaction mixture was added in small portions to water (815 parts), and precipitated yellow solids were filtered. The yellow solids were dissolved in dichloromethane (260 parts). To the resulting solution, water (150 parts) was added, and then 24% KOH aqueous solution (6.7 parts) was added to alkalinize the aqueous phase. After stirring the resulting mixture for one hour, the aqueous phase was removed by a separation operation, and the organic phase was washed with water (130 parts) three times. Then, the organic phase was dried over anhydrous sodium sulfate, and the organic solvent was evaporated under reduced pressure. As a result, 8.7 parts of an intermediate (C122-2-1) was obtained (as yellow solids). The intermediate (C122-2-1) was a mixture of 2-methylthioxanthone and 3-methylthioxanthone.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:25][C:13]1[S:12][C:11]2[CH:26]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:8]=[CH:9][C:10]=2[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: C1CCNCC1
Product: Cc1sc2cc(OCCCCN3CCCCC3)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and piperidine were converted to yield 1-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-piperidine as yellowish oil, MS: 448 (MH+).
Reaction SMILES: [CH2:1]([CH:4]1[C:9]([CH3:11])([CH3:10])[NH:8][C:7]([CH3:13])([CH3:12])[CH:6]=[C:5]1N1CCCCC1)[CH:2]=[CH2:3].C([O-])(=[O:22])C.[Na+].C(=O)(O)[O-].[Na+].N>C(O)(=O)C.O>[CH2:1]([CH:4]1[C:5](=[O:22])[CH2:6][C:7]([CH3:13])([CH3:12])[NH:8][C:9]1([CH3:11])[CH3:10])[CH:2]=[CH2:3]
Reactant: CC(=O)[O-]
Reactant: C=CCC1C(N2CCCCC2)=CC(C)(C)NC1(C)C
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CCC1C(=O)CC(C)(C)NC1(C)C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
1.46 g of the 5-allyl-1,2,5,6-tetrahydro-2,2,6,6-tetramethyl-4-piperidinopyridine thus obtained were dissolved in a mixture of 3 ml of acetic acid, 1.5 g of sodium acetate and 3 ml of water, and the solution was allowed to stand overnight. To the solution were then added 6.0 g of sodium bicarbonate and 3 ml of concentrated aqueous ammonia; the mixture was then extracted with hexane. The extract was dried over anhydrous magnesium sulphate and then treated with charcoal. 0.91 g of the title compound was obtained after removal of the hexane. The compound showed a single spot on thin layer chromatography using a 0.25 mm thick layer of alumina and a mixture of benzene/hexane/ethyl acetate/triethylamine (2:2:1:0.5 by volume) as developing solvent; Rf value 0.70.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([CH:7]([F:9])[F:8])[S:4][C:3]=1[CH:10]=[O:11].[C:12]([Mg]Br)#[CH:13]>>[Cl:1][C:2]1[CH:6]=[C:5]([CH:7]([F:8])[F:9])[S:4][C:3]=1[CH:10]([OH:11])[C:12]#[CH:13]
Reactant: O=Cc1sc(C(F)F)cc1Cl
Reactant: C#C[Mg]Br
Product: C#CC(O)c1sc(C(F)F)cc1Cl

Procedure:
Using the procedure of Stage B of Preparation 2, 0.64 g of the product of Stage C above and 8.5 ml of ethynyl magnesium bromide were reacted to obtain 0.67 g of the expected product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH:22]([CH3:27])[CH2:23][C:24]([OH:26])=[O:25])[CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([CH3:28])[CH:4]=1)#[N:2].[OH-:29].[Na+].OO>CS(C)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH:22]([CH3:27])[CH2:23][C:24]([OH:26])=[O:25])[CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([CH3:28])[CH:4]=1)(=[O:29])[NH2:2]
Reactant: [OH-]
Reactant: COc1ccc(-c2ccn(C(C)CC(=O)O)c2-c2ccc(C#N)cc2C)cc1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2ccn(C(C)CC(=O)O)c2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of the crude 3-(2-(4-cyano-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)butanoic acid (120 mg) in DMSO (5 mL) was added a solution NaOH (26 mg, 0.65 mmol) in a mixture of water (0.5 mL) and H2O2 (0.33 mmol). After being stirred at room temperature for 2 hours, the mixture was purified by preparative HPLC to give 26 mg of 3-(2-(4-carbamoyl-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)butanoic acid (yield 20% in two steps) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:15]([N:18]([CH2:23][CH:24]=[CH2:25])[S:19]([NH2:22])(=[O:21])=[O:20])[CH2:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:22][S:19]([N:18]([CH2:23][CH2:24][CH3:25])[CH2:15][CH:16]=[CH2:17])(=[O:21])=[O:20])=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: C=CCN(CCC)S(N)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CCC)S(=O)(=O)NC(=O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At from −5° C. to 0° C., 11.62 g (0.0474 mol) of 2-chloro-4-fluoro-5-nitrobenzoyl chloride in 50 ml methylene chloride were added with stirring, over 30 minutes, to a mixture of 8.50 g (0.048 mol) of N′-propyl-N′-allylsulfamide, 10.38 g (0.103 mol) of triethylamine and 0.09 g (0.736 mmol) of 4-N,N-dimethylaminopyridine in 90 ml of methylene chloride. The funnel was rinsed with 10 ml of the solvent. The mixture was initially stirred at 0° C. for 1 hour and then at 22° C. for 2 hours. 50 ml of 1N hydrochloric acid were then added, the mixture was stirred and the phases were separated. The organic phase was washed two more times with 1N hydrochloric acid and the aqueous phase was extracted with methylene chloride. Drying of the organic phase over magnesium sulfate was followed by filtration and concentration of the solution. The residue was triturated with diethyl ether/pentane, filtered off with suction and dried, giving 18.41 g (91.9% of theory) of the title compound of melting point (m.p.) of 110-112° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]1(B2OC(C)(C)C(C)(C)O2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=1>>[NH2:30][C:29]1[S:28][C:27]([CH:39]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: CC1(C)OB(C2=CCCCCC2)OC1(C)C
Product: Cn1ncc(NC(=O)c2nc(C3CCCCCC3)sc2N)c1N1CCC(CN)CC1
Yield: 30 %

