Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13][C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:13][C:14]1[S:18][C:17]([S:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[NH:12][N:11]=[N:10][N:9]=3)[CH:3]=2)(=[O:21])=[O:20])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1

Procedure:
A solution of 5-(3-aminophenyl)tetrazole (8.1 mg, 0.05 mmol), 5-bromothiophene-2-sulfonyl chloride (14 mg, 0.055 mmol) and pyridine (12 μL, 0.015 mmol) in CH2Cl2 (200 μL) was stirred at room temperature over night. The title compound was obtained after purification by preparative HPLC (16.7 mg, 43%). MS (ESI+) m/z 386 [M+H]+. The procedure was repeated on a larger scale with a modified purification method (flash chromatography, 10% MeOH in CH2Cl2), giving enough of the title compound to be used as starting material for further derivatisations.
Reaction SMILES: [CH:1](O)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:37][C@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[CH:55]=2)=[CH:50][CH:49]=1)[CH2:39][C@:40]([CH2:45][OH:46])([CH3:44])[C:41]([OH:43])=[O:42]>CN(C=O)C>[Cl:60][C:56]1[CH:55]=[C:54]([C:51]2[CH:52]=[CH:53][C:48]([CH2:47][C@@H:38]([NH:37][CH:1]=[O:2])[CH2:39][C@:40]([CH2:45][OH:46])([CH3:44])[C:41]([OH:43])=[O:42])=[CH:49][CH:50]=2)[CH:59]=[CH:58][CH:57]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Reactant: O=CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC=O)C(=O)O
Reaction time: 0.08 h
Yield: 4.2 %

Procedure:
Formic acid (3 mg, 32 μmol) was combined with HATU (12 mg, 32 μmol) and DMF (0.2 mL) and stirred for 5 minutes. DIPEA (17 μl, 96 μmol) was added, followed by (2S,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-pentanoic acid (79 mg, 38 μmol) pre-dissolved in DMF (0.5 mL) and DIPEA (17 μl, 96 μmol). The resulting mixture was stirred for 15 minutes. The solvent was removed in vacuo and the residue was dissolved in AcOH and purified by preparative HPLC to yield the title compound (0.5 mg). MS m/z [M+H]+ calc'd for C20H22ClNO4, 376.12. found 376.2.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:11][C:12](=[O:34])[CH:13]([C:24](=[O:33])[NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[NH:23])[NH2:22])=[CH:17][CH:16]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(#N)C>O>[CH2:26]([NH:25][C:24]([CH:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[NH:22])[NH2:23])=[CH:19][CH:20]=1)[C:12]([NH:11][C@@H:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:3]([OH:35])=[O:2])=[O:34])=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)NCc1ccccc1)C1CCCCC1
Solvent: O
Solvent: CC#N
Product: N=C(N)c1ccc(CC(C(=O)NCc2ccccc2)C(=O)N[C@H](C(=O)O)C2CCCCC2)cc1
Temperature: 25 °C

Procedure:
The above [2-(R,S)-benzylcarbamoyl-3-(4-carbamimidoyl-phenyl)-propionylamino]-(S)-cyclohexyl-acetic acid methyl ester was suspended in water/concentrated hydrochloric acid (1/1, 200 ml) and stirred at room temperature. After 8 days acetonitrile (100 ml) was added and stirred for 2 more days. The reaction mixture was filtered and poured into ice-water. The precipitate was collected by fractionized crystallization:
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH:19]=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([C@H:19]2[O:12][CH2:11][C@H:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:13][O:14]2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: CCCC1CCC(C(CO)CO)CC1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H]([C@H]2CO[C@H](c3ccc(F)c(F)c3)OC2)CC1

Procedure:
In 40 cm3 of dichloromethane, 1.5 g (0.008 mol) of 2-(4'-propylcyclohexyl)propane-1,3-diol, 1.5 g (0.01 mol) of 3,4-difluorobenzaldehyde (manufactured by Aldrich), and 0.1 g of TsOH were refluxed for 3 hours over a hot water bath fitted with a Dean-Stark trap and the water formed was removed continuously from the reaction system. The reaction solution was washed with water and the dichloromethane was distilled off. The distillation residue was recrystallized from a solvent mixture of acetone and methanol to yield 1.6 g (0.005 mol) of trans-2-(3',4'-difluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane. The phase transition points, measured by DSC, were: ##STR31## wherein C is the crystal phase, N is the nematic phase and I is the isotropic liquid phase.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[O:29]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([O:33][C:32]([F:31])([F:43])[F:44])[CH:35]=3)[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20]1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4cccc(OC(F)(F)F)c4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3-trifluoromethoxyphenylboronic acid in step C. MS (ESI): mass calcd. for C19H11F3N4O4, 416.1; m/z found, 417.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.06-12.92 (m, 2H), 8.99 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 8.22 (dd, J=8.4, 1.8 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.79 (s, 2H), 7.66 (t, J=8.0 Hz, 1H), 7.46-7.40 (m, 1H).
Reaction SMILES: C[O-].[Na+].C(O)C.[NH2:7][C:8]([NH2:10])=[S:9].[C:11]([CH2:15][C:16](OC)=[O:17])(=O)[CH2:12][CH3:13]>O>[SH:9][C:8]1[NH:10][C:16](=[O:17])[CH:15]=[C:11]([CH2:12][CH3:13])[N:7]=1
Reactant: NC(N)=S
Reactant: CCC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1cc(=O)[nH]c(S)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.8 %

