Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11]>CO.O>[N+:10]([C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1)([O-:12])=[O:11]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cccc(Nc2ncc(F)c(Nc3cccc([N+](=O)[O-])c3)n2)c1
Temperature: 100 °C
Yield: 75.8 %

Procedure:
2,4-Dichloro-5-fluoropyrimidine (4.7 g, 28.1 mmol) was dissolved in a mixture of MeOH (150 ml) and H2O (15 ml). 3-nitroaniline (15.5 g, 112 mmol) was added and the mixture was refluxed for 20 hours (100° C. oil-bath temperature). The mixture was cooled to 22° C. and filtered. The residue was washed carefully with 200 ml MeOH—H2O (1:1; v/v) and dried under vacuum to give 7.89 g (76%) of N2,N4-bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine as yellow crystals. 1H NMR (DMSO-d6+D2O): δ 8.63 (m, 2H), 8.21 (m, 1H), 8.08 (d, 1H, J=8.41 Hz), 7.88 (d, 1H, J=8.4 Hz), 7.79 (d, 1H, J=8.4 Hz), 7.70 (d, 1H, J=8.4 Hz), 7.57 (d, 1H, J=8.4 Hz), 7.45 (t, 1H, J=8.4 Hz); LCMS: purity: 100%; MS (m/e): 371.30 (M+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40]>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:37]3[CH2:38][CH2:39][NH:34][C:35](=[O:40])[CH2:36]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: COCCO
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCNC(=O)C4)c(OC)cc23)c2c1OCO2
Temperature: 110 °C
Yield: 71.7 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.200 g) was dissolved in 2-methoxyethanol (6 ml) and piperazine-2-one (0.821 g) was then added and the mixture heated to 110° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. There was thus obtained the title compound (0.162 g) as a white powder, NMR Spectrum: (d6-DMSO) 2.10 (quin, 2H), 2.66 (m, 4H), 3.12 (s, 2H), 3.33 (m, 2H), 3.44 (s, 3H), 4.01 (s, 3H), 4.24 (t, 2H), 4.34 (s, 2H), 6.09 (s, 2H), 7.04 (, 1H), 7.06 (s, 1H), 7.19 (s, 1H), 7.77 (s, 1H), 8.46 (s, 1H), 9.04 (s, 1H); Mass Spectrum: M+H+ 554/556.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:48]=[CH:47][C:23]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([NH:34][C:35]4[N:40]=[C:39]([C:41]5[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=5)[CH:38]=[CH:37][N:36]=4)[CH:28]=3)=[O:25])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1>ClCCl>[CH3:12][N+:13]1([O-:6])[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([NH:34][C:35]4[N:40]=[C:39]([C:41]5[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=5)[CH:38]=[CH:37][N:36]=4)[CH:28]=3)=[O:25])=[CH:47][CH:48]=2)[CH2:15][CH2:14]1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(CN3CC[N+](C)([O-])CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3-Chloroperoxybenzoic acid (Fluka, Buchs, Switzerland; 2.06 g of 55%, 4.27 mmol) is added to a stirred mixture of 4-[(4-methyl-1-piperazinyl)-methyl]-N-{4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]-phenyl}-benzamide (prepared as described in EP 0 564 409 B1, Example 21; 2.00 g, 4.05 mmol) in dichloromethane (70 mL) at −20° C. The resulting mixture is then stirred at RT for 72 h. The solvent is then evaporated off under reduced pressure to yield a mixture which is purified by column chromatography on silica gel, eluent dichloromethane-methanol-water (70:30:5), to give the title compound as a yellow crystalline solid, m.p. 154-158° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[CH:12]1(I)[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:12]1([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([I:1])=[N:3]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2C1CCCC1
Temperature: 45 °C