Procedure:
Following the procedure for Example 281 starting with tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 1-cycloheptenylboronic acid pinacol ester gave 299 as an off-white solid (24 mg, 30% over three steps). 1H NMR (400 MHz, d4-MeOD) δ 7.46 (s, 1H), 3.72 (s, 3H), 3.21-3.08 (m, 4H), 3.07-2.96 (m, 1H), 2.66 (d, J=6.7 Hz, 2H), 2.18-2.09 (m, 2H), 1.85-1.46 (m, 13H), 1.44-1.30 (m, 2H). LCMS (ES+) m/z 432 (M+1)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:28](=[O:29])[CH2:27][C:26](=[O:30])[NH:25][C:24]3[C:31]4[C:36]([CH:37]=[CH:38][C:23]2=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:18][CH:17]=1>ClC(Cl)C>[Cl:1][C:2]1[C:3]([C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:28](=[O:29])[CH2:27][C:26](=[O:30])[NH:25][C:24]4[C:31]5[C:36]([CH:37]=[CH:38][C:23]3=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:18][CH:17]=2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(O)c1ncccc1Cl
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ncccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 44.9 %

Procedure:
3-Chloropyridine-2-carboxylic acid (47 mg, 0.3 mmol) was treated with thionyl chloride in dichloroethane, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63 mg, 0.2 mmol) obtained in Example 1, (3), the title compound (41 mg, yield 45%) was obtained as pale brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:4][CH2:3][O:2][CH3:1])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
2-Bromoethyl methyl ether (0.94 mL) was added dropwise to a suspension of piperazine-4-carboxylic acid tert-butyl ester (1.87 g) and potassium carbonate (1.38 g) in N,N-dimethylformamide (20 mL) at room temperature, and the resultant mixture was stirred at 60° C. for 24 hours. The reaction mixture was partitioned by use of ice-water and ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an oily product (1.39 g, 57%).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[F:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[C:20]([CH3:29])[CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][C:20]=2[CH3:29])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: Cc1cc(F)ccc1/C=C/[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)ccc1C1CN(Cc2ccccc2)CC1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (1.95 g, 8.21 mmol) in CH2Cl2 (30 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 4-fluoro-2-methyl-1-((E)-2-nitro-vinyl)-benzene (1.49 g, 8.22 mmol) and trifluoroacetic acid (0.60 ml, 0.82 mmol) in CH2Cl2 (30 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:6) afforded 0.77 g (30%) of the title compound as a light yellow oil. ES-MS m/e: 315.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[CH:16]1[CH:23]2[CH:19]([O:20][CH:21]([CH:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:22]2)[CH:18]([CH2:32]O)[O:17]1)=[O:5])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:56][O:57][C:58]([CH:60]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:59]>C(#N)C.C(OCC)(=O)C>[CH3:56][O:57][C:58](=[O:59])[CH:60]=[CH:32][CH:18]1[CH:19]2[CH:23]([O:22][CH:21]([CH:24]=[CH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:20]2)[CH:16]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[O:17]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNC(=O)Nc1ncnc2c1ncn2C1OC(CO)C2OC(C=Cc3ccccc3)OC21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCNC(=O)Nc1ncnc2c1ncn2C1OC(C=CC(=O)OC)C2OC(C=Cc3ccccc3)OC21
Reaction time: 2 h
Yield: 52 %

Procedure:
1-Ethyl-3-[9-(6-hydroxymethyl-2-styryl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl]-urea (5.0 g, 11 mmol) was suspended in dry acetonitrile (50 mL) and Dess-Martin periodinate (6.7 g, 16 mmol) was added. The suspension was stirred 2 h, after which time proton NMR of an aliquot showed complete conversion to the aldehyde. (Methoxycarbonylmethylene)triphenylphosphorane (3.9 g, 12 mmol) was added and stirring was continued overnight. The reaction mixture was then diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate/thiosulfate solution (100 mL), dried with sodium sulfate and filtered. The filtrate was evaporated and the solid was dissolved in hot isopropyl alcohol (50 mL). It was allowed to cool, then heptane was added and it was stirred overnight. The resulting precipitate was washed with heptane and dried under vacuum, affording the desired product (2.9 g, 71%). 1H-NMR (300 MHz, d6DMSO) 1.15 (t, 3H, J=7 Hz), 3.21 (q, 2H, J=7 Hz), 3.59 (s, 3H), 4.98 (m, 1H), 5.28 (ψt, 1H, J=6 Hz), 5.51 (dd, 1H, J=6 Hz, <2 Hz), 5.70 (d, 1H, J=16 Hz), 5.90 (d, 1H, J=6 Hz), 6.30 (dd, 1H, J=6 Hz, 16 Hz), 6.45 (d, 1H, J=2 Hz), 6.95 (d, 1H, J=15 Hz), 7.35 (m, 3H), 7.45 (d, 2H, J=7 Hz), 8.50 (s, 1H), 8.60 (s, 1H), 9.30 (t, 1H, J=6 Hz), 9.60 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][CH2:15][N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:17][CH2:18]Cl.O>CS(C)=O>[Cl:1][C:2]1[C:3]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH2:15][CH2:14]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN(CCCl)CCCl)cc1
Reactant: N#CCc1ncccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN2CCC(C#N)(c3ncccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 3-chloro-2-pyridylacetonitrile [prepared by the method described in JP08295663] (1.46 g, 9.57 mmol) in DMSO (19 mL) was slowly added to NaH (60% oil dispersion, 1.01 g, 25.3 mmol), and the mixture was stirred at room temperature for 1 h. A solution of N,N-bis(2-chloroethyl)-p-methoxybenzylamine (2.21 g, 8.43 mmol) in DMSO (19 ml,) was added, and the resulting mixture was stirred at 75° C. for 4 h. After cooling, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to give 4-(3-chloro-2-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine 1 (1.91 g, 60%) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:30][CH3:31])([C:27](O)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:25][CH3:26])([C:27]([N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[O:28])[CH2:30][CH3:31])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)N1CCCC1
Reaction time: 5 h
Yield: 54.7 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-hydroxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.084 mmol), pyrrolidine (12 mg, 0.17 mmol), HATU (63.5 mg, 0.17 mmol) and DMAP (40.8 mg, 0.33 mmol) in DMF (2 mL) was stirred for 5 h. Then the mixture was poured into water and extracted with EtOAc thrice. The combined organic layers were washed with saturated NaCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a white solid (30 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1.[CH:22](OCC)(OCC)OCC.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:22][NH:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1
Reactant: CN(C)CCC=C1c2cc(N)ccc2CCn2cccc21
Reactant: CCOC(OCC)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ccc2c(c1)C(=CCCN(C)C)c1cccn1CC2
Reaction time: 2 h

Procedure:
A solution of 9-amino-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine in triethyl orthoformate (2.8 g.; 10 mmoles in 80 ml.) was refluxed for 5 hours. The volatiles were removed under vacuum and the residue dissolved in 100 ml. of absolute ethanol was stirred in an ice bath as sodium borohydride (0.88 g., 0.024 moles) was added over a period of 10 minutes. The mixture was stirred for a period of 2 hours. After concentration of the ethanol, the residue was dissolved in ethyl acetate, washed with water, dried over Na2SO4 and concentrated to dryness to yield 9-methylamino-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2](C)=[CH2:3].[C:8]1(C)[CH:13]=CC=C[CH:9]=1>>[CH2:7]([O:6][C:1](=[O:5])[CH:2]=[CH2:3])[CH2:9][CH2:8][CH3:13]
Reactant: Cc1ccccc1
Reactant: C=C(C)C(=O)OC
Product: C=CC(=O)OCCCC
Reaction time: 4 h

Procedure:
In a 50 ml internal volume flask, 1 g of the olefin copolymer obtained in the above described step (1) was introduced, and 3 ml of toluene and 5 ml of methyl methacrylate were added under nitrogen gas atmosphere. Thermal graft polymerization of methyl methacrylate was conducted at 80° C. for 4 hours.