Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C@@H:6]([N:13]([CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:15][CH3:16])[CH2:7][O:8]2)=O.S([CH2:30][N+:31]#[C-:32])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:39][NH2:40]>CO>[NH3:13].[CH3:30][N:31]1[C:1]([C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][C@@H:6]([N:13]([CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:15][CH3:16])[CH2:7][O:8]3)=[CH:39][N:40]=[CH:32]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CN
Reactant: CCCN(C(C)C)[C@H]1COc2cccc(C=O)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCN(C(C)C)[C@H]1COc2cccc(-c3cncn3C)c2C1
Product: N
Reaction time: 1 h
Yield: 0.5 %

Procedure:
(R)-5-Formyl-3-(N-isopropyl-N-n-propylamino)chroman (0.4 g, 1.5 mmol) was dissolved in methanol (15 mL), saturated with methylamine. Some molcular sieves (3Å) were added. The solvent was removed in vacuo. The residue was dissolved in methanol (30 mL) under nitrogen atmosphere. Tosylmethylisocyanide (0.36 g, 1.8 mmol) and K2CO3 (0.25 g, 1.8 mmol) were added and the reaction mixture was reluxed for 1 hour. Additionally tosylmethylisocyanide (0.36 g, 1.8 mmol) and K2CO3 (0.25 g, 1.8 mmol) were added and the reflux was continued for 3 hours. Tosylmethylisocyanide (0.1 g, 5.2 mmol) was added once more and the reflux was continued for 12 hours. The solvent was removed in vacuo. The residue was dissolved in diethyl ether/2M NH3. The layers were separated and the water-phase was extracted once more with ether. The organic layers were combined and dried (Na2SO4). The solvent was removed in vacuo to give a brown oily residue which was purified by flash chromatography (SiO2, first CH2Cl2 /EtOAc, 5:1, also containing 0.5% of NH3 and then EtOAc/EtOH, 50:1+0.5% of NH3) to give 200 mg of the title compound (42 yield). [α]D21 -37° (c 30 mg/mL, MeOH). The HCl-salt was precipitated from diethyl ether at 0° C. and recrystallized from ethanol/diethyl ether. mp 159°-161° C. (dec).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:10][CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCNCC1
Reactant: ClCCc1ccccc1
Product: O=C1CCN(CCc2ccccc2)CC1

Procedure:
1-(2-phenylethyl)-4-piperidone is prepared from 4-piperidone and (2-chloroethyl)benzene essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OCC)(OCC)O[CH2:16][CH3:17]>>[N+:1]([C:4]1[CH:12]=[C:8]([C:9]([O:11][CH2:16][CH3:17])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1O

Procedure:
1.5 kg (8.2 mol) of 5-nitrosalicylic acid was dissolved in 2000 ml of triethyl orthoformate. The obtained solution was refluxed under heating for 3 hours to remove formed ethanol by distillation. The reaction mixture was cooled and then concentrated under reduced pressure. The obtained residue was crystallized from isopropyl ether to give 1.74 kg of the title compound as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH3:14])[C@@H:10]([OH:13])[CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[C:23]([Si:20]([CH3:22])([CH3:21])[O:12][CH2:11][C@H:10]([OH:13])[C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:14])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@H](c1ccc(Cl)c(Cl)c1)[C@@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)c(Cl)c1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a stirred solution of (2R,3R)-3-(3,4-dichloro-phenyl)-butane-1,2-diol (3.20 g, 13.6 mmol) and imidazole (1.39 g, 20.4 mmol) in DCM (28 mL) at rt was added tert-butyldimethylsilyl chloride (TBSCl; 2.15 g, 14.3 mmol). The solution was stirred for 1 h then quenched by addition of satd. aq. NH4Cl (100 mL). The mixture was stirred for 5 min, the layers were separated, and the aqueous layer was extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to yield a viscous yellow liquid. The product was purified by flash chromatography (EtOAc/hexanes) to afford 4.52 g (95%) of the desired product as a colorless viscous liquid. 1H NMR (400 MHz, CDCl3): 7.37 (d, J=8.3, 1H), 7.36 (d, J=2.1, 1H), 7.10 (dd, J=8.2, 2.1, 1H), 3.75-3.68 (m, 1H), 3.65 (dd, J=9.9, 3.8, 1H), 3.45 (dd, J=9.9, 7.1, 1H), 2.81 (quint, J=7.0, 1H), 2.37 (d, J=4.0, 1H), 1.25 (d, J=7.2, 3H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[Cl:12].[H][H]>CO.[Ni]>[Cl:12][C:4]1[C:3]([N:2]([CH3:13])[CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:9]
Reactant: [H][H]
Reactant: CN(C)c1cccc([N+](=O)[O-])c1Cl
Agent: [Ni]
Solvent: CO
Product: CN(C)c1cccc(N)c1Cl
Yield: 49.5 %

Procedure:
30.4 g of N,N-dimethyl-2-chloro-3-nitroaniline is dissolved in about 300 ml of MeOH and hydrogenated at 20° C. and 5 bars pressure of hydrogen using Raney nickel as catalyst. The solvent is evaporated down and the product is purified by chromatography (silica gel, eluant: petroleum ether/ethyl acetate (3/1)). 12.8 g of 2-chloro-3-dimethylaminoaniline is obtained as a brown oil.