Procedure:
To a solution of sodium methoxide(24 g, 0.44 mol) and ethanol(180 ml) were added thiourea(15.22 g, 0.2 mol) and methyl propionylacetate(25.1 ml, 0.2 mol). After distillating solvent slowly, water(200 ml) was added to the reaction mixture, which was then heated to reflux for 30 minutes. Active carbon was added to the reaction mixture, which was then stirred for 5 minutes and filtered. The filtrate was cooled to a room temperature and acidified by glacial acetic acid and the resulting solid was filtered and dried to give 29 g of the titled compound. (Yield: 93%)
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)[C@@H:3]([C@H:5]1[CH2:14][C:13]2[C:8](=[C:9]([O:16][CH3:17])[CH:10]=[CH:11][C:12]=2[Br:15])[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[OH:4].C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>O1CCCC1>[C:41]([NH:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)[C@@H:3]([C@H:5]1[CH2:14][C:13]2[C:8](=[C:9]([O:16][CH3:17])[CH:10]=[CH:11][C:12]=2[Br:15])[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[OH:4])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)C2
Yield: 88 %

Procedure:
Slurry tert-butyl (3R)-3-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxy-propyl]-5-bromo-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (59.4 mg, 0.000113 mol) in tetrahydrofuran (1.00 mL). Add triethylamine (15.7 uL, 0.000113 mol) and acetic anhydride (10.6 uL, 0.000113 mol) and stir for 45 minutes. Dilute dichloro-methane (25 mL) and wash with water (1×10 mL), 0.1N HCl (1×10 mL), saturated aqueous sodium bicarbonate (1×10 mL), saturated aqueous sodium chloride (1×10 mL) and dry over magnesium sulfate. Concentrate the filtrate to give the desired product (57.9, 88%) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23](=[O:24])[C:22]3[NH:21][C:20](C4C=CC(I)=CC=4)=[N:19][C:18]=3[N:17]([CH2:32][CH2:33][CH3:34])[C:16]2=[O:35])=[CH:11][CH:10]=1.B(O)O.CC[N:41]([CH2:44][CH3:45])CC>CC([O-])=O.CC([O-])=O.[Cu+2].C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23](=[O:24])[C:22]3[N:21]([C:4]4[CH:5]=[C:45]([CH:7]=[CH:8][CH:3]=4)[C:44]#[N:41])[CH:20]=[N:19][C:18]=3[N:17]([CH2:32][CH2:33][CH3:34])[C:16]2=[O:35])=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: CCCn1c(=O)n(-c2ccc(-c3ccccc3SC)cc2)c(=O)c2[nH]c(-c3ccc(I)cc3)nc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: ClCCl
Product: CCCn1c(=O)n(-c2ccc(-c3ccccc3SC)cc2)c(=O)c2c1ncn2-c1cccc(C#N)c1
Reaction time: 12 h
Yield: 88.1 %

Procedure:
A 25-mL round bottom flask equipped with a stir bar was charged with 6 (180 mg, 0.46 mmol) and CH2Cl2 (5.0 mL). The reaction mixture was treated with boronic acid 7 (135 mg, 0.92 mmol), Et3N (0.13 mL, 0.92 mmol), crushed 4 A mol. sieves (720 mg, 4× weight) and Cu(OAc)2 (167 mg, 0.92 mmol) at 25° C. After 12 h, the reaction was filtered through a plug of Celite® and washed with CH2Cl2 (100 mL). The organic phase was washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography of the residue on silica (40-50% EtOAc/hexanes) provided 8 (100 mg, 44%) as a white solid: ESI-MS m/z: [C28H23N5O2S+H]+ 494; 1H NMR (300 MHz, CDCl3) δ 7.90-7.00 (m, 13H), 4.19 (t, J 7.5 Hz, 2H), 2.33 (s, 3H), 1.99-1.85 (m, 2H), 1.03 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:19][CH3:20])[C:10]([N:11]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nn2c(Br)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (658 mg) in N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil; 116 mg) at room temperature under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. (Bromomethyl)cyclopropane (0.286 mL) was added thereto at the same temperature, and the reaction mixture was stirred for 1 hour at 60° C. After completion of the reaction, the reaction mixture was gradually added to ice, ethyl acetate was added and the organic extract was washed with water and brine, after which it was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamate.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1)=O.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([CH2:30][C:31]([NH2:33])=[O:32])=[CH:26][NH:27]2)=[CH:23][CH:22]=1>>[C:6]1([C:4]2[C:3](=[O:2])[NH:33][C:31](=[O:32])[C:30]=2[C:25]2[C:24]3[C:28](=[CH:29][C:21]([C:20]([F:34])([F:19])[F:35])=[CH:22][CH:23]=3)[NH:27][CH:26]=2)[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1
Reactant: NC(=O)Cc1c[nH]c2cc(C(F)(F)F)ccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(C(F)(F)F)ccc12

