Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]#[C:14][C:11]1[CH:10]=[N:9][C:8]([NH2:7])=[N:13][CH:12]=1
Reactant: CN(C)CCCC#Cc1cnc(NC(=O)OC(C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCC#Cc1cnc(N)nc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of 1.47 g (3.2 mmol) of [5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-yl]-carbamic acid tert-butyl ester in 16 ml CH2Cl2 was treated at 0° C. with 8 ml TFA (during 20 min). The solution was warmed up to room temperature during 1 h, concentrated and the residual oil was extracted with aqueous sat. NaHCO3 (+Na2CO3)(3×)/CH2Cl2(3×). The organic phases were washed with aqueous 10% NaCl solution, dried (Na2SO4) and evaporated to yield 0.62 g (95%) of 5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-ylamine, mp: 126-127° C.; MS: 205 (MH+).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Li]CCCC.CON(C)[C:15](=[O:17])[CH3:16]>C1COCC1.O>[Cl:1][C:2]1[S:3][C:4]([C:15](=[O:17])[CH3:16])=[CH:5][N:6]=1
Reactant: Clc1nccs1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of 2-chlorothiazole (2.5 g, 21 mmol) in THF (10 mL) was added dropwise to a chilled (−75° C.) 2.5 M hexanes solution of n-BuLi (9.2 mL, 23 mmol) in THF (70 mL). After the addition was complete the reaction mixture was stirred for 1 hr. Then a solution of N-methoxy-N-methylacetamide (2.4 g, 23 mmol) in THF (5 mL) was added. The reaction was allowed to stir overnight while warming to 25° C. The reaction was diluted with H2O and thrice extracted with ethyl ether. The organic portions were combined, washed with brine and then dried (Na2SO4). Filtration and removal of solvent gave a residue that was purified by flash chromatography on silica eluting with 5 percent Et2O in pentane, affording product as a white solid, 2.5 g, 15.5 mmol, 73 percent yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:8]2[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]2)[CH:7]=1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][C:12]1[CH2:13][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:16])[CH2:9][C:10](=[O:15])[CH:11]=1
Reactant: [NH4+]
Reactant: Cc1ccc(F)cc1C1CC(=O)CC(=O)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccc(F)cc1C1CC(=O)C=C(N)C1

Procedure:
A solution of 5-(5-fluoro-2-methylphenyl)cyclohexane-1,3-dione (3.0 g) and ammonium acetate (3.1 g) in ethanol (50 ml) was refluxed for 14 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The mixture was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 1-amino-5-(5-fluoro-2-methylphenyl)cyclohexen-3-one, which was dissolved in ethanol (70 ml) and toluene (120 ml). To the mixture were added 3-oxobutylaldehydedimethylacetal (4.1 g) and powdery potassium hydroxide (0.57 g), and the mixture was refluxed. To the mixture was added powdery potassium hydroxide (0.14 g) 30 minutes later; powdery potassium hydroxide (0.14 g) and 3-oxobutylaldehydedimethylacetal (0.33 g) 1 hour later; and powdery potassium hydroxide (0.14 g) 1.5 hours later. Then, the mixture was stirred at the same temperature for 2 hours and cooled. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, ethyl acetate was evaporated, and the residue was subjected to silica gel column (ethyl acetate-hexane) to give crystals, which were recrystallized from ethyl acetate-hexane to give 7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[C:6]=2[CH:20]=1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1)#[N:22]>>[CH2:18]([C:7]1([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C:6]2[CH:20]=[C:2]([C:25]3[CH:24]=[C:23]([CH:28]=[C:27]([F:29])[CH:26]=3)[C:21]#[N:22])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: CCC1(c2ccsc2)OCC(=O)Nc2ccc(Br)cc21
Product: CCC1(c2ccsc2)OCC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-3-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-cyano-5-fluorobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.07 (s, 1H), 8.07 (t, J=1.5 Hz, 1H), 7.94 (dt, J=10.3, 2.0 Hz, 1H), 7.80 (m, 1H), 7.73 (dd, J=8.3, 2.0 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.57 (dd, J=4.9, 2.9 Hz, 1H), 7.27 (m, 2H), 7.17 (dd, J=4.9, 1.5 Hz, 1H), 4.02 (d, J=15.6 Hz, 1H), 3.96 (d, J=15.6 Hz, 1H), 2.54 (m, 1H), 2.49 (m, 1H), 0.74 (t, J=7.3 Hz, 3H); MS (ES) m/z 393 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH2:23]Br>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[C:17]2[C:16](=[CH:21][CH:20]=1)[CH2:15][N:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([CH3:13])=[CH:8][CH:7]=1)(=[O:10])=[O:11])[CH2:23]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Clc1ccc(CBr)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccc(Cl)cc3C2)cc1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
To a suspension of 60% sodium hydride (3.0 g, 0.125 mmol) in mineral oil in 80 ml of anhydrous DMF (100 ml) was dropwise added a solution of para-toluene sulphonamide (5.6 g, 32.60 mmol) in 30 ml of DMF over 1 hour with vigorous stirring at room temperature. After the addition, the mixture was stirred for 1 hour at room temperature and another 1 hour heating at 90° C. To this mixture was added dropwise a solution of 1,2-bis-bromomethyl-4-chloro-benzene (4 g, 14.18 mmol) in 20 ml of anhydrous DMF at 60° C. and then stirred overnight at room temperature. The resultant mixture was poured onto ice and the resulting precipitate was collected by filtration. The precipitate was washed with 1N hydrochloric acid, 5% sodium carbonate and brine then dried (MgSO4), filtered and evaporated to give 2.8 g of 5-Chloro-2-(toluene-4-sulphonyl)-2,3-dihydro-1H-isoindole as a pale yellow solid. MS: [M+H]+ 308.
Reaction SMILES: COC1C=C(OC)C=C(OC)C=1C[NH:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=1.[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:32].COCCOCCOC>O>[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[O:32][C:11]1[N:10]=[CH:9][N:8]=[C:7]([NH2:6])[CH:12]=1
Reactant: COc1cc(OC)c(CNc2cc(Cl)ncn2)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: O
Solvent: COCCOCCOC
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 160 °C
Reaction time: 4 h
Yield: 25.1 %

Procedure:
A mixture of N-(2,4,6-trimethoxybenzyl)-6-chloropyrimidin-4-amine (2.2 g, 7.11 mmol), 2-fluoro-4-nitrophenol (1.1 g, 7.0 mmol), and 2-methoxyethyl ether (50 mL) was heated at 160° C. for 60 h. The reaction mixture was cooled to RT and poured into H2O (200 mL). The solid was collected, washed with 2 M aqueous Na2CO3 and H2O, and then vacuum dried on a Büchner funnel. The crude product was treated with TFA (20 mL) in dioxane (40 mL) and stirred at RT for 4 h. The reaction mixture was concentrated, the residue partitioned between EtOAc and saturated NaHCO3 solution. The EtOAc phase was separated, dried (MgSO4), concentrated and the crude product purified by flash chromatography using 1-2% MeOH in CH2Cl2 as the eluent to give 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine (440 mg, 31%). 1H NMR (DMSO-d6) δ 8.31 (dd, 1H, J=10.4, 2.5 Hz), 8.14 (dd, 1H, J=9.8, 2.0 Hz), 8.04 (s, 1H), 7.61 (dd, 1H, J=8.3, 8.3 Hz), 7.07 (s, 2H), 6.02 (s, 1H); MS(ESI+) m/z 251.15 (M+H)+.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:21]=[C:22]([C@H:27]2[N:31]3[C:32](=[O:45])[CH:33](P(=O)(OCC)OCC)[CH2:34][CH2:35][CH2:36][C@H:30]3[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[F:26].C(O)C>O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]([C@H:27]2[N:31]3[C:32](=[O:45])/[C:33](=[CH:8]/[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[CH2:34][CH2:35][CH2:36][C@H:30]3[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: CCOP(=O)(OCC)C1CCC[C@H]2CC[C@@H](c3ccc(F)c(F)c3)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CCC[C@H]3CC[C@@H](c4ccc(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Lithium hydroxide (0.0668 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.20 g) and diethyl [(3S,9aS)-3-(3,4-difluorophenyl)-5-oxooctahydropyrrolo[1,2-a]azepin-6-yl]phosphonate obtained above (0.52 g) in tetrahydrofuran (1 mL)-ethanol (4 mL), and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was added to ice-sodium bicarbonate water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.223 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([SH:19])=[N:16][C:15]=2[CH:20]=1)=[O:10])[CH2:5][CH2:6][CH3:7].N[C:22]1C=C(C=CC=1O)C(NC(CCC)CCC)=O>CCO>[CH3:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([S:19][CH3:22])=[N:16][C:15]=2[CH:20]=1)=[O:10])[CH2:3][CH2:2][CH3:1]
Reactant: CCCC(CCC)NC(=O)c1ccc2oc(S)nc2c1
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(N)c1
Solvent: CCO
Product: CCCC(CCC)NC(=O)c1ccc2oc(SC)nc2c1
Temperature: 80 °C
Yield: 55 %

Procedure:
N-(Heptan-4-yl)-2-(mercapto)benzo[d]oxazole-5-carboxamide: To a solution 3-amino-4-hydroxy-N-(1-propylbutyl)benzamide (example 41a) (250 mg, 1.0 mmol) in EtOH was added KSCSOEt (160 mg, 1.0 mmol). The resulting reaction mixture was heated at 80° C. overnight. The solvent was removed under reduced pressure. And the residue was taken up in water. The resulting mixture was acidified with HOAc to pH ˜5 and then filtered. The residue was washed with water to afford the product as a white solid (160 mg, 55%). MS (M+H, 293.1).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[BrH:25]>C(Cl)(Cl)Cl>[Br:25][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1]
Reactant: Br
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: ClC(Cl)Cl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2α, 3α-Epoxy-5α-pregnane-11,20-dione (502 mg) was dissolved in chloroform (30 ml.) and the solution was treated with hydrobromic acid (48 %, 10 ml.). The mixture was stirred vigorously at room temperature for 30 minutes, and then poured into chloroform. The organic solution was washed with dilute sodium bicarbonate solution, then with water, and was then dried over sodium sulphate and evaporated to give a crystalline residue which was recrystallised from acetone-ether to give 2β-bromo-3α-hydroxy-5α-pregnane-11,20-dione (483 mg.) as colourless crystals, m.p. 206°-210° [α]D + 106°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: C1CCNC1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCCC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and pyrrolidine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H33N6O4SF2 [(M+H)+] 539.2247, observed 539.2252.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[O:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][C:23]=1[CH:24]=O>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][C:23]=1/[CH:24]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[O:16][N:15]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(C)on2)cc1
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)Nc2cc(C)on2)cc1

Procedure:
The title compound was prepared in a similar manner as Ex-1 using 4-acetyl-N-(5-methyl-isoxazol-3-yl)benzenesulfonamide (Ex-1B, 0.30 g, 1.07 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 0.25 g, 1.07 mmol) as a dark red solid, mp 164–165° C. 1H-NMR (300 MHz, CDCl3) δ 8.09–7.93 (m, 4H), 7.35 (d, J=15.3 Hz, 1H), 7.05 (s, 1H), 6.48 (s, 1H), 6.24 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.29–3.18 (m, 4H), 2.38 (s, 3H), 2.02–1.91 (s, 4H). MS m/z: 498 (M+), 100%.
Reaction SMILES: C([NH:18][C@H:19]([C:24]([S:26][NH:27][C@H:28]([CH2:36][OH:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH:38]1[C:50]2[CH:49]([CH2:51][O:52][C:53]([NH:55][C@@H:56]([C:61]([OH:63])=O)[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>N1CCCCC1.CN(C=O)C>[C:53]([NH:55][C@@H:56]([C:61]([NH:18][C@H:19]([C:24]([S:26][NH:27][C@H:28]([CH2:36][OH:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:63])[CH2:57][CH:58]([CH3:59])[CH3:60])([O:52][CH2:51][CH:49]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]2[C:50]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:54]
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)SN[C@H](CO)Cc1ccccc1
Reactant: CC(C)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)SN[C@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
Dipeptide Fmoc-NH-L-Ile-S-Phe-CH2OH (1b) (2.0 g, 4.11 mmol) was taken in 20% piperidine in DMF (20 mL) and stirred for 15 minutes at 25° C., TLC examination showed complete removal of the Fmoc protecting group (NH2-L-Ile-S-Phe-CH2OH), further confirmed by LC/MS examination, which showed M+−1 (263.3) peak. The reaction mixture was concentrated in vacuo, excess of the piperidine was removed by co-evaporating with toluene (2×20 mL), the free amino dipeptide was further dried over high vacumn for 30 minutes, and then redissolved in dry DMF (5 mL) and added to the mixture of N-(9-fluorenylmethoxycarbonyl)-D-leucine (1.59 g, 4.52 mmol), DCC (931 mg, 4.52 mmol) and HOBt (610.0 mg, 4.52 mmol) in dry DMF (150 mL) at 25° C. The stirring was further continued for 14 h at 25° C. After 14 h white colored crystals precipitated out (DCU), which was filtered. The filterate was checked on TLC (5% MeOH: CH2Cl2) which showed formation of a new compound at higher Rf (0.5), LC/MS also showed molecular ion peak corresponding to the tripeptide 2b with other impurities peaks. The crude product was chromatographed on silica gel (Silica gel 60, 63-200μ) column and eluted with 4% MeOH: CH2Cl2 to give 450 mg of the tripeptide Fmoc-NH-D-Leu-L-Ile-S-Phe-CH2OH (2b) as a white solid. Checked on LC/MS which showed M++1 (600.3) and M++Na (622.3).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[CH:14][C:13]=1[NH:21][C:22]1[C:31]2[C:26](=[CH:27][C:28](F)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]=1[C:35]#[N:36].C(=O)(O)[O-].[Na+]>CS(C)=O>[CH2:3]([O:10][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:21][C:13]3[CH:14]=[C:15]([O:19][CH3:20])[C:16]([Cl:18])=[CH:17][C:12]=3[Cl:11])=[C:23]([C:35]#[N:36])[CH:24]=[N:25]2)=[CH:30][C:29]=1[O:32][CH3:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(Nc2c(C#N)cnc3cc(OCc4ccccc4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73.1 %

Procedure:
To a mixture of sodium hydride (122 mg, 3.04 mmol) in 6 mL of dimethylsulfoxide is added benzyl alcohol (91 mg, 0.84 mmol). The solution is stirred at room temperature for 40 minutes. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (300 mg, 0.76 mmol) is added and the reaction mixture is heated at 100° C. for 3 hours then cooled to room temperature and allowed to stir overnight. The reaction mixture is poured into saturated sodium bicarbonate and the solids are collected by filtration. Purification by flash column chromatography eluting with 10% ethyl acetate in dichloromethane provides 267 mg of 7-benzyloxy-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-quinolinecarbonitrile, mp 198-200° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.[CH3:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1Br)=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:28]2[CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:27]=2[NH:26][C:24](=[O:25])[CH3:23])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(C(F)(F)F)cc1Br
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(C(F)(F)F)cc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1
Yield: 70.1 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.15 g, Example 33), 2-bromo-4-(trifluoromethyl)acetanilide (0.28 g), 2M aqueous sodium carbonate (0.57 ml) and tetrakis(triphenylphosphine)palladium (0) (0.014 g) in ethanol (5 ml) with heating at reflux for 2 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-5% ethanol in dichloromethane to give the title compound as a solid (0.16 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:22][S:23]([O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Yield: 100.4 %

Procedure:
A mixture of (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (21.5 g, 107 mmol) and triethylamine (30 mL, 214 mmol) in dichloromethane (250 mL) was cooled to 0° C. Methanesulfonyl chloride (12.5 mL, 160.5 mmol) was added dropwise via an addition funnel and the resulting mixture was stirred at 0° C. then gradually warmed to room temperature over 3 h. A 10% aqueous citric acid solution was added and the two layers were separated. The organic layer was washed with 10% aqueous citric acid, sat'd aqueous NaHCO3, and brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed on a rotary evaporator to afford 30 g of (R)-tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate as an orange oil that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 4.17 (m, 2H), 3.33 (m, 2H), 3.20 (m, 1H), 3.18 (s, 3H), 3.00 (m, 1H), 2.55 (m, 1H), 2.01 (m, 1H), 1.53 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][CH3:29]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:27][CH2:28][CH3:29])[C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: CCCBr
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Product: CCCn1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)c(C#N)c1=O
Yield: 72.6 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and 1-bromopropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 72.6%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCOCC>[O:19]=[C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccccn1
Reaction time: 0.42 h

Procedure:
A solution of n-butyllithium (100 mL, 1.6 M, 160 mmol) in hexanes was added over 2 min. to a stirred solution of 2-bromopyridine (15.0 mL, 24.9 g, 157 mmol) in 500 mL of ether cooled in a dry ice/i-PrOH bath, causing a temporary rise in temperature to 47° C. After 25 min., the solution was transferred rapidly to a stirred 0° C. solution of diethyl oxalate (75 mL, 81 g, 550 mmol) in 1000 mL of ether. After 2 h at 0° C., the mixture was washed with saturated aq. NaHCO3 (900 ml), water (900 mL), and saturated aq. NaCl (450 mL). The organic layer was dried (MgSO4), filtered, and evaporated. Distillation gave the title compound as 11.68 g of yellow liquid, B.p. 96-108° C. (0.3 mm Hg pressure). For the title compound: 1H NMR (500 MHz, CDCl3) δ 8.78 (d, J=5, 1H), 8.13 (d, J=8, 1H), 7.93 (td, J=8, 2, 1H), 7.56 (ddd, J=8, 5, 1, 11H), 4.51 (q, J=7,22H), 1.44 (t, J=7, 3H).