Reaction SMILES: CS(N(C1C=CC(Cl)=CC=1)[C@@H](C(O)=O)C)(=O)=O.[C:18]([NH:25][C@H:26]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:27]([NH:29][N:30]1[CH2:33][CH:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:31]1)=[O:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].BrC[C:51]([O:53][CH3:54])=[O:52]>>[C:18]([NH:25][C@H:26]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=1)[C:27]([NH:29][N:30]1[CH2:31][CH:32]([N:34]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:51]([O:53][CH3:54])=[O:52])[CH2:33]1)=[O:28])([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC(NC2CCCCC2)C1
Reactant: COC(=O)CBr
Agent: C[C@H](C(=O)O)N(c1ccc(Cl)cc1)S(C)(=O)=O
Product: COC(=O)N(C1CCCCC1)C1CN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared following the procedure described in Step A of Intermediate 135 using (2R)-2-(BOC)amino-N-[3-(cyclohexylamino)azetidine-1-yl]-3-(4-chlorophenyl)propionamide prepared in Intermediate 202 and methyl bromoacetate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[OH:38][CH2:39][C:40]([CH3:45])([CH3:44])[C:41](=[S:43])[NH2:42]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:43][C:41]([C:40]([CH3:45])([CH3:44])[CH2:39][OH:38])=[N:42][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(CO)C(N)=S
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Product: CC(C)(CO)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described for Intermediate 9 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (750 mg, 1.7 mmol), NBS (317 mg, 1.782 mmol), and 3-hydroxy-2,2-dimethylpropanethioamide (248 mg, 1.86 mmol), the title compound was obtained as an yellow foam (460 mg, 45%). A portion of the sample was crystallized from ethyl acetate-hexanes. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H) 8.54 (d, J=5.31 Hz, 1H) 7.64-7.74 (m, 1H) 7.41-7.50 (m, 2H) 7.31-7.36 (m, 1H) 7.24 (t, J=8.97 Hz, 2H) 6.87 (d, J=5.31 Hz, 1H) 5.2-5.4 (br s, 1H) 3.54 (s, 2H) 1.36 (s, 6H). MS (ESI): 555.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([CH2:14][CH2:15][CH3:16])([CH2:11][CH2:12][CH3:13])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(Cl)(=O)C([Cl:25])=O>>[C:1]1([C:7]([CH2:14][CH2:15][CH3:16])([CH2:11][CH2:12][CH3:13])[C:8]([Cl:25])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(CCC)(C(=O)O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCCC(CCC)(C(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of the product of Example 1C (4.13 g, 18.77 mmol) and N,N-dimethylformamide (1.45 mL, 18.77 mmol) in hexanes (700 mL) was treated with oxalyl chloride (4.91 mL, 56.31 mmol) and stirred at 25° C. for 2 hours. The mixture was treated with Celite®, and then filtered through a pad of Celite®. The filtrate was concentrated in vacuo to afford the title compound which was used directly in the next procedure.
