Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:30])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:30][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[N:9]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CBr)cc2)nc1Cl

Procedure:
The solution of 2-chloro-6-(4-methylphenyl)-5-phenylnicotinonitrile (1-4; 0.066 g, 0.217 mmol), NBS (0.046 g, 0.26 mmol) and benzoylperoxide (0.010 g, 0.043 mmol) in CDCl3 (2 mL) was heated to reflux overnight. The mixture was concentrated to give 6-[4-(bromomethyl)phenyl]-2-chloro-5-phenylnicotinonitrile (1-5) and used without further purification. LRMS m/z (M+H) Calcd: 383.7, found: 383.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=O)[O:17]C3C=CC=CC=3)=[CH:11][CH:10]=2)[O:3]1.[CH3:26][NH2:27].C1COCC1>C1COCC1>[CH3:26][NH:27][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:25])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5]2)=[CH:10][CH:11]=1)=[O:17]
Reactant: CN
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2)OC1(C)C
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
A mixture of phenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (26 g, 76.6 mmol)), 2.0M Methylamine/THF (265 mL, 530 mmol) in 150 mL of THF was stirred at room temperature for 6 hours, then excess solvent was distilled off from the reaction mixture; residue was dissolved into water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude product was purified by silica gel column chromatography by using 5-60% ethyl acetate in pet-ether as an eluent. to give 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]urea. (20 g, 88% yield) as white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:25]=[CH:24][C:10]2[S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Cl)=[CH:14][C:13]=3[C:9]=2[CH:8]=1)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+]>O1CCCC1>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:25]=[CH:24][C:10]3[S:11][C:12]4[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:14][C:13]=4[C:9]=3[CH:8]=2)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCl)c1ccc2sc3ccc(C(=O)CCCCl)cc3c2c1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCN1CCCCC1)c1ccc2sc3ccc(C(=O)CCCN4CCCCC4)cc3c2c1
Temperature: 125 °C
Reaction time: 24 h

Procedure:
A mixture of 28.0 g (0.072 mole) of 2,8-bis(4-chlorobutyryl)dibenzothiophene, 49.4 g (0.58 mole) of piperidine and 2.0 g of potassium iodide in 200 ml of tetrahydrofuran is heated at 125° C. with stirring for 24 hours in a Parr general purpose bomb. The reaction mixture is cooled, filtered, and the filtrate is evaporated in vacuo leaving a residue which is washed with water and recrystallized twice from acetone to give 2,8-bis(4-piperidinobutyryl)dibenzothiophene, M.P. 93°-95° C.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[O:9][C:8]([C:10]2[O:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21](=[NH:24])[NH:22][OH:23])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)=[NH:4].[C:25](OC(=O)C)(=[O:27])[CH3:26].[C:32](O)(=[O:34])[CH3:33]>>[C:25]([O:1][NH:2][C:3]([C:5]1[O:9][C:8]([C:10]2[O:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21](=[NH:24])[NH:22][O:23][C:32](=[O:34])[CH3:33])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)=[NH:4])(=[O:27])[CH3:26]
Reactant: CC(=O)O
Reactant: N=C(NO)c1ccc(-c2ccc(-c3ccc(C(=N)NO)o3)o2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)ONC(=N)c1ccc(-c2ccc(-c3ccc(C(=N)NOC(C)=O)o3)o2)cc1
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 6 (262 mg, 0.8 mmol) in glacial acetic acid (8 mL) was slowly added acetic anhydride (0.28 mL). After stirring overnight, TLC indicated complete acylation of the starting material. The reaction mixture was poured onto ice water, the precipitate was filtered, washed with water and dried to give 7 in 89% yield, mp 212-213° C. 1H NMR (DMSO-d6); δ 2.17 (s, 6H), 6.85 (br s, 4H), 6.98 (d, J=3.6 Hz, 1H), 7.00 (d, J=3.6 Hz, 1H), 7.14 (d, J=3.6Hz, 1H), 7.24 (d, J=3.6 Hz, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H). 13C NMR (DMSO-d6); δ 168.4, 168.1, 155.8, 152.4, 148.9, 146.1, 144.8, 144.3, 131.2, 130.6, 127.2, 123.3, 113.1, 109.6, 109.3, 107.6, 19.8, 19.7. Calcd for C20H18N4O6: C, 58.53; H, 4.42. Found. C, 58.71; H, 4.50.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f20) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]([F:17])[F:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]([F:17])[F:16])[C:11]([NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH2:29][C@@H:27]3[CH2:26][O:25][C:24]([CH3:36])([CH3:23])[O:28]3)[N:31]=2)=[O:13])[C:7](=[O:18])[CH:6]=1
Reactant: O=C(O)C(CC(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-butyric acid (166 mg, 0.50 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 118 mg, 0.60 mmol) in N,N-dimethylformamide (4 mL). To this mixture was added N,N-diisopropyethylamine (250 μL, 1.5 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (330 mg, 0.75 mmol) and stirred overnight at 25° C. After this time, the mixture was diluted with ethyl acetate (25 mL) and washed with a saturated aqueous solution of ammonium chloride (25 mL), saturated aqueous solution of sodium bicarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL), dried over sodium sulfate, and then concentrated with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 80% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-4,4-difluoro-butyramide (185 mg, 72%) as a cream colored foam: HR-ES-MS m/z calculated for C23H25N4O5ClF2 [M+H]+ 511.1555, observed 511.1555.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH:2]=[CH2:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[CH2:1]([N:4]([CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[C:25](=[O:26])[CH2:24][Cl:23])[CH:2]=[CH2:3]
Reactant: C=CCNCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C=CCN(CC1OCCO1)C(=O)CCl

Procedure:
N-Allyl-N-(1,3-dioxolan-2-ylmethyl)amine (9.2 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (5 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-allyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH3:27])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24](Br)=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH2:26])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[Cl:28][C:29]1[C:37]2[S:36][C:35]([SH:38])=[N:34][C:33]=2[CH:32]=[CH:31][CH:30]=1>>[C:1]([O:4][C@@H:5]([CH3:27])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[C:24]([S:38][C:35]3[S:36][C:37]4[C:29]([Cl:28])=[CH:30][CH:31]=[CH:32][C:33]=4[N:34]=3)=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH2:26])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: Sc1nc2cccc(Cl)c2s1
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCC(CCn2c(Br)nc3c(N)ncnc32)CC1
Product: CC(=O)O[C@@H](C)C(=O)N1CCC(CCn2c(Sc3nc4cccc(Cl)c4s3)nc3c(N)ncnc32)CC1

Procedure:
The title product was prepared according to the procedure described for example 81 using (1S)-2-{4-[2-(6-amino-8-bromo-9H-purin-9-yl)ethyl]piperidin-1-yl}-1-methyl-2-oxoethyl acetate and 7-chloro-2-mercaptobenzothiazole. LC-MS [M+H]+ 562.1, along with hydrolyzed product, the mixture was used for the next step without any further purification.
Reaction SMILES: C[OH:2].[OH-].[K+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.O.[CH3:21][CH2:22][CH2:23]CCC>ClCCl>[OH:2][CH2:23][CH2:22][CH2:21][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CCCCCC
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(-c2ccc(OCCCO)cc2)cc1

Procedure:
To 400 ml of a methanol solution having 5.7 wt % potassium hydroxide, 50 g of the compound 6 and 49.1 g of 4-hydroxy-4′-cyanobiphenyl were added, followed by reflux. After they were completely reacted, water and dichloromethane were added thereto, and the organic layer was extracted. Then, saturated aqueous sodium chloride was added thereto, and the organic layer was extracted, followed by washing with water. Anhydrous magnesium sulfate was added thereto, the mixture was subjected to filtration under reduced pressure, and the filtrate was extracted. The filtrate was subjected to column chromatography by using dichloromethane as a developing solution, and dichloromethane was distilled off at 30° C. to obtain powder crystals. n-Hexane was added thereto to conduct recrystallization, and 40.0 g of the compound 7, i.e. 4-(3-hydroxypropyloxy)-4′-cyanobiphenyl was obtained.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]C1.IC1C=CC(OCCCN2CCC[C@H]2C)=CC=1.CN1C=CC(C(O)=O)=C1.[N:45]1([C:50]([C:52]2[CH:56]=[CH:55][NH:54][CH:53]=2)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46]1>>[CH3:9][C@@H:10]1[CH2:3][CH2:4][CH2:1][N:5]1[CH2:6][CH2:7][CH2:8][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:54]2[CH:55]=[CH:56][C:52]([C:50]([N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)=[O:51])=[CH:53]2)=[CH:16][CH:17]=1
Reactant: O=C(c1cc[nH]c1)N1CCCC1
Reactant: Ic1ccc(OC2CCN(C3CCC3)CC2)cc1
Agent: C[C@@H]1CCCN1CCCOc1ccc(I)cc1
Agent: Cn1ccc(C(=O)O)c1
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2ccc(C(=O)N3CCCC3)c2)cc1

Procedure:
The titled compound was prepared as a colorless amorphous substance by repeating the procedure of Example 1, except that the 1-cyclobutyl-4-(4-iodophenoxy)piperidine was replaced by (2R)-1-[3-(4-iodophenoxy)propyl]-2-methylpyrrolidine (which can be synthesized in accordance with the method described in WO2009063953) and the methyl 1H-pyrrole-3-carboxylic acid by 3-(pyrrolidin-1-ylcarbonyl)-1H-pyrrole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].[Cl-].[Li+]>C(N(CC)CC)C.CN(C)C=O.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)cc1I
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cc(Cl)cnc1N
Temperature: 40 °C

Procedure:
A suspension of 2.54 g of 5-chloro-3-iodopyridin-2-ylamine, 2.12 ml of ethynyltrimethylsilane, 0.38 g of copper iodide and 0.47 g of lithium chloride in 7 ml of triethylamine and 75 ml of dimethylformamide is degassed under argon for approximately 15 minutes. 0.408 g of [1,1′-bis(diphenylphosphino)ferrocene] palladium(II) chloride is added to the above suspension. The mixture is heated at around 40° C. for approximately 19 hours and then concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 50 ml of water, and extracted with three times 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. 1.63 g of 5-chloro-3-trimethylsilanylethynylpyridin-2-ylamine are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:4][C@H:3]1[CH2:16][OH:17].C(N(CC)CC)C.CS(C)=O>ClCCl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:5]2[O:4][C@@H:3]([CH:16]=[O:17])[C:2]([CH3:18])([CH3:1])[CH2:7][O:6]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C2OCC(C)(C)[C@H](CO)O2)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(C2OCC(C)(C)[C@H](C=O)O2)cc1
Yield: 93.8 %

Procedure:
Following the general procedure for the oxidation reaction of Description 7, 23.0 g (91.2 mmol) of [(4R)-5,5-dimethyl-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]methan-1-ol (8a) in 650 mL of dichloromethane (DCM) in the presence of 63.5 mL (46.1 g, 456 mmol) of triethylamine and 52.0 mL (57.3 g, 733 mmol) of dimethylsulfoxide (DMSO) was reacted with 43.5 g (274 mmol) of sulfur trioxide pyridine complex to afford 21.4 g (94% yield) of the crude title compound (8b) as a yellow oil. The crude material was of sufficient purity to be used in the next step without further isolation and purification. Rf=0.53 (MTBE/Hxn=1:2). 1H NMR (400 MHz, CHCl3): δ=1.03 (s, 3H), 1.26 (s, 3H), 3.67 (d, J=11.6 Hz, 1H), 3.72 (d, J=11.6 Hz, 1H), 3.83 (s, 3H), 3.95 (d, J=1.2 Hz, 1H), 5.51 (s, 1H), 6.90-6.96 (m, 2H), 7.46-7.51 (m, 2H), 9.65 (d, J=1.6 Hz, 1H) ppm. MS (ESI) m/z: 251.1 (M+H)+, 272.9 (M+Na)+. The analytical data for the compound was consistent with the proposed structure and with the data given in the literature (Blakemore, et al., J. Org. Chem. 2005, 70, 5449-5460; and Shiina, et al., Bull. Chem. Soc. Jpn. 2001, 74, 113-122). Similar yields were obtained using classical Swern-oxidation conditions.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:31]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1(C)C=CC=CC=1.[Pt]>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH2:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reaction time: 8 h
Yield: 76.6 %

Procedure:
tert-Butyl[4-(7-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate (39.92 g, 85.57 mmol) was dissolved in toluene (1700 mL) and added to a Parr vessel charged with 5% platinum on carbon (3.9 g) and a small volume of toluene. The vessel was placed under hydrogen pressure (50 psi, 3.4×105 Pa). The hydrogen was replaced three times, and the reaction was shaken overnight. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol (700 mL). The filtrate was concentrated under reduced pressure to provide 28.62 g of tert-butyl{4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate as a brown solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.C(O)(=O)C.C1C=C[NH+]=CC=1.[Br:32][Br-]Br.O>ClCCl>[Br:32][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)=[O:11]
Reactant: COC(=O)c1ccc(C(=O)Cc2ccc(SC)cc2)cc1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C(=O)C(Br)c2ccc(SC)cc2)cc1
Reaction time: 1 h

Procedure:
To a solution of methyl 4-{[4-(methylthio)phenyl]acetyl}benzoate (5 g) in dichloromethane (250 ml) were added acetic acid (0.65 ml) and pyridinium bromide perbromide (6.51 g) at 0° C., and the mixture was stirred for 1 h at the same temperature. The reaction mixture was poured into water (250 ml) and extracted with ethyl acetate (250 ml). The organic layer was washed with water and brine, dried over magnesium sulfate and evapolated. The residue was washed with diisopropylethyl ether and collected by filtration to give methyl 4-{2-bromo[4-(methylthio)phenyl]acetyl}benzoate as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[O:22][CH2:21][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[NH:13][C:12]4=[O:20])[C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:46][C:47]1[O:48][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:50][CH:51]=1.ClCC1C=NC(OC)=NC=1>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[O:22][CH2:21][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]([CH2:46][C:47]5[O:48][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:50][CH:51]=5)[C:12]4=[O:20])[C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23]
Reactant: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)Nc2ccccc21
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: COc1ncc(CCl)cn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using 3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 5-(chloromethyl)-2-methoxypyrimidine, 3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione was obtained (59%) as a colorless solid: mp 198-199° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 7.37-7.30 (m, 1H), 7.23-7.18 (m, 3H), 7.12-7.03 (m, 2H), 6.77 (s, 1H), 6.56 (s, 1H), 5.17-4.99 (m, 2H), 4.91-4.75 (m, 2H), 3.31 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.2, 156.8, 154.3, 152.9, 141.5, 136.1, 132.9, 131.4, 128.9, 123.6, 123.3, 121.5, 114.0 (2C), 109.8, 109.2, 104.2, 92.4, 79.3, 57.2, 36.4, 28.1; MS (ES+) m/z 456.4 (M+1).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH3:7][NH:8][CH:9]=[O:10]>C(Cl)(Cl)Cl>[CH3:7][N:8]([CH:9]=[O:10])[C:3](=[O:4])[CH:2]([Cl:6])[Cl:1]
Reactant: CNC=O
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(C=O)C(=O)C(Cl)Cl
Yield: 86 %

Procedure:
25 g of dichloroacetyl chloride (1.25 eq.) was added to a solution of 50 g N-methylformamide (NMF) in chloroform at ambient temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried with magnesium sulfate and the solvent was evaporated off in vacuum to give N-methyl-N-formyl-α,α-dichloroacetamide (86% yield) in high purity as a yellow oil. The chemical structure was confirmed by APCI-MS, FT-IR, 1H and 13C magnetic resonance spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH2:12]Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]([S:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=2)=[CH2:12])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(SC(CCl)S(=O)(=O)c2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(Sc1ccc(C(C)(C)C)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
p-t-Butylphenyl 1-(p-chlorophenylsulfonyl)-2-chloroethyl sulfide (16.12 g, 40.0 mmoles) was dissolved in 80 ml of tetrahydrofuran at 25° C. The solution was treated with 5.6 ml (4.08 g, 40.3 mmoles) of triethylamine and allowed to stand for 30 minutes. After filtration had separated the triethylamine hydrochloride, the filtrate was freed of solvent by evaporation at reduced pressure. The residue was a colorless solid, m.p. 74°-79°. Recrystallization from 25 ml of ethanol gave 12.2 g (84%) of pure product m.p. 79°-81°.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[CH:17]=O.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[CH2:17][NH:23][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: Cn1c(=O)c(C=O)c(N)n(-c2ccccc2)c1=O
Product: CCCCNCc1c(N)n(-c2ccccc2)c(=O)n(C)c1=O

Procedure:
Reductive amination of 6-amino-5-formyl-3-methyl-1-phenyl-2,4 (1H, 3H)-pyrimidinedione with N-butylamine was performed in substantially the same manner as Example 18 to thereby give an intermediate, 6-amino-5-(N-butylaminomethyl)-3-methyl-1-phenyl-2,4 (1H, 3H)-pyrimidinedione. The intermediate was reacted with 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid by a conventional condensation method to give the title compound (yield 36%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:46][CH2:47][CH:48]([OH:60])[CH2:49][N:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12](=[O:14])[NH:46][CH2:47][CH:48]([OH:60])[CH2:49][N:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH2:51]2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (2.5 g, 10.5 mmol) in DCM (25 mL) was added EDCI (3.0 g, 15.7 mmol), HOBt (2.1 g, 15.7 mmol), Et3N (2.1 g, 21 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (2.2 g, 10.5 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography to give the title product (3.2 g, Yield 71%). LCMS (m/z): 426.3 (M+1).