Procedure:
Beginning with (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester and 6-(trifluoromethyl)indole-3-acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:22])[N:5]([C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:6]2=[O:12].CN(CCN(C)C)C.[I:31]I>C1COCC1>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:31])=[C:7]2[C:3]=1[CH:4]([OH:22])[N:5]([C:13]([CH3:14])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:21])[C:6]2=[O:12]
Reactant: Cc1ccc2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Reactant: II
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: Cc1cc(I)c2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 62.8 %

Procedure:
In a similar manner to Step. 3 of Example 16, 4-chloro-5-methyl-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (400 mg, 1.27 mmol) was dissolved in THF (16 mL), and the solution was treated with TMEDA (0.33 mL, 2.2 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 2.8 mL, 2.8 mmol) and iodine (387 mg, 1.52 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=95/5 to 80/20 to 70/30) to obtain 4-chloro-5-methyl-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (352 mg, yield 63%).
Reaction SMILES: [N:1]([C@@H:4]([C@H:40]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=1)[C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25])[N:18]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17]1)=[O:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][C@@H:4]([C@H:40]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=1)[C:41]1[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[O:25])[N:18]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(F)cc2)c2cccc(Cl)c2)OC[C@@H]1COC(=O)NCC(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(F)cc2)c2cccc(Cl)c2)OC[C@@H]1COC(=O)NCC(F)(F)F

Procedure:
The product from Step 2 (255 mg, 0.33 mmol) was dissolved in 3 mL THF and to the stirred solution was added triphenylphosphine (128 mg, 0.49 mmol) and water (0.3 mL). The mixture was heated to reflux for 24 h. The solvents were removed in vacuo and the residue was purified on a 12 g silica gel column eluting with a gradient of 0-30% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give a dense gum. LCMS: RT=1.23 min, M+H=756.5 (2 min gradient).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:13]1[CH:14]=[C:15]([C:18]([F:20])([F:21])[F:19])[CH:16]=[CH:17][C:12]=1[F:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cc(C(F)(F)F)ccc1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 29.6 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 0.50 g, 3.4 mmol), 2-fluoro-5-(trifluoromethyl)phenylboronic acid (Aldrich; 561 mg, 3.4 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2-fluoro-5-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (310 mg, 31%) as a colorless oil that solidified.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]=O)[CH:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:32][O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH:1][CH:2]2[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=3)[CH2:6][CH2:7]2)[CH:36]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: NC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(CNC2CCC(CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
To a mixture of N4-(4-amino-cyclohexylmethyl)-5-nitro-N2-(2-trifluoromethoxy-benzyl)-pyrimidine-2,4-diamine (100 mg, 0.23 mmol) and 3-formyl-benzoic acid methyl ester (41 mg, 0.25 mmol) in DCM (1 mL) was added sodium triacetoxyborohydride (58 mg, 0.27 mmol). The mixture was stirred at room temperature for 18 h then quenched with excess water. The mixture was diluted with DCM and the organic layer separated and dried over Na2SO4. The solvent was removed in vacuo and the residue purified by column chromatography using an ISCO combi-flash cartridge (silica gel, DCM/MeOH) to afford 3-[(4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexylamino)-methyl]-benzoic acid methyl ester (76 mg, 57%), m/z 589 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:5][NH:6][C:7]1[C:12]([C:13](=[O:22])[NH:14][CH2:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:11]([O:23][CH3:24])[N:10]=[C:9](S(C)=O)[N:8]=1.[NH:33]1[CH2:39][CH2:38][CH2:37][C@H:34]1[CH2:35][OH:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:5][NH:6][C:7]1[C:12]([C:13](=[O:22])[NH:14][CH2:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:11]([O:23][CH3:24])[N:10]=[C:9]([N:33]2[CH2:39][CH2:38][CH2:37][CH:34]2[CH2:35][OH:36])[N:8]=1
Reactant: OC[C@@H]1CCCN1
Reactant: COc1ccc(CNc2nc(S(C)=O)nc(OC)c2C(=O)NCc2ncccn2)cc1Cl
Product: COc1ccc(CNc2nc(N3CCCC3CO)nc(OC)c2C(=O)NCc2ncccn2)cc1Cl

Procedure:
4-(3-Chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]-6-methoxy-2-methylsulfinylpyrimidine (prepared in the above (4)) and L-prolinol is treated in the same manner as Example 321(5) to give 4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]-6-methoxy-2-(2-hydroxymethyl-1-pyrrolodinyl)pyrimidine as a colorless crystalline powder 88 mg. mp 153–154° C.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[N:9]=[C:8](Cl)[C:7]([CH:11]=O)=[CH:6][N:5]=1.O>C1COCC1>[Cl:3][C:4]1[N:9]=[C:8]2[NH:1][N:2]=[CH:11][C:7]2=[CH:6][N:5]=1
Reactant: O=Cc1cnc(Cl)nc1Cl
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: Clc1ncc2cn[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of hydrazine (Aldrich, 64 mg, 2 mmol) in THF (5 mL), 2,4-Dichloro-pyrimidine-5-carbaldehyde (Example 17, 176 mg, 1 mmol) was added and the mixture was stirred at room temperature for 30 min. The mixture was poured into water and extracted with EtOAc. The extract was dried with sodium sulfate and the solvent was removed to give an orange solid. 128 mg, 82%. MS (M+H)+, 155.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:15][NH:16][CH3:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[C:12]([N:16]([CH3:17])[CH3:15])=[O:14])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1/C=C/C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(Br)cc1/C=C/C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of (2E)-3-(5-bromo-2-methoxypyridin-3-yl)acrylic acid (1.00 g, 3.87 mmol) in DCM (10 mL) were added dimethylamine (2.0 M in THF, 5.80 mmol), DIEA (2.02 mL, 11.6 mmol) and TBTU (1.49 g, 4.65 mmol). The reaction mixture was allowed to stir at rt overnight. The reaction was quenched with water and then the aqueous solution was extracted with DCM. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (2E)-3-(5-bromo-2-methoxypyridin-3-yl)-N,N-dimethylacrylamide (1.05 g, 95%) as a white solid. LCMS (FA): Rt=1.68 min, m/z=285.1 (M+H).
Reaction SMILES: [C@H:1]1([NH2:8])[CH2:6][CH2:5][C@H:4]([NH2:7])[CH2:3][CH2:2]1.[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH:15]=O)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH2:15][NH:7][C@H:4]1[CH2:5][CH2:6][C@H:1]([NH:8][CH2:15][C:14]2[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH3:22])=[C:12]([O:11][CH2:9][CH3:10])[CH:13]=2)[CH2:2][CH2:3]1)[CH3:10]
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCOc1ccc(C=O)cc1OCC
Product: CCOc1ccc(CN[C@H]2CC[C@H](NCc3ccc(OCC)c(OCC)c3)CC2)cc1OCC

Procedure:
The title compound was prepared by a similar way as in Preparation Example 1, except that trans-1,4-cyclohexane diamine was used instead of trans-1,2-cyclohexane diamine and 3,4-diethoxybenzaldehyde was used instead of veratraldehyde.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=O.[CH:20]1([NH:23][C:24]2[S:25][CH2:26][C:27](=[O:29])[N:28]=2)[CH2:22][CH2:21]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:20]1([NH:23][C:24]2[S:25]/[C:26](=[CH:1]\[C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]4[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])/[C:27](=[O:29])[N:28]=2)[CH2:22][CH2:21]1
Reactant: CC(C)COc1c(C#N)cnc2ccc(C=O)cc12
Reactant: O=C1CSC(NC2CC2)=N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)COc1c(C#N)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-isobutoxy-quinoline-3-carbonitrile (example 66b), 2-cyclopropylamino-thiazol-4-one (example 37c), sodium acetate and acetic acid to give 6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-isobutoxy-quinoline-3-carbonitrile. LC-MS m/e 393 (MH+).
Reaction SMILES: [Na].[CH:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([OH:11])[CH:3]=1.[Br:12][CH:13](Br)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:12][CH2:13][CH2:14][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[CH:2][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCBr)cc1

Procedure:
1.97 g of the sodium salt of p-nitrophenol(0.01 mol), 2.16 ml of dibromoethane (0.025 mol) and 0.5 g of potassium carbonate were taken in 50 ml of dry acetone (4A activated molecular sieves) and refluxed overnight. Potassium carbonate was filtered and the solvent was removed by rotary evaporation to yield 4-(2-bromoethoxy)nitrobenzene (L) in almost quantitative yield.