Reaction SMILES: CC1C=C2[C:8](=[CH:9][CH:10]=1)N[C:6](=[O:11])C2.[CH3:12][C:13]([O-:15])=O.[Na+].[C:17](O)(=O)C>>[CH3:6][OH:11].[O:15]([CH:9]([CH3:8])[CH3:10])[CH:13]([CH3:12])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)O
Agent: [Na+]
Product: CC(C)OC(C)C
Product: CO
Temperature: 0 °C

Procedure:
A mixture of 5-methyl-2-oxindole (2.94 g, 0.02 mol), 3,5-di-tertiary-butyl-4-hydroxybenzoldehyde (4.68 g, 0.02 mol), and anyydrous NaOAc (5.75 g, 0.07 mol) in glacial acetic acid (100 mL) was heated to reflux for 18 hours. The cooled reaction mixture was poured into ice-water mixture when a yellow product precipitated out. It was recrystallized from CH2Cl2 --CH3OH-iso-Pr2O to give the analytical sample. Yield 2.16 g (28.7%), mp 230°-234° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[N:18][C:19]=3[NH2:21])[N:14]([C@@H:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)[N:13]=2)=[CH:8][CH:7]=1.Cl.[CH:31]1([N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40])[CH2:34][CH2:33][CH2:32]1.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>CN(C=O)C.CC(=O)OCC>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([C@@H:22]3[CH2:26][CH2:25][N:24]([C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][N:35]([CH:31]4[CH2:34][CH2:33][CH2:32]4)[CH3:42])[CH2:23]3)[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][C:4]4[CH:27]=[CH:28][CH:29]=[C:2]([F:1])[CH:3]=4)=[CH:7][CH:8]=3)[C:20]=12
Reactant: CN(C/C=C/C(=O)O)C1CCC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3)cc1)nn2[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4)cc3)c3c(N)ncnc32)C1)C1CCC1
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
To a solution of 4a (134 mg, 0.344 mmol), (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acid hydrochloride (0.344 mmol) and HATU (122 mg, 0.38 mmol) in DMF (1.5 ml) was dropwise added DIPEA (134 mg, 1.032 mmol) at rt. Stirring was continued for 30 min at rt (monitored by HPLC). The reaction mixture was diluted with EA, washed with water and brine, and dried over sodium sulfate. Filtration followed by concentration under reduced pressure provided a residue which was purified by flash chromatography using silica gel (1-12% MeOH/DCM) to give 32 mg of the title compound (4b). MS (ESI) m/e (M+1H)+: 542.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH:26]1([N:29]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27]1>>[CH:26]1([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:20])[CH2:31][CH2:30]2)[CH2:28][CH2:27]1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: C1CNCCN(C2CC2)C1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCCN(C5CC5)CC4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-cyclopropyl-1,4-diazepane. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.66-1.06 (m, 4 H) 1.94-2.23 (m, 2 H) 2.33 (d, J=2.02 Hz, 3 H) 2.81-3.07 (m, 1 H) 3.41-4.30 (m, 8 H) 7.54-7.70 (m, 1 H) 7.75 (t, J=7.45 Hz, 1 H) 7.98-8.65 (m, 4 H). ESI-MS m/z [M+H]+ 461.3.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.Cl.[NH2:28][CH2:29][C@H:30]([N:35]1[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]1)[C:31]([O:33][CH3:34])=[O:32].O>ClCCl>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:28][CH2:29][C@H:30]([N:35]2[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)[C:31]([O:33][CH3:34])=[O:32])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)[C@H](CN)N1CCN(S(C)(=O)=O)CC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.1 ml (7.8 mmol) of triethylamine and then 730 mg (2.6 mmol) of 4-benzyloxybenzenesulfonyl chloride in 8 ml of dichloromethane are added to a solution of 800 mg (2.4 mmol) of methyl (S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate dihydrochloride in 20 ml of dichloromethane and the reaction medium is stirred at ambient temperature for 3 h. After the addition of water, the product is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1>CC(N(C)C)=O.[Na+].[Cl-].CCOC(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH:12]=[CH:11][N:10]=1
Reactant: c1nc[nH]n1
Reactant: Clc1ccnc(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Clc1cc(-n2cncn2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60 wt. %. in mineral oil, 400 mg, 10.0 mmol, 5.0 eq) was carefully suspended in 5 mL of DMA (caution: intensive gas development). To the mixture was added carefully 1,2,4-triazole (691 mg, 10.0 mmol, 5.0 eq) and the mixture was stirred at room temperature for 30 min. 2,4-Dichloropyridine (300 mg, 2.0 mmol, 1.0 eq) was added in portions and the reaction mixture was heated at 100° C. for 3.5 hours. The mixture was allowed to cool to room temperature and diluted with saturated NaCl solution (25 mL) and EtOAc (15 mL). The separated aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic layers were washed with saturated NaCl solution (25 mL), dried over sodium sulfate and concentrated under reduced pressure. Purification by silica column chromatography with EtOAc/hexanes (3/1) provided 2-chloro-4-(1H-1,2,4-triazol-1-yl)pyridine as a white solid. Yield: 290 mg. ES/MS m/z 181.1 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=2)=[CH:24][N:23]=[C:22]([NH:32][CH2:33][CH2:34][NH:35]C2N=CC(C#N)=CC=2)[N:21]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:27][CH:28]=[C:29]([CH3:31])[N:30]=2)=[CH:24][N:23]=[C:22]([NH:32][CH2:33][CH2:34][NH:35][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[N:21]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C(F)(F)F)cn3)nc2-c2ccc(Cl)cc2Cl)n1