Procedure:
The intermediate 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) (0.5 g, 1.9 mmol; Apsel et al., 2008) was combined with cyclopentyl iodide (0.24 mL, 2.1 mmol), and 1.06 g K2CO3 in 20 mL DMF and heated to 45° C. under argon for 2 hours. The reaction was filtered to remove solid K2CO3. The filtrate was combined with brine, and the organic product was extracted in CH2Cl2 (3×50 mL). The combined organic layer was concentrated in vacuo and purified by silica gel chromatography (MeOH/chloroform; 5:95) to afford 1-cyclopentyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 330.0, calculated 330.0). 4-nitrophenyl boronic acid (190 mg, 1.1 mmol; Sigma-Aldrich) was coupled to 1-cyclopentyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.456 mmol) via the Suzuki reaction in 6 mL 1,2 methoxy ethane, 1 mL of saturated sodium carbonate, 1.65 mL EtOH, and 200 mg of polymer-bound tetrakis palladium. The reaction was stirred under argon for 12 hours at room temperature, filtered through Whatman paper to remove palladium, mixed with brine, extracted in chloroform, and the product was subsequently purified on silica in EtOAc and concentrated in vacuo. The purified solid 1-cyclopentyl-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 325.0, calculated 325.1; 100 mg, 0.31 mmol) was combined with zinc dust (605 mg, 9.25 mmol), 10 mL THF, and 0.35 mL HOAc for 12 hours at room temperature under argon. The reaction was filtered through Celite®, extracted with EtOAc, and concentrated in vacuo to yield 3-(4-aminophenyl)-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 295.0, calculated 295.2). To this reduced product, molar equivalents of 3-(trifluoromethyl)phenyl isocyanate (Sigma-Aldrich) were added dropwise in ice-cold CH2Cl2. The reaction proceeded until completion as judged by TLC, was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to yield AD60 1-(4-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (ESI-MS m/z [M+H]+ found 482.2, calculated 482.0).
Reaction SMILES: C([CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[C:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[C:26]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:27]=[CH:28][C:29]([CH2:30][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:3][C:4]([OH:6])=[O:5])=[CH:12][CH:11]=2)=[CH:32][CH:33]=1
Reactant: CCC(C(=O)O)c1ccc(O)cc1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 84.4 %

Procedure:
To a solution of ethyl 4-hydroxyphenylacetic acid (3.6 g) in DMF (50 ml) were added potassium carbonate (2.5 g) and 4-phenylbenzyl chloride (4 g) sequentially. After stirring at 60° C. for 6 hr, the reaction mixture was poured onto water and the resulting crystals were suspended in ethyl acetate. The suspension was washed with water and concentrated. The resulting crude crystals were dissolved in THF (100 ml)/ethanol (50 ml) and 2 N sodium hydroxide (20 ml) was added to the solution. The reaction mixture was heated under stirring at 60° C. for 18 hr and concentrated. The residue was acidified with 2 N hydrochloric acid and the resulting crystals were collected by filtration and washed with ethyl ether to obtain the titled compound (5.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:5])[CH3:2].O.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C)c[nH]c1CCNCCN1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A stirred solution of 4-methyl-2-[(2-piperidin-1-yl-ethyl carbamoyl)-methyl]-1H-pyrrole-3-carboxylic acid ethyl ester (3.46 g, 10.8 mmol) in anhydrous tetrahydrofuran (20 ml) was added dropwise slowly with 1M borane-tetrafuran complex in tetrafuran (32.4 ml, 32.4 mmol) under an argon atmosphere. Upon completion of the addition, the mixture was stirred at room temperature for 1 hour and heated to reflux for another 5 hours. The mixture was added with cold water (5 ml) and 1N hydrochloric acid (15 ml) dropwise and stirred for 5 minutes. The mixture was adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (10 ml×5). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-methyl-2-[2-(2-piperidin-1-yl-ethylamino)-ethyl]-1H-pyrrole-3-carboxylic acid ethyl ester (3.07 g) as a brown oil which was used as such.
Reaction SMILES: [C:1]([S:9][CH2:10][CH:11]([CH3:15])[C:12](O)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[C:1]([S:9][CH2:10][CH:11]([CH3:15])[C:12]([Cl:18])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(CSC(=O)c1ccccc1)C(=O)O
Solvent: Cc1ccccc1
Product: CC(CSC(=O)c1ccccc1)C(=O)Cl

Procedure:
3-Benzoylthio-2-methylpropanoic acid (11.6 g) in toluene (78 ml) was treated with thionyl chloride (4.6 ml). The resulting solution was warmed to 80° for 2.5 hours and then evaporated to dryness under reduced pressure to yield 3-benzoylthio-2-methylpropanoyl chloride. A solution of (±)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid hydrochloride (10.7 g) in pyridine (65 ml) was treated dropwise with the crude 3-benzoylthio-2-methylpropanoyl chloride with vigorous stirring. After stirring overnight, the reaction mixture was added to ice (900 g), acidified with 20% hydrochloric acid (130 ml), and extracted with ether (700 ml). The ether layer was dried over sodium sulfate and activated charcoal, and then concentrated to dryness to yield a viscous oil (25 g) which was dissolved in acetonitrile (100 ml) and treated with dicyclohexylamine (13 ml). The crystalline product, (±) 1-(3-benzoyl-2-methyl-1-oxopropyl)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid dicyclohexylamine salt, was collected by filtration; yield 3.6 g, m.p. 170°-173°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[NH:34][C:33]2=[O:41])[CH2:28][CH2:27]1>CN(C)C=O>[O:41]=[C:33]1[N:32]([CH:29]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:31][CH2:30]2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCN2c3cccc4cccc(c34)S2(=O)=O)CC1
Temperature: 20 °C
Yield: 13.5 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7.2 g), triethylamine (3.6 cc) and 1-(4-piperidinyl)-2-benzimidazolinone (5.6 g) in dimethylformamide (100 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethanol (95-5 vol) as eluant, and recrystallization from boiling acetonitrile (200 cc), 2-{3-[4-(2-oxo-1-benzimidazolinyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.6 g) is obtained, m.p. 253° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH2:10][N:9]=1.[CH2:23]1[O:25][CH2:24]1.[OH-].[NH4+]>C(Cl)CCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[O:25][CH2:24][CH2:23][N:9]1[CH2:10][C:11](=[O:22])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=12
Reactant: C1CO1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C1CN2CCOC2(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
Reaction time: 0.13 h

Procedure:
A solution of 5.2 g (0.02 M) of stannic chloride in 60 ml of dry ethylene dichloride under nitrogen was treated with 2.9 g (0.0091 M) of 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. The reaction was cooled in an ice bath, and 2.6 g (0.06 M) of ethylene oxide in 10 ml of ethylene dichloride was added with stirring over an 8 min period. After 18 hr at room temperature, the solution was made basic with concentrated ammonium hydroxide and filtered. The filtrates were washed with a saturated solution of brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of dichloromethane, methanol and petroleum ether to give the above named product as white rods, melting at 201°-203°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([OH:17])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][OH:24]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([O:17][CH2:22][CH2:23][OH:24])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(O)C2=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(OCCO)C2=O

Procedure:
Employing 8-tert-butyloxycarbonyl-2-hydroxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.56 g) and 2-bromoethanol (210 μl), reaction was conducted in the same manner as in Example 40 to obtain 0.40 g of a coloress solid, m.p. 97° to 98° C.
Reaction SMILES: [CH:1]([Si:3]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])=[CH2:2].[SH:13][CH2:14][CH2:15][CH2:16][Si:17]([O:22][CH3:23])([O:20][CH3:21])[O:18][CH3:19]>>[Si:3]([CH2:1][CH2:2][S:13][CH2:14][CH2:15][CH2:16][Si:17]([O:22][CH3:23])([O:18][CH3:19])[O:20][CH3:21])([O:4][CH2:5][CH3:6])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: C=C[Si](OCC)(OCC)OCC
Reactant: CO[Si](CCCS)(OC)OC
Product: CCO[Si](CCSCCC[Si](OC)(OC)OC)(OCC)OCC
Temperature: 150 °C
Reaction time: 48 h

Procedure:
(CH3CH2O)3SiCH2CH2SCH2CH2CH2Si(OCH3)3 was prepared by reacting 2.28 moles of vinyltriethoxysilane and 2.28 moles of gamma-mercaptopropyltrimethoxysilane. The reaction was heated to 150° C. and maintained at that temperature. After 48 hours the reaction was stopped.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([C:15]#[C:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BrH:26].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[Br:26][C:16]1[CH:15]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:17]=1
Reactant: Br
Reactant: COc1cc(C(=O)C#CCNC(=O)OC(C)(C)C)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(-c2cc(Br)cn2C(=O)OC(C)(C)C)cc(OC)c1OC
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
To a stirred solution of 3-(tert-butoxycarbonylamino)-1-propinyl 3,4,5-trimethoxyphenyl ketone (1.0 g, 2.78 mmol, Example 76c) in CH2Cl2 (10 ml) a solution of HBr (732 μl, 1.5 equiv., 33% in acetic acid) is added at 4° C. The reaction mixture is stirred for 45 min at 4° C., and poured onto ice, saturated aqueous NaHCO3 solution and ethyl acetate. The organic layer is dried (MgSO4), the solvents are evaporated and the residue chromatographed on SiO2 with ethyl acetate/hexane (1:3) to yield the title compound (1.0 g, 89.9%) as a white solid. 1H-NMR (300 MHz, DMSO-d6): 7.45 (d, J=2.0, 1H); 6.66 (s, 2H); 6.38 (d, J=2.0, 1H); 3.77 (s, 2MeO); 3.67 (s, MeO); 1.33 (s, tBu).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH:22]=O)=[CH:20][C:19]([Cl:24])=[CH:18][N:17]=1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH2:22][N:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)=[CH:20][C:19]([Cl:24])=[CH:18][N:17]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=Cc1cc(Cl)cnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)N1CCN(Cc2cc(Cl)cnc2Oc2ccc3c(nnn3CC3CC3)c2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-{[4-bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]oxy}-5-chloropyridine-3-carbaldehyde (32, 2.60 g, 6.38 mmol) was dissolved in anhydrous dichloroethane (63.8 mL, 0.1M) and treated with 1-(methylsulfonyl)piperazine (2.10 g, 12.8 mmol, 2 equiv.) and acetic acid (3.65 mL, 63.8 mmol, 10 equiv.). After 30 minutes the solution formed a thick suspension and was treated with sodium triacetoxyborohydride (1.76 g, 8.29 mmol, 1.3 equiv) in small portions over 1 hour. After completion of this addition, the reaction was allowed to stir an additional 2 h at ambient temperature. Upon completion as judged by TLC and LCMS, the reaction was quenched by the slow addition of water (20 mL) and NaHCO3. The mixture was extracted 3× with dichloromethane (3×30 mL), and the combined organic layers were dried over MgSO4. The crude mixture was purified using flash column chromatography (Redisep SiO2, 80 g, 0-100% EtOAc/hexanes) to provide pure 198: 1H NMR (300 MHz, CDCl3) δ 7.89 (d, 1H, J=2.5 Hz), 7.84 (d, 1H, J=2.5 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.33 (d, 1H, 8.8 Hz), 4.53 (d, 2H, J=7.1 Hz), 3.82 (s, 2H), 3.33 (m, 4H), 2.83 (s, 3H), 2.74 (m, 4H), 1.41 (m, 1H), 0.69 (m, 2H), 0.52 (dd, 2H, J=10.8, 5.1 Hz, 2H). LRMS m/z (M+H) 556.9 found, 556.9 required.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1.Cl[C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:15][C:14]1[C:9]([C:4]2([C:6]#[N:7])[CH2:5][C:2](=[CH2:1])[CH2:3]2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Fc1cccnc1Cl
Reactant: C=C1CC(C#N)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C1CC(C#N)(c2ncccc2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89767.9 %

Procedure:
To a solution of 3-methylenecyclobutanecarbonitrile (150 g, 1.61 mol, 1 equiv) and 2-chloro-3-fluoropyridine (212 g, 1.61 mmol, 1 equiv) in toluene (1 L) was added NaHMDS (2 M in THF, 885 mL, 1.1 equiv) dropwise at 0-10° C. Upon completion of addition, the reaction mixture was warmed to rt, stirred overnight, and quenched with NH4Cl(sat.) solution. The organic layer was washed with water (2×500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated to give the crude title compound (272 g, 90%) which was used in next step without further purification. LRMS (M+H+) m/z 189.1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:12][OH:13])[C:10]#[N:11].[C:16](OCC)(=[O:18])[CH3:17]>CCCCCC>[C:16]([O:13][CH2:12][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:15])[F:1])[C:10]#[N:11])(=[O:18])[CH3:17]
Reactant: N#CC(CO)c1ccccc1C(F)(F)F
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)OCC(C#N)c1ccccc1C(F)(F)F

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(2-(trifluoromethyl)phenyl)-3-hydroxypropanenitrile was used in place of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 2-(2-(trifluoromethyl)phenyl)-3-hydroxypropanenitrile is described in Example 9. The recovered ester product was a colorless oil (95% yield), Rf 0.35 (silica gel, ethyl acetate:hexane=1:4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]([NH2:24])=O)=[CH:18]2)(=[O:11])=[O:10].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22](=[S:35])[NH2:24])=[CH:18]2)(=[O:11])=[O:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(N)=O)[nH]c12
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(N)=S)[nH]c12
Temperature: 70 °C
Reaction time: 3 h
Yield: 154.9 %

Procedure:
A mixture of 7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indole-2-carboxamide (2.82 g), Lawesson's reagent (1.6 g) and tetrahydrofuran (250 mL) was stirred at 70° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (2.3 g, yield: 78%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]([F:16])([F:15])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([O:12]C)=O)=[CH:5][C:4]=1[I:14].[CH3:17][CH2:18][CH:19]([NH2:22])[CH2:20][CH3:21].Cl>C(#N)C>[Cl:1][C:2]([F:16])([F:15])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([NH:22][CH:19]([CH2:20][CH3:21])[CH2:18][CH3:17])=[O:12])=[CH:5][C:4]=1[I:14]
Reactant: COC(=O)c1cc(I)c(C(F)(F)Cl)[nH]c1=O
Reactant: CCC(N)CC
Agent: Cl
Solvent: CC#N
Product: CCC(CC)NC(=O)c1cc(I)c(C(F)(F)Cl)[nH]c1=O

Procedure:
At room temperature, 400 mg (1.1 mmol) of methyl 6-[chloro(difluoro)methyl]-5-iodo-2-oxo-1,2-dihydropyridine-3-carboxylate were dissolved in 5 ml of acetonitrile and stirred with 0.5 ml of 3-pentylamine for 12 h. The reaction mixture was then added to 1N of hydrochloric acid, and the resulting precipitate was filtered off with suction and washed with water. Drying gave 370 mg (72% of theory) of the product.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH2:43][C:44]([O:47][CH3:48])([CH3:46])[CH3:45])[C:39](=[O:49])[CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([CH:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH2:43][C:44]([O:47][CH3:48])([CH3:46])[CH3:45])[C:39](=[O:49])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: COC(C)(C)Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: COC(C)(C)Cn1ccc(-c2ccc(C(C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-(2-methoxy-2-methyl-propyl)-1H-pyridin-2-one following a procedure analogous to that described in Example 75 Method 1. Mass spectrum (ESI+): m/z=533 [M+H]+.