Procedure:
[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl](2-{[5-(trifluoro-methyl)(2-pyridyl)]amino}ethyl)amine was prepared from 2-chloro-5-(trifluoromethyl)pyridine using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[O:14])=[CH:11][C:10]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:4][CH:3]=1.[NH:39](C(OC(C)(C)C)=O)[C@H:40]([C:43](O)=[O:44])[CH2:41][CH3:42].C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[NH2:39][CH:40]([CH2:41][CH3:42])[C:43]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)=[O:14])=[CH:11][C:10]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:4][CH:3]=1)=[O:44]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(N)C(=O)Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 51E (59 mg, 0.1 mmol) and Boc-Abu-OH (22 mg, 0.11 mmol) in tetrahydrofuran (5 ml) was added 3-(diethoxyphosphoryloxy)-1,2,3-benzo-triazin-4(3H)-one (36 mg, 0.11 mmol) and triethylamine (0.07 ml, 0.5 mmol). The mixture was stirred at room temperature for 16 hours then poured into saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and evaporated. To the residue was added dichloromethane (2 ml) and trifluoroacetic acid (2 ml) then stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by HPLC with NH4OH to provide the title compound. (62 mg, 85%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.90 (t, J=7.54 Hz, 3 H) 1.33 (d, J=6.99 Hz, 6 H) 1.48 (m, 1 H) 1.66 (m, 1 H) 1.90 (s, 3 H) 3.22 (m, 2 H) 7.02 (m, 2 H) 7.40 (d, J=8.46 Hz, 2 H) 7.52 (d, J=8.46 Hz, 2 H) 7.61 (d, J=8.46 Hz, 1 H) 7.72 (m, 5 H) 7.94 (s, 1 H) 8.52 (s, 1 H) 8.79 (s, 1 H) 10.33 (s, 1 H); MS (ESI+) m/z 670, 672 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[O:28]=[S:29]1(=[O:43])[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1>>[O:43]=[S:29]1(=[O:28])[CH2:30][CH2:31][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:38][CH:37]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCS(=O)(=O)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1,1-dioxo-thiomorpholin-4-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C28H27N3O5S
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(O)=O.[CH3:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH2:20][CH2:21][NH:22][CH2:23][C@H:24]2[O:28][C:27](=[O:29])[N:26]([C:30]3[CH:31]=[CH:32][C:33]4[S:34][CH2:35][C:36](=[O:40])[NH:37][C:38]=4[N:39]=3)[CH2:25]2)[C:10]1=[O:41]>CN(C=O)C.CCOCC>[CH3:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH2:20][CH2:21][N:22]([CH2:23][C@H:24]2[O:28][C:27](=[O:29])[N:26]([C:30]3[CH:31]=[CH:32][C:33]4[S:34][CH2:35][C:36](=[O:40])[NH:37][C:38]=4[N:39]=3)[CH2:25]2)[C:1](=[O:3])[CH3:2])[C:10]1=[O:41]
Reactant: Cn1c(=O)n(CCNC[C@@H]2CN(c3ccc4c(n3)NC(=O)CS4)C(=O)O2)c(=O)c2ccccc21
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC(=O)N(CCn1c(=O)c2ccccc2n(C)c1=O)C[C@@H]1CN(c2ccc3c(n2)NC(=O)CS3)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
Acetyl chloride (0.009 ml) was added to a solution of the compound of Example 55 (56 mg) and TEA (0.017 ml) in DMF (2 ml). The mixture was stirred at rt overnight. The reaction mixture was partitioned between water and EA/MeOH 9:1. The aq. layer was extracted with EA/MeOH 9:1 and the combined org. layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting material was purified by CC (EA/MeOH 19:1) and afforded, after stirring in ether, a slightly yellow solid (175 mg; 42% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[C:3]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:39]1[CH2:43]OC[CH2:40]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[C:3]=1[CH:24]([CH2:40][CH2:39][CH3:43])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1Cc1cccc(OC)c1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1Cc1cccc(OC)c1)CCCC3
Yield: 57.3 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(m-anisyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.327 g; 0.85 mmol), LHMDS 1N in THF (1.27 mL; 1.27 mmol), 1-iodopropane (0.166 mL; 1.7 mmol) in DMF (4.2 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.213 g (59%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].P(Cl)(Cl)([Cl:15])=O.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:15])=[N:4][CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Oc1ncnc(C(F)(F)F)c1Br
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1ncnc(Cl)c1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
24.3 g (100.0 mmoles) of 5-bromo-4-hydroxy-6-trifluoromethylpyrimidine was suspended in 18.5 g (120.0 mmoles) of phosphorus oxychloride. The suspension was stirred at 100° C. for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was gradually poured into water and extraction with chloroform was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 21.5 g (yield: 82.4%